Safety Evaluations of Nivolumab (Anti-PD-1) Added To Chemotherapy (CRT) Platforms In Patients With Intermediate And High-Risk Local-Regionally Advanced Head and Neck Squamous Cell Carcinoma
Phase: PHASE1
Conditions: Head and Neck Squamous Cell Carcinoma (HNSCC)
Sponsor: RTOG Foundation, Inc.

R T O G F O U N D A TI O N  
 
 
R T O G 3 5 0 4 
 
( Cli nic al Tri als. g ov N C T #: 0 2 76 4 5 9 3 ) 
 
 
S A F E T Y E V A L U A TI O N S O F NI V O L U M A B ( A N TI -P D -1) A D D E D T O 
C H E M O R A DI O T H E R A P Y ( C R T) P L A T F O R M S I N P A TI E N T S WI T H 
I N T E R M E DI A T E A N D HI G H-RI S K L O C A L -R E GI O N A L L Y A D V A N C E D 
H E A D A N D N E C K S Q U A M O U S C E L L C A R CI N O M A  
 
 
A me n d me nt 4:  Dece m ber  2 6, 2 0 17 

 
 
R T O G F o u n d ati o n C oll a b or ati o n wit h Brist ol- M yers S q ui b b 
 
R T O G 3 5 0 4 
 
A Li mite d P a rtici p ati o n St u d y 
 
S A F E T Y E V A L U A TI O N S O F NI V O L U M A B ( A N TI-P D - 1) A D D E D T O 
C H E M O R A DI O T H E R A P Y ( C R T) P L A T F O R M S I N P A TI E N T S WI T H 
I N T E R M E DI A T E A N D HI G H- RI S K L O C A L- R E GI O N A L L Y A D V A N C E D H E A D A N D 
N E C K S Q U A M O U S C E L L C A R CI N O M A  
 
 
S p o ns or: R T O G F o u n dati o n  
 
 
C o -Pri nci p al I n vesti g at or / Me dical O nc ol o g y 
a n d Tra nslati o nal Scie n ce  
Ma ura Gillis o n, M D, P h D  
C o -Pri nci p al  I n vesti g at or/ S ur gic al O nc ol o g y 
a n d Tra nslati o nal Scie n ce  
R o bert Ferris, M D, P h D  
 
 
St u d y C o -C h airs  
 
Me dical O nc ol o g y  
A. D imitri os C ole vas, M D  
Ra diati o n O nc ol o g y  
L ore n K. Mell, M D  
Ra di ol o g y  
Cla u dia Kirsc h, M D  
Me dical P h ysics  
Ke vi n M o ore, P h D  
Q ualit y of Lif e  
Mi n h -Ta m Tr u o n g, M D  
Pat h ol o g y  
C hristi na K o n g, M D  
Pat h ol o g y  
Ric har d J or da n, D D S, P h D  
 
 
Se ni or Statisticia n  
J o nat han Harris , M S  
 
Pr ot oc ol Acce pta n ce 
O n be half of t h e R T O G F o u n dati o n, I nc. 
 
Walter J. C urra n, Jr., M D  
  
  
  
Date: Dece m ber 2 6, 2 0 1 7 
R T O G F o u n dati o n C hair ma n  
 
 

R T O G 3 5 0 4 
1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
 
R T O G 3 5 0 4 
( Cli nic al Tri als. g ov N C T # N C T 0 2 7 6 4 5 9 3 ) ( 5/ 5/ 2 0 1 6) 
 
A L i mite d P artici p ati o n St u d y 
 
S A F E T Y E V A L U A TI O N S O F NI V O L U M A B ( A N TI-P D - 1) A D D E D T O 
C H E M O R A DI O T H E R A P Y ( C R T) P L A T F O R M S I N P A TI E N T S WI T H 
I N T E R M E DI A T E A N D HI G H- RI S K L O C A L- R E GI O N A L L Y A D V A N C E D H E A D A N D 
N E C K S Q U A M O U S C E L L C A R CI N O M A  
 
 
St u d y Te a m 
C o -Pri nci p al I n vesti g at or  
Me dical O nc ol o g y a n d Tra nslati o nal Scie nce  
Ma ura Gillis o n, M D, P h D  
T he U ni versit y of Te x as M D A n ders o n Ca nce r 
Ce nter  
1 5 1 5 H olc o m be  B o ule v ar d , U nit 4 3 2 
H o ust o n, Te x as 7 7 0 3 0  
7 1 3 -7 9 2 -6 3 6 3 / F A X 7 1 3 -7 9 2 -1 2 2 0  
m gillis o n @ m da n ders o n. or g  
Ra diati o n O nc ol o g y C o -C hair  
L ore n K. Mell, M D  
U ni versit y of Calif or nia Sa n Die g o  
3 8 5 5 Healt h Scie nces Dri ve, M C 0 8 4 3  
La J olla, C A 9 2 0 9 3  
8 5 8 -2 4 6 -0 4 7 1/ F A X 8 5 8 -8 2 2 -5 5 6 8  
l mell @ ucs d.e d u 
 
 
C o -Pri nci p al I n vesti g at or  
S ur gical O nc ol o g y a n d Tra nslati o nal Scie nce  
R o bert Ferris, M D, P h D  
U ni versit y of Pitts b ur g h Me dical Ce nter  
5 1 1 7 Ce ntre A ve n u e  
Pitts b ur g h, P A 1 5 2 1 3  
4 1 2 -6 2 3 -0 3 2 7/ F A X 4 1 2 -6 2 3 -4 8 4 0  
ferrrl @ U P M C.e d u 
Me dical P h ysics C o -C hair  
Ke vi n M o ore, P h D  
U ni versit y of Calif or nia, Sa n Die g o  
3 8 5 5 Healt h Scie nces Dri ve, # 0 8 4 3  
La J olla, C A 9 2 0 9 3  
8 5 8 -8 2 2 -6 0 5 6/ F A X 8 5 8 -8 2 2 -5 5 6 8  
ke vi n m o ore @ ucs d.e d u  
 
 
Me dical O nc ol o g y C o -C hair  
A. Di mitri os C ole vas, M D  
Sta nf or d U ni versit y  
8 7 5 Bla ke Wil b ur Dri ve, C C -2 2 2 8  
Sta nf or d, C A 9 4 3 0 5  
6 5 0 -7 2 4 -9 7 0 7/ F A X 6 5 0 -4 9 8 -5 8 0 0  
c ole vas @sta nf or d.e d u  
Q ualit y of Lif e C o -C hair  
Mi n h -Ta m Tr u o n g, M D  
B ost o n Me dical Ce nter  
8 3 0 Harris o n A v e., M oa kle y Bl d g., L L 2 3 8  
B ost o n, M A 0 2 1 1 8  
6 1 7 -6 3 8 -7 0 7 0/ F A X 6 1 7 -6 3 8 -7 0 3 7  
Mi n h -Ta m. Tr u o n g @ b mc. or g  
 
 
  
  
  
  
 
St u d y Te a m c o nti n ue d o n ne xt p a ge  

R T O G 3 5 0 4 
2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R T O G F O U N D A TI O N  
R T O G 3 5 0 4 
 
S A F E T Y E V A L U A TI O N S O F NI V O L U M A B ( A N TI-P D - 1) A D D E D T O 
C H E M O R A DI O T H E R A P Y ( C R T) P L A T F O R M S I N P A TI E N T S WI T H 
I N T E R M E DI A T E A N D HI G H- RI S K L O C A L- R E GI O N A L L Y A D V A N C E D H E A D A N D 
N E C K S Q U A M O U S C E L L C A R CI N O M A  
 
St u d y Te a m (c o nti n ue d) ( 2 6 Dec 2 0 1 7) 
Pat h ol o g y C o -C hair  
C hristi na K o n g, M D  
Sta nf or d U ni versit y  
3 0 0 Paste ur Dr., R o o m L 2 3 5  
Sta nf or d, C A 9 4 3 0 5  
6 5 0 -7 2 3 -9 0 1 6/ F A X 6 5 0 -7 2 5 -6 9 0 2  
c k o n g @sta nf or d.e d u  
Pat h ol o g y C o -C hair  
Ric har d J or da n, D D S, P h D  
Bi os peci me n Ba n k at U C S F  
2 3 4 0 S utter Street, R m S 3 4 1  
Sa n Fra n cisc o, C A 9 4 1 1 5  
4 1 5 -4 7 6 -7 8 6 4/ F A X 4 1 5 -4 7 6 -5 2 7 1  
ric har d.j or d a n @ ucsf.e d u 
 
 
Ra di ol o g y C o -C hair  
Cla u dia K irsc h, M D 
N ort h S h ore U ni v. H os pital Healt h S yste m  
3 0 0 C o m m u nit y Dri v e  
Ma n hasset, N Y 1 1 0 3 0  
5 1 6 5 6 2 -4 8 0 0/ F A X 5 1 6 5 6 2 -4 7 9 4  
c kirsc h @ ns hs.e d u  
Se ni or Statisticia n  
J o nat ha n Harris, M S  
R T O G F o u n dati o n  
1 8 1 8 Mar ket Street, S uite 1 7 2 0  
P hila del p hia, P A 1 9 1 0 3  
2 1 5 -5 7 4 -3 2 0 2 / F A X 2 1 5 -9 2 8 -0 1 5 3  
j harris@acr. or g  
 
R T O G F o u n d ati o n He a d q u arters C o nt act I nf or m ati o n  
D at a M a n a gers :   
F or q uesti o ns c o n cer ni n g eli gi bilit y or data 
s u b missi o n 
Va nita Patel, 2 1 5 -5 7 4 -3 1 7 0, v patel @acr. or g  
J a nelle R o bi ns o n, 2 1 5-7 1 7 -0 8 3 7,  
jr o bi ns o n @acr. or g 
Tiffa n i Si m ps o n -S mall, 2 1 5 -5 7 4 -3 1 6 4, 
ts mall @acr. or g 
A C R C ore L a b or at or y/ R T Q A :  
F or q uesti o ns c o n cer ni n g R T data s u b missi o n  
Na nc y Li n ne ma n n, 2 1 5 -7 1 7 -0 8 5 3,  
nli n ne ma n n @acr. or g  
Mars ha Ra d de n, 2 1 5 -7 1 7 -2 7 5 7  
mra d de n @acr. or g  
A C R C ore L a b or at or y/ R T Q A :   
F or q uesti o ns c o n cer ni n g data s u b missi o n t o 
T RI A D  
Tria d -S u p p ort @acr. or g  
A C R Di a g n ostic I m a gi n g : 
F or q uesti o ns c o n cer ni n g ce ntral i ma gi n g 
re vie w 
E milie C o n n ors , 2 1 5 -5 7 4 -3 2 0 1 , 
ec o n n ors @acr. or g  
Seri o us A d verse E ve nt C o or di n at or  
F or q uesti o ns c o n cer ni n g  seri o us a d verse e v e nt 
re p orti n g pr oce d ures, ti m eli nes, a n d q ueri es 
Sara Mc Cart n e y, 2 6 7 -9 4 0 -9 4 0 4,  
s mccart ne y @ acr. or g 
 
 

R T O G 3 5 0 4 
3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R T O G F O U N D A TI O N  
R T O G 3 5 0 4 
 
S A F E T Y E V A L U A TI O N S O F NI V O L U M A B ( A N TI-P D - 1) A D D E D T O 
C H E M O R A DI O T H E R A P Y ( C R T) P L A T F O R M S I N P A TI E N T S WI T H 
I N T E R M E DI A T E A N D HI G H- RI S K L O C A L- R E GI O N A L L Y A D V A N C E D H E A D A N D 
N E C K S Q U A M O U S C E L L C A R CI N O M A  
 
 
R T O G F o u n d ati o n He a d q u arters C o nt act I nf or m ati o n  ( C o nti n ue d) (2 6 Dec 2 0 1 7 ) 
Pr oject M a n a ger : F or q uesti o ns c o ncer ni n g  
re g ulat or y d oc u m e ntati o n, p 1 6 testi n g stat us 
a n d n otificati o n of testi n g res ults, 
i n vesti gati o nal dr u g s u p pl y a n d/ or s hi p me nt 
iss ues. 
Tree n a Da vis -Tr ot ma n, 2 1 5 -5 7 4 -3 2 0 5  
ttr ot ma n @acr. or g 
Pr ot oc ol A d mi nistr at or : F or q uesti o ns 
c o ncer ni n g pr ot oc ol versi o ns & a me n d me nts  
Sara Mc Cart n e y, 2 6 7 -9 4 0 -9 4 0 4,  
s mccart ne y @ acr.or g   
Me m bers hi p : F or q uesti o ns c o ncer ni n g 
c o ntracts a n d rei m b urse me nt  
R T O G -Me m bers hi p @ acr. or g  
F or C o de Brea ks, 8: 3 0 a. m. t o 5 p. m. E T  
2 1 5 -5 7 4 -3 1 5 0, as k f or t he S u p p orti n g 
Statisticia n  
F or C o de Brea ks aft er b usi ness h o urs or o n 
wee ke n ds or h oli da ys  
2 1 5 -4 5 9 -3 5 7 6  
 
Pr ot oc ol A g e nts 
A ge nt  
S u p pl y  
I N D # 
I N D S p o ns or 
Cis plati n  
C o m mercial  
E x e m pt  
N/ A  
Cet u xi ma b  C o m mercial  
E x e m pt  
N/ A  
Ni v ol u ma b  Brist ol -M yers S q ui b b , cli nical 
s u p pl y 
I N D#  1 2 9 8 4 1  
R T O G F o u n dati o n, I n c.  
 
P artici p ati n g Sites :  A list of sites partici pati n g i n t he trial ca n be accesse d o n t he R T O G 
we bsite. 
 
D oc u me nt Hist or y  
 
 
Versi o n D ate  
Rele ase  D ate  
A me n d me nt 4  
Dece m b er 2 6, 2 0 1 7  
 
A me n d me nt 3  
Ma y 2 5 , 2 0 1 7 
J ul y 3, 2 0 1 7 
A me n d me nt 2  
Se pte m ber 1 4 , 2 0 1 6 
N o ve m ber 1 6 , 2 0 1 6 
A me n d me nt 1  
Ma y 1 9, 2 0 1 6  
J u ne 1, 2 0 1 6 
A p pr o ve d O nl y  
 A pril 1 4 , 2 0 1 6 
 
 
 
 
 
T his pr ot oc ol w as desi g ne d a n d de vel o pe d b y R T O G F o u n d ati o n, I nc. 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 R T O G  n or d oes 
R T O G 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.  

R T O G 3 5 0 4 
4   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
  
 
T A B L E O F C O N T E N T S ( 2 6 Dec 2 0 1 7)  
S C H E M A ......................................................................................................................................... 6  
1.  
O B J E C TI V E S ...................................................................................................................... 7 
1. 1  
P ri mar y O bj ecti ves .................................................................................................. 7 
1. 2  
S ec o n dar y O bj ecti ve  ............................................................................................... 7  
2.  
B A C K G R O U N D ................................................................................................................. 7  
2. 1 S t u d y O ver vie w  ............................................................................................................. 7 
2. 2 He a d a n d Nec k C a ncer................................................................................................... 8  
2. 3 H P V a n d Hea d a n d N ec k Ca ncer S ur vi val .................................................................... 8  
2. 4 P ri mar y C R T f or Hea d a n d Nec k C a ncer ...................................................................... 9 
2. 5 He a d a n d Nec k C a ncer a n d I m m u nit y ......................................................................... 1 1  
2. 6 S t u d y Desi g n ................................................................................................................ 1 7 
2. 7 B i o mar ker St u dies ........................................................................................................ 1 9 
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 9  
3. 1  
P atie nt Selecti o n G ui deli nes .................................................................................. 2 0  
3. 2  
Eli g i bilit y Criteria  ................................................................................................. 2 0 
3. 3  
In eli gi bilit y Criteri a ............................................................................................... 2 2  
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  .......... 2 4 
5. T R E A T M E N T P L A N/ Re gi me n des cri pti o n .............................................................................. 3 0  
5. 1  
C he m ot hera p y/ Ot her A ge nt- Base d T hera p y .......................................................... 3 0  
5. 2  
R a diati o n T hera p y .................................................................................................. 3 4  
5. 3  
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 1  
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 2  
6. 1  Ni v ol u m a b D ose M o dificati o ns .................................................................................. 4 2  
6. 2  C et u xi ma b D ose M o dificati o ns .................................................................................. 4 5  
6. 3  
C is plati n D ose M o dificati o ns ................................................................................ 5 2 
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 ................................................. 5 5  
7. 1 P r ot oc ol A ge nts ............................................................................................................ 5 5 
7. 2  
A d ve rse E v e nts ( A Es) ............................................................................................ 5 5 
7. 3  
S eri o us A d verse E v e nts ( S A Es)............................................................................. 5 7  
7. 4  
S eri o us A d verse E v e nt ( S A E) Re p orti n g Re q uir e me nts ....................................... 5 7  
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 ............................................. 6 1  
8. 1  
Re g ulat or y Re q uire me nts....................................................................................... 6 1  
8. 2  
R T Re gistrati o n Re q uire me nts ............................................................................... 6 1  
8. 3  
P atie nt E nr oll me nt ................................................................................................. 6 1  
9  
D R U G  I N F O R M A TI O N ................................................................................................... 6 1 
9. 1  
I n v esti gati o nal St u d y A ge nt ................................................................................... 6 1 

R T O G 3 5 0 4 
5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
9. 2  
C o m mercial A ge nts ............................................................................................... 6 2  
1 0. P at h ol o g y/ BI O S P E CI M E N S ................................................................................................... 6 2  
1 0. 1     p 1 6 I m m u n o hist oc he mistr y f or Or o p har y n x Ca ncers ............................................ 6 2  
1 0. 2  
Tiss u e/ S peci me n S u b missi o n................................................................................. 6 3  
1 0. 3 Ma n dat or y St u dies ..................................................................................................... 6 5  
1 0. 4 O pti o nal S peci me n C ollecti o n f or R T O G 3 5 0 4 Researc h a n d Ba n ki n g .................... 6 6  
1 1.  
S P E CI A L st u dies ( N o n- Tiss ue) ......................................................................................... 6 7  
1 2. M o da lit y Re vie ws .................................................................................................................... 6 7 
1 2. 1  
R a diati o n T hera p y Q u alit y Ass ura nce Re vie ws .................................................... 6 7  
1 2. 2  
Dr u g Q ualit y Ass ura n ce Re vie ws .......................................................................... 6 7  
1 2. 3  
S ur gical Q ualit y Ass ura n ce Re vie ws ..................................................................... 6 8  
1 3.  
D A T A A N D R E C O R D S ................................................................................................... 6 8  
1 4. S T A TI S TI C A L C O N SI D E R A TI O N S .................................................................................... 6 9  
1 4. 1  
S t u d y Desi g n .......................................................................................................... 6 9 
1 4. 2  
S t u d y E n d p oi nts ..................................................................................................... 6 9 
1 4. 3  
P ri mar y O bj ecti ves St u d y Desi g n .......................................................................... 6 9 
1 4. 4  
Ac cr ual/ St u d y D urati o n C o nsi derati o ns ................................ ................................ 7 0 
1 4. 5  
D ose  Le vel G ui d eli nes ........................................................................................... 7 0 
R E F E R E N C E S .............................................................................................................................. 7 1  
A P P E N DI X I:  Ni v ol u ma b ( B M S- 9 3 6 5 5 8) P har m ac y Refere n ce Ma n u al ................................... 8 6  
A P P E N DI X II: BI O S P E CI M E N B A N K A T U C S F:  BI O S P E CI M E N C O L L E C TI O N, 
P R O C E S SI N G, A N D S HI P PI N G I N S T R U C TI O N S F O R F F P E  .................................... 9 2  
A P P E N DI X III: Ferris La b orat or y: Pre p arati o n, Pr ocessi n g a n d s hi p pi n g of Peri p heral Bl o o d .. 9 4  
 
 
 

R T O G 3 5 0 4 
6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
Or o p har y n x ca ncer patie nts: p 1 6 
i m m u n o hist oc he mistr y t o c o nfir m 
eli gi bilit y re q uire d pri or t o Ste p 2 
Re gistrati o n  
 
Ar m 3 * * ( N = 8 
e val ua ble) 
 
Ni v ol u ma b, 2 4 0 m gs 
q 1 4 da ys x 1 0 
starti n g 1 4 da ys pri or 
t o I M R T, t he n 4 8 0 
m gs q 2 8 da ys x 7 
d oses 
 
Cet u xi ma b, 4 0 0 
m g/ m 2 l oa di n g, t he n 
 2 5 0 m g/ m2 x q 7 
da y s x 7 
 
I M R T: 7 0 G y 
Ste p 1 Re gistr ati o n  
Oral ca vit y, lar y n x a n d 
h y p o p har y n x ca ncer patie nts 
pr ocee d t o Ste p 2 re gistrati o n.  
 
Se q ue nti al Re gistr ati o n t o Ar ms 1, 2, a n d 3 *  
Ar m 4 ( N = 8 e val ua ble ) 
1 t o 4 of t he f oll o wi n g:  
 ≥ 7 0  ye ars ol d; Z u br o d 
of  2; ≥ 3 gr a de 
ne ur o p at h y; ≥2  
he ari n g l oss ; Cr Cl < 5 0 
ml/ mi n  
 
Ni v ol u ma b, 2 4 0 m gs 
q 1 4 da ys x 1 0 starti n g 
1 4 da ys pri or t o I M R T, 
t he n 4 8 0 m gs q 2 8 da ys x 
7 d oses  
  
I M R T: 7 0 G y 
Ar m 1 * * :  ( N = 8 
e val ua ble) 
Ni v ol u ma b, 2 4 0 m gs 
q 1 4 da ys x 1 0  
starti n g 1 4 da ys pri or 
t o I M R T, t he n 4 8 0 
m gs q 2 8 da ys x 7 
d oses 
 
Cis plati n, 4 0 m g/ m 2 
q 7 da ys x 7 
 
I M R T: 7 0 G y 
 
Ar m 2 * * : ( N = 8 
e val ua ble) 
Ni v ol u ma b, 2 4 0 m gs 
starti n g 1 4 da ys pri or 
t o I M R T, t he n 3 6 0 
m gs da y 1 of I M R T 
a n d q 2 1 da ys 
x 6 d oses, t he n 4 8 0 
m gs q 2 8 da ys x 7 
d oses 
 
Cis plati n, 1 0 0 m g/ m 2 
q 2 1 da ys x 3 
 
I M R T: 7 0 G y 
 
R T O G F O U N D A TI O N  
R T O G 3 5 0 4 
 
S afet y E v al u ati o ns of Ni v ol u m a b ( A nti- P D - 1) A d de d t o C he m o r a di ot her a p y ( C R T) 
P l atf or ms i n P atie nts wit h I nter me di ate a n d Hi g h- Ris k L oc al- Re gi o n all y A d v a nce d He a d 
a n d Nec k S q u a m o us Cell C arci n o m a 
 
S C H E M A ( 2 6 D E C 2 0 1 7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* All p atie nts will be re gistere d t o Ar m 1 u ntil t he s a m ple size is re ac he d, t he n t o Ar m 2, t he n t o Ar m 3.  
* * N ote: T he fe asi bilit y of 7 m o nt hs of a dj u v a nt ni v ol u m a b will be deter mi ne d i n t he first 8 e v al u a ble 
p atie nts.  
    
 
                  
 
 
Or o p har y n x ca ncer t hat is p 1 6 -p ositi ve b y i m m u n o hist oc he mistr y wit h s m o ki n g stat us 
> 1 0 Pac k -years sta ge T 1 -2 N 2 b -N 3  or  T 3 -4 N 0 -3 O R ≤ 1 0 pac k -years sta ge T 4 N 0 -N 3, 
T 1 -3 N 3  
 
Oral ca vit y, lar y n x, h y p o p har y n x, or p 1 6 -ne gati ve or o p har y n x ca ncer, sta ge T 1 -2 N 2a -
N 3  or  T 3 -4 N 0 -3  

R T O G 3 5 0 4 
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1.  O B J E C TI V E S 
1. 1  Pri m ar y O bjecti ves ( 2 6 Dec 2 0 1 7) 
 T o e val uate t he s afet y of t he a d diti o n of ni v ol u ma b (a nti P D- 1 i m m u n ot hera p y) t o 
c he m ora di ot hera p y wit h wee kl y cis plati n ( 4 0 m g/ m 2/ wee k x 7) f or patie nts wit h 
i nter me diate or hi g h-ris k  hea d a n d n ec k s q ua m o us cell carci n o ma ( H N S C C) ( Ar m 
1) ; 
 T o e val uate t he s afet y of t he a d diti o n of ni v ol u ma b (a nti P D- 1 i m m u n ot hera p y) t o 
c hem ora di ot hera p y wit h hi g h- d ose cis plati n ( 1 0 0 m g/ m 2 q 2 1 da ys x 3) f or patie nts 
wit h i nter me diate or hi g h-ris k  hea d a n d nec k s q u a m o us cell carci n o ma ( H N S C C) 
( Ar m 2); 
 T o e val uate t he s afet y of t he a d diti o n of ni v ol u ma b (a nti P D- 1 i m m u n ot hera p y) t o 
c he m ora di ot hera p y wit h wee kl y cet u xi ma b ( 4 0 0 m g/ m 2 l oa d, 2 5 0 m g/ m2/ week x 7) 
f or patie nts wit h i nter me diate- or hi g h-ris k hea d a n d nec k s q ua m o us cell carci n o ma 
(H N S C C) ( Ar m 3); 
 T o e val uate t he s afet y of t he a d diti o n of ni v ol u ma b (a nti P D- 1 i m m u n ot hera p y) t o 
ra di ot hera p y f or patie nts wit h i nter me diate or hi g h-ris k  hea d a n d nec k s q u a m o us cell 
carci n o ma ( H N S C C) wit h o ne t o f o ur of t he f oll o wi n g:  a ge ≥ 7 0 years; Z u br o d 
P erf or ma nce Stat us 2; baseli ne gra de ≥ 3 n e ur o pat h y; gra d e ≥2  heari n g l oss; Cr Cl < 
5 0 ml / mi n ( Ar m 4).  
1. 2    Sec o n d ar y O bjecti ve  
T o e val uate t he s afet y, feasi bilit y a n d patie nt c o m plia nce wit h a dj u va nt a d mi nistrati o n 
of si n gle a ge nt ni v ol u ma b t o a ma xi m u m of 1 year of t hera p y ( ni v ol u ma b, 4 8 0 m gs q 2 8 
da ys x 7) 
2.  B A C K G R O U N D 
2. 1 St u d y O ver vie w 
T he st u d y is a s afet y e v al uati o n of t he a d diti o n of ni v ol u ma b t o se veral 
c he m ora di ot hera p y platf or ms wit h wee kl y cis plati n, hi g h- d ose cis plati n, cet u xi ma b or 
ra di ot hera p y al o ne. T he 4 ar ms will i ncl u de 3 2 e v al ua ble patie nts. Patie nts wit h 
i nter me diate- or hi g h-ris k H N S C C will be se q ue ntiall y assi g ne d t o recei ve  ( Ar m 1) 
ni v ol u ma b ( 2 4 0 m gs q 1 4 da ys x 1 0) starti n g o n da y - 1 4 pri or t o I M R T wit h wee kl y 
cis plati n ( 4 0 m g/ m 2 X 7)- base d c h e m ora di ot hera p y t he n ( Ar m 2) ni v ol u ma b ( 2 4 0 m gs o n 
da y - 1 4 pri or t o I M R T f oll o we d b y ni v ol u ma b 3 6 0 m gs q 2 1 da ys x 7) wit h hi g h- d ose 
cis plati n ( 1 0 0 m g/ m 2 I V da y 1, 2 2, a n d 4 3)- b ase d c he m ora di ot hera p y t he n ( Ar m 3) 
ni v ol u ma b ( 2 4 0 m gs q 1 4 da ys x 1 0) wit h cet u xi ma b- base d c he m or a di ot hera p y. Ar m 4 is 
o pe n f or plati n u m-i nel gi ble patie nts (see b el o w). I n t he e ve nt t hat > 2 of 8 e val ua ble 
patie nts e x perie nce a d ose-li miti n g t o xicit y ( D L T), t he ar m will be c o nsi dere d n ot w ort h y 
of f urt her st u d y d u e t o safet y c o ncer ns.  If ≤ 2 of 8 patie nts e x perie nce a D L T i n Ar m 1, 
t he re gi me n will be c o nsi dere d w ort h y of a d diti o nal st u d y. T he st u d y will als o e val uate 
t he safet y a n d feasi bilit y of a dj u va nt a d mi nistrati o n of ni v ol u ma b 4 8 0 m gs q 2 8 da ys x 7, 
starti n g 3 m o nt hs after e n d of R T. Feasi bilit y will be e val uat e d i n t he first ei g ht patie nts 
o n a n y ar m a n d if m or e t ha n 4 recei ve less t ha n 7 d oses a dj u va nt t hera p y will be 
c o nsi dere d i nf easi ble. 
 
I n mel a n o ma a n d l u n g ca ncer a dj u v a nt trials, si n gl e a ge nt ni v ol u ma b is a d mi nistere d f or 
u p t o a year after pri mar y t hera p y. T his ti me fra m e is base d u p o n o bser vati o ns i n 
rec urre nt metastatic dise ase de m o nstrati n g pr ol o n ge d ti me t o stea d y st ate a nti b o d y le vels, 

R T O G 3 5 0 4 
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as well as dela ye d res p o nses t o t hera p y be y o n d 4 m o nt hs of t hera p y. I n t he or y, c o nti n ue d 
i m m u n ot hera p y d uri n g t his ti me fra me ma y facilitate i m m u ne cleara nce of micr o-
metastatic disease a n d pre ve nt or pr ol o n g diseas e pr o gressi o n. T he o pti mal d urati o n of 
a dj u va nt i m m u n ot hera p y is u n k n o w n b ot h i n a ni mal m o dels a n d i n h u ma n s u bjects. Als o 
u n k n o w n are t h e p ote ntial l o n g-ter m t o xicities of t his t hera p y i n hea d a n d n ec k ca ncer 
patie nts. Hist oricall y, h ea d a n d nec k ca ncer patie nts are p o orl y i ncli ne d t o war d a dj u va nt 
t hera pies, a n d rates of ref usal or disc o nti n uati o n of a dj u va nt t hera pies i n cl u de d i n cli nical 
trials are hi g h. T heref ore, we will e val uate t h e safet y a n d feasi bilit y of a dj u va nt 
i m m u n ot hera p y i n t he p atie nt p o p ulati o n. I n t his pr ot oc ol, t he ter m “a dj u va nt t hera p y” 
will be defi ne d as a d mi nistrati o n of ni v ol u ma b starti n g 3 m o nt hs after c o m pleti o n of 
c he m ora di ot hera p y f or 7 m o nt hs.  
2. 2 He a d a n d Nec k C a ncer 
H N S C C is a maj or ca use of m or bi dit y a n d m ortalit y w orl d wi d e, wit h o ver 6 1 0, 0 0 0 ne w 
cases dia g n os e d eac h year ( Ferla y 2 0 1 1). T he A m erica n Ca n cer S oci et y esti mates t hat 
5 3, 6 4 0 ne w cas es a n d 1 1, 5 2 0 deat hs fr o m H N S C C occ urre d i n t he U. S. i n 2 0 1 3 ( Sie gel 
2 0 1 3) . W hile t he maj orit y of H N S C C w orl d wi de are attri b uta ble t o t o bacc o a n d alc o h ol 
use, oral H P V i nfecti o n is ne wl y a p preciate d as t he pri nci pal ca use of a disti nct f or m of 
H N S C C ( Gillis o n 2 0 0 8). T hese ca ncers arise pre d o mi na ntl y fr o m t he t o nsil a n d base of 
t o n gue wit hi n t he or o p h ar y n x. W hile i nci de nce rates f or H N S C C o verall decli ne d fr o m 
1 9 9 2- 2 0 0 5 i n t he U. S., t he i nci de nce rates f or or o p har y n geal ca ncer are risi n g (Je mal 
2 0 1 3) . A n a nal ysis of N CI S E E R oral c a ncer s peci me ns re veale d t hat t he i nci de nce rates 
f or H P V- ne gati ve or o p har y n geal ca ncer decrease d b y 5 0 % fr o m 1 9 8 4- 2 0 0 4, w hereas 
rates f or H P V- p ositi ve or o p har y n geal s q u a m o us cell carci n o ma ( O P C) i ncrease d b y 
2 2 5 % d uri n g t h e sa me ti me peri o d ( C hat ur v e di 2 0 1 1).  It is h y p ot hesize d t hat t hese tre n ds 
are d ue t o k n o w n re d u cti o ns i n t o bacc o s m o ki n g i n t he U. S. o ver t he last se veral deca des 
co nc o mita nt wit h i ncreasi n g rat es of oral H P V i nfecti o n. H P V- p ositi ve O P S C C is 
pr ojecte d t o be t he pre d o mi na nt t y pe of H N S C C i n t he U. S. b y 2 0 3 0 ( C hat ur ve di 2 0 1 1, 
P i g n o n 2 0 0 9). 
2. 3 H P V a n d He a d a n d Nec k C a ncer S ur vi v al 
T u m or H P V stat us has bee n s h o w n t o be a str o n g, i n de pe n de nt pr o g n ostic bi o mar ker f or 
patie nts wit h H N S C C treate d wit h cis plati n- or cet u xi ma b- base d R T ( R ose nt hal 2 0 1 4). 
P atie nts wit h H P V- p ositi ve O P S C C ha ve a 5 8 % ( H R 0. 4 2, 9 5 % CI 0. 2 7- 0. 6 6) re d ucti o n 
i n ris k of deat h w he n c o m pare d t o patie nts wit h H P V- ne gati ve O P S C C ( A n g 2 0 1 0), after 
a dj ust me nt f or ot her pr o g n ostic fact ors. H P V- p ositi ve ca ncers ha v e bee n s h o w n t o h a ve 
hi g her res p o nse rates t o c he m ot hera p y a n d C R T ( Fa k hr y 2 0 0 7), res ulti n g i n hi g her l o cal-
re gi o nal disease c o ntr ol. F urt her m ore, t he c o m bi n ati o n of H P V stat us, pac k- years of 
t o bacc o s m o ki n g, a n d t u m or sta ge has bee n s h o w n t o classif y p atie nts as h a vi n g a l o w, 
i nter me diate, or hi g h ris k of deat h.  T hree- year rat es of O S were 9 3 % ( 9 5 % CI, 8 8. 3- 9 7. 7) 
i n t he l o w-ris k gr o u p, 7 0. 8 % ( 9 5 % CI 6 0. 7- 8 0. 8) i n t he i nter me diate-ris k gr o u p, a n d 
4 6. 2 % ( 9 5 % CI 3 4. 7- 5 7. 5) i n t he hi g h-ris k gr o u p ( A n g 2 0 1 0, Gillis o n 2 0 1 2). N o vel 
t hera pies are t h us nee de d i n b ot h i nter me diate a n d hi g h-ris k p atie nts t o i m pr o ve b ot h 
l ocal-re gi o n al c o ntr ol a n d re d uce ris k of dista nt metastases. 
 
A d diti o nal a nal ys es c o n d ucte d b y O’ S ulli va n, et al. ( 2 0 1 3) ha ve i n dicate d t hat patie nts 
wit h p 1 6 - p ositi ve O P S C C wit h T 4 or N 2 C- N 3 disease ha v e a hi g h-ris k of disease 
pr o gressi o n, e ve n if t o bacc o e x p os ure is < 1 0 pac k- years. T heref ore, t h ese patie nts are 

R T O G 3 5 0 4 
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Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
als o c o nsi dere d eli gi ble f or t his cli nical trial. T he sa m ple siz e calc ulati o ns prese nte d i n 
t his pr ot oc ol c o nsi der t he o utc o me of all of t hese eli gi ble patie nts base d o n o bser vati o ns 
fr o m R T O G 0 5 2 2.It is i m p orta nt t o n ote t hat ma n y of t he cli nical trials i n vesti gati n g t he 
i m pact of t u m or H P V stat us o n s ur vi val ha ve utilize d a vali date d s urr o gate; t u m or p 1 6-
e x pressi o n stat us as meas ure d b y i m m u n o hist oc he mistr y. P 1 6-e x pressi o n has bee n s h o w n 
t o ha ve ~ 9 2 % se nsiti vit y a n d ~ 9 0 % s pecificit y i n c o m paris o n t o t he g ol d sta n dar d of 
e x pressi o n of hi g h-ris k H P V o nc o ge nes E 6 a n d E 7 (J or da n 2 0 1 2). 
2. 4 P ri m ar y C R T f or H e a d a n d Nec k C a ncer 
T he  maj orit y ( ~ 6 0 %) of H N S C C patie nts is dia g n ose d wit h l ocal-re gi o n all y a d v a nce d 
disease, a n d t he 5- year s ur vi val f or t his s u bset is hea vil y d e pe n d e nt o n H P V stat us. T he 
c urre nt n o ns ur gi cal sta n d ar d of care f or t he maj orit y of patie nts wit h l ocal-re gi o n all y 
a d va nce d ( Sta ge III-I V) or o p har y n x, lar y n x, h y p o p har y n x, a n d u nresecta ble oral ca vit y 
ca ncers is or ga n preser vati o n C R T.  Cis plati n- base d C R T has bee n s h o w n t o i m pr o ve 
l ocal-re gi o n al c o ntr ol, P F S, a n d O S w he n c o m p are d t o ra di ot hera p y al o ne. Altere d 
fracti o nati o n of ra diati o n d oes n ot see m t o eli mi nate t he be nefit of t h e a d diti o n of 
c o nc urre nt c he m ot hera p y ( B u dac h 2 0 0 6, Bla nc har d 2 0 1 1, B o ur his 2 0 1 2).  A rece nt meta-
a nal ysis esti mate d t he a bs ol ute be nefit of c o n c o mita nt c he m ora di ot hera p y o ver 
ra di ot hera p y t o b e 6. 5 % at 5- years f or all hea d a n d nec k ca ncer patie nts ( Pi g n o n 2 0 0 9). A 
rece ntl y c o m plet e d, lar ge ra n d o mize d p hase III tri al ( R T O G 1 0 1 6) is testi n g w het her 
C R T wit h cis plati n vs. cet u xi ma b res ults i n e q ui vale nt s ur vi val or w het her o ne or t he 
ot her  re gi me n is s u peri or i n p 1 6- p ositi ve or o p har y n x ca ncer patie nts. S ur ve ys of 
co m m u nit y o nc ol o g y practices i n dicate a p pr o xi matel y e q ui v ale nt use of cis plati n- a n d 
cet u xi ma b- base d C R T f or t he pri mar y tr eat me nt of H N S C C.   
 
W hile hi g h- d ose cis plati n ( 7 5- 1 0 0 m g/ m
2) e ver y 2 1 da ys is t he m ost c o m m o n sc he d ule 
use d ( Briz el 1 9 9 8, Bec k ma n n 2 0 0 5, F orastiere 1 9 9 3, J ere mic 2 0 0 0, Q u o n 2 0 1 1, Bac ha u d 
1 9 9 6), b ol us cis plati n ( 7 5- 1 0 0 m g/ m 2 e ver y 2 1 d a ys) is ass ociate d wit h fre q ue nt t o xicities 
s uch as na usea a n d v o miti n g, re n al i m pair me nt, c yt o pe nias, a n d ot ot o xicit y. As a res ult of 
t hese t o xicities, ~ 3 0 % of i n di vi d uals i n ra n d o mize d cli nical trials i n R T O G d o n ot 
recei v e all 3 c ycl es of c h e m ot hera p y ( F orastiere 2 0 0 3, A n g 2 0 1 0). T o o verc o me t hese 
c halle n ges, se v eral cli nical trials ha ve i n vesti gate d wee kl y cis plati n sc he d ul es. Wee kl y 
sc he d ules ha v e ra n ge d i n d ose bet wee n cis plati n 2 0- 5 0 m g/ m 2/ wee k. A ra n d o mize d st u d y 
of 2 0 m g/ m 2/ wee k faile d t o s h o w i m pr o ve me nt vs. ra diati o n al o ne ( Q u o n 2 0 1 1). 
H o we ver, ot her sc h e d ules of hi g her d ose wee kl y cis plati n ( 3 3- 4 0 m g/ m 2 wit h ra diati o n) 
ha ve pr o ve n t o b e effecti ve, feasi ble, a n d t olera bl e i n H N S C C ( Me di na 2 0 0 6, Ma g uir e 
2 0 1 1, C ha n 2 0 0 5). F or nas o p har y n geal ca n cer, ra n d o mize d cli nical trials ha ve 
de m o nstrate d a s ur vi v al a d va nta ge f or cis plati n 3 0 m g/ m 2/ week i n c o m paris o n t o 
ra di ot hera p y al o ne f or sta ge II dise ase ( C h e n 2 0 1 1) a n d f or cis plati n 4 0 m g/ m 2/ week f or 
sta ge II-I V diseas e ( C ha n 2 0 0 4). F or H N S C C, a Fre nc h ra n d o mize d trial als o 
de m o nstrate d a s ur vi v al be nefit fr o m cis plati n 5 0 m g/ w eek ( ~ 3 0 m gs/ m 2) i n c o m paris o n 
t o R T al o ne ( Bac ha u d 1 9 9 6) a n d d oses as l o w as cis plati n 6 m g/ m2/ da y of R T ha ve als o 
s h o w n a s ur vi val be n efit, wit h hi g h treat me nt d eli ver y a n d re d uce d t o xicit y (Jere mic 
2 0 0 4).  
 
W hate ver t he re gi me n, a f or mal a nal ysis of cis plati n d osi n g i n dicate d t hat a c u m ulati ve 
d ose of cis plati n 2 0 0 m g/ m 2 c o nc urre nt wit h ra diati o n is m ost ofte n ass ociate d wit h 

R T O G 3 5 0 4 
1 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
mea ni n gf ul i m pr o ve me nt i n t u m or c o ntr ol a n d/ or s ur vi val ( A n g 2 0 0 4). Wee kl y re gi me ns 
are m or e br oa dl y t olera bl e a n d t heref ore, m ore a me na ble as a platf or m o n w hic h t o a d d 
a d diti o nal c he m ot hera p e utic or bi ol o gical a nti-ca ncer a ge nts.  T his c ha n ge t o a wee kl y 
cis plati n d osi n g has bee n t he a p pr oac h of t he R T O G f or se v eral of its rece nt st u dies, 
i ncl u di n g i n t he a dj u va nt setti n g f or hi g h-ris k patie nts ( R T O G 0 2 3 4 a n d 1 2 1 6) a n d l o w-
ris k H P V- p ositi ve ca ncer ( N R G- H N 0 0 2). F ort u n atel y, t he us e of i m m u n os u p pressi ve 
steroi ds f or c o ntr ol of n a usea is n ot us uall y necess ar y wit h wee kl y d osi n g. T his trial will 
i ncl u de a n e v al uati o n of t he safet y a n d feasi bilit y of t he a d diti o n of ni v ol u ma b t o b ot h 
cis plati n re gi me ns (cis plati n 4 0 m g/ m 2/ wee k x 7 wit h ni v ol u ma b [ 2 4 0 m gs] e ver y 1 4 
da ys  a n d cis plati n 1 0 0 m g/ m 2 da y 1, 2 2 a n d 4 3 of ra di ot hera p y wit h ni v ol u ma b [ 5 
m g / k g] e ver y 2 1 da ys), 
 
I nteresti n gl y, d ata e xist t hat cis plati n C R T i n a n H P V- p ositi ve m uri ne H N S C C m o del 
req uires t he a da pti ve i m m u ne s yste m t o me diate t he o pti mal t hera pe utic effect ( S pa n os 
2 0 0 9), s u p p orti n g t he c o m bi nati o n wit h a nti- P D - 1 m A b bl oc ka de t o e n ha nce t his effect, 
as pr o p ose d here. 
 
T he a d diti o n of cet u xi ma b, a m o n ocl o nal a nti b o d y tar gete d t o t he E G F R rece pt or, has 
bee n s h o w n i n a si n gle ra n d o mize d c o ntr olle d trial t o i ncrease l o cal-re gi o nal, 
pr o gressi o n-free s ur vi val ( P F S) a n d 5- year o verall s ur vi val ( O S) ( b y 9 %) i n c o m paris o n 
t o ra diati o n t hera p y al o ne ( B o n n er 2 0 0 6, B o n ner 2 0 1 0). S u b gr o u p  a nal ysis re veal e d t hat 
t he be nefit of cet u xi ma b was greater f or a patie nt wit h a cli nical pr ofile c o nsiste nt wit h 
H P V- p ositi ve O P S C C ( male, a ge < 6 5 years, l o w T sta ge, a d v a nce d N sta ge, g o o d 
pe rf or ma n ce stat us) ( B o n ner 2 0 1 0). T h ese data pr o m pte d t he R T O G t o e val uate w het her 
s u bstit uti o n of cis plati n wit h cet u xi ma b res ults i n c o m para ble 5- year O S f or patie nts wit h 
l ocal-re gi o n all y a d va nce d H P V- p ositi ve or o p har y n geal ca n cer ( R T O G 1 0 1 6). Rece ntl y, 
t he be nefit of cet u xi ma b f or H P V- p ositi ve O P S C C was retr os pecti vel y e v al uate d usi n g 
t u m or s peci me ns fr o m t h e ori gi n al B o n n er trial, d e m o nstrati n g si g nifica nt cli nical be nefit 
i n p 1 6- p ositi ve O P S C C patie nts fr o m t he a d diti o n of cet u xi ma b t o ra di ot hera p y 
( R ose nt hal 2 0 1 4). I n K a pla n- Meier a nal ysis, cet u xi ma b si g nifica ntl y i m pr o ve d o verall 
s ur vi val ( O S, 3- year 8 8 vs. 7 2 %, H R 0. 3 8, 9 5 % CI 0. 1 5- 0. 9 4) i n c o m paris o n t o 
ra di ot hera p y al o ne a m o n g patie nts wit h p 1 6- p ositi ve O PS C C. R T O G 1 0 1 6 has met its 
accr ual g oals, b ut defi niti ve res ults fr o m t his st u d y are n ot li kel y t o be a v aila ble u ntil 
2 0 1 8. I n a ntici pati o n of t he res ults of R T O G 1 0 1 6, we ha ve i n cl u de d a cet u xi ma b- base d 
che m ora di ot hera p y ar m t his trial.  
 
Beca use of t h e t o xicities ass ociate d wit h cis plati n- base d ra di ot hera p y, a si g nifica nt 
n u m ber of patie nts c a n n ot recei ve cis plati n. T his i ncl u des patie nts wit h a Z u br o d 
Perf or ma nce Stat us of 2, f or w h o m ra di ot hera p y al o ne is t he sta n dar d of care ( N C C N 
g ui deli nes). Patie nts als o ma y n ot be c o nsi dere d ca n di dates f or cis plati n bas e d u p o n 
pre e xisti n g re nal i ns ufficie nc y ( Cr Cl < 5 0), heari n g l oss, or peri p heral ne ur o pat h y.  
A d diti o nall y, meta- a nal ysis of cis plati n trials as well as a s u bset a nal ys es of t he B o n n er 
cet u xi ma b st u d y h a ve n ot de m o nstrate d i m pr o ve me nt o ver ra di ot hera p y al o ne a m o n g 
i n divi d uals 7 0 years of a ge a n d ol der. T h eref ore, ra di ot hera p y al o n e ( or cet u xi ma b R T) is 
t he c urre nt sta n dar d of care f or a s u bset of patie nts (a ge > 7 0 years, Z u br o d P S 2, 
i nt olera nt t o cis plati n). T his trial will als o t heref ore i ncl u de a ni v ol u ma b R T ar m t o 

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e val uate t he s afet y a n d feasi bilit y of t his re gi me n i n t his patie nt p o p ulati o n. 
2. 5 He a d a n d Nec k C a ncer a n d I m m u nit y 
I m m u ne d ysf u ncti o n ma y pla y a r ole i n t he pat h o ge n esis a n d pr o gressi o n of H N S C C. 
D o w n-re g ul ati o n of T cell f u ncti o n has bee n re p ort e d i n H N S C C, a n d is me diate d b y 
m ul ti ple mec ha nis ms i ncl u di n g: re d uce d e x pressi o n of c o-sti m ulati n g m ol ec ules of t he 
B 7 - C D 2 8 fa mil y ( Al bers 2 0 0 5); i ncreas e d e x pressi o n of P D- L 1 i n t u m or cells a n d t u m or 
ass ociate d fi br o bl asts; a n d l oss of H L A-class I a n d selecti ve d o w n-re g ulati o n of H L A- A, 
B, C l oc us e x pressi o n res ulti n g i n defecti ve a nti ge n prese ntati o n ( L o p ez- Al baiter o 2 0 0 6,  
L ei b o witz 2 0 1 3). A d diti o nall y, H P V- p ositi ve H N S C C patie nts ha ve e x pa n de d 
p o p ulati o ns of vir us -s pecific T cells wit h a n i neffecti ve a ntit u m or p he n ot y p e ( Al bers 
2 0 0 5). 
 
M o n ocl o nal A nti b o d y- Base d I m m u n ot hera p y of H N S C C 
T o da y t h e m ost wi del y use d f or m of ca ncer i m m u n ot hera p y is m A b t hera p y ( Ferris 
2 0 1 0 ). T his i ncl u des t u m or a nti ge n ( T A)-tar gete d m A bs, c yt o ki ne-tar get e d m A bs, t u m or 
necr osis fact or rece pt or ( T N F R)-fa mil y c osti m ulat or y tar gete d m A bs a n d i m m u ne 
c hec k p oi nt-tar gete d m A bs. T he m ost e xte nsi vel y st u die d (a n d F D A a p pr o ve d f or 
H N S C C) of t hese is cet u xi ma b, a m o use – h u ma n c hi meric I g G 1 a nti-e pi der mal gr o wt h 
fact or rece pt or m A b ( Y e wale 2 0 1 3). E G F R is a n attracti ve tar get i n H N S C C beca use it is 
o ve re x presse d i n 8 0 – 9 0 % of H N S C C a n d lea ds t o t u m or cell pr oliferati o n, i n vasi o n, 
an gi o ge nesis, t u m or s ur vi val, a n d c o nse q ue ntl y, p o or s ur vi val a n d pr o g n osis ( R u bi n 
Gra n dis 1 9 9 8).  
 
A nti - E G F R m A b me diat e a nti ge n-s pecific i m m u ne res p o nses t o tar gete d t u m ors t hr o u g h 
t w o maj or mec ha nis ms: direct killi n g via l ytic i m m u ne cell ( N K cell or m o n oc yt es) a n d 
c o m ple me nt fi x ati o n, or o ps o nizati o n of t u m or f or p ha g oc yt osis a n d s u bse q ue nt a nti ge n 
pr oc essi n g. T he latter w o ul d i n d uce T A-s pecific c yt ot o xic T l y m p h o c ytes ( C T L) t o 
rec o g niz e a n d l yse t u m or cells. O ne of t he m ost direct met h o ds b y w hic h a nti b o dies ca n 
ca use t u m or l ysis is via a nti b o d y- de p e n de nt cell ular c yt ot o xicit y ( A D C C) me diate d b y 
N K cells a n d pr o b a bl y m o n oc yt es a n d ne utr o p hils. T he e xte nt of A D C C is hea vil y 
i nfl ue nce d b y ge n etic p ol y m or p his ms i n Fcγ RIIIa, als o k n o w n as C D 1 6 ( L o pez- Al baiter o 
2 0 0 9 ), h o we ver c o nfir m at or y cli nical data i n H N S C C patie nts are lac ki n g.  I n a d diti o n t o 
dire ct acti vati o n of N K cell l ysis of t u m or cells, T A-s pecific m A bs ca n elicit C D 8 + T cell 
res p o nses t o t u m or- deri ve d a nti ge ns t hr o u g h i nteracti o n wit h Fcγ Rs o n a nti ge n-
prese nti n g cells ( A P C). T his a nti ge n-s p ecific T cell acti vati o n was n ote d i n 7 8 % of 
patie nts treate d wit h trast uz u ma b f or breast c a ncer a n d t his acti vati o n see m e d t o c orrelate 
p ositi vel y wit h cli nical res p o nse ( Ta yl or 2 0 0 7, Hers h ma n 2 0 0 7). S pecific T cell 
acti vati o n has bee n d e m o nstrate d i n H N S C C patie nts treate d wit h cet u xi ma b ( Lee 2 0 1 1, 
S ri vasta va 2 0 1 3), al o ne or i n c o m bi nati o n wit h cis plati n c he m ot hera p y. 
 
 
I m m u ne C hec k p oi nts a n d I n hi bit ors 
T cell acti vati o n occ urs t hr o u g h a c o m bi nati o n of T cell rece pt or e n ga ge me nt a n d c o-
sti m ulat or y m olec ules. T he d urati o n a n d e xte nt of i m m u ne res p o nses, f or e x a m ple t o 
i nfecti o ns, is re g ulate d b y “i m m u ne c hec k p oi nts” or i n hi bit or y pat h w a ys w hic h pre ve nt 
e x cessi ve i nfla m mat or y res p o nses as well as d e vel o p me nt of a ut oi m m u nit y. I m m u ne 

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c hec k p oi nts ha ve als o be e n s h o w n t o pla y a n i m p orta nt r ole i n t he t u m or 
micr oe n vir o n me nt a n d ca n be ma ni p ulate d as a m ec ha nis m of t u m or i m m u ne e vasi o n 
( Ra msa y 2 0 1 3). T he i m m u ne c hec k p oi nt pat h w a ys are me diat e d b y li ga n d a n d rece pt or 
i nteracti o ns, a n d e x a m ples i ncl u de c yt ot o xic T-l y m p h oc yte a nti ge n- 4 ( C T L A- 4) a n d its 
li ga n ds C D 8 0 a n d C D 8 4 a n d pr o gra m me d d eat h- 1 ( P D- 1) a n d its li ga n ds P D- L 1 a n d P D-
L 2. Bl oc ki n g a nti- C T L A- 4 A b t hera p y res ults i n r ejecti o n of m uri ne ca ncers ( Leac h 
1 9 9 6). A m A b a gai nst C T L A- 4, i pil u m u ma b, was t he first dr u g i n t his class t o 
de m o nstrate cli nical be n efit a n d was a p pr o ve d b y t he F D A f or patie nts wit h metastatic 
mela n o ma ( H o di 2 0 1 0). Tre meli m u ma b is als o a v aila ble f or C L T A- 4 tar geti n g. M ore 
rece ntl y, a nti-P D - 1 or P D- L 1 A bs ha v e de m o nstr ate d cli nical efficac y, al o ne ( T o palia n 
2 0 1 2, H o di 2 0 1 2, Ha mi d 2 0 1 3) or i n c o m bi nati o n wit h i pili m u ma b ( Calla ha n 2 0 1 2). 
 
P D - L 1 Pat h w a y Tar geti n g i n H N S C C 
Pr o gra m me d deat h r ece pt or- 1 ( P D- 1, C D 2 7 9), a 5 5 k D t y pe I tra ns me m bra ne pr otei n, is a 
me m ber of t he C D 2 8 fa mil y of T-cell c o-sti m ulat or y rece pt ors t hat als o i ncl u des C D 2 8, 
C T L A 4, I C O S, a n d B T L A. P D- 1 c o ntai ns a n i ntracell ular me m bra n e pr o xi mal 
i mm u n orece pt or t yr osi ne i n hi bit or y m otif (I TI M) a n d a me m bra n e distal i m m u n orece pt or 
tyr osi ne- base d s witc h m otif (I T S M). T w o li ga n ds s pecific f or P D- 1 ha v e bee n i de ntifie d: 
P D - L 1 ( B 7- H 1/ C D 2 7 4) a n d P D- L 2 ( B 7- D C/ C D 2 7 3). P D- L 1 a n d P D- L 2 h a ve bee n 
s h o w n t o d o w n-re g ulat e T-cell acti vati o n u p o n bi n di n g t o P D- 1 i n b ot h m uri ne a n d 
h u ma n s yste ms. P D- 1 deli vers a ne gati ve si g n al, s u p pressi n g t y p e 1 base d a ntit u m or 
i m m u nit y ( Li 2 0 1 4) b y t h e recr uit me nt of S H P- 2 t o t he p h os p h or yl ate d t yr osi ne resi d ue 
i n t he I T S M i n its c yt o pl as mic re gi o n, s ke wi n g t h e i m m u ne res p o nse a wa y fr o m a 
be neficial “t y p e 1” res p o nse.  P D- 1 is pri maril y e x presse d o n acti vate d T cells, B cells, 
a n d m yel oi d cells. P D- 1 bl oc ka de has t he p ot e ntial t o acti vate a nti-self T cell res p o nses, 
b ut t hese res p o nses are v aria ble a n d d e pe n d e nt u p o n vari o us h ost ge netic fact ors.  
T u m or i m m u ne e vasi o n ca n occ ur b y hi g h t u m or e x pressi o n of P D- L 1 a n d/ or t u m or 
i m m u ne i nfiltrati o n b y P D- 1 + T l y m p h oc ytes. Preli mi nar y a n al ys es i n dicat e t hat P D- L 1 
is e x presse d i n 5 0- 6 0 % of H N S C C, a n d t hat t u m or i nfiltrati o n b y P D- 1 + Tre g m a y be 
m ore c o m m o n f or H P V- p ositi ve t ha n H P V- ne gati ve H N S C C.  Str o me a n d c ollea g ues 
rep orte d me m bra ne a n d or i ntrac yt o plas mic P D- L 1 e x pressi o n i n 6 6 % ( 1 6 of 2 4) of 
H N S C C. Ba d o ual a n d c ollea g u es re p orte d t u m or i nfiltrati o n b y P D- 1 + C D 8 + a n d P D-
1 + C D 4 + l y m p h o c ytes was m ore c o m m o n a m o n g H P V- p ositi ve t ha n H P V- ne gati ve 
H N S C C ( C o nc ha- Be na v e nte 2 0 1 6). I n 3 3 ( 5 5 %) of 6 4 H N S C C, hi g h le vels of P D- L 1 
ex pressi o n were o bser ve d, b ut t here was n o ass ociati o n bet wee n P D- L 1 e x pressi o n a n d 
t u m or H P V stat us ( Ba d o ual 2 0 1 3).  Jie a n d c ollea g ues o bs er ve d hi g h er e x pressi o n of 
i mm u ne-c hec k p oi nt rece pt ors ( C T L A- 4 a n d P D- 1) i n i ntrat u m oral Tre g cells t ha n o n 
matc he d peri p h eral bl o o d sa m ples fr o m 2 7 patie nts wit h H N S C C ( 2 0 1 3). T hese data 
str o n gl y s u p p ort a r ole f or P D- 1 i n hi biti o n i n t he t hera p y of H N S C C. Rece nt data s h o w 
t hat circ ulati n g T cells a n d N K cells e x press detecta ble c o-i n hi bit or y c h ec k p oi nt 
rece pt ors, a n d c orrelat e wit h disease sta ge a n d st at us ( Ba d o ual 2 0 1 3, Jie 2 0 1 3, L yf or d-
P i ke 2 0 1 3, Jie 2 0 1 5). 
 
I nte grati o n of A nti-P D - 1 Base d I m m u n ot hera p y i nt o Pre vi o usl y U ntreate d, L ocall y 
A d va nce d H N S C C 
F or H P V- p ositi ve, pre vi o usl y u ntreate d, l ocall y a d va nce d ( P U L A) H N S C C, t he cli nical 

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nee d is m ore tar gete d, less t o xic t hera p y, a n d t o deter mi ne t he se q ue n ci n g a n d o pti mal 
c he m o-ra diati o n re gi me ns t hat d o n ot i n hi bit i m m u n ot hera pe utic efficac y.  S pecificall y 
trials nee d t o har ness t his n o vel s yste mic t hera p y t o ma ke a n i m pact o n t he b ur de n of 
u nc o m m o n, t h o u g h let hal dista nt metastatic disease f or “ hi g h-ris k” a d v a nce d disease ( T 4, 
N 2c / N 3, > 1 0 pack - year s m o kers) H P V- p ositi ve patie nts.  Trials i ncl u de eli mi nati n g 
s yste mic c yt ot o xic c he m ot hera p y b y c o m bi ni n g I M R T wit h cet u xi ma b a n d a nti- C T L A- 4 
m A b (i pili m u ma b, N C T 0 1 9 3 5 9 2 1), i n w hic h t he o verla p of m A b e x p os ure be gi ns at 
we e k 5 of cet u xi ma b/ R T.  A d diti o nall y, “i nter me diate ris k” H P V- p ositi ve a n d “ hi g h-
ris k” H P V- ne gati ve patie nts c o ul d be treate d wit h c o nc urre nt, wee kl y cis plati n C R T. 
 
F or H P V- n e gati ve P U L A H N S C C patie nts, disease free s ur vi val ( D F S) has n ot i m pr o ve d 
be y o n d t h e hist orical 5 0 % rate f or deca des – d es pite c o nc o mita nt treat me nt 
i nte nsificati o n. T h us, t he cli nical i m pact of i m m u n ot hera p y w o ul d be t o i m pr o ve D F S, 
gi ve n t hat i nte nsificati o n usi n g c o n v e nti o nal m o dalities has bee n u nacce pta bl y t o xic.  
Inte nsif yi n g t hera p y t o e n ha nce s ur vi v al usi n g a nti- P D - 1 m A b pl us C R T m ust be teste d 
f or H P V- ne gati ve diseas e. T h us, f or H P V- p ositi v e a n d H P V- n e gati ve l ocall y a d va n ce d 
H N S C C, c hec k p oi nt i n hi bit ors (a nti- P D - 1 or a nti- C T L A- 4) are bei n g de v el o pe d f or 
adj u va nt, p ost- o perati ve P U L A H P V- ne gati ve dis ease c o m bi ne d wit h cis plati n/I M R T, or 
f or u pfr o nt treat me nt of “ hi g h ris k” a d va nce d dise ase sta ge H P V- p ositi ve or H P V-
ne gati ve P U L A H N S C C, i n c o m bi nati o n wit h c o nc o mita nt cis plati n- or cet u xi ma b-I M R T 
(Jie 2 0 1 5), w hile re versi n g i m m u n os u p pressi ve si g nals o n circ ulati n g a n d t u m or 
i nfiltrati n g T cells. Rece ntl y a p has e I trial r e p orte d safet y of t he c o m bi nati o n of a nti-P D -
1 pe m br oliz u ma b wit h cis plati n c he m ora diati o n, usi n g a re gi me n si milar t o t hat pla n ne d 
i n t his trial ( P o well, A S C O, 2 0 1 6). 
 
C hec k p oi nt Rece pt or T ar get e d m A bs i n C o m bi nati o n wit h Cet u xi ma b 
Cet u xi ma b t hera p y alters e x pressi o n of c hec k p oi nt rece pt ors o n circ ulati n g a n d i ntra-
t u m oral TI L.  S pecificall y, t he fre q u e nc y of Tre g s u p press or cells t hat e x pr ess C T L A- 4 
a n d P D- 1 are e nri c he d i n t he t u m or micr oe n vir o n me nt (Jie 2 0 1 3, Jie 2 0 1 5). F urt her m ore, 
cet u xi ma b t hera p y i n crease d t he fre q u e nc y of C D 4 + C D 2 5 hi C D 3 9 + F O X P 3 + Tre g 
( p = 0. 0 1), i n dicati n g t hat t his treat me nt e x pa n ds Tre g i n p atie nts wit h H N S C C.  C T L A-
4 +/ C D 3 9 + cells were si g nifica ntl y i ncreas e d a m o n g t he maj orit y of C D 4 + F O X P 3 + Tre g 
fr o m patie nts pri or t o a n d after cet u xi ma b treat me nt, i n dicati n g t hat C T L A- 4 tar geti n g 
ma y pr o vi d e e n ha n ce d b e nefit i n cet u xi ma b treate d patie nts (Jie 2 0 1 5). Rece nt data i n 
N S C L C i n dicates t hat t h e E G F R pat h w a y ma y c o ntri b ute t o re g ulati o n of P D- L 1 
e x pressi o n ( A k ba y 2 0 1 3), a fi n di n g c orr o b orate d i n H N S C C ( C o nc ha- Be na ve nte a n d 
F erris, u n p u blis he d data). 
 
T hese e mer gi n g d ata s u p p ort t he i nc or p orati o n of c hec k p oi nt i n hi bit or y m A b i nt o 
c o n ve nti o nal H N S C C t hera p y, eit her t o d e plete Tre g or t o disr u pt t he P D- 1: P D -L 1 
s u p pressi ve si g n al tra ns mitte d t o C D 8 + effect or T l y m p h oc ytes. T hese s u p presse d N K 
cells a n d T cells e x press t he ne gati ve re g ulat or y P D- 1 rece pt or, at hi g her le vels a n d 
ge n erati n g greater i n hi bit or y si g nals i n t u m or i nfiltrati n g l y m p h oc ytes, pr o vi di n g str o n g 
rati o nale f or c o m bi ni n g cet u xi ma b wit h a nti-P D - 1 m A b t hera p y i n a c urati v e setti n g i n 
w hic h tra diti o nal c yt ot o xic c he m ot hera p y ma y i m part deleteri o us effect(s) o n t he 
ge n erati o n a n d pr oliferati o n of be nefi cial a ntit u m or l y m p h oc yte res p o nses. 

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C hec k p oi nt I n hi bit ors a n d Ra di ot hera p y 
I n a d diti o n t o direct c yt ot o xic effects, ra di ot hera p y ma y i n d uce a n i m m u ne effect 
i m p orta nt t o t u m or cell deat h ( De m aria 2 0 0 5).  Precli nical data s u p p ort s y n er g y bet wee n 
chec k p oi nt i n hi bit ors a n d ra di ot hera p y. M o us e m o dels of p o orl y i m m u n o ge nic t u m ors 
ha ve de m o nstrat e d t hat c o nc o mita nt a d mi nistrati o n of a nti- C T L A- 4 a nti b o dies a n d 
radi ot hera p y res ults i n a ntit u m or T cell res p o nses b ot h i n t he ra diati o n fiel d as well as 
o utsi de of it (a n a bsc o p al effect) ( De maria 2 0 0 5, De wa n 2 0 0 9). P D- 1 bl oc ka de aft er 
co m pleti o n of ra di ot hera p y als o h as bee n s h o w n t o i n d uce rejecti o n of persiste nt t u m ors 
i n m o use m o dels ( De n g 2 0 1 4).  C o m bi nati o n P D- 1 bl oc ka de a n d a nti- C D 1 3 7 sti m ulati o n 
i ncreas e d res p o ns e t o ra di ot hera p y i n a m o use m o del of tri ple ne gati ve breast ca ncer 
( Ver br u g ge 2 0 1 2) a n d P D- L 1 bl oc ka d e c o nc o mit a nt wit h ra di ot hera p y i m pr o ve d s ur vi val 
i n c o m paris o n t o eit her t hera p y al o n e i n m o use m o dels of gli o ma ( Ze n g 2 0 1 3).  I n h u ma n 
s u bjects, case-re p orts s u p p ort t he e xiste nce of a cli nicall y si g nifica nt a bsc o p al effect f or 
patie nts wit h mela n o ma w h o ha ve recei v e d i pili m u ma b pri or t o ra di ot hera p y ( P ost o w 
2 0 1 2, Sta mell 2 0 1 3).  T hese data s u p p ort a h y p ot hesis t hat ra di ot hera p y-i n d uce d cell 
de at h ma y res ult i n alterati o ns i n t he t u m or i m m u ne e n vir o n me nt ( via u pre g ulati o n of 
M H C class I, I C A M- 1, C D 8 0) as well as prese nt ati o n of n o vel t u m or a n d ge nerati o n of 
a nti-t u m or i m m u ne res p o nses ( Te n g 2 0 1 5 ). 
 
I n a d diti o n t o n o vel a nti ge n prese nt ati o n, rece nt i n vi v o data i n dicate t hat r a di ot hera p y 
ca n i n d uce i n crease d P D L 1 e x pressi o n i n t u m ors a n d t here b y i n hi bit acti vati o n of 
c yt ot o xic C D 8 + T cell res p o nses, t h us re d uci n g t h e effi cac y of ra di ot hera p y. C o nc urre nt 
a d mi nistrati o n of a nti- P D 1 a nti b o dies i m pr o ve d res p o nse t o ra di ot hera p y a n d s ur vi val i n 
m o use m o dels w hereas s e q ue ntial t hera p y di d n ot ( D o ve di 2 0 1 5, D o ve di 2 0 1 4 ). 
 
T he se data s u p p ort a h y p ot hesis t hat c hec k p oi nt i n hi bit ors a d mi nistere d pri or t o or 
c o nc o mita nt wit h ra di ot hera p y ca n i n d uce cli nicall y si g nifica nt a nti-t u m or i m m u ne 
res p o nses i n d uce d b y “ vacci nati o n” t o t u m or-s pecific a nti ge ns e x p ose d d uri n g ra diati o n-
i n d uce d cell deat h ( F or m e nti 2 0 1 2).  S uc h a p he n o me n o n ma y b e partic ul arl y rel e va nt t o 
viral-i n d uce d t u m ors, s uc h as H P V- p ositi ve H N S C C a n d t o hi g hl y ge neticall y u nsta ble 
t u m ors s uc h as H P V- ne gati ve H N S C C. 
 
Ni v ol u ma b D ose a n d Sc he d ule 
Ni v ol u ma b m o n ot hera p y has bee n e xte nsi vel y st u die d i n N S C L C patie nt p o p ulati o ns 
wit h b o d y wei g ht n or maliz e d d osi n g ( m g/ k g). Ni v ol u ma b p har mac o ki netics ( P K) a n d 
e x p os ures of patie nts ha v e bee n c haracterize d b y p o p ulati o n p har mac o ki netic ( P P K) 
a nal ysis of data c ollecte d fr o m t hese st u dies, t o get her wit h P K data fr o m se veral p has e I, 
II, a n d III cli nical st u dies of ni v ol u ma b m o n ot hera p y i n s oli d t u m ors. Ni v ol u ma b P K was 
de ter mi ne d t o be li near, wit h d ose pr o p orti o nal e x p os ures o ver a d ose ra n ge of 0. 1 t o 1 0 
m g/ k g. Ni v ol u ma b cle ara nce a n d v ol u me of distri b uti o n was f o u n d t o i ncrease wit h 
i ncreasi n g b o d y w ei g ht, b ut t he i ncreas e was less t ha n pr o p orti o nal, i n dicati n g t hat a 
m g/ k g d ose re pres e nts a n o ver-a dj ust me nt f or t h e effect of b o d y wei g ht o n ni v ol u ma b 
P K. C o n versel y, gi v e n t he relati o ns hi p bet wee n ni v ol u ma b P K a n d b o d y wei g ht, a flat 
d ose is e x pecte d t o lea d t o l o wer e x p os ures i n hea vi er patie nts, relati ve t o t he e x p os ures 
i n li g hter patie nts. 

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Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
T he ta ble bel o w prese nts s u m mar y statistics of t he esti mate d ni v ol u ma b stea d y-stat e 
tr o u g h, p ea k, a n d ti me- a vera ge d c o nce ntrati o n ( C mi nss, C ma xss, a n d Ca v gss, 
res pecti vel y) i n N S C L C patie nts recei vi n g 3 m g/ k g, t o get her wit h c orres p o n di n g 
statistics of e x p os ures pre dicte d f or a flat ni v ol u ma b d ose of 2 4 0 m g. It s h o ul d be n ote d 
t hat a d ose of ni v ol u ma b 2 4 0 m g  is i de ntical t o a d ose of 3 m g/ k g f or patie nts wei g hi n g 
8 0 k g, w hic h is t he a p pr o xi mate me dia n b o d y wei g ht of N S C L C p atie nts i n t he 3 p hase II 
a n d III cli nical st u dies of ni v ol u ma b m o n ot hera p y i n N S C L C p atie nts. As e vi de nt fr o m 
t he data pres e nte d i n t he ta ble, t he ge o metric m ea n val ues of C mi nss, C ma xss, a n d 
Ca v gss wit h flat d osi n g are sli g htl y ( < 1 5 %) hi g her t ha n t hat pr o d uce d b y a 3 m g/ k g 
d ose , a n d t he c o effici e nt of variati o n (c v %) i n t hes e meas ures of e x p os ure are o nl y 
sli g htl y ( < 1 0 %) great er t ha n t hat of 3 m g/ k g d osi n g. 
 
S u m m ar y St atistics of Ni v ol u m a b Ste a d y-st ate E x p os ure  
 
Ni v ol u m a b  
D ose  
C mi nss  Ge o.  M e a n  
[ u g/ m L] (c v %)  
C m a xss  Ge o.  M e a n  
[ u g/ m L] (c v %)  
C a v gss  Ge o.  M e a n  
[ u g/ m L] (c v %)  
2 4 0  m g  
6 1. 5  ( 4 4. 6) 
1 3 3. 7  ( 3 5. 0) 
8 2. 4  ( 3 8. 2) 
3  m g/ k g  
5 4. 7  ( 4 1. 9) 
1 1 8. 9  ( 3 1. 8) 
7 3. 3  ( 3 5. 6) 
 
Ni v ol u ma b has bee n s h o w n t o be safe a n d well t olerate d u p t o a d os e le vel of 1 0 m g/ k g, 
a n d t he relati o ns hi p bet w ee n ni v ol u ma b e x p os ure pr o d uce d b y 3 m g/ k g a n d efficac y has 
bee n f o u n d t o be relati vel y flat. T a ke n t o get h er, t h e P K, safet y, a n d effi cac y dat a i n dicate 
t hat t he safet y a n d effi cac y pr ofile of 2 4 0 m g ni v ol u ma b will be si milar t o t hat of 3 
m g/ k g ni v ol u ma b. As t he P K of ni v ol u ma b is li near, t he c orres p o n di n g flat d ose f or Q 3 W 
a n d Q 4 W are 3 6 0 m g/ k g a n d 4 8 0 m gs, res pecti vel y. T he si m ulate d C mi nss, C ma xss a n d 
C a v gss wit h 3 6 0 m g Q 3 W a n d 4 8 0 m g Q 4 W are less t ha n 1 0 m g/ k g Q 2 W, a n d he nce 
t hese re gi me ns are e x pecte d t o be safe a n d t olera ble.   
 
T he P K a n d safet y of ni v ol u ma b ha ve bee n e val u ate d i n t he Asia n p o p ulati o n. T he 
c o m paris o n of P K para m eters i n gl o b al a n d J a pa n ese patie nts s u g gests t hat t he P K of 
ni v ol u ma b is si milar i n t hese p o p ulati o ns. Ni v ol u ma b is s h o w n t o be safe a n d well 
t olerate d i n J a pa nese pati e nts. T he si milar P K a n d safet y pr ofile of ni v ol u ma b bet wee n 
gl o bal a n d J a pa nes e patie nts s u p p orts t he use of si milar d osi n g i n t he Asia n p o p ulati o n as 
is bei n g use d i n gl o bal cli nical st u dies.  
 
Ni v ol u ma b i n C o m bi nati o n wit h Cis plati n 
I n ter ms of safet y a n d efficac y of c o m bi ni n g a nti-P D - 1 m A b wit h cis plati n, 
a d mi nistrati o n of ni v ol u ma b i n c o m bi nati o n wit h hi g h- d ose cis plati n has b ee n s h o w n t o 
ha ve acce pt a ble t o xicit y i n a p hase I cli nical trial i n patie nts wit h N S C L C ( Riz vi 2 0 1 3). A 
p hase I cli nic al trial e val uati n g t he safet y of ni v ol u ma b ( 1 0 m gs/ k g q 3 wee ks) i n 
c o m bi nati o n wit h plati n u m- base d d o u blets ( ge m cita bi ne/cis plati n, pe metre x e d/cis plati n, 
car b o plati n/ paclita x el) has bee n c o m plete d i n 4 3 p atie nts wit h c he m ot hera p y- n aï ve 
a d va nce d N S C L C. I m p orta ntl y, n o d ose li miti n g t o xicities ( D L Ts) were o bser ve d acr oss 
all 3 re gi me ns. Gra d e 3- 4 t o xicit y was o bser ve d i n 4 9 % of patie nts, a n d gra de 3- 4 t o xic 
e ve nts li kel y attri b uta ble t o ni v ol u ma b ( p ne u m o nitis, ras h, ne p hritis, a n d c olitis) were 

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1 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
o bser ve d i n 7 ( 1 6 %) pati e nts. O ne deat h d u e t o p ne u m o nitis was o bser ve d.  Si n gle a ge nt 
ni v ol u ma b has de m o nstrate d cli nical acti vit y i n refract or y s q u a m o us N S C L C. A p hase III 
st u d y c o m pari n g si n gle a ge nt ni v ol u ma b t o d oceta x el i n patie nts wit h metastatic N S C L C 
has bee n st o p pe d earl y b eca use of s u peri or O S i n t he ni v ol u ma b ar m, per a Brist ol- M yers 
S q ui b b press releas e. Ni v ol u ma b is n o w F D A a p pr o ve d f or sec o n d li ne use i n patie nts 
wit h s q ua m o us l u n g ca n cer base d u p o n t h ese res ults. 
 
C hec k p oi nt I n hi bit ors a n d C hr o nic Viral I nfecti o ns 
P D - 1/ P D- L 1 i nteracti o ns ma y c o ntri b ute t o T cell e x ha usti o n i n t he setti n g of c hr o nic 
viral i nfecti o ns s uc h as H P V. Bl oc ka d e of P D- 1/ P D- L 1 i nteracti o ns has bee n s h o w n t o 
rest ore pr olif erati o n a n d c yt o ki ne s ecreti o n of f u ncti o nall y i m paire d C D 8 + T cells a n d t o 
rest ore t heir a bilit y t o l ys e cells a n d decrease vir al l oa d i n a m o del of c hr o nic 
l y m p h oc ytic c h ori o me ni n gitis ( L C M V) i nfecti o n ( Bar ber 2 0 0 6). P D- 1 als o has bee n 
s h o w n t o be u pre g ulate d i n HI V i nfecti o n a n d bl o c ka de e n ha nce d HI V-s pecific T cell 
res p o nses i n vitr o ( Ka uf ma n n 2 0 0 8). P D- 1 bl oc ka de als o has b ee n o bser ve d t o res ult i n 
cleara nce of c hr o ni c, persiste nt he patitis B i nfecti o n i n a m o use m o del ( Tze n g 2 0 1 2). P D-
1 a n d P D- L 1 ha ve rece ntl y bee n s h o w n t o be u pre g ulate d i n t he t u m or micr oe n vir o n me nt 
i n a m o use m o del of he p atitis- C i n d uce d he pat ocell ular carci n o ma, c o ntri b uti n g t o t u m or-
a nti ge n-s pecifi c t olera n ce ( Willi ms k y 2 0 1 3). Preli mi nar y st u dies als o s u g gest t hat 
patie nts wit h pre-e xisti n g a nti b o dies t o t u m or-s pecific a nti ge ns (e. g. N Y- E S O- 1, a n 
a nti ge n e x presse d i n 3 0- 4 0 % of patie nts wit h a d va nce d mel a n o ma) ha v e a n i ncreas e d 
res p o nse t o i pili m u ma b ( P ost o w 2 0 1 2). N ota bl y, a p pr o xi matel y 7 0 % of patie nts wit h 
H P V 1 6- p ositi ve H N S C C ha ve hi g h titers t o t he E 6 or E 7 o nc o pr otei ns at dia g n osis, 
i n dicati n g i m m u ne e x p os ure t o t hese t u m or-s pecific a nti ge ns ( Gillis o n 2 0 0 8). 
N o net heless, p ote ntial i m m u ne e x ha usti o n of H P V E 6/ 7-s pecific T cells e xist, w hic h are 
ofte n dri ve n i nt o a ter mi n all y differe ntiat e d p he n ot y p e ( Al bers 2 0 0 5). T hese data s u g gest 
t hat P D- 1 bl oc ka de has pr o mise f or t he e n h a nce me nt of sta n dar d of care t h era pies f or 
H P V- p ositi ve ca ncers as well. 
 
Cli nical trials of c hec k p oi nt i n hi bit ors i n patie nts wit h hea d a n d nec k ca ncer 
Cli nical acti vit y of c h ec k p oi nt i n hi bit ors has n o w bee n de m o nstrat e d i n cli nical trials f or 
patie nts wit h plati n u m-refract or y, rec urre nt a n d m etastatic H N S C C. A p has e 1 b cli nical 
trial t hat i ncl u de d 6 0 patie nts wit h H N S C C wit h P D- L 1 e x pressi o n ≥1 % o bser ve d a 
cli nical res p o nse rate of 1 8 %. Gra d e 3- 4 dr u g-rel ate d a d verse e v e nts were e x perie nce d b y 
1 7 % ( Sei wert 2 0 1 6). I n C hec k Mate 1 4 1, 3 6 1 pati e nts wit h rec urre nt, metastatic H N S C C 
w h o pr o gresse d wit hi n si x m o nt hs of plati n u m i n t he pri mar y, a dj u v a nt or rec urre nt, 
metastatic setti n g w ere ra n d o mize d i n a 2: 1 rati o  t o recei v e ni v ol u ma b 3 m g/ k g I V e ver y 
2 wee ks or si n gle- a ge nt s yste mic t hera p y of i n vesti gat or’s c h oice ( met h otre x at e, 
d oceta x el or cet u xi ma b). Patie nts treate d o n t he ni v o ul ma b ar m ha d  a si g nifica nt 
i m pr o ve me nt i n o verall s ur vi val  ( H R 0. 7 1, 9 7. 7 3 % CI 0. 5 1- 0. 9 6; p = 0. 0 1), ha d hi g h er 
res p o nse rates ( 1 3. 3 vs 5. 8 %) , re d u ce d gra de 3- 4 treat me nt r elate d a d v erse e ve nts ( 1 3. 1 
vs. 3 5. 1 %) a n d s ustai ne d p h ysical, e m oti o nal a n d s ocial f u ncti o ni n g c o m pare d t o 
i n vesti gat or’s c h oice t h era p y ( Gillis o n M L, A A C R, 2 0 1 6, Ferris, A S C O, 2 0 1 6). T hese 
data pr o vi de str o n g e vi d e nce of cli nical acti vit y f or a nti- P D - 1 tar gete d t hera p y i n p atie nts 
wit h H N S C C.  
 

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Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
Preli mi nar y res ults of a p hase II tri al were re p orte d at A S C O 2 0 1 6 i n dicati n g t hat a nti-
P D - 1 t hera p y ( pe m br oliz u ma b) was safe w he n c o m bi ne d wit h c o nc urre nt, plati n u m-
base d c he m ora di ot hera p y i n patie nts wit h sta ge III-I V H N S C C. Treat me nt c o nsiste d of a 
l oa di n g d ose of pe m br oli z u ma b 2 0 0 m gs I V starti n g 7 da ys pri or t o c he m ora di ot hera p y 
f oll o we d b y a t otal of 8 d oses e ver y 3 wee ks. C he m ora di ot hera p y was a d mi nistere d t o a 
t otal of 7 0 G y wit h wee kl y cis plati n 4 0 m g/ m 2. A t otal e nr oll me nt of 3 9 patie nts is 
pla n ne d, a n d n o D L Ts h a ve bee n o bser ve d t o dat e wit h 2 8 patie nts ha vi n g c o m plete d 
che m o R T. T hese d ata pr o vi de str o n g e vi de nce t hat a nti- P D - 1 t hera p y ca n be 
a d mi nistere d safel y o n t h e t hera p e utic platf or m pr o p ose d f or t his trial.  
S u m mar y of Rati o nale 
 
 O ur a nal ysis of R T O G 0 5 2 2 i ncl usi ve of t he patie nts w h o meet t he eli gi bilit y 
criteria f or t his trial i n dicates t hat 4 0 % of patie nts wit h i nter me diate or hi g h-ris k, 
l ocal-re gi o n all y a d va nce d H N S C C will e x perie nce disease pr o gressi o n wit hi n 5 
years of C R T. N o vel t hera pe utic a p pr oac h es are n ee de d t o i m pr o ve dise ase c o ntr ol 
( An g 2 0 1 0, O’ S ulli va n 2 0 1 3).  
 
A r a n d o mize d p hase III trial has de m o nstrate d t h at ni v ol u ma b i m pr o ve d s ur vi val f or 
patie nts wit h plati n u m-refract or y H N S C C i n c o m paris o n t o si n gle a ge nt t hera p y of 
i n vesti gat or’s c h oice.  
 
O ver 5 0 % of H P V- p ositi ve a n d H P V- n e gati ve H N S C C e x press P D- L 1, a n d t u m or 
i nfiltrati o n b y P D- 1 + C D 8 + T cells is fre q u e ntl y prese nt i n H P V- p ositi ve H N S C C. 
We n ote, h o we ver, t hat res p o nses t o ni v ol u ma b ha ve bee n o bser ve d i n b ot h P D- L 1 
p osi ti ve a n d ne gati ve H N S C C ( Sei wert 2 0 1 4). 
 
Ni v ol u ma b ca n be safel y a d mi nistere d wit h hi g h d ose cis plati n.  
 
Preli mi nar y d ata i n dicate t hat a nti- P D - 1 t hera p y ca n be safel y a d mi nistere d i n 
c o m bi nati o n wit h wee kl y cis plati n a n d ra di ot hera p y f or patie nts wit h ne wl y 
dia g n ose d sta ge III-I V H N S C C.  
 
P D - 1 bl oc ka de h as de m o nstrate d s y ner gistic acti vit y wit h ra di ot hera p y i n vi v o.  
 
P D - 1 bl oc ka de ca n re verse T cell e x ha usti o n t o c hr o nic viral i nfecti o ns s uc h as H P V 
a n d t heref ore, ma y b e partic ularl y effecti v e i n viral-i n d uce d t u m ors.  
 
P D - 1 bl oc ka de ma y re verse i m m u ne esca p e i n carci n o ge n-i n d uce d ca n cers ( H P V-
ne gati ve H N S C C) wit h a hi g h m utati o nal b ur de n b y e n h a nci n g t he i m m u n e res p o nse 
t o ne o-a nti ge ns ge n erate d d uri n g R T- me di ate d t u m or destr ucti o n ( Stra ns k y 2 0 1 3, Y u 
2 0 1 4). 
2. 6 St u d y Desi g n 
2. 6 . 1    St u d y Desi g n  
I n Ar ms 1, 3, a n d 4 ( 8 e v al ua ble patie nts per c o h ort), t he ni v ol u ma b d ose will start at a 
fi x e d d ose  of ni v ol u ma b ( 2 4 0 m g s q 1 4 da ys) a n d will be de-escalate d i n t h e e ve nt of 
d ose  li miti n g t o xicities ( D L T) attri b uta ble t o ni v ol u ma b t o a fi x e d d ose of 8 0 m gs.  I n 
Ar m 2 o nl y, t he ni v ol u m a b d ose aft er da y - 1 4 will be m o difie d t o e ver y 3 wee k d osi n g 
( 3 6 0 m gs) t o acc o m m o date t he q 2 1 da y d osi n g of hi g h- d ose cis plati n. T here will be at 
least 8 e val ua ble p atie nts e nr olle d i nt o eac h of t he cis plati n- base d, cet u xi ma b- base d or 
ni v ol u ma b m o n ot hera p y c he m ora di ot hera p y platf or ms, f or a mi ni m u m o verall sa m ple 
siz e of 3 2. Ni v ol u ma b a d mi nistrati o n will start 1 4 da ys pri or t o t he i nitiati o n of 
ra di ot hera p y c o nc o mita nt wit h eit her wee kl y cis pl ati n ( 4 0 m g/ m2/ wee k x 7), hi g h- d ose 
cis plati n ( 1 0 0 m g/ m 2 q 2 1 da ys X 3)  or cet u xi ma b ( 4 0 0 m g/ m2 l oa d foll o we d b y 2 5 0 
m g/ m 2 x 7) or as m o n ot hera p y. I n all ar ms of t he trial, ni v ol u ma b t hera p y will c o nti n ue 

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Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
f or 3 m o nt hs after t he c o m pleti o n of c he m ora di ot hera p y.  Starti n g 3 m o nt hs after 
co m pleti o n of ra diati o n, patie nts will be a d mi nistere d a dj u v a nt ni v ol u ma b 4 8 0 m gs q 2 8 
da ys x 7 d oses (t his is e q ui vale nt t o a t otal of 1 ye ar of ni v ol u ma b a d mi nistrati o n). T he 
feasi bilit y of t he ni v ol u m a b will be assesse d i n t he first 8 e val ua ble p atie nts. If m ore t ha n 
4 of 8 patie nts disc o nti n ue a dj u va nt ni v ol u ma b, t he n a dj u va nt a d mi nistrati o n will cease 
f or all s u bse q ue ntl y e nr olle d patie nts. T he pri nci pal o utc o me of i nterest i n t he d ose 
fi n di n g st u d y is safet y.  
 
T he g ui di n g pri n ci ple of t he st u d y is t o e val uat e t he safet y of t h e a d diti o n of ni v ol u ma b t o 
sta n dar d of care t hera p y. Ni v ol u ma b is a m olec ularl y tar gete d i m m u n ot hera p y wit h 
mi ni mal o verla p pi n g t o xicities wit h m olec ularl y-tar gete d cet u xi ma b (e. g. ras h, li ver 
f u ncti o n a b n or malities) a n d cis plati n (e. g. fati g ue, re nal). Cli nical trials ha v e n ot yet 
i n vesti gate d t he s afet y of ni v ol u ma b i n c o m bi nati o n wit h ra di ot hera p y. H o we ver, t he 
co m bi nati o n of i pili m u ma b a n d ra di ot hera p y is w ell t olerate d a n d preli mi nar y data 
pre se nte d at A S C O 2 0 1 6 i n dicate a nti-P D - 1 tar get t hera p y wit h pe m br oliz u ma b ca n be 
safel y a d mi nistere d i n c o m bi nati o n wit h c he m ora di ot hera p y wit h wee kl y cis plati n 4 0 
m g/ m 2. Alt h o u g h p eri p h eral r ece pt or s at urati o n is ac hie ve d at 0. 3 m g/ k g, a p hase I si n gle 
age nt trial de m o nstrate d l ess cli nical be nefit bel o w 3 m g/ k g ( bi oe q ui vale nt of fi x e d d ose 
of 2 4 0 m gs) i n p atie nts wit h N S C L C a n d i ncrease d gra de 3- 4 t o xicities at 1 0 m g/ k g. 
Precli nical data i n dicate t hat i nitiati o n of c hec k p oi nt bl oc ka ge pri or t o r a di ot hera p y ma y 
res ult i n a n a bsc o pal effect a n d e n ha n ce d a nti-t u m or i m m u ne res p o nses a n d pre ve nti o n of 
t he R T i n d uced u pre g ulati o n of P D L 1 o n t u m ors. T heref ore, a si n gle d os e of ni v ol u ma b 
will be a d mi nistere d 2 w ee ks pri or t o i nitiati o n of C R T. P hase I st u dies of si n gle a ge nt 
ni v ol u ma b i n patie nts wit h refract or y dise ase ha v e o bser ve d s ustai ne d res p o nses wit h 3- 4 
m o nt hs of t hera p y. I n Ar ms 1, 3, a n d 4, ni v ol u ma b d osi n g will start at t he fi x e d d ose 
bi oe q ui va le nt ( 2 4 0 m gs) of t he rec o m me n de d F D A a p pr o ve d d os e of ni v ol u ma b ( 3 
m g/ k g).  I n t he e ve nt of a > 2 i n 8 d ose li miti n g t o xicit y ( D L T), t he re gi me n will be 
co nsi dere d n ot w ort h y of f urt her st u d y. F or Ar m 2 o nl y, t o acc o m m o date t h e q 2 1 da y 
sc he d ule of cis plati n, t he ni v ol u ma b d ose a n d sc he d ule will be m o difie d t o 3 6 0 m gs q 2 1 
da ys a n d d ose re d ucti o ns will be t o  1 2 0 m gs. T his d ose a n d sc he d ul e (as w ell as 1 0 
m g/ k g) was utiliz e d i n p hase I trials of ni v ol u ma b i n c o m bi nati o n wit h plati n u m d o u blets 
i n patie nts with N S C L C.  Base d o n t his desi g n, it is esti mate d t hat t here will be at least 8 
e val ua ble p atie nts per ar m i n eac h of t he 4 p atie nt s u b gr o u ps, f or a mi ni m u m o verall 
sam ple siz e of 3 2 e val ua ble patie nts.   
  
I n t his pr ot oc ol, w e will e val uate t he feasi bilit y of a dj u va nt a d mi nistrati o n of ni v ol u ma b 
f or a t otal of 1 year of t h era p y. It s h o ul d be n ote d t hat patie nts i n t he 4 ar ms of t he trial 
will  recei ve ni v ol u ma b u p t o t hree m o nt hs after t h e e n d of ra diati o n t hera p y. T he t er m 
“adj u va nt t hera p y” t heref ore refers t o t he 7 a d diti o nal m o nt hs of ni v ol u ma b t hera p y after 
t his ti me p oi nt. Hist oricall y, t he hea d a n d n ec k pati e nt p o p ulati o n has bee n n o nc o m plia nt 
wit h a dj u va nt t hera p y, de m o nstrati n g t he i nfeasi bilit y of t his a p pr oac h. F or e x a m ple, 
c o m plia nce wit h a year of a dj u va nt t hera p y of si n gle a ge nt cet u xi ma b was 1 4 % i n E C O G 
3 3 0 3 a n d wit h 9 m o nt hs or m ore of si n gle a ge nt la pati ni b i n a p hase III ra n d o mize d trial, 
co m plia nce w as o nl y 6 0 %.   
 
T heref ore, o ur s afet y a n d feasi bilit y e v al uati o n will i ncl u de a n e val u ati o n of a dj u va nt 

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1 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
a d mi nistrati o n ( ni v ol u ma b, 4 8 0 m gs q 2 8 da ys x 7). We will pr os pecti vel y m o nit or 
co m plia nce wit h t hera p y i n all ar ms of t he t he trial. T he peri o d of o bs er vati o n f or 
feasi bilit y is fr o m t he start of a dj u va nt ni v ol u m a b t hr o u g h 7 m o nt hs of a dj u va nt t hera p y. 
W e will e val uate t he first 8 patie nts. If m ore t ha n 4 patie nts st o p t he a dj u va nt t hera p y 
bef ore 7 m o nt hs, w e will c o nsi der t he a dj u v a nt t hera p y i nfeasi ble. A d mi nistrati o n w o ul d 
t he n be disc o nti n ue d.  
2. 6 .2     Partici pati n g Sites  
A mi ni m u m of t e n i nstit uti o ns wit h pri or e x perie nce wit h i m m u n oc he m ot hera pe utics a n d 
p hase I cli nic al trials f or hea d a n d n ec k ca ncer will be selecte d t o partici pat e i n t he t his 
cli nical trial. I nter-i nstit uti o nal c o m m u nicati o n re gar di n g accr ual, e nr oll me nt, a n d patie nt 
safet y a n d t o xicit y will be facilitate d b y wee kl y e- mail c o m m u nicati o ns a n d bi- wee kl y 
c o nfere nce calls f or all i n vesti gat ors.   
2. 7 Bi o m ar ker St u dies 
2. 7 . 1    T u m or P D- L 1 E x pressi o n 
T he effect of t u m or P D- L 1 e x pressi o n o n treat me nt res p o nse t o a nti- P D - 1 tar gete d 
i m m u n ot hera p y is c urre ntl y u nclear a n d a matter of o n g oi n g i n vesti gati o n. I de ntificati o n 
of pre dicti ve bi o mar k ers of res p o nse t o t hera p y pr otects patie nts fr o m e x p os ure t o ris ks 
of i neffecti ve t hera pies a n d i m pr o ves c ost-effecti v e ness. S u b missi o n of f or mali n-fi x e d 
a n d paraffi n e m be d d e d t u m or sa m ples ( bl oc ks or 3 m m c ores ) is re q uir e d f or all patie nts 
at t he ti me of st u d y e nr oll me nt. A nal ysis of P D- L 1 e x pressi o n will be perf or me d b y use 
of t he 2 8- 8 a nti b o d y t o P D- L 1  ( B M S) usi n g t he Da k o I H C platf or m ( Ta u be 2 0 1 2). P D-
L 1 me m bra ne stai ni n g will be assesse d b y li g ht micr osc o p y. Eit her c o m plete 
circ u mfere ntial or partial li near plas ma me m br a ne stai ni n g will c o nstit ute p ositi ve P D- L 1 
stai ni n g. W hile c yt o plas mic stai ni n g ma y be o bs er ve d, it will n ot be use d i n t he 
e val uati o n of tiss ue sa m ple stat us.   
2. 7 .2    Peri p heral bl o o d C D 6 9/ 1 3 7 + acti vate d- p ositi ve T cells 
Acti vate d T cells e x pressi n g mar k ers C D 6 9 a n d/ or C D 1 3 7 ha ve bee n i de ntifie d i n t he 
circ ulati o n of hea d a n d n ec k c a ncer patie nts b ut at a l o w le vel (Jie 2 0 1 3, Al bers 2 0 0 5, 
L yf or d- Pi ke, 2 0 1 3). T h es e cells w o ul d be e x pecte d t o i ncrease after a nti- P D - 1 t hera p y, 
re versi n g T cell “e x ha usti o n” a n d e na bli n g t heir reacti vati o n. T his detecta bl e p o p ulati o n 
will be meas ure d at baseli ne a n d l o n git u di nall y i n t he c o ntr ol a n d ni v ol u ma b-treate d 
c o h orts. Wit hi n t his s u bset of acti vate d, circ ulati n g T cells, we will p he n ot y p e t h e m b y 
me m or y/ naï v e stat us ( usi n g mar k ers C D 4 5 Ra a n d C C R 7) a n d b y o nc o ge ne s pecificit y 
a gai nst H P V- 1 6 E 6 or E 7 (acc or di n g t o t he patie nt’s H L A t y pe). Acti vate d T cells 
ex pressi n g mar k ers C D 6 9 a n d/ or C D 1 3 7 will be meas ure d at baseli ne a n d l o n git u di nall y 
b y use of fl o w c yt o metr y. We will als o sec o n daril y meas ure me m or y st at us, H P V 
o nc o ge ne s pecificit y a n d P D 1- p ositi vit y wit hi n t his p o p ulati o n of circ ulati n g T cells 
usi n g fl o w c yt o metr y (Jie 2 0 1 3, Al bers 2 0 0 5, L yf or d- Pi ke, 2 0 1 3) Pre- p ost c o m paris o n of 
t hese fre q u e ncies will be perf or me d f or eac h p atie nt d uri n g t hera p y, usi n g eac h p atie nt’s 
baseli ne as t he c o ntr ol ti me p oi nt, a n d c o m pari n g t hese val ues t o t he c o ntr ol ar m c o h ort 
(cis plati n/ R T). 
 
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 
 
N ote: 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, pl ease c o nt act t he Bi ostatistical/ Data Ma na ge me nt Ce nter ( via t he 
c o ntact list o n t he R T O G we bsite ). F or ra di ati o n t hera p y-relate d eli gi bilit y q uesti o ns, 

R T O G 3 5 0 4 
2 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
please c o nta ct A C R C ore La b orat or y/ R T Q A ( via t he c o ntact list o n t he R T O G we bsite).  
3. 1  
P ati e nt Selecti o n G ui deli nes 
Alt h o u g h t he 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 v esti gat ors als o 
s h o ul d c o nsi der all ot her rele va nt f act ors ( m e dical a n d n o n- me dical), as well as t he ris 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 dat e 
f or t his trial. 
3. 1. 1  Patie nts m ust ha ve t he ps yc h ol o gical a bilit y a n d ge neral h ealt h t hat per mits c o m pleti o n of 
t he st u d y re q uire me nts a n d re q uire d f oll o w u p. 
3. 1. 2 
W o me n of c hil d beari n g p ote ntial a n d me n w h o  are se x uall y acti ve m ust be willi n g a n d 
a ble t o use me dicall y acce pta ble f or ms of c o ntrace pti o n d uri n g t he trial. 
3. 1. 3  I n v esti gat ors s h o ul d c hec k wit h t heir site Pat h ol o g y de p art me nt r e gar di n g release of 
bi os p eci me ns bef ore a p pr oac hi n g patie nts a b o ut p artici pati o n i n t he trial. ( See details of 
s u b missi o ns i n S ecti o n 1 0.) 
 
3. 2  
Eli gi bilit y Criteri a ( 2 6 D ec 2 0 1 7) 
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 m et. 
 
Ste p 1: Re gistrati o n  
3. 2 . 1 H ist ol o gicall y or c yt ol o gic all y-c o nfir me d dia g n osis of H N S C C of t he oral ca vit y, 
or o p har y n x, lar y n x, or h y p o p har y n x; A hist ol o gical or p at h ol o gical s peci me n fr o m 
cer vical l y m p h n o des 
wit h a 
well- defi ne d pri mar y site d oc u me nte d cli nicall y or 
ra di ol o gic all y is acce pta ble; 
3. 2. 2 
Inter me diate-ris k Gr o u p: Or o p har y n x ca ncer t hat is p 1 6- p ositi ve b y 
i m m u n o hist oc he mistr y wit h s m o ki n g stat us 
 > 1 0 Pac k- years, stage T 1 - 2 N 2 b- N 3 or T 3- 4 N 0- 3 O R  
 ≤ 1 0 pac k- years, sta ge T 4 N 0- N 3 or T 1 -3 N 3 ;  
O R  
Hi g h-ris k Gr o u p: Oral ca vit y, l ar y n x, h y p o p h ar y n x, or p 1 6- ne gati ve or o p har y n x ca ncer, 
sta ge T 1- 2 N 2 a- N 3 or T 3- 4 N 0- 3 bas e d o n t he f oll o wi n g dia g n ostic w or k u p:   
 Ma n dat or y s u b missi o n of H & E a n d p 1 6 stai ne d sli des t o t he Bi os peci me n Ba n k at 
U C S F f or ce ntral r e vie w of p 1 6 stai ni n g is re q uir e d f or or o p har y n geal p ati e nts a n d 
H & E stai ne d sli de a n d bl oc k ( or p u nc h bi o ps y of paraffi n bl oc k) f or P D -L 1 
e x pressi o n a nal ysis f or all patie nts; see Secti o n 1 0  f or details. 
 Hist or y/ p h ysical e x a mi nati o n wit hi n 2 8  da ys pri or t o re gistrati o n; 
 E x a mi nati o n b y Ra diati o n O nc ol o gist, 
Me dical O nc ol o gist, a n d E N T or Hea d & 
Nec k S ur ge o n wit hi n 2 8 da ys pri or t o re gistrati o n; 
 F i ber o ptic e x a m wit h lar y n g o p har y n g osc o p y, as cli nicall y i n dicate d, wit hi n 2 8 da ys 
pri or t o re gistrati o n; 
 Dia g n ostic q u alit y, cr oss secti o nal i ma gi n g of t he t h ora x wit hi n 2 8 da ys pri or t o 
re gistrati o n; 
1 8- F- F D G- P E T/ C T 
or 
c o n ve nti o nal 
C T 
are 
acce pt a ble. 
See 
“Rec o m me n dati o ns f or I ma gi n g” i n Secti o n 4  f or g ui da nce.  
 Dia g n ostic q ualit y C T or 
M RI of nec k, wit h c o ntrast,  wit hi n 2 8 da ys pri or t o 
re gistrati o n; a 1 8- F- F D G- P E T/ C T of t he nec k o nl y is acce pta ble as a s u bstit ute if t he 
C T is of dia g n ostic q ualit y a n d wit h I V c o ntr ast. 
3. 2 . 3 A ge ≥ 1 8;  

R T O G 3 5 0 4 
2 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
3. 2. 4 
T he  trial is o pe n t o b ot h ge n d ers;   
 
3. 2. 5 
Z u br o d Perf or ma nce Stat us of 0- 1 wit hi n 1 4 da ys pri or t o re gistrati o n; ( N ot e: Z u br o d 
Perf or ma nce Stat us 2 patie nts are eli gi ble f or t he ni v ol u ma b R T o nl y ar m, Ar m 4, of t he 
st u d y (refer t o secti o n 3. 2. 1 6), all ot her eli gi bilit y criteria m ust be met.) 
3. 2. 6 
A de q uate h e mat ol o gi c f u ncti o n wit hi n 1 4 da ys pri or t o re gistrati o n defi ne d as f oll o ws: 
 W B C ≥ 2 0 0 0/ μ L ; 
 A bs ol ut e ne utr o p hil c o u nt ( A N C) ≥ 1, 5 0 0 cells/ m m 3; 
 P latelets ≥ 1 0 0, 0 0 0 cells/ m m 3; 
 He m o gl o bi n ≥ 9 . 0 g/ dl; N ote: T he use of tr a nsf usi o n or ot her i nter ve nti o n t o ac hie ve 
H g b ≥ 9. 0 g/ dl is acce pta ble. 
3. 2. 7 
A de q uate re nal f u n cti o n wit hi n 1 4  da ys pri or t o r e gistrati o n defi n e d as f oll o ws: 
 Ser u m creati ni ne < 1. 5 m g/ dl or creati ni ne cleara n ce ( C C) ≥ 5 0 ml/ mi n deter mi ne d b y 
2 4 - h o ur c ollecti o n or esti mate d b y C oc k cr oft- Ga ult f or m ula: 
  
 
C Cr male = [( 1 4 0 –  a ge) x ( wt i n k g)] 
  
 
  
 [( Ser u m Cr m g/ dl) x ( 7 2)] 
 
 
C Cr fe male = 0. 8 5 x ( Cr Cl male)  
N ote :  Patie nts wit h Cr Cl < 5 0 ml/ mi n are eli gi ble f or t he ni v ol u ma b/R T - o nl y ar m, Ar m 
4, of t he st u d y (refer t o s ecti o n 3. 2. 1 6), all ot her eli gi bilit y criteri a m ust be met.   
3. 2. 8 
A de q uate h e patic f u ncti o n wit hi n 1 4 da ys pri or t o re gistrati o n defi ne d as f oll o ws: 
 T ota l bilir u bi n  ≤ 1. 5 x U L N (e x ce pt patie nts wit h Gil bert S y n dr o me w h o ca n ha ve 
t otal bilir u bi n < 3. 0 m g/ d L); 
 A S T or A L T < 3 x t he u p per li mit of n or mal. 
3. 2 . 9 Na, K, Cl, gl u c ose, Ca, M g, al b u mi n,  A L P, A m yl ase, li pase, T S H wit hi n 1 4 da ys pri or t o 
re gistrati o n; 
3. 2. 1 0 Ne gati ve ser u m pre g na n c y test wit hi n 1 4 da ys pri or t o re gistrati o n f or w o me n of 
c hil d beari n g p ote ntial (see S ecti o n 4); 
3. 2. 1 1 A gree me nt of w o me n of c hil d beari n g p ote ntial t o use hi g hl y effecti ve c o ntr ace pti o n 
d uri n g recei pt of st u d y dr u g a n d u p t o 1 6 1 d a ys ( 2 3 wee ks) fr o m t he last d ose of 
ni v ol u ma b a n d 
me n recei vi n g ni v ol u ma b w h o are se x uall y acti ve wit h w o me n of 
c hil d beari n g p ote ntial t o use hi g hl y effecti ve c o ntrace pti o n d uri n g recei pt of st u d y dr u g 
f or 3 1 wee ks fr o m t he last d ose of ni v ol u ma b; 
3. 2. 1 2  Ne gati ve test f or H Bs A g, H C V A b ( or H C V R N A) wit hi n 1 4 da ys pri or t o re gistrati o n; 
3. 2. 1 3 All patie nts m ust pr o vi de t heir p ers o nal s m o ki n g hist or y pri or t o re gistrati o n. T h e 
calc ulati o n of pac k- years will be perf or me d b y us e of t he sa me s ur ve y utilize d o n R T O G 
1 0 1 6. T he s ur v e y will be a d mi nistere d b y use of a c o m p uter assiste d, self-i nter vi e w 
( C A SI) a p plicati o n t hat will be a vaila ble via a we b- bas e d p ortal or d o w nl oa d. See t he 
R T O G F o u n dati o n 3 5 0 4 pr ot oc ol pa ge o n t he R T O G we bsite f or details. 
3. 2. 1 4 T he  patie nt m ust pr o vi de st u d y-s p ecific i nf or me d c o nse nt pri or t o st u d y e ntr y. Patie nts 
w h o lac k t he ps yc h ol o gic al or i ntellect ual ca pacit y t o c o nse nt f or t he msel ves are 
e x cl u de d. 
 
  
Ste p 2 Se q ue ntial assi g n me nt t o ar ms of t he trial ( or o p har y n geal ca n cer patie nts o nl y) 
3. 2. 1 5  F or or o p har y n geal ca ncer p atie nts: p 1 6 det er mi nati o n b y i m m u n o hist oc he mistr y ( defi n e d 
as greater t ha n 7 0 % str o n g n ucl ear or n u clear a n d c yt o plas mic stai ni n g of t u m or cells), 

R T O G 3 5 0 4 
2 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
c o nfir me d b y ce ntr al pat h ol o g y re vi e w; (see Secti o n 3. 1. 3  a b o ve a n d Secti o n 1 0. 1  f or 
details).  N ote : F or patie nts wit h oral ca vit y, lar y n geal, a n d h y p o p har y n geal ca n cer, t h e 
site ca n pr ocee d t o Ste p 2 i m me diatel y after c o m pleti n g Ste p 1. 
3. 2. 1 6 N ote: Patie nts (i n cl usi ve of p 1 6- p ositi ve or o p har y n x patie nts) w h o meet all of t h e 
eli gi bilit y criteria n ote d a b o ve, b ut h a ve 1 t o 4 of t he f oll o wi n g pre-e xisti n g c o n diti o ns 
(a ge ≥ 7 0 years; Z u br o d perf or ma n ce stat us 2; b aseli ne gra de ≥ 3 peri p h eral ne ur o pat h y; 
g ra de ≥ 2  heari n g l oss; re nal i ns uffi cie nc y [ Cr Cl < 5 0 ml/ mi n]) t hat i n t he o pi ni o n of t h e 
treati n g p h ysicia n ma kes t he m u ns uita ble f or cis plati n, ma y be e nr olle d i n t he st u d y a n d 
treate d o n t he ni v ol u ma b/ R T-al o ne ar m, Ar m 4. 
3. 2. 1 7  T he patie nt has meas ura ble disease as defi ne d b y t he prese nce of at least o ne meas ura ble 
lesi o n per R E CI S T 1. 1. 
 
3. 3  
I neli gi bilit y Criteri a 
P atie nt s wit h o ne or m ore 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. 
  
Ste p 1: Re gistrati o n 
3. 3 . 1 Defi niti ve cli nical or ra di ol o gic e vi d e nce of dista nt ( be y o n d cer vical l y m p h n o de a n d 
nec k tiss ue) metastatic disease; 
3. 3. 2   Patie nts wit h oral ca vit y ca n cer are e x cl u de d fr o m partici p ati o n if resecti o n of t he pri mar y 
t u mor is c o nsi dere d tec h nicall y feasi ble b y a n oral or hea d a n d nec k ca ncers s ur gical 
s u bs pecialist ( Please c o ns ult t he S ur gical O nc ol o g y C o- PI, R o bert Ferris, M D , P h D, if 
clarificati o n is nee de d o n a n i n di vi d ual case).  
3. 3. 3   Carci n o ma of t he nec k of u n k n o w n pri mar y site ori gi n (e v e n if p 1 6- p ositi ve);  
3. 3. 4   A bse nce of R E CI S T, v. 1. 1 defi ne d meas ura ble diseas e; 
3. 3. 5 
Gr oss t otal e x cisi o n of b ot h pri mar y a n d n o d al disease; t his i ncl u d es t o nsillect o m y, l o cal 
e x cisi o n of pri mar y site, a n d n o dal e x cisi o n t hat re m o ves all cli nicall y a n d 
ra di o gra p hic all y e vi de nt disease. Patie nts wit h R E CI S T, v. 1. 1 e val ua ble re mai ni n g 
ca ncer eit her i n t he nec k or pri mar y site re m ai n eli gi ble. 
3. 3. 6    Si m ulta ne o us pri mar y ca n cers or se parate bilateral pri mar y t u m or sites; 
3. 3. 7    Pri or i n vasi v e mali g na nc y (e x ce pt n o n- mela n o mat o us s ki n ca n cer) u nless disease free f or 
a mi ni m u m of 3 years; (f or e x a m ple, carci n o ma i n sit u of t he breast, oral ca vit y, or cer vi x 
are all per missi ble); 
3. 3. 8 
P ri or s yste mic c he m ot hera p y f or t he st u d y ca n cer; n ote t hat pri or c he m ot hera p y f or a 
differe nt ca ncer is all o wa ble if t he criteri o n i n Secti o n 3. 3. 7 is met; 
3. 3 .9  Pri or ra di ot hera p y t o t h e re gi o n of t h e st u d y ca ncer t hat w o ul d res ult i n o verla p of 
ra diati o n t hera p y fiel ds; 
3. 3. 1 0 S e vere, acti ve c o- m or bi dit y defi ne d as f oll o ws: 
 P atie nts wit h acti ve a ut oi m m u ne disease, wit h e x ce pti o ns of vitili g o, t y pe I dia betes 
mellit us, h y p ot h yr oi dis m a n d ps oriasis; 
 Use of s yste mic c ortic oster oi ds ( > 1 0 m g d ail y pre d nis o ne or e q ui vale nt) or ot her 
i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da ys of st u d y dr u g a d mi nistrati o n, wit h 
e x ce pti o n of i n hale d or t o pical ster oi ds; 
 K n o w n i m m u n os u p pressi ve disease, f or e x a m ple HI V i nfecti o n or hist or y of b o n e 
marr o w tra ns pl a nt or C L L; 
 P ositi ve test f or he patitis B vir us s urface a nti ge n or he patitis C vir us i n dicati n g ac ute 
or c hr o nic i nf ecti o n; 

R T O G 3 5 0 4 
2 3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 U nsta ble a n gi na a n d or c o n gesti ve heart fail ure re q uiri n g h os pitalizati o n i n t he last 6 
m o nt hs; 
 M y ocar dial i nfarcti o n wit hi n t he last 6 m o nt hs; 
 Ac ti ve bacteri al or f u n gal i nfecti o n re q uiri n g i ntra ve n o us a nti bi otic at t he ti me of 
re gistrati o n; 
 C hr o nic O bstr ucti ve P ul m o nar y Disease e x acer bati o n or ot her res pir at or y ill ness 
re q uiri n g h os pitaliz ati o n or precl u di n g st u d y t hera p y wit hi n 3 0 da ys of re gistrati o n; 
 As t here is p ote ntial f or he patic t o xicit y wit h ni v ol u ma b, dr u gs wit h a pre dis p ositi o n 
t o he pat o xicit y s h o ul d be use d wit h ca uti o n. 
 Hist or y of s e vere h y pers e nsiti vit y reacti o n t o a n y m o n ocl o nal a nti b o d y. 
3. 3. 1 1  Pre g n a nc y, n ursi n g fe males, or w o me n of c hil d beari n g p ot e ntial a n d me n w h o are 
se xuall y acti ve a n d n ot willi n g/a ble t o use me dicall y acce pt a ble f or ms of c o ntrace pti o n; 
t his e x cl usi o n is necessar y beca use t h e treat me nt i n v ol ve d i n t his st u d y ma y be 
si g nifica ntl y terat o ge nic. 
3. 3. 1 2  Gra de 3- 4 ( C T C A E, v 4) ele ctr ol yt e a b n or malities:  
 S er u m calci u m (i o nize d or a dj uste d f or al b u mi n) < 7 m g/ dl  or > 1 2. 5 m g/ dl  des pite 
i nter ve nti o n t o n or malize le vels; 
 Gl uc ose < 4 0 m g/ dl  or > 2 5 0 m g/ dl ; 
 Ma g n esi u m < 0. 9 m g/ dl  or > 3 m g/ dl  des pite i nter ve nti o n t o n or malize le vels; 
 P otassi u m < 3. 0 m m ol/ L or > 6 m m ol/ L des pite i nter ve nti o n t o n or malize le vels; 
 S o di u m < 1 3 0 m m ol/ L or > 1 5 5 m m ol/ L des pite i nter ve nti o n t o n or malize le vels. 
3. 3. 1 3  Pri or aller gic reacti o n t o cis plati n or cet u xi ma b. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

R T O G 3 5 0 4 
2 4   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
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  
 
N O T E : I N S TI T U TI O N S A R E R E Q UI R E D T O C O M P L Y WI T H D A T A S U B MI S SI O N 
W I T HI N A 1 4- D A Y WI N D O W F O R E A C H A S S E S S M E N T I N DI C A T E D B E L O W 
( A D V E R S E E V E N T R E P O R TI N G G UI D E LI N E S H A V E S H O R T E R R E P O R TI N G 
I N T E R V A L S, S E E S E C TI O N 7 .) 
 
P R E- T R E A T M E N T A S S E S S M E N T S ( 2 6 Dec 2 0 1 7) 
Assess me nts  
Pri o r t o Ste p 1 Re gistr ati o n  
(c ale n d ar d a ys) 
Pri o r t o Tre at me nt  
(c ale n d ar d a ys) 
I nf or me d C o nse nt 
Wit hi n 3 0 da ys, i ncl u di n g da y 
of Ste p 1 Re gistrati o n  
 
Ma n dat or y tiss ue c ollecti o n 
Pri or t o Ste p 2 Re gistrati o n  
 
Hist or y / p h ysical e xa m 
2 8  
 
A d mi nistrati o n of t o bacc o 
s m o ki n g s ur ve y ( via we b -b ase d 
p ortal or d o w nl oa d ) 
2 8  
 
E xa m b y Ra d O nc, Me d O nc, 
a n d E N T or H & N S ur ge o n  
2 8  
 
 
F i ber o ptic e xa m wit h 
lar y n g o p har y n g osc o p y (as 
cli nicall y i n dicate d)  
2 8  
 
C T or M RI of nec k, wit h 
c o ntrast 
2 8  
 
C T sca n of c hest  or 1 8 -F -F D G -
P E T/ C T of t he nec k a n d c hest  
 
2 8  
 
W h ole b o d y 1 8 -F -F D G -
P E T/ C T  
 
Rec o m me n de d: 2 8  
Perf or ma nce Stat us  
1 4  
 
C B C  w/ diff & A N C  
1 4  
 
T otal bilir u bi n; A L P, A S T or 
A L T  
1 4  
 
Creati ni ne or  
Creati ni ne Cleara nce  
1 4  
 
Ser u m pre g na nc y test ( f or 
w o me n of c hil d beari n g 
p ote ntial ) 
1 4  
 
Na, K, Cl, gl uc ose, Ca, M g, 
al b u mi n,  A m ylase, li pase, T S H   
1 4  
 
H Bs A g, H C V A b ( or H C V 
R N A)  
1 4  
 
De ntal assess me nt  
 
Rec o m me n de d: 5 6  
S wall o wi n g e val uati o n  (see n ote 
bel o w)  
 
Re q uire d  2 8  
C harls o n C o m or bi dit y I n de x 
( C CI)  
 
Re q uire d: 2 8  
A u di o gra m  
 
Rec o m me n de d: 8 4  

R T O G 3 5 0 4 
2 5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
N utriti o n/fee di n g t u be e val  
 
Rec o m me n de d: 1 4  
A d verse e ve nt e val uati o n  
 
Re q uire d: 1 4  
S peci me n c ollecti o n f or ba n ki n g  
 
If patie nt c o nse nts: 1 4 
See Secti o n 1 0  f or det ails. 
 
N otes f or Pre- Treat me nt Assess me nts (ta ble a b o v e) 
 T he H & N e x a m ca n be d o ne b y M e dical, Ra diati o n, a n d/ or S ur gi cal O nc ol o gist. 
 T he  fi ber o ptic e x a m wit h lar y n g o p har y n g os c o p y ca n be d o ne b y t he treati n g s ur ge o n, 
me dic al o nc ol o gist, or ra diati o n o nc ol o gist wit h e x perie nce i n e n d osc o pic e x a mi nati o ns 
of ca ncer patie nts. 
 T he  de ntal assess me nt is b y a p h ysi cia n or desi g nee (s uc h as a p h ysicia n's assista nt, n urse 
or n urse practiti o ner, or a de ntist/ h y gi e nist) t o assess n u m ber of teet h a n d o verall de ntal 
healt h wit h ma na ge me nt (refer t o t he st u d y-s pecifi c g ui d e f or d etails) ;  
 T he  s wall o wi n g assess m e nt is a si n gle q uesti o n c o m plete d b y t he p h ysici a n a n d/ or 
researc h ass o ciate t o des cri be t he c o nsiste n cies of f o o dst uff t hat t he patie nt is a ble t o 
s wall o w.  
 Rec o m me n d ati o ns f or I m a gi n g : All C Ts s h o ul d be of dia g n ostic q ualit y wit h i o di nate d 
c o ntrast wit h c o nti g u o us 3 m m mi ni m u m a xial slice t hic k ness, wit h t he sa me a n g ulati o n 
a n d ga ntr y tilt as perf or me d o n t he i nitial st u d y ( w here p ossi ble), wit h r ec o nstr ucti o ns 
perf or me d i n t he a xial a n d c or o nal pla nes, wit h t he sa me fiel ds of vi e w ( F O V), m A, k V P, 
a n d si milar wi n d o w a n d l e vel s etti n gs o n f oll o w- u p e x a mi nati o ns. If t here is e xte nsi ve 
de ntal a mal ga m, a b utterfl y tec h ni q u e a dj usti n g t h e ga ntr y i n t w o pla nes t o mi ni mize 
de ntal strea k artifact a n d 1. 5 T M RI wit h ga d oli ni u m als o s h o ul d be o btai ne d t o i m pr o ve 
vis ualizati o n of t he t u m or mar gi ns f or b aseli ne a n d f oll o w u p i ma gi n g. All M RIs of t he 
he a d a n d n ec k i de all y s h o ul d i ncl u de a Sa gittal T 1 l ocalizer, a xial a n d c or o nal T 1 pre a n d 
p ost- ga d oli ni u m i ma ges wit h fat sat urati o n, a n d a n a xial T 2, D WI, a n d c or o nal S TI R 
se q ue nce. 
 A 1 8 - F- F D G- P E T/ C T of t he nec k o nl y is acce pta ble as a s u bstit ute if t he C T is of 
dia g n ostic q ualit y ( n ote d a b o ve) a n d wit h I V c o ntr ast. N ote : Diag n ostic q ualit y C T sca n 
of nec k wit h c o ntrast a n d/ or 1 8- F- F D G- P E T/ C T perf or me d f or ra diati o n pla n ni n g ma y 
ser ve as b ot h sta gi n g a n d pla n ni n g t o ols.  
 N utriti o nal e val uati o n t o i ncl u de t he p h ysi cia n’s e val uati o n f or place me nt of pr o p h yl actic 
gastr ost o m y or ot her t y p e of fee di n g t u be; n ote: T he decisi o n t o place a fee di n g t u be 
s h o ul d be i n di vi d ualiz e d a n d is n ot ma n date d. I n v esti gat ors ma y c o nsi der a n u m ber of 
fact ors i ncl u di n g: pri or wei g ht l oss, c urre nt n utriti o nal stat us, size a n d l ocati o n of t he 
pri mar y t u m or (i m pacti n g hi g h d ose tar get v ol u me), a vaila bilit y of fee di n g t u be 
place me nt ser vices, a v aila bilit y of s peec h a n d s w all o wi n g s pecialists, dieticia n 
c o u nseli n g, a n d s ocial s u p p ort. Fee di n g t u bes m a y be place d after start of tr eat me nt at t he 
discreti o n of t he cli nical t ea m. If a t u be is place d, t he site will d oc u me nt o n t he 
a p pr o priate case re p ort f or m if t he t u be was place d pr o p h yl acticall y (as a pre ve ntati ve 
mea s ure) or t hera pe uticall y ( beca us e of n utriti o nal c o m pr o mise or ot her cli nical 
i n dicati o ns). It is hi g hl y rec o m me n de d as part of t he sta n dar d of care t hat all patie nts, b ut 
partic ularl y t h ose w h o re q uire fee di n g t u b es, be pr o vi de d wit h pr ofessi o nal s wall o wi n g 
e val uati o ns a n d c o u ns eli n g d uri n g a n d after treat me nt. 
 T he  C harls o n C o m or bi dit y I n de x ( C CI) is re q uir e d.  T he i n vesti gat or a n d/ or researc h 
ass ociate will c ollect t he data b y e xtracti n g i nf or m ati o n fr o m t he patie nt’s hist or y a n d/ or 
c hart.  

R T O G 3 5 0 4 
2 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
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 ( 2 6 Dec 2 0 1 7)                                                         
[D a y - 1 4  ( 1 4 d a ys pri or t o I M R T) t o 1 2 wee ks after C he m o R T]  
Assess me nts  
Wee kl y  ( ± 2 d a ys) d uri n g 
r a di ati o n t he n  pri or t o e ac h 
d ose of ni v ol u m a b/ pl ace b o  
As cli nic all y i n dic ate d  
Brief hist or y  
X  
 
P h ysical  e x a m b y R a d O nc, 
Me d O nc, or ass ociate d 
N P/ P A  
X  
 
C B C  w/ diff & A N C  
X  
 
Creati ni ne or Creati ni ne 
Cleara nce  
X  
 
Na, K, Cl, gl u c ose, Ca, M g, 
al b u mi n  
X  
 
A L T, A S T, T Bili, A L P, 
a m ylas e, li pase, T S H  
Wit hi n 7 2 h o urs pri or t o eac h 
d ose of ni v ol u ma b  
 
W h ole b o d y 1 8 -F -F D G -
P E T/ C T  
 
If s us pici o n of t u m or 
rec urre nce 
C T or M RI or 1 8 -F -F D G -
P E T/ C T of nec k, wit h 
c o ntrast  
 
If s us pici o n of t u m or 
rec urre nce 
Bi o ps y  
 
If s us pici o n of t u m or 
rec urre nce 
A d verse E v e nt e val uati o n  
X  
X  
 
N otes f or Assess me nts d uri n g Treat me nt (t a ble a b o ve) 
 F or Ar m 2, assess me nts will ta ke place q 3 wee ks  (rat her t h a n q 2 wee ks) pri or t o eac h 
d ose  of ni v ol u ma b. 
 

R T O G 3 5 0 4 
2 7   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
A S S E S S M E N T S I N F O L L O W U P (st arti n g 3 m o nt hs after e n d of R T) ( 2 6 Dec 2 0 1 7) 
Assess me nts  
q 2 8 d a ys  d uri n g 
a dj u v a nt 
ni v ol u m a b f or 
all a r ms  
2 wee ks 
after l ast 
d ose of 
ni v ol u m a b 
or pl ace b o  
q 3 m os.  ( ± 2 
wee ks)  fr o m e n d 
of R T f or 2 yrs  
As 
cli nic all y 
i n dic ate d 
Brief hist or y  
X  
X  
X  
 
E x a m b y  Ra d O nc or M e d 
O nc or E N T or H & N 
S ur ge o n  
X  
X  
X  
 
C T or M RI of nec k, wit h 
c o ntrast  
 
 
At 3, 6, 9, a n d 1 2 
m os. after R T, 
t he n q 6 m os. x 1 
year  
 
Perf or ma nce Stat us  
X  
X  
X  
 
C B C w/ diff & A N C  
X  
X  
At 3 m os.  fr o m 
last d ose of 
ni v ol u ma b or 
place b o  
 
T otal bilir u bi n; A S T or 
A L T, A L P, a m yl ase, li pase, 
T S H  
X  
X  
At 3 m os.  fr o m 
last d ose of 
ni v ol u ma b or 
place b o  
 
Na, K, Cl, gl u c ose, Ca, M g, 
al b u mi n  
X  
X  
At 3 m os.  fr o m 
last d ose of 
ni v ol u ma b or 
place b o  
 
W h ole b o d y 1 8 -F -F D G -
P E T/ C T  
 
 
Rec o m me n de d 3 
m os. after R T  
If s us pici o n 
of t u m or 
rec urre nce 
De ntal Assess me nt  
 
 
X  
 
N utriti o n/fee di n g t u b e e v al  
 
 
X  
 
C hest C T  
 
 
At 3, 6, 9, a n d 1 2 
m os. after R T, 
t he n q 6 m os. x 1 
year  
If s us pici o n 
of t u m or 
rec urre nce 
Bi o ps y  
 
 
 
If s us pici o n 
of t u m or 
rec urre nce 
A d verse e ve nt e v al uati o n  
X  
X (see n ote 
bel o w)  
At eac h f oll o w -u p visit  
S peci me n c ollecti o n f or 
ba n ki n g , if t he p atie nt 
c o nse nts : See Secti o n 1 0  
f or details. 
 
 
3 a n d 6 m o nt hs 
fr o m e n d of R T   
 
 

R T O G 3 5 0 4 
2 8   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
N otes f or Assess me nts i n F oll o w U p (ta ble a b o ve) 
 N ote: T he feasi bilit y of a dj u va nt a d mi nistrati o n of ni v ol u ma b will be e val uate d a m o n g 
t he first 8 e val ua ble p atie nts. If m ore t ha n 4 of 8 disc o nti n ue t hera p y b ef ore 7 m o nt hs, 
t he n a dj u va nt a d mi nistrati o n will be disc o nti n ue d i n all ar ms of t he trial.  
 D ur i n g t h e trial, a d verse e ve nt e val u ati o ns perf or me d at 2 a n d 4 wee ks aft er t he last 
ra di ot hera p y tr eat me nt are wit hi n t he wi n d o w of t he D L T defi niti o n. A d diti o nal a d verse 
eve nt e val u ati o ns are t o o cc ur at 1 a n d 2 m o nt hs after t he last d ose of ni v ol u ma b b ut will 
n ot c o ntr i b ute t o t he D L T defi niti o n.  
 N ote: All a d verse e ve nts occ urri n g u p t o 1 0 0 da ys after t he l ast d ose of ni v ol u ma b are 
re q uire d t o be s u b mitte d re gar dl ess of attri b uti o ns t o ni v ol u ma b. F or i n di vi d u als n ot 
recei vi n g t he 7 m o nt hs of a dj u va nt ni v ol u ma b, t his e xte n ds t o t he 6- m o nt h p ost-
radi ot hera p y visit. F or i n di vi d uals recei vi n g a dj u v a nt ni v ol u ma b, t his e xte n ds t o t he 3-
m o nt h visit after c o m pleti o n of 7 m o nt hs of a dj u va nt ni v ol u ma b (c orres p o n di n g t o t he 
1 5- m o nt h p ost-c o m pleti o n of ra di ot hera p y visit).  
 T he  de ntal assess me nt is b y a p h ysi cia n or desi g nee (s uc h as a p h ysicia n's assista nt, n urse 
or n urse practiti o ner, or a de ntist/ h y gi e nist) t o assess n u m ber of teet h a n d o verall de ntal 
healt h wit h ma na ge me nt ( Refer t o t he st u d y-s p ecific g ui de f or det ails); 
 
Defi niti o n of Disease Assess me nts  
Res p o nse t o i nitial t hera p y at t he t u m or pri mar y a n d/ or re gi o nal i n v ol ve d l y m p h n o des is n ot a n 
e n d p oi nt i n t his st u d y. H o we ver, pr o gressi o n-free s ur vi val is a n i m p orta nt sec o n dar y e n d p oi nt. 
Pr o gressi o n of hea d a n d nec k ca ncer will be assesse d at defi ne d ti me p oi nts b y ra di ol o gical 
i ma gi n g as i n dicat e d i n t he Assess me nt Ta bles a b o ve. A d diti o nall y, a n y cli nical e vi de nce of 
disease pr o gressi o n as deter mi ne d b y t h e treati n g p h ysicia n o utsi de of t h es e defi ne d ti me p oi nts 
d uri n g tr eat me nt a n d i n f oll o w u p s h o ul d tri g ger c o nfir mati o n b y ra di ol o gi cal i ma gi n g a n d 
bi o ps y, if cli nicall y feasi ble a n d ass ociat e d wit h acce pta bl e ris k t o t he patie nt. 
 
T he pr ot oc ol will utiliz e R E CI S T, v. 1. 1 f or t he p ur p oses of e v al uati n g pr o gressi ve diseas e o nl y. 
I n v esti gat ors will n ot be re q uire d t o r e p ort res p o nse or best o verall res p o ns e.  
 
As descri be d i n R E CI S T, v. 1. 1, it is str o n gl y rec o m me n de d t hat t he i ma gi n g st u dies perf or me d 
at baseli ne be p erf or me d i n f oll o w u p o n t he sa me e q ui p me nt wit h t he sa me tec h ni q ues as n ote d 
a b o ve i n Rec o m me n dati o ns f or I ma gi n g. C T nec k a n d c hest wit h c o ntr ast of dia g n ostic q ualit y 
(slice t hic k ness n o greater t ha n 3 m m) is preferre d, wit h C T hea d, a b d o me n/ pel vis a d de d if 
cli nicall y i n dicat e d. 1 8- F- F D G- P E T/ C T (i ncl usi ve of t he c hest) ma y b e use d as ra di o gra p hic 
eval uati o n f or o v erall ca ncer stat us.  
 
F or t he p ur p os es of t his pr ot oc ol, pr o gressi ve dise ase will be defi n e d as f oll o ws: 
1.  C li nical e vi de nce of disease pr o gressi o n i n a ra diate d fiel d t hat is c o nfir me d b y c yt ol o g y 
or hist o pat h ol o g y ( see N ote bel o w) O R 
2.  P r o gressi ve disease as defi ne d b y R E CI S T, v. 1. 1 criteria ( Eise n ha uer 2 0 0 9) 
a)  At least a 2 0 % i ncreas e i n t he s u m of t he dia meters of tar get lesi o ns; t he s u m als o 
m ust de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m O R 
b)  u ne q ui v ocal pr o gressi o n of n o n-tar get lesi o ns O R 
c)  t he a p peara nce of o ne or m ore ne w lesi o ns 
 
N ote : A p ositi ve bi o ps y at t he pri mar y site or i n v ol ve d n o des t hat occ urs ≤ 2 0 wee ks fr o m t he 

R T O G 3 5 0 4 
2 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
e n d of R T will be cate g orize d as disease persiste nce a n d  > 2 0 wee ks as pr o gressi o n. 
 
It is a ntici pate d t hat meas ura ble, tar get lesi o ns b y R E CI S T, v. 1. 1 f or hea d a n d nec k ca ncer 
w o ul d i ncl u de  t he pri mar y t u m or a n d u p t o 4 meas ura ble cer vical l y m p h n o des wit h a s h ort a xis 
of ≥ 1 5 m m. N o n-tar get l esi o ns w o ul d i ncl u de cer vical l y m p h n o des > 1 0 m m a n d < 1 5 m m.  
 
L oc al or re gi o nal pr o gressi o n d uri n g pri mar y c he m ora di ot hera p y f or hea d a n d nec k ca ncer is 
u n us ual; h o we ver, it ma y occ ur a n d w o ul d be defi ne d b y m eeti n g R E CI S T, v. 1. 1 criteria i n 
co m paris o n t o t he i ma gi n g st u dies perf or me d at baseli ne/e nr oll me nt. Per R E CI S T, v. 1. 1. 
pr o gr essi ve dise ase is defi ne d b y at least a 2 0 % i n creas e i n t he s u m of t he dia meters of tar get 
lesi o ns, ta ki n g as a refere nce t he s mallest s u m o n st u d y. It is a ntici pate d t hat t he first re q uire d 
i ma gi n g ti me p oi nt after c o m pleti o n of c he m or a di ot hera p y ( 3 m o nt hs aft er R T) will be t he 
refere nce sca n f or d efi ni n g pr o gressi o n. H o we v er, f urt her decli ne i n meas ure me nt of tar get 
lesi o ns ma y occ ur be y o n d t he 3- m o nt h p ost R T e val uati o n ti me p oi nt, I n t hat i nsta nce, t he 
refere nce sca n c o ntai ni n g t he s mallest s u m ma y occ ur be y o n d t he 3- m o nt h p ost- R T ti me p oi nt.  
 
R E CI S T, v. 1. 1 rec o g niz es t hat it ca n be diffi c ult t o deter mi ne pr o gressi ve disease i n a 
pre vi o usl y irra diate d or pre vi o usl y tr eate d area (e. g. after nec k dissecti o n). I n t he e ve nt of 
cli nical s us pici o n of pr o gressi ve diseas e wit hi n a n irra diate d fi el d i n t he a bs e nce of m eeti n g 
f ormal R E CI S T defi niti o n, i n vesti gat ors are str o n gl y e n c o ura ge d t o perf or m f urt her 
i n vesti gati o n, i ncl u di n g: 
a)  Re peat C T i ma gi n g at a s h ort i nter val (e. g. si x wee ks). If s h ort i nter v al i ma gi n g res ults i n 
c o nfir mati o n of pr o gressi ve disease b y R E CI S T, v. 1. 1 defi niti o n, t he date of pr o gressi o n 
will  be defi ne d b y t he first sca n.  
b)  1 8- F- F D G- P E T/ C T: Per R E CI S T, pr o gressi ve disease w o ul d be i n dicate d o n 1 8- F- F D G-
P E T C T  if a pre vi o usl y n e gati ve 1 8- F- F D G- P E T/ C T bec o mes p ositi ve at a ne w lesi o n. F or 
t his pr ot oc ol, a pre vi o usl y ne gati ve meas ura ble lesi o n t hat bec o mes p ositi ve b y F D G- P E T 
als o w o ul d be c o nsi dere d pr o gressi o n. Bi o ps y c o nfir mati o n, h o we ver, is still str o n gl y 
rec o m me n de d.  
c)  Bi o ps y  
 
I n a d diti o n t o f or mal e val uati o n of pr o gressi ve dis ease b y R E CI S T, v. 1. 1, i n vesti gat ors will be 
as ke d at t he ti me of first pr o gressi o n t o re p ort w h et her pr o gressi ve diseas e was l ocal ( at t he 
pri mar y t u m or), re gi o n al ( wit hi n t he hea d a n d n ec k, i ncl u di n g cer vical l y m p h n o des) or dista nt 
(i ncl usi ve of brai n a n d bel o w t he cla vicles). Sites of dista nt disease pr o gressi o n s h o ul d be n ote d. 
T his will acc o m m o date a nal ysis of patter ns of fail ure. 
 
All i m a ges s h o ul d be re vie we d a n d re p orte d b y t he l oc al st u d y i n vesti g at ors b y R E CI S T, v. 
1. 1.   
 
C ase-re p ort f or ms f or i n v esti gat or i nter pret ati o n of pr o gressi ve dise ase b y R E CI S T, v. 1. 1 are 
a vaila ble i n Me di data Ra ve.  
 
 
 

R T O G 3 5 0 4 
3 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
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 
5. 1  
C he m ot her a p y/ Ot her A ge nt- B ase d T her a p y  
P r ot oc ol t re at me nt (first d ose of ni v ol u m a b) m ust be gi n wit hi n 7 d a ys after Ste p 2 
re gistr ati o n.  
 
 
Niv ol u m a b ( Ar ms 1, 3, a n d 4) 
 
St arti n g D ose  
2 4 0 m gs  
 
Niv ol u m a b ( Ar m 2 o nl y) 
 
St arti n g D ose  ( D a y 1) 
3 6 0 m gs  
 
  
 
  
C o h orts of 8 patie nts eac h will be se q ue ntiall y e nr olle d i nt o all 4 ar ms of t he st u d y. T h e 
first c o h ort i n Ar ms 1, 3, a n d 4 will recei v e ni v ol u ma b 2 4 0 m gs I V st arti n g 1 4 da ys pri or 
t o t he first I M R T d ose a n d e ver y 2 wee ks f or a t ot al of 1 0 d oses.  F or Ar m 2 o nl y ( hi g h-
d ose  cis plati n 1 0 0 m g/ m2 x 3), a l oa di n g d ose of 2 4 0 m gs will be gi ve n starti n g 1 4 da ys 
pri or  t o t he first I M R T d ose a n d t he n ni v ol u ma b 3 6 0 m gs I V q 2 1 d a ys f or  6 d oses will 
be  i nitiate d o n da y 1 of I M R T. All treat me nt ar ms will recei ve a dj u va nt a d mi nistrati o n of 
ni v ol u ma b. T his is defi ne d as ni v ol u ma b 4 8 0 m gs I V q 2 8 da ys starti n g 1 2 wee ks after 
e n d of R T f or a ma xi m u m of 7 d oses (res ulti n g i n a t otal of 1 year of ni v ol u ma b t hera p y). 
 
  
All patie nts will recei ve ni v ol u ma b as a 3 0 mi n ute I V i nf usi o n 1 4 da ys pri or t o t he first 
I M R T d ose a n d pri or t o c he m ot hera p y i nf usi o n.  
 
 
F or Ar ms 1, 3, a n d 4, dr u g will be a d mi nistere d e v er y 1 4 da ys f or a t otal of 1 0 d oses. F or 
Ar m 2, after t h e first i nf usi o n o n da y - 1 4, st arti n g o n da y 1 of I M R T, ni v ol u ma b, 3 6 0 
m gs will be a d mi nistere d q 2 1 da ys f or a m a xi m u m of  6 d oses.  
 
 
Dr u g s h o ul d be a d mi nistere d o n a M o n d a y or T u es da y pri or t o t he first I M R T d ose a n d 
pri or t o c he m ot hera p y. 
 
  
Patie nts ma y be d os e d n o less t ha n 1 2 da ys fr o m t he pre vi o us d ose f or q 1 4 da y d osi n g, 
an d n o less t ha n 1 9 da ys f or q 2 1 da y d osi n g ( Ar m 2 o nl y).  
 
 
T here will be n o i ntra- patie nt d ose escal ati o n or re d ucti o ns of ni v ol u ma b.  
 
  
 See S ecti o n 5. 1. 2  f or det ails c o ncer ni n g ni v ol u ma b d osi n g sc he d ul e. See S ecti o n 6 f or 
Ni v ol u ma b D ose M o dificati o ns.  
  
 
  
T he peri o d of o bs er vati o n f or a D L T is fr o m da y - 1 4 (first d ose of ni v ol u ma b) t hr o u g h t o 
2 8 da ys after t h e c o m pleti o n of ra di ot hera p y. 
 

R T O G 3 5 0 4 
3 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
A ni v ol u ma b attri b uta ble, d ose-li miti n g t o xicit y ( D L T) will be defi n e d as f oll o ws: 
1)  A n y ≥ gra de 3 a d vers e e ve nt ( C T C A E, v. 4) t hat is relate d t o ni v ol u ma b t hat d oes n ot 
res ol ve t o gra d e 1 or less wit hi n 2 8 da ys;  
2)  A dela y i n ra di ot hera p y of > 2 wee ks d ue t o t o xicit y relate d t o ni v ol u ma b; 
3)  I na bilit y t o c o m plete ra di ot hera p y d ue t o t o xicit y relate d t o ni v ol u ma b; 
4)  I n a bilit y t o recei ve a n a d e q uate d ose ( ≥ 7 0 %) of cis plati n ( Ar m 1 a n d 2) or cet u xi ma b 
( Ar m 3) d ue t o t o xicit y d efi nitel y relate d t o ni v ol u ma b. 
 
 
N ote : T o x cit y rel ate d t o ni v ol u ma b t hat d oes n ot affect deli ver y of eit her c he m ot hera p y 
or ra di ot hera p y is n ot a d ose li miti n g t o xicit y u nless it satisfies criteria 1 n ote d a b o ve.  
  
  
 
If a d ose of ni v ol u ma b is dela ye d, it s h o ul d be a d d e d t o t he e n d of tr eat me nt f or a t otal of 
1 0 d oses ( Ar ms 1, 3, 4)  if t he patie nt is n ot t o recei ve a dj u va nt ni v ol u ma b t hera p y. F or 
Ar m 2, t his is e q ui vale nt t o a t otal of 6 d oses of ni v ol u ma b 3 8 0 m gs q 2 1 da ys. F or 
pa tie nts recei vi n g a dj u va nt t hera p y, patie nts s h o ul d pr ocee d wit h a dj u va nt m o nt hl y 
d osi n g starti n g 3 m o nt hs after ra diati o n t hera p y, as s pecifie d bel o w. 
 
A dj uv a nt Niv ol u m a b 
I n Ar ms 1, 3 a n d 4, a dj u v a nt a d mi nistrati o n of ni v ol u ma b s h o ul d be gi n a mi ni m u m of 2 
a n d a ma xi m u m of 4 wee ks after t he last d ose of ni v ol u ma b i n t he pri mar y t hera p y 
setti n g. I n Ar m 2, a dj u va nt a d mi nistrati o n of ni v ol u ma b s h o ul d be gi n a mi ni m u m of 3 
a n d a ma xi m u m of 5 wee ks after t he last d ose of ni v ol u ma b.   
 
All patie nts will recei ve a dj u va nt ni v ol u ma b 4 8 0 m gs as a 3 0 mi n ute I V i nf usi o n 
a d mi nistere d q 2 8 da ys f or a ma xi m u m of  7 d oses. Patie nts ma y be d os e d n o less t ha n 2 6 
da ys fr o m t he pre vi o us d ose. T here will be n o i ntra- patie nt d ose escalati o n or re d ucti o ns 
of a dj u va nt ni v ol u ma b.  
 
Cet uxi m a b a n d Cis pl ati n 
 
 
Cet uxi m a b D ose A d mi nistr ati o n ( Ar m 3) 
Patie nts o n t he cet u xi ma b ar ms will recei v e a n i nitial d ose of cet u xi ma b, 4 0 0 m g/ m 2, 
( usi n g act ual b o d y wei g ht f or all B S A calc ulati o ns) i ntra ve n o usl y (i v) o ver 1 2 0 mi n utes 7 
da ys f oll o wi n g t he first ni v ol u ma b d ose a n d c orres p o n di n g t o 7 da ys pri or t o t he first 
ra diati o n d ose.  
 
T he l oa di n g d os e of cet u xi ma b m ust prece de t h e first ra diati o n treat me nt b y at least 5, b ut 
n o m ore t ha n 7, da ys (t he da y of t he l oa di n g d ose is n ot i ncl u de d i n t hese 5 da ys).  
Patie nts will t he n recei ve cet u xi ma b, 2 5 0 m g/ m 2, intra ve n o usl y (i v) o ver 6 0 mi n utes o n a 
wee kl y basis o nce a w ee k o n M o n da y or T ues da y f or a t otal of 7 d oses c o n c urre nt wit h 
ra diati o n t hera p y.  T h e i nf usi o n rate of cet u xi ma b m ust ne ver e x cee d 5 m L/ mi n. 
 
N ote: If a w ei g ht c ha n ge of ≥ 1 0 % occ urs, t he cet u xi ma b d ose s h o ul d be a dj uste d. 
 
Patie nts will recei ve a t ot al of 8 d oses of cet u xi ma b o ver 8 wee ks, i ncl u di n g t he i nitial 
l oa di n g d ose a n d 7 d oses c o nc urre nt wit h ra diati o n t hera p y. 

R T O G 3 5 0 4 
3 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
If a d ose of cet u xi ma b is o mitte d, it will n ot be ma de u p or a d de d t o t he e n d of treat me nt. 
T he o mitte d d ose a n d t he reas o n f or t he o missi o n s h o ul d be rec or de d i n t he site’s s o urce 
d oc u me ntati o n. 
 
Cet u xi m a b S u p p orti ve C are G ui deli nes 
N ote t he blac k b o x war ni n g f or car di o p ul m o nar y arrest i n patie nts recei vi n g ra diati o n 
t hera p y i n c o m bi nati o n wit h cet u xi ma b. C A U TI O N: I nf usi o n re acti o ns m a y o cc ur 
d uri n g or f oll o wi n g cet u xi m a b a d mi nistr ati o n.  M ost i nf usi o n re acti o ns occ ur wit h 
t he first i nf usi o n of cet u xi m a b, b ut s o me p atie nts’ first i nf usi o n re acti o ns h a ve bee n 
re p orte d f oll o wi n g s u bse q ue nt d oses. T he i nf usi o n re acti o n m a y occ ur d uri n g t he 
i nf usi o n or be del a ye d u ntil a n y ti me after t he i nf usi o n.  
Patie nts s hall recei ve pri or t o t he first d ose of cet u xi ma b:  5 0 m g of di p he n h y dra mi ne, P O 
or I V. 
 
Pri or t o all d oses of s u bse q ue nt cet u xi ma b, pate nts s hall recei ve:  2 5- 5 0 m g of 
di p he n h y dra mi ne P O or I V per p h ysicia n discreti o n. 
 
T he use of ster oi ds s h o ul d be mi ni mize d w here p ossi ble.  Pre me dicati o ns are 
rec o m me n de d pri or t o s u bse q ue nt d oses, b ut at t he I n vesti gat or’s discreti o n, t he d ose of 
di p he n h y dra mi ne ma y be re d uce d. 
 
It is rec o m me n de d t hat t h e me dical staff cl osel y o bser ve patie nts f or treat me nt-relate d 
a d verse e ve nts, es p eciall y i nf usi o n r eacti o ns (see Secti o n 6  f or ma na ge me nt) d uri n g t he 
cet u xi ma b i nf usi o n per l ocal i nstit uti o nal sta n dar ds. I n t he e ve nt t hat a patie nt 
e x perie nces a n i nf usi o n r eacti o n, see Secti o n 6  f or pr o per ma n a ge me nt. 
 
F or s u bse q u e nt i nf usi o ns, it is rec o m me n de d t hat t he patie nt be o bser ve d f or 1 h o ur p ost-
i nf usi o n. 
  
 
D ose m o dificati o ns (see Secti o n 6 ) will be ma de base d u p o n s pecific criteria defi ne d b y 
t he t y pe, gra de a n d ti me t o res ol uti o n of t o xicit y. 
 
Weekl y Cis pl ati n D ose A d mi nistr ati o n ( Ar m 1) 
Patie nts o n t he wee kl y cis plati n ar ms will recei ve cis plati n 4 0 m g/ m 2/ wee k ( usi n g act ual 
b o d y w ei g ht f or all B S A calc ulati o ns) i ntra v e n o usl y (i v) o n a wee kl y b asis o nce a wee k o n 
M o n da y or T ues da y f or a t otal of 7 d oses c o nc urre nt wit h ra diati o n t hera p y.  
 
D ose m o dificati o ns will be ma de bas e d u p o n s pecific criteria d efi ne d b y t h e t y p e, gra d e 
a n d ti me t o res ol uti o n of t o xicit y. N o  s u bstit uti o n of c ar b o pl ati n f or cis pl ati n will be 
p er mitte d . See S ecti o n 6  f or d ose m o dificati o ns. 
 
Cis pl ati n S u p p orti ve C are G ui deli nes 
Hi g h d ose cis plati n is hi g hl y e met o ge nic. 
W hile t his pr ot oc ol is usi n g m ore fre q u e nt 
d osi n g of cis plati n t hat is c o nsi dere d m o deratel y e met o ge nic, i n vesti gat ors s h o ul d be 
pre pare d t o us e a g gressi ve pr o p h ylactic a ntie metics a n d h y drati o n. Ma n y i nstit uti o ns will 

R T O G 3 5 0 4 
3 3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
ha ve sta n d ar d g ui deli nes f or t he a d mi nistrati o n of cis plati n at t he d oses us e d i n t his st u d y. 
F or p ur p oses of t his pr ot oc ol, i n di vi d u al i n vesti g at ors m a y use t hese l oc al g ui deli nes 
f or cis pl ati n a d mi nistr ati o n. 
O ne p ossi ble a p pr o ac h is o utli ne d bel o w. T h ese 
g ui deli nes ma y nee d t o be m o difie d base d o n l ocal g ui deli nes a n d patie nt relate d fact ors 
(e. g. t he s u bstit uti o n of n or mal sali ne i n dia betic patie nts). Si milarl y, t he a nti-e metic 
re gi me n is t o be deter mi ne d b y t he l ocal i n vesti gat or, alt h o u g h o ne p ossi bl e a p pr oac h is 
o utli ne d bel o w. 
 
L o w- d ose Cis pl ati n a nti-e metic a d mi nistr ati o n g ui deli nes :  5- H T 3 a nta g o nists a n d 
deca dr o n s h o ul d be gi ve n ( pal o n osetr o n 0. 2 5 m g I V a n d deca dr o n 1 2 m g pri or t o 
cis plati n is preferre d). T he use of ster oi ds s h o ul d be mi ni mize d were p ossi ble. 
T he ref ore, f or pre v e nti o n of dela ye d n a usea a n d v o miti n g, use of 5- H T 3 a nta g o nist 
m o n ot hera p y or N K- 1 a nta g o nist is preferre d o v er ster oi d m o n ot hera p y. Us e of ot her 
a nti- na usea me ds s u c h as a pre pita nt, met ocl o pra mi de, or pr oc hl or perazi ne is left t o 
t he discreti o n of t he i n vesti gat or. 
 L o w- d ose Cis pl ati n pre- hy dr ati o n g ui deli nes : Pre- h y drati o n wit h 1 liter D 5 ½ N S a n d 
4 0 me q K C L/ liter x 1 liter pri or t o cis plati n s h o ul d be gi ve n. M a n nit ol 1 2. 5 g m I V 
i m me diatel y pri or t o cis plati n ma y b e gi ve n. Use of ma n nit ol is left t o t h e discreti o n 
of t he  i n vesti gat or. 
 L o w- d ose Cis pl ati n a d mi nistr ati o n : Sta n dar d a d mi nistrati o n is cis plati n, 4 0 m g/ m 2 
o ver 3 0- 6 0 mi n utes I V i n 2 5 0 cc N S.  I nf usi o n rate n ot t o e x cee d 2 m gs p er mi n. See 
Secti o n 6  f or d ose m o dificati o ns. See a b o ve disc ussi o n o n sc he d uli n g a n d n u m ber of 
d oses c o nc urre nt wit h ra diati o n. 
 L o w- d ose Cis pl ati n p ost- hy dr ati o n g ui deli nes : F oll o wi n g t he e n d of t he cis plati n 
a d mi nistrati o n, a n a d diti o nal liter of D 5 ½ N S wit h 1 0 me q K C L/ L, 8 me q M g S O 4/ L, 
a n d  2 5 g m a n nit ol s h o ul d be i nf use d o ver 2 h o urs. O n t he sec o n d a n d t hir d da y 
f oll o wi n g cis plati n, patie nt s h o ul d be e nc o ura ge d t o ta ke at least 2 liters of fl ui d per 
da y orall y.  Patie nts u na ble t o orall y s elf- h y drate s h o ul d be c o nsi dere d f or a d diti o nal 
I V h y drati o n o n t hese d a ys wit h N S. T he a m o u nt of pre- a n d p ost- h y drati o n is left t o 
t he discreti o n of t he i n vesti gat or.  
 
Hi g h - D ose Cis pl ati n ( Ar m 2) 
Patie nts will recei ve cis plati n, 1 0 0 m g/ m 2, a d mi nistere d i ntra ve n o usl y o n da ys 1, 2 2 a n d 
4 3 of t he treat me nt c o urs e ( N ote: cis plati n gi ve n wit hi n 2 4 h o urs of da ys 1, 2 2 a n d 4 3 d u e 
t o h oli da ys, f or e x a m ple, is acce pta bl e). Wee ke n ds c o u nt as da ys. 
 
Hi g h- D ose Cis pl ati n A nti- E m etic A d mi nistr ati o n G ui deli nes :  Hi g h- d ose cis plati n is a 
hi g hl y e met o ge nic re gi me n wit h si g nifica nt i nci de nce of dela ye d na us ea a n d v o miti n g. 
I nstit uti o nal or N C C N g ui deli nes f or hi g hl y e met o ge ni c re gi me ns s h o ul d be f oll o we d.  
 
Hi g h- D ose Cis pl ati n Pre- Hy dr ati o n G ui deli nes : A s u g geste d re gi me n is pre h y drati o n 
wit h a 1 liter of D 5 N S o ver 2- 4 h o urs a n d m a n nit ol, 1 2. 5 g i v b ol us i m me diatel y pri or t o 
cis plati n. T he n cis plati n, 1 0 0 m g/ m 2, i n 5 0 0- 1 0 0 0 ml N S is a d mi nistere d o ver 1- 2 h o urs 
f oll o we d b y a n a d diti o nal 1 t o 1. 5 liters of fl ui d. A n y pre-e xisti n g de h y drati o n m ust be 
c orrecte d pri or t o cis plati n a d mi nistrati o n. S h o ul d e xtra vasati o n occ ur, t he treati n g 
p h ysicia n s h o ul d f oll o w i nstit uti o nal g ui deli nes f or ma na ge me nt. 
 

R T O G 3 5 0 4 
3 4   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
O ver ni g ht h os pitaliz ati o n f or h y drati o n after cis plati n s h o ul d be c o nsi dere d if it is 
all o we d b y t he p atie nt's i ns ura nce c o m pa n y. A d diti o nal i v h y drati o n a n d B U N/creati ni ne 
c hec k als o s h o ul d be c o nsi dere d, if necessar y, later i n t he 
wee k after cis plati n 
a d mi nistrati o n, i n or der t o a d dress a n y d e h y drati o n or se vere fl ui d/electr ol yt e i m bala nce. 
 
5. 2  
R a di ati o n T her a p y  ( 2 6 Dec 2 0 1 7) 
P r ot oc ol t re at me nt (first d ose of ni v ol u m a b) m ust be gi n wit hi n 7 d a ys after Ste p 2 
re gistr ati o n.  
 
N ote: All p arti ci p ati n g i nstit uti o ns m ust be cre de nti ale d f or he a d a n d nec k I M R T 
a n d I G R T pri or t o re gisteri n g p atie nts t o t he st u d y. See S ecti o n 8. 2  f or det ails. 
 
I nte nsit y M o d ulate d Ra di ati o n T hera p y (I M R T) a n d I ma ge- G ui d e d Ra diati o n T hera p y 
(I G R T) are ma n d at or y f or t his st u d y. Pr ot o n t hera p y is n ot per mitte d. 
 
IM R T will be gi ve n i n 3 5 fracti o ns o ver 7 wee ks , 5 fracti o ns per wee k. Misse d treat me nts 
d ue t o h oli da ys or l o gistic al reas o ns ca n b e c o m pe nsate d b y deli veri n g a d diti o nal BI D 
fracti o ns, wit h a mi ni m u m i nter-fracti o n i nter val of 6 h o urs, or b y treati n g o n Sat ur da y or 
S u n da y. 
5. 2. 1  Treat me nt Tec h n ol o g y 
Me ga v olta ge e n er g y p h ot o n bea m irra di ati o n wit h a p h ot o n bea m of ≥ 4 M V is re q uire d. 
A n y tr eat me nt deli ver y m o dalit y t hat pre vi o usl y has bee n cre d e ntiale d f or hea d a n d n ec k 
IM R T f or pre vi o us R T O G trials is acce pt a ble. N ote : T o mot hera p y re q uires se parat e 
crede ntiali n g.  
 
I G R T I nstr ucti o ns 
B o ne y a n at o m y I G R T cre de ntiali n g is r e q uire d (see Secti o n 8. 2 ). Dail y i m a ge g ui da nce 
of I M R T ma y be ac hie ve d usi n g a n y o n e or m ore of t he f oll o wi n g  t ec h ni q ues: 
 Ort h o g o n al kil o v olta ge ( K V) i ma ges; 
 L i ne ar- accelerat or m o u nte d k V a n d M V c o ne bea m C T i ma ges; 
 L i ne ar- accelerat or m o u nte d M V C T i ma ges. 
 
T he i nstit uti o n’s pr oce d ure f or re gisteri n g dail y tr eat me nt i ma gi n g d atasets wit h a 
refere nce datas et s h o ul d c o m pl y wit h t he f oll o wi n g rec o m me n dati o ns: 
 R e gi o n-of -I nterest ( R OI) or “cli p b o x ” f or f usi o n s h o ul d be set t o e nc o m pass t he hi g h 
d ose P T V a n d a dja ce nt s pi nal c or d; if t he s u pracla vic ular re gi o n is a p art of t he tar get 
v ol u me t he R OI s h o ul d e xte n d t o t he C 6 le vel; 
  If t he f usi o n s oft ware all o ws t he user t o create a n irre g ular R OI, treat me nt r o o m 
o bjects see n o n i n-r o o m x-ra ys s h o ul d be e x cl u de d fr o m t he re gistrati o n; 
 B ot h ma n ual ( e. g. dra g-a n d- dr o p s yst e m base d o n b o n y a n at o m y m atc hi n g) a n d 
aut o matic (e. g. bas e d o n m ut ual i nf or mati o n) t y pes of re gistrati o n ca n b e use d; t he 
res ult of t he f usi o n m ust be vis uall y c h ec k e d f or t he ali g n m e nt of t he b o n y a nat o m y, 
s uc h as verte bral b o dies a n d a p plica ble s oft tiss ue str uct ures (e. g. o ptic ner ves a n d/ or 
o ptic c hias m). 
 F oll o wi n g t he re gistrati o n, t he tra nslati o nal a n d (if t he a p pr o pri ate tec h n ol o g y is 
a vaila ble) r otati o nal c orrecti o ns s h o ul d be a p plie d t o t he treat me nt c o uc h. If all t he 

R T O G 3 5 0 4 
3 5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
varia nces are < 2. 5 m m (t his t y picall y c orres p o n ds t o o ne half of t he us ual 
P R V mar gi n), t he tr eat me nt ca n pr ocee d wit h o ut c orrecti o n ( h o we ver, t he 
p h ysicia n/tea m ma y ele ct t o perf or m a dj ust me nts e ve n f or a v aria n ce < 2. 5 m m). If 
o ne  or m ore c orrecti o ns are 2. 5 t o 5 m m, a dj ust me nt is necessar y pri or t o treat me nt; 
h o we ver, rei ma gi n g is n ot ma n dat or y. If o ne or m ore of t he c orrecti o ns are > 5 m m, 
t he i ma gi n g m ust be re peate d i n a d diti o n t o perf or mi n g ta ble/ p ositi o ni n g a dj ust me nts. 
H o we ver, t he use of n u m er o us re p eat I G R T st u dies s h o ul d be a v oi de d; 
 Ima gi n g d os e t o t he patie nt ma y bec o me si g nifica nt if re peat e d st u dies are perf or me d 
f or patie nts wit h se vere s et u p pr o ble ms (e. g., re q uiri n g fre q ue nt c orrecti o ns of m ore 
t ha n 5 m m). It is r ec o m m e n de d t hat pati e nts de m o nstrati n g se v ere s et u p pr o ble ms 
d uri n g t he first 7 cale n d ar da ys of treat me nt be re-si m ulate d or m o ve d t o a treat me nt 
wit h lar ger mar gi ns. 
5. 2. 2  I m m o biliz ati o n a n d Si m ulati o n 
 
I m m o biliz ati o n 
T he use of a t h er m o plastic hea d a n d s h o ul der mas k is ma n dat or y f or hea d a n d nec k 
I M R T. Patie nts will be pla n ne d i n t he s u pi ne p ositi o n wit h t heir ar ms at t heir si des, 
e ns uri n g t h e s h o ul ders are sit uate d as far i nferi or as p ossi ble t o a v oi d e ntr y a n d e xit 
t hr o u g h t he s h o ul ders. 
 
Pl a n ni n g C T Sc a n 
T he treat me nt pla n ni n g C T sca n is ma n dat or y f or defi ni n g tar get v ol u mes a n d n or mal 
or ga n at ris k. T he pl a n ni n g C T sca n s h o ul d be d o ne wit h  c o ntrast ( u nless 
co ntrai n dicate d). C T sca n t hic k ness s h o ul d be a mi ni m u m of 0. 3 c m, a n d t he C T sca n 
s h o ul d be ac q uire d wit h t he patie nt i n t he sa me p ositi o n a n d usi n g t he sa me 
i m m o bilizati o n de vice as f or treat me nt. All tiss ues recei vi n g irra diati o n s h o ul d be 
i ncl u de d i n t he C T sca n li mits. T he sca n ni n g li mits s h o ul d at least e nc o m pass t he or bits 
s u peri orl y, a n d e xte n d at least 1 c m bel o w t he s u praster nal n otc h i nf eri orl y.  
5. 2. 3  I ma gi n g f or Str uct ure Defi niti o n, I ma ge Re gistrati o n/ F usi o n a n d F oll o w u p 
  
A dia g n ostic C T or M RI f or str uct ure d eli neati o n is rec o m me n de d.  T h ese ma y b e f use d       
            t o t he pla n ni n g C T sca ns t o facilitate tar get a n d str uct ure defi niti o n.  W he n a vaila ble  
            1 8-F- F D G P E T/ C T i ma ges m a y als o be f us e d t o t he pla n ni n g C T d ata set. 
5. 2. 4  
Defi niti o n of D ose Pres cri pti o ns, Tar get V ol u mes, a n d Mar gi ns 
Ge ner al 
T he pri mar y t u m or a n d i n v ol ve d n o des will be e n c o m passe d b y P T V _ 7 0 0 0 a n d will 
recei v e 2 G y per fracti o n x 3 5 fracti o ns, w hile s u bcli nical disease sites will be 
enc o m passe d b y P T V _ 5 6 0 0 w hic h will recei v e 1. 6 G y p er fracti o n x 3 5 fracti o ns.  
Tr eat me nt of b ot h v ol u m es will occ ur at t he s a me ti me usi n g a si m ulta ne o us i nte grate d 
b o ost ( SI B) te c h ni q ue deli vere d at 5 fracti o ns per wee k o ver 7 wee ks. F or re gi o ns 
co nsi dere d t o be at hi g h ris k f or micr osc o pic disease, P T V _ 6 1 2 5 ma y b e treate d t o a d ose  
of 6 1. 2 5 G y at 1. 7 5 G y p er fracti o n x 3 5 fracti o ns. T he treat me nt pla n us e d f or eac h 
pa tie nt will be base d o n a n a nal ysis of t he v ol u metric d ose, i ncl u di n g d ose- v ol u me 
hist o gra m ( D V H) a nal ys es of t he P T Vs a n d critical n or mal str uct ures. I n verse pla n ni n g 
wit h c o m p uteriz e d o pti miz ati o n s h o ul d be use d. 
 
Gr oss T u m or V ol u me ( G T V) re pres e nts t he re gi o n j u d ge d t o c o nt ai n gr oss pri mar y t u m or 
or i n v ol ve d n o de(s) b ase d o n cli nical a n d e n d osc o pic e x a mi nati o ns, C T sca n, a n d, w he n 

R T O G 3 5 0 4 
3 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
a p plica ble, ot her i ma gi n g tec h ni q ues. Gr ossl y p ositi ve l y m p h n o des are defi ne d as a n y 
l y m p h n o des > 1 c m or n o des wit h a necr otic ce nt er. 
 
Cli nic al T ar get V ol u me ( C T V)  is defi ne d as t he G T V pl us areas c o nsi dere d at ris k f or 
c o ntai ni n g micr os c o pic disease deli neate d b y t he treati n g p h ysicia n. C T V _ 7 0 0 0 
re pres e nts G T V pl us a m ar gi n of ge n erall y 5- 1 0 m m, a n d C T V _ 5 6 0 0 re pres e nts 
C T V _ 7 0 0 0 wit h a mar gi n of 1 0 m m, pl us n o dal re gi o ns t o recei v e electi ve irra diati o n. 
W he n t he t u m or is i nfiltrati ve (e n d o p h ytic) or w h e n t he b or der is ill defi ne d, it mi g ht be 
de sira ble t o deli ver a n i nter me diate d os e  t o a v ol u me ( C T V _ 6 1 2 5) t hat is sli g htl y l ar ger 
t ha n C T V _ 7 0 0 0. T he C T V mar gi ns ca n b e narr o wer w he n G T V is i n t he pr o xi mit y of t h e 
s pi nal c or d or critical n or mal tiss ues. C T V s h o ul d be cr o p pe d t o e x cl u de a n at o mical 
barriers t o t u m or s prea d s uc h as air ca vities, u ni n v ol ve d b o ne, a n d e xter nal b o d y 
c o nt o urs. 
 
G ui deli nes f or C T base d deli neati o n of l y m p h n o d e le vels f or n o d e ne gati v e patie nts ca n 
be f o u n d at t he R T O G w e b site: 
htt ps:// w w w.rt o g. or g/ C ore La b/ C o nt o uri n g Atlas es/ H N Atlases.as p x. F or pati e nts wit h 
p ositi ve nec k n o des, c o ns ult Gre g oire et al. ( 2 0 0 6) f or t he deli neati o n of t he n o dal C T V. 
 
Pl a n ni n g T ar get V ol u me ( P T V)  re prese nts a n a d diti o nal mar gi n ar o u n d C T V t o 
c o m pe nsate f or t he varia bilit y of treat me nt set- u p a n d i nter nal or ga n m oti o n. A mi ni m u m 
mar gi n of 3 m m ar o u n d t he C T V is re q uire d i n all directi o ns t o defi ne eac h res pecti ve 
P T V, e x ce pt f or sit uati o ns i n w hic h t he C T V is a djace nt t o s pi nal c or d or ot her critic al 
n or ma l tiss ues. I n s u c h sit uati o ns, t he mar gi n ca n be re d uce d j u dici o usl y at t he discreti o n 
of t he treati n g p h ysicia n.  
 
W he n e x pa nsi o n of a C T V res ults i n a P T V t hat e xte n ds be y o n d t he patie nt’s b o d y 
s urface, t he P T V s h o ul d be c o nstrai ne d t o at least 3 m m fr o m wit hi n t he e xter nal c o nt o ur, 
w hile sti ll i ncl u di n g t he C T V. T he use of tiss ue e q ui vale nt b ol us material is i n dicate d i n 
sit uati o ns w here t he disease is at or j ust u n der t he s ki n s urface. T he P T V s h o ul d ali g n 
wit h t he s ki n s urface w he n b ol us is use d.  Ot her v ol u mes s uc h as t u ni n g or a v oi da nce or 
o pti mizati o n str uct ures,  ca n be e m pl o ye d t o dri ve t he I M R T treat me nt pla n ni n g pr ocess.  
S uc h v ol u mes s h o ul d be c o nsi dere d t o be tr eat me nt- pla n ni n g t o ols t hat are n ot re p orte d 
or se nt f or w ar d f or re vie w.   
 
T he f oll o wi n g P T V v ol u mes m ust be se nt f or re vi e w.  W he n disease wit h a p pr o priate 
mar gi n e xte n ds t o t he s ki n s urface a n d b ol us is use d or w he n t h e disease wit h mar gi n is 
m ore t ha n 8 m m fr o m t he s ki n s urface, t he P T V v ol u me (i de ntifie d as P T V _ 7 0 0 0 i n t he 
ta ble bel o w) m ust be se nt f or re vie w.  F or sit uati o ns w here t he dis ease pl us mar gi n falls 
bet wee n 8 m m fr o m t he s ki n s urface a n d t he b o d y s urface, a s pecial v ol u me (i de ntifie d as  
P T V _ 7 0 0 0- 0 8 i n t he ta ble bel o w) m ust be se nt i n a d diti o n t o t he P T V v ol u me i n dicate d 
ab o ve. 
 
T he de nsit y c orrecte d d ose distri b uti o ns s hall be calc ulate d, a n d t he d ose prescri pti o n is 
t o be base d o n a d os e distri b uti o n c orrect e d f or h eter o ge neities. 
5. 2. 5  
Defi niti o n of Critical Str uct ures a n d M ar gi ns 

R T O G 3 5 0 4 
3 7   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
All s u b mitte d tre at me nt pl a ns m ust strictl y a d here t o t he str uct ure n a mes liste d 
bel o w : 
 
St a n d ar d N a me  
Descri pti o n  
V ali d ati o n  
Re q uire d/ Re q uire d w he n 
o pti o n al/ O pti o n al  
G T V  
Pri mar y t u m or a n d i n v ol ve d n o des  
 
Re q uire d  
C T V _ 7 0 0 0  
G T V + 5 -1 0 m m  mar gi n , e xcl u di n g 
a nat o mic b o u n daries t o t u m or s prea d  
Re q uire d  
P T V _ 7 0 0 0  
 
C T V -t o-P T V 5 m m mar gi n t hat ca n be 
re d uce d t o 3 m m i n s o me sit uati o ns 
Re q uire d  
C T V _ 5 6 0 0  
C T V _ 7 0 0 0 + 1c m mar gi n  (e xcl u di n g 
a nat o mic b o u n daries  
t o t u m or s prea d), pl us electi ve n o dal  
re gi o ns 
Re q uire d  
P T V _ 5 6 0 0  
 
C T V -t o-P T V 5 m m mar gi n t hat ca n be 
re d uce d t o 3 m m i n s o me sit uati o ns 
Re q uire d  
C T V _ 6 1 2 5  
C T V _ 7 0 0 0 pl us re gi o ns at hi g h -ris k f or 
s u bcli nical disease 
Re q uire d w he n a p plic a ble  
P T V _ 6 1 2 5  
 
C T V -t o-P T V 5 m m mar gi n t hat ca n be 
re d uce d t o 3 m m i n s o me sit uati o ns 
Re q uire d w he n a p plic a ble  
S pi nal C or d  
S pi nal C or d  
 
Re q uire d  
S pi nal C or d _ 0 5  
Pla n ni n g Ris k V ol u me of 5 m m  mar gi n 
ar o u n d S pi nal C or d 
Re q uire d  
Brai n Ste m  
 
Brai n Ste m  
Re q uire d  
Brai n Ste m _ 0 5  
 
Pla n ni n g Ris k V ol u me of 5 m m  mar gi n 
ar o u n d Brai n Ste m  
Re q uire d  
Par oti d _ L  
 
Left Par oti d  
Re q uire d  
Par oti d _ R  
 
Ri g ht Par oti d  
Re q uire d  
Oral Ca vit y  
 
Oral Ca vit y  
Re q uire d  
Li ps  
 
Li ps  
Re q uire d  
Ma n di ble  
 
Ma n di ble  
Re q uire d  
P har y n x  
 
U ni n v ol ve d p osteri or p har y n geal  wall 
pl us  a djace nt c o nstrict or m uscles  
 
Re q uire d  
Es o p ha g us _ U p  
 
U p per Cer vical Es o p ha g us  
Re q uire d  
Lar y n x G S L  
 
Gl ottic/ S u pra gl ottic ( G S L)  
Re q uire d  
S u b ma n di b ula _ R  
Ri g ht S u b ma n di b ular Gla n d  
 
Re q uire d  
S u b ma n di b ula _ L  
Left S u b ma n di b ular Gla n d   
Re q uire d  

R T O G 3 5 0 4 
3 8   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
E xter nal  
E xter nal b or der of patie nt use d t o 
defi ne  
U ns pecifie d Tiss ue  
 
Re q uire d  
 
P T V _ 7 0 0 0 -0 8  
P T V _ 7 0 0 0 , n ot i ncl u di n g p orti o n of  
P T V near ( < 8 m m s ki n)  
 
Re q uire d  w he n a p plic a ble  
N o n P T V  
E xter nal mi n us P T Vs  
                                               
Re q uire d  
 
Defi niti o ns of N or m al Tiss ues/ Or g a ns at Risk ( O A Rs) 
S pi nal C or d: T he s pi nal c or d be gi ns at t he cra nial-cer vical j u ncti o n (i.e. t he t o p of t he C 1 
verte bral b o d y). S u peri or t o t his is brai nste m a n d i nferi or t o t his is c or d. T h e i nferi or 
b or der of t he s pi n al c or d is at a p pr o xi matel y T 3- 4 (i.e., j ust bel o w t he l o west slice le vel 
t hat has P T V o n it). T he s pi nal c or d s hall be defi ne d base d o n t he treat me nt pla n ni n g C T 
sca n. I n a d diti o n, h o we v er, a Pla n ni n g Ris k V ol u me ( P R V) s pi nal c or d s h all be defi ne d. 
T he P R V c or d = s pi nal c or d + 5 m m i n eac h di me nsi o n. T his is irres pecti ve of t he use of 
I G R T f or mar gi n re d ucti o n. 
 
Brai nste m: T he i nf eri or m ost p orti o n of t he brai nste m is at t he cra nial-cer vical j u ncti o n 
w here it meets t he s pi nal c or d. F or t he p ur p oses of t his st u d y, t he s u p eri or m ost p orti o n of 
t he brai nste m is a p pr o xi matel y at t he le vel of t he t o p of t he p osteri or cli n oi d pr ocess. T he 
brai nste m s hall be defi n e d base d o n t he treat me nt pla n ni n g C T sca n. I n a d diti o n, 
h o we ver, a Pla n ni n g Ris k V ol u me ( P R V) brai nst e m s hall be defi ne d. T h e P R V brai nste m 
=  brai nste m + 5 m m i n eac h di me nsi o n. T his is irres pecti ve of t h e use I G R T f or mar gi n 
re d ucti o n. 
 
Li ps a n d Oral Ca vit y: T h ese s h o ul d be c o nt o ur e d as 2 se parate str uct ur es as t he g oal is t o 
kee p t he li p d ose m uc h l o wer t ha n t he oral ca vit y d ose. T he defi niti o n of li ps is self-
e x pla nat or y. T h e oral c a vit y will be defi ne d as a c o m p osite str uct ure c o nsisti n g of t he 
a nteri or o ne h alf t o t w o t hir ds of t he oral t o n g ue/fl o or of m o ut h, b uccal m u c osa, a n d 
palate. 
 
Par oti d Gla n ds: Par oti d gla n ds are d efi ne d bas e d o n t he treat me nt pla n ni n g C T sca n. 
 
P har y n x: T his is defi ne d as t he “ u ni n v ol ve d” p ost eri or p har y n geal w all pl us a djace nt 
c o nstrict or m uscles. T his e xte n ds fr o m t he s u peri or c o nstrict or re gi o n (t he i nferi or 
pter y g oi d plat es le vel) t o t he cric o p har y n geal i nlet ( p osteri or cri c oi d cartila ge le vel). 
 
Cer vical Es o p ha g us ( Es o p ha g us _ U p): T his is defi ne d as a t u b ular str uct ure t hat st arts at 
t he b ott o m of p har y n x a n d e xte n ds t o t he t h oracic i nlet. 
 
Gl ottic/ S u pra gl ottic Lar y n x ( Lar y n x G S L): T h e G S L be gi ns j ust i nferi or t o t he h y oi d 
b o ne a n d e xte n ds t o t he cric oi d cartila ge i nferi orl y a n d e xte n ds fr o m t he a nt eri or 
c o m miss ure t o i ncl u de t he ar yte n oi ds. T his i ncl u d es t he i nfra h y oi d b ut n ot s u pra h y oi d 
e pi gl ottis. 

R T O G 3 5 0 4 
3 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
Ma n di ble: T he ma n di ble i ncl u des t he e ntire b o n y str uct ure fr o m T MJ t hr o u g h t he 
s y m p h ysis. 
 
U ns pecifie d Tiss ue o utsi de of t he Tar gets: T his tiss ue is l ocate d bet wee n t he s k ull base 
a n d t h oracic i nlet t hat is n ot i ncl u de d i n eit her t he tar get v ol u mes or t he n or mal tiss ues 
descri be d a b o ve. 
5. 2. 6  
D ose t o N or mal Str uct ur es  
S pi nal C or d: T he c or d s h o ul d n ot e xcee d 4 8 G y t o a n y v ol u me i n e x cess of 0. 0 3 cc 
(a p pr o xi matel y 3 m m x 3 m m x 3 m m). T he P R V s pi nal c or d s h o ul d n ot e xcee d 5 0 G y t o 
an y v ol u me i n e x cess of 0. 0 3 cc. I n tr eat me nt pla n ni n g, t he s pi nal c or d P R V s h o ul d be 
gi ve n t he hi g h est pri orit y.  
 
Brai nste m: T he P R V brai nste m s h o ul d n ot e x cee d 5 4 G y t o a n y v ol u me i n e x cess of 0. 0 3 
cc (a p pr o xi matel y 3 m m x 3 m m x 3 m m). I n treat me nt pla n ni n g, t he P R V brai nste m 
s h o ul d be gi ve n less pri orit y t ha n t he P R V s pi nal c or d b ut m ore pri orit y t h a n t he ot her 
critical str uct ures liste d b el o w.  
 
Li ps: Re d uce t h e d ose as m uc h as p ossi ble. T he m ea n d ose i deall y s h o ul d b e < 2 0 G y. 
 
Oral Ca vit y: Re d u ce t he d ose as m uc h as p ossi ble. T he mea n d ose i d eall y s h o ul d be < 3 0 
G y f or t he n o n -i n v ol ve d oral ca vit y. Eff orts s h o ul d als o be ma de t o a v oi d h ot s p ots ( > 6 0 
G y) wit hi n t he n o n-i n v ol ve d oral ca vit y.  
 
Par oti d Gla n ds: I n m ost c ases, it will be easier t o s pare o ne p ar oti d t ha n t he ot her. T he 
treat me nt pla n ni n g g oal will be f or t his i n di vi d ual par oti d gla n d t o recei ve a mea n d ose of 
< 2 6 G y. 
 
C o ntralateral s u b ma n di b ular gl a n d: If c o ntralateral le vel I is n ot a t ar get, ai m t o re d uce 
mea n c o ntral ateral s u b m a n di b ular gla n d t o < 3 9 G y. 
 
P har y n x: Re d uce t he d os e as m uc h as p ossi ble. S o me rec o m me n d e d ( b ut n ot ma n dat or y) 
treat me nt g oals i ncl u de: 1) N o m ore t ha n 3 3 % of t he p har y n x e x cee ds 5 0 G y; 2) M ea n 
d ose < 4 5 G y; 3) N o m or e t ha n 1 5 % of t he p h ar y n x e x cee ds 6 0 G y. 
 
Cer vical Es o p ha g us ( Es o p ha g us _ U p): Re d uce t he d ose as m uc h as p ossi ble. Atte m pt t o 
mai ntai n mea n d ose < 3 0 G y a n d ma x d ose ( defi n e d f or a v ol u me of 0. 0 3cc )  < 6 0 G y. 
 
Gl ottic a n d S u pra gl ottic l ar y n x ( Lar y n x G S L): Re d uce t he d ose as m uc h as p ossi ble. 
Atte m pt t o mai ntai n mea n d ose < 2 0 G y. If w h ole- nec k I M R T is use d, u n d er- d osa ge of 
P T V a djace nt t o t he gl ottic lar y n x will be li mite d t o < 1 0 % recei vi n g 9 5 % of t he 
prescri be d d os e. 
 
Ma n di ble: Re d uce t he d ose as m uc h as p ossi ble. H ot s p ots wit hi n t he ma n di ble s h o ul d be 
a v oi de d. It is rec o m me n d e d t hat ma xi m u m d ose wit hi n t he ma n di ble be < 7 0 G y 
 

R T O G 3 5 0 4 
4 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
U ns pecifie d Tiss ue o utsi de of t he Tar gets: N o m ore t ha n 1cc of u ns pecifie d tiss ue o utsi de 
t he tar gets c a n recei ve 7 4 G y or m ore. 
5. 2. 7  
C o m plia nce Criteria 
Treat me nt br ea ks m ust be clearl y i n dicate d i n t he treat me nt rec or d al o n g wit h t he 
reas o n(s) f or t he tr eat me nt brea k(s). Treat me nt br ea ks, if necessar y, i deall y s h o ul d n ot 
e x cee d 5 da ys at a ti me a n d 1 0 da ys t otal. Treat me nt brea ks s h o ul d be all o we d o nl y f or 
res ol uti o n of se vere ac ut e t o xicit y a n d/ or f or i nterc urre nt ill ness a n d n ot f or s ocial or 
l o gistical reas o ns. 
 
Na me of Str uct ure  
Per Pr ot oc ol  
Variati o n Acce pta ble  
De viati o n 
U nacce pta ble  
T otal R T d ose t o  P T V _ 7 0 0 0   
(t o 9 5 % of t he P T V) 
7 0 G y  
6 9. 3 t o 7 0. 7 
e xcl u di n g 7 0 G y 
>  7 0. 7  
Mi ni m u m d ose (“c ol d s p ot” 
wit hi n P T V _ 7 0 0 0 -0 8 , n ot 
i ncl u di n g p orti o n of P T V near 
( < 8 m m s ki n) defi ne d f or a 
p oi nt t hat is 0. 0 3 cc i n size  
 
6 6. 5 G y (e q uals 
9 5 % of  
prescri be d d ose)  
< 6 6. 5 b ut > 6 3 G y  
 
< =  6 3 G y  
Ma xi m u m d ose (“ h ot s p ot” > 
1cc) wit hi n  P T V _ 7 0 0 0  
< =  7 7 G y  
> 7 7 b ut < =  8 2 G y  
> 8 2 G y  
Ma xi m u m d ose t o N o n P T V 
(“ h ot s p ot” > 1cc o utsi de t he 
P T Vs)  
< 7 4 G y  
7 4 -7 7 G y  
> 7 7 G y  
T otal d ose t o  P T V _ 6 1 2 5   (t o 
9 5 % of t he P T V -I N T) 
6 1. 2 5 G y  
> =  5 9. 5 b ut < =  6 3 G y  
< 5 9. 5 or >  6 3 G y  
T otal d ose t o  P T V _ 5 6 0 0   (t o 
9 5 % of t he P T V)  
5 6 G y  
< 5 6 G y b ut > 5 0. 4 
G y  
< =  5 0. 4 G y  
T otal R T d ose t o S pi nal C or d 
_ 0 5  ( 0. 0 3 cc) 
< =  5 0 G y  
> =  5 0 b ut < =  5 2 G y  
> 5 2 G y  
T otal R T d ose t o 
Brai n Ste m _ 0 5( 0. 0 3cc)  
< =  5 4 G y  
    >  5 4 G y b ut < =  
5 6 G y  
> 5 6 G y  
 
 
 
 
O verall R T treat me nt ti me  
 
< 5 0  
da ys  
5 0 -5 4  da ys ( wit h o ut a 
me dicall y a p pr o priate 
i n dicati o n f or dela y) 
> 5 4  da ys ( wit h o ut a 
me dicall y a p pr o priate 
i n dicati o n f or dela y) 
N o n -Me dicall y I n dicate d 
Treat me nt I nterr u pti o ns  ( Da ys) 
0 -2  
2 -4  
> 4  
 
Rec o m me n de d d ose acce pta nce criteria f or ot her n or mal tiss ue b ut n ot t o be use d f or pla n sc ore 
 
Str uct ure  
 
Rec o m me n de d d ose acce pt a nce criteri a  
Par oti d  
D mea n < 2 6 G y ( f or at least o ne par oti d)  
Li ps  
D mea n < 2 0 G y  
Lar y n x G S L  
D mea n < 2 0 G y  
P har y n x  
D mea n < 4 5 G y  
S u b ma n di b ula _ R or  
D mea n < 3 9 G y  

R T O G 3 5 0 4 
4 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
S u b ma n di b ula _ L         (c o ntralateral)  
Oral Ca vit y ( n o n -i n v ol ve d oral ca vit y) 
D mea n < 3 0 G y  
Es o p ha g us _ U p  
D mea n < 3 0 G y  
Ma n di ble  
D ma x < 7 0 G y  
 
5. 2. 8  Treat me nt Pla n ni n g Pri orities a n d I nstr u cti o ns 
Pri oritiz ati o n of I M R T Pla n ni n g 
1.  S pi nal C or d 
2.  Brai nste m 
3.  P T V _ 7 0 0 0 
4.  P T V _ 6 1 2 5 (if a p plica ble) 
5.  P T V _ 5 6 0 0 
6.  a. P har y n x 
b. P ar oti d gla n d c o ntralat eral t o pri mar y t u m or site 
7.  a. Lar y n x G S L 
  
b. Es o p ha g us _ U p 
8.  a. Li ps 
  
b. Oral Ca vit y 
9.  a. Par oti d gla n d i psilateral t o pri mar y t u m or site 
  
b. Ma n di ble 
1 0. U ns pe cifie d tiss ue o utsi de t he tar gets 
 
Resi m ul ati o n 
I n cases of wei g ht l oss > 1 0 %, or si g nifi ca nt s hri n ka ge of l y m p ha de n o p at h y d uri n g 
t hera p y, it is rec o m me n d e d t hat t he i m m o bilizati o n mas k be a dj uste d or re ma de a n d a 
ne w pla n be p erf or me d t o assess t he d ose distri b uti o ns wit h t he c urre nt a nat o m y. W het her 
a ne w I M R T pla n will be ge n erat e d is at t he discreti o n of t he treati n g p h ysi cia n. If a ne w 
pla n is ma de, t he tar gets s h o ul d be t he sa me as t h ose use d f or t he i nitial pl a n. T he ne w 
C T c o nt o ur s h o ul d be use d f or I G R T i ma ge re gistrati o n wit h t he ne w pla n.  
5. 3  
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 .3 . 1 Per mitte d S u p p orti ve/ A ncillar y C are 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 ysici a 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. 
 
5 .3 . 2 Pr o hi bite d T hera pies  
T he use of a mif osti ne or palifer mi n as a ra di o pr ot ecta nt is n ot all o we d. T h e use of 
gra n ul oc yte c ol o n y sti m ulati n g fact or or er yt hr o p oieti n is n ot all o we d. Tra nsf usi o n is t o 
be perf or me d at t he discreti o n of t he treati n g p h ysicia n. A n y e x ce pti o ns m ust be 
a p pr o ve d b y t he C o- Pri n ci pal I n vesti gat or, Dr. Gillis o n. 
5 .3. 3  Partici pati o n i n Ot her Tri als  
Patie nts ma y n ot partici p ate i n ot her cli nical trials t hat are i nte n de d t o treat t he dia g n os e d 
hea d a n d n ec k ca ncer or i nte n de d t o re d uce t o xicit y of t hera p y. 
 
5. 5  
D ur ati o n of T her a p y 
In t he a bse n ce of treat me nt dela ys d u e t o a d verse e ve nt(s), tr eat me nt ma y c o nti n ue as 

R T O G 3 5 0 4 
4 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
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: 
 Dise ase pr o gressi o n; 
 Interc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt; 
 U na cce pta ble a d vers e e v e nt(s); 
 P atie 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; 
 Ge neral or s pecific c h a n ges i n t he p atie nt's c o n diti o n re n der t he p atie nt u nacce pta bl e 
f or f urt her treat me nt i n t he j u d g me nt of t h e i n vesti gat or; 
 Ne w data relate d t o t he e x peri me ntal a ge nt w hi c h w o ul d s u g gest t hat c o nti n ui n g 
treat me nt o n pr ot oc ol w o ul d i m p ose u n warra nte d p ote ntial ris ks be y o n d w hat was 
k n o w n at t he ti me of  treat me nt i nitiati o n. 
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 
Ni v ol u m a b, cet u xi ma b, a n d cis plati n s h o ul d be deli vere d o nl y if t here is n o i n dicati o n f or 
h ol di n g t he ra di ati o n a n d if all ot her he mat ol o gical a n d n o n- he mat ol o gical t o xicit y criteri a are 
met.  
 
Ra diati o n t hera p y ma y c o nti n ue at t h e discreti o n of t he treati n g p h ysicia n if ni v ol u ma b, 
cet u xi ma b, or cis plati n are hel d u nless s pecifi c crit eria t o h ol d ra di ot hera p y are met.  
 
T he  treati n g p h ysicia n m a y elect t o c o nti n ue cet u xi ma b or cis plati n i n t he e ve nt t hat 
ni v ol u ma b is dela ye d d u e t o t o xicities relate d t o ni v ol u ma b.  
 
H o w e ver, ni v ol u ma b t hera p y s h o ul d be dela ye d i n t he e ve nt cet u xi ma b or cis plati n t hera p y is 
hel d wit h t he s pecific e x ce pti o ns liste d bel o w i n Secti o n 6. 1. 2. 
6. 1  Ni v ol u m a b D ose M o dific ati o ns ( 2 6 Dec 2 0 1 7) 
6. 1. 1 Ma na ge me nt Al g orit h ms f or I m m u n o- O nc ol o g y A ge nts 
I m m u n o- o n c ol o g y (I- O) a ge nts are ass ociat e d wit h a d verse e ve nts t hat ca n differ i n 
se verit y a n d d urati o n fr o m a d verse e ve nts ca us e d b y ot her t h era p e utic class es. Ni v ol u ma b 
is c o nsi dere d t o be a n i m m u n o- o nc ol o g y a ge nt i n t his pr ot oc ol. Ma na ge me nt al g orit h ms 
ha ve bee n de vel o p e d t o assist i n vesti gat ors i n assessi n g a n d ma na gi n g t h e f oll o wi n g gr o u ps 
of a d vers e e ve nts: G astr oi ntesti nal, Re nal, P ul m o nar y, He p atic, E n d ocri n o p at hies, S ki n, 
a n d Ne ur ol o gic al; se e t he ni v ol u ma b I n vesti gat or Br oc h ure (I B) f or t h e t o xicit y 
ma na ge me nt al g orit h ms.  
 
Earl y rec o g niti o n a n d i nter ve nti o n are rec o m me n d e d acc or di n g t o t he ma na ge m e nt 
al g orit h ms. I n a d diti o n, t he ni v ol u ma b I n v esti gat or Br oc h ure (I B) i ncl u des o p ht hal m ol o gic 
eval uati o ns f or a n y vis u al s y m pt o ms i n or der t o e val uate f or ni v ol u ma b rel ate d u veitis. 
I n v esti gat ors s h o ul d be g ui de d b y t he al g orit h ms i n t he I B f or i m m u ne-relate d e ve nts. 
 
N ot e: T he al g orit h ms are  g ui des f or A E ma n a ge me nt, b ut t he g ui da nce pr o vi de d i n t hese 
al g orit h ms s h o ul d n ot re place t he i n vesti gat or’s me dical j u d g m e nt b ut s h o ul d c o m ple me nt 
it.  
 
F or patie nts e x pecte d t o re q uire m ore t h a n 4 wee ks of c ortic oster oi ds or ot h er 
i m m u n os u p pressa nts t o ma na ge a n a d verse e v e nt, c o nsi der t he f oll o wi n g 
rec o m me n dati o ns:  

R T O G 3 5 0 4 
4 3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
A nti micr o bial/a ntif u n gal pr o p h yla xis per i nstit uti o nal g ui deli nes t o pre ve nt 
o p p ort u nistic i nfecti o ns s uc h as P ne u m oc ystis jir o veci a n d f u n gal i nfecti o ns. 
 
Earl y c o ns ultati o n wit h a n i nfecti o us disease s peci alist s h o ul d be c o nsi dere d. 
De pe n di n g o n t he prese ntati o n, c o ns ultati o n wit h a p ul m o n ol o gist f or br o nc h osc o p y 
or a gastr oe nt er ol o gist f or e n d osc o p y ma y als o be a p pr o priate. 
 
I n p atie nts w h o de vel o p r ec urre nt a d verse e v e nts i n t he setti n g of o n g oi n g or pri or 
i m m u n os u p pressa nt use, a n o p p ort u nistic i nfecti o n s h o ul d be c o nsi dere d i n t he 
differe ntial dia g n osis. 
 
A d diti o nal details o n t he safet y of ni v ol u ma b, i ncl u di n g res ults fr o m cli nical st u dies, are 
a vaila ble i n t he I B. 
6 . 1. 2 D ose Dela y Criteria  
Ni v ol u ma b a d mi nistrati o n s h o ul d be dela ye d f or C T C A E, v. 4 t o xicities, as rec o m me n de d 
i n the treat me nt al g orit h ms l ocate d i n t he I B, t h at i n t he o pi ni o n of t he treati n g p h ysicia n 
are rel ate d t o t he st u d y dr u g . Ple ase n ote ni v ol u m a b t her a p y will n ot be del a ye d f or 
t he f oll o wi n g: 
 Gra de 2 wei g ht l oss; 
 Gr a de 2 or 3 na usea t hat i n t he o pi ni o n of t he i n vesti gat or is rel ate d t o cis plati n;  
 G ra de 3 ra diati o n der m atitis; 
 A n y Gra d e 2 - 3 m uc ositis, d ys p hasia, or p har y n g ol ar y n geal p ai n t hat i n t he o pi ni o n 
of t he treati n g p h ysicia n is relate d t o ra di ati o n t hera p y f or hea d a n d n ec k ca ncer; 
 Gr a de 2 h y p o k ale mia or h y p o ma g n ese mia t hat i n t he o pi ni o n of t he i n vesti gat or is 
relate d t o c et u xi ma b or cis plati n; 
 Gr a de 2 ras h t hat i n t he o pi ni o n of t he i n vesti gat or is relate d  t o cet u xi ma b; 
 Gr a de 2 or greater h eari n g i m pair me nt t hat i n t he o pi ni o n of t he treati n g p h ysicia n is 
relate d t o cis plati n; 
 Gr a de 3 or 4 is olate d l y m p h o pe nia ; 
 Gr a de 3 is olate d a ne mia if, i n t he o pi ni o n of t he treati n g p h ysici a n, t he a n e mia is n ot 
relate d t o t he st u d y dr u g (e. g. rel ate d t o c hr o nic disease, ir o n deficie nc y, 
radi ot hera p y). 
6. 1. 3 Criteria t o Res u me Treat me nt 
Patie nts ma y res u me treat me nt wit h ni v ol u ma b w he n t he dr u g-relate d A E(s) res ol ve t o t he 
gra de s pecifie d i n t he ma na ge me nt al g orit h ms i n t he I B.  
 
If t he criteria t o res u m e treat me nt are met, t he pati e nt s h o ul d restart treat me nt at t he ne xt 
sc he d ule d ti me p oi nt (t w o- wee k i nter val) per t he pr ot oc ol. 
6. 1. 4 Disc o nti n uati o n Criteria 
Treat me nt wit h ni v ol u ma b s h o ul d be per ma ne ntl y disc o nti n ue d as s pecifie d i n t he 
g ui deli nes f or ma na ge me nt i n t he I B. A d diti o nal criteria f or disc o nti n uati o n i ncl u de: 
 A n y Gra d e 2 dr u g-relate d u veitis or e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d t o 
t o pical t hera p y a n d d o es n ot i m pr o ve t o Gra de 1 s e verit y wit hi n t he re-treat me nt peri o d 
O R re q uires s yste mic treat me nt; 
 Gra de 3 dr u g-relate d u veitis, p ne u m o nitis, br o nc h os pas m, diarr hea, c olitis, ne ur ol o gi c 
a d verse e ve nt, h y perse nsiti vit y r eacti o n, or i nf usi o n reacti o n of a n y d urati o n re q uires 
disc o nti n uati o n; 
 Gra de 3 dr u g-relate d t hr o m b oc yt o pe ni a > 7 da ys or ass ociate d wit h bl ee di n g re q uires 

R T O G 3 5 0 4 
4 4   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
disc o nti n uati o n; 
 A n y Gra d e 4 dr u g-relate d a d verse e ve nt or la b orat or y a b n or malit y, wit h t he e x ce pti o n of 
t h ose n ote d bel o w: 
 Is olat e d Gra d e 4 a m ylas e or li pase a b n or malities t hat are n ot ass o ciate d wit h 
s y m pt o ms or cli nical ma nifestati o ns of pa ncreatitis a n d decrease t o < Gra d e 4 wit hi n 
1 wee k of o ns et; 
 Is olat e d Gra d e 4 ele ctr ol yt e i m bala nces/a b n or malities t hat are n ot ass ociat e d wit h 
cli nical se q uela e a n d are c orrecte d wit h s u p ple me ntati o n/a p pr o priate ma na ge m e nt 
wit hi n 7 2 h o urs of t heir o nset. 
 A n y gra de 3 or 4 dr u g-relate d la b orat or y a b n or malit y or electr ol yt e a b n or m alit y n ot 
ass ociate d wit h u n derl yi n g or ga n pat h ol o g y t hat d oes n ot re q uire tr eat me nt e x ce pt 
f or ele ctr ol yt e re pla ce me nt O R h or m o ne/ster oi d re place m e nt d oes n ot  re q uire 
treat me nt disc o nti n uati o n. 
 A n y a d vers e e ve nt, la b orat or y a b n or malit y, or i nterc urre nt ill ness w hic h, i n t he j u d g me nt 
of t he I n vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he patie nt wit h c o nti n ue d 
ni v ol u ma b d osi n g; 
 A dela y i n ni v ol u ma b treat me nt of > 6 wee ks.   
6. 1. 5 Treat me nt of Ni v ol u ma b - Relate d I nf usi o n Reacti o ns 
Si nce ni v ol u ma b c o ntai ns o nl y h u ma n i m m u n o gl o b uli n pr otei n se q ue nces, it is u nli kel y t o 
be i m m u n o ge nic a n d i n d uce i nf usi o n or h y perse nsiti vit y reacti o ns. H o we v er, if s uc h a 
reacti o n w ere t o o cc ur, it mi g ht ma nifest wit h fe v er, c hills, ri g ors, hea dac he, ras h, pr uritis, 
art hral gias, h y p o- or h y p erte nsi o n, br o nc h os p as m, or ot her s y m pt o ms.  
 
All Gra de 3 or 4 i nf usi o n reacti o ns s h o ul d be re p orte d as a n S A E if criteria are met. 
I nf usi o n reacti o ns s h o ul d be gra de d acc or di n g t o C T C A E, v. 4 g ui deli nes. 
 
Tr eat me nt r ec o m me n dati o ns are pr o vi d e d bel o w a n d ma y b e m o difie d base d o n l ocal 
treat me nt sta n dar ds a n d g ui deli nes as a p pr o pri ate: 
 
F or Gr a de 1 s y m pt o ms ( Mil d reacti o n; i nf usi o n i nterr u pti o n n ot i n dicate d; i nter ve nti o n 
n ot i n dicate d): Re mai n at be dsi de a n d m o nit or pati e nt u ntil rec o ver y fr o m s y m pt o ms. T he 
f oll o wi n g pr o p h yla ctic pre me dicati o ns are rec o m me n de d f or f ut ure i nf usi o ns: 
di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or aceta mi n o p he n 3 2 5 t o 1 0 0 0 m g at least 3 0 
mi n utes bef ore a d diti o nal ni v ol u ma b a d mi nistrati o ns. 
 
F or Gr a de 2 s y m pt o ms  ( M o derate reacti o n re q uires t hera p y or i nf usi o n i nterr u pti o n b ut 
res p o n ds pr o m ptl y t o s y m pt o matic treat me nt [ e. g. a nti hista mi nes, n o n-ster oi dal a nti- 
i nflam mat or y dr u gs, narc otics, c ortic oster oi ds, br o nc h o dilat ors, I V fl ui ds]; pr o p h ylactic 
me dicati o ns i n dicate d f or  2 4 h o urs): St o p t he ni v ol u ma b i nf usi o n, be gi n a n I V i nf usi o n of 
n or ma l sali ne, a n d treat t he patie nt wit h di p he n h y dra mi ne 5 0 m g I V ( or e q ui vale nt) a n d/ or 
aceta mi n o p he n 3 2 5 t o 1 0 0 0 m g; re mai n at be dsi de a n d m o nit or patie nt u ntil res ol uti o n of 
s y m pt o ms. C ortic oster oi d or br o nc h o dilat or t hera p y ma y als o be a d mi nistere d as 
a p pr o priate. If t he i nf usi o n is i nterr u pte d, t he n rest art t he i nf usi o n at 5 0 % of t he ori gi nal 
i nf usi o n rate w he n s y m pt o ms res ol ve; if n o f urt her c o m plicati o ns e ns ue aft er 3 0 mi n utes, 
t he rate ma y b e i ncrease d t o 1 0 0 % of t he ori gi nal i nf usi o n rate. M o nit or patie nt cl osel y. If 
s y m pt o ms rec ur t he n n o f urt her ni v ol u ma b will be a d mi nistere d at t hat visit. A d mi nister 

R T O G 3 5 0 4 
4 5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
di p he n h y dra mi ne 5 0 m g I V, a n d re mai n at be dsi d e a n d m o nit or t he patie nt u ntil res ol uti o n 
of s y m pt o ms. T he a m o u nt of st u d y dr u g i nf us e d m ust be rec or de d o n t he el ectr o nic case 
re p ort f or m (e C R F). T h e f oll o wi n g pr o p h ylactic pre me dicati o ns are rec o m me n de d f or 
f ut ure i nf usi o ns: di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or aceta mi n o p he n  3 2 5 t o 
1 0 0 0 m g  s h o ul d be a d mi nistere d at least 3 0 mi n utes bef ore a d diti o nal ni v ol u ma b 
a d mi nistrati o ns. If necess ar y, c ortic oster oi ds (rec o m me n de d d ose: u p t o 2 5 m g of I V 
h y dr oc ortis o ne or e q ui vale nt) ma y b e use d. 
 
F or Gr a de 3 or Gr a de 4 s y m pt o ms  ( Se vere reacti o n, Gra de 3: pr ol o n ge d [ie, n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic me dicati o n a n d/ or brief i nterr u pti o n of i nf usi o n]; rec urre n ce of 
s y m pt o ms f oll o wi n g i nitial i m pr o ve me nt; h os pitalizati o n i n dicate d f or ot her cli nical 
se q uelae [e g, re nal i m pair me nt, p ul m o nar y i nfiltrates]). Gra de 4: (life t hr eat e ni n g; pr ess or 
or ve ntilat or y s u p p ort i n dicate d): I m me diatel y disc o nti n ue i nf usi o n of ni v ol u ma b. Be gi n a n 
I V i nf usi o n of n or mal sali ne, a n d treat t he p atie nt as f oll o ws. Rec o m me n d br o nc h o dilat ors, 
e pi ne p hri ne 0. 2 t o 1 m g of a 1: 1, 0 0 0 s ol uti o n f or s u bc uta ne o us a d mi nistrati o n or 0. 1 t o 0. 2 5 
m g of a 1: 1 0, 0 0 0 s ol uti o n i njecte d sl o wl y f or I V a d mi nistrati o n, a n d/ or di p he n h y dra mi ne 
5 0 m g I V wit h met h yl pr e d nis ol o ne 1 0 0 m g I V ( or e q ui vale nt), as n ee de d. P atie nt s h o ul d be 
m o nit ore d u ntil t he i n vesti gat or is c o mf orta ble t hat t he s y m pt o ms will n ot rec ur. 
Ni v ol u m a b will be per ma ne ntl y disc o nti n ue d. I n v esti gat ors s h o ul d f oll o w t heir i nstit uti o nal 
g ui deli nes f or t he treat me nt of a na p h yla xis. Re mai n at be dsi de a n d m o nit or patie nt u ntil 
rec o ver y fr o m s y m pt o ms. I n t he cas e of late- occ urri n g h y perse nsiti vit y s y m pt o ms (e g, 
a p peara nce of a l o calize d or ge neralize d pr uritis wit hi n 1 wee k after treat m e nt), 
s y m pt o matic treat me nt ma y b e gi ve n (e g, oral a nti hista mi ne, or c ortic oster oi ds). 
6. 2  Cet u xi m a b D ose M o dific ati o ns 
N ote : If a d v erse e ve nts pre ve nt t he a d mi nistrati o n of c he m ot hera p y, t he patie nt ma y 
c o nti n ue t o recei ve ra di ati o n t hera p y. 
 
I n t he e ve nt of cet u xi ma b treat me nt dela y, t here will be n o rel oa di n g cet u xi ma b i nf usi o n. 
Res u me at t he a p pr o priat e d ose as i n dicat e d bel o w. 
 
6. 2 . 2  Cet u xi ma b D ose M o dificati o ns f or He mat ol o gic A d v erse E v e nts 
Cet u xi ma b will n ot be d ose re d uce d or hel d f or he mat ol o gic a d v erse e ve nts, s uc h as 
ne utr o pe nia, ne utr o pe nic fe ver, or t hr o m b oc yt o pe nia. 
6. 2 . 3  Cet u xi ma b D ose M o dificati o ns f or N o n- He mat ol o gic A d verse E ve nts 
See Secti o n 6. 2. 5 f or i nstr ucti o ns f or ras h. 
 
T o xicit y Gr a de  
(C T C A E, v. 4)  
Cet u xi m a b D ose  a 
Re n al -C alc ul ate d  
Cre ati ni ne Cle ar a nce  
 
≥ 5 0 m L/ mi n  
Mai ntai n d ose le vels   
< 5 0 m L/ mi n  
Mai ntai n d ose le vels  
F ati g ue ( Ast he ni a)  
≥ Gra de 3  
 
Mai ntai n d ose le vels   
N a use a/ V o miti n g  
≤ Gra de 2 wit h ma xi mal  
 
Mai ntai n d ose le vels  

R T O G 3 5 0 4 
4 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
me dical ma na ge m e nt  
≥ Gra de 3 wit h ma xi mal  
me dical ma na ge m e nt  
 
H ol d dr u g u ntil ≤ gra d e 2 , t he n res u me at 
sa me d ose le vel  
Ot her N o n -he m at ol o gic  
A d verse E ve nts  a , b   
 
Gra de 3 - 4, if p ossi bl y relate d t o 
cet u xi ma b, or li kel y t o be 
e x acer bate d b y c o nti n uati o n of 
cet u xi ma b, e. g. diarr hea, e x ce pt f or 
wei g ht l oss or m uc ositis  
H ol d dr u g u ntil < gra de 3, t he n res u me at 
sa me d ose le vel  
 
A n y gra de 1 -2  
 
Mai ntai n d ose le vels   
 
a. Wit h t he e x ce pti o n of i nf usi o n reacti o n;  
b.  F or de presse d K or M g, a d mi nister re place m e nt t hera p y. C he m ot hera p y s h o ul d 
c o nti n ue at t he discreti o n of t he treati n g p h ysicia n (see ta ble b el o w f or m a n a ge me nt 
of h y p o m a g nese mia). 
 
H y p o ma g n ese mia 
C T C A E, 
v. 4 
Gr a de  
Ser u m M a g nesi u m  
G ui deli nes f or 
m a n a ge me nt  
Acti o n  
m g/ d L  
m m ol/ L  
1  
< L L N –  1. 2  
< L L N –  
0. 5  
C o nsi der re place me nt wit h 
I V ma g nesi u m s ulfate 2-5 g 
i n n or mal sali ne or D 5 W. 
I nf usi o n sc he d ule base d o n 
i nstit uti o nal g ui deli nes.  
Mai ntai n d ose a n d 
sc he d ule 
2  
< 1. 2 –  0. 9  
< 0. 5 –  0. 4  
As a b o ve f or gra d e 1 a n d 
c o nsi der pr o p h ylactic 
wee kl y i nf usi o n of 
ma g n esi u m a n d/ or oral 
ma g n esi u m s u p ple me ntati o n  
(e. g. ma g nesi u m o xi de) if 
gra de 2 of hi g h er 
h y p o ma g n ese mia persists.  
N ote t hat ma g nesi u m o xi de 
is a n os m otic la x ati ve. 
C o nsi der use of c o m bi ne d 
ma g n esi u m o xi de pl us 
al u mi n u m o xi de 
pre parati o ns t o a v oi d 
i n d uci n g diarr hea wit h P O  
ma g n esi u m s u p ple me ntati o n  
Mai ntai n d ose a n d 
sc he d ule 

R T O G 3 5 0 4 
4 7   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
3  
< 0. 9 –  0. 7  
< 0. 4 –  0. 3  As a b o ve f or gra d es 1 a n d 2  
H ol d cet u xi ma b u ntil 
rec o ver y t o <  gra de 2, 
t he n res u me at sa m e 
d ose le vel  
4  
< 0. 7  
< 0. 3  
As a b o ve f or gra d es 1 a n d 2  
H ol d cet u xi ma b u ntil 
rec o ver y t o <  gra de 2, 
t he n res u me at sa m e 
d ose le vel  
 
6. 2 . 4  Cet u xi ma b I nf usi o n Reacti o n Ma na ge me nt 
 
C T C A E, v. 4  
A d verse E ve nt Gr a de  
Tre at me nt G ui deli nes a 
Gra de 1:   
Mil d tra nsie nt reacti o n;  
i nf usi o n i nterr u pti o n n ot 
i n dicate d; i nter ve nti o n n ot 
i n dicate d 
F or mil d i nf usi o n reacti o ns, sl o w t he i nf usi o n rate f or 
cet u xi ma b b y 5 0 % w he n t he dr u g is restarte d. F or 
reacti o ns ma nif esti n g o nl y as d ela ye d dr u g fe v er, c o nsi der 
a d mi nisteri n g pr o p h ylactic a nti hista mi ne me dicati o ns f or 
s u bse q ue nt d oses.  Mai nt ai n t he cetu xi ma b d ose.  
Aceta mi n o p he n or a n o n -ster oi dal a nti-i nfla m mat or y dr u g 
( N S AI D) ma y b e a d mi nistere d pri or t o s u bse q u e nt 
cet u xi ma b i nf usi o ns, if n ot ot her wise c o ntrai n dicate d i n 
patie nt s. 
Gra de 2:  
T hera p y or i nf usi o n 
i nterr u pti o n i n dicate d b ut 
res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt 
(e. g., a nti hista mi nes, 
N S AI D S, narc otics, I V 
fl ui ds); pr o p h yla ctic 
me dicati o ns i n dicate d f or ≤ 
2 4 hrs  
F or m o derate i nf usi o n reacti o ns, sl o w t he i nf usi o n rate f or 
cet u xi ma b b y 5 0 % w he n t he dr u g is restarte d a n d c o nsi der 
a d mi nisteri n g a nti hista mi ne me dicati o ns a n d/ or ster oi dal 
me dicati o ns.  
Mai ntai n  
t he  
cet u xi ma b  
d ose.  
Aceta mi n o p he n or a n o n -ster oi dal a nti-i nfla m mat or y dr u g 
( N S AI D) 
m a y be a d mi nistere d pri or t o s u bse q ue nt 
cet u xi ma b i nf usi o ns, if n ot ot her wise c o ntrai n dicate d i n 
patie nt s. 
Gra de 3:  
Pr ol o n ge d (e. g., n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief  
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms 
f oll o wi n g i nitial 
i m pr o ve me nt; 
h os pitaliz ati o n i n dicate d 
f or 
cli nical se q uela e  
N O F U R T H E R C E T U XI M A B . Se vere i nf usi o n reacti o ns 
re q uire i m me di ate i nterr u pti o n of cet u xi m a b i nf usi o n 
a n d per m a ne nt disc o nti n u ati o n fr o m f urt her tre at me nt 
wit h cet u xi m a b. A p pr o priate me dical t hera p y i ncl u di n g 
e pi ne p hri ne,  
c ortic oster oi ds,  
di p he n h y dra mi ne, 
br o nc h o dilat ors, a n d o x y ge n s h o ul d be a vaila ble f or use i n 
t he treat me nt of s u c h reacti o ns.  Patie nt s s h o ul d be 
caref ull y o bs er ve d u ntil t he c o m plete res ol uti o n of all si g ns 
a n d s y m pt o ms.  
 
 

R T O G 3 5 0 4 
4 8   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
Gra de 4:  
Lif e -t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d 
N O F U R T H E R C E T U XI M A B . Life t hreate ni n g i nf usi o n 
reacti o ns re q uire i m me di ate i nterr u pti o n of cet u xi m a b 
i nf usi o n a n d per m a ne nt disc o nti n u ati o n fr o m f urt her 
tre at me nt wit h cet u xi m a b.  A p pr o priate me dical t hera p y 
i ncl u di n g e pi ne p hri n e, c ortic oster oi ds, di p he n h y dra mi ne, 
br o nc h o d ilat ors, a n d o x y ge n s h o ul d be a vaila ble f or use i n 
t he treat me nt of s u c h reacti o ns.  Patie nt s s h o ul d be 
caref ull y o bs er ve d u ntil t he c o m plete res ol uti o n of all si g ns 
a n d s y m pt o ms.  
a. Cet u xi m a b Retre at me nt F oll o wi n g I nf usi o n Re acti o ns g ui d a nce : I nstit uti o n al 
g ui dlei nes f or cet u xi m a b i nf usi o n r ates  will a p pl y. I n ge ner al, it is rec o m me n de d 
t h at o nce a cet u xi m a b i nf usi o n r ate h as bee n decre ase d d ue t o a n i nf usi o n 
re acti o n, it will re m ai n decre ase d f or all s u bse q ue nt i nf usi o ns. If t he p atie nt h as a 
sec o n d i nf usi o n re acti o n > gr a de 2 wit h t he sl o wer i nf usi o n r ate, t he i nf usi o n 
s ho ul d be st o p pe d, a n d t he p atie nt s h o ul d recei ve n o f urt her cet u xi m a b tre at me nt. 
If a p atie nt e x perie nces a Gr a de 3 o r 4 i nf usi o n re acti o n at a n y ti me, t h e p atie nt 
s ho ul d recei ve n o f urt her cet u xi m a b tre at me nt. If t here is a n y q uesti o n as t o 
w het her a n o bser ve d re acti o n is a n i nf usi o n re acti o n of Gr a des 3 or 4, t he St u d y 
C h ai r or Me dic al O nc ol o g y C o- C h air s h o ul d be c o nt acte d i m me di atel y t o disc uss 
a n d gr a de t he re acti o n. 
6. 2 . 5  Cet u xi ma b S pecial I nstr u cti o ns 
Wee kl y cet u xi ma b will be hel d if ra di ati o n t hera p y is bei n g hel d. If cet u xi ma b is o mitte d 
f or m ore t ha n f o ur c o ns ec uti ve i nf usi o ns f or a d verse e ve nts d ue t o cet u xi ma b, or f or a n 
i nterc urre nt ill ness (e. g., i nfecti o n) re q uiri n g i nterr u pti o n of t hera p y, t he patie nt s h o ul d be 
disc o nti n ue d fr o m f urt her cet u xi ma b t hera p y. If a d verse e v e nts pre v e nt t he a d mi nistrati o n 
of c et u xi ma b, t he patie nt ma y c o nti n ue t o recei ve ni v ol u ma b a n d ra diati o n t hera p y.  
 
If a d ose of cet u xi ma b is hel d, it will n ot be ma de u p or a d de d t o t he e n d of treat me nt, 
u nle ss it is bei n g hel d be ca use ra diati o n treat me nt is bei n g hel d, a n d n ot b eca use of 
cet u xi ma b relate d A Es.  I n t hat case, cet u xi ma b will be a d mi nistere d f or u p t o a t otal of 8 
d oses (i ncl u di n g t he l o a di n g d ose pri or t o ra diati o n i nitiati o n). T he o mitte d d ose a n d t he 
reas o n f or t he o missi o n s h o ul d be rec or de d i n t he site’s s o urce d o c u me ntati o n. T here will 
be  N O rel oa di n g d ose if cet u xi ma b is hel d. 
 
Tre at me nt of Is ol ate d Dr u g Fever   
I n t he e ve nt of is olate d dr u g fe ver, t he i n vesti gat or m ust use cli nical j u d g m e nt t o 
deter mi ne if t he fe ver is relate d t o t he st u d y dr u g or t o a n i nfecti o us eti ol o g y. 
 
If a patie nt e x perie nces is olate d dr u g fe v er, f or t he ne xt d ose, pre-treat wit h 
aceta mi n o p he n or n o n-st er oi dal a nti-i nfla m mat or y a ge nt (i n vesti gat or discreti o n), re p ea t 
a nti p yretic d ose 6 a n d 1 2 h o urs after cet u xi ma b i nf usi o n.  T he i nf usi o n rate will re mai n 
u nc ha n ge d f or f ut ur e d os es. 
 
If a patie nt e x perie nces r ec urre nt is olate d dr u g fe ver f oll o wi n g pre- me dicati o n a n d p ost-
d osi n g wit h a n a p pr o priate a nti p yretic, t he i nf usi o n rate f or s u bs e q ue nt d osi n g s h o ul d be 
5 0 % of pre vi o us rate.  If fe ver rec urs f oll o wi n g i nf usi o n rate c h a n ge, t he i n vesti gat or 

R T O G 3 5 0 4 
4 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
s h o ul d assess t he patie nt’s le vel of disc o mf ort wit h t he e ve nt a n d use cli nical j u d g me nt t o 
deter mi ne if t he p atie nt s h o ul d recei ve f urt her cet u xi ma b. 
 
Cet uxi m a b-rel ate d R as h  
 
Ma nifestati o ns : Ras h ass ociate d wit h E G F R-i n hi bit ors is a relati vel y ne w 
der mat ol o gi c c o n diti o n. It a p pears t o be “ac neif or m” b ut it is N O T c o nsi dere d a f or m of 
ac ne; r at her, it is a f or m of f ollic ulitis. S ki n c ha n ges ma y b e ma nifeste d i n a n u m ber of 
wa ys: er yt he ma; f ollicle base d pa p ules, w hi c h ma y ulcerate; p ai n; itc hi n g; c os metic 
dist ur ba nce; a n d/ or n ail dis or ders. T he ras h ma y b ec o me i nfecte d a n d tr a nsf or m i nt o 
cell ulitis. 
 
Gr a di n g of Cet u xi ma b-i n d uce d Ras h : Acc or di n g t o p h ysicia n j u d g me nt, if a patie nt 
e x perie nces ≥ gra de 3 ras h (acc or di n g t o eit her t he “ o utsi de of t he ra di ati o n fiel d” or t he 
“i nsi de of t he ra di ati o n fiel d” defi niti o ns bel o w), cet u xi ma b treat me nt a dj ust me nts s h o ul d 
be ma de acc or di n g t o t he Cet u xi ma b D ose M o dificati o n ta ble t hat f oll o ws. I n p atie nts 
wit h mil d a n d m o derate s ki n a d verse e ve nts, cet u xi ma b s h o ul d c o nti n ue wit h o ut 
a dj ust me nt. 
 
N O T E : Ras h i nte nsit y (i. e., t he size a n d n u m ber of pa p ules or t he le v el of disc o mf ort a n d 
e xte nt of er yt h e ma) ma y be a n i m p orta nt c o nsi derati o n. H o we ver, t he a bs ol ute n u m ber of 
lesi o ns, wit h o ut ass oci ate d p h ysic al disc o mf ort , d oes n ot necess aril y c o nstit ute a basis 
f or a d ose re d ucti o n or d ela y. Ras h c o nsi dere d “i nt olera ble” ( beca use of pai n, itc hi n g, or 
a p peara nce) or t hat h as f aile d t o res p o n d t o s y m pt o matic ma na ge me nt ma y be c o nsi dere d 
gra de 3 a n d t h us pr o m pt d ose re d ucti o n or d ela y of cet u xi ma b. T he cli nic al j u d g me nt of 
t he tre ati n g p h ysici a n is critic al t o g r a di n g a n d will ulti m atel y dict ate d ose 
m o dific ati o n.  
 Ac ute S ki n C ha n ges:  
 Ras h Occ urri n g O utsi de of t he Ra diati o n Fiel d: S h o ul d be gra de d usi n g t h e f oll o wi n g 
C T C A E, v. 4 ter ms. A ras h c o m plicate d b y sec o n dar y i nfecti o n or cell ulitis s h o ul d be 
gra de d per a d diti o nal C T C A E ter ms (see ta bl e bel o w). 
 R as h Occ urri n g I nsi de t h e Ra diati o n Fiel d: Ac ute ra diati o n der matitis ma y be 
ex acer bate d b y cet u xi ma b or c he m ot hera p y. T he s e verit y of s uc h ras h s h o ul d be 
gra de d usi n g C T C A E,  v. 4 criteria f or ra di ati o n der matitis (see ta ble b el o w).  
 L at e S ki n C ha n ges: A p ote ntial late c ha n ge of i nterest is c o nse q ue ntial sc arri n g/ p oc k 
mar ki n g i n or o ut of t h e ra diati o n fiel d. T his ma y be re p ort e d b y usi n g t he Me d D R A 
c o de, “ S ki n a n d s u bc uta n e o us tiss ue dis or ders - Ot her, s pecif y”, wit h t he f oll o wi n g 
pr ot oc ol-s pecifi c gra di n g scale as g ui da nce: 
 Gr a de 1: Mil d (see n o nl y o n cl ose i ns pecti o n) 
 Gra de 2: M o derate (scarri n g, i nter ve nti o n or c os metic c o vera ge/i nter v e nti o n 
i n dicate d) 
 Gr a de 3: Se vere (si g nifica nt disfi g ure me nt, dee p s carri n g, or ul cerati o n) 
 Gra de 4: D ee p crateri n g/scarri n g, s ki n necr osis, or disa bli n g 

R T O G 3 5 0 4 
5 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R as h Occ urri n g O utsi de of t he R a di ati o n Fiel d  
 
1  
2  
3  
4  
Pr urit us *  
Mil d or 
l ocalize d 
I nte ns e or 
wi des prea d  
I nte ns e or 
wi des prea d a n d 
i nterferi n g wit h 
A D L  
- 
R as h/ ac neif or m *  Pa p ules a n d/ or 
p ust ules 
c o veri n g < 1 0 % 
B S A, w hic h 
ma y or m a y 
n ot be 
ass ociate d wit h 
s y m pt o ms of 
pr urit us or 
te n der ness 
Pa p ules a n d/ or 
p ust ules c o veri n g 
1 0 -3 0 % B S A, 
w hic h ma y or ma y 
n ot be ass ociate d 
wit h s y m pt o ms of 
pr urit us or  
te n der ness; 
ass ociate d wit h 
ps yc h os o cial 
i m pact; li miti n g 
i nstru me ntal A D LI  
Pa p ules a n d/ or 
p ust ules 
c o veri n g > 3 0 % 
B S A, w hic h 
ma y or m a y n ot 
be ass ociate d 
wit h s y m pt o ms 
of pr urit us or 
te n der ness; 
li miti n g self -
care A D L; 
ass ociate d wit h 
l ocal 
s u peri nfecti o n 
wit h oral 
a nti bi otics 
i n dicate d 
Pa p ules a n d/ or 
p ust ules  
c o veri n g a n y 
% B S A, w hic h 
ma y or m a y 
n ot be 
ass ociate d  
wit h s y m pt o ms 
of pr urit us or  
te n der ness a n d 
are ass o ciate d  
wit h e xte nsi ve 
s u peri nfecti o n 
wit h I V 
a nti bi otics 
i n dicate d; life 
t hreate ni n g 
c o nse q ue nces  
P ar o n yc hi a *  
Nail f ol d 
e de ma or 
er yt h e ma; 
disr u pti o n of 
t he c uticle 
L ocalize d 
i nter ve nti o n 
i n dicate d; oral 
i nter ve nti o n 
i n dicate d (e. g., 
a nti bi otic, 
a ntif u n gal, 
a nti viral);  
nail f ol d e de ma or 
er yt h e ma wit h 
pai n; ass ociate d 
wit h disc har ge or 
nail plate  
se parati o n; li miti n g 
i nstr u me ntal A D L 
S ur gical 
i nter ve nti o n or I V 
a nti bi otics 
i n dicate d; 
li miti n g self 
care A D L  
- 
* O nset of gra d e 3 will re q uire m o dificati o n. See t he ta ble bel o w, Cet u xi ma b D ose M o dificati o n 
G ui deli nes f or D er mat ol o gic C ha n ges. 
 

R T O G 3 5 0 4 
5 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R as h Occ urri n g I nsi de t he R a di ati o n Fiel d  
 
 
1  
2  
3  
4  
Ra diati o n recall 
reacti o n 
( der mat ol o gic); 
Der matitis 
ra diati o n 
 
Fai nt er yt he m a 
or dr y 
des q ua mati o n  
M o derate t o bris k 
er yt h e ma; patc h y 
m oist 
des q ua mati o n, 
m ostl y c o nfi ne d t o 
s ki n f ol ds a n d 
creas es; m o derat e 
e de ma  
M oist 
des q ua mati o n 
ot her t ha n s ki n 
f ol ds a n d creases; 
blee di n g i n d u ce d 
b y mi n or tra u m a 
or a brasi o n  
Lif e -t hreate ni n g 
c o nse q ue nces;  
s ki n necr osis or 
ulcerati o n of f ull  
t hic k ness 
der mis; 
s p o nta ne o us 
blee di n g fr o m 
i n v ol ve d site; 
s ki n 
graft i n dicate d  
 
Cet u xi m a b D ose M o dific ati o n G ui deli nes f or  Der m at ol o gic C h a n ges ( ≥ Gr a de 3)  
 
Cet u xi ma b  
O utc o me  
Cet u xi ma b D ose 
M o dificati o n  
 
Dela y i nf usi o n 1 t o 2 
wee ks  
I m pr o v e me nt t o ≤ 
Gra de 2  
Res u me at 2 5 0 m g/ m 2 
 
 
N o I m pr o ve me nt; 
re mai ns gra d e 3 
C o nti n ue t o  h ol d cet u xi ma b 
f or u p t o 4 wee ks 
  If cet u xi ma b is hel d f or f o ur 
c o nsec uti ve i nf usi o ns f or 
a d verse e ve nts t he patie nt 
s h o ul d be disc o nti n ue d fr o m 
f urt her cet u xi ma b t hera p y 
 
Dr u g Relate d Ras h Ma n a ge m e nt: Patie nts de vel o pi n g der m at ol o gic a d verse e ve nts w hile 
recei vi n g cet u xi ma b s h o ul d be m o nit ore d f or t he de vel o p me nt of i nfla m m at or y or i nfecti o us 
se q uelae, a n d a p pr o priate treat me nt of t hese s y m pt o ms i nitiate d.  Bel o w are s u g gesti o ns f or 
ma na gi n g cet u xi ma b-i n d uce d ras h *: 
 
 
A nti bi otics : T he be nefit of r o uti ne a nti bi otics i n u nc o m plicate d ( u ni nfecte d) ras h is 
u nclear. S o me cli nicia ns ha ve us e d oral mi n oc ycli ne ( Mi n oci n), m u pir oci n ( Bactr o ba n), 
or t o pical cli n da m yci n ( Cle oci n). Ras h c o m plicate d b y cell ulitis s h o ul d be tr eate d wit h 
a p pr o priate a nti bi otics base d o n cli nical j u d g m e nt or micr o bial se nsiti vit y a nal ysis. 
 
A nti hist a mi nes : Be n a dr yl or Atara x ma y b e hel pf ul t o c o ntr ol itc hi n g. 
 
T o pic al Ster oi ds : T he be nefit of t o pical ster oi ds is u nclear. 
 
Reti n oi ds : N o data t o s u p p ort use. Use is n ot a d vise d. 
 
Be nz o yl per o xi de : S h o ul d N O T be use d--ma y a g gra vate ras h. 
 
M a ke u p : Ras h ca n be c o vere d wit h ma ke u p; t his s h o ul d n ot ma ke it w orse ( use a 
der mat ol o gist- a p pr o ve d c o ver- u p, e. g., Der ma ble n d, or a n y ot her t y p e of f o u n dati o n). 
Re m o ve ma ke u p wit h a s ki n-frie n dl y li q ui d clea nser, e. g., Ne utr o ge n a, D o ve, or I v or y 
S ki n Clea nsi n g Li q ui- Gel. 

R T O G 3 5 0 4 
5 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
M oist urizers : 
Us e e m ollie nts t o pre ve nt a n d alle viate t he s ki n dr y n ess, e. g., 
Ne utr o ge na N or we gia n F or m ula Ha n d Crea m or Vaseli ne I nte nsi ve Care A d va nce d 
Heali n g L oti o n. 
 
S u nli g ht : It is rec o m me n de d t hat p atie nts wear s u nscree n a n d hats a n d li mit s u n 
e x p os ure w hile recei vi n g cet u xi ma b as s u nli g ht ca n e x acer bat e a n y s ki n reacti o ns t hat 
ma y o cc ur. 
 
O ver-t he- c o u nter 
me di c ati o ns : O ver-t h e-c o u nt er ac ne v ul garis 
me di cati o ns (e. g., 
be nz o yl per o xi de) are n ot a d vise d. T his ras h is n ot li ke ac ne v ul garis a n d t hese 
treat me nts c o ul d ma ke it w orse. 
 
  
* A da pte d fr o m Perez- S oler R, Del or d J, Hal per n A, et al. H E R 1/ E G F R i n hi bit or-
ass ociate d ras h: F ut ur e directi o ns f or ma na ge me nt a n d i n vesti gati o n o utc o mes fr o m t he 
H E R 1/ E G F R I n hi bit or Ras h Ma na ge m e nt F or u m. T he O nc ol o gist . 1 0: 3 4 5 – 3 5 6, 2 0 0 5. 
6. 3  
Cis pl ati n D ose M o dific ati o ns 
6. 3 . 1 Wee kl y Cis plati n D ose M o dificati o ns d uri n g C o nc urre nt Ra diati o n 
N ote : S u bstit uti o n of car b o plati n f or cis plati n d uri n g a d v erse e ve nts is N O T all o we d. 
  
P atie nts will be e x a mi ne d a n d gra de d f or s u bjecti ve/ o bjecti ve e vi de nce of de vel o pi n g 
t o xicit y wee kl y acc or di n g t o C T C A E, v. 4 w hile recei vi n g c o n c urre nt cis plati n wit h 
ra di ot hera p y. If a d v erse e ve nts pre ve nt t he a d mi nistrati o n of cis plati n, t he patie nt ma y 
c o nti n ue t o recei ve ni v ol u ma b a n d ra diati o n t hera p y 
 
Treat me nt i nterr u pti o ns are all o we d if t h ere is s y m pt o matic m uc ositis or s ki n reacti o n 
t hat, i n t he j u d g me nt of t he cli nicia n, warra nts a brea k. F or c h e m ot hera p y- attri b uta ble 
A Es re q uiri n g a brea k i n treat me nt, res u m pti o n of c o nc urre nt cis plati n ma y be gi n w h e n 
A E s ha ve rec o vere d t o t h e le vels s pecifi e d bel o w. C he m ot hera p y s h o ul d be disc o nti n ue d 
i n the e ve nt of m ore t h a n 2 e ve nts re q uiri n g d ose re d ucti o n (e. g. if gra de 3 or great er n o n-
he mat ol o gic or he mat ol o gic e ve nt occ urs at t he re d uce d d ose of cis plati n, at 2 3 
m g/ m 2/ wee k). 
 
If a n A E d o es n ot res ol ve t o t he le vels s pecifie d i n t he secti o ns bel o w pri or t o t he 
cale n dar wee k of t he last ra diati o n treat me nt ( See Secti o n 5. 1  f or details c o ncer ni ng 
para meters f or ti mi n g of last all o wa ble c o nc urre nt cis plati n d ose), t he n c he m ot hera p y 
s h o uld be disc o nti n ue d.  
 
T here will be n o d ose re- escalati o n f or c o nc urre nt cis plati n.  
 
C he m ot hera p y d osa ge m o dificati o ns are b ase d u p o n la b val ues o btai ne d wit hi n t h e 2 4 
h o urs pri or t o cis plati n a n d i nteri m n o n- he mat ol o gic t o xicities d uri n g t he wee k pri or t o a 
partic ular cis plati n d ose. 
6. 3 . 2    Wee kl y Cis plati n D ose M o dificati o ns f or He mat ol o gi c A d verse E v e nts d uri n g 
C o nc urre nt Ra diati o n 
 
St arti n g D ose  
D ose Le vel -1  
D ose Le vel -2  
4 0 m g/ m 2 
3 0 m g/ m 2 
2 3 m g/ m 2 
 

R T O G 3 5 0 4 
5 3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
C he m ot hera p y m ust n ot be a d mi nistere d u ntil t he A N C is ≥ 1, 0 0 0 m m 3 a n d platelets are 
≥ 7 5, 0 0 0  m m 3. If n ot, d ela y 7 d a ys. Cis plati n s h o ul d be hel d e ver y wee k u ntil t he a b o ve 
A N C a n d platelet para meters are m et. D ose re d ucti o ns w he n cis plati n is res u me d after 
dela y f or l o w A N C or platelets will be as f oll o ws, base d u p o n c o u nts at ti me cis plati n 
was hel d. 
 
A N C  
 
Pl at elets  
Re d ucti o n  
< 1 0 0 0 m m 3  
or  
< 7 5, 0 0 0  
O ne d ose le vel  
N ote : He m at ol o gic gr o wt h f act ors f or ne utr o pe ni a or a ne mi a are n ot all o we d d uri n g 
c o nc urre nt cis pl ati n a n d r a di ati o n tre at me nt. 
 
Ne utr o pe nic Fever : Gra d e 3 ( C T C A E, v 4) ne utr o pe nic fe v er ( A N C < 1 0 0 0/ m m3 wit h a 
si n gle te m perat ure of > 3 8. 3 de grees C [ 1 0 1 de grees F] or a s ustai ne d te m p erat ur e of ≥ 3 8 
de grees C [ 1 0 0. 4 de grees F] f or m ore t ha n 1 h o ur) is a n e x pecte d p ote ntial c o m plicati o n 
of c o nc urre nt c h e m ot hera p y a n d ra di ot hera p y or c he m ot hera p y al o n e. If ne utr o pe nic 
fe ver is n ote d, t he c he m ot hera p y d ose re d ucti o n will be deter mi ne d b y t he wee kl y bl o o d 
c o u nts. See a b o ve.  
6. 3 . 3    Wee kl y Cis plati n D ose M o dificati o ns f or N o n- He mat ol o gic A d v erse E ve nts d uri n g 
C o nc urre nt Ra diati o n 
 
Re n al A dverse E ve nts : D ose will be m o difie d base d o n t he ser u m creati ni ne pri or t o eac h 
cis plati n d ose. If t he ser u m creati ni ne is ≤ 1. 5 m g/ d L, creati ni ne cleara nce is n ot 
ne cessar y f or tr eat me nt wit h f ull d ose. If t he ser u m creati ni ne is > 1. 5 m g/ d L, a creati ni ne 
cleara nce s h o ul d b e o btai ne d b y uri ne c ollecti o n or n o m o gra m cal c ulati o n ( vali d o nl y if 
ser u m creati ni ne is n ot c ha n gi n g ra pi dl y). 
 
Cis pl ati n m ust n ot be a d mi nistere d u ntil cre ati ni ne is ≤ 1. 5 or cre ati ni ne cle ar a nce ≥ 
5 0.  O nce t he creati ni ne has met t he a b o ve p ara m eters, cis plati n ma y be restarte d wit h t he 
be l o w m o dificati o ns base d o n t he creati ni ne at t he ti me t he cis pl ati n was hel d: I n ge n eral, 
cis plati n s h o ul d be hel d f or wee kl y i nter vals (rat h er t ha n restarti n g cis plati n later i n t he 
sa me wee k t h at a d ose li miti n g A E is see n). 
 
Cis pl ati n d ose m o dific ati o ns f or cre ati ni ne d uri n g c o nc urre nt r a di ati o n  
Creati ni ne ( m g/ d L)  
 
Creati ni ne 
cleara nce, m eas ure d 
or calc ulat e d ml/ mi n  
Cis plati n d ose 
re d ucti o n 
≤ 1. 5  
or  
> 5 0  
N o c ha n ge  
> 1. 5  
a n d 
4 0 -5 0  
O ne d ose le vel  
 
 
<  4 0  
H ol d dr u g   
 
Ne ur ol o gic ( n e ur o p at hy) A dverse Eve nts: 
 
Gr a de ( C T C A E, v. 4)  
D ose Re d ucti o n  
0 -1  
N o ne  
2  
O ne d ose le vel  
3 -4  
H ol d dr u g  

R T O G 3 5 0 4 
5 4   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
Ot ot oxicity:   S h o ul d patie nts de vel o p cli nical e vi d e nce of ot ot o xicit y, f urt h er a u di o metric 
e val uati o n is re q uire d. A ne ur ol o gi c defi cit s h o ul d be disti n g uis he d fr o m a c o n d ucti ve 
l oss fr o m o bstr ucti o n of t he E ustac hia n t u be l ea di n g t o a mi d dle ear eff usi o n. Beca use n o 
A E  scale, i ncl u di n g t he C T C A E, v. 4, has bee n v ali date d i n ter ms of c orrelati o n wit h 
cli nicall y rele va nt h eari n g l oss, t here are n o pr ot o c ol ma n dates re q uiri n g d ose re d ucti o n 
f or a u di o gra m- deter mi ne d se ns ori ne ural h eari n g l oss wit h o ut a n a nal o g o us cli nical hi g h 
gra de heari n g l oss. H o we ver, f or cli nical gra d e 3 or hi g her heari n g l oss, cis plati n s h o ul d 
be  hel d a n d f or gra d e 2 cli nical heari n g l oss, o ne d ose le vel re d u cti o n s h o ul d be 
i m ple me nte d. 
 
All Ot her N o n- He m at ol o gic A dverse Eve nts Attri b ut a ble t o Cis pl ati n d uri n g C o nc urre nt 
R a di ati o n:  F or all ot her n o n- he mat ol o gi c a d verse e ve nts i n w hic h t o xicit y is  ≥ gra de 2 
( C T C A E v. 4), i n vesti gat ors are a d vise d t o e val u ate a n d ma na ge c orrecta ble iss ues 
pr o m ptl y t o pre v e nt w ors e ni n g of t o xicit y. F or t hese e ve nts i n w hic h t o xicit y is ≥ gra d e 3, 
i n vesti gat ors s h o ul d h ol d cis plati n, wit h wee kl y re-e val uati o n u ntil A E gra d e falls t o 0- 1,  
t he n restart cis plati n at o ne l o wer d ose l e vel. N ote: Gra de 3 m uc ositis is c o m m o nl y 
e x perie nce d b y hea d a n d nec k ca ncer patie nts; t he i n vesti gat or ge nerall y w o ul d n ot h ol d 
t he cis plati n d osi n g i n t his case, u nless t here is u n us ual c o ncer n f or pr o gressi o n t o gra d e 4 
m uc ositi s.  
6. 3. 4    Hi g h- D ose Cis plati n D ose M o dificati o ns, Da ys 2 2 a n d 4 3 f or Ar m 2 o nl y 
 
Ne utr o pe ni a:  If o n t h e d a y of sc he d ul e d tr eat me nt wit h cis plati n t he a bs ol ute ne utr o p hil 
c o u nt ( A N C) is < 1 2 0 0, h ol d treat me nt u ntil A N C ≥ 1 2 0 0, t he n treat at 1 0 0 % d ose. 
Ne utr o pe nic fe ver will re q uire per ma ne nt 2 5 % d ose re d ucti o n. Per C T C A E, v. 3. 0, 
fe brile ne utr o p e nia is fe ver of u n k n o w n ori gi n wit h o ut cli nicall y or micr o bi ol o gicall y 
d oc u me nte d i nfecti o n; A N C < 1. 0 x 1 0e 9 L, fe ver > 3 8. 5° C. 
 
T hr o m b ocyt o pe ni a:  If o n t he da y of sc he d ule d treat me nt wit h cis plati n t he platelet c o u nt 
is < 7 5, 0 0 0, h ol d treat me nt u ntil platelets are > 7 5, 0 0 0, t he n treat at 1 0 0 % d ose. 
T hr o m b oc yt o p e nia t hat r es ults i n blee di n g will re q uire a 2 5 % d os e re d u cti o n.  
 
Ne ur ot oxicity : If a n y si g ns of gra de 3 or greater ne ur ot o xicit y o cc ur, disc o nti n ue 
cis plati n. C o nti n ue R T  
 
Re n al A dvers e Eve nts : Cis plati n s h o ul d be a d mi nistere d o n t he sc h e d ule d da y of 
treat me nt usi n g t h e f oll o wi n g g ui deli nes: 
 
N ote : If creati ni ne is > 1. 2 m g/ dl, cleara nce m ust be d o ne i n or der t o ma ke d ose 
a dj ust me nt. If t he calc ulate d n o m o gra m is 5 0 
m L/ mi n or a b o ve, a 2 4- h o ur uri ne 
c ollecti o n is n ot nee de d, b ut if t he n o m o gra m calc ulati o n is less t ha n 5 0 m L/ mi n, a 2 4-
h o ur uri ne c ollecti o n is ma n date d. 
 
Cre at i ni ne 
Cle ar a nce  
Cis pl ati n D ose  
> 5 0 ml/ mi n.  
1 0 0 m g/ m 2 
4 0 -5 0 ml/ mi n.  
5 0 m g/ m 2 

R T O G 3 5 0 4 
5 5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
< 4 0 ml/ mi n.  
Disc o nti n ue  
 
Ot her A dverse Eve nts:  
 
M uc ositis:  Gra de 4 will re q uire a 2 5 % d ose re d ucti o n  
 
Ot ot o xicit y: F or n e w cli nical heari n g l oss n ot re q uiri n g a heari n g ai d or f or 
ti n nit us t hat i nterferes wit h acti vities of dail y li vi n g, tr eat at 5 0 % d ose re d ucti o n. 
F or h eari n g l oss re q uiri n g a heari n g ai d, disc o nti n ue cis plati n. C o nti n ue R T ( Ar m 
1).  
 
If t h e p h ysici a n is u ns ure a b o ut t he se verit y of t he heari n g l oss, a n a u di o gra m is 
e nc o ura ge d. 
 
If t he sec o n d d ose of cis plati n is dela ye d m ore t ha n 2 1 da ys b eca us e of he mat ol o gic or 
re nal a d v erse e ve nts, t he n t he t hir d d ose will be o mitte d. 
 
If a w ei g ht c ha n ge of ≥ 1 0 % occ urs, t h e cis plati n d ose s h o ul d be a dj uste d. 
 
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 nt 
T he i n vesti gati o nal a ge nt a d mi nistere d i n R T O G 3 5 0 4, ni v ol u ma b, is bei n g ma de a vaila ble 
b y t he R T O G F o u n dati o n a n d distri b ute d b y a t hir d part y dr u g distri b ut or.   F or ni v ol u ma b, 
de ter mi nati o n of w het h er a n a d verse e v e nt meets e x pe dite d re p orti n g criteri a, see t he 
re p orti n g ta ble i n Secti o n 7. 4  of t he pr ot oc ol.  
C o m mercial A ge nts 
T he c o m mercial a ge nts i n R T O G 3 5 0 4 are cis plati n a n d cet u xi ma b. 
7. 1. 1 
A d verse E ve nts f or I n vesti g ati o n al St u d y A ge nts  
In v esti gat ors m ust o btai n t he c urre nt versi o n of t h e B M S- 9 3 6 5 5 8 ( ni v ol u m a b) 
I n v esti gat or Br oc h ure (I B) f or c o m pre he nsi ve p h ar mac ol o gic a n d safet y i nf or mati o n. T he 
IB ca n be accesse d o n t h e R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol pa ge of t h e R T O G we bsite, 
w w w.rt o g. or g. Sites m ust use t heir user na m e a n d pass w or d t o access t he pr ot oc ol pa ge 
an d t he I B.  
7. 1. 2 
A d verse E ve nts f or C o m merci al St u d y A ge nts  
Re fer t o t he p ac k a ge i nserts f or cis pl ati n a n d cet u xi m a b f or det aile d p h ar m a c ol o gic 
a n d s afet y i nf or m ati o n  
 
7. 2  
A d verse E ve nts ( A Es)  
T his st u d y will use t h e C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts ( C T C A E) 
versi o n 4 f or a d verse e ve nt 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 4. 
7. 2. 1    Defi niti o n of a n A d verse E v e nt ( A E)  
A n y u nt o w ar d me dic al occ urre nce ass ociat e d wit h t he use of a dr u g i n h u ma ns, w het her 
or n ot c o nsi dere d dr u g relate d.  T heref ore, a n A E ca n be a n y u nfa v ora ble a n d u ni nte n de d 
si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease t e m p orall y 
ass ociate d wit h t he use of a me dici nal (i n v esti gati o nal) pr o d uct, w h et her or n ot 
c o nsi dere d relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct (attri b uti o n of   relate d or 
u nrelate d). (I nter n ati o nal C o nfere nce o n Har m o nisati o n [I C H], E 2 A, E 6).  

R T O G 3 5 0 4 
5 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
F or m ulti- m o dalit y trials, a d verse e ve nt r e p orti n g e nc o m passes all as pects of pr ot oc ol 
treat me nt i ncl u di n g ra diati o n t hera p y, s ur ger y, d e vice, a n d dr u g. 
 
A Es, as defi ne d a b o v e, e x perie nce d b y patie nts accr ue d t o t his pr ot oc ol s h o ul d be 
re p orte d o n t he A E secti o n of t he a p pr o priate case re p ort f or m (see Secti o n 1 2. 1 ). All 
n o nseri o us a d vers e e ve nts ( n ot o nl y t h ose dee me d treat me nt-relate d) are t o be c ollecte d 
c o nti n u o usl y d uri n g t he treat me nt peri o d a n d f or a mi ni m u m of 1 0 0 da ys f oll o wi n g t h e 
last d ose of st u d y treat me nt. F oll o w u p als o is re q uir e d f or n o nseri o us A Es t hat ca use 
i nterr u pti o n or disc o nti n uati o n of st u d y dr u g a n d f or t h ose pres e nt at t he e n d of st u d y 
treat me nt as a p pr o pri ate. All i de ntifie d n o nseri o us A Es m ust be rec or de d a n d descri be d 
o n t he n o nseri o us A E pa ge of t he C R F.   
 
T he f oll o wi n g la b orat or y t est res ult a b n or malities s h o ul d be ca pt ur e d o n t he n o nseri o us 
A E C R F pa ge a n d S A E Re p ort F or m, if t he y meet seri o us ness criteria: 
 A n y l a b orat or y t est res ult t hat is cli ni call y si g nifica nt or meets t he d efi niti o n of a n 
S A E; 
 A n y l a b orat or y test res ult a b n or malit y t hat re q uir e d t he s u bj ect t o h a ve st u d y dr u g 
disc o nti n ue d or i nterr u pt e d; 
 A n y la b orat or y test res ult a b n or malit y t hat re q uir e d t he s u bject t o recei ve s pecific 
c orrecti ve t hera p y. 
It is e x pecte d t h at w here ver p ossi ble, t he cli nical rat her t h a n la b orat or y ter m w o ul d be 
use d b y t h e re p orti n g i n v esti gat or (e g, a n e mia vers us l o w he m o gl o bi n val u e). 
 
Defi niti o n o f I m m u n e- M e diate d A d verse E ve nts (I M A E S)  
I M A Es i ncl u de e ve nts, re gar dless of ca usalit y, occ urri n g wit hi n 1 0 0 da ys of t he last d ose. 
I M A Es are s p ecific e ve nts (t hat i ncl u de p ne u m o nitis, diarr hea/c olitis, he patitis, 
ne p hritis/re nal  
d ysf u n cti o n,  
ras h,  
a n d  
e n d ocri ne  
[a dre nal  
i ns ufficie nc y, 
h y p ot h yr oi dis m/t h yr oi ditis, h y p ert h yr oi dis m, dia betes mellit us, a n d h y p o p h ysitis]) f or 
w hic h s u bjects recei v e d i m m u n os u p pressi ve me dicati o n f or tr eat me nt of t he e ve nt, wit h 
t he e x ce pti o n 
of e n d ocri ne e v e nts ( h y p ot h yr oi dis m/t h yr oi ditis, 
h y pert h yr oi dis m, 
h y p o p h ysitis, dia betes m ellit us, a dre nal i ns ufficie nc y), w hic h are i ncl u d e d re gar dl ess of 
treat me nt si nce t h ese e v e nts are ofte n ma na ge d wit h o ut i m m u n os u p pressi o n. T he ta ble 
bel o w pr o vi des a s u m mar y of t he I M A Es cate g or y a n d t h eir res p ecti ve preferre d ter ms. 
 
Preferre d Ter ms I ncl u de d i n A n al ysis of I M A Es 
 t o S u p p ort W ar ni n gs a n d Prec a uti o ns 
I M A E C ate g o r y 
P Ts i ncl u de d u n der I M A E C ate g or y  
P ne u m o nitis  
P ne u m o nitis, I nt erstitial l u n g diseas e  
Diarr hea/ C olitis  
Diarr hea, C olitis, E nter oc olitis  
He patitis  
He pat ot o xicit y, He patitis, He patitis ac ute, A ut oi m m u ne 
he patitis, A S T i ncrease d, A L T i n crease d, Bilir u bi n 
i ncreas e d, A L P i ncrease d 
A dre nal i ns uffi cie nc y  
A dre nal i ns uffi cie nc y  

R T O G 3 5 0 4 
5 7   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
Preferre d Ter ms I ncl u de d i n A n al ysis of I M A Es 
 t o S u p p ort W ar ni n gs a n d Prec a uti o ns 
H y p ot h yr oi dis m/ T h yr oi ditis  
H y p ot h yr oi dis m, T h yr oi ditis  
T h yr oi ditis ac ute (c olla ps e d wit h t h yr oi ditis f or 
fre q ue n c y), A ut oi m m u ne t h yr oi ditis (c olla pse d wit h 
t h yr oi ditis f or fre q ue n c y) 
H y p ert h yr oi dis m  
H y p ert h yr oi dis m  
H y p o p h ysitis  
H y p o p h ysitis  
Dia betes mellit us  
Dia betes mellit us, Dia betic ket oaci d osis  
Ne p hritis a n d re n al 
d ysf u n cti o n  
Ne p hritis, Ne p hritis aller gic, T u b ul oi nterstitial ne p hritis, 
Ac ute re n al fail ure, Re nal fail ure, I ncrease d creati ni ne  
Ras h  
Ras h, Ras h mac ul o pa p ul ar  
 
N O T E: If t he e ve nt is a Seri o us A d verse E v e nt ( S A E) (see ne xt secti o n), f urt her 
re p orti n g will be re q uir e d. Re p orti n g A Es o nl y f ulfills Data 
Ma n a ge me nt re p orti n g 
re q uire me nts.  
 
7. 3  
Seri o us A d verse E ve nts ( S A Es)  
S eri o us A d verse E v e nts t hat meet e x pe dite d re p orti n g criteria defi n e d i n t he ta ble bel o w 
will be re p orte d via t he S A E re p ort f or m i n Ra ve.  S A Es t hat re q uire 2 4 h n otificati o n are 
defi ne d i n t he e x pe dite d re p orti n g ta bl e. 
 
Defi niti o n of a n S A E: A n y a d verse dr u g e v e nt (e x perie nce) o cc urri n g at a n y d ose t h at 
res ults i n a n y of t he f oll o wi n g o utc o mes: 
 De at h; 
 A life -t hreate ni n g a d verse dr u g e x perie nce; 
 In p atie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
 A pe rsiste nt or si g nifica nt disa bilit y/i nca p acit y; 
 A c o n ge nital a n o mal y/ birt h defect; 
 Im p ort a nt me dical e ve nts t hat ma y n ot res ult i n deat h, b e life t hreate ni n g, or 
re q uire h os pitaliz ati o n ma y be c o nsi dere d a n S A E, w he n, b ase d u p o n me dical 
j u d g me nt, t he y m a y j e o par dize t he patie nt a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t he defi niti o n.  
 
D ue t o t he ris k of i ntra uteri ne e x p os ure of a fet us t o p ote ntiall y t erat o ge nic a ge nts, t he 
pre g na nc y of a st u d y partici pa nt m ust be re p orte d i n a n e x pe dite d ma n ner. 
 
  
7. 4  
Seri o us A d verse E ve nt ( S A E) Re p orti n g Re q uire me nts 
It is t he res p o nsi bilit y of t he i n vesti gat or t o d oc u me nt all a d verse e ve nts w hic h occ ur 
d uri n g t he st u d y. All s eri o us a d verse e v e nts t hat meet e x pe dite d re p orti n g criteria 
defi ne d i n t he re p orti n g ta ble bel o w will be re p ort e d via t he R T O G S A E Re p ort F or m i n 
R A V E. R T O G will re p ort S A Es t o Brist ol- M yers S q ui b b wit hi n 2 4 h o urs of a ware n ess. 
R T O G will re p ort u ne x pecte d a n d relate d S A Es t o t he F D A a n d Brist ol- M yers S q ui b b 

R T O G 3 5 0 4 
5 8   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
via t he Me d Watc h F or m 3 5 0 0 A per t he re q uire me nts set f ort h i n t he C o de of Fe deral 
Re g ulati o ns, Secti o n 3 1 2. 3 2.  
7. 4 . 1 
Re p orti n g S A Es  
F oll o wi n g t he p atie nt’s writte n c o nse nt t o partici pate i n t he st u d y, all S A Es, w het her 
relate d or n ot relate d t o st u d y dr u g, m ust be c ollecte d, i ncl u di n g t h ose t h o u g ht t o be 
ass ociate d wit h pr ot oc ol-s pecifie d pr oce d ures. All S A Es m ust be re p orte d per t he 
re p orti n g t a ble bel o w t h at occ ur fr o m ti me of c o nse nt a n d wit hi n 1 0 0 d a ys of t he 
l ast d ose of st u d y dr u g. Patie nts, w h o are ra n d o mize d a n d ne ver recei ve treat me nt , 
m ust ha ve S A Es c ollecte d f or 3 0 da ys fr o m t he date of ra n d o mizati o n. If a p plica ble, 
S A Es m ust be c ollecte d t hat relate t o a n y later pr ot oc ol-s pecifi e d pr oce d ure (e. g. a 
f oll o w- u p s ki n bi o ps y). 
 
T he i n vesti gat or s h o ul d re p ort a n y S A E t h at occ urs after t hese ti me peri o ds a n d t hat is 
belie ve d t o be relate d t o st u d y dr u g or pr ot oc ol-s p ecifie d pr oce d ur e.  
 
A n S A E re p ort s h o ul d be c o m plete d f or a n y e ve nt w here d o u bt e xists re gar di n g its 
seri o us ness. If t h e i n vesti gat or b elie ves t hat a n S A E is n ot relate d t o st u d y dr u g, b ut is 
p ote ntiall y relate d t o t he c o n diti o ns of t he st u d y (s uc h as wit h dra wal of pre vi o us t hera p y 
or a c o m plicati o n of a st u d y pr oce d ure), t he relati o ns hi p s h o ul d be s pecifie d i n t he 
narrati ve s ecti o n of t he S A E Re p ort F or m.  
 
 
T he S A E re p ort s h o ul d c o m prise a f ull writte n s u m mar y, detaili n g rele va nt as pects of 
t he S A E i n q uesti o n. T he S A E s u m mar y als o m ust i ncl u de t he i n vesti gat or’s assess me nt 
of rel ate d ness t o all c o m p o ne nts of pr ot o c ol tr eat me nt. A me n d t he S A E re p ort wit h 
f oll o w- u p i nf or mati o n, w he n it bec o mes a vaila ble, I n t he rare e v e nt w he n I nter n et 
co n necti vit y is disr u pte d, a 2 4- h o ur n otificati o n m ust be ma de t o R T O G O perati o ns 
Office b y p h o ne, 2 1 5- 5 7 4- 3 1 9 1.  A n electr o nic re p ort m ust be s u b mitte d i m me diatel y 
u p o n r e-esta blis h me nt of t he I nt er net c o n necti o n.  
 
S A Es t hat occ ur d uri n g t he f oll o w- u p peri o d b e gi n ni n g 1 0 0 da ys after e n d of tr eat me nt 
a n d are c o nsi d ere d b y t he i n vesti gat or t o be relate d t o pr ot oc ol treat me nt m ust be 
re p orte d e x pe diti o usl y vi a t he S A E Re p ort F or m.  
 
All S A Es m ust be re p orte d i n R a ve wit hi n t he desi g n ate d ti mefr a me o utli ne d i n t he 
re p orti n g t a ble bel o w. R T O G will c o m plete a preli mi n ar y re vie w of t he S A E det ails 
a n d will c o nt act t he site wit h q ueries as nee de d. R T O G will re p ort t he S A E t o 
Brist ol- M yers S q ui b b wit hi n 2 4 h o urs of n otific ati o n of t he e ve nt. R T O G will 
re p ort t o t he F D A per 2 1 C F R 3 1 2. 
 
Pre g n a ncy   
Patie nts 
w h o bec o me pre g n a nt d uri n g t he st u d y s h o ul d disc o nti n ue t he st u d y 
i m me diatel y.  I n v esti gat ors s h o ul d re p ort t he pre g na n c y, i ncl u di n g a mal e partici pa nt’s 
i m pre g n ati o n of his part n er, e x pe diti o usl y as a gra de 3 S A E c o de d i n t he C T C A E v. 4 as 
“ pre g na n c y, p uer peri u m a n d peri natal c o n diti o ns, ot her — pre g n a nc y” o n t he S A E Re p ort 
F or m (i n R A V E) a n d s u b mit t he Pre g na n c y Re p ort F or m i n Ra ve wit hi n 1 4 da ys of 

R T O G 3 5 0 4 
5 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
n otificati o n. R T O G will re p ort t he pr e g n a nc y t o Brist ol- M yers S q ui b b wit hi n 2 4 h o urs 
of n otificati o n of t he e v e nt. Patie nts s h o ul d be i nstr ucte d t o n otif y t he i n v esti gat or if it is 
deter mi ne d after c o m pleti o n of t he st u d y t h at t h e y bec o me pre g na nt (i ncl u di n g a male 
partici pa nt’s i m pre g n ati o n of his part n er) eit her d uri n g t h e treat me nt p has e of t he st u d y 
or wit hi n 1 0 0 cale n dar da ys after t he e n d of tr eat me nt. T he pre g n a nc y o utc o me f or 
pa tie nts o n st u d y s h o ul d be re p orte d t o R T O G. R T O G will re p ort t h e st at us t o Brist ol-
M yers S q ui b b. 
 
 

R T O G 3 5 0 4 
6 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
P h ase 1 a n d E arl y P h as e 2 St u dies:  E x pe dite d Re p orti n g Re q uire me nts f or A d verse 
E ve nts t h at Occ ur o n St u dies u n der a n I N D/I D E wit hi n 1 0 0 D a ys of t he L ast 
A d m i nistr ati o n of t he I n vesti g ati o n al A ge nt/I nter ve nti o n 1, 2 
F D A R E P O R TI N G R E Q UI R E M E N T S F O R S E RI O U S A D V E R S E E V E N T S ( 2 1 C F R P art 3 1 2)  
N O T E:   I n vesti gat ors M U S T  i m me diatel y re p ort t o t he s p o ns or ( N CI) A N Y Seri o us A d verse E ve nts, 
w het her or n ot t he y are c o nsi dere d relate d t o t he i n vesti gati o nal a ge nt(s)/i nter ve nti o n ( 2 1 C F R 
3 1 2. 6 4)  
A n a d verse e ve nt is c o nsi dere d seri o us if it res ults i n A N Y  of t he f oll o wi n g o utc o mes:   
1)  Deat h  
2)  A life -t hreate ni n g a d verse e ve nt  
3)  A n a d verse e ve nt t hat res ults i n i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g 
h os pitalizati o n f or ≥ 2 4 h o urs  
4)  A persiste nt or si g nifica nt i nca p acit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal 
life f u ncti o ns  
5)  A c o n ge nital a n o mal y/ birt h defect.  
6)  I m p orta nt Me dical E ve nts (I M E) t hat ma y n ot res ult i n deat h, be life t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d seri o us w he n , base d u p o n me dical j u d g me nt, t he y ma y 
je o par dize t he patie nt or s u bj ect a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne 
of t he o utc o mes liste d i n t his defi niti o n. ( F D A, 2 1 C F R 3 1 2. 3 2; I C H E 2 A a n d I C H E 6).  
 
A L L  S E RI O U S  a d verse e ve nts t hat  meet t he a b o ve criteria M U S T  be i m me diatel y re p orte d t o R T O G 
H Q  wit hi n t he ti mefra mes detaile d i n t he ta ble bel o w.  
H os pit aliz ati o n  
Gr a de 1 a n d Gr a de 2 Ti mef r a mes  
Gr a de 3 -5  
Ti mefr a mes  
Res ulti n g i n 
H os pitalizati o n  
≥ 2 4 hrs  
1 0 Cale n dar Da ys  
2 4 -H o ur 5 Cale n dar 
Da ys  
N ot res ulti n g i n 
H os pitalizati o n  
≥ 2 4 hrs  
N ot re q uire d  
E x pe dite d A E re p orti n g ti meli nes are defi ne d as:  
o  “ 2 4-H o ur; 5 Cale n dar Da ys” - T he A E m ust i nitiall y be re p orte d wit hi n 2 4 h o urs of lear ni n g of 
t he A E, f oll o we d b y a c o m plete e x pe dite d re p ort wit hi n 5 cale n dar da ys of t he i nitial 2 4-h o ur 
re p ort. 
o  “ 1 0 Cale n dar Da ys” - A c o m plete e x pe dite d re p ort o n t he A E m ust be s u b mitte d wit hi n 1 0 
cale n dar da ys of lear ni n g of t he A E.  
1Seri o us a d verse e ve nts t hat occ ur m ore t ha n 1 0 0  da ys after t he last a d mi nistrati o n of i n vesti gati o nal 
a ge nt/i nter ve nti o n a n d  are c o nsi dere d  relate d t o pr ot oc ol treat me nt  re q uire re p orti n g as f oll o ws:  
E x pe dite d 2 4 -h o ur n otific ati o n f oll o we d b y c o m plete re p ort wit hi n 5 c ale n d ar d a ys f or:  
 
All Gra de 3, 4, a n d Gra de 5 A Es  
E x pe dite d 1 0 c ale n d ar d a y re p orts f or:  
 
Gra de 2 A Es res ulti n g i n h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n  
2F or st u dies usi n g 1 8 -F -F D G -P E T / C T or S P E C T I N D a ge nts, t he A E re p orti n g peri o d is li mite d t o 1 0 
ra di oacti ve half-li ves, r o u n de d U P t o t he nearest w h ole da y, after t he a ge nt/i nter ve nti o n was last 
a d mi nistere d.  F o ot n ote “ 1” a b o ve a p plies after t his re p orti n g peri o d.  
 

R T O G 3 5 0 4 
6 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
S pecific Pr ot oc ol E xce pti o ns t o E x pe dite d Re p orti n g ( S P E E R): 
T he f oll o wi n g a d vers e e v e nts are s pecific pr ot o c ol e xce pti o ns t o e x pe dite d re p orti n g. Re p ort t he 
f oll o wi n g A Es i n a n e x pe dite d ma n ner o nl y if t he y e x cee d t he gra d e ( C T C A E, v. 4) i n 
pare nt hes es ne xt t o t he A E:  diarr hea ( gra d e 2), fati g ue ( gra d e 2), pr urit us ( gra de 2), ras h 
mac ul o- pa p ular ( gra de 2), l y m p h oc yte c o u nt decrease ( gra de 4), a ne mia ( gra de 4), W B C 
decrease ( gra d e 4), m uc ositis oral ( gra de 3), ra diati o n der matitis ( gra de 3), t hr o m b oe m b olic 
e ve nt ( gra de 3).   
 
A d diti o n al Pr ot oc ol- S pecific I ncl usi o ns  t o E x pe dite d Re p orti n g Re q uire me nts 
He m o p ha g oc ytic l y m p h o histi oc yt osis is a n i ncl usi o n t o e x pe dite d re p orti n g. He m o p ha g oc ytic 
ly m p h o histi oc yt osis is a rare b ut p ote ntiall y fatal disease of n or m al b ut o veracti ve histi oc ytes 
a n d l y m p h oc yt es. It is a ma nifest ati o n of c yt o ki ne releas e s y n dr o me. Occ urri n g at a n y gra d e, 
he m o p ha g oc ytic l y m p h o histi oc yt osis m ust be re p ort e d i n a n e x pe dite d ma n ner as a s eri o us 
ad verse e ve nt.   
 
8.  R E G I 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 RE S   
8. 1 
Re g ul at or y Re q uire me nts  
P lease refer t o t he st u d y-s pecific g ui de f or i n vesti gat ors a n d res earc h staff f or detaile d 
pr oce d ures re gar di n g  re q uire me nts f or re g ulat or y c ollecti o n. T he st u d y-s pecific g ui de is 
a v ail a ble o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge o n t he R T O G we bsite, 
w w w.rt o g. or g .  
 
8. 2 R T  Re gistr ati o n Re q uir e me nts  
All sites will be I M R T a n d I G R T cre d e ntiale d pri or t o re gisteri n g p atie nts t o t he st u d y. 
Please  
refer  
t o  
t he  
M D  
A n ders o n  
D osi meter y  
La b  
we bsit e 
(htt p://r pc. m da n ders o n. or g/ m da dl/ R T O G _ F o u n d ati o n/ R T O G _ 3 5 0 4. ht m ),  
f or  
d etails 
re gar di n g R T  re gistrati o n re q uire me nts.   
8. 2 .1  Di gital R T Data S u b missi o n t o R T O 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 R T O G F o u n dati o n. See t he st u d y-
s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge o n t he R T O G we bsite, 
w w w.rt o g. or g , f or det ails of T RI A D. 
 
8. 3 
P ati e nt E nr oll me nt 
S ee t he st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge o n t he 
R T O G w e bsite, w w w.rt o g. or g , f or det ails of p atie nt e nr oll me nt.  
 
9  
D R U G I N F O R M A TI O N  
9 . 1 I n vesti g ati o n al St u d y A ge nt 
Ni v ol u ma b, I N D # 1 2 9 8 4 1 
T o s u p ple me nt t he t o xicit y i nf or mati o n c o nt ai ne d i n t his d oc u me nt, i n vesti gat ors m ust 
o btai n t he c urre nt versi o n of t he B M S- 9 3 6 5 5 8 ( ni v ol u ma b) I n vesti gat or Br oc h ure (I B), f or 
co m pre he nsi ve p h ar mac ol o gic a n d s afet y i nf or mati o n. Als o see A p pe n di x I . 
 
T he I B c a n be accesse d o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he R T O G 
w e bsite, w w w.rt o g. or g . Sites m ust use t hei r user n a me a n d p ass w or d t o access t he 
pr ot oc ol p a ge a n d t he I B.   

R T O G 3 5 0 4 
6 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 
T a ble  
Pr o d uct Descri pti o n  
Pr o d uct 
Descri pti o n a n d 
D os a ge F or m  
P ote nc y  
Pri m ar y 
P ac k a gi n
g  
( V ol u me)
/ L a bel 
T y pe  
Sec o n d ar y 
P ac k a gi n g  
( Qt y) / L a bel 
T y pe  
A p pe ar a nce  
St o r a ge C o n diti o ns  
( per l a bel) 
Ni v ol u ma b B M S -
9 3 6 5 5 8 S ol uti o n 
f or I nj ecti o na 
1 0 0 m g ( 1 0 
m g/ m L)  
1 0 m L 
vial  
5 -1 0 vials per 
cart o n/ O pe n -
la bel 
Clear t o o palesce nt 
c ol orless t o pale 
yell o w li q ui d. Ma y 
c o ntai n particles  
2 ° t o 8° C;  pr otect 
fr om li g ht , freezi n g, 
a n d s ha ki n g  
* Ni v ol u ma b ma y b e la bele d as B M S- 9 3 6 5 5 8 S ol uti o n f or I njecti o n 
If st ore d i n a glass fr o nt refri gerat or, vials s h o ul d be st ore d i n t he cart o n. Rec o m me n de d 
safet y me as ures f or pre p arati o n a n d ha n dli n g of ni v ol u ma b i ncl u de la b orat or y c o ats a n d 
gl o ves. 
F or a d diti o nal details o n pre pare d dr u g st or a ge a n d use ti me of ni v ol u ma b u n der r o o m 
te m perat ur e/li g ht a n d refri gerati o n, pleas e refer t o A p pe n di x I  a n d t he B M S- 9 3 6 5 5 8 
( ni v ol u ma b) I n vesti gat or 
Br oc h ure secti o n f or “ Rec o m me n de d St or a ge a n d 
Use 
C o n diti o ns”.  
9. 1. 1     A vaila bilit y/ S u p pl y 
Brist ol- M yers S q ui b b will s u p pl y ni v ol u ma b free of c har ge t o patie nts o n st u d y i n t he 
U. S. a n d Ca na d a.  A n o n-site u n bli n de d p har macist will be res p o nsi ble f or mi xi n g 
place b o per i nstr ucti o ns pr o vi de d i n A p pe n di x I, “ Ni v ol u ma b P har m ac y Refere nce 
S heet ”. T h e dr u g will be distri b ute d b y a t hir d- part y v e n d or u n der c o ntract t o R T O G. 
Dr u g acc o u nta bilit y rec or ds m ust be mai ntai n e d at all sites acc or di n g t o g o o d cli nical 
practices.  
 
S ee t he st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he 
R T O G w e bsite, w w w.rt o g. or g , f or det ails of dr u g s hi p me nt. 
 
9 . 2 
C o m merci al A ge nts   
 
Cet u xi ma b a n d Cis plati n 
Sites m ust refer t o t he pac ka ge i ns ert f or det aile d p har mac ol o gic a n d safet y i nf or m ati o n.  
9 . 2. 1 
A vaila bilit y/ S u p pl y  
Please see Secti o n 5  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 ge 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 p arati o n, ha n dli n g, a n d st ora ge. 
 
1 0. P A T H O L O G Y/ BI O S P E CI M E N S  
1 0. 1     p 1 6 I m m u n o hist oc he mistr y f or Or o p h ar y n x C a ncers 
  
T u m or p 1 6 stat us is a n esta blis he d cli nical s urr o gate of t u m or H P V stat us. p 1 6 stat us is 
a n i nte gral bi o mar k er, as t u m or p 1 6 stat us is a stratificati o n fact or.  E val uati o n of t u m or 
p 1 6 stat us ma y be p erf or me d l ocall y, b ut t he assa y is t o be perf or me d b y us e of a m o use 
m o n ocl o nal a nti b o d y t o p 1 6 ( CI Ntec E 6 H 4, M T M La b orat ories, Hei del b er g, Ger ma n y) 

R T O G 3 5 0 4 
6 3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
vis ualize d wit h t he Ve nta na X T a ut ostai ner ( or e q ui vale nt) usi n g t he 1- vie w sec o n dar y 
detecti o n kit ( Ve nta n a) ( or e q ui vale nt) as descri b e d b y J or da n, et al. ( 2 0 1 2). Ot her 
acce pta ble p 1 6 a nti b o d y t y pes i ncl u de 1 6 P 0 4 a n d J C 8. Pat h ol o gical i nter pretati o n of 
t u m or p 1 6-stat us ma y b e perf or me d l o call y a n d re vie we d ce ntrall y per J or da n et al 
( 2 0 1 2). Ce ntral r e vie w of l ocal p 1 6 I H C res ults b y Dr Ric har d J or da n will be re q uire d f or 
or o p h ar y n geal patie nts pri or t o ra n d o mizati o n.   
1 0. 2 
Tiss ue/ S peci me n S u b missi o n  
In t his st u d y, it is re q uire d  t hat tiss ue be s u b mitte d t o t he Bi os peci me n Ba n k at U C S F 
f or t he p ur p ose of p 1 6 ce ntral re vie w f or patie nts wit h or o p har y n geal carci n o mas a n d f or 
P D - L 1 e x pressi o n a nal ysis f or all patie nts. It is hi g hl y rec o m me n de d ( b ut o pti o nal f or t he 
patie nt) t hat if a n y tiss ue re mai ns after a n al ysis, it will be st ore d at t he Bi os peci me n Ba n k 
at U C S F f or f ut ure res earc h. 
 
I n a d diti o n, it is hi g hl y rec o m me n de d ( b ut o pti o nal f or t he patie nt) t hat peri p heral bl o o d 
s peci me ns be s u b mitte d f or t he test descri b e d i n Secti o n 1 0. 4  ( Peri p heral bl o o d 
C D 6 9/ 1 3 7 + acti vate d T cells a n d p he n ot y p e) a n d f or ba n ki n g f or f ut ure tra nslati o nal 
researc h.  
 
Tiss ue fr o m a bi o ps y or s ur gic al s peci me n will be o btai ne d fr o m f or m ali n fi x e d a n d 
paraffi n e m be d de d ( F F P E) i n tiss ue bl oc ks. I nstit uti o ns m ust s hi p F F P E tiss ue as o utli ne d 
i n Secti o n 1 0. 2  t o t he Bi os peci me n Ba n k at U C S F b y o ver ni g ht c o urier. 
 
S u b missi o n of H & E a n d p 1 6 stai ne d sli des t o t he Bi os peci me n Ba n k at U C S F f or ce ntral 
revie w of p 1 6 st ai ni n g is  re q uire d  f or or o p h ar y n geal patie nts a n d s u b missi o n of t he 
H & E a n d bl oc k ( or p u n c hes) is  re q uire d f or all patie nts f or P D- L 1 e x pressi o n a nal ysis. 
T he  F F P E sa m ples m ust ha ve s uffici e nt t u m or material f or b ot h a n al ys es.   
 
See t he ta ble bel o w. 
 
Ce ntral re vie w of p 1 6 f or patie nts wit h or o p har y n geal carci n o mas will be c o n d ucte d wit h 
ra pi d t ur nar o u n d ( 1- 2 b usi ness da ys fr o m recei pt of t he sli des) c o or di nat e d b y Dr. 
Ric har d J or da n at t he Bi os peci me n Ba n k. S pecifics of t y pe a n d s o urce of p 1 6 a nti b o d y 
a n d testi n g met h o d will b e re q uest e d (alt h o u g h n ot re q uire d) at t he ti me of s peci me n 
s u b missi o n. E ver y eff ort s h o ul d be ma de t o o btai n a n d s u b mit t his i nf or mati o n at t he ti me 
of s pe ci me n tra ns missi o n, i n or der t o e ns ure t he fastest p ossi ble res ol uti o n s h o ul d t here 
be a n y q uesti o ns a b o ut stai ni n g tec h ni q ue. 
 
N ote : D ue t o p ote ntial dela ys i n c ust o ms, Ca na dia n sites will be p er mitte d t o s u b mit a n 
A peri o di gital i ma ge of t he H & E a n d p 1 6 stai ne d sli de f or re m ote ce ntral re vie w b y Dr. 
J or da n.  Pri or a p pr o val f or t his m ust be o btai ne d fr o m t he Bi os peci me n Ba n k at U C S F. I n 
cases i n w hic h Dr. J or da n deter mi nes t hat t he i ma ge q u alit y or st ai ni n g is i na de q uate, t h e 
site will be re q uire d t o se n d t he ori gi nal sli des t o t he Bi os pe ci me n Ba n k dir ectl y. H & E 
sli des will still ha ve t o be s u b mitte d b y C a na dia n sites al o n g wit h t he F F P E bl oc k as per 
secti o n 1 0. 2 f or t he P D L e x pressi o n a nal ysis. 
 
H & E stai ne d sli des will be use d t o c o nfir m prese nce of t u m or i n t he sa m ple a n d t o ai d i n 

R T O G 3 5 0 4 
6 4   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
assa y i nter pretati o n a n d m ust be s u b mitte d wit h bl oc ks. T he pri mar y re vie wer will be t he 
P at h ol o g y C o- C hair, Ric har d J or da n, D D S, P h D, wit h sec o n dar y a nal ysis b y t he 
Pat h ol o g y C o- C hair, C hristi na K o n g, M D.  I nt er pretati o n of eac h p 1 6 i m m u n ostai ne d 
sli de will be perf or me d usi n g t he H-s c ore m et h o d descri be d b y J or da n, et al. ( 2 0 1 2) t hat 
has bee n vali dat e d as a relia ble, re pr o d uci ble, a n d acc urate met h o d t o sc ore p 1 6 i n 
s q ua m o us cell carci n o ma of t he hea d a n d nec k. p 1 6 I H C will be sc ore d as e val ua ble if 
str o n g a n d diff use p ositi vit y was o bser ve d i n t he tiss ue m o u nte d o n eac h sli de. T he 
hi g hest i nte nsit y of p 1 6 stai ni n g pres e nt i n t he t u m or will be sc ore d o n a n or di nal sc or e of 
0- 3, relati ve t o t he i nte nsit y of t he p ositi ve (sc ore 3) a n d ne gati ve (sc ore 0). T he perce nt 
of t u m or sta i ni n g at t he hi g hest i nte nsit y als o will be esti mate d wit hi n 5 % i ncre me nts. 
T he H sc ore is deri ve d fr o m t he cr oss pr o d uct of t he i nte nsit y sc ore ( 0 t o 3), a n d t he 
pe rce nt of t u m or stai ni n g at t he hi g h est i nte nsit y ( 0- 1 0 0 %).  A n o pti mal H-sc ore c ut- p oi nt 
of 6 0 o n a scal e of 0- 3 0 0 yi el ds a n a vera ge se nsiti vit y of 9 1. 6 % a n d s pecifi cit y of 9 0. 4 % 
f or H R- H P V o nc o ge ne e x pressi o n a n d t h us a n H-sc ore c ut- p oi nt of 6 0 i n di cates t hat a 
t u m or wit h diff use l o w-i nte nsit y n uclear a n d c yt o plas mic p 1 6 stai ni n g i n t he maj orit y of 
t he t u m or is a tr ue p ositi ve (J or da n 2 0 1 2).  Hi g h a gree me nt o n i nter-rater i nter pretati o n 
has bee n re p orte d ( Sc hle c ht 2 0 1 1, T ha varaj 2 0 1 1), i n dicati n g t he fa miliarit y of 
pat h ol o gists wit h i nter pretati o n of I H C assa ys.  Si milarl y, c o m para ble assa y perf or ma n ce 
f or p 1 6 t o t hat o bser ve d here has als o bee n pre vi o usl y re p orte d ( Sc hlec ht 2 0 1 1, T ha varaj 
2 0 1 1). T he m ost c o m m o n p 1 6 m o n ocl o nal a nti b o d y i n use is E 6 H 4 ( CI Nt ec). Ot her 
acce pta ble p 1 6 a nti b o d y t y pes i ncl u de 1 6 P 0 4 a n d J C 8.  If a differe nt p 1 6 a nti b o d y is 
use d, disc ussi o n wit h t he P at h ol o g y C o- C hairs is str o n gl y e n c o ura ge d. 
 
In cases i n w hi c h a maj or discre pa n c y arises b et wee n t he pri mar y e val uat or a n d t he 
ce ntral r e vie wer ( Dr. J or da n), t he p 1 6 stai ne d sli d e a n d t he ass o ciate d pr o b e a n d testi n g 
s pecifics will be se nt t o a sec o n dar y ce ntr al re vie wer, Dr. C. K o n g at Sta nf or d U ni versit y, 
t o res ol ve t he disa gree me nt. If p 1 6 st ai ni n g ca n n ot be esta blis he d as p ositi ve t hr o u g h t he 
ce ntral r e vie w pr ocess, t h e patie nt is n ot c o nsi dere d eli gi ble. 
 
S hi p F F P E bi os peci me ns f or m a n d at or y ce ntr al re vie w a n d P D - L 1 e x pressi o n, a n d 
f or o pti o n al b a n ki n g t o:  
( d o not s hi p fres h peri p her al bl o o d t o t his a d dress)  
Bi os peci me n Ba n k at U C S F 
2 3 4 0 S utter Street, R o o m S 3 4 1 ( B o x 1 8 0 0) 
Sa n Fra n cisc o, C A 9 4 1 1 5 
4 1 5 - 4 7 6- 7 8 6 4; R T O G @ ucsf.e d u   
 
S hi p all fres h peri p her al bl o o d  t o:  
Ferris La b orat or y  
Att n.: Sa n dra P o ve da Gi bs o n 
U ni versit y of Pitts b ur g h Ca ncer I nstit ute 
R o o m 2. 2 6 Hill ma n Researc h Pa vili o n 
5 1 1 7 C e ntre A ve n u e 
Pitts b ur g h, P A 1 5 2 1 3 
F or q uesti o ns: 4 1 2- 6 2 3 - 7 7 3 8 or 4 1 2- 4 4 3- 8 6 7 3; p o ve das @ u p mc.e d u  
 

R T O G 3 5 0 4 
6 5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
Alter nati vel y, c o nta ct Dr. Ferris: 4 1 2- 2 9 8- 7 0 0 2; ferrisrl @ u p mc.e d u 
 
 
See t he t a bles bel o w f or m a n d at or y a n d o pti o n al s peci me n c ollecti o n a n d A p pe n di x 
III f or f urt her det ails. 
 
See f urt her det ails of s peci me n c ollecti o n/ pr ocessi n g/s hi p pi n g o n t he R T O G we b 
site, htt p:// w w w.rt o g. or g/ Li n k Clic k. as p x ?filetic ket = 1 S Fl E V x S ui 4 % 3 d &t a bi d = 2 8 1 . 
1 0. 3  M a n d at or y St u dies ( 2 6 Dec 2 0 1 7) 
M a n d at or y  St u d y # 1: S peci me n C ollecti o n f or Ce ntr al p 1 6 C o nfir m ati o n  f or 
Or o p h ar y n ge al C a ncer P ati e nts  
T he s peci me ns are b ei n g c ollecte d f or c o nfir mati o n b y ce ntral r e vie w. I nstit uti o ns m ust 
scree n or o p har y n geal patie nts b y  i m m u n o hist oc he mistr y pri or t o re gistrati o n  
 
 Re q uire d F or ms: S T f or m  a n d pat h ol o g y re p orts  wit h accessi o n n u m ber , d ate of 
pr oce d ure,  a n d p 1 6 stai ni n g res ult; a n y ot h er pers o nal healt h i nf or mati o n ( P HI) 
s h o ul d be re dacte d. 
 S hi p pi n g c osts : S u b mitti n g site p a ys c ost of s hi p pi n g.  
 Resi d ual Material:  p 1 6 sli des will be retai ne d u nl ess ret ur n is r e q u este d b y t he 
s u b mitti n g site; sites s h o ul d s u b mit a ret ur n re q uest f or m wit h a ret ur n air bill . 
H & E sli de will be retai ne d f or all cas es.  
 
 
S hi p ce ntr al re vie w s peci me ns t o:  
Bi os peci me n B a n k at U C S F  
2 3 4 0 S utter Street, R o o m S 3 4 1  
S a n Fr a ncisc o, C A 9 4 1 1 5  
 
F or q uesti o ns, c o nta ct:   
Bi os peci me n Ba n k at U C S F ; R T O G @ ucsf.e d u ; 4 1 5-4 7 6 -7 8 6 4/ F A X 4 1 5 -4 7 6 -5 2 7 1  
S peci me n T y pe  
C ollecti o n Ti me 
P oi nts  
C ollecti o n 
I nf or m ati o n a n d 
Re q uire me nts  
S hi p pi n g  
O ne H & E sli de  
O ne p 1 6 stai ne d 
I H C sli de 
 
N ote: B ot h sli des 
m ust be fr o m t he 
sa me bl oc k. T he 
H & E ca n be a 
d u plicate c ut sli de.  
Pre -Treat me nt  
E nr olli n g i nstit uti o n, 
usi n g a C LI A certifie d 
la b orat or y, scree ns 
patie nt wit h p 1 6 testi n g 
b y I H C . Th e n 
Bi os peci me n Ba n k 
d oes ce ntr al re vie w . 
 
Sli des s hi p pe d 
a m bie nt  t o t he 
U C S F Bi os peci me n 
Ba n k  
M a n d at or y  St u d y # 2 : T u m or P D -L 1 E x pressi o n f or All P atie nts  
S peci me ns are b ei n g c oll ecte d t o deter mi ne if pati e nts wit h P D -L 1 p ositi ve t u m ors will 
ha ve a n i m pr o ve d P F S w he n treate d wit h ni v ol u ma b i n c o m paris o n t o patie nts wit h P D -
L 1 ne gati ve t u m ors  (see Secti o n 2. 7  f or f urt her details). 
 F F P E bl oc ks a n d p u n c hes m ust ha ve s uffici e nt t u m or cells prese nt i n t he s a m ple 

R T O G 3 5 0 4 
6 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
bei n g s u b mitte d f or P D L 1 testi n g.  
 Re q uire d F or m: S T f or m  a n d pat h ol o g y re p orts wit h accessi o n n u m ber, d at e of 
pr oce d ure; a n y ot her p ers o nal healt h i nf or mati o n ( P HI) s h o ul d b e re d acte d.  
 S hi p pi n g c osts: Ret ur n la bels are  pr o vi d e d f or fr oze n bi os peci me ns o nl y.  
 
S hi p s peci me ns t o:  
Bi os peci me n B a n k at U C S F  
2 3 4 0 S utter Street, R o o m S 3 4 1  
S a n Fr a ncisc o, C A 9 4 1 1 5  
 
F or q uesti o ns, c o nta ct:   
Bi os peci me n Ba n k at U C S F; R T O G @ ucsf.e d u ; 4 1 5 -4 7 6 -7 8 6 4/ F A X 4 1 5 -4 7 6 -5 2 7 1  
S peci me n T y pe  
C ollecti o n Ti me 
P oi nts  
C ollecti o n 
I nf or m ati o n a n d 
Re q uire me nts  
S hi p pi n g  
Re prese ntati ve H & E 
stai ne d sli des of t he 
pri mar y t u m or  or 
metastatic l y m p h 
n o de . Ca n be a 
d u plicate c ut sli de, 
d oes n ot ha ve t o be 
t he dia g n ostic sli de.  
Pre -treat me nt 
H & E stai ne d sli de  
(ca n be t h e sa me 
o ne s u b mitte d f or 
ce ntral r e vie w, if 
a p plica ble)  
 
Sli de s hi p pe d 
a m bie nt  t o t he 
U C S F Bi os peci me n 
Ba n k  
A c orres p o n di n g  
paraffi n -e m be d d e d 
tiss ue bl oc k or o ne 
t o t w o 3 m m 
p u nc hes of t he 
pri mar y t u m or  or 
metastatic l y m p h 
n o de  ta ke n bef ore 
i nitiati o n of 
treat me nt 
Pre -treat me nt 
Paraffi n -e m be d de d 
tiss ue bl oc k or 
p u nc h bi o psies fr o m 
t he bl oc k. If 
e m be d de d p u nc h es 
are s u b mitte d t he 
H & E fr o m t he 
p u nc h bl oc k m ust 
als o be se nt  
Bl oc k or p u n c hes  
s hi p pe d a m bie nt 
(s hi p wit h a c ol d 
pac k d uri n g h ot 
weat her)  t o t he 
Bi os peci me n Ba n k  
 
 
1 0. 4 O pti o n al S peci me n C ollecti o n f or R T O G 3 5 0 4 Rese arc h a n d B a n ki n g   
 
O pti o n al St u d y # 1 : Peri p her al bl o o d C D 6 9/ 1 3 7 + acti v ate d  T cells  a n d p he n ot y pe  
Patie nts m ust be offere d t he o p p ort u nit y t o c o ns e nt t o o pti o nal s peci me n c ollecti o n. If t he 
patie nt c o nse nts t o partici pate, t he site is re q uire d t o s u b mit t he patie nt’s s peci me ns as 
s pecifie d i n t he pr ot oc ol. Sites are n ot per mitte d t o delete t he s peci me n c o m p o ne nt fr o m 
the pr ot oc ol or fr o m t he s a m ple c o nse nt.  
 
S peci me ns are b ei n g c oll ecte d t o deter mi ne if acti vate d, C D 6 9 + or C D 1 3 7 + T cells will 
i ncreas e i n t he circ ul ati o n of ni v ol u ma b-treate d patie nts (see Secti o n 2. 7  f or f urt her 
details)  a n d t o c orrelate t heir p he n ot y pe, a n d c o -sti m ulat or y/c o-i n hi bit or y rece pt ors wit h 
cli nical res p o nse.  
 

R T O G 3 5 0 4 
6 7   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
 Re q uire d F or m: St u d y s pecific S T f or m  f or peri p h eral bl o o d 
 S hi p pi n g da ys: M o n da y -We d nes da y ( U. S. sites); M o n da y -T ues da y ( Ca na d a a n d 
N o n -N ort h A me rica n). 
 S hi p pi n g la bels will be pr o vi de d wit h kits f or peri p heral bl o o d  fr o m t he U C S F 
Bi os peci me n Ba n k .  
S hi p s peci me ns t o :  
Ferris La b orat or y  
Att n.: Sa n dra P o ve da Gi bs o n  
R o o m 2. 2 6  Hill ma n Researc h Pa vili o n  
5 1 1 7 Ce ntre A ve n u e  
Pitts b ur g h, P A 1 5 2 1 3  
 
F or q uesti o ns, c o nta ct:  Sa n dra Gi bs o n ( Ferris L a b ), 4 1 2-6 2 3 -7 7 3 8 or 4 1 2 -4 4 3 -8 6 7 3; 
p o ve das @ u p mc.e d u  
Sites s h o ul d e mail t he Ferris la b trac ki n g i nf or mati o n bef ore s hi p pi n g t he s a m ples.  
 
Alter nati vel y, c o nta ct Dr. Ferris: 4 1 2 -2 9 8 -7 0 0 2; ferrisrl @ u p mc.e d u 
 
S peci me n T y pe  
C ollecti o n Ti me 
P oi nts  
C ollecti o n 
I nf or m ati o n a n d 
Re q uire me nts  
S hi p pi n g  
Peri p heral Bl o o d 
M o n o n uclear Cells 
( P B M C) –  f o ur 1 0 
ml or fi ve 8 ml 
g ree n t o p ( h e pari n) 
t u bes 
 Pre -treat me nt 
( da y -1 4)  
 P ost -treat me nt: 3 
a n d 6 m o nt hs 
after R T  
See A p pe n di x I V  
f or pr ocess i n g a n d 
s hi p pi n g 
i nf or mati o n  
S hi p fres h at r o o m 
te m perat ur e 
o ver ni g ht f or 
m or ni n g deli ver y  t o 
t he Ferris 
La b o rat or y 
 
1 1. 
S P E CI A L S T U DI E S ( N O N- TI S S U E) 
N ot A p plic a ble 
 
1 2. M O D A LI T Y R E VI E W S 
1 2. 1 
R a di ati o n T her a p y Q u alit y Ass ur a nce Re vie ws  
T he  Ra diati o n O nc ol o g y C o- C hair, L ore n Mell, M D will perf or m o n g oi n g re m ote R T 
Q ualit y Ass ura nce Re vie w after cases e nr olle d ha ve bee n recei ve d at R T Q A. 
 
T he  g o al of t he re vie w is t o e val uate pr ot oc ol c o m plia nce.  T he re vie w pr ocess is 
c o nti n ge nt o n ti mel y s u b missi o n of ra di ot hera p y treat me nt data as s pecifi e d i n Secti o n 
1 3 .1 . T he sc ori n g mec h a nis m is: Per Pr ot oc ol, Variati o n Acce pt a ble, a n d De viati o n 
U nacce pta ble. 
1 2 . 2 
Dr u g Q u alit y Ass ur a nce Re vie ws  
T he C o -Pri nci pal I n vesti gat or/ M e dical O n c ol o g y, Ma ura Gillis o n, M D, P h D a n d Me dical 
O nc ol o g y C o- C h air, A. Di mitri os C ole vas, M D, will perf or m a C he m ot hera p y Ass ura n ce 
Re vie w of all patie nts w h o recei v e or are t o r ecei v e dr u g t hera p y i n t his trial.  T he g o al of 
t he re vie w is t o e v al uate pr ot oc ol c o m plia nce.  T h e re vie w pr ocess is c o nti n ge nt o n 
ti mel y s u b missi o n of dr u g treat me nt data as s pecifie d i n Secti o n 1 3 . T he sc ori n g 

R T O G 3 5 0 4 
6 8   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
mec ha nis m is: Per Pr ot oc ol/ Acce pta ble Variati o n, U nacce pta ble De viati o n, a n d N ot 
E val ua ble.  A re p ort is se nt t o eac h i nstit uti o n o nce per year t o n otif y t he i nstit uti o n a b o ut 
c o m plia nce f or eac h cas e re vie we d i n t h at year. 
 
Dr s. Gillis o n a n d C ole vas will perf or m a Q ualit y Ass ura nce Re vie w after R T O G 
He a d q uarters has recei ve d c o m plete data f or t he first 2 0 cases e nr olle d. Drs. Gillis o n a n d 
C ole vas will perf or m t he ne xt re vie w after R T O G Hea d q uarters has recei ve d c o m plete 
data f or t he n e xt 2 0 cases e nr olle d. T he fi n al cas es will be re vie we d wit hi n 3 m o nt hs after 
t his st u d y h as reac he d t h e tar get accr ual or as s o o n as R T O G Hea d q uarters has recei ve d 
co m plete data f or all cas es e nr olle d, w hic he v er occ urs first. 
1 2. 3 
S ur gic al Q u alit y Ass ur a nce Re vie ws  
P atie nts wit h oral ca vit y ca ncer are e x cl u de d fr o m partici pati o n if res ecti o n of t he 
pri mar y t u m or is c o nsi dere d tec h nicall y feasi ble b y a n oral or h ea d a n d n ec k ca ncers 
s ur gic al s u bs pecialist. C o- Pri nci pal I n vesti gat or/ S ur gi cal O nc ol o g y, Dr. R o bert Ferris 
M D , P h D, will re vie w i n di vi d ual cases as t he y arise t o d oc u me nt a p pr o pri ate ness f or 
accr ual a n d reas o n(s) f or dee mi n g cases u nresecta ble.  
 
Drs. Ferris als o will re vie w cases after R T O G Hea d q uarters has recei ve d c o m plete data 
f or t he first 5 s uc h oral c a vit y cases e nr olle d, a n d after eac h 5 cases t h ereafter. T he fi nal 
cases will be re vie we d wit hi n 3 m o nt hs after t his st u d y has reac he d t he tar get accr ual or 
as s o o n as R T O G Hea d q uarters has recei ve d c o m plete data f or all cas es e nr olle d, 
w hic he ver occ urs first.  
 
1 3.  D A T A A N D R E C O R D S  
T his st u d y will utilize 
Me di d at a R a ve. See t he D at a C ollecti o n/ R A V E D at a F o r ms 
G ui de i n t he st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he 
R T O G w e bsite, w w w.rt o g. or g,  f or f urt her det ails. 
1 3. 1 S u m m ar y of D osi metr y Di git al D at a S u b missi o n ( S u b mit t o R T O G vi a T RI A D; see  t he 
st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he R T O G 
w e bsite, w w w.rt o g. or g , f or det ails  of d at a s u b missi o n a n d T RI A D.) ( 2 6 Dec 2 0 1 7) 
 
Ite m 
D ue   
DI C O M It e ms  
DI C O M C T I m a ge  
Wit hi n 1 
wee k of 
st art of R T 
 
 
 
 
 
 
 
 
 
DI C O M Str uct ure  
DI C O M D ose  
DI C O M R T Pla n  
All re q uire d str uct ure s m ust be l a bele d per t he t a ble i n Secti o n  
5. 2. 5 .  
D V H A nal ysis W or ks heet  ( o pti o nal) t o be s u b mitte d via T RI A D wit h 
R T Di gital Data liste d a b o ve: 
htt ps:// w w w.rt o g. or g/ Cli nical Trials/ R T O G F o u n d ati o n St u dies/ R T O G F o
u n dati o n St u d y 3 5 0 4/ R T O G 3 5 0 4 F or ms.as p x  
  

R T O G 3 5 0 4 
6 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
U p o n s u b missi o n of t he di gital d ata vi a T RI A D, c o m plete a n o nli n e 
Di git al  
D at a  
S u b missi o n  
I nf or m ati o n  
F or m  
( D D SI) :  
htt ps: // w w w.rt o g. or g/ C orela b/ T RI A D.as p x 
N O T E : A L L SI M U L A TI O N A N D P O R T A L FI L M S A N D/ O R DI GI T A L FI L M I M A G E S 
WI L L B E K E P T B Y T H E I N S TI T U TI O N A N D O N L Y S U B MI T T E D I F R E Q U E S T E D.  
 
1 4. S T A TI S TI C A L C O N SI D E R A TI O N S 
1 4. 1 
St u d y Desi g n  
1 4 . 1.1 T otal Accr ual  
 
4 0 ( mi ni m u m) t o ha ve 8  e val ua ble p atie nts per ar m.  
1 4. 2 
St u d y E n d p oi nts ( 2 6 Dec 2 0 1 7) 
Pri m ary E n d p oi nts:  
 D ose  li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b (a nti P D- 1 i m m u n ot hera p y) 
t o c he m ora di ot hera p y wit h wee kl y cis plati n ( 4 0 m g/ m2/ wee k x 7) f or patie nts 
wit h i nter me diate- or hi g h-ris k  hea d a n d nec k s q u a m o us cell carci n o ma 
( HN S C C); 
 D ose  li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b t o c he m ora di ot hera p y wit h 
hi g h- d ose cis plati n ( 1 0 0 m g/ m 2  q 2 1 da ys x 3) f or patie nts wit h i nter me diate- or 
hi g h-ris k  h ea d a n d n ec k s q ua m o us cell carci n o ma ( H N S C C); 
 D ose  li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b t o c he m ora di ot hera p y wit h 
wee kl y cet u xi ma b ( 4 0 0 m g/ m 2 l oa d, 2 5 0 m g/ m2/wee k x 7) f or patie nts wit h  
i nter me diate- or hi g h-ris k  hea d a n d n ec k s q ua m o us cell carci n o ma ( H N S C C); 
 D ose  li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b t o ra di ot hera p y f or pati e nts 
wit h i nter me diate- or hi g h-ris k  hea d a n d nec k s q u a m o us cell carci n o ma 
( HN S C C) wit h o ne t o f o ur of t he f oll o wi n g :  a ge ≥ 7 0 years; Z u br o d Perf or ma nce 
Stat us 2; baseli ne gra de ≥ 3 ne ur o pat h y; gra d e ≥2  heari n g l oss; Cr Cl < 5 0 
ml/ mi n. 
Sec o n d ary E n d p oi nt : T o e val uate t he s afet y, feasi bilit y a n d patie nt c o m plia nce wit h 
a dj u va nt a d mi nistrati o n of si n gle a ge nt ni v ol u ma b f or a ma xi m u m of 1 year of t hera p y 
( Ni v ol u ma b, 4 8 0 m gs q 2 8 da ys x 7).  
 
  
Als o t o be e val uate d at t he c o m pleti o n of t his trial will be t he a bilit y of pati e nts t o 
t olerate t he pla n n e d treat me nt per pr ot oc ol. A patie nt will be c o nsi dere d t o ha ve t olerat e d 
pr ot oc ol t hera p y if t he f oll o wi n g criteria are met: 
i) 
Ra diati o n t hera p y was d eli vere d wit hi n 8 wee ks; 
ii) 
Patie nt was a d mi nistere d ≥7 0 % of t he ni v ol u ma b d ose per pr ot o c ol (e x cl u di n g 
adj u va nt t hera p y); 
iii) 
Patie nt was a d mi nistere d ≥7 0 % of t he cet u xi ma b d ose per pr ot o c ol, w here 
a p plica ble; 
i v) 
Patie nt was a d mi nistere d  ≥7 0 % of t he cis plati n d ose per pr ot oc ol, w here 
a p plica ble. 
1 4. 3 
Pri m ar y O bjecti ves St u d y Desi g n  
1 4 . 3.1  Sa m ple Siz e a n d P o wer Calc ulati o ns 
Patie nts will be se q ue nci all y e nr olle d i nt o Ar ms 1, 2 a n d 3. T he g oal of Ar m 1 is t o 
c o nfir m t he safet y of a nti- P D - 1 t hera p y a d mi nistere d i n c o m bi nati o n wit h wee kl y 

R T O G 3 5 0 4 
7 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
cis plati n- base d c h e m ora di ot hera p y.  Ar ms 1, 3, a n d 4 will start at t he fi x e d- d ose 
bi oe q ui va le nt ( 2 4 0 m gs) of t he F D A-a p pr o ve d  d ose a n d sc he d ul e  of ni v ol u ma b ( 3 
m g s/ k g q 1 4 da ys). F or a n y ar m, i n t he e ve nt of 0- 2 D L T e ve nts, t he re gi me n will be 
co nsi dere d w ort h y of a d diti o nal st u d y. If > 2 of 8 D L Ts o cc ur, t h e re gi me n will be 
c o nsi dere d t o o t o xic f or f urt her st u d y. O bser vati o n of t he last patie nt f or t he peri o d of 
D L T ( 2 8 da ys p ost-c o m pleti o n of R T) is ma n dat or y. A D L T will be defi ne d as: ( 1) A n y ≥ 
gra de 3  a d v erse e ve nt ( C T C A E, v. 4) t hat is relate d t o ni v ol u ma b t hat d oes n ot res ol ve t o 
g ra de 1 or l ess wit hi n 2 8 da ys; ( 2) A del a y i n ra di ot hera p y of > 2 wee ks d u e t o t o xicit y 
relate d t o ni v ol u ma b;  ( 3) I n a bilit y t o c o m plete ra di ot hera p y d ue t o t o xicit y relate d t o 
ni v ol u ma b; or ( 4) I na bilit y t o recei ve a n a d e q uate d ose ( ≥ 7 0 %) of cis plati n ( Ar m 1 a n d 
2) or cet u xi ma b ( Ar m 3) d ue t o t o xicit y defi nitel y relate d t o ni v ol u ma b.   Wit h a c o h ort 
of 8 p atie nts, t he  pr o ba bilit y of t he ni v ol u ma b ar m bei n g j u d ge d t o b e t o o t o xic w he n t he 
tr ue t o xicit y rate is 4 5 % or hi g her is at least 7 8 %. If t he tr ue t o xicit y rate is 2 0 % or l o wer, 
t he pr o ba bilit y t hat t he t h era p y will be safe is 8 0 %. T he peri o d of o bs er vati o n f or D L T is 
fr o m t he start of ni v ol u ma b t hr o u g h 2 8 da ys p ost-c o m pleti o n of ra di ot hera p y.  
 
W e will accr ue 1 0 p atie nts per c o h ort t o get 8 e v al ua ble patie nts, if m ore t h a n 8 patie nts 
are e v al ua ble, w e will a n al yze dat a fr o m t he first 8 patie nts. All patie nts w h o recei v e at 
least o ne d ose of ni v ol u ma b are c o nsi dere d e val u a ble f or D L T, s h o ul d a D L T o cc ur. I n 
t he a bse nce of D L T, p atie nts m ust ha ve recei ve d at least o ne fracti o n of ra diati o n t hera p y, 
at least o ne d ose of cis plati n or cet u xi ma b ( w here a p plica ble), a n d ha ve c o m plete d t he 
D L T o bs er vati o n peri o d t o be e val ua bl e f or D L T. P atie nts c o nsi dere d i ne val ua ble ma y be 
replace d t o e ns ure a mi ni m u m of 8 e val ua ble patie nts per ar m. T heref ore, t h e t otal 
n u m ber of patie nts e nr olle d i nt o a n y o n e ar m of t he st u d y ma y e x cee d 1 0. A nal ysis 
res ults will be re vie we d b y t he R T O G F o u n dati o n D M C.  
 
In t his trial, we will e val uate t he feasi bilit y of 7 m o nt hs of a dj u va nt ni v ol u ma b. We will 
pr os pecti vel y m o nit or c o m plia nce wit h t hera p y i n all 4 ar ms of t he t he trial. T he peri o d of 
o bser vati o n f or feasi bilit y is fr o m t he start of a dj u va nt ni v ol u ma b t hr o u g h 7 m o nt hs of 
t hera py.  We will e val uat e t he first 8 patie nts fr o m all 4 ar ms. If m ore t h a n 4 patie nts st o p 
t he adj u va nt t hera p y b ef ore 7 m o nt hs, we will c o nsi der t he a dj u va nt t hera p y i nfeasi ble. 
E vi de nce of i nfeasi bilit y w o ul d i ncl u de: patie nt ref usal; disc o nti n uati o n d ue t o dr u g 
relate d t o xicit y; p h ysici a n decisi o n t hat t hera p y is n o l o n ger i n t he best i nterests of t he 
patie nt i n t he a bse nce of disease pr o gressi o n. I n t h at e ve nt, a d mi nistrati o n of a dj u va nt 
ni v ol u ma b w o ul d be disc o nti n ue d. Wit h a c o h ort of 8 patie nts fr o m all 4 ar ms, t he 
pr o ba bilit y of t he ni v ol u ma b ar m bei n g j u d ge d t o be i nfeasi ble w he n t he tr ue 
n o nc o m plia nce rate is 7 0 % or hi g h er is at least 8 1 %. If t he tr u e n o nc o m plia nce rate is 
4 0 % or l o wer, t h e pr o ba bilit y t hat t he t hera p y will be feasi ble is 8 3 %. 
 
1 4. 4 
Accr u al/ St u d y D ur ati o n C o nsi der ati o ns  
All n o n - Ar m 4 patie nts will be re gistere d t o Ar m 1 i nitial d ose u ntil t he sa m ple siz e is 
reac h e d, t he n t o Ar m 2 i nitial d ose, t he n t o Ar m 3 i nitial d ose. Ar m 4 will be o pe n 
co nc urre ntl y wit h Ar ms 1/ 2/ 3. T he accr ual ti me f or t he 4 c o h orts i n p hase I will ta ke 
ap pr o xi matel y 5 m o nt hs ( 1 0 sites). T he st u d y ti me will be a p pr o xi matel y 1 2- 1 8 m o nt hs.  
1 4. 5 
D ose Le vel G ui deli nes 
 
S ee Secti o n 5. 1. 1 . 

R T O G 3 5 0 4 
7 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R E F E R E N C E S 
 
A k ba y E A, et al. Acti vati o n of t he P D- 1 pat h wa y c o ntri b utes t o i m m u ne esca pe i n E G F R- dri ve n 
l u n g t u m ors. C a ncer Dis c ov . 2 0 1 3; 3( 1 2): 1 3 5 5- 6 3. 
 
Al bers A, et al. A ntit u m or acti vit y of h u ma n pa pill o ma vir us t y pe 1 6 E 7-s pecific T cells a gai nst 
virall y i nf ecte d s q ua m o us cell carci n o ma of t he h ea d a n d n ec k. C a ncer R es . 2 0 0 5; 6 5( 2 3): 
1 1 1 4 6- 5 5. 
 
Al bers A E, et al. T cell-t u m or i nteracti o n directs t he de vel o p me nt of i m m u n ot hera pies i n hea d 
a n d nec k ca ncer. Cli n Dev I m m u n ol . 2 0 1 0; 2 0 1 0: 2 3 6 3 7 8.  
 
A n g K K. C o nc urre nt ra di ati o n c he m ot hera p y f or l ocall y a d va n ce d hea d a n d nec k carci n o ma: are 
we a d dressi n g b ur ni n g s u bjects? J Cli n O nc ol . 2 2( 23): 4 6 5 7- 9, 2 0 0 4. E p u b 2 0 0 4 N o v 8. P MI D: 
1 5 5 3 4 3 6 1 
 
A n g K, et al. H u ma n p a pill o ma vir us a n d s ur vi val of patie nts wit h or o p har y n geal ca n cer. N E J M.  
2 0 1 0; 3 6 3( 1): 2 4- 3 5. 
 
A nt o nia S, Gr oss o J F, H ora k, C E, et al. Ass ociati o n of t u m or P D- L 1 e x pressi o n a n d i m m u ne 
bi o mar kers wit h cli nical acti vit y i n patie nts wit h N S C L C treate d wit h ni v ol u ma b. Oral 
prese ntati o n, 2 0 1 3. W orl d C o n gress o n L u n g Ca n cer, P 2. 1 1- 0 3 5. 
 
Bac h a u d J M, C o he n-J o nat ha n E, Alzie u C, et al. C o m bi ne d p ost o perati ve ra di ot hera p y a n d 
wee kl y cis plati n i nf usi o n f or l ocall y a d v a nce d h ea d a n d nec k carci n o ma: fi nal re p ort of a 
ra n d o mize d trial. IJ R O B P. 3 6( 5): 9 9 9- 1 0 0 4, 1 9 9 6. P MI D: 8 9 8 5 0 1 9 
 
Ba d o ual C, et al. P D- 1-e x pressi n g t u m or-i nfiltrati n g T cells are a fa v ora ble pr o g n ostic bi o mar k er 
i n H PV-ass ociate d h ea d a n d nec k ca ncer. C a ncer R es. 2 0 1 3; 7 3( 1): 1 2 8- 3 8. 
 
Ba hi g H, F orti n B, Aliz a de h M, et al. Pre dicti ve fact ors of s ur vi v al a n d treat me nt t olera nce i n 
ol der patie nts treat e d wit h c he m ot hera p y a n d ra di ot hera p y f or l o call y a d va nce d hea d a n d nec k 
ca ncer. Or al O nc ol . 2 0 1 5 Ma y; 5 1( 5): 5 2 1- 8. 
 
Bar ber D L, et al. Rest ori n g f u ncti o n i n e x ha uste d C D 8 T cells d uri n g c hr o nic viral i nfecti o n. 
N at ure . 2 0 0 6; 4 3 9( 7 0 7 7): 6 8 2- 7. 
 
Ba uer n h ofer T, et al. Prefere ntial a p o pt osis of C D 5 6 di m nat ural killer cell s u bset i n patie nts wit h 
ca ncer. E ur J I m m u n ol . 2 0 0 3; 3 3( 1): 1 1 9- 2 4. 
 
B a ujat B, et al. H y p erfracti o nate d or accel erate d ra di ot hera p y f or hea d a n d nec k ca ncer. 
C oc hr a ne D at a b ase Syst Rev . 2 0 1 0; ( 1 2): C D 0 0 2 0 2 6. 
 
Ba u ma n J E, Ferris R L. I nte grati n g n o v el t hera pe utic m o n ocl o nal a nti b o dies i nt o t he ma na ge me nt 
of hea d a n d n ec k ca ncer. C a ncer.  2 0 1 3 2 0 1 3 N o v 1 2. d oi: 1 0. 1 0 0 2/c ncr. 2 8 3 8 0. [ E p u b a hea d of 
pri nt]. 
 

R T O G 3 5 0 4 
7 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R E F E R E N C E S ( C o nti n ue d) 
 
Bec k m a n G K, H o p p e F, Pfre u n d ner L, et al. H y perfracti o nate d accel erate d ra di ot hera p y i n 
c o m bi nati o n wit h wee kl y cis plati n f or l ocall y a d va nce d hea d a n d nec k ca ncer. He a d Neck  2 7( 1): 
3 6- 4 3, 2 0 0 5. P MI D: 1 5 4 5 9 9 1 8 
 
B ers o n A M, Stei n N F, et al. Varia bilit y of gr oss t u m or v ol u me deli neati o n i n hea d a n d nec k 
ca ncer usi n g P E T/ C T f usi o n, part II: T he i m pact of a c o nt o uri n g pr ot oc ol. Me d. D osi metry . 2 0 0 9; 
3 4 ( 1 ), 3 0- 3 5. 
 
B la nc h ar d P, et al. Meta- a nal ysis of c he m ot hera p y i n hea d a n d nec k ca ncer ( M A C H- N C): A 
c o m pre he nsi ve a nal ysis b y t u m o ur site. R a di ot her O nc ol . 2 0 1 1; 1 0 0( 1): 3 3- 4 0. 
 
B M S- 9 3 6 5 5 8 ( ni v ol u ma b) I n vesti gat or Br oc h ure, Versi o n 1 3. Brist ol- M yers S q ui b b, Pri ncet o n, 
Ne w J erse y, 2 8 J ul y 2 0 1 4.  
 
B o n ner J A, et al. Ra di ot h era p y pl us cet u xi ma b f or l oc ore gi o nall y a d va n ce d hea d a n d n ec k 
ca ncer: 5- year s ur vi val d ata fr o m a p h ase 3 ra n d o mise d trial, a n d relati o n bet wee n cet u xi ma b-
i n d uce d ras h a n d s ur vi val. L a ncet O nc ol . 2 0 1 0; 1 1( 1): 2 1- 8. 
 
B o n ner J A, et al. Ra di ot h era p y pl us cet u xi ma b f or s q ua m o us-cell carci n o ma of t he hea d a n d 
nec k. N EJ M . 2 0 0 6; 3 5 4( 6): 5 6 7- 7 8. 
 
B o ur his J, et al. C o nc o mita nt c he m ora di ot hera p y v ers us accelerati o n of ra di ot hera p y wit h or 
wit h o ut c o nc o mita nt c he m ot hera p y i n l ocall y a d v a nce d h ea d a n d n ec k carci n o ma ( G O R T E C 9 9-
0 2): A n o pe n-la b el p hase 3 ra n d o mise d trial. L a ncet O nc ol . 2 0 1 2; 1 3( 2): 1 4 5- 5 3. 
 
B o ur his J, et al. H y p erfracti o nate d or accel erate d ra di ot hera p y i n hea d a n d nec k ca ncer: a meta-
a nal ysis. L a ncet. 2 0 0 6; 3 6 8( 9 5 3 8): 8 4 3- 5 4. 
 
Bra h m er J R, et al. Safet y a n d acti vit y of a nti- P D - L 1 a nti b o d y i n patie nts wit h a d va nce d ca ncer. 
N EJ M . 2 0 1 2; 3 6 6( 2 6): 2 4 5 5- 6 5. 
 
B rizel D M, et al. H y perfracti o nate d irra diati o n wit h or wit h o ut c o nc urre nt c he m ot hera p y f or 
l ocall y a d va nce d hea d a n d nec k ca ncer. N EJ M . 1 9 9 8; 3 3 8( 2 5): 1 7 9 8- 8 0 4. 
 
B u dac h V, et al. H y p erfracti o nate d accel erat e d c h e m ora diati o n wit h c o nc urre nt fl u or o uracil-
mi t o m yci n is m ore effecti ve t ha n d ose-es calate d h y p erfracti o nate d accelerate d ra diati o n t hera p y 
al o ne i n l ocall y a d va n ce d hea d a n d n ec k ca ncer: Fi nal res ults of t he ra di ot hera p y c o o perati ve 
cli nical trials gr o u p of t h e Ger ma n C a ncer S ociet y 9 5- 0 6 Pr os pecti ve Ra n d o mize d Trial. J Cli n 
O nc ol . 2 0 0 5; 2 3( 6): 1 1 2 5- 3 5. 
 
B u dac h W, et al. A m eta- a nal ysis of h y perfracti o nate d a n d accelerat e d ra di ot hera p y a n d 
c o m bi ne d c he m ot hera p y a n d ra di ot hera p y re gi me ns i n u nresecte d l ocall y a d va nce d s q ua m o us 
cell carci n o ma of t he h ea d a n d nec k. B M C C a ncer . 2 0 0 6; 6: 2 8. 
 
 

R T O G 3 5 0 4 
7 3   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R E F E R E N C E S ( C o nti n ue d) 
 
Calla ha n M K, W olc h o k J D. At t he be dsi de: C T L A- 4- a n d P D- 1- bl o c ki n g a nti b o dies i n ca ncer 
i mm u n ot hera p y. J Le uk o c Bi ol . 2 0 1 3; 9 4( 1): 4 1- 5 3. 
 
Car m o na R, Za keri K, Gree n G, et al. N o vel met h o d t o stratif y el d erl y pati e nts wit h hea d a n d 
nec k ca ncer. Pr oc A mer S oc Cli n O nc ol . 2 0 1 5 s u p pl; a bstr 1 4 7 4 0 2. 
 
Cella D F, T uls k y D S, Gra y G, et al. T he F u ncti o n al Assess me nt of Ca ncer T hera p y scale: 
D e vel o p me nt a n d v ali dati o n of t he ge neral meas ure. J Cli n O nc ol .  1 9 9 3; 1 1: 5 7 0- 9. 
 
C ella D, Y o u nt S, R ot hr oc k N, et al. P R O MI S C o o perati ve Gr o u p. T he Patie nt- Re p orte d 
O utc o mes Meas ur e me nt I nf or mati o n S yste m ( P R O MI S): Pr o gress of a n NI H R oa d ma p 
c o o perati ve gr o u p d uri n g its first t w o years. Me d C are . 2 0 0 7; 4 5( 5 S u p pl 1):S 3 -S 1 1. 
 
Cella D, Lai J, Garcia S F, et al. T he Patie nt Re p orte d O utc o mes Meas ure m e nt I nf or mati o n 
S yste m- Ca ncer ( P R O MI S- Ca): Ca ncer-s pecifi c a p plicati o n of a ge neric fati g ue meas ure. 
[ A bstract]. J Cli n O nc ol. 2 0 0 8; 2 6, 6 5 3 7. 
 
C ha n A T, Te o P M, H ua n g D P. Pat h o ge nesis a n d treat me nt of n as o p har y n geal carci n o ma. Se mi n 
O nc ol. 3 1( 6): 7 9 4- 8 0 1, 2 0 0 4. P MI D: 1 5 5 9 9 8 5 7 
 
C ha n A T, Le u n g S F, N ga n R K, et al.  O verall s ur vi val after c o nc urre nt cis plati n-ra di ot hera p y 
co m pare d wit h r a di ot hera p y al o ne i n l oc ore gi o nall y a d v a nce d n as o p har y n geal carci n o ma. J N CI. 
9 7( 7) : 5 3 6- 9, 2 0 0 5. P MI D 1 5 8 1 2 0 8 0 
 
C harls o n M E, P o m pei P, Ales K L, Mac Ke nzie C R. A ne w met h o d of classif yi n g pr o g n ostic 
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8 3. 
 
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meas ure me nts. Ot ol o gy a n d Ne ur ot ol o gy . 2 0 1 2; 1 4 7 ( 4): 7 3 7- 7 4 3. 
 
W ater b oer T, et al. M ulti ple x h u ma n pa pill o ma vir us ser ol o g y b ase d o n i n sit u- p urifie d 
gl utat hi o ne s-tr a nsferase f usi o n pr otei ns. Cli n C he m . 2 0 0 5; 5 1( 1 0): 1 8 4 5- 5 3. 
 
W hitesi de T L. I m m u ne cells i n t he t u m or micr oe n vir o n me nt. Mec ha nis ms res p o nsi ble f or 
f u ncti o nal a n d si g nali n g defects. A d v Ex p Me d Bi ol . 1 9 9 8; 4 5 1: 1 6 7- 7 1. 
 
W ilc o x R A, et al. Si g nali n g t hr o u g h N K cell-ass ociate d C D 1 3 7 pr o m otes b ot h hel per f u ncti o n 
f or C D 8 + c yt ol ytic T cells a n d res p o nsi ve ness t o I L- 2 b ut n ot c yt ol ytic acti vit y. J I m m u n ol . 
2 0 0 2; 1 6 9( 8): 4 2 3 0- 6. 
 
Willi ms k y G, et al. Vir us-i n d uce d he p at ocell ular carci n o mas ca use a nti ge n-s pecific l ocal 
t olera nce. J Cli n I nvest . 2 0 1 3; 1 2 3( 3): 1 0 3 2- 4 3. 
 
W u A W, J ac o bs o n K D, Fric k D L, et al. Vali dit y a n d res p o nsi ve n ess of t he E Q- 5 D as a meas ure 
of healt h-relate d q ualit y of life i n pe o ple e nr olle d i n a n AI D S cli nical trial. Q u al Life Res . 2 0 0 2; 
1 1( 3) : 2 7 3- 8 2. 
 
Xia o C, Ha nl o n A, Z ha n g Q, et al. S y m pt o m cl usters i n patie nts wit h hea d a n d nec k ca ncer 
recei vi n g c o n c urre nt c he m ora di ot hera p y. Or al O n c ol . 2 0 1 3; 4 9( 4): 3 6 0- 6. d oi: 
1 0. 1 0 1 6/j . oral o nc ol o g y. 2 0 1 2. 1 0. 0 0 4. E p u b 2 0 1 2 N o v 1 7. 
 
Ye wale C, Bara dia D, V h ora I, Patil S, Misra A. E pi der mal gr o wt h fact or rece pt or tar geti n g i n 
ca ncer: a r e vie w of tre n ds a n d strate gies. Bi o m ateri als .  2 0 1 3; 3 4( 3 4): 8 6 9 0- 8 7 0 7. 
 
Za k eri K, R ose B S, G ula ya S, D' A mic o A V, Mell L K. C o m peti n g e v e nt ris k stratificati o n ma y 
i m pr o ve t he desi g n a n d efficie nc y of cli nical trials: sec o n dar y a nal ysis of S W O G 8 7 9 4. C o nte m p 
Cli n Tri als . 2 0 1 3 J a n; 3 4( 1): 7 4- 9. 
 
Z el e n M. T he ra n d o mizati o n a n d stratificati o n of p atie nts t o cli nical trials. J C hr o n Dis . 2 7: 3 6 5-
3 7 5, 1 9 7 4. 
 
Z e n g J, et al. A nti-P D - 1 bl oc ka de a n d stere otactic ra diati o n pr o d uce l o n g-ter m s ur vi val i n mice 
wit h i ntracra nial gli o mas. IJ R O B P. 2 0 1 3; 8 6( 2): 3 43 - 9. 
 

R T O G 3 5 0 4 
8 5   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R E F E R E N C E S ( C o nti n ue d) 
 
Z ha o B, O x nar d G R, M os k o witz C S, et al. A pil ot st u d y of v ol u me meas ure me nt as a met h o d of 
t u m or res p o nse e v al uati o n t o ai d bi o mar ker de v el o p me nt. Cli n C a ncer Rese arc h . 2 0 1 0; 1 6: 4 6 4 7-
5 3. 
 
 
 

R T O G 3 5 0 4 
8 6   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R T O G 3 5 0 4  
A P P E N DI X I:  NI V O L U M A B ( B M S- 9 3 6 5 5 8) P H A R M A C Y R E F E R E N C E M A N U A L 
 
1          O B J E C TI V E 
T he o bjecti ve of t his pr o ce d ure m a n ual is t o pr o vi de t he st u d y site wit h cl ear a n d det aile d 
i nf or mati o n f or t he st ora ge, h a n dli n g, pre parati o n a n d a d mi nistrati o n of Ni v ol u ma b use d i n t he 
R T O G 3 5 0 4/ C A 2 0 9- 4 1 0 st u d y 
  
2          B M S C LI NI C A L P R O D U C T C O N T A C T 
If c o ncer ns re gar di n g t he q ualit y or a p p eara nce of t he st u d y dr u g, or q uesti o ns re gar di n g 
a d mi nistrati o n arise, d o n ot dis pe nse t he st u d y dr u g a n d c o ntact t he Brist ol- M yers S q ui b b 
i m me diatel y: 
 
Q uesti o ns wit h re gar d t o dr u g pre parati o n a n d p har mac y ma n ual c o nte nt:  
 
Peter Tri m b oli, R P h 
P har mac y Ser vices, Dr u g S u p pl y M a na ge me nt  
            Brist ol- M yers S q ui b b Researc h a n d De v el o p me nt 
Tele p h o ne: 6 0 9- 2 5 2- 4 8 6 2 
E ma il:  p har mac yser vices @ b ms.c o m  
 
3          NI V O L U M A B I N J E C TI O N   
3. 1. 1    Descri pti o n 
  
Pr o d uct N a me    
Ni v ol u ma b I njecti o n ( B M S 9 3 6 5 5 8), 1 0 0 m g/ vial ( 1 0 m g/ m L)    
Pr o d uct des cri pti o n 
a n d P ac k a gi n g   
P ack a gi n g:   Vials ass e m ble d i nt o w hite dis pe nsi n g b o x es c o ntai ni n g 
1 0 0 m g vials.   
Vi als:   1 0 cc T y pe I gl ass vial. 2 0 m m st o p per a n d seal, res pecti vel y.  
A p pe ar a nce:  Clear t o o p alesce nt, c ol orless t o pale yell o w li q ui d, 
li g ht (fe w) partic ulates m a y b e pres e nt. 
Pr o d uct I n gr e die nts  
 Eac h vial c o ntai ns 1 0 0 m g Ni v ol u ma b    
 
3. 1. 2 H a n dli n g a n d D ose pre p ar ati o n  
As wit h all i njecta ble dr u gs, care s h o ul d b e ta ke n w he n ha n dli n g a n d pre pari n g Ni v ol u ma b.  
W he ne ver p ossi ble, Ni v ol u ma b i nf usi o ns s h o ul d be pre pare d i n a l a mi nar fl o w h o o d, gl o ve b o x, 
or sa fet y ca bi net usi n g sta n dar d pr o ce d ures f or t h e safe h a n dli n g of i ntra ve n o us a ge nts a p pl yi n g 
ase ptic tec h ni q ues. Gl o ves are re q uir e d. If ni v ol u ma b s ol uti o n c o mes i n c o ntact wit h t he s ki n or 
m uc osa, i m me diatel y a n d t h or o u g hl y w as h wit h s oa p a n d wat er.  
D ose Pre p ar ati o n a n d a d mi nistr ati o n 
Vis uall y i ns pect dr u g pr o d uct s ol uti o n f or partic ul ate matter a n d dis c ol orati o n pri or t o 
A P P E N DI X I (c o nti n ue d)  

R T O G 3 5 0 4 
8 7   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
a d mi nistrati o n. Ni v ol u ma b is a clear t o o palesce nt, c ol orless t o pale yell o w s ol uti o n. Discar d t he 
vial if t he  s ol uti o n is cl o u d y, disc ol or e d, or c o ntai ns e xtra ne o us partic ulate matter ot her t ha n a 
fe w tra nsl uc e nt-t o- w hite, pr otei nace o us p articles. D o n ot s ha ke t he vial. 
Pre p ar ati o n  
 W it h dra w t he re q uire d v ol u me of Ni v ol u ma b a n d tra nsfer i nt o a n i ntra ve n o us 
co ntai ner.  
 Dil ut e Ni v ol u ma b wit h eit her 0. 9 % S o di u m C hl ori de I nj ecti o n, U S P or 5 % 
De xtr ose I nje cti o n, U S P t o pre pare a n i nf usi o n wit h a fi nal c o nce ntrati o n ra n gi n g 
fr o m 1 m g/ m L t o 1 0 m g/ m L (see e x a m ple bel o w) 
 Mi x  dil ute d s ol uti o n b y ge ntle i n versi o n. D o n ot s ha ke. 
 Disc ar d partiall y us e d vials or e m pt y vi als of Ni v ol u ma b.  
St or a ge of I nf usi o n  
T he pr o d uct d oes n ot c o ntai n a preser vati ve. After pre parati o n, st ore t he Ni v ol u ma b 
i nf usi o n eit her: 
 at r o o m te m perat ur e f or n o m ore t ha n 4 h o urs fr o m t he ti me of 
pre parati o n. T his i ncl u des r o o m te m perat ur e st ora ge of t he i nf usi o n i n t he 
I V c o ntai ner a n d ti me f or a d mi nistrati o n of t he i nf usi o n  
or 
 u n de r refri gerati o n at 2° C t o 8° C ( 3 6° F t o 4 6° F) f or n o m ore t ha n 2 4 h o urs 
fr o m t he ti me of i nf usi o n pre parati o n. 
D o n ot f reeze. 
A d mi nistr ati o n 
A d mi nister t he i nf usi o n o ver 3 0  mi n utes t hr o u g h a n i ntra ve n o us li ne c o nt ai ni n g a sterile, n o n-
p yr o ge nic, l o w pr otei n bi n di n g i n-li ne filter ( p ore siz e of 0. 2 micr o meter t o 1. 2 micr o meter). D o 
n ot c oa d mi nister ot her dr u gs t hr o u g h t he s a me i ntr a ve n o us li ne. Fl us h t he i ntr a ve n o us li ne at 
e n d of i nf usi o n wit h a p pr o pri ate a m o u nt of dil ue nt ( e. g. 1 5- 2 0 ml) t o e ns ure t h at t he t ot al 
d ose is a d mi nistere d. T ot al i nf usi o n a n d fl us h ti me s h o ul d e q u al t o 3 0. 
D ose  selecti o n f or Ni v ol u ma b s h o ul d be assi g n e d per s u bject as o utli ne d i n t he cli nical pr ot oc ol 
st u dy dr u g d osi n g secti o n of t he cli nical pr ot oc ol. T he ex a m ples b el o w use a t ot al v ol u me of 6 0 
ml t o all o w f or a pr actic al a d mi nistr ati o n r ate, h o wever ot her v ol u m es m ay be use d f or 
N iv ol u m a b pre p ar ati o n s o as l o n g as t he fi n al c o nce ntr ati o n re m ai n bet wee n 1 - 1 0 m g/ ml (e. g. 
1 0 0 ml) . 
N O T E: W he n Niv ol u m a b Pl ace b o is re q uire d, pl ace b o s h all be c o nsi dere d a n e q u al v ol u m e of 
dr u g dil ue nt al o ne ( N S, D 5 W) w hic h is st a n d ar d t o site pr actice f or mi xi n g active Niv ol u m a b 
( 6 0 ml, or 1 0 0 ml) a n d s h o ul d be i nf use d at t he s a m e r ate ( 3 0 mi n utes). 
 
 
 

R T O G 3 5 0 4 
8 8   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
A P P E N DI X I (c o nti n ue d) 
Pre parati o n e x a m ple 2 4 0 m g d ose; 
Niv ol u m a b 2 4 0 m g ( 2 4 ml  Niv ol u m a b 1 0 m g/ ml s ol uti o n, l oc al r o u n di n g r ules a p plic a ble) m ay b e 
mixe d wit h 3 6 ml N S or D 5 W t o a t ot al v ol u me = 6 0 ml w hic h c a n be i nf use d over 3 0 mi n utes at 
2 ml/ mi n f oll o we d by fl us h.  
P re parati o n e x a m ple 4 8 0 m g d ose; 
Niv ol u m a b 4 8 0 m g ( 4 8 ml  Niv ol u m a b 1 0 m g/ ml s ol uti o n, l oc al r o u n di n g r ules a p plic a ble) m ay b e 
mixe d wit h 1 2 ml N S or D 5 W t o a t ot al v ol u me = 6 0 ml w hic h c a n be i nf use d over 3 0 mi n utes at 
2 ml/ mi n f oll o we d by fl us h.   
3. 1. 3 P r o d uct St o r a ge a n d St a bilit y 
Ni v ol u ma b 1 0 0 m g vials f or i njecti o n s h o ul d be refri gerat e d at 2° C t o 8° C ( 3 6° F t o 4 6° F). 
Pr otecte d fr o m li g ht a n d s h o ul d n ot be fr oze n. D o n ot use be y o n d t he e x pirati o n date o n t he 
vial.  Pr otect t he vials fr o m li g ht b y st ori n g i n t he ori gi nal pac ka ge u ntil ti me of use.  Vials d o 
n ot c o nta i n preser vati ve a n d t h us are i nte n d e d f or si n gle use o nl y a n d s h o ul d be discar de d after 
use  a n d pr o d uct rec o n ciliati o n. 
Ni v ol u ma b s h o ul d n ot be i nf use d c o nc o mita ntl y i n t he sa me i ntra ve n o us li n e wit h ot her a ge nts. 
N o p h ysic al or bi oc he mi cal c o m pati bilit y st u dies ha ve bee n c o n d uct e d t o e val uate t he c o-
ad mi nistrati o n of Ni v ol u ma b wit h ot her a ge nts. 
4    S I T E T E M P E R A T U R E E X C U R SI O N S A N D T R A N SI T                                              
Dr u g m ust be st ore d u n d er t he pr o per c o n diti o ns as liste d o n t he cli nical s u p pl y la bel.   If a n y 
te m perat ur e e x c ursi o ns are e nc o u nt ere d d uri n g o n site st ora ge, pleas e re p ort t hese t o B M S f or 
assess me nt as o utli ne d i n t he Brist ol- M yers S q ui b b, “I n vesti gati o nal Me dici nal Pr o d uct (I M P) 
ha n dli n g at I n v esti gati o nal Sites: S hi p me nt, Re cei pt, St ora ge, Use Dat e E xte nsi o n a n d 
Ret ur n/ Destr ucti o n” g ui d eli ne usi n g t he Te m perat ure E x c ursi o n Res p o nse F or m. See F or m 1  
Pr o per st or a ge c o n diti o ns m ust be m ai nt ai ne d d uri n g m o ve me nt of i n ve nt or y wit hi n a n 
i n vesti g ati o n al site. St ora ge c o n diti o ns f or me dicati o ns re q uiri n g st or a ge at 2º C t o 8º C ( 3 6º F-
4 6º F ) m ust be mai ntai ne d t hr o u g h o ut t he tr a ns p ort wit h d oc u me ntati o n mai ntai ne d wit hi n t he 
site files. W here c o ntr oll e d st ora ge c o n diti o ns (f or e x a m ple, te m perat ur e, relati ve h u mi dit y, li g ht, 
etc.) are re q uire d d uri n g tra nsit, t he necessar y e n vir o n me ntal c o ntr ols m ust be i n place t o e ns ure 
t hat t he dr u g pr o d uct r e mai ns wit hi n t he acce pt a ble te m perat ure ra n ge. Te m perat ure m o nit ori n g 
de vices s uc h as mi n ma x de vice m ust be i m ple me nte d d uri n g tr a nsit.  
 
5    P R O D U C T R E C EI P T, A C C O U T A BI LI T Y, A N D D E S T R U C TI O N 
Dr u g Recei pt 
 
S hi p me nt I ns pecti o n I nstr ucti o ns 
1.  O pe n b o x i m me di at el y u p o n recei pt.  
2.  Caref ull y i ns pect kits e ns uri n g all of t he s u p plies were recei ve d i n g o o d c o n diti o n, c orrect 
q ua ntit y recei ve d, a n d all of t he c o ntai ner I D #s were recei ve d as n ote d o n pac ki n g sli p.   
3.  S i g n a n d date ( date of recei pt) pac ki n g sli p a n d fil e wit h st u d y-s p ecific d oc u me nts. 
 

R T O G 3 5 0 4 
8 9   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
A P P E N DI X I (c o nti n ue d) 
4.  L o g i n all s u p plies i n eac h s hi p me nt o n t he a p pr o priate I n ve nt or y l o g F or m  
 
 
Acc o u nt a bilit y  
It is t he res p o nsi bilit y of t he i n vesti gat or t o e ns ure t hat a c urre nt dis p ositi o n rec or d of 
i n vesti gati o nal pr o d uct acc o u nta bilit y a n d rec o nciliati o n is mai ntai ne d at eac h st u d y site w here 
st u d y dr u g is i n ve nt orie d a n d dis pe nse d.  
 
I n a d diti o n, rec or ds or l o gs m ust c o m pl y wit h l ocal re g ulati o ns a n d g ui deli nes f or t he c o n d ucti o n 
a n d ha n dli n g of cli nical s u p plies s h o ul d i ncl u de b ut n ot li mite d t o o: 
 
 A m o u nt recei ve d a n d pla ce d i n st ora ge area 
 A m o u nt c ur re ntl y i n st ora ge area 
 L a b el I D n u m ber or bat c h n u m ber 
 A m o u nt dis pe nse d t o a n d ret ur ne d b y s u bject, i ncl u di n g u ni q ue s u bject i de ntifiers 
 A m o u nt t ra nsferre d t o a n ot her area/site f or dis pe nsi n g or st ora ge 
 N o n -st u d y dis p ositi o n (e. g. l ost, waste d) 
 A m o u nt destr o ye d at st u d y site, if a p plica ble 
 A m o u nt re t ur ne d t o t he S p o ns or, if a p plica ble 
 Da tes a n d i nitials of pers o n res p o nsi ble f or I n v esti gati o nal Pr o d uct (I P) 
 Dis pe nsi n g/a cc o u nta bilit y, as p er t he Site Si g n at ure a n d Dele gati o n L o g. 
 
St u d y Dr u g Destr ucti o n 
St u d y dr u gs ca n  be d estr o ye d o n site if l ocal p olicies all o w t o d o s o. It is t he I n v esti gat or’s 
res p o nsi bilit y t o e ns ure t hat arra n ge me nts ha v e bee n ma de f or t he dis p osal, pr oce d ures f or pr o per 
dis p osal ha ve bee n esta blis he d acc or di n g t o a p plica ble re g ulati o ns, g ui deli nes a n d i nstit uti o nal 
pr oce d ures, a n d a p pr o pri ate rec or ds of t he dis p osal ha ve bee n d o c u me nte d.   
  
 
 
 
 
 
 
 
 
 
 
 

R T O G 3 5 0 4 
9 0   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
F or m 1 
B rist ol- M yers S q ui b b 
Te m per at ure E x c ursi o n Res p o nse F o r m f or I n vesti g ati o n al Me dici n al Pr o d ucts 
 
Secti o n A.  T o be c o m pl ete d b y t he site at t he ti me of Site St or a ge Te m pe r at ure E x c ursi o n: 
Pr ot oc ol N u m ber:  
Site N u m ber/I n vesti g at or N a me/ C o u ntr y:  
 
Descri pti o n of Dr u g Pr o d ucts i n v ol ve d i n E x c ursi o n:  
 
B atc h n u m ber (s) pri nte d o n l a bel:  
C o nt ai ner n u m bers:  
 
 
 
 
 
 
Descri pti o n of E x c ursi o n (te m p er at ure hi g hs/l o ws a n d d ur ati o n):  
B el o w l a bel st or a ge l o w er li mit …...° C                    D ur ati o n: … … … ….                           L o w e xtre me t°:  …..° C  
 
A b o ve l a bel st or a ge u p pe r li mit ….. ° C                    D ur ati o n: … … …...                           Hi g h e xtre me t°:  …..° C  
 
Re as o n f or e x c ursi o n:  
 
 
H as t he iss ue bee n res ol ve d ?  
 
H a ve t hese s pecific c o nt ai ners bee n i n v ol ve d i n a pr e vi o us e x c ursi o n ?               N O 
       Y E S  
   
 If yes, ple ase pr o vi de: 
B atc h n u m ber (s):  
C o nt ai ner n u m bers:  
Te m per at ure hi g hs/l o ws a n d d ur ati o n  
 
 
 
 
 
 
 
 
 
W he n is t he ne xt pl a n ne d p atie nt visit w he n t hes e s u p plies m a y be dis pe nse d ?
 
 
 
E x c ursi o n i nf or m ati o n s u b mitt e d b y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D ate: _ _ _ _ _ _ _ _ _ _ _ _     
 
 
 
 
 
        Pri nt/ Si g n at ure/ Title of site st aff  
Secti o n B.  Us a ge Decisi o n t o be m a de b y B rist ol- M y ers S q ui b b: 
 
Te m per at ure e x c ursi o n det ails f or t he pr o d ucts liste d a b o ve h a ve bee n e v al u ate d.  Us a ge decisi o n is b ase d o n t he te m per at ure d at a 
t h at w ere m a de a v ail a ble b y t he i n vesti g ati o n al site.  
C o ncl usi o n ( a n d c o m me nts) : 
 
 All  pr o d ucts ar e s uit a ble f or c o nti n ue d use  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 All  pr o d ucts ar e N O T  s uit a ble f or f urt he r dis pe ns ati o n.  Ple ase re m o ve s u p plies fr o m a v ail a ble i n ve nt or y a n d w or k wit h y o ur 
Site M a n a ger/ Site M o nit or t o h a ve s u p plies dest r o ye d a n d  I V R S u p d ate d if a p plic a ble. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Assess me nt c o m pl ete d b y: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      D ate  _ _ _ _ _ _ _ _ _ _ _  
                                                                           Pri nt/ Si g n at ure/ Title  
 

R T O G 3 5 0 4 
9 1   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
T e m pl at e s a s pr o vi d e d vi a s e p ar at e att a c h m e nt or b el o w m a y s er v e a s a s a m pl e f or d o s a g e c al c ul ati o n s 
a n d m a y b e pri nt e d o ut a n d u s e d t o d o c u m e nt a n y c al c ul ati o n s a n d i nf u si o n ti m e s a s r e q uir e d b y t h e 
cli ni c al st u d y t e a m. C o nt e nt i n t hi s att a c h m e nt m a y b e a d d e d or o mitt e d. 
 
Dr u g D os e a n d V ol u m e C alc ul at or  
f or I V I nf usi o n 
  
  
Dr u g Pr o d uct :  
 
Pr ot oc ol n u m b er  
 
P ati e nt n a m e or I D:  
 
Pr e p ar ati o n d at e a n d ti m e:  
 
  
 
Dr u g Str e n gt h ( m g/ mL)  
 
S u bj ect b o d y w ei g ht ( k g)  
 
1D os e i n m g  
 
V ol u m e of Dr u g ( mL)  
 
T ot al V ol u m e of i nf usi o n ( mL)  
 
V ol u m e of Dil u e nt ( mL) N S or D 5 W  
 
I nf usi o n d ur ati o n ( mi n) 
 
I nf usi o n R at e ( mL/ mi n) 
 
I nf usi o n h a n g ti m e 
  
I nf usi o n c o m pl eti o n ti m e 
  
 
 
N ot e: If r e q uir e d, fl us h li n e wit h s e p ar at e v ol u m e of s a m e dil u e nt ( e. g. 1 5-2 0 ml) as o utli n e d 
i n t h e st u dy p h ar m acy m a n u al 
  
 
 
 
 

R T O G 3 5 0 4 
9 2   
Versi o n Date:  Dece m ber 2 6, 2 0 1 7  
 
R T O G 3 5 0 4  
 
A P P E N DI X II: BI O S P E CI M E N B A N K A T U C S F:  BI O S P E CI M E N C O L L E C TI O N, 
P R O C E S SI N G, A N D S HI P PI N G I N S T R U C TI O N S F O R F F P E  
 
 F F P E S peci me ns: 
o  Sli des s h o ul d be s hi p pe d i n plastic sli de h ol der/sli de b o x. Place a s mall wa d of pa d di n g 
i n t o p of t he c o ntai ner. If y o u ca n hear sli des s ha ki n g t he y ca n brea k d uri n g s hi p pi n g.  
o  F F P E Bl oc ks ca n be s hi p pe d i n a plastic bl oc k h ol der or wra p pe d wit h pa per or place d 
i n a pa per e n vel o pe, a n d place d i n a car d b oar d b o x wit h pa d di n g. D o n ot wra p bl oc ks 
wit h b u b ble wra p or ga uze. Place pa d di n g i n t o p of c o ntai ner s o t hat if y o u s ha ke t he 
c o ntai ner t he bl oc ks are n ot s ha ki n g. If y o u ca n h ear bl oc ks s ha ki n g t he y ma y brea k 
d uri n g s hi p pi n g.  D uri n g war m weat her m o nt hs t he use of c ol d p ac ks is rec o m me n de d 
t o pre ve nt wa x fr o m melti n g. 
o  S li des, Bl oc ks, or Pl u gs ca n be s hi p pe d a m bie nt or wit h a c ol d pac k eit her b y U nite d 
States P ostal Ser vice ( U S P S) t o t he U S P S a d dress ( 9 4 1 4 3) or b y C o urier t o t he Street 
A d dress ( 9 4 1 1 5). D o N O T s hi p o n Dr y Ice .  
o  Ur ge nt o ver ni g ht s hi p me nts (ce ntral r e vie w) s h o ul d al wa ys be se nt b y C o urier. 
o  If patie nts c o nse nt e d t o ba n ki n g D O N O T s hi p F F P E s peci me ns wit h a ret ur n re q uest. 
We ca n n ot acce pt or ba n k sa m ples t hat we ca n n ot kee p. Al wa ys s e n d w hat ca n be 
ba n ke d ( d u plicat e H & Es, Bl oc ks or p u n c hes or u nstai ne d as s pecifi e d i n t he pr ot oc ol). 
We ca n p u nc h a n d ret ur n bl oc ks if n ote d i n t he pr ot oc ol. P u nc h kits ca n be re q ueste d 
fr o m us b y e mail (R T O G @ ucsf.e d u ) f or sites t hat wis h t o p u nc h t he bl oc k t he msel ves.  
 
 
 F or Q uesti o ns re g ar di n g c ollecti o n/s hi p pi n g ple ase c o nt act t he Bi os peci me n B a n k at 
U C S F b y e- m ail: R T O G @ ucsf.e d u or p h o ne: 4 1 5- 4 7 6- 7 8 6 4 or F a x: 4 1 5- 4 7 6- 5 2 7 1. 
 
 

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A P P E N DI X II ( C o nti n ue d) 
 
S hi p pi n g I nstr ucti o ns f or F F P E: ( See A p pe n di x III f or pr ocessi n g a n d s hi p pi n g i nf or mati o n 
f or peri p heral bl o o d) 
 
U S P ost al Ser vi ce M aili n g A d dress:  
Use o nl y f or n o n -ur ge nt a m bie nt 
s peci me ns- F F P Es, sli des, bl oc ks:  
 
C o urier A d dress ( Fe d E x, U P S, etc.):  
F or Fr oze n, Ur ge nt or Tr ac k a ble S peci me ns:  
Bi os peci me n B a n k  at U C S F  
U C S F -  B o x 1 8 0 0  
2 3 4 0 S utter St, r o o m S 3 4 1  
S a n Fr a ncisc o, C A 9 4 1 4 3 -1 8 0 0  
Bi os peci me n B a n k  at U C S F  
U ni versit y of C alif or ni a S a n Fr a ncisc o  
2 3 4 0 S utter St, r o o m S 3 4 1  
S a n Fr a ncisc o, C A 9 4 1 1 5  
 
 I n cl u de all re q uire d s peci me n pa per w or k i n p oc ket of bi o hazar d ba g.  
 C hec k t hat t he S peci me n Tra ns mittal ( S T) F or m h as bee n c o m plet el y fille d o ut  
 C hec k t hat all sa m ples are la bele d wit h t he st u d y a n d case n u m ber, a n d i ncl u de date of 
c ollecti o n as well as c ollecti o n ti me p oi nt (e. g., pretreat me nt, p ost-tr eat me nt). 
 
 
N ot e: See A p pe n di x I II f or pr ocessi n g a n d s hi p pi n g i nf or m ati o n f or peri p her al bl o o d.  
 
 

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A P P E N DI X III: F E R RI S L A B O R A T O R Y: P R E P A R A TI O N, P R O C E S SI N G A N D 
S HI P PI N G O F P E RI P H E R A L B L O O D 
 
Kit C o nte nts f or e a c h ti me p oi nt: 
F o ur 1 0 ml or fi ve 8 ml He pari n Bl o o d ( gree n t o p) dra w t u bes  
T u be h ol der 
O uter b o x f or t u be h ol der 
Sec o n dar y plastic b a g wit h a bs or be nt 
St u d y s p ecific S T F or m 
Fe d E x Cli nical Pa k wit h la bels a n d stic kers 
I nstr u cti o ns h o w t o pac k a n d s hi p t he sa m ples 
 
 
Pr o cessi n g: 
1.  Sites s h o ul d o nl y dra w bl o o d sa m ples o n M o n da y- We d nes da ys a n d o nl y s hi p M o n da y-
We d nes da ys.   
2.  Dr a w bl o o d i n f o ur 1 0 ml or fi ve 8 ml  gree n t o p ( he pari n) t u bes.  
3.  Mi x  ge ntl y. 
4.  P lace t u bes i n st yr of oa m t u be h ol der a n d o uter b o x pr o vi de d wit h Kit.  
5.  S eal u p t u be h ol der b o x a n d place i n sec o n d ar y plastic ba g wit h a bs or be nt. Use of 
a m bie nt gel pac ks wit h i ns ulate d pac ks are e n c o ura ge d d uri n g c ol d wi nter a n d h ot 
s u m mer m o nt hs. 
6.  P lace S T f or m i n p o uc h of ba g.  
7.  P lace ba g wit h t u be bo x i n t he Fe d E x Cli nical Pa k pr o vi de d. 
8.  P lace pr o vi de d fe d e x la bel i n s hi p pi n g p o uc h, a n d stic k t o Fe d E x e n vel o pe. 
9.  P lace “ kee p a w a y fr o m h eat” a n d “ peris h a ble” Stic kers pr o vi de d wit h kit o n e n vel o pe 
 
S hi p t he bl o o d at r o o m te m perat ure f or o ver ni g ht deli ver y sa me da y t o Dr Ferris’s la b. 
L a b el is pr o vi de d o n t he Cli nical Pa k. 
1 0.  If sites dra w t h e bl o o d sa m ple late i n t he da y, t he site s h o ul d refri gerate t he sa m ple u ntil 
it is s hi p pe d a n d n ote t he st ora ge c o n diti o ns o n t he S T f or m. 
 
S hi p pi n g A d dress: N ote: D o N O T  s hi p peri p h eral bl o o d t o Bi os peci me n Ba n k at U C S F. 
Ferris L a b or at or y 
Att n.: S a n dr a P o ve d a Gi bs o n 
R o o m 2. 2 6 Hill m a n Res e arc h P a vili o n 
5 1 1 7 Ce ntre A ve n ue 
Pitts b ur g h, P A 1 5 2 1 3 
 
 
 
F or q uesti o ns, c o nt act: S a n dr a Gi bs o n ( Ferris L a b), 4 1 2- 6 2 3- 7 7 3 8 or 4 1 2- 4 4 3- 8 6 7 3 ; 
p o ve d as @ u p mc.e d u 
 
Alter nati vel y, c o nta ct Dr. Ferris: 4 1 2- 2 9 8- 7 0 0 2; ferrisrl @ u p mc.e d u