r t o g f
cis pl ati n s

Hi g h d ose cis plati n is hi g hl y e met o ge nic. W hile t his pr ot oc ol is usi n g m ore fre q u e nt d osi n g of cis plati n t hat is c o nsi dere d m o deratel y e met o ge nic, i n vesti gat ors s h o ul d be pre pare d t o us e a g gressi ve pr o p h yla ctic a ntie metics a n d h y drati o n. Ma n y i nstit uti o ns will ha ve sta n d ar d g ui deli nes f or t he a d mi nistrati o n of cis plati n at t he d oses us e d i n t his st u d y.  
F or p ur p oses of t his pr ot oc ol, i n di vi d u al i n vesti g at ors m a y use t hese l oc al g ui deli nes f or cis pl ati n a d mi nistr ati o n. O ne p ossi ble a p pr o ac h is o utli ne d bel o w. T h ese g ui deli nes ma y nee d t o be m o difie d base d o n l ocal g ui deli nes a n d patie nt relate d fact ors  
(e. g. t he s u bstit uti o n of n or mal sali ne i n dia betic patie nts). Si milarl y, t he a nti-e metic re gi me n is t o be deter mi ne d b y t he l oc al i n vesti gat or, alt h o u g h o ne p ossi bl e a p pr oac h is  
```
o utli ne d bel o w.

L o w- d ose Cis pl ati n a nti-e metic a d mi nistr ati o n g ui deli nes : 5- H T 3 a nta g o nists a n d

deca dr o n s h o ul d be gi ve n ( pal o n osetr o n 0. 2 5 m g I V a n d deca dr o n 1 2 m g pri or t o

cis plati n is preferre d). T he use of ster oi ds s h o ul d be mi ni miz e d were p ossi ble.

T he ref ore, f or pre v e nti o n of dela ye d n a usea a n d v o miti n g, use of 5- H T 3 a nta g o nist

m o n ot hera p y or N K- 1 a nta g o nist is preferre d o v er ster oi d m o n ot hera p y. Us e of ot her

a nti- na usea me ds s u c h as a pre pita nt, met ocl o pra mi de, or pr oc hl or perazi ne is left t o

t he discreti o n of t he i n vesti gat or.

L o w- d ose Cis pl ati n pre- hy dr ati o n g ui deli nes : Pre- h y drati o n wit h 1 liter D 5 ½ N S a n d

4 0 me q K C L/ liter x 1 liter pri or t o cis plati n s h o ul d be gi ve n. M a n nit ol 1 2. 5 g m I V

i m me diatel y pri or t o cis plati n ma y b e gi ve n. Use of ma n nit ol is left t o t h e discreti o n

of t he i n vesti gat or.

L o w- d ose Cis pl ati n a d mi nistr ati o n : Sta n dar d a d mi nistrati o n is cis plati n, 4 0 m g/ m

o ver 3 0- 6 0 mi n utes I V i n 2 5 0 cc N S. I nf usi o n rate n ot t o e x cee d 2 m gs p er mi n. See

Secti o n 6 f or d ose m o dificati o ns. See a b o ve disc ussi o n o n sc he d uli n g a n d n u m ber of

d oses c o nc urre nt wit h ra diati o n.

L o w- d ose Cis pl ati n p ost- hy dr ati o n g ui deli nes : F oll o wi n g t he e n d of t he cis plati n

a d mi nistrati o n, a n a d diti o nal liter of D 5 ½ N S wit h 1 0 me q K C L/ L, 8 me q M g S O 4/ L,

a n d 2 5 g m a n nit ol s h o ul d be i nf use d o ver 2 h o urs. O n t he sec o n d a n d t hir d da y

f oll o wi n g cis plati n, patie nt s h o ul d be e nc o ura ge d t o ta ke at least 2 liters of fl ui d per

da y orall y. Patie nts u na ble t o orall y s elf- h y drate s h o ul d be c o nsi dere d f or a d diti o nal

I V h y drati o n o n t hese d a ys wit h N S. T he a m o u nt of pre- a n d p ost- h y drati o n is left t o

t he discreti o n of t he i n vesti gat or.

Hi g h - D ose Cis pl ati n ( Ar m 2)

Patie nts will recei ve cis plati n, 1 0 0 m g/ m , a d mi nistere d i ntra ve n o usl y o n da ys 1, 2 2 a n d

4 3 of t he treat me nt c o urs e ( N ote: cis plati n gi ve n wit hi n 2 4 h o urs of da ys 1, 2 2 a n d 4 3 d u e

t o h oli da ys, f or e x a m ple, is acce pta bl e). Wee ke n ds c o u nt as da ys.


```  
Hi g h- D ose Cis pl ati n A nti- E m etic A d mi nistr ati o n G ui deli nes : Hi g h- d ose cis plati n is a hi g hl y e met o ge nic re gi me n wit h si g nifica nt i nci de nce of dela ye d na us ea a n d v o miti n g.  
I nstit uti o nal or N C C N g ui deli nes f or hi g hl y e met o ge ni c re gi me ns s h o ul d be f oll o we d.  
Hi g h- D ose Cis pl ati n Pre- Hy dr ati o n G ui deli nes : A s u g geste d re gi me n is pre h y drati o n wit h a 1 liter of D 5 N S o ver 2- 4 h o urs a n d m a n nit ol, 1 2. 5 g i v b ol us i m me diatel y pri or t o cis plati n. T he n cis plati n, 1 0 0 m g/ m , i n 5 0 0- 1 0 0 0 ml N S is a d mi nistere d o ver 1- 2 h o urs f oll o we d b y a n a d diti o nal 1 t o 1. 5 liters of fl ui d. A n y pre- e xisti n g de h y drati o n m ust be c orrecte d pri or t o cis plati n a d mi nistrati o n. S h o ul d e xtra vasati o n occ ur, t he treati n g p h ysicia n s h o ul d f oll o w i nstit uti o nal g ui deli nes f or ma na ge me nt. O ver ni g ht h os pitaliz ati o n f or h y drati o n after cis plati n s h o ul d be c o nsi dere d if it is all o we d b y t he p atie nt's i ns ura nce c o m pa n y. A d diti o nal i v h y drati o n a n d B U N/creati ni ne c hec k als o s h o ul d be c o nsi dere d, if necessar y, later i n t he wee k after cis plati n a d mi nistrati o n, i n or der t o a d dress a n y d e h y drati o n or se vere fl ui d/electr ol yt e i m bala n ce.  
```
5. 2 R a di ati o n T her a p y ( 2 6 Dec 2 0 1 7)

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.


```  
N ote: All p arti ci p ati n g i nstit uti o ns m ust be cre de nti ale d f or he a d a n d nec k I M R T  
a n d I G R T pri or t o re gisteri n g p atie nts t o t he st u d y. See ecti o n 8. 2 f or det ails.  
I nte nsit y M o d ulate d Ra di ati o n T hera p y (I M R T) a n d I ma ge- G ui d e d Ra diati o n T hera p y  
(I G R T) are ma n d at or y f or t his st u d y. Pr ot o n t hera p y is n ot per mitte d.  
M R T will be gi ve n i n 3 5 fracti o ns o ver 7 wee ks , 5 fracti o ns per wee k. Misse d treat me nts d ue t o h oli da ys or l o gistic al reas o ns ca n b e c o m pe nsate d b y deli veri n g a d diti o nal BI D  
fracti o ns, wit h a mi ni m u m i nter-fracti o n i nter val of 6 h o urs, or b y treati n g o n Sat ur da y or  
```
u n da y.

5. 2. 1 Treat me nt Tec h n ol o g y

Me ga v olta ge e n er g y p h ot o n bea m irra di ati o n wit h a p h ot o n bea m of ≥ 4 M V is re q uire d.

A n y tr eat me nt deli ver y m o dalit y t hat pre vi o usl y has bee n cre d e ntiale d f or hea d a n d n ec k

M R T f or pre vi o us R T O G trials is acce pt a ble. N ote : T o mot hera p y re q uires se parat e

crede ntiali n g.


I G R T I nstr ucti o ns

B o ne y a n at o m y I G R T cre de ntiali n g is r e q uire d (see Secti o n 8. 2 ). D ail y i m a ge g ui da nce

of I M R T ma y be ac hie ve d usi n g a n y o n e or m ore of t he f oll o wi n g t ec h ni q ues:

Ort h o g o n al kil o v olta ge ( K V) i ma ges;

i ne ar- accelerat or m o u nte d k V a n d M V c o ne bea m C T i ma ges;

i ne ar- accelerat or m o u nte d M V C T i ma ges.


```  
T he i nstit uti o n's pr oce d ure f or re gisteri n g dail y tr eat me nt i ma gi n g d atasets wit h a refere nce datas et s h o ul d c o m pl y wit h t he f oll o wi n g rec o m me n dati o ns:  
e gi o n-of -I nterest ( R OI) or "cli p b o x " f or f usi o n s h o ul d be set t o e nc o m pass t he hi g h d ose P T V a n d a dja ce nt s pi nal c or d; if t he s u pracla vic ular re gi o n is a p art of t he tar get v ol u me t he R OI s h o ul d e xte n d t o t he C 6 le vel; If t he f usi o n s oft ware all o ws t he user t o create a n irre g ular R OI, treat me nt r o o m o bjects see n o n i n-r o o m x-ra ys s h o ul d be e x cl u de d fr o m t he re gistrati o n; ot h ma n ual ( e. g. dra g-a n d- dr o p s yst e m base d o n b o n y a n at o m y m atc hi n g) a n d ut o matic (e. g. bas e d o n m ut ual i nf or mati o n) t y pes of re gistrati o n ca n b e use d; t he res ult of t he f usi o n m ust be vis uall y c h ec k e d f or t he ali g n m e nt of t he b o n y a nat o m y, s uc h as verte bral b o dies a n d a p plica ble s oft tiss ue str uct ures (e. g. o ptic ner ves a n d/ or o ptic c hias m).  
oll o wi n g t he re gistrati o n, t he tra nslati o nal a n d (if t he a p pr o pri ate tec h n ol o g y is a vaila ble) r otati o nal c orrecti o ns s h o ul d be a p plie d t o t he treat me nt c o uc h. If all t he
varia nces are < 2. 5 m m (t his t y picall y c orres p o n ds t o o ne half of t he us ual P R V mar gi n), t he tr eat me nt ca n pr ocee d wit h o ut c orrecti o n ( h o we ver, t he p h ysicia n/tea m ma y ele ct t o perf or m a dj ust me nts e ve n f or a v aria n ce < 2. 5 m m). If o ne or m ore c orrecti o ns are 2. 5 t o 5 m m, a dj ust me nt is necessar y pri or t o treat me nt; h o we ver, rei ma gi n g is n ot ma n dat or y. If o ne or m ore of t he c orrecti o ns are > 5 m m, t he i ma gi n g m ust be re peate d i n a d diti o n t o perf or mi n g ta ble/ p ositi o ni n g a dj ust me nts.  
H o we ver, t he use of n u m er o us re p eat I G R T st u dies s h o ul d be a v oi de d; ma gi n g d os e t o t he patie nt ma y bec o me si g nifica nt if re peat e d st u dies are perf or me d f or patie nts wit h se vere s et u p pr o ble ms (e. g., re q uiri n g fre q ue nt c orrecti o ns of m ore t ha n 5 m m). It is r ec o m m e n de d t hat pati e nts de m o nstrati n g se v ere s et u p pr o ble ms d uri n g t he first 7 cale n d ar da ys of treat me nt be re-si m ulate d or m o ve d t o a treat me nt  
```
wit h lar ger mar gi ns.

5. 2. 2 I m m o biliz ati o n a n d Si m ulati o n

I m m o biliz ati o n

T he use of a t h er m o plastic hea d a n d s h o ul der mas k is ma n dat or y f or hea d a n d nec k

I M R T. Patie nts will be pla n ne d i n t he s u pi ne p ositi o n wit h t heir ar ms at t heir si des,

e ns uri n g t h e s h o ul ders are sit uate d as far i nferi or as p ossi ble t o a v oi d e ntr y a n d e xit

t hr o u g h t he s h o ul ders.


Pl a n ni n g C T Sc a n

T he treat me nt pla n ni n g C T sca n is ma n dat or y f or defi ni n g tar get v ol u mes a n d n or mal

or ga n at ris k. T he pl a n ni n g C T sca n s h o ul d be d o ne wit h c o ntrast ( u nless

o ntrai n dicate d). C T sca n t hic k ness s h o ul d be a mi ni m u m of 0. 3 c m, a n d t he C T sca n

s h o ul d be ac q uire d wit h t he patie nt i n t he sa me p ositi o n a n d usi n g t he sa me

i m m o bilizati o n de vice as f or treat me nt. All tiss ues recei vi n g irra diati o n s h o ul d be

i ncl u de d i n t he C T sca n li mits. T he sca n ni n g li mits s h o ul d at least e nc o m pass t he or bits

s u peri orl y, a n d e xte n d at least 1 c m bel o w t he s u praster nal n otc h i nf eri orl y.

5. 2. 3 I ma gi n g f or Str uct ure Defi niti o n, I ma ge Re gistrati o n/ F usi o n a n d F oll o w u p

A dia g n ostic C T or M RI f or str uct ure d eli neati o n is rec o m me n de d. T h ese ma y b e f use d

t o t he pla n ni n g C T sca ns t o facilitate tar get a n d str uct ure defi niti o n. W he n a vaila ble

1 8-F- F D G P E T/ C T i ma ges m a y als o be f us e d t o t he pla n ni n g C T d ata set.

5. 2. 4 Defi niti o n of D ose Pres cri pti o ns, Tar get V ol u mes, a n d Mar gi ns

Ge ner al

T he pri mar y t u m or a n d i n v ol ve d n o des will be e n c o m passe d b y P T V _ 7 0 0 0 a n d will

recei v e 2 G y per fracti o n x 3 5 fracti o ns, w hile s u bcli nical disease sites will be

nc o m passe d b y P T V _ 5 6 0 0 w hic h will recei v e 1. 6 G y p er fracti o n x 3 5 fracti o ns.

Tr eat me nt of b ot h v ol u m es will occ ur at t he s a me ti me usi n g a si m ulta ne o us i nte grate d

b o ost ( SI B) te c h ni q ue deli vere d at 5 fracti o ns per wee k o ver 7 wee ks. F or re gi o ns

o nsi dere d t o be at hi g h ris k f or micr osc o pic disease, P T V _ 6 1 2 5 ma y b e treate d t o a d ose

of 6 1. 2 5 G y at 1. 7 5 G y p er fracti o n x 3 5 fracti o ns. T he treat me nt pla n us e d f or eac h

pa tie nt will be base d o n a n a nal ysis of t he v ol u metric d ose, i ncl u di n g d ose- v ol u me

hist o gra m ( D V H) a nal ys es of t he P T Vs a n d critical n or mal str uct ures. I n verse pla n ni n g

wit h c o m p uteriz e d o pti miz ati o n s h o ul d be use d.


```  
Gr oss T u m or V ol u me ( G T V) re pres e nts t he re gi o n j u d ge d t o c o nt ai n gr oss pri mar y t u m or or i n v ol ve d n o de(s) b ase d o n cli nical a n d e n d osc o pic e x a mi nati o ns, C T sca n, a n d, w he n a p plica ble, ot her i ma gi n g tec h ni q ues. Gr ossl y p ositi ve l y m p h n o des are defi ne d as a n y l y m p h n o des > 1 c m or n o des wit h a necr otic ce nt er.  
Cli nic al T ar get V ol u me ( C T V) is defi ne d as t he G T V pl us areas c o nsi dere d at ris k f or c o ntai ni n g micr os c o pic disease deli neate d b y t he treati n g p h ysicia n. C T V _ 7 0 0 0 re pres e nts G T V pl us a m ar gi n of ge n erall y 5- 1 0 m m, a n d C T V _ 5 6 0 0 re pres e nts C T V _ 7 0 0 0 wit h a mar gi n of 1 0 m m, pl us n o dal re gi o ns t o recei v e electi ve irra diati o n.  
W he n t he t u m or is i nfiltrati ve (e n d o p h ytic) or w h e n t he b or der is ill defi ne d, it mi g ht be de sira ble t o deli ver a n i nter me diate d os e t o a v ol u me ( C T V _ 6 1 2 5) t hat is sli g htl y l ar ger t ha n C T V _ 7 0 0 0. T he C T V mar gi ns ca n b e narr o wer w he n G T V is i n t he pr o xi mit y of t h e s pi nal c or d or critical n or mal tiss ues. C T V s h o ul d be cr o p pe d t o e x cl u de a n at o mical barriers t o t u m or s prea d s uc h as air ca vities, u ni n v ol ve d b o ne, a n d e xter nal b o d y c o nt o urs.  
G ui deli nes f or C T base d deli neati o n of l y m p h n o d e le vels f or n o d e ne gati v e patie nts ca n be f o u n d at t he R T O G w e b site:  
htt ps:// w w w.rt o g. or g/ C ore La b/ C o nt o uri n g Atlas es/ H N Atlases.as p x. F or pati e nts wit h p ositi ve nec k n o des, c o ns ult Gre g oire et al. ( 2 0 0 6) f or t he deli neati o n of t he n o dal C T V.  
Pl a n ni n g T ar get V ol u me ( P T V) re prese nts a n a d diti o nal mar gi n ar o u n d C T V t o c o m pe nsate f or t he varia bilit y of treat me nt set- u p a n d i nter nal or ga n m oti o n. A mi ni m u m mar gi n of 3 m m ar o u n d t he C T V is re q uire d i n all directi o ns t o defi ne eac h res pecti ve T V, e x ce pt f or sit uati o ns i n w hic h t he C T V is a djace nt t o s pi nal c or d or ot her critic al n or ma l tiss ues. I n s u c h sit uati o ns, t he mar gi n ca n be re d uce d j u dici o usl y at t he discreti o n of t he treati n g p h ysicia n.  
W he n e x pa nsi o n of a C T V res ults i n a P T V t hat e xte n ds be y o n d t he patie nt's b o d y s urface, t he P T V s h o ul d be c o nstrai ne d t o at least 3 m m fr o m wit hi n t he e xter nal c o nt o ur, w hile sti ll i ncl u di n g t he C T V. T he use of tiss ue e q ui vale nt b ol us material is i n dicate d i n sit uati o ns w here t he disease is at or j ust u n der t he s ki n s urface. T he P T V s h o ul d ali g n wit h t he s ki n s urface w he n b ol us is use d. Ot her v ol u mes s uc h as t u ni n g or a v oi da nce or o pti mizati o n str uct ures, ca n be e m pl o ye d t o dri ve t he I M R T tr eat me nt pla n ni n g pr ocess.  
uc h v ol u mes s h o ul d be c o nsi dere d t o be tr eat me nt- pla n ni n g t o ols t hat are n ot re p orte d or se nt f or w ar d f or re vie w.  
T he f oll o wi n g P T V v ol u mes m ust be se nt f or re vi e w. W he n disease wit h a p pr o priate mar gi n e xte n ds t o t he s ki n s urface a n d b ol us is use d or w he n t h e disease wit h mar gi n is m ore t ha n 8 m m fr o m t he s ki n s urface, t he P T V v ol u me (i de ntifie d as P T V _ 7 0 0 0 i n t he ta ble bel o w) m ust be se nt f or re vie w. F or sit uati o ns w here t he dis ease pl us mar gi n falls bet wee n 8 m m fr o m t he s ki n s urface a n d t he b o d y s urface, a s pecial v ol u me (i de ntifie d as P T V _ 7 0 0 0- 0 8 i n t he ta ble bel o w) m ust be se nt i n a d diti o n t o t he P T V v ol u me i n dicate d b o ve.  
T he de nsit y c orrecte d d ose distri b uti o ns s hall be calc ulate d, a n d t he d ose prescri pti o n is t o be base d o n a d os e distri b uti o n c orrect e d f or h eter o ge neities.  
5. 2. 5 Defi niti o n of Critical Str uct ures a n d M ar gi ns  
| bel o w :                                                   |                                                                                                                                         |                                          |
|-------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|
| St a n d ar d N a me                                        | Descri pti o n                                                                                                                          | V ali d ati o n                          |
| Re q uire d/ Re q uire d w he n  o pti o n al/ O pti o n al |                                                                                                                                         |                                          |
| G T V                                                       | Pri mar y t u m or a n d i n v ol ve d n o des                                                                                          | Re q uire d                              |
| C T V _ 7 0 0 0                                             | G T V +                                                                                                                                 | 1 0 m m mar gi n , e xcl u di n g        |
| a nat o mic b o u n daries t o t u m or s prea d            | Re q uire d                                                                                                                             |                                          |
| P T V _ 7 0 0 0                                             | C T V                                                                                                                                   | t o P T V 5 m m mar gi n t hat ca n be   |
| re d uce d t o 3 m m i n s o me sit uati o ns               | Re q uire d                                                                                                                             |                                          |
| C T V _ 5 6 0 0                                             | C T V _ 7 0 0 0 + 1c m mar gi n (e xcl u di n g  a nat o mic b o u n daries  t o t u m or s prea d), pl us electi ve n o dal re gi o ns | Re q uire d                              |
| P T V _ 5 6 0 0                                             | C T V                                                                                                                                   | t o P T V 5 m m mar gi n t hat ca n be   |
| re d uce d t o 3 m m i n s o me sit uati o ns               | Re q uire d                                                                                                                             |                                          |
| C T V _ 6 1 2 5                                             | C T V _ 7 0 0 0 pl us re gi o ns at hi g h                                                                                              | ris k f or                               |
| s u bcli nical disease                                      | Re q uire d w he n a p plic a ble                                                                                                       |                                          |
| P T V _ 6 1 2 5                                             | C T V                                                                                                                                   | t o P T V 5 m m mar gi n t hat ca n be   |
| re d uce d t o 3 m m i n s o me sit uati o ns               | Re q uire d w he n a p plic a ble                                                                                                       |                                          |
| S pi nal C or d                                             | S pi nal C or d                                                                                                                         | Re q uire d                              |
| S pi nal C or d _ 0 5                                       | Pla n ni n g Ris k V ol u me of 5 m m mar gi n  ar o u n d S pi nal C or d                                                              | Re q uire d                              |
| Brai n Ste m                                                | Brai n Ste m                                                                                                                            | Re q uire d                              |
| Brai n Ste m _ 0 5                                          | Pla n ni n g Ris k V ol u me of 5 m m mar gi n  ar o u n d Brai n Ste m                                                                 | Re q uire d                              |
| Par oti d _ L                                               | Left Par oti d                                                                                                                          | Re q uire d                              |
| Par oti d _ R                                               | Ri g ht Par oti d                                                                                                                       | Re q uire d                              |
| Oral Ca vit y                                               | Oral Ca vit y                                                                                                                           | Re q uire d                              |
| Li ps                                                       | Li ps                                                                                                                                   | Re q uire d                              |
| Ma n di ble                                                 | Ma n di ble                                                                                                                             | Re q uire d                              |
| P har y n x                                                 | U ni n v ol ve d p osteri or p har y n geal                                                                                             | wall                                     |
| pl us a djace nt c o nstrict or m uscles                    | Re q uire d                                                                                                                             |                                          |
| Es o p ha g us _ U p                                        | U p per Cer vical Es o p ha g us                                                                                                        | Re q uire d                              |
| Lar y n x G S L                                             | Gl ottic/ S u pra gl ottic ( G S L)                                                                                                     | Re q uire d                              |
| S u b ma n di b ula _ R                                     | Ri g ht S u b ma n di b ular Gla n d                                                                                                    | Re q uire d                              |
| S u b ma n di b ula _ L                                     | Left S u b ma n di b ular Gla n d                                                                                                       | Re q uire d                              |
| R T O G 3 5 0 4                                             | 3 7                                                                                                                                     | Versi o n Date: D ece m ber 2 6, 2 0 1 7 |  
All s u b mitte d tre at me nt pl a ns m ust strictl y a d here t o t he str uct ure n a mes liste d  
| E xter nal                                                                        | E xter nal b or der of patie nt use d t o  defi ne U ns pecifie d Tiss ue   | Re q uire d           |
|-----------------------------------------------------------------------------------|-----------------------------------------------------------------------------|-----------------------|
| P T V _ 7 0 0 0 , n ot i ncl u di n g p orti o n of  P T V near ( < 8 m m s ki n) | Re q uire d                                                                 | w he n a p plic a ble |
| P T V _ 7 0 0 0                                                                   | 0 8                                                                         |                       |
| N o n P T V                                                                       | E xter nal mi n us P T Vs                                                   | Re q uire d           |  
Defi niti o ns of N or m al Tiss ues/ Or g a ns at Risk ( O A Rs)  
S pi nal C or d: T he s pi nal c or d be gi ns at t he cra nial- cer vical j u ncti o n (i.e. t he t o p of t he C 1 verte bral b o d y). S u peri or t o t his is brai nste m a n d i nferi or t o t his is c or d. T h e i nferi or b or der of t he s pi n al c or d is at a p pr o xi matel y T 3- 4 (i.e., j ust bel o w t he l o west slice le vel t hat has P T V o n it). T he s pi nal c or d s hall be defi ne d base d o n t he treat me nt pla n ni n g C T  
sca n. I n a d diti o n, h o we v er, a Pla n ni n g Ris k V ol u me ( P R V) s pi nal c or d s h all be defi ne d.  
T he P R V c or d = s pi nal c or d + 5 m m i n eac h di me nsi o n. T his is irres pecti ve of t he use of I G R T f or mar gi n re d ucti o n.  
Brai nste m: T he i nf eri or m ost p orti o n of t he brai nste m is at t he cra nial- cer vical j u ncti o n w here it meets t he s pi nal c or d. F or t he p ur p oses of t his st u d y, t he s u p eri or m ost p orti o n of t he brai nste m is a p pr o xi matel y at t he le vel of t he t o p of t he p osteri or cli n oi d pr ocess. T he brai nste m s hall be defi n e d base d o n t he treat me nt pla n ni n g C T sca n. I n a d diti o n, h o we ver, a Pla n ni n g Ris k V ol u me ( P R V) brai nst e m s hall be defi ne d. T h e P R V brai nste m brai nste m + 5 m m i n eac h di me nsi o n. T his is irres pecti ve of t h e use I G R T f or mar gi n re d ucti o n.  
Li ps a n d Oral Ca vit y: T h ese s h o ul d be c o nt o ur e d as 2 se parate str uct ur es as t he g oal is t o kee p t he li p d ose m uc h l o wer t ha n t he oral c a vit y d ose. T he defi niti o n of li ps is selfe x pla nat or y. T h e oral c a vit y will be defi ne d as a c o m p osite str uct ure c o nsisti n g of t he a nteri or o ne h alf t o t w o t hir ds of t he oral t o n g ue/fl o or of m o ut h, b uccal m u c osa, a n d palate.  
Par oti d Gla n ds: Par oti d gla n ds are d efi ne d bas e d o n t he treat me nt pla n ni n g C T sca n.  
P har y n x: T his is defi ne d as t he " u ni n v ol ve d" p ost eri or p har y n geal w all pl us a djace nt c o nstrict or m uscles. T his e xte n ds fr o m t he s u peri or c o nstrict or re gi o n (t he i nferi or pter y g oi d plat es le vel) t o t he cric o p har y n geal i nlet ( p osteri or cri c oi d cartila ge le vel).  
Cer vical Es o p ha g us ( Es o p ha g us _ U p): T his is defi ne d as a t u b ular str uct ure t hat st arts at t he b ott o m of p har y n x a n d e xte n ds t o t he t h oracic i nlet.  
Gl ottic/ S u pra gl ottic Lar y n x ( Lar y n x G S L): T h e G S L be gi ns j ust i nferi or t o t he h y oi d b o ne a n d e xte n ds t o t he cric oi d cartila ge i nferi orl y a n d e xte n ds fr o m t he a nt eri or c o m miss ure t o i ncl u de t he ar yte n oi ds. T his i ncl u d es t he i nfra h y oi d b ut n ot s u pra h y oi d e pi gl ottis. Ma n di ble: T he ma n di ble i ncl u des t he e ntire b o n y str uct ure fr o m T MJ t hr o u g h t he s y m p h ysis.  
U ns pecifie d Tiss ue o utsi de of t he Tar gets: T his tiss ue is l ocate d bet wee n t he s k ull base a n d t h oracic i nlet t hat is n ot i ncl u de d i n eit her t he tar get v ol u mes or t he n or mal tiss ues  
```
descri be d a b o ve.

5. 2. 6 D ose t o N or mal Str uct ur es

S pi nal C or d: T he c or d s h o ul d n ot e x cee d 4 8 G y t o a n y v ol u me i n e x cess of 0. 0 3 cc

(a p pr o xi matel y 3 m m x 3 m m x 3 m m). T he P R V s pi nal c or d s h o ul d n ot e xcee d 5 0 G y t o

n y v ol u me i n e x cess of 0. 0 3 cc. I n tr eat me nt pla n ni n g, t he s pi nal c or d P R V s h o ul d be

gi ve n t he hi g h est pri orit y.


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

5. 2. 7 C o m plia nce Criteria

Treat me nt br ea ks m ust be clearl y i n dicate d i n t he treat me nt rec or d al o n g wit h t he

reas o n(s) f or t he tr eat me nt brea k(s). Treat me nt br ea ks, if necessar y, i deall y s h o ul d n ot

e x cee d 5 da ys at a ti me a n d 1 0 da ys t otal. Tr eat me nt brea ks s h o ul d be all o w e d o nl y f or

res ol uti o n of se vere ac ut e t o xicit y a n d/ or f or i nterc urre nt ill ness a n d n ot f or s ocial or

l o gistical reas o ns.


```  
| Na me of Str uct ure                                                                                                                                                                      | Per Pr ot oc ol                                    | Variati o n Acce pta ble                                                               | De viati o n         |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|----------------------------------------------------------------------------------------|----------------------|---------|
| U nacce pta ble                                                                                                                                                                           |                                                    |                                                                                        |                      |         |
| T otal R T d ose t o                                                                                                                                                                      | P T V _ 7 0 0 0                                    |                                                                                        |                      |         |
| (t o 9 5 % of t he P T V)                                                                                                                                                                 | 7 0 G y                                            | 6 9. 3 t o 7 0. 7                                                                      |                      |         |
| e xcl u di n g 7 0 G y                                                                                                                                                                    | 7 0. 7                                             |                                                                                        |                      |         |
| Mi ni m u m d ose ("c ol d s p ot"  wit hi n P T V _ 7 0 0 0 0 8 , n ot  i ncl u di n g p orti o n of P T V near  ( < 8 m m s ki n) defi ne d f or a  p oi nt t hat is 0. 0 3 cc i n size | 6 6. 5 G y (e q uals  9 5 % of prescri be d d ose) | < 6 6. 5 b ut > 6 3 G y                                                                | < = 6 3 G y          |         |
| Ma xi m u m d ose (" h ot s p ot" >  1cc) wit hi n P T V _ 7 0 0 0                                                                                                                        | < = 7 7 G y                                        | > 7 7 b ut < = 8 2 G y                                                                 | > 8 2 G y            |         |
| Ma xi m u m d ose                                                                                                                                                                         | t o N o n P T V                                    |                                                                                        |                      |         |
| (" h ot s p ot" > 1cc o utsi de t he  P T Vs)                                                                                                                                             | < 7 4 G y                                          | 7 4 7 7 G y                                                                            | > 7 7 G y            |         |
| T otal d ose t o                                                                                                                                                                          | P T V _ 6 1 2 5                                    | (t o                                                                                   |                      |         |
| 9 5 % of t he P T V I N T)                                                                                                                                                                | 6 1. 2 5 G y                                       | > = 5 9. 5 b ut < = 6 3 G y                                                            | < 5 9. 5 or          | 6 3 G y |
| T otal d ose t o                                                                                                                                                                          | P T V _ 5 6 0 0 (t o                               |                                                                                        |                      |         |
| 9 5 % of t he P T V)                                                                                                                                                                      | 5 6 G y                                            | < 5 6 G y b ut > 5 0. 4  G y                                                           | < = 5 0. 4 G y       |         |
| T otal R T d ose t o                                                                                                                                                                      | pi nal                                             | or d                                                                                   |                      |         |
| _ 0 5 ( 0. 0 3 cc)                                                                                                                                                                        | < = 5 0 G y                                        | > = 5 0 b ut < = 5 2 G y                                                               | > 5 2 G y            |         |
| T otal R T d ose t o  Brai n Ste m _ 0 5( 0. 0 3cc)                                                                                                                                       | < = 5 4 G y                                        |                                                                                        | 5 4 G y b ut < =     |         |
| 5 6 G y                                                                                                                                                                                   | > 5 6 G y                                          |                                                                                        |                      |         |
| O verall R T treat me nt ti me                                                                                                                                                            | < 5 0 da ys                                        | > 5                                                                                    | da ys ( wit h o ut a |         |
| me dicall y a p pr o priate  i n dicati o n f or dela y)                                                                                                                                  |                                                    |                                                                                        |                      |         |
| N o n                                                                                                                                                                                     | Me dicall y I n dicate d                           |                                                                                        |                      |         |
| Treat me nt I nterr u pti o ns                                                                                                                                                            | ( Da ys)                                           | 5 0 5 4 da ys ( wit h o ut a  me dicall y a p pr o priate  i n dicati o n f or dela y) | > 4                  |         |  
Rec o m me n de d d ose acce pta nce criteria f or ot her n or mal tiss ue b ut n ot t o be use d f or pla n sc ore  
| Str uct ure                | Rec o                                             | m   | me n de d d ose acce pt a nce criteri a   |
|----------------------------|---------------------------------------------------|-----|-------------------------------------------|
| Par oti d                  | D mea n < 2 6 G y ( f or at least o ne par oti d) |     |                                           |
| Li ps                      | D mea n < 2 0 G y                                 |     |                                           |
| Lar y n x G S L            | D mea n < 2 0 G y                                 |     |                                           |
| P har y n x                | D mea n < 4 5 G y                                 |     |                                           |
| S u b ma n di b ula _ R or | D mea n < 3 9 G y                                 |     |                                           |  
| S u b ma n di b ula _ L   | (c o ntralateral)            |                   |
|---------------------------|------------------------------|-------------------|
| Oral Ca vit y ( n o n     | i n v ol ve d oral ca vit y) | D mea n < 3 0 G y |
| Es o p ha g us _ U p      | D mea n < 3 0 G y            |                   |
| Ma n di ble               | D ma x < 7 0 G y             |                   |  
```
5. 2. 8 Treat me nt Pla n ni n g Pri orities a n d I nstr u cti o ns

Pri oritiz ati o n of I M R T Pla n ni n g

1. S pi nal C or d

2. Brai nste m

3. P T V _ 7 0 0 0

4. P T V _ 6 1 2 5 (if a p plica ble)

5. P T V _ 5 6 0 0

6. a. P har y n x

b. P ar oti d gla n d c o ntralat eral t o pri mar y t u m or site

7. a. Lar y n x G S L

b. Es o p ha g us _ U p

8. a. Li ps

b. Oral Ca vit y

9. a. Par oti d gla n d i psilateral t o pri mar y t u m or site

b. Ma n di ble

1 0. U ns pe cifie d tiss ue o utsi de t he tar gets


Resi m ul ati o n

I n cases of wei g ht l oss > 1 0 %, or si g nifi ca nt s hri n ka ge of l y m p ha de n o p at h y d uri n g

t hera p y, it is rec o m me n d e d t hat t he i m m o biliz ati o n mas k be a dj uste d or re ma de a n d a

ne w pla n be p erf or me d t o assess t he d ose distri b uti o ns wit h t he c urre nt a nat o m y. W het her

a ne w I M R T pla n will be ge n erat e d is at t he discreti o n of t he treati n g p h ysi cia n. If a ne w

pla n is ma de, t he tar gets s h o ul d be t he sa me as t h ose use d f or t he i nitial pl a n. T he ne w

T c o nt o ur s h o ul d be use d f or I G R T i ma ge re gistrati o n wit h t he ne w pla n.

5. 3 Ge ner al C o nc o mit a nt Me dic ati o n a n d S u p p orti ve C are G ui deli nes

. 1 Per mitte d S u p p orti ve/ A ncillar y C are a n d C o nc o mita nt Me dicati o ns

All s u p p orti ve t hera p y f or o pti mal me dical care will be gi ve n d uri n g t he st u d y peri o d at

t he discreti o n of t he att e n di n g p h ysici a n(s) wit hi n t he para m eters of t he pr ot oc ol a n d

d oc u me nte d o n eac h site's s o urce d oc u m e nts as c o nc o mita nt me dicati o n.


. 2 Pr o hi bite d T hera pies

T he use of a mif osti ne or palifer mi n as a ra di o pr ot ecta nt is n ot all o we d. T h e use of

gra n ul oc yte c ol o n y sti m ulati n g fact or or er yt hr o p oieti n is n ot all o we d. Tra nsf usi o n is t o

be perf or me d at t he discreti o n of t he treati n g p h ysicia n. A n y e x ce pti o ns m ust be

a p pr o ve d b y t he C o- Pri n ci pal I n vesti gat or, Dr. Gillis o n.

3. Partici pati o n i n Ot her Tri als

Patie nts ma y n ot partici p ate i n ot her cli nical trials t hat are i nte n de d t o treat t he dia g n os e d

hea d a n d n ec k ca ncer or i nte n de d t o re d uce t o xicit y of t hera p y.


```  
5. 5 D ur ati o n of T her a p y n t he a bse n ce of treat me nt dela ys d u e t o a d verse e ve nt(s), tr eat me nt ma y c o nti n ue as s pecifie d i n t he a b o v e treat me nt m o dalit y secti o ns or u ntil o ne of t he f oll o wi n g criteria  
a p plies:  
Dise ase pr o gressi o n; nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt; U na cce pta ble a d vers e e v e nt(s);  
atie nt deci des t o wit h dra w c o nse nt f or partici p ati o n i n t he st u d y; Ge neral or s pecific c h a n ges i n t he p atie nt's c o n diti o n re n der t he p atie nt u na cce pta bl e f or f urt her treat me nt i n t he j u d g me nt of t h e i n vesti gat or; Ne w data relate d t o t he e x peri me ntal a ge nt w hi c h w o ul d s u g gest t hat c o nti n ui n g treat me nt o n pr ot oc ol w o ul d i m p ose u n warra nte d p ote ntial ris ks be y o n d w hat was k n o w n at t he ti me of treat me nt i nitiati o n.  
6. T R E A T M E N T M O DI FI C A TI O N S/ M A N A G E M E N T  
Ni v ol u m a b, cet u xi ma b, a n d cis plati n s h o ul d be deli vere d o nl y if t here is n o i n dicati o n f or h ol di n g t he ra di ati o n a n d if all ot her he mat ol o gical a n d n o n- he mat ol o gical t o xicit y criteri a are met.  
Ra diati o n t hera p y ma y c o nti n ue at t h e discreti o n of t he treati n g p h ysicia n if ni v ol u ma b, cet u xi ma b, or cis plati n are hel d u nless s pecifi c crit eria t o h ol d ra di ot hera p y are met.  
T he treati n g p h ysicia n m a y elect t o c o nti n ue cet u xi ma b or cis plati n i n t he e ve nt t hat ni v ol u ma b is dela ye d d u e t o t o xicities relate d t o ni v ol u ma b.  
H o w e ver, ni v ol u ma b t hera p y s h o ul d be dela ye d i n t he e ve nt c et u xi ma b or cis plati n t hera p y is hel d wit h t he s pecific e x ce pti o ns liste d bel o w i n Secti o n 6. 1. 2.  
```
6. 1 Ni v ol u m a b D ose M o dific ati o ns ( 2 6 Dec 2 0 1 7)

6. 1. 1 Ma na ge me nt Al g orit h ms f or I m m u n o- O n c ol o g y A ge nts

I m m u n o- o n c ol o g y (I- O) a ge nts are ass ociat e d wit h a d verse e ve nts t hat c a n differ i n

se verit y a n d d urati o n fr o m a d verse e ve nts ca us e d b y ot her t h era p e utic class es. Ni v ol u ma b

is c o nsi dere d t o be a n i m m u n o- o nc ol o g y a ge nt i n t his pr ot oc ol. Ma na ge me nt al g orit h ms

ha ve bee n de vel o p e d t o assist i n vesti gat ors i n assessi n g a n d ma n a gi n g t h e f oll o wi n g gr o u ps

of a d vers e e ve nts: G astr oi ntesti nal, Re nal, P ul m o nar y, He p atic, E n d ocri n o p at hies, S ki n,

a n d Ne ur ol o gic al; se e t he ni v ol u ma b I n vesti gat or Br oc h ure (I B) f or t h e t o xicit y

ma na ge me nt al g orit h ms.


```  
Earl y rec o g niti o n a n d i nter ve nti o n are rec o m me n d e d acc or di n g t o t he ma na ge m e nt al g orit h ms. I n a d diti o n, t he ni v ol u ma b I n v esti gat or Br oc h ure (I B) i ncl u des o p ht hal m ol o gic val uati o ns f or a n y vis u al s y m pt o ms i n or der t o e val uate f or ni v ol u ma b rel ate d u veitis.  
I n v esti gat ors s h o ul d be g ui de d b y t he al g orit h ms i n t he I B f or i m m u ne-relate d e ve nts.  
N ot : T he al g orit h ms are g ui des f or A E ma n a ge me nt, b ut t he g ui da n ce pr o vi de d i n t hese al g orit h ms s h o ul d n ot re place t he i n vesti gat or's me dical j u d g m e nt b ut s h o ul d c o m ple me nt it.  
or patie nts e x pecte d t o re q uire m ore t h a n 4 wee ks of c ortic oster oi ds or ot h er i m m u n os u p pressa nts t o ma na ge a n a d vers e e v e nt, c o nsi der t he f oll o wi n g rec o m me n dati o ns:  
A nti micr o bial/a ntif u n gal pr o p h yla xis per i nstit uti o nal g ui deli nes t o pr e ve nt o p p ort u nistic i nfecti o ns s uc h as P ne u m oc ystis jir o veci a n d f u n gal i nfecti o ns.  
Earl y c o ns ultati o n wit h a n i nfecti o us disease s peci alist s h o ul d be c o nsi dere d.  
De pe n di n g o n t he prese ntati o n, c o ns ultati o n wit h a p ul m o n ol o gist f or br o nc h osc o p y or a gastr oe nt er ol o gist f or e n d osc o p y ma y als o be a p pr o priate.  
I n p atie nts w h o de vel o p r ec urre nt a d verse e v e nts i n t he setti n g of o n g oi n g or pri or i m m u n os u p pressa nt use, a n o p p ort u nistic i nfecti o n s h o ul d be c o nsi dere d i n t he differe ntial dia g n osis.  
A d diti o nal details o n t he safet y of ni v ol u ma b, i ncl u di n g res ults fr o m cli nical st u dies, are  
```
a vaila ble i n t he I B

. 1. 2 D ose Dela y Criteria

Ni v ol u ma b a d mi nistrati o n s h o ul d be dela ye d f or C T C A E, v. 4 t o xicities, as rec o m me n de d

i n the treat me nt al g orit h ms l ocate d i n t he I B, t h at i n t he o pi ni o n of t he treati n g p h ysicia n

re rel ate d t o t he st u d y dr u g . Ple ase n ote ni v ol u m a b t her a p y will n ot be del a ye d f or

t he f oll o wi n g:

Gra de 2 wei g ht l oss;

Gr a de 2 or 3 na usea t hat i n t he o pi ni o n of t he i n vesti gat or is rel ate d t o cis plati n;

ra de 3 ra diati o n der m atitis;

A n y Gra d e 2 - 3 m uc ositis, d ys p hasia, or p har y n g ol ar y n geal p ai n t hat i n t he o pi ni o n

of t he treati n g p h ysicia n is relate d t o ra di ati o n t hera p y f or hea d a n d n ec k ca ncer;

Gr a de 2 h y p o k ale mia or h y p o ma g n ese mia t hat i n t he o pi ni o n of t he i n vesti gat or is

relate d t o c et u xi ma b or cis plati n;

Gr a de 2 ras h t hat i n t he o pi ni o n of t he i n vesti gat or is relate d t o cet u xi ma b;

Gr a de 2 or greater h eari n g i m pair me nt t hat i n t he o pi ni o n of t he treati n g p h ysicia n is

relate d t o cis plati n;

Gr a de 3 or 4 is olate d l y m p h o pe nia ;

Gr a de 3 is olate d a ne mia if, i n t he o pi ni o n of t he treati n g p h ysici a n, t he a n e mia is n ot

relate d t o t he st u d y dr u g (e. g. rel ate d t o c hr o nic disease, ir o n deficie n c y,

radi ot hera p y).

6. 1. 3 Criteria t o Res u me Treat me nt

Patie nts ma y res u me treat me nt wit h ni v ol u ma b w he n t he dr u g-relate d A E(s) res ol ve t o t he

gra de s pecifie d i n t he ma na ge me nt al g orit h ms i n t he I B.


```  
f t he criteria t o res u m e treat me nt are met, t he pati e nt s h o ul d restart treat me nt at t he ne xt sc he d ule d ti me p oi nt (t w o- wee k i nter val) per t he pr ot oc ol.  
```
6. 1. 4 Disc o nti n uati o n Criteria

Treat me nt wit h ni v ol u ma b s h o ul d be per ma ne ntl y disc o nti n ue d as s pecifie d i n t he

g ui deli nes f or ma na ge me nt i n t he I B. A d diti o nal criteria f or disc o nti n uati o n i ncl u de:

A n y Gra d e 2 dr u g-relate d u veitis or e ye pai n or bl urre d visi o n t hat d oes n ot res p o n d t o

t o pical t hera p y a n d d o es n ot i m pr o ve t o Gra de 1 s e verit y wit hi n t he re-treat me nt peri o d

O R re q uires s yste mic treat me nt;

Gra de 3 dr u g-relate d u veitis, p ne u m o nitis, br o nc h os pas m, diarr hea, c olitis, ne ur ol o gi c

a d verse e ve nt, h y perse nsiti vit y r eacti o n, or i nf usi o n reacti o n of a n y d urati o n re q uires

disc o nti n uati o n;

Gra de 3 dr u g-relate d t hr o m b oc yt o pe ni a > 7 da ys or ass ociate d wit h bl ee di n g re q uires

```  
R T O G 3 5 0 4 4 3 Versi o n Date: D ece m ber 2 6, 2 0 1 7  
```
disc o nti n uati o n;

A n y Gra d e 4 dr u g-relate d a d verse e ve nt or la b orat or y a b n or malit y, wit h t he e x ce pti o n of

t h ose n ote d bel o w:

Is olat e d Gra d e 4 a m ylas e or li pase a b n or malities t hat are n ot ass o ciate d wit h

s y m pt o ms or cli nical ma nifestati o ns of pa ncreatitis a n d decrease t o < Gra d e 4 wit hi n

1 wee k of o ns et;

Is olat e d Gra d e 4 ele ctr ol yt e i m bala n ces/a b n or malities t hat are n ot ass ociat e d wit h

cli nical se q uela e a n d are c orrecte d wit h s u p ple me ntati o n/a p pr o priate ma na ge m e nt

wit hi n 7 2 h o urs of t heir o nset.

A n y gra de 3 or 4 dr u g-relate d la b orat or y a b n or malit y or ele ctr ol yt e a b n or m alit y n ot

ass ociate d wit h u n derl yi n g or ga n pat h ol o g y t hat d oes n ot re q uire tr eat me nt e x ce pt

f or ele ctr ol yt e re pla ce me nt O R h or m o ne/ster oi d re place m e nt d oes n ot re q uire

treat me nt disc o nti n uati o n.

A n y a d vers e e ve nt, la b orat or y a b n or malit y, or i nterc urre nt ill ness w hic h, i n t he j u d g me nt

of t he I n vesti gat or, prese nts a s u bsta ntial cli nical ris k t o t he patie nt wit h c o nti n ue d

ni v ol u ma b d osi n g;

A dela y i n ni v ol u ma b treat me nt of > 6 wee ks.

6. 1. 5 Treat me nt of Ni v ol u ma b - Relate d I nf usi o n Reacti o ns

Si nce ni v ol u ma b c o ntai ns o nl y h u m a n i m m u n o gl o b uli n pr otei n se q ue nces, it is u nli kel y t o

be i m m u n o ge nic a n d i n d uce i nf usi o n or h y perse nsiti vit y reacti o ns. H o we v er, if s uc h a

reacti o n w ere t o o cc ur, it mi g ht ma nifest wit h fe v er, c hills, ri g ors, h ea dac he, ras h, pr uritis,

art hral gias, h y p o- or h y p erte nsi o n, br o nc h os p as m, or ot her s y m pt o ms.


```  
All Gra de 3 or 4 i nf usi o n reacti o ns s h o ul d be re p orte d as a n S A E if criteria are met.  
I nf usi o n reacti o ns s h o ul d be gra de d acc or di n g t o C T C A E, v. 4 g ui deli nes.  
Tr eat me nt r ec o m me n dati o ns are pr o vi d e d bel o w a n d ma y b e m o difie d base d o n l ocal treat me nt sta n dar ds a n d g ui deli nes as a p pr o pri ate:  
F or Gr a de 1 s y m pt o ms ( Mil d reacti o n; i nf usi o n i nterr u pti o n n ot i n dicate d; i nter ve nti o n n ot i n dicate d): Re mai n at be dsi de a n d m o nit or pati e nt u ntil rec o ver y fr o m s y m pt o ms. T he f oll o wi n g pr o p h yla ctic pre me dicati o ns are rec o m me n de d f or f ut ure i nf usi o ns:  
di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or aceta mi n o p he n 3 2 5 t o 1 0 0 0 m g at least 3 0 mi n utes bef ore a d diti o nal ni v ol u ma b a d mi nistrati o ns.  
F or Gr a de 2 s y m pt o ms ( M o derate reacti o n re q uires t hera p y or i nf usi o n i nterr u pti o n b ut res p o n ds pr o m ptl y t o s y m pt o matic treat me nt [ e. g. a nti hista mi nes, n o n-ster oi dal a ntii nflam mat or y dr u gs, narc otics, c ortic oster oi ds, br o nc h o dilat ors, I V fl ui ds]; pr o p h yla ctic me dicati o ns i n dicate d f or 2 4 h o urs): St o p t he ni v ol u ma b i nf usi o n, be gi n a n I V i nf usi o n of n or ma l sali ne, a n d treat t he patie nt wit h di p he n h y dra mi ne 5 0 m g I V ( or e q ui vale nt) a n d/ or aceta mi n o p he n 3 2 5 t o 1 0 0 0 m g; re mai n at be dsi de a n d m o nit or patie nt u ntil res ol uti o n of s y m pt o ms. C ortic oster oi d or br o nc h o dilat or t hera p y ma y als o be a d mi nistere d as a p pr o priate. If t he i nf usi o n is i nterr u pte d, t he n rest art t he i nf usi o n at 5 0 % of t he ori gi nal i nf usi o n rate w he n s y m pt o ms res ol ve; if n o f urt her c o m plicati o ns e ns ue aft er 3 0 mi n utes, t he rate ma y b e i ncrease d t o 1 0 0 % of t he ori gi nal i nf usi o n rate. M o nit or patie nt cl osel y. If s y m pt o ms rec ur t he n n o f urt her ni v ol u ma b will be a d mi nistere d at t hat visit. A d mi nister di p he n h y dra mi ne 5 0 m g I V, a n d re mai n at be dsi d e a n d m o nit or t he patie nt u ntil res ol uti o n of s y m pt o ms. T he a m o u nt of st u d y dr u g i nf us e d m ust be rec or de d o n t he el ectr o nic case re p ort f or m (e C R F). T h e f oll o wi n g pr o p h yla ctic pre me dicati o ns are rec o m me n de d f or f ut ure i nf usi o ns: di p he n h y dra mi ne 5 0 m g ( or e q ui vale nt) a n d/ or aceta mi n o p he n 3 2 5 t o 1 0 0 0 m g s h o ul d be a d mi nistere d at least 3 0 mi n utes bef ore a d diti o nal ni v ol u ma b a d mi nistrati o ns. If necess ar y, c ortic oster oi ds (rec o m me n de d d ose: u p t o 2 5 m g of I V  
h y dr oc ortis o ne or e q ui vale nt) ma y b e use d.  
F or Gr a de 3 or Gr a de 4 s y m pt o ms ( Se vere reacti o n, Gra de 3: pr ol o n ge d [ie, n ot ra pi dl y res p o nsi ve t o s y m pt o matic me dicati o n a n d/ or brief i nterr u pti o n of i nf usi o n]; rec urre n ce of s y m pt o ms f oll o wi n g i nitial i m pr o ve me nt; h os pitalizati o n i n dicate d f or ot her cli nical se q uelae [e g, re nal i m pair me nt, p ul m o nar y i nfiltrates]). Gra de 4: (life t hr eat e ni n g; pr ess or or ve ntilat or y s u p p ort i n dicate d): I m me diatel y disc o nti n ue i nf usi o n of ni v ol u ma b. Be gi n a n I V i nf usi o n of n or mal sali ne, a n d treat t he p atie nt as f oll o ws. Rec o m me n d br o nc h o dilat ors, e pi ne p hri ne 0. 2 t o 1 m g of a 1: 1, 0 0 0 s ol uti o n f or s u bc uta ne o us a d mi nistrati o n or 0. 1 t o 0. 2 5 m g of a 1: 1 0, 0 0 0 s ol uti o n i njecte d sl o wl y f or I V a d mi nistrati o n, a n d/ or di p he n h y dra mi ne 5 0 m g I V wit h met h yl pr e d nis ol o ne 1 0 0 m g I V ( or e q ui vale nt), as n ee de d. P atie nt s h o ul d be m o nit ore d u ntil t he i n vesti gat or is c o mf orta ble t hat t he s y m pt o ms will n ot rec ur.  
Ni v ol u m a b will be per ma ne ntl y disc o nti n ue d. I n v esti gat ors s h o ul d f oll o w t heir i nstit uti o nal g ui deli nes f or t he treat me nt of a na p h yla xis. Re mai n at be dsi de a n d m o nit or patie nt u ntil rec o ver y fr o m s y m pt o ms. I n t he cas e of late- occ urri n g h y perse nsiti vit y s y m pt o ms (e g, a p peara nce of a l o calize d or ge neralize d pr uritis wit hi n 1 wee k after treat m e nt),  
s y m pt o matic treat me nt ma y b e gi ve n (e g, oral a nti hista mi ne, or c ortic oster oi ds).  
```
6. 2 Cet u xi m a b D ose M o dific ati o ns

N ote : If a d v erse e ve nts pre ve nt t he a d mi nistrati o n of c he m ot hera p y, t he patie nt ma y

c o nti n ue t o recei ve ra di ati o n t hera p y.


```  
I n t he e ve nt of cet u xi ma b treat me nt dela y, t here will be n o rel oa di n g cet u xi ma b i nf usi o n.  
Res u me at t he a p pr o priat e d ose as i n dicat e d bel o w.
r t o g f
6. . 2 cet u

Cet u xi ma b will n ot be d ose re d uce d or hel d f or he mat ol o gic a d v erse e ve nts, s uc h as ne utr o pe nia, ne utr o pe nic fe ver, or t hr o m b oc yt o pe nia.  
6. . 3 Cet u xi ma b D ose M o dificati o ns f or N o n- H e mat ol o gic A d vers e E ve nts See Secti o n 6. 2. 5 f or i nstr ucti o ns f or ras h.  
| T o xicit y Gr a de  C T C A E, v. 4)      | Cet u xi                 | m a b D ose   |
|--------------------------------------------|--------------------------|---------------|
| Re n al                                    | C alc ul ate d           |               |
| Cre ati ni ne Cle ar a nce ≥ 5 0 m L/ mi n | Mai ntai n d ose le vels |               |
| < 5 0 m L/ mi n                            | Mai ntai n d ose         | le vels       |
| F ati g ue ( Ast he ni a) ≥ Gra de 3       | Mai ntai n d ose le vels |               |
| N a use a/ V o                             | miti n g                 |               |
| ≤ Gra de 2 wit h ma xi mal                 | Mai ntai n d ose le vels |               |  
| me dical ma na ge m e nt ≥ Gra de 3 wit h ma xi mal  me dical ma na ge m e nt                                                                               | H ol d dr u g u ntil                                                    | gra d e 2 , t he n res u me at   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|----------------------------------|
| sa me d ose le vel                                                                                                                                          |                                                                         |                                  |
| Ot her N o n                                                                                                                                                | he                                                                      | m at ol o gic                    |
| A d verse E ve nts                                                                                                                                          | ,                                                                       |                                  |
| Gra de 3                                                                                                                                                    | 4, if p ossi bl y relate d t o                                          |                                  |
| cet u xi ma b, or li kel y t o be  e x acer bate d b y c o nti n uati o n of  cet u xi ma b, e. g. diarr hea, e x ce pt f or  wei g ht l oss or m uc ositis | H ol d dr u g u ntil < gra de 3, t he n res u me at  sa me d ose le vel |                                  |
| n y gra de 1                                                                                                                                                | Mai ntai n d ose le vels                                                |                                  |
| a.                                                                                                                                                          | Wit h t he e x ce pti o n of i nf usi o n reacti o n;                   |                                  |  
```
a. Wit h t he e x ce pti o n of i nf usi o n reacti o n;

b. or de presse d K or M g, a d mi nister re place m e nt t hera p y. C he m ot hera p y s h o ul d

c o nti n ue at t he discreti o n of t he treati n g p h ysicia n (see ta ble b el o w f or m a n a ge me nt

of h y p o m a g nese mia).


```  
| H y p o ma g n ese mia  C T C A E,  v. 4  Gr a de Ser u m                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | M a g nesi u                        | m       | G ui deli nes f or                  |       |          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------|---------|-------------------------------------|-------|----------|
| m g/ d L                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | m                                   | m ol/ L | m a n a ge                          | me nt | Acti o n |
| C o nsi der re place me nt wit h  I V ma g nesi u m s ul ate 2 5 g  i n n or mal sali ne or D 5 W.  I nf usi o n sc he d ule b ase d o n  i nstit uti o nal g ui deli nes.                                                                                                                                                                                                                                                                                                                                                |                                     |         |                                     |       |          |
| < L L N                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                     |         |                                     |       |          |
| < L L N                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | 1. 2                                | 0. 5    | Mai ntai n d ose a n d  sc he d ule |       |          |
| As a b o ve f or gra d e 1 a n d  c o nsi der pr o p h yla ctic  wee kl y i nf usi o n of  ma g n esi u m a n d/ or oral  ma g n esi u m s u p ple me ntati o n (e. g. ma g nesi u m o xi de) if  gra de 2 of hi g h er  h y p o ma g n ese mia persists. N ote t hat ma g nesi u m o xi de  is a n os m otic la x ati ve.  C o nsi der use of c o m bi ne d  ma g n esi u m o xi de pl us  al u mi n u m o xi de  pre parati o ns t o a v oi d  i n d uci n g diarr hea wit h P O  ma g n esi u m s u p ple me ntati o n | Mai ntai n d ose a n d  sc he d ule |         |                                     |       |          |
| < 1. 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | 0. 9                                | < 0. 5  | 0. 4                                |       |          |  
| H ol d cet u xi ma b u ntil  rec o ver y t o gra de 2,  t he n res u me at sa m e  d ose le vel   |        |                                     |      |                                     |                                                                                                 |
|---------------------------------------------------------------------------------------------------|--------|-------------------------------------|------|-------------------------------------|-------------------------------------------------------------------------------------------------|
| < 0. 9                                                                                            | 0. 7   | < 0. 4                              | 0. 3 | As a b o ve f or gra d es 1 a n d 2 | H ol d cet u xi ma b u ntil  rec o ver y t o gra de 2,  t he n res u me at sa m e  d ose le vel |
| < 0. 7                                                                                            | < 0. 3 | As a b o ve f or gra d es 1 a n d 2 |      |                                     |                                                                                                 |  
6. . 4 Cet u xi ma b I nf usi o n Reacti o n Ma na ge me nt  
| C T C A E, v. 4 A d verse E ve nt Gr a de                                                                                                                                                                                                                                                          | Tre at                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | me nt G ui deli nes                                                     |                                    |        |     |                 |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|------------------------------------|--------|-----|-----------------|
| Gra de 1: Mil d tra nsie nt reacti o n; i nf usi o n i nterr u pti o n n ot  i n dicate d; i nter ve nti o n n ot  i n dicate d                                                                                                                                                                    | F or mil d i nf usi o n reacti o ns, sl o w t he i nf usi o n rate f or  cet u xi ma b b y 5 0 % w he n t he dr u g is restarte d. F or  reacti o ns ma nif esti n g o nl y as d ela ye d dr u g fe v er, c o nsi der  a d mi nisteri n g pr o p h yla ctic a nti hista mi ne me dicati o ns f or  s u bse q ue nt d oses. Mai nt ai n t he cetu xi ma b d ose.  Aceta mi n o p he n or a n o n ster oi dal a nti i nfla m mat or y dr u g  ( N S AI D) ma y b e a d mi nistere d pri or t o s u bse q u e nt  cet u xi ma b i nf usi o ns, if n ot ot her wise c o ntrai n dicate d i n  patie nt s. |                                                                         |                                    |        |     |                 |
| Gra de 2: T hera p y or i nf usi o n  i nterr u pti o n i n dicate d b ut  res p o n ds pr o m ptl y t o  s y m pt o matic treat me nt  (e. g., a nti hista mi nes,  N S AI D S, narc otics, I V  fl ui ds); pr o p h yla ctic  me dicati o ns i n dicate d f or ≤  2 4 hrs                        | F or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | m o derate i nf usi o n reacti o ns, sl o w t he i nf usi o n rate f or |                                    |        |     |                 |
| cet u xi ma b b y 5 0                                                                                                                                                                                                                                                                              | % w h e n t he dr u g is restarte d a n d c o nsi der                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                         |                                    |        |     |                 |
| a d mi nisteri n g a nti hista mi ne                                                                                                                                                                                                                                                               | me dicati o ns a n d/ or ster oi dal                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                         |                                    |        |     |                 |
| me dicati o ns.                                                                                                                                                                                                                                                                                    | Mai ntai n                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | t he                                                                    | cet u xi ma b                      | d ose. |     |                 |
| Aceta mi n o p he n or a n o n                                                                                                                                                                                                                                                                     | ster oi dal a nti i nfla m mat or y dr u g                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                         |                                    |        |     |                 |
| ( N S AI D)                                                                                                                                                                                                                                                                                        | m a y                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | be                                                                      | a d mi nistere d                   | pri or | t o | s u bse q ue nt |
| cet u xi ma b i nf usi o ns, if n ot ot her wise c o ntrai n dicate d i n  patie nt s.                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                         |                                    |        |     |                 |
| Gra de 3: Pr ol o n ge d (e. g., n ot ra pi dl y  res p o nsi ve t o s y m pt o matic  me dicati o n a n d/ or brief i nterr u pti o n of i nf usi o n);  rec urre nce of s y m pt o ms  f oll o wi n g i nitial  i m pr o ve me nt; h os pitaliz ati o n i n dicate d  f or cli nical se q uela e | N O F U R T H E R C E T U XI                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | M A B . Se vere i nf usi o n reacti o ns                                |                                    |        |     |                 |
| re q uire i                                                                                                                                                                                                                                                                                        | m                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | me di ate i nterr u pti o n of cet u xi                                 | m a b i nf usi o n                 |        |     |                 |
| a n d per                                                                                                                                                                                                                                                                                          | m a ne nt disc o nti n u ati o n fr o                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | m f urt her tre at                                                      | me nt                              |        |     |                 |
| wit h cet u xi                                                                                                                                                                                                                                                                                     | m a b.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | A p pr o priate                                                         | me dical t hera p y i ncl u di n g |        |     |                 |
| e pi ne p hri ne,                                                                                                                                                                                                                                                                                  | c ortic oster oi ds,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | di p he n h y dra mi ne,                                                |                                    |        |     |                 |
| br o nc h o dilat ors, a n d o x y ge n s h o ul d be a vaila ble f or use i n  t he treat me nt of s u c h reacti o ns. Patie nt s s h o ul d be  caref ull y o bs er ve d u ntil t he c o m plete res ol uti o n of all si g ns  a n d s y m pt o ms.                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                         |                                    |        |     |                 |  
| Gra de 4: Lif e t hreate ni n g  c o nse q ue nces; ur ge nt  i nter ve nti o n i n dicate d                                                                                                                                                                                                                                              | N O F U R T H E R C E T U XI          | M A B . Life t hreate ni n g i nf usi o n                                        |                     |           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|----------------------------------------------------------------------------------|---------------------|-----------|
| reacti o ns re q uire i                                                                                                                                                                                                                                                                                                                   | m                                     | me di ate i nterr u pti o n of cet u xi                                          | m a b               |           |
| i nf usi o n a n d per                                                                                                                                                                                                                                                                                                                    | m a ne nt disc o nti n u ati o n fr o | m f urt her                                                                      |                     |           |
| tre at                                                                                                                                                                                                                                                                                                                                    | me nt wit h cet u xi                  | m a b. A p pr o priate                                                           | me dical t hera p y |           |
| i ncl u di n g e pi ne p hri n e, c ortic oster oi ds, di p he n h y dra mi ne,  br o nc h o d ilat ors, a n d o x y ge n s h o ul d be a vaila ble f or use i n  t he treat me nt of s u c h reacti o ns. Patie nt s s h o ul d be  caref ull y o bs er ve d u ntil t he c o m plete res ol uti o n of all si g ns  a n d s y m pt o ms. |                                       |                                                                                  |                     |           |
| a. Cet u xi                                                                                                                                                                                                                                                                                                                               | m a b Retre at                        | me nt F oll o wi n g I nf usi o n Re acti o ns g ui d a nce : I nstit uti o n al |                     |           |
| g ui dlei nes f or cet u xi                                                                                                                                                                                                                                                                                                               | m a b i nf usi o n r ates             | will a p pl y. I n ge ner al, it is rec o                                        | m                   | me n de d |  
```
a n d s y m pt o ms.

a. Cet u xi m a b Retre at me nt F oll o wi n g I nf usi o n Re acti o ns g ui d a nce : I nstit uti o n al

g ui dlei nes f or cet u xi m a b i nf usi o n r ates will a p pl y. I n ge ner al, it is rec o m me n de d

t h at o nce a cet u xi m a b i nf usi o n r ate h as bee n decre ase d d ue t o a n i nf usi o n

re acti o n, it will re m ai n decre ase d f or all s u bse q ue nt i nf usi o ns. If t he p atie nt h as a

sec o n d i nf usi o n re acti o n > gr a de 2 wit h t he sl o w er i nf usi o n r ate, t he i nf usi o n

s ho ul d be st o p pe d, a n d t he p atie nt s h o ul d recei ve n o f urt her cet u xi m a b tre at me nt.

If a p atie nt e x perie nces a Gr a de 3 o r 4 i nf usi o n re acti o n at a n y ti me, t h e p atie nt

s ho ul d recei ve n o f urt her cet u xi m a b tre at me nt. If t here is a n y q uesti o n as t o

w het her a n o bser ve d re acti o n is a n i nf usi o n re acti o n of Gr a des 3 or 4, t he St u d y

C h ai r or Me dic al O nc ol o g y C o- C h air s h o ul d be c o nt acte d i m me di atel y t o disc uss

a n d gr a de t he re acti o n.

6. . 5 Cet u xi ma b S pecial I nstr u cti o ns

Wee kl y cet u xi ma b will be hel d if ra di ati o n t hera p y is bei n g hel d. If cet u xi ma b is o mitte d

f or m ore t ha n f o ur c o ns ec uti ve i nf usi o ns f or a d verse e ve nts d ue t o cet u xi ma b, or f or a n

i nterc urre nt ill ness (e. g., i nfecti o n) re q uiri n g i nterr u pti o n of t hera p y, t he patie nt s h o ul d be

disc o nti n ue d fr o m f urt her cet u xi ma b t hera p y. If a d verse e v e nts pre v e nt t he a d mi nistrati o n

of c et u xi ma b, t he patie nt ma y c o nti n ue t o recei ve ni v ol u ma b a n d ra diati o n t hera p y.


```  
f a d ose of cet u xi ma b is hel d, it will n ot be ma de u p or a d de d t o t he e n d of treat me nt, u nle ss it is bei n g hel d be ca use ra diati o n treat me nt is bei n g hel d, a n d n ot b eca use of cet u xi ma b relate d A Es. I n t hat case, cet u xi ma b will be a d mi nistere d f or u p t o a t otal of 8 d oses (i ncl u di n g t he l o a di n g d ose pri or t o ra diati o n i nitiati o n). T he o mitte d d ose a n d t he reas o n f or t he o missi o n s h o ul d be rec or de d i n t he site's s o urce d o c u me ntati o n. T here will be N O rel oa di n g d ose if cet u xi ma b is hel d.
r t o g f
tre at me nt of

I n t he e ve nt of is olate d dr u g fe ver, t he i n vesti gat or m ust use cli nical j u d g m e nt t o deter mi ne if t he fe ver is relate d t o t he st u d y dr u g or t o a n i nfecti o us eti ol o g y.  
If a patie nt e x perie nces is olate d dr u g fe v er, f or t he ne xt d ose, pre-treat wit h aceta mi n o p he n or n o n-st er oi dal a nti-i nfla m mat or y a ge nt (i n vesti gat or discreti o n), re p ea t a nti p yretic d ose 6 a n d 1 2 h o urs after cet u xi ma b i nf usi o n. T he i nf usi o n rate will re mai n u nc ha n ge d f or f ut ur e d os es.  
If a patie nt e x perie nces r ec urre nt is olate d dr u g fe ver f oll o wi n g pre- me dicati o n a n d p ostd osi n g wit h a n a p pr o priate a nti p yretic, t he i nf usi o n rate f or s u bs e q ue nt d osi n g s h o ul d be 5 0 % of pre vi o us rate. If fe ver rec urs f oll o wi n g i nf usi o n rate c h a n ge, t he i n vesti gat or s h o ul d assess t he patie nt's le vel of disc o mf ort wit h t he e ve nt a n d use cli nic al j u d g me nt t o deter mi ne if t he p atie nt s h o ul d recei ve f urt her cet u xi ma b.  
```
Cet uxi m a b-rel ate d R as h

Ma nifestati o ns : Ras h ass ociate d wit h E G F R-i n hi bit ors is a relati vel y ne w

der mat ol o gi c c o n diti o n. It a p pears t o be "ac neif or m" b ut it is N O T c o nsi dere d a f or m of

ac ne; r at her, it is a f or m of f ollic ulitis. S ki n c ha n ges ma y b e ma nifeste d i n a n u m ber of

wa ys: er yt he ma; f ollicle base d pa p ules, w hi c h ma y ulc erate; p ai n; itc hi n g; c os metic

dist ur ba nce; a n d/ or n ail dis or ders. T he ras h ma y b ec o me i nfecte d a n d tr a nsf or m i nt o

cell ulitis.

Gr a di n g of Cet u xi ma b-i n d uce d Ras h : Acc or di n g t o p h ysicia n j u d g me nt, if a patie nt

e x perie nces ≥ gra de 3 ras h (acc or di n g t o eit her t he " o utsi de of t he ra di ati o n fiel d" or t he

"i nsi de of t he ra di ati o n fiel d" defi niti o ns bel o w), cet u xi ma b treat me nt a dj ust me nts s h o ul d

be ma de acc or di n g t o t he Cet u xi ma b D ose M o dificati o n ta ble t hat f oll o ws. I n p atie nts

wit h mil d a n d m o derate s ki n a d verse e ve nts, cet u xi ma b s h o ul d c o nti n ue wit h o ut

a dj ust me nt.


```  
N O T E : Ras h i nte nsit y (i. e., t he size a n d n u m ber of pa p ules or t he le v el of disc o mf ort a n d e xte nt of er yt h e ma) ma y be a n i m p orta nt c o nsi derati o n. H o we ver, t he a bs ol ute n u m ber of lesi o ns, wit h o ut ass oci ate d p h ysic al disc o mf ort , d oes n ot necess aril y c o nstit ute a basis f or a d ose re d ucti o n or d ela y. Ras h c o nsi dere d "i nt olera ble" ( beca use of pai n, itc hi n g, or a p peara nce) or t hat h as f aile d t o res p o n d t o s y m pt o matic ma na ge me nt ma y be c o nsi dere d gra de 3 a n d t h us pr o m pt d ose re d ucti o n or d ela y of cet u xi ma b. T he cli nic al j u d g me nt of t he tre ati n g p h ysici a n is critic al t o g r a di n g a n d will ulti m atel y dict ate d ose  
```
m o dific ati o n.

Ac ute S ki n C ha n ges:

Ras h Occ urri n g O utsi de of t he Ra diati o n Fiel d: S h o ul d be gra de d usi n g t h e f oll o wi n g

C T C A E, v. 4 ter ms. A ras h c o m plicate d b y sec o n dar y i nfecti o n or cell ulitis s h o ul d be

gra de d per a d diti o nal C T C A E ter ms (see ta bl e bel o w).

as h Occ urri n g I nsi de t h e Ra diati o n Fiel d: Ac ute ra diati o n der matitis ma y be

x acer bate d b y cet u xi ma b or c he m ot hera p y. T he s e verit y of s uc h ras h s h o ul d be

gra de d usi n g C T C A E, v. 4 criteria f or ra di ati o n der matitis (see ta ble b el o w).

at e S ki n C ha n ges: A p ote ntial late c ha n ge of i nterest is c o nse q ue ntial sc arri n g/ p oc k

mar ki n g i n or o ut of t h e ra diati o n fiel d. T his ma y be re p ort e d b y usi n g t he Me d D R A

c o de, " S ki n a n d s u bc uta n e o us tiss ue dis or ders - Ot her, s pecif y", wit h t he f oll o wi n g

pr ot oc ol-s pecifi c gra di n g scale as g ui da n ce:

Gr a de 1: Mil d (see n o nl y o n cl ose i ns pecti o n)

Gra de 2: M o derate (scarri n g, i nter ve nti o n or c os metic c o vera ge/i nter v e nti o n

i n dicate d)

Gr a de 3: Se vere (si g nifica nt disfi g ure me nt, dee p s carri n g, or ul cerati o n)

Gra de 4: D ee p crateri n g/scarri n g, s ki n necr osis, or disa bli n g

```  
| R as h Occ urri n g O utsi de of t he R a di ati o n Fiel d                                                                                                                                                                                                                                      |                                                                                                  |                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                  |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Pr urit us *                                                                                                                                                                                                                                                                                     | Mil d or  l ocalize d                                                                            | I nte ns e or  wi des prea d a n d  i nterferi n g wit h  A D L                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                  |
| R as h/ ac neif or                                                                                                                                                                                                                                                                               | m *                                                                                              | Pa p ules a n d/ or  p ust ules  c o veri n g < 1 0 %  B S A, w hic h  ma y or m a y  n ot be  ass ociate d wit h  s y m pt o ms of  pr urit us or  te n der ness                                                                                     | I nte ns e or  wi des prea d                                                                                                                                                                                                                                                                | Pa p ules a n d/ or  p ust ules c o veri n g a n y  % B S A, w hic h  ma y or m a y  n ot be  ass ociate d wit h s y m pt o ms  of pr urit us or te n der ness a n d  are ass o ciate d wit h e xte nsi ve  s u peri nfecti o n wit h I V  a nti bi otics  i n dicate d; life  t hreate ni n g c o nse q ue nces |
| P ar o n yc hi a *                                                                                                                                                                                                                                                                               | Nail f ol d  e de ma or  er yt h e ma;  disr u pti o n of  t he c uticle                         | Pa p ules a n d/ or  p ust ules c o veri n g  1 0 3 0 % B S A,  w hic h ma y or ma y  n ot be ass ociate d  wit h s y m pt o ms of  pr urit us or te n der ness;  ass ociate d wit h  ps yc h os o cial  i m pact; li miti n g i nstru me ntal A D LI | Pa p ules a n d/ or  p ust ules  c o veri n g > 3 0 %  B S A, w hic h  ma y or m a y n ot  be ass ociate d  wit h s y m pt o ms  of pr urit us or  te n der ness;  li miti n g self  care A D L;  ass ociate d wit h  l ocal  s u peri nfecti o n  wit h oral  a nti bi otics  i n dicate d |                                                                                                                                                                                                                                                                                                                  |
| L ocalize d  i nter ve nti o n  i n dicate d; oral  i nter ve nti o n  i n dicate d (e. g.,  a nti bi otic,  a ntif u n gal,  a nti viral); nail f ol d e de ma or  er yt h e ma wit h  pai n; ass ociate d  wit h disc har ge or  nail plate se parati o n; li miti n g  i nstr u me ntal A D L | S ur gical  i nter ve nti o n or I V  a nti bi otics  i n dicate d;  li miti n g self care A D L |                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                  |
| O nset of gra d e 3 will re q uire m o dificati o n. See t he ta ble bel o w, Cet u xi ma b D ose                                                                                                                                                                                                | M o dificati o n                                                                                 |                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                  |
| G ui deli nes f or D er mat ol o gic C ha n ges.                                                                                                                                                                                                                                                 |                                                                                                  |                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                  |  
| R as h Occ urri n g I nsi de t he R a di ati o n Fiel d                                                                                                                    |                                                 |                                                                                                                                                            |                                                                                                                                          |       |                 |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|-------|-----------------|
| Ra diati o n recall  reacti o n  ( der mat ol o gic);  Der matitis  ra diati o n                                                                                           | Fai nt er yt he m a  or dr y  des q ua mati o n | M o derate t o bris k  er yt h e ma; patc h y  m oist  des q ua mati o n,  m ostl y c o nfi ne d t o  s ki n f ol ds a n d  creas es; m o derat e  e de ma | M oist  des q ua mati o n  ot her t ha n s ki n  f ol ds a n d creases;  blee di n g i n d u ce d  b y mi n or tra u m a  or a brasi o n | Lif e | t hreate ni n g |
| c o nse q ue nces; s ki n necr osis or  ulcerati o n of f ull t hic k ness  der mis;  s p o nta ne o us blee di n g fr o m  i n v ol ve d site;  s ki n graft i n dicate d |                                                 |                                                                                                                                                            |                                                                                                                                          |       |                 |  
| Cet u xi                                                                                                                                                                                | m a b D ose                                                | M o dific ati o n G ui deli nes f or   | Der   | m at ol o gic C h a n ges ( ≥ Gr a de 3)   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|----------------------------------------|-------|--------------------------------------------|
| Cet u xi ma b                                                                                                                                                                           | O utc o me                                                 | Cet u xi ma b D ose  M o dificati o n  |       |                                            |
| Dela y i nf usi o n 1 t o 2  wee ks                                                                                                                                                     | I m pr o v e me nt t o ≤  Gra de 2                         | Res u me at 2 5 0 m g/ m               |       |                                            |
| N o I m pr o ve me nt;  re mai ns gra d e 3                                                                                                                                             | o nti n ue t o h ol d cet u xi ma b  f or u p t o 4 wee ks |                                        |       |                                            |
| If cet u xi ma b is hel d f or f o ur  c o nsec uti ve i nf usi o ns f or  a d verse e ve nts t he patie nt  s h o ul d be disc o nti n ue d fr o m  f urt her cet u xi ma b t hera p y |                                                            |                                        |       |                                            |  
Dr u g Relate d Ras h Ma n a ge m e nt: Patie nts de vel o pi n g der m at ol o gic a d verse e ve nts w hile recei vi n g cet u xi ma b s h o ul d be m o nit ore d f or t he de vel o p me nt of i nfla m m at or y or i nfecti o us se q uelae, a n d a p pr o priate treat me nt of t hese s y m pt o ms i nitiate d. Bel o w are s u g gesti o ns f or ma na gi n g cet u xi ma b-i n d uce d ras h *:  
A nti bi otics : T he be nefit of r o uti ne a nti bi otics i n u nc o m plicate d ( u ni nfecte d) ras h is u nclear. S o me cli nicia ns ha ve us e d oral mi n oc ycli ne ( Mi n oci n), m u pir oci n ( Bactr o ba n),  
or t o pical cli n da m yci n ( Cle oci n). Ras h c o m plicate d b y cell ulitis s h o ul d be tr eate d wit h a p pr o priate a nti bi otics base d o n cli nical j u d g m e nt or micr o bial se nsiti vit y a nal ysis.  
A nti hist a mi nes : Be n a dr yl or Atara x ma y b e hel pf ul t o c o ntr ol itc hi n g.  
T o pic al Ster oi ds : T he be nefit of t o pical ster oi ds is u nclear.  
Reti n oi ds : N o data t o s u p p ort use. Use is n ot a d vise d.  
Be nz o yl per o xi de : S h o ul d N O T be use d--ma y a g gra vate ras h.  
M a ke u p : Ras h ca n be c o vere d wit h ma ke u p; t his s h o ul d n ot ma ke it w orse ( use a der mat ol o gist- a p pr o ve d c o ver- u p, e. g., D er ma ble n d, or a n y ot her t y p e of f o u n dati o n).  
Re m o ve ma ke u p wit h a s ki n-frie n dl y li q ui d clea nser, e. g., Ne utr o ge n a, D o ve, or I v or y S ki n Clea nsi n g Li q ui- Gel.  
M oist urizers : Us e e m ollie nts t o pre ve nt a n d alle viate t he s ki n dr y n ess, e. g.,  
Ne utr o ge na N or we gia n F or m ula H a n d Crea m or Vaseli ne I nte nsi ve Care A d v a nce d Heali n g L oti o n.  
S u nli g ht : It is rec o m me n de d t hat p atie nts wear s u nscree n a n d hats a n d li mit s u n e x p os ure w hile recei vi n g cet u xi ma b as s u nli g ht ca n e x acer bat e a n y s ki n reacti o ns t hat ma y o cc ur.  
O ver-t he- c o u nter me di c ati o ns : O ver-t h e-c o u nt er ac ne v ul garis me di cati o ns (e. g.,  
be nz o yl per o xi de) are n ot a d vise d. T his ras h is n ot li ke ac ne v ul garis a n d t hese treat me nts c o ul d ma ke it w orse.  
```
* A da pte d fr o m Perez- S oler R, Del or d J, Hal per n A, et al. H E R 1/ E G F R i n hi bit orass ociate d ras h: F ut ur e directi o ns f or ma na ge me nt a n d i n vesti gati o n o utc o mes fr o m t he

H E R 1/ E G F R I n hi bit or Ras h Ma na ge m e nt F or u m. T he O nc ol o gist . 1 0: 3 4 5 - 3 5 6, 2 0 0 5.

6. 3 Cis pl ati n D ose M o dific ati o ns

6. . 1 Wee kl y Cis plati n D ose M o dificati o ns d uri n g C o nc urre nt Ra diati o n

N ote : S u bstit uti o n of car b o plati n f or cis plati n d uri n g a d v erse e ve nts is N O T all o we d.

atie nts will be e x a mi ne d a n d gra de d f or s u bjecti ve/ o bjecti ve e vi de n ce of de vel o pi n g

t o xicit y wee kl y acc or di n g t o C T C A E, v. 4 w hile recei vi n g c o n c urre nt cis plati n wit h

ra di ot hera p y. If a d v erse e ve nts pre ve nt t he a d mi nistrati o n of cis plati n, t he patie nt ma y

c o nti n ue t o recei ve ni v ol u ma b a n d ra diati o n t hera p y


```  
Treat me nt i nterr u pti o ns are all o we d if t h ere is s y m pt o matic m uc ositis or s ki n reacti o n t hat, i n t he j u d g me nt of t he cli nicia n, warra nts a brea k. F or c h e m ot hera p y- attri b uta ble A Es re q uiri n g a brea k i n treat me nt, res u m pti o n of c o nc urre nt cis plati n ma y be gi n w h e n A E s ha ve rec o vere d t o t h e le vels s pecifi e d bel o w. C he m ot hera p y s h o ul d be disc o nti n ue d  
```
i n the e ve nt of m ore t h a n 2 e ve nts re q uiri n g d ose re d ucti o n (e. g. if gra de 3 or great er n o nhe mat ol o gic or he mat ol o gic e ve nt oc c urs at t he re d uce d d ose of cis plati n, at 2 3

g/ m / wee k).


```  
f a n A E d o es n ot res ol ve t o t he le vels s pecifie d i n t he secti o ns bel o w pri or t o t he cale n dar wee k of t he last ra diati o n treat me nt ( See Secti o n 5. 1 f or details c o ncer ni ng para meters f or ti mi n g of last all o wa ble c o nc urre nt cis plati n d ose), t he n c he m ot hera p y s h o uld be disc o nti n ue d.  
T here will be n o d ose re- escalati o n f or c o nc urre nt cis plati n.  
he m ot hera p y d osa ge m o dificati o ns are b ase d u p o n la b val ues o btai ne d wit hi n t h e 2 4 h o urs pri or t o cis plati n a n d i nteri m n o n- he mat ol o gic t o xicities d uri n g t he wee k pri or t o a  
```
partic ular cis plati n d ose.

6. 3 . 2 Wee kl y Cis plati n D ose M o dificati o ns f or He mat ol o gi c A d vers e E v e nts d uri n g

C o nc urre nt Ra diati o n


```  
| St arti n g D ose   | D ose Le vel   | D ose Le vel   |
|---------------------|----------------|----------------|
| 4 0 m g/ m          | 3 0 m g/ m     | 2 3 m g/ m     |  
C he m ot hera p y m ust n ot be a d mi nistere d u ntil t he A N C is ≥ 1, 0 0 0 m m a n d platelets are  
≥ 7 5, 0 0 0 m m . If n ot, d ela y 7 d a ys. Cis plati n s h o ul d be hel d e ver y wee k u ntil t he a b o ve A N C a n d platelet para meters are m et. D ose re d ucti o ns w he n cis plati n is res u me d after dela y f or l o w A N C or platelets will be as f oll o ws, base d u p o n c o u nts at ti me cis plati n was hel d.  
| A N C           | Pl at elets                                                     | Re d ucti o n                       |                   |
|-----------------|-----------------------------------------------------------------|-------------------------------------|-------------------|
| < 1 0 0 0 m m 3 | or                                                              | < 7 5, 0 0 0                        | O ne d ose le vel |
| N ote : He      | m at ol o gic gr o wt h f act ors f or ne utr o pe ni a or a ne | mi a are n ot all o w e d d uri n g |                   |  
c o nc urre nt cis pl ati n a n d r a di ati o n tre at me nt.  
Ne utr o pe nic Fever : Gra d e 3 ( C T C A E, v 4) ne utr o pe nic fe v er ( A N C < 1 0 0 0/ m m wit h a si n gle te m perat ure of > 3 8. 3 de grees C [ 1 0 1 de grees F] or a s ustai ne d te m p erat ur e of ≥ 3 8 de grees C [ 1 0 0. 4 de grees F] f or m ore t ha n 1 h o ur) is a n e x pecte d p ote ntial c o m plicati o n of c o nc urre nt c h e m ot hera p y a n d ra di ot hera p y or c he m ot hera p y al o n e. If ne utr o pe nic fe ver is n ote d, t he c he m ot hera p y d ose re d ucti o n will be deter mi ne d b y t he wee kl y bl o o d  
```
c o u nts. See a b o ve.

6. . 3 Wee kl y Cis plati n D ose M o dificati o ns f or N o n- He mat ol o gic A d v erse E ve nts d uri n g

C o nc urre nt Ra diati o n


```  
Re n al A dverse E ve nts : D ose will be m o difie d base d o n t he ser u m creati ni ne pri or t o eac h cis plati n d ose. If t he ser u m creati ni ne is ≤ 1. 5 m g/ d L, creati ni ne cleara nce is n ot ne cessar y f or tr eat me nt wit h f ull d ose. If t he ser u m creati ni ne is > 1. 5 m g/ d L, a creati ni ne cleara nce s h o ul d b e o btai ne d b y uri ne c ollecti o n or n o m o gra m cal c ulati o n ( vali d o nl y if ser u m creati ni ne is n ot c ha n gi n g ra pi dl y).  
Cis pl ati n m ust n ot be a d mi nistere d u ntil cre ati ni ne is ≤ 1. 5 or cre ati ni ne cle ar a nce ≥  
5 0. O nce t he creati ni ne has met t he a b o ve p ara m eters, cis plati n ma y be restarte d wit h t he be l o w m o dificati o ns base d o n t he creati ni ne at t he ti me t he cis pl ati n was hel d: I n ge n eral, cis plati n s h o ul d be hel d f or wee kl y i nter vals (rat h er t ha n restarti n g cis plati n later i n t he sa me wee k t h at a d ose li miti n g A E is see n).  
| Cis pl ati n d ose                                  | m o dific ati o ns f or cre ati ni ne d uri n g c o nc urre nt r a di ati o n   |       |               |                   |
|-----------------------------------------------------|---------------------------------------------------------------------------------|-------|---------------|-------------------|
| Creati ni ne ( m g/ d L)                            | Creati ni ne                                                                    |       |               |                   |
| cleara nce, m eas ur e d  or calc ulat e d ml/ mi n | Cis plati n d ose  re d ucti o n                                                |       |               |                   |
| ≤ 1. 5                                              | or                                                                              | > 5 0 | N o c ha n ge |                   |
| > 1. 5                                              | a n d                                                                           | 4 0   | 5 0           | O ne d ose le vel |
| 4 0                                                 | H ol d dr u g                                                                   |       |               |                   |  
Ne ur ol o gic ( n e ur o p at hy) A dverse Eve nts:  
| Gr a de ( C T C A E, v. 4)   | D ose Re d ucti o n N o ne O ne d ose le vel  H ol d dr u g   |
|------------------------------|---------------------------------------------------------------|  
Ot ot oxicity: S h o ul d patie nts de vel o p cli nical e vi d e nce of ot ot o xicit y, f urt h er a u di o metric e val uati o n is re q uire d. A ne ur ol o gi c defi cit s h o ul d be disti n g uis he d fr o m a c o n d ucti ve l oss fr o m o bstr ucti o n of t he E ustac hia n t u be l ea di n g t o a mi d dle ear eff usi o n. Beca use n o A E scale, i ncl u di n g t he C T C A E, v. 4, has bee n v ali date d i n ter ms of c orrelati o n wit h cli nicall y rele va nt h eari n g l oss, t here are n o pr ot o c ol ma n dates re q uiri n g d ose re d ucti o n f or a u di o gra m- deter mi ne d se ns ori ne ural h eari n g l oss wit h o ut a n a nal o g o us cli nical hi g h gra de heari n g l oss. H o we ver, f or cli nical gra d e 3 or hi g her heari n g l oss, cis plati n s h o ul d be hel d a n d f or gra d e 2 cli nical heari n g l oss, o ne d ose le vel re d u cti o n s h o ul d be i m ple me nte d.  
All Ot her N o n- He m at ol o gic A dverse Eve nts Attri b ut a ble t o Cis pl ati n d uri n g C o nc urre nt R a di ati o n: F or all ot her n o n- he mat ol o gi c a d verse e ve nts i n w hic h t o xicit y is ≥ gra de 2  
( C T C A E v. 4), i n vesti gat ors are a d vise d t o e val u ate a n d ma na ge c orrecta ble iss ues pr o m ptl y t o pre v e nt w ors e ni n g of t o xicit y. F or t hese e ve nts i n w hic h t o xicit y is ≥ gra d e 3, i n vesti gat ors s h o ul d h ol d cis plati n, wit h wee kl y re-e val uati o n u ntil A E gra d e falls t o 0- 1, t he n restart cis plati n at o ne l o wer d ose l e vel. N ote: Gra de 3 m uc ositis is c o m m o nl y e x perie nce d b y hea d a n d nec k ca ncer patie nts; t he i n vesti gat or ge nerall y w o ul d n ot h ol d t he cis plati n d osi n g i n t his case, u nless t here is u n us ual c o ncer n f or pr o gressi o n t o gra d e 4  
```
m uc ositi s.

6. 3. 4 Hi g h- D ose Cis plati n D ose M o dificati o ns, Da ys 2 2 a n d 4 3 f or Ar m 2 nl y


```  
Ne utr o pe ni a: If o n t h e d a y of sc he d ul e d tr eat me nt wit h cis plati n t he a bs ol ute ne utr o p hil c o u nt ( A N C) is < 1 2 0 0, h ol d treat me nt u ntil A N C ≥ 1 2 0 0, t he n treat at 1 0 0 % d ose.  
Ne utr o pe nic fe ver will re q uire per ma ne nt 2 5 % d ose re d ucti o n. Per C T C A E, v. 3. 0, fe brile ne utr o p e nia is fe ver of u n k n o w n ori gi n wit h o ut cli nicall y or micr o bi ol o gic all y d oc u me nte d i nfecti o n; A N C < 1. 0 x 1 0e 9 L, fe ver > 3 8. 5° C.  
T hr o m b ocyt o pe ni a: If o n t he da y of sc he d ule d treat me nt wit h cis plati n t he platelet c o u nt is < 7 5, 0 0 0, h ol d treat me nt u ntil platelets are > 7 5, 0 0 0, t he n treat at 1 0 0 % d ose.  
T hr o m b oc yt o p e nia t hat r es ults i n blee di n g will re q uire a 2 5 % d os e re d u cti o n.  
Ne ur ot oxicity : If a n y si g ns of gra de 3 or greater ne ur ot o xicit y o cc ur, disc o nti n ue cis plati n. C o nti n ue R T  
Re n al A dvers e Eve nts : Cis plati n s h o ul d be a d mi nistere d o n t he sc h e d ule d da y of treat me nt usi n g t h e f oll o wi n g g ui deli nes:  
N ote : If creati ni ne is > 1. 2 m g/ dl, cleara nce m ust be d o ne i n or der t o ma ke d ose a dj ust me nt. If t he calc ulate d n o m o gra m is 5 0 m L/ mi n or a b o ve, a 2 4- h o ur uri ne c ollecti o n is n ot nee de d, b ut if t he n o m o gra m calc ulati o n is less t ha n 5 0 m L/ mi n, a 2 4h o ur uri ne c ollecti o n is ma n date d.  
| Cre at i ni ne               | Cis pl ati n D ose   |            |
|------------------------------|----------------------|------------|
| Cle ar a nce > 5 0 ml/ mi n. | 1 0 0 m g/ m         |            |
| 4 0                          | 5 0 ml/ mi n.        | 5 0 m g/ m |  
```
Ot her A dverse Eve nts:

M uc ositis: Gra de 4 will re q uire a 2 5 % d ose re d ucti o n

Ot ot o xicit y: F or n e w cli nical heari n g l oss n ot re q uiri n g a heari n g ai d or f or

ti n nit us t hat i nterferes wit h acti vities of dail y li vi n g, tr eat at 5 0 % d ose re d ucti o n.

F or h eari n g l oss re q uiri n g a heari n g ai d, disc o nti n ue cis plati n. C o nti n ue R T ( Ar m

1).

If t h e p h ysici a n is u ns ure a b o ut t he se verit y of t he heari n g l oss, a n a u di o gra m is

e nc o ura ge d.


```  
If t he sec o n d d ose of cis plati n is dela ye d m ore t ha n 2 1 da ys b eca us e of he mat ol o gic or re nal a d v erse e ve nts, t he n t he t hir d d ose will be o mitte d.  
If a w ei g ht c ha n ge of ≥ 1 0 % occ urs, t h e cis plati n d ose s h o ul d be a dj uste d.
r t o g f
7. a d v e

```
7. 1 Pr ot oc ol A g e nts

I n v esti gati o nal A ge nt

T he i n vesti gati o nal a ge nt a d mi nistere d i n R T O G 3 5 0 4, ni v ol u ma b, is bei n g ma de a vaila ble

y t he R T O G F o u n dati o n a n d distri b ute d b y a t hir d part y dr u g distri b ut or. F or ni v ol u ma b,

de ter mi nati o n of w het h er a n a d vers e e v e nt meets e x pe dite d re p orti n g criteri a, see t he

re p orti n g ta ble i n Secti o n 7. 4 of t he pr ot oc ol.


C o m mercial A ge nts

T he c o m mercial a ge nts i n R T O G 3 5 0 4 are cis plati n a n d cet u xi ma b.

7. 1. 1 A d verse E ve nts f or I n vesti g ati o n al St u d y A ge nts

n v esti gat ors m ust o btai n t he c urre nt versi o n of t h e B M S- 9 3 6 5 5 8 ( ni v ol u m a b)

I n v esti gat or Br oc h ure (I B) f or c o m pre he nsi ve p h ar mac ol o gic a n d safet y i nf or mati o n. T he

B ca n be accesse d o n t h e R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol pa ge of t h e R T O G we bsite,

w w w.rt o g. or g. Sites m ust use t heir user na m e a n d pass w or d t o access t he pr ot oc ol pa ge

n d t he I B.

7. 1. 2 A d verse E ve nts f or C o m merci al St u d y A ge nts

Re fer t o t he p ac k a ge i nserts f or cis pl ati n a n d cet u xi m a b f or det aile d p h ar m a c ol o gic

a n d s afet y i nf or m ati o n


7. 2 A d verse E ve nts ( A Es)

T his st u d y will use t h e C o m m o n Ter mi n ol o g y Criteria f or A d v erse E v e nts ( C T C A E)

versi o n 4 f or a d verse e ve nt re p orti n g. All a p pr o priate treat me nt areas s h o ul d ha ve access

t o a c o p y of t he C T C A E versi o n 4.

7. 2. 1 Defi niti o n of a n A d verse E v e nt ( A E)

A n y u nt o w ar d me dic al occ urre nce ass ociat e d wit h t he use of a dr u g i n h u ma ns, w het her

or n ot c o nsi dere d dr u g relate d. T heref ore, a n A E ca n be a n y u nfa v ora ble a n d u ni nte n de d

si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease t e m p orall y

ass ociate d wit h t he use of a me dici nal (i n v esti gati o nal) pr o d uct, w h et her or n ot

c o nsi dere d relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct (attri b uti o n of relate d or

u nrelate d). (I nter n ati o nal C o nfere nce o n H ar m o nisati o n [I C H], E 2 A, E 6).

```  
F or m ulti- m o dalit y trials, a d verse e ve nt r e p orti n g e nc o m passes all as pects of pr ot oc ol treat me nt i ncl u di n g ra diati o n t hera p y, s ur ger y, d e vice, a n d dr u g.  
A Es, as defi ne d a b o v e, e x perie nce d b y patie nts accr ue d t o t his pr ot oc ol s h o ul d be re p orte d o n t he A E secti o n of t he a p pr o priate case re p ort f or m (see Secti o n 1 2. 1 ). All n o nseri o us a d vers e e ve nts ( n ot o nl y t h ose dee me d treat me nt-relate d) are t o be c ollecte d c o nti n u o usl y d uri n g t he treat me nt peri o d a n d f or a mi ni m u m of 1 0 0 da ys f oll o wi n g t h e last d ose of st u d y treat me nt. F oll o w u p als o is re q uir e d f or n o nseri o us A Es t hat ca use i nterr u pti o n or disc o nti n uati o n of st u d y dr u g a n d f or t h ose pres e nt at t he e n d of st u d y treat me nt as a p pr o pri ate. All i de ntifie d n o nseri o us A Es m ust be rec or de d a n d descri be d o n t he n o nseri o us A E pa ge of t he C R F.  
T he f oll o wi n g la b orat or y t est res ult a b n or malities s h o ul d be ca pt ur e d o n t he n o nseri o us A E C R F pa ge a n d S A E Re p ort F or m, if t he y me et seri o us ness criteria:  
A n y l a b orat or y t est res ult t hat is cli ni call y si g nifica nt or meets t he d efi niti o n of a n  
```
S A E;

A n y l a b orat or y test res ult a b n or malit y t hat re q uir e d t he s u bj ect t o h a ve st u d y dr u g

disc o nti n ue d or i nterr u pt e d;

A n y la b orat or y test res ult a b n or malit y t hat re q uir e d t he s u bject t o recei ve s pecific

c orrecti ve t hera p y.

It is e x pecte d t h at w here ver p ossi ble, t he cli nical rat her t h a n la b orat or y ter m w o ul d be

use d b y t h e re p orti n g i n v esti gat or (e g, a n e mia vers us l o w he m o gl o bi n val u e).


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r t o g f
defi niti o n o

I M A Es i ncl u de e ve nts, re gar dless of ca usalit y, occ urri n g wit hi n 1 0 0 da ys of t he last d ose.  
I M A Es are s p ecific e ve nts (t hat i ncl u de p ne u m o nitis, diarr hea/c olitis, he patitis, ne p hritis/re nal d ysf u n cti o n, ras h, a n d e n d ocri ne [a dre nal i ns ufficie nc y, h y p ot h yr oi dis m/t h yr oi ditis, h y p ert h yr oi dis m, dia betes mellit us, a n d h y p o p h ysitis]) f or w hic h s u bjects recei v e d i m m u n os u p pressi ve me dicati o n f or tr eat me nt of t he e ve nt, wit h t he e x ce pti o n of e n d ocri ne e v e nts ( h y p ot h yr oi dis m/t h yr oi ditis, h y pert h yr oi dis m, h y p o p h ysitis, dia betes m ellit us, a dre nal i ns ufficie nc y), w hic h are i ncl u d e d re gar dl ess of treat me nt si nce t h ese e v e nts are ofte n ma n a ge d wit h o ut i m m u n os u p pressi o n. T he ta ble bel o w pr o vi des a s u m mar y of t he I M A Es cate g or y a n d t h eir res p ecti ve preferre d ter ms.  
| Preferre d Ter               | ms I ncl u de d i n A n al ysis of I                                                                                                                                   | M A Es                                   |                    |
|------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------|--------------------|
| t o S u p p ort              | W ar ni n gs a n d Prec a uti o ns                                                                                                                                     |                                          |                    |
| I                            | M A E C ate g o r y                                                                                                                                                    | P Ts i ncl u de d u n der I              | M A E C ate g or y |
| P ne u m o nitis             | P ne u m o nitis, I nt erstitial l u n g diseas e                                                                                                                      |                                          |                    |
| Diarr hea/ C olitis          | Diarr hea, C olitis, E nter oc olitis                                                                                                                                  |                                          |                    |
| He patitis                   | He pat ot o xicit y, He patitis, He patitis ac ute, A ut oi m m u ne  he patitis, A S T i ncrease d, A L T i n crease d, Bilir u bi n  i ncreas e d, A L P i ncrease d |                                          |                    |
| A dre nal i ns uffi cie nc y | A dre nal i ns uffi cie nc y                                                                                                                                           |                                          |                    |
| R T O G 3 5 0 4              | 5 6                                                                                                                                                                    | Versi o n Date: D ece m ber 2 6, 2 0 1 7 |                    |  
| Preferre d Ter                                                                                             | ms I ncl u de d i n A n al ysis of I                                                                                                         | M A Es   |
|------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------|----------|
| t o S u p p ort                                                                                            | W ar ni n gs a n d Prec a uti o ns                                                                                                           |          |
| H y p ot h yr oi dis m/ T h yr oi ditis                                                                    | H y p ot h yr oi dis m, T h yr oi ditis                                                                                                      |          |
| T h yr oi ditis ac ute (c olla ps e d wit h t h yr oi ditis f or                                           |                                                                                                                                              |          |
| re q ue n c y), A ut oi m m u ne t h yr oi ditis (c olla pse d wit h  t h yr oi ditis f or fre q ue n c y) |                                                                                                                                              |          |
| H y p ert h yr oi dis m                                                                                    | H y p ert h yr oi dis m                                                                                                                      |          |
| H y p o p h ysitis                                                                                         | H y p o p h ysitis                                                                                                                           |          |
| Dia betes mellit us                                                                                        | Dia betes mellit us, Dia betic ket oaci d osis                                                                                               |          |
| Ne p hritis a n d re n al  d ysf u n cti o n                                                               | Ne p hritis, Ne p hritis aller gic, T u b ul oi nterstitial ne p hritis,  Ac ute re n al fail ure, Re nal fail ure, I ncrease d creati ni ne |          |
| Ras h                                                                                                      | Ras h, Ras h mac ul o pa p ul ar                                                                                                             |          |  
N O T E: If t he e ve nt is a Seri o us A d verse E v e nt ( S A E) (see ne xt secti o n), f urt her re p orti n g will be re q uir e d. Re p orti n g A Es o nl y f ulfills Data Ma n a ge me nt re p orti n g re q uire me nts.  
```
7. 3 Seri o us A d verse E ve nts ( S A Es)

eri o us A d verse E v e nts t hat meet e x pe dite d re p orti n g criteria defi n e d i n t he ta ble bel o w

will be re p orte d via t he S A E re p ort f or m i n Ra ve. S A Es t hat re q uire 2 4 h n otificati o n are

defi ne d i n t he e x pe dite d re p orti n g ta bl e.


```  
Defi niti o n of a n S A E: A n y a d vers e dr u g e v e nt (e x perie nce) o cc urri n g at a n y d ose t h at  
res ults i n a n y of t he f oll o wi n g o utc o mes:  
De at h; A life -t hreate ni n g a d vers e dr u g e x perie nce; n p atie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitaliz ati o n; A pe rsiste nt or si g nifica nt disa bilit y/i nca p acit y; A c o n ge nital a n o mal y/ birt h defect; m p ort a nt me dical e ve nts t hat ma y n ot res ult i n deat h, b e life t hreate ni n g, or re q uire h os pitaliz ati o n ma y be c o nsi dere d a n S A E, w he n, b ase d u p o n me dical j u d g me nt, t he y m a y j e o par dize t he patie nt a n d ma y re q uire me dical or s ur gic al i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t he defi niti o n.  
D ue t o t he ris k of i ntra uteri ne e x p os ure of a fet us t o p ote ntiall y t erat o ge nic a ge nts, t he pre g na nc y of a st u d y partici pa nt m ust be re p orte d i n a n e x pe dite d ma n ner.  
```

7. 4 Seri o us A d verse E ve nt ( S A E) Re p orti n g Re q uire me nts

t is t he res p o nsi bilit y of t he i n vesti gat or t o d oc u me nt all a d verse e ve nts w hic h occ ur

d uri n g t he st u d y. All s eri o us a d vers e e v e nts t hat meet e x pe dite d re p orti n g criteria

defi ne d i n t he re p orti n g ta ble bel o w will be re p ort e d via t he R T O G S A E Re p ort F or m i n

R A V E. R T O G will re p ort S A Es t o Brist ol- M yers S q ui b b wit hi n 2 4 h o urs of a w are n ess.

T O G will re p ort u ne x pecte d a n d relate d S A Es t o t he F D A a n d Brist ol- M yers S q ui b b

```  
via t he Me d Watc h F or m 3 5 0 0 A per t he re q uire me nts set f ort h i n t he C o de of Fe deral  
```
Re g ulati o ns, Secti o n 3 1 2. 3 2.

7. 4 . 1 Re p orti n g S A Es

F oll o wi n g t he p atie nt's writte n c o nse nt t o partici pate i n t he st u d y, all S A Es, w het her

relate d or n ot relate d t o st u d y dr u g, m ust be c ollecte d, i ncl u di n g t h ose t h o u g ht t o be

ass ociate d wit h pr ot oc ol-s pecifie d pr oce d ures. All S A Es m ust be re p orte d per t he

re p orti n g t a ble bel o w t h at occ ur fr o m ti me of c o nse nt a n d wit hi n 1 0 0 d a ys of t he

l ast d ose of st u d y dr u g. Patie nts, w h o are ra n d o mize d a n d ne ver recei ve treat me nt ,

m ust ha ve S A Es c ollecte d f or 3 0 da ys fr o m t he date of ra n d o mizati o n. If a p plica ble,

S A Es m ust be c ollecte d t hat relate t o a n y later pr ot oc ol-s pecifi e d pr oce d ure (e. g. a

f oll o w- u p s ki n bi o ps y).


```  
T he i n vesti gat or s h o ul d re p ort a n y S A E t h at occ urs after t hese ti me peri o ds a n d t hat is belie ve d t o be relate d t o st u d y dr u g or pr ot oc ol-s p ecifie d pr oce d ur e.  
A n S A E re p ort s h o ul d be c o m plete d f or a n y e ve nt w here d o u bt e xists re gar di n g its seri o us ness. If t h e i n vesti gat or b elie ves t hat a n S A E is n ot relate d t o st u d y dr u g, b ut is p ote ntiall y relate d t o t he c o n diti o ns of t he st u d y (s uc h as wit h dra wal of pre vi o us t hera p y or a c o m plicati o n of a st u d y pr oce d ure), t he relati o ns hi p s h o ul d be s pecifie d i n t he narrati ve s ecti o n of t he S A E Re p ort F or m.  
T he S A E re p ort s h o ul d c o m prise a f ull writte n s u m mar y, detaili n g rele v a nt as pects of t he S A E i n q uesti o n. T he S A E s u m mar y als o m ust i ncl u de t he i n vesti gat or's assess me nt of rel ate d ness t o all c o m p o ne nts of pr ot o c ol tr eat me nt. A me n d t he S A E re p ort wit h f oll o w- u p i nf or mati o n, w he n it bec o mes a vaila ble, I n t he rare e v e nt w he n I nter n et o n necti vit y is disr u pte d, a 2 4- h o ur n otificati o n m ust be ma d e t o R T O G O perati o ns Office b y p h o ne, 2 1 5- 5 7 4- 3 1 9 1. A n electr o nic re p ort m ust be s u b mitte d i m me diatel y u p o n r e-esta blis h me nt of t he I nt er net c o n necti o n.  
A Es t hat occ ur d uri n g t he f oll o w- u p peri o d b e gi n ni n g 1 0 0 da ys after e n d of tr eat me nt a n d are c o nsi d ere d b y t he i n vesti gat or t o be relate d t o pr ot oc ol treat me nt m ust be re p orte d e x pe diti o usl y vi a t he S A E Re p ort F or m.  
All S A Es m ust be re p orte d i n R a ve wit hi n t he desi g n ate d ti mefr a me o utli ne d i n t he re p orti n g t a ble bel o w. R T O G will c o m plete a preli mi n ar y re vie w of t he S A E det ails a n d will c o nt act t he site wit h q ueries as nee de d. R T O G will re p ort t he S A E t o Brist ol- M yers S q ui b b wit hi n 2 4 h o urs of n otific ati o n of t he e ve nt. R T O G will re p ort t o t he F D A per 2 1 C F R 3 1 2.
r t o g f
pre g n a ncy

Patie nts w h o bec o me pre g n a nt d uri n g t he st u d y s h o ul d disc o nti n ue t he st u d y i m me diatel y. I n v esti gat ors s h o ul d re p ort t he pre g na n c y, i ncl u di n g a mal e partici pa nt's i m pre g n ati o n of his part n er, e x pe diti o usl y as a gra de 3 S A E c o de d i n t he C T C A E v. 4 as  
" pre g na n c y, p uer peri u m a n d peri natal c o n diti o ns, ot her - pre g n a nc y" o n t he S A E Re p ort or m (i n R A V E) a n d s u b mit t he Pre g na n c y Re p ort F or m i n Ra ve wit hi n 1 4 da ys of n otificati o n. R T O G will re p ort t he pr e g n a nc y t o Brist ol- M yers S q ui b b wit hi n 2 4 h o urs of n otificati o n of t he e v e nt. Patie nts s h o ul d be i nstr ucte d t o n otif y t he i n v esti gat or if it is deter mi ne d after c o m pleti o n of t he st u d y t h at t h e y bec o me pre g na nt (i ncl u di n g a male partici pa nt's i m pre g n ati o n of his part n er) eit her d uri n g t h e treat me nt p has e of t he st u d y or wit hi n 1 0 0 cale n dar da ys after t he e n d of tr eat me nt. T he pre g n a nc y o utc o me f or pa tie nts o n st u d y s h o ul d be re p orte d t o R T O G. R T O G will re p ort t h e st at us t o Brist olyers S q ui b b.  
P h ase 1 a n d E arl y P h as e 2 St u dies: E x pe dite d Re p orti n g Re q uire me nts f or A d verse E ve nts t h at Occ ur o n St u dies u n der a n I N D/I D E wit hi n 1 0 0 D a ys of t he L ast  
```
A d m i nistr ati o n of t he I n vesti g ati o n al A ge nt/I nter ve nti o n

1, 2


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F D A R E P O R TI N G R E Q UI R E M E N T S F O R S E RI O U S A D V E R S E E V E N T S ( 2 1 C F R P art 3 1 2)  
N O T E: I n vesti gat ors M U S T i m me diatel y re p ort t o t he s p o ns or ( N CI) A N Y Seri o us A d verse E ve nts, w het her or n ot t he y are c o nsi dere d relate d t o t he i n vesti gati o nal a ge nt(s)/i nter ve nti o n ( 2 1 C F R  
3 1 2. 6 4)  
A n a d verse e ve nt is c o nsi dere d seri o us if it res ults i n A N Y of t he f oll o wi n g o utc o mes:  
1) Deat h 2) A life t hreate ni n g a d verse e ve nt 3) A n a d verse e ve nt t hat res ults i n i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n f or ≥ 2 4 h o urs 4) A persiste nt or si g nifica nt i nca p acit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns 5) A c o n ge nital a n o mal y/ birt h defect.  
6) I m p orta nt Me dical E ve nts (I M E) t hat ma y n ot res ult i n deat h, be life t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d seri o us w he n , base d u p o n me dical j u d g me nt, t he y ma y je o par dize t he patie nt or s u bj ect a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. ( F D A, 2 1 C F R 3 1 2. 3 2; I C H E 2 A a n d I C H E 6).  
A L L S E RI O U S a d verse e ve nts t hat meet t he a b o ve criteria M U S T be i m me diatel y re p orte d t o R T O G  
| Gr a de 3                      |                                          |                         |
|--------------------------------|------------------------------------------|-------------------------|
| H os pit aliz ati o n          | Gr a de 1 a n d Gr a de 2 Ti mef r a mes | Ti mefr a mes           |
| Res ulti n g i n               |                                          |                         |
| H os pitalizati o n  ≥ 2 4 hrs | 1 0 Cale n dar Da ys                     | 2 4 H o ur 5 Cale n dar |
| N ot res ulti n g i n          | Da ys                                    |                         |
| H os pitalizati o n  ≥ 2 4 hrs | N ot re q uire d                         |                         |  
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E x pe dite d A E re p orti n g ti meli nes are defi ne d as:

" 2 4 H o ur; 5 Cale n dar Da ys" T he A E m ust i nitiall y be re p orte d wit hi n 2 4 h o urs of lear ni n g of

t he A E, f oll o we d b y a c o m plete e x pe dite d re p ort wit hi n 5 cale n dar da ys of t he i nitial 2 4 h o ur

re p ort.

" 1 0 Cale n dar Da ys" A c o m plete e x pe dite d re p ort o n t he A E m ust be s u b mitte d wit hi n 1 0

cale n dar da ys of lear ni n g of t he A E.

Seri o us a d verse e ve nts t hat occ ur m ore t ha n 1 0 0 da ys after t he last a d mi nistrati o n of i n vesti gati o nal

a ge nt/i nter ve nti o n a n d are c o nsi dere d relate d t o pr ot oc ol treat me nt re q uire re p orti n g as f oll o ws:

E x pe dite d 2 4 h o ur n otific ati o n f oll o we d b y c o m plete re p ort wit hi n 5 c ale n d ar d a ys f or:

All Gra de 3, 4, a n d Gra de 5 A Es

E x pe dite d 1 0 c ale n d ar d a y re p orts f or:

Gra de 2 A Es res ulti n g i n h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n

F or st u dies usi n g 1 8 F D G P E T / C T or S P E C T I N D a ge nts, t he A E re p orti n g peri o d is li mite d t o 1 0

ra di oacti ve half li ves, r o u n de d U P t o t he nearest w h ole da y, after t he a ge nt/i nter ve nti o n was last

a d mi nistere d. F o ot n ote " 1" a b o ve a p plies after t his re p orti n g peri o d.

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r t o g f
s pecific pr ot oc

T he f oll o wi n g a d vers e e v e nts are s pecific pr ot o c ol e x ce pti o ns t o e x pe dite d re p orti n g. Re p ort t he f oll o wi n g A Es i n a n e x pe dite d ma n ner o nl y if t he y e x cee d t he gra d e ( C T C A E, v. 4) i n pare nt hes es ne xt t o t he A E: diarr hea ( gra d e 2), fati g ue ( gra d e 2), pr urit us ( gra de 2), ras h mac ul o- pa p ular ( gra de 2), l y m p h oc yte c o u nt decrease ( gra de 4), a ne mia ( gra de 4), W B C  
decrease ( gra d e 4), m uc ositis oral ( gra de 3), ra diati o n der matitis ( gra de 3), t hr o m b oe m b olic e ve nt ( gra de 3).
r t o g f
a d diti o n

y m p h o histi oc yt osis is a rare b ut p ote ntiall y fatal disease of n or m al b ut o veracti ve histi oc ytes a n d l y m p h oc yt es. It is a ma nifest ati o n of c yt o ki ne releas e s y n dr o me. O cc urri n g at a n y gra d e, he m o p ha g oc ytic l y m p h o histi oc yt osis m ust be re p ort e d i n a n e x pe dite d ma n ner as a s eri o us d verse e ve nt.
r t o g f
8. r e g i

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8. 1 Re g ul at or y Re q uire me nts

lease refer t o t he st u d y-s pecific g ui de f or i n vesti gat ors a n d res earc h staff f or detaile d

pr oce d ures re gar di n g re q uire me nts f or re g ulat or y c ollecti o n. T he st u d y-s pecific g ui de is

a v ail a ble o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge o n t he R T O G we bsite,

w w w.rt o g. or g


8. 2 R T Re gistr ati o n Re q uir e me nts

All sites will be I M R T a n d I G R T cre d e ntiale d pri or t o re gisteri n g p atie nts t o t he st u d y.

Please refer t o t he M D A n ders o n D osi meter y La b we bsit e

htt p://r pc. m da n ders o n. or g/ m da dl/ R T O G _ F o u n d ati o n/ R T O G _ 3 5 0 4. ht m ), f or d etails

re gar di n g R T re gistrati o n re q uire me nts.

8. 2 Di gital R T Data S u b missi o n t o R T O G Usi n g T RI A D

T RI A D is t he i ma ge e x c ha n ge a p plicati o n use d b y t he R T O G F o u n dati o n. See t he st u d ys pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge o n t he R T O G w e bsite,

w w w.rt o g. or g , f or det ails of T RI A D.


8. 3 P ati e nt E nr oll me nt

ee t he st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge o n t he

R T O G w e bsite, w w w.rt o g. or g , f or det ails of p atie nt e nr oll me nt.


D R U G I N F O R M A TI O N

. 1 I n vesti g ati o n al St u d y A ge nt

Ni v ol u ma b, I N D # 1 2 9 8 4 1

T o s u p ple me nt t he t o xicit y i nf or mati o n c o nt ai ne d i n t his d oc u me nt, i n vesti gat ors m ust

o btai n t he c urre nt versi o n of t he B M S- 9 3 6 5 5 8 ( ni v ol u ma b) I n vesti gat or Br oc h ure (I B), f or

o m pre he nsi ve p h ar mac ol o gic a n d s afet y i nf or mati o n. Als o see A p pe n di x I .


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T he I B c a n be accesse d o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he R T O G  
w e bsite, w w w.rt o g. or g . Sites m ust use t hei r user n a me a n d p ass w or d t o access t he pr ot oc ol p a ge a n d t he I B.  
| T a ble                                                           | Pr o d uct Descri pti o n                       |                           |                                                                                              |                    |                                            |
|-------------------------------------------------------------------|-------------------------------------------------|---------------------------|----------------------------------------------------------------------------------------------|--------------------|--------------------------------------------|
| Pr o d uct  Descri pti o n a n d  D os a ge F or m                | P ote nc y                                      | Pri m ar y  P ac k a gi n | Sec o n d ar y  P ac k a gi n g ( Qt y) / L a bel  T y pe                                    | A p pe ar a nce    | St o r a ge C o n diti o ns ( per l a bel) |
| ( V ol u me) / L a bel  T y pe                                    |                                                 |                           |                                                                                              |                    |                                            |
| Ni v ol u ma b B M S 9 3 6 5 5 8 S ol uti o n  f or I nj ecti o n | 1 0 0 m g ( 1 0                                 | 1 0 m L                   | 1 0 vials per                                                                                |                    |                                            |
| m g/ m L)                                                         | vial                                            | cart o n/ O pe n la bel   | Clear t o o palesce nt  c ol orless t o pale  yell o w li q ui d. Ma y  c o ntai n particles | t o 8° C; pr otect |                                            |
| r om li g ht                                                      | freezi n g,                                     |                           |                                                                                              |                    |                                            |
| a n d s ha ki n g                                                 |                                                 |                           |                                                                                              |                    |                                            |
| * Ni v ol u ma b ma y b e la bele d as B                          | M S- 9 3 6 5 5 8 S ol uti o n f or I njecti o n |                           |                                                                                              |                    |                                            |  
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* Ni v ol u ma b ma y b e la bele d as B M S- 9 3 6 5 5 8 S ol uti o n f or I njecti o n

If st ore d i n a glass fr o nt refri gerat or, vials s h o ul d be st ore d i n t he cart o n. Rec o m me n de d

safet y me as ures f or pre p arati o n a n d ha n dli n g of ni v ol u ma b i ncl u de la b orat or y c o ats a n d

gl o ves.

F or a d diti o nal details o n pre pare d dr u g st or a ge a n d use ti me of ni v ol u ma b u n der r o o m

te m perat ur e/li g ht a n d refri gerati o n, pleas e refer t o A p pe n di x I a n d t he B M S- 9 3 6 5 5 8

( ni v ol u ma b) I n vesti gat or Br oc h ure secti o n f or " Rec o m me n de d St or a ge a n d Use

C o n diti o ns".

9. 1. A vaila bilit y/ S u p pl y

Brist ol- M yers S q ui b b will s u p pl y ni v ol u ma b free of c har ge t o patie nts o n st u d y i n t he

U. S. a n d Ca na d a. A n o n-site u n bli n de d p har macist will be res p o nsi ble f or mi xi n g

place b o per i nstr ucti o ns pr o vi de d i n A p pe n di x I, " Ni v ol u ma b P har m ac y Refere nce

S heet ". T h e dr u g will be distri b ute d b y a t hir d- part y v e n d or u n der c o ntract t o R T O G.

Dr u g acc o u nta bilit y rec or ds m ust be mai ntai n e d at all sites acc or di n g t o g o o d cli nical

practices.


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ee t he st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he R T O G w e bsite, w w w.rt o g. or g , f or det ails of dr u g s hi p me nt.  
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. 2 C o m merci al A ge nts

Cet u xi ma b a n d Cis plati n

Sites m ust refer t o t he pac ka ge i ns ert f or det aile d p har mac ol o gic a n d safet y i nf or m ati o n.

. 2. 1 A vaila bilit y/ S u p pl y

Please see Secti o n 5 f or a d mi nistrati o n i nstr ucti o ns. Please refer t o t he c urre nt F D Aa p pr o ve d pac ka ge i nsert pr o vi de d wit h eac h dr u g a n d t he site-s pecific p har mac y f or

t o xicit y i nf or mati o n a n d i nstr ucti o ns f or dr u g pre p arati o n, ha n dli n g, a n d st ora ge.


1 0. P A T H O L O G Y/ BI O S P E CI M E N S

1 0. 1 p 1 6 I m m u n o hist oc he mistr y f or Or o p h ar y n x C a ncers

T u m or p 1 6 stat us is a n esta blis he d cli nical s urr o gate of t u m or H P V stat us. p 1 6 stat us is

a n i nte gral bi o mar k er, as t u m or p 1 6 stat us is a stratificati o n fact or. E v al uati o n of t u m or

p 1 6 stat us ma y be p erf or me d l ocall y, b ut t he assa y is t o be perf or me d b y us e of a m o use

m o n ocl o nal a nti b o d y t o p 1 6 ( CI Ntec E 6 H 4, M T M La b orat ories, Hei del b er g, Ger ma n y)

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vis ualize d wit h t he Ve nta na X T a ut ostai ner ( or e q ui vale nt) usi n g t he 1- vie w sec o n dar y detecti o n kit ( Ve nta n a) ( or e q ui vale nt) as descri b e d b y J or da n, et al. ( 2 0 1 2). Ot her acce pta ble p 1 6 a nti b o d y t y pes i ncl u de 1 6 P 0 4 a n d J C 8. Pat h ol o gical i nter pretati o n of t u m or p 1 6-stat us ma y b e perf or me d l o call y a n d re vie we d ce ntrall y per J or da n et al  
( 2 0 1 2). Ce ntral r e vie w of l ocal p 1 6 I H C res ults b y Dr Ric har d J or da n will be re q uire d f or or o p h ar y n geal patie nts pri or t o ra n d o mizati o n.  
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1 0. 2 Tiss ue/ S peci me n S u b missi o n

n t his st u d y, it is re q uire d t hat tiss ue be s u b mitte d t o t he Bi os peci me n Ba n k at U C S F

f or t he p ur p ose of p 1 6 ce ntral re vie w f or patie nts wit h or o p har y n geal carci n o mas a n d f or

P D - L 1 e x pressi o n a nal ysis f or all patie nts. It is hi g hl y rec o m me n de d ( b ut o pti o nal f or t he

patie nt) t hat if a n y tiss ue re mai ns after a n al ysis, it will be st ore d at t he Bi os peci me n Ba n k

at U C S F f or f ut ure res earc h.


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I n a d diti o n, it is hi g hl y rec o m me n de d ( b ut o pti o nal f or t he patie nt) t hat peri p heral bl o o d s peci me ns be s u b mitte d f or t he test descri b e d i n Secti o n 1 0. 4 ( Peri p heral bl o o d C D 6 9/ 1 3 7 + acti vate d T cells a n d p he n ot y p e) a n d f or ba n ki n g f or f ut ure tra nslati o nal researc h.  
Tiss ue fr o m a bi o ps y or s ur gic al s peci me n will be o btai ne d fr o m f or m ali n fi x e d a n d paraffi n e m be d de d ( F F P E) i n tiss ue bl oc ks. I nstit uti o ns m ust s hi p F F P E tiss ue as o utli ne d i n Secti o n 0. 2 t o t he Bi os peci me n Ba n k at U C S F b y o ver ni g ht c o urier.  
S u b missi o n of H & E a n d p 1 6 stai ne d sli des t o t he Bi os peci me n Ba n k at U C S F f or ce ntral revie w of p 1 6 st ai ni n g is re q uire d f or or o p h ar y n geal patie nts a n d s u b missi o n of t he H & E a n d bl oc k ( or p u n c hes) is re q uire d f or all patie nts f or P D- L 1 e x pressi o n a nal ysis.  
T he F F P E sa m ples m ust ha ve s uffici e nt t u m or material f or b ot h a n al ys es.
r t o g f
see t he ta ble

Ce ntral re vie w of p 1 6 f or patie nts wit h or o p har y n geal carci n o mas will be c o n d ucte d wit h ra pi d t ur nar o u n d ( 1- 2 b usi ness da ys fr o m recei pt of t he sli des) c o or di nat e d b y Dr.  
Ric har d J or da n at t he Bi os peci me n Ba n k. S pecifics of t y pe a n d s o urce of p 1 6 a nti b o d y a n d testi n g met h o d will b e re q uest e d (alt h o u g h n ot re q uire d) at t he ti me of s peci me n s u b missi o n. E ver y eff ort s h o ul d be ma de t o o btai n a n d s u b mit t his i nf or mati o n at t he ti me of s pe ci me n tra ns missi o n, i n or der t o e ns ur e t he fastest p ossi ble res ol uti o n s h o ul d t here be a n y q uesti o ns a b o ut stai ni n g te c h ni q ue.  
N ote : D ue t o p ote ntial dela ys i n c ust o ms, Ca na dia n sites will be p er mitte d t o s u b mit a n A peri o di gital i ma ge of t he H & E a n d p 1 6 stai ne d sli de f or re m ote ce ntral re vie w b y Dr.  
J or da n. Pri or a p pr o val f or t his m ust be o btai ne d fr o m t he Bi os peci me n Ba n k at U C S F. I n cases i n w hic h Dr. J or da n deter mi nes t hat t he i ma ge q u alit y or st ai ni n g is i na de q uate, t h e site will be re q uire d t o se n d t he ori gi nal sli des t o t he Bi os pe ci me n Ba n k dir ectl y. H & E  
sli des will still ha ve t o be s u b mitte d b y C a na dia n sites al o n g wit h t he F F P E bl oc k as per secti o n 1 0. 2 f or t he P D L e x pressi o n a nal ysis.  
H & E stai ne d sli des will be use d t o c o nfir m pr ese nce of t u m or i n t he sa m ple a n d t o ai d i n assa y i nter pretati o n a n d m ust be s u b mitte d wit h bl oc ks. T he pri mar y re vie wer will be t he at h ol o g y C o- C hair, Ric har d J or da n, D D S, P h D, wit h sec o n dar y a nal ysis b y t he Pat h ol o g y C o- C hair, C hristi na K o n g, M D. I nt er pretati o n of eac h p 1 6 i m m u n ostai ne d sli de will be perf or me d usi n g t he H-s c ore m et h o d descri be d b y J or da n, et al. ( 2 0 1 2) t hat has bee n vali dat e d as a relia ble, re pr o d uci ble, a n d acc urate met h o d t o sc ore p 1 6 i n s q ua m o us cell carci n o ma of t he hea d a n d nec k. p 1 6 I H C will be sc ore d as e val ua ble if str o n g a n d diff use p ositi vit y was o bser ve d i n t he tiss ue m o u nte d o n eac h sli de. T he hi g hest i nte nsit y of p 1 6 stai ni n g pres e nt i n t he t u m or will be sc ore d o n a n or di nal sc or e of 0- 3, relati ve t o t he i nte nsit y of t he p ositi ve (sc ore 3) a n d ne gati ve (sc ore 0). T he perce nt of t u m or sta i ni n g at t he hi g hest i nte nsit y als o will be esti mate d wit hi n 5 % i ncre me nts.  
T he H sc ore is deri ve d fr o m t he cr oss pr o d uct of t he i nte nsit y sc ore ( 0 t o 3), a n d t he pe rce nt of t u m or stai ni n g at t he hi g h est i nte nsit y ( 0- 1 0 0 %). A n o pti mal H-sc ore c ut- p oi nt of 6 0 o n a scal e of 0- 3 0 0 yi el ds a n a vera ge se nsiti vit y of 9 1. 6 % a n d s pecifi cit y of 9 0. 4 %  
f or H R- H P V o nc o ge ne e x pressi o n a n d t h us a n H-sc ore c ut- p oi nt of 6 0 i n di cates t hat a t u m or wit h diff use l o w-i nte nsit y n ucle ar a n d c yt o plas mic p 1 6 stai ni n g i n t he maj orit y of t he t u m or is a tr ue p ositi ve (J or da n 2 0 1 2). Hi g h a gree me nt o n i nter-rater i nter pretati o n has bee n re p orte d ( Sc hle c ht 2 0 1 1, T ha varaj 2 0 1 1), i n dicati n g t he fa miliarit y of pat h ol o gists wit h i nter pretati o n of I H C assa ys. Si milarl y, c o m para ble assa y perf or ma n ce f or p 1 6 t o t hat o bser ve d here has als o bee n pre vi o usl y re p orte d ( Sc hlec ht 2 0 1 1, T ha varaj 2 0 1 1). T he m ost c o m m o n p 1 6 m o n ocl o nal a nti b o d y i n use is E 6 H 4 ( CI Nt ec). Ot her cce pta ble p 1 6 a nti b o d y t y pes i ncl u de 1 6 P 0 4 a n d J C 8. If a differe nt p 1 6 a nti b o d y is use d, disc ussi o n wit h t he P at h ol o g y C o- C hairs is str o n gl y e n c o ura ge d.  
n cases i n w hi c h a maj or discre pa n c y arises b et wee n t he pri mar y e val uat or a n d t he ce ntral r e vie wer ( Dr. J or da n), t he p 1 6 stai ne d sli d e a n d t he ass o ciate d pr o b e a n d testi n g s pecifics will be se nt t o a sec o n dar y ce ntr al re vie wer, Dr. C. K o n g at Sta nf or d U ni versit y, t o res ol ve t he disa gree me nt. If p 1 6 st ai ni n g ca n n ot be esta blis he d as p ositi ve t hr o u g h t he ce ntral r e vie w pr ocess, t h e patie nt is n ot c o nsi dere d eli gi ble.  
S hi p F F P E bi os peci me ns f or m a n d at or y ce ntr al re vie w a n d P D - L 1 e x pressi o n, a n d f or o pti o n al b a n ki n g t o:  
( d o not s hi p fres h peri p her al bl o o d t o t his a d dress)  
Bi os peci me n Ba n k at U C S F  
2 3 4 0 S utter Street, R o o m S 3 4 1 ( B o x 1 8 0 0)  
Sa n Fra n cisc o, C A 9 4 1 1 5 4 1 5 - 4 7 6- 7 8 6 4; R T O G @ ucsf.e d u S hi p all fres h peri p her al bl o o d t o Ferris La b orat or y Att n.: Sa n dra P o ve da Gi bs o n U ni versit y of Pitts b ur g h Ca ncer I nstit ute R o o m 2. 2 6 Hill ma n Researc h Pa vili o n 5 1 1 7 C e ntre A ve n u e Pitts b ur g h, P A 1 5 2 1 3 or q uesti o ns: 4 1 2- 6 2 3 - 7 7 3 8 or 4 1 2- 4 4 3- 8 6 7 3; p o ve das @ u p mc.e d u Alter nati vel y, c o nta ct Dr. Ferris: 4 1 2- 2 9 8- 7 0 0 2; ferrisrl @ u p mc.e d u See t he t a bles bel o w f or m a n d at or y a n d o pti o n al s peci me n c ollecti o n a n d A p pe n di x III f or f urt her det ails.  
See f urt her det ails of s peci me n c ollecti o n/ pr ocessi n g/s hi p pi n g o n t he R T O G w e b site, htt p:// w w w.rt o g. or g/ Li n k Clic k. as p x ?filetic ket = 1 S Fl E V x S ui 4 % 3 d &t a bi d = 2 8 1  
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1 0. M a n d at or y St u dies ( 2 6 Dec 2 0 1 7)

M a n d at or y St u d y # 1: S peci me n C ollecti o n f or Ce ntr al p 1 6 C o nfir m ati o n f or

Or o p h ar y n ge al C a ncer P ati e nts

T he s peci me ns are b ei n g c ollecte d f or c o nfir mati o n b y ce ntral r e vie w. I nstit uti o ns m ust

scree n or o p har y n geal patie nts b y i m m u n o hist oc he mistr y pri or t o re gistrati o n


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| Re q uire d F or ms: S T f or m                                                                                                                                                                                                                                                                                                                                                                                                                                          | a n d pat h ol o g y re p orts wit h accessi o n n u m ber , d ate of   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|
| pr oce d ure, a n d p 1 6 stai ni n g res ult; a n y ot h er pers o nal healt h i nf or mati o n ( P HI)  s h o ul d be re dacte d. S hi p pi n g c osts S u b mitti n g site p a ys c ost of s hi p pi n g. Resi d ual Material: p 1 6 sli des will be retai ne d u nl ess ret ur n is r e q u este d b y t he  s u b mitti n g site; sites s h o ul d s u b mit a ret ur n re q uest f or m wit h a ret ur n air bill H & E sli de will be retai ne d f or all cas es. |                                                                         |
| S hi p ce ntr al re vie w s peci me ns t o: Bi os peci me n B a n k at U C S F 2 3 4 0 S utter Street, R o o m S 3 4 1                                                                                                                                                                                                                                                                                                                                                   |                                                                         |  
| F or q uesti o ns, c o nta ct: Bi os peci me n Ba n k at U C S F                                                            | R T O G                       | @ ucsf.e d u ; 4 1 5 4 7 6   | 7 8 6 4/ F A X 4 1 5                                                                                                                                                                        | 4 7 6                                                                     | 5 2 7 1   |
|-----------------------------------------------------------------------------------------------------------------------------|-------------------------------|------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|-----------|
| S peci                                                                                                                      | me n T y pe                   | C ollecti o n Ti             | me                                                                                                                                                                                          |                                                                           |           |
| P oi nts                                                                                                                    | C ollecti o n                 |                              |                                                                                                                                                                                             |                                                                           |           |
| I nf or                                                                                                                     | m ati o n a n d               |                              |                                                                                                                                                                                             |                                                                           |           |
| Re q uire                                                                                                                   | me nts                        | S hi p pi n g                |                                                                                                                                                                                             |                                                                           |           |
| O ne H & E sli de O ne p 1 6 stai ne d  I H C sli de                                                                        | Pre                           | Treat me nt                  | E nr olli n g i nstit uti o n,  usi n g a C LI A certifie d  la b orat or y, scree ns  patie nt wit h p 1 6 testi n g  b y I H C . Th e n  Bi os peci me n Ba n k  d oes ce ntr al re vie w | Sli des s hi p pe d  a m bie nt t o t he  U C S F Bi os peci me n  Ba n k |           |
| N ote: B ot h sli des  m ust be fr o m t he  sa me bl oc k. T he  H & E ca n be a  d u plicate c ut sli de. M a n d at or y | St u d y #                    | : T u                        | m or P D                                                                                                                                                                                    | L 1 E x pressi o n f or All P atie nts                                    |           |
| S peci me ns are b ei n g c oll ecte d t o deter mi ne if pati e nts wit h P D                                              | L 1 p ositi ve t u m ors will |                              |                                                                                                                                                                                             |                                                                           |           |  
ha ve a n i m pr o ve d P F S w he n treate d wit h ni v ol u ma b i n c o m paris o n t o patie nts wit h P D  
L 1 ne gati ve t u m ors (see Secti o n 2. 7 f or f urt her details).  
F F P E bl oc ks a n d p u n c hes m ust ha ve s uffici e nt t u m or cells prese nt i n t he s a m ple  
bei n g s u b mitte d f or P D L 1 testi n g.  
Re q uire d F or m: S T f or m a n d pat h ol o g y re p orts wit h accessi o n n u m ber, d at e of pr oce d ure; a n y ot her p ers o nal healt h i nf or mati o n ( P HI) s h o ul d b e re d acte d.  
S hi p pi n g c osts: Ret ur n la bels are pr o vi d e d f or fr oze n bi os peci me ns o nl y.  
| S hi p s peci                                                                                                                                                                                                     | me ns t o:                                                                                                                             |                  |                                                                                                              |                                                                          |         |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|------------------|--------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|---------|
| Bi os peci                                                                                                                                                                                                        | me n B a n k at U C S F                                                                                                                |                  |                                                                                                              |                                                                          |         |
| 2 3 4 0 S utter Street, R o o                                                                                                                                                                                     | m S 3 4 1                                                                                                                              |                  |                                                                                                              |                                                                          |         |
| S a n Fr a ncisc o, C A 9 4 1 1 5 F or q uesti o ns, c o nta ct: Bi os peci me n Ba n k at U C S F; R T O G                                                                                                       | @ ucsf.e d u ; 4 1 5                                                                                                                   | 4 7 6            | 7 8 6 4/ F A X 4 1 5                                                                                         | 4 7 6                                                                    | 5 2 7 1 |
| S peci                                                                                                                                                                                                            | me n T y pe                                                                                                                            | C ollecti o n Ti | me                                                                                                           |                                                                          |         |
| P oi nts                                                                                                                                                                                                          | C ollecti o n                                                                                                                          |                  |                                                                                                              |                                                                          |         |
| I nf or                                                                                                                                                                                                           | m ati o n a n d                                                                                                                        |                  |                                                                                                              |                                                                          |         |
| Re q uire                                                                                                                                                                                                         | me nts                                                                                                                                 | S hi p pi n g    |                                                                                                              |                                                                          |         |
| Re prese ntati ve H & E  stai ne d sli des of t he  pri mar y t u m or or  metastatic l y m p h  n o de . Ca n be a  d u plicate c ut sli de,  d oes n ot ha ve t o be  t he dia g n ostic sli de.                | Pre                                                                                                                                    | treat me nt      | H & E stai ne d sli de (ca n be t h e sa me  o ne s u b mitte d f or  ce ntral r e vie w, if  a p plica ble) | Sli de s hi p pe d  a m bie nt t o t he  U C S F Bi os peci me n  Ba n k |         |
| A c orres p o n di n g paraffi n e m be d d e d  tiss ue bl oc k or o ne  t o t w o 3 m m  p u nc hes of t he  pri mar y t u m or or  metastatic l y m p h  n o de ta ke n bef ore  i nitiati o n of  treat me nt | Pre                                                                                                                                    | treat me nt      | Paraffi n                                                                                                    | e m be d de d                                                            |         |
| tiss ue bl oc k or  p u nc h bi o psies fr o m  t he bl oc k. If  e m be d de d p u nc h es  are s u b mitte d t he  H & E fr o m t he  p u nc h bl oc k m ust  als o be se nt                                    | Bl oc k or p u n c hes s hi p pe d a m bie nt (s hi p wit h a c ol d  pac k d uri n g h ot  weat her) t o t he  Bi os peci me n Ba n k |                  |                                                                                                              |                                                                          |         |
r t o g f
1 0. 4 o pti

Patie nts m ust be offere d t he o p p ort u nit y t o c o ns e nt t o o pti o nal s peci me n c ollecti o n. If t he patie nt c o nse nts t o partici pate, t he site is re q uire d t o s u b mit t he patie nt's s peci me ns as s pecifie d i n t he pr ot oc ol. Sites are n ot per mitte d t o delete t he s peci me n c o m p o ne nt fr o m he pr ot oc ol or fr o m t he s a m ple c o nse nt.  
S peci me ns are b ei n g c oll ecte d t o deter mi ne if acti vate d, C D 6 9 + or C D 1 3 7 + T cells will i ncreas e i n t he circ ul ati o n of ni v ol u ma b treate d p atie nts (see Secti o n 2. f or f urt her details) a n d t o c orrelate t heir p he n ot y pe, a n d c o sti m ulat or y/c o i n hi bit or y rece pt ors wit h cli nical res p o nse.  
Re q uire d F or m: St u d y s pecific S T f or m f or peri p h eral bl o o d S hi p pi n g da ys: M o n da y We d nes da y ( U. S. sites); M o n da y T ues da y ( Ca na d a a n d N o n N ort h A me rica n).  
S hi p pi n g la bels will be pr o vi de d wit h kits f or peri p heral bl o o d fr o m t he U C S F  
Bi os peci me n Ba n k .  
S hi p s peci me ns t o :  
Ferris La b orat or y Att n.: Sa n dra P o ve da Gi bs o n R o o m 2. 2 6 Hill ma n Researc h Pa vili o n 5 1 1 7 Ce ntre A ve n u e Pitts b ur g h, P A 1 5 2 1 3 F or q uesti o ns, c o nta ct: Sa n dra Gi bs o n ( Ferris L a b ), 4 1 2 6 2 3 7 7 3 8 or 4 1 2 4 4 3 8 6 7 3; p o ve das @ u p mc.e d u Sites s h o ul d e mail t he Ferris la b trac ki n g i nf or mati o n bef ore s hi p pi n g t he s a m ples.  
Alter nati vel y, c o nta ct Dr. Ferris: 4 1 2 2 9 8 7 0 0 2; ferrisrl @ u p mc.e d u  
| S peci                                                                                                                     | me n T y pe                                                                    | C ollecti o n Ti                                                                                                      | me   |
|----------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------|------|
| P oi nts                                                                                                                   | C ollecti o n                                                                  |                                                                                                                       |      |
| I nf or                                                                                                                    | m ati o n a n d                                                                |                                                                                                                       |      |
| Re q uire                                                                                                                  | me nts                                                                         | S hi p pi n g                                                                                                         |      |
| Peri p heral Bl o o d  M o n o n uclear Cells  ( P B M C) f o ur 1 0  ml or fi ve 8 ml  ree n t o p ( h e pari n)  t u bes | Pre                                                                            | treat me nt                                                                                                           |      |
| ( da y 1 4) P ost treat me nt: 3  a n d 6 m o nt hs  after R T                                                             | See A p pe n di x I f or pr ocess i n g a n d  s hi p pi n g  i nf or mati o n | S hi p fres h at r o o m  te m perat ur e  o ver ni g ht f or  m or ni n g deli ver y t o  t he Ferris  La b rat or y |      |  
```
1 1. S P E CI A L S T U DI E S ( N O N- TI S S U E)

ot A p plic a ble


1 2. M O D A LI T Y R E VI E W S

1 2. 1 R a di ati o n T her a p y Q u alit y Ass ur a nce Re vie ws

T he Ra diati o n O nc ol o g y C o- C hair, L ore n Mell, M D will perf or m o n g oi n g re m ote R T

Q ualit y Ass ura nce Re vie w after cases e nr olle d ha ve bee n recei ve d at R T Q A.


```  
T he g o al of t he re vie w is t o e val uate pr ot oc ol c o m plia nce. T he re vie w pr ocess is c o nti n ge nt o n ti mel y s u b missi o n of ra di ot hera p y treat me nt data as s pecifi e d i n Secti o n  
. T he sc ori n g mec h a nis m is: Per Pr ot oc ol, Variati o n Acce pt a ble, a n d De viati o n  
```
U nacce pta ble.

. 2 Dr u g Q u alit y Ass ur a nce Re vie ws

T he C o Pri nci pal I n vesti gat or/ M e dical O n c ol o g y, Ma ura Gillis o n, M D, P h D a n d Me dical

O nc ol o g y C o- C h air, A. Di mitri os C ole vas, M D, will perf or m a C he m ot hera p y Ass ura n ce

Re vie w of all patie nts w h o recei v e or are t o r ecei v e dr u g t hera p y i n t his trial. T he g o al of

t he re vie w is t o e v al uate pr ot oc ol c o m plia nce. T h e re vie w pr ocess is c o nti n ge nt o n

ti mel y s u b missi o n of dr u g treat me nt data as s pecifie d i n Secti o n 1 3 . T he sc ori n g

```  
mec ha nis m is: Per Pr ot oc ol/ Acce pta ble Variati o n, U nacce pta ble D e viati o n, a n d N ot E val ua ble. A re p ort is se nt t o eac h i nstit uti o n o nce per year t o n otif y t he i nstit uti o n a b o ut c o m plia nce f or eac h cas e re vie we d i n t h at year.  
Dr s. Gillis o n a n d C ole vas will perf or m a Q u alit y Ass ura nce Re vie w after R T O G  
He a d q uarters has recei ve d c o m plete data f or t he first 2 0 cases e nr olle d. Drs. Gillis o n a n d C ole vas will perf or m t he ne xt re vie w after R T O G Hea d q uarters has recei ve d c o m plete data f or t he n e xt 2 0 cases e nr olle d. T he fi n al cas es will be re vie we d wit hi n 3 m o nt hs after t his st u d y h as reac he d t h e tar get a ccr ual or as s o o n as R T O G Hea d q uarters has recei ve d o m plete data f or all cas es e nr olle d, w hic he v er occ urs first.  
```
1 2. 3 S ur gic al Q u alit y Ass ur a nce Re vie ws

atie nts wit h oral ca vit y ca ncer are e x cl u de d fr o m partici pati o n if res ecti o n of t he

pri mar y t u m or is c o nsi dere d tec h nic all y feasi ble b y a n oral or h ea d a n d n ec k ca ncers

s ur gic al s u bs pecialist. C o- Pri nci pal I n vesti gat or/ S ur gi cal O nc ol o g y, Dr. R o bert Ferris

M D , P h D, will re vie w i n di vi d ual cases as t he y arise t o d oc u me nt a p pr o pri ate ness f or

ccr ual a n d reas o n(s) f or dee mi n g cases u nresecta ble.


```  
Drs. Ferris als o will re vie w cases after R T O G Hea d q uarters has recei ve d c o m plete data f or t he first 5 s uc h oral c a vit y cases e nr olle d, a n d after eac h 5 cases t h ereafter. T he fi nal ases will be re vie we d wit hi n 3 m o nt hs after t his st u d y has r eac he d t he tar get accr ual or as s o o n as R T O G Hea d q uarters has recei ve d c o m plete data f or all cas es e nr olle d, w hic he ver occ urs first.  
```
1 3. D A T A A N D R E C O R D S

his st u d y will utilize Me di d at a R a ve. See t he D at a C olle cti o n/ R A V E D at a F o r ms

G ui de i n t he st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he

R T O G w e bsite, w w w.rt o g. or g, f or f urt her det ails.

1 3. 1 S u m m ar y of D osi metr y Di git al D at a S u b missi o n ( S u b mit t o R T O G vi a T RI A D; see t he

st u d y-s pecific g ui de o n t he R T O G F o u n d ati o n 3 5 0 4 pr ot oc ol p a ge of t he R T O G

w e bsite, w w w.rt o g. or g , f or det ails of d at a s u b missi o n a n d T RI A D.) ( 2 6 Dec 2 0 1 7)


```  
| Ite                                                                                                                                                                                                 | m                                    | D ue                                                   |                |          |    |        |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|--------------------------------------------------------|----------------|----------|----|--------|----|
| DI C O                                                                                                                                                                                              | M It e ms                            | DI C O                                                 | M C T I m a ge | Wit hi n | 1  | w ee k | of |
| DI C O                                                                                                                                                                                              | M Str uct ure                        | st art of R T                                          |                |          |    |        |    |
| DI C O                                                                                                                                                                                              | M D ose                              |                                                        |                |          |    |        |    |
| DI C O                                                                                                                                                                                              | M R T Pla n                          |                                                        |                |          |    |        |    |
| All re q uire d str uct ure s                                                                                                                                                                       | m ust be l a bele d per t he t a ble | i n Secti o n                                          |                |          |    |        |    |
| 5. 2. 5 D V H A nal ysis                                                                                                                                                                            | W or ks heet                         | ( o pti o nal) t o be s u b mitte d via T RI A D wit h |                |          |    |        |    |
| R T Di gital Data liste d a b o ve:  htt ps:// w w w.rt o g. or g/ Cli nical Trials/ R T O G F o u n d ati o n St u dies/ R T O G F o u n dati o n St u d y 3 5 0 4/ R T O G 3 5 0 4 F or ms.as p x |                                      |                                                        |                |          |    |        |    |  
U p o n s u b missi o n of t he di gital d ata vi a T RI A D, c o m plete a n o nli n e Di git al D at a S u b missi o n I nf or m ati o n F or m ( D D SI) :  
htt ps: // w w w.rt o g. or g/ C orela b/ T RI A D.as p x N O T E : A L L SI M U L A TI O N A N D P O R T A L FI L M S A N D/ O R DI GI T A L FI L M I M A G E S  
WI L L B E K E P T B Y T H E I N S TI T U TI O N A N D O N L Y S U B MI T T E D I F R E Q U E S T E D.  
```
1 4. S T A TI S TI C A L C O N SI D E R A TI O N S

1 4. 1 St u d y Desi g n

1 4 . 1.1 T otal Accr ual

4 0 ( mi ni m u m) t o ha ve 8 e val ua ble p atie nts per ar m.

1 4. 2 St u d y E n d p oi nts ( 2 6 Dec 2 0 1 7)

Pri m ary E n d p oi nts:

D ose li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b (a nti P D- 1 i m m u n ot hera p y)

t o c he m ora di ot hera p y wit h wee kl y cis plati n ( 4 0 m g/ 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 nec k s q u a m o us cell carci n o ma

( HN S C C);

D ose li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b t o c he m ora di ot hera p y wit h

hi g h- d ose cis plati n ( 1 0 0 m g/ m

2
q 2 1 da ys x 3) f or patie nts wit h i nter me diate- or

hi g h-ris k h ea d a n d n ec k s q ua m o us cell carci n o ma ( H N S C C);

D ose li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b t o c he m ora di ot hera p y wit h

wee kl y cet u xi ma b ( 4 0 0 m g/ m l oa d, 2 5 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);

D ose li miti n g t o xicit y f or t he a d diti o n of ni v ol u ma b t o ra di ot hera p y f or pati e nts

wit h i nter me diate- or hi g h-ris k hea d a n d nec k s q u a m o us cell carci n o ma

( HN S C C) wit h o ne t o f o ur of t he f oll o wi n g : a ge ≥ 7 0 years; Z u br o d Perf or ma nce

Stat us 2; baseli ne gra de ≥ 3 ne ur o pat h y; gra d e ≥ 2 heari n g l oss; Cr Cl < 5 0

ml/ mi n.

Sec o n d ary E n d p oi nt : T o e val uate t he s afet y, feasi bilit y a n d patie nt c o m plia nce wit h

a dj u va nt a d mi nistrati o n of si n gle a ge nt ni v ol u ma b f or a ma xi m u m of 1 year of t hera p y

( Ni v ol u ma b, 4 8 0 m gs q 2 8 da ys x 7).


```  
Als o t o be e val uate d at t he c o m pleti o n of t his trial will be t he a bilit y of pati e nts t o t olerate t he pla n n e d treat me nt per pr ot oc ol. A p atie nt will be c o nsi dere d t o ha ve t olerat e d  
```
pr ot oc ol t hera p y if t he f oll o wi n g criteria are met:

i) Ra diati o n t hera p y was d eli vere d wit hi n 8 wee ks;

ii) Patie nt was a d mi nistere d ≥ 7 0 % of t he ni v ol u ma b d ose per pr ot o c ol (e x cl u di n g

dj u va nt t hera p y);

iii) Patie nt was a d mi nistere d ≥ 7 0 % of t he cet u xi ma b d ose per pr ot o c ol, w here

a p plica ble;

i v) Patie nt was a d mi nistere d ≥ 7 0 % of t he cis plati n d ose per pr ot oc ol, w here

a p plica ble.

1 4. 3 Pri m ar y O bjecti ves St u d y Desi g n

1 4 . 3. Sa m ple Siz e a n d P o wer Calc ulati o ns

Patie nts will be se q ue nci all y e nr olle d i nt o Ar ms 1, 2 a n d 3. T he g oal of Ar m 1 is t o

c o nfir m t he safet y of a nti- P D - 1 t hera p y a d mi nistere d i n c o m bi nati o n wit h wee kl y

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

All n o n - Ar m 4 patie nts will be re gistere d t o Ar m 1 i nitial d ose u ntil t he sa m ple siz e is

reac h e d, t he n t o Ar m 2 i nitial d ose, t he n t o Ar m 3 i nitial d ose. Ar m 4 will be o pe n

o nc urre ntl y wit h Ar ms 1/ 2/ 3. T he accr ual ti me f or t he 4 c o h orts i n p hase I will ta ke

p pr o xi matel y 5 m o nt hs ( 1 0 sites). T he st u d y ti me will be a p pr o xi matel y 1 2- 1 8 m o nt hs.

1 4. 5 D ose Le vel G ui deli nes

ee Secti o n 5. 1. 1

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