r t o g f
t o g 3 5

( 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 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  
| Ma ura Gillis o n,   | M D, P h D   |
|----------------------|--------------|  
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. mitri 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 h n 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  
T O G F o u n dati o n C hair ma n  
```
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 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 f
t o g 3 5

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                                                                                                                                                                             | 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  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 vers e 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 f
r t o g f

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.  
| 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    | , 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          | , 2 0 1 6           |                            |  
D oc u me nt Hist or y 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 3 Versi o n Date: D ece m ber 2 6, 2 0 1 7
r t o g f
table of contents (26dec2017)

| TABLE OF CONTENTS (26Dec2017)                                                                                                            |                                                                                                                                                            |                                                                                                                                |
|------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------|
| SCHEMA                                                                                                                                   |                                                                                                                                                            |                                                                                                                                |
| 1.                                                                                                                                       | OBJECTIVES ..............................................................................................................................................7 |                                                                                                                                |
| Primary Objectives ....................................................................................................................7 |                                                                                                                                                            |                                                                                                                                |
| 1.1                                                                                                                                      |                                                                                                                                                            |                                                                                                                                |
| 1.2                                                                                                                                      | Secondary Objective  .....................................................................................................................7                |                                                                                                                                |
| 2.                                                                                                                                       | BACKGROUND .                                                                                                                                               |                                                                                                                                |
| 2.1 Study Overview .                                                                                                                     |                                                                                                                                                            |                                                                                                                                |
| 2 Head and Neck Cancer                                                                                                                   |                                                                                                                                                            |                                                                                                                                |
| 2.3 HPV and Head and Neck Cancer Survival ..............................................................................8                |                                                                                                                                                            |                                                                                                                                |
| 2.4 Primary CRT for Head and Neck Cancer .                                                                                               |                                                                                                                                                            |                                                                                                                                |
| 2.5 Head and Neck Cancer and Immunity                                                                                                    |                                                                                                                                                            |                                                                                                                                |
| 2.6 Study Design                                                                                                                         |                                                                                                                                                            |                                                                                                                                |
| 2.7 Biomarker Studies                                                                                                                    |                                                                                                                                                            |                                                                                                                                |
| PATIENT SELECTION, ELIGIBILITY, AND INELIGIBILITY CRITERIA                                                                               |                                                                                                                                                            |                                                                                                                                |
| 3.                                                                                                                                       | 3.1                                                                                                                                                        | Patient Selection Guidelines ...............................................................................................20 |
| 3.2                                                                                                                                      | Eligibility Criteria ...................................................................................................................20                 |                                                                                                                                |
| 3.3                                                                                                                                      | Ineligibility Criteria .                                                                                                                                   |                                                                                                                                |
| 4.                                                                                                                                       | REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........24                                                                                        |                                                                                                                                |
| 5. TREATMENT PLAN/Regimen description                                                                                                    |                                                                                                                                                            |                                                                                                                                |
| 5.1                                                                                                                                      | Chemotherapy/Other Agent-Based Therapy..............................................................30                                                     |                                                                                                                                |
| 5.2                                                                                                                                      | RADIATION THERAPY                                                                                                                                          |                                                                                                                                |
| General Concomitant Medication and Supportive Care Guidelines ........................41                                                 |                                                                                                                                                            |                                                                                                                                |
| 5.3                                                                                                                                      |                                                                                                                                                            |                                                                                                                                |
| 6. TREATMENT MODIFICATIONS/managEment.................................................................................42                 |                                                                                                                                                            |                                                                                                                                |
| 6.1 Nivolumab Dose Modifications                                                                                                         |                                                                                                                                                            |                                                                                                                                |
| 6.2 Cetuximab Dose Modifications ..............................................................................................45        |                                                                                                                                                            |                                                                                                                                |
| Cisplatin Dose Modifications ....................................................................................................52      |                                                                                                                                                            |                                                                                                                                |
| 6.3                                                                                                                                      |                                                                                                                                                            |                                                                                                                                |
| 7.                                                                                                                                       | ADVERSE EVENTS REPORTING REQUIREMENTS                                                                                                                      |                                                                                                                                |
| 7.1 Protocol Agents                                                                                                                      |                                                                                                                                                            |                                                                                                                                |
| Adverse Events (AEs)                                                                                                                     |                                                                                                                                                            |                                                                                                                                |
| 7.2                                                                                                                                      |                                                                                                                                                            |                                                                                                                                |
| 7.3                                                                                                                                      | Serious Adverse Events (SAEs)                                                                                                                              |                                                                                                                                |
| 7.4                                                                                                                                      | Serious Adverse Event (SAE) Reporting Requirements .............................................57                                                         |                                                                                                                                |
| 8.                                                                                                                                       | REGISTRATION AND STUDY ENTRY PROCEDURES ..........................................................61                                                       |                                                                                                                                |
| 8.1                                                                                                                                      | Regulatory Requirements                                                                                                                                    |                                                                                                                                |
| 8.2                                                                                                                                      | RT Registration Requirements                                                                                                                               |                                                                                                                                |
| 8.3                                                                                                                                      | Patient Enrollment ...............................................................................................................................61       |                                                                                                                                |
| 9                                                                                                                                        | DRUG INFORMATION .                                                                                                                                         |                                                                                                                                |
| 9.1                                                                                                                                      | Investigational Study Agent                                                                                                                                |                                                                                                                                |
| RTOG 3504                                                                                                                                | 4                                                                                                                                                          | Version Date:  December 26, 2017                                                                                               |  
| 9. 2                                                                                                                                                                                                                                                                                                  | 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.                                                                                                                                                                                                                                                                                                  | 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 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 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 t u d y Desi g n 6 9 1 4. 2 t u d y E n d p oi nts 6 9 1 4. 3 ri mar y O bj ecti ves St u d y D esi 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 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 f
table of contents (26dec2017)

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)  
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  
  
* * 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.


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 / 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 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 l oa d, 2 5 0 m g/ m / 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

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. 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 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 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, 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 ometastatic 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 w ar 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 ba cc 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 c a 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 (J e 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 c a 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 de ca des

o 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,

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).

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 calre 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 hr ee- 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 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 6e 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 metaa 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 h et 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

o 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

et 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 ) 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 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 / wee k. A ra n d o mize d st u d y of 2 0 m g/ m / 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 w ee kl y cis plati n ( 3 3- 4 0 m g/ m 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 / 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 / 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 ) 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/ m / 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 (J ere mic 2 0 0 4).  
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 c o nc urre nt wit h ra diati o n is m ost ofte n ass ociate d wit h 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 re 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 r ece 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 wris 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 / 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 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 h a 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 he 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  
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

ss 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,

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, n 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 c ell 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 nic al 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 nprese 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, H ers h ma n 2 0 0 7). S pecific T cell cti 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, 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.
r t o g f
i m m u ne

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 osti 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 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 D2. 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).
r t o g f
p d - l 1

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 br a 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 yr 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 D1 + 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 x 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 di 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 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 effic ac 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 pac - 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 hris 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.  
nte 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 dj 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 Vne 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 ntrat 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, et 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 A4 +/ 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 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 h ese 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. 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 uc e 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). Pr ecli nical data s u p p ort s y n er g y bet wee n hec 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) ( D e maria 2 0 0 5, De wa n 2 0 0 9). P D- 1 bl oc ka de aft er o 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 reje cti 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 ni 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.
r t o g f
ni v ol u ma

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 w ei 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. 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 ur es 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.  
| Ni v ol u m a b   | C mi nss            | Ge o.               | M e a n             | C m a xss   | Ge o.   | M e a n   | C a v gss   | Ge o.   | M e a n   |
|-------------------|---------------------|---------------------|---------------------|-------------|---------|-----------|-------------|---------|-----------|
| D ose             | [ u g/ m L] (c v %) | [ u g/ m L] (c v %) | [ 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)    |             |         |           |             |         |           |
| 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 effic ac 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 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.
r t o g f
ni v ol u ma

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 w ee 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, ar 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 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 a cti 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 oc eta 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.
r t o g f
c hec k p oi

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 k a 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 D1 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 ora 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 v a 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 nic al 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.  
```
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 ntiP D - 1 t hera p y ( pe m br oliz u ma b) was safe w h e n c o m bi ne d wit h c o nc urre nt, plati n u mbase 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 w as 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

he 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 Vne 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 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/ m / wee k x 7), hi g h- d ose

cis plati n ( 1 0 0 m g/ m q 2 1 da ys X 3) or cet u xi ma b ( 4 0 0 m g/ m

2
l oa d foll o we d b y 2 5 0

m g/ m 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

```  
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 o 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 o 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 ge 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 o 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 c et 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, o 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 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 o 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.  
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 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 w ee 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 ncle ar 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

t 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 D a k o I H C platf or m ( T a u be 2 0 1 2). P D1 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

x 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 me as 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, 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 x cl 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 sele cti 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 gic al 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 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 ecti o n 1 0.)


3. 2 Eli gi bilit y Criteri a ( 2 6 D ec 2 0 1 7)

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 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 gic al or p at h ol o gic al 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 nter 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, tage 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 dic al 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;

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 n ce.

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

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;

3. 2. 4 T he trial is o pe n t o b ot h ge n d ers;

3. 2. 5 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 : 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

latelets ≥ 1 0 0, 0 0 0 cells/ m m ;

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 v e

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 cle ara 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 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 utiliz e 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

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), 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; 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 gic al

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

larificati 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. 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

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 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 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 e vere, acti ve c o- m or bi dit y defi ne d as f oll o ws:

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 b etes

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;

```  
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 pitaliz ati o n i n t he last 6  
```
m o nt hs;

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:

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;

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;

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 f
4. r e q ui

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  
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)  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 Assess me nts | Pri o r t o Ste p 1 R e gistr ati o n (c ale n d ar d a ys) 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                                                                 |                                                    |         |
| 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 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 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 4                                                                 | Versi o n Date: D ece 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            |
| peci me n c ollecti o n f or ba n ki n g | f 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 u esti 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, siz e 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

ss 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.

```  
| D a y - 1 4                                                                                                                                                                                                                                                   | ( 1 4 d a ys pri or t o I                                      | M R T) t o 1 2 w ee 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 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 C B C w/ diff & A N C Creati ni ne or Creati ni ne  Cleara nce Na, K, Cl, gl u c ose, Ca, M g,  al b u mi n 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 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 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                                                                                                                                                                                                                             |                                                                |                                     |                         |  
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)  
```
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 w ee 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.

```  
| 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                                          |
| dj u v a nt  ni v ol u m a b f or  all a r ms                                                                | 2 w ee ks  after l ast  d ose of  ni v ol u m a b  or pl ace b o                                         | q 3                                         | m os. ( ± 2                                        |
| w ee 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 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 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 C B C w/ diff & A N C                                                                 | 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                                     | 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                                                                                                  | 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 D G                                       |                                                    |
| P E T/ C T                                                                                                   | If s us pici o n  of t u m or  rec urre nce                                                              |                                             |                                                    |
| De ntal Assess me nt N utriti o n/fee di n g t u b e e v al 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 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 |                                                    |
| 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 (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                                                                 |                                             |                                                    |  
```
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

ve 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 ostradi 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);


```
r t o g f
defi niti o n of

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 gic al 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 a cce 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 u alit 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 val 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. 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. 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 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.  
t 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 o 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 GE 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 s 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.  
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 f
5. t r e a

5. 1 C he m ot her a p y/ Ot her A ge nt- B ase d T her a p y 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 e gistr ati o n.  
Niv ol u m a b ( Ar ms 1, 3, a n d 4)  
  
Niv ol u m a b ( Ar m 2 o nl y)  
  
```

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 w ee ks f or a t ot al of 1 0 d oses. F or Ar m 2 o nl y ( hi g hd ose cis plati n 1 0 0 m g/ m

2
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, n 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 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 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.

```  
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.  
```

f 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.


```
r t o g f
a dj uv a nt

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.
r t o g f
cet uxi m a b

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 ,  
( 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 , 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. 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 miz e 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 p atie 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 osti 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.
r t o g f
weekl y cis pl ati

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 / 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 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 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 er mitte d . See ecti o n 6 f or d ose m o dificati o ns.