Multimodality Therapy With Induction Carboplatin/Nab-Paclitaxel/Durvalumab Followed by Surgical Resection and Risk-adapted Adjuvant Therapy for the Treatment of Locally-Advanced and Surgically Resectable Squamous Cell Carcinoma of the Head and Neck
Phase: PHASE2
Conditions: Carcinoma, Squamous Cell, Oral Cancer, Oropharynx Cancer, Larynx Cancer, Lip Cancer, Esophageal Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L                           
 Dece m ber 1, 2 0 2 1  
 
 
 
 
P R O T O C O L A M E N D M E N T # 4 
 
 
A M E N D M E N T # 4 I N C O R P O R A T E S: 
 
 
      A d mi nistrati ve c ha n ges  
X _ Scie ntific C ha n ges 
X _    T hera p y C ha n ges 
_    Eli gi bilit y C ha n ges 
 
R ati o n ale f or A me n d me nt : T he pri mar y reas o n f or t his a me n d me nt is u p date t he d osi n g 
m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes t o a n u p date d versi o n. S pecificall y 
u p dati n g t he g ui da nce f or d ose m o dificati o ns f or bi o ps y- pr o ve n i m m u ne me diate d 
m y ocar ditis.  
 
Scie ntific:  
 
1.  A p pe n di x D, Secti o n 1 1. 4:  
a. D osi n g m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes re place d a n d 
u p date d wit h g ui da nce Oct o ber 2 8, 2 0 2 1.  
b.  A E SI la n g ua ge f or d ur val u ma b u p date d i n secti o n 5. 1. 7. 
2.  Ti me a n d E ve nts Ta ble f o ot n ote 9 u p date d t o i ncl u de a m ylase a n d li pase a nal ysis 
i n ser u m c he mistries.  
 
T he att ac he d versi o n d ate d Dece m ber 1, 2 0 2 1  i nc or p or ates t he a b ove revisi o ns 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L                           
 Dece m ber 1, 2 0 2 1  
 
 
P R O T O C O L A M E N D M E N T # 3  
 
 
A M E N D M E N T # 3 I N C O R P O R A T E S: 
X A d mi nistrati ve c ha n ges  
_ Scie ntific C ha n ges  
_ T hera p y C ha n ges 
_ Eli gi bilit y C ha n ges  
 
R ati o n ale f or A me n d me nt : T he pri mar y reas o n f or t his a me n d me nt is t o ma ke e dit orial 
c ha n ges a n d a d d clarificati o ns t o t he pre vi o us pr ot oc ol a me n d me nt. 
 
A d mi nistr ati ve c h a n ges  
1.  U p date d Secti o n 3. 1. 1 t o clarif y t hat AJ C C Ca ncer Sta gi n g Ma n ual, 7t h 
e diti o n s h o ul d be use d i n or der t o sta ge s u bjects f or eli gi bilit y verificati o n. 
2.  U p date d Secti o n 4. 1 5 a n d Secti o n 6. 8. 1 t o state t hat s u bjects nee d t o c o me i n 
f or initial f oll o w u p visit 8  t o 1 2 wee ks after treat me nt disc o nti n uati o n a n d 
matc h ti me p oi nt prese nte d i n Ti me a n d E ve nts ta ble. 
3.  U p date d f o ot n ote of 4 of Ti me a n d E ve nts ta ble t o matc h t he la n g ua ge i n 
secti o n 4. 5. 3 re gar di n g re q uire me nts f or p ost-o perati ve c he m ora di ot hera p y.  
4.  U p date d Secti o n 4. 6. 1 t o clarif y t hat treati n g p h ysicia n ma y c h o ose n ot t o d o 
d ose a dj ust me nt base d o n cli nical j u d ge me nt . 
5.  Re vise d a n d u p date d Dr u g I nf or mati o n secti o n t o f oll o w t he te m plate 
pr o vi de d b y U N C I n vesti gati o nal Dr u g Ser vice . 
6.  Re m o ve d pe diatric d ose m o dificati o n c o nsi derati o ns fr o m A p pe n di x D as n ot 
a p plica ble.  
7.  U p date d secti o ns 7. 4. 1. 3, 9. 3, 9. 4 a n d 9. 5 t o reflect c urre nt U N C re g ulat or y 
re q uire me nts. 
 
 
Eli gi bilit y c h a n ges  
1.  U p date d secti o n 9. 5. 2 t o state t hat eli gi bilit y si n gle s u bject e xce pti o ns are n ot 
per mitte d f or Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter I n vesti gat or I nitiate d 
Trials.  
2.  Re vise d e xcl usi o n criteri o n 3. 2. 5 f or clarificati o n t o state f or disease of t he 
or o p har y n x a n d k n o w n H P V.   
 
 
 
 
 
 
T he att ac he d versi o n d ate d J a n u ary  1 7 , 2 0 1 9 i nc or p or ates t he a b ove revisi o ns 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L                           
 Dece m ber 1, 2 0 2 1  
 
 
P R O T O C O L A M E N D M E N T # 2  
 
 
A M E N D M E N T # 2 I N C O R P O R A T E S ( C hec k all t h at a p pl y):  
X E dit orial a n d A d mi nistrati ve c ha n ges  
X Scie ntific C ha n ges  
X T hera p y C ha n ges 
X Eli gi bilit y C ha n ges  
 
R ati o n ale f or A me n d me nt : T he pri mar y reas o n f or t his a me n d me nt is t o pr o vi de 
u p date d safet y i n vesti gati o nal dr u g i nf or mati o n f or d ur val u ma b, as well t o ass ure safet y 
re p orti n g is c o nsiste nt wit h t he U N C I R B p olic y. 
 
E dit ori al c h a n ges  
8.  E dite d  Secti o n s 4. 2  a n d 4. 4 t o i ncl u de p ost s ur ger y i n d ucti o n 1 -4 wee ks  
 
Scie ntific c h a n ges  
1.  U p date d Secti o n 5. 1. 4 base d o n d ur val u ma b m o n ot hera p y p o ole d dataset.  
2.  U p date d Secti o n 7. 3 o n S A E re p orti n g t o be c o nsiste nt wit h t he U N C I R B 
p olic y.  
 
T her a p y c h a n ges  
1.  U p date d Secti o n 1 1. 4 t o i ncl u de re vise d d ose m o dificati o ns a n d t o xicit y 
ma na ge me nt f or d ur val u ma b. 
 
Eli gi bilit y c h a n ges  
3.  U p date d secti o n 9. 3 t o state t hat eli gi bilit y si n gle s u bject e xce pti o ns are n ot 
per mitte d f or Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter I n vesti gat or I nitiat e d 
Trials.  
 
 
 
 
 
 
 
 
 
 
 
T he att ac he d versi o n d ate d Fe br u ary 2 0, 2 0 1 8 i nc or p or ates t he a b ove revisi o ns  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L                           
 Dece m ber 1, 2 0 2 1  
 
 
P R O T O C O L A M E N D M E N T # 1  
 
 
A M E N D M E N T # 1 I N C O R P O R A T E S:  
X 
E dit orial a n d A d mi nistrati ve c ha n ges  
X 
Scie ntific C ha n ges  
  
T hera p y C ha n ges 
X 
Eli gi bilit y C ha n ges  
 
R ati o n ale f or A me n d me nt : T he pri mar y reas o n f or t his a me n d me nt is t o pr o vi de 
i n vesti gati o nal dr u g i nf or mati o n f or na b-paclita xel  f or its use i n hea d a n d nec k ca ncer.  I n 
a d diti o n, e dit orial a n d scie ntific clarificati o ns ha ve bee n a d de d t o t he te xt. 
 
E dit ori al a n d A d mi nistr ati ve c h a n ges  
1.  Re m o ve d c o -i n vesti gat or na mes fr o m t he fr o nt of t he pr ot oc ol  
2.  Mi n or e dit orial  c ha n ges ma de t o secti o ns 1. 1, 1. 2. 2, 1. 2. 4, 1. 2. 5, 2. 2. 3,  a n d 2. 2. 4  
3.  Dr u g I nf or mati o n Secti o n  5. 3 Na b -paclita xel secti o n u p date d wit h a p pr o priate la n g ua ge f or 
i n vesti gati o nal pr o d uct t o re place la n g ua ge a p pr o priate f or a c o m mercial pr o d uct i ncl u di n g 
secti o ns 5. 3. 1 S u p plier, 5. 3. 3 Pre parati o n a n d A d mi nistrati o n . S pecial Ha n dli n g i nstr ucti o ns 
a n d t he p olic y f or u n use d na b -paclita xel  dr u g s u p pl y  i nc or p orate d i nt o t he pr ot oc ol. A cr oss 
refere nce t o secti o n 4. 3. 2 is pr o vi de d i n 5. 3. 3 w hic h refers rea der t o secti o n t hat descri bes 
i n d ucti o n c he m ot hera p y d osi n g wit h na b-paclita xel, car b o plati n a n d d ur val u ma b.   
4.  Secti o n 5. 2. 3 f or Car b o plati n als o u p date d wit h cr oss -refere nce t o secti o n 4. 3. 3 
5.  I n Secti o n 7. 3. 2. 2: T he a d dress f or e x pe dite d re p orti n g t o Cel ge ne was u p date d, t he defi niti o n 
of a n o ver d ose of na b - paclita xel a d de d a n d u n der pre g na nc y secti o n f or A E re p orti n g 
re q uireme nts g ui da nce pr o vi de d o n male s u bjects recei vi n g na b -paclita xel w h o i m pre g nate a 
fe male part ner is pr o vi de d. Male s u bjects  treate d wit h na b-paclita xel are a d vise d n ot t o fat her 
a c hil d d uri n g a n d u p t o 6 m o nt hs after treat me nt wit h na b -paclita xel.  
6.  Re m o ve d w or di n g i n secti o n 4. 3. 2 t o state t hat Na b -paclita xel will be pre pare d acc or di n g t o 
i nstit uti o nal sta n dar ds. 
7.  A d de d refere nce t o secti o n 4. 3. 3 t o Dr u g i nf or mati o n secti o n 5. 2. 3. re gar di n g  car b o plati n 
d osi n g d uri n g i n d ucti o n  
 
Scie ntific c h a n ges  
1.  U p date d secti o ns 4. 5. 2 a n d 4. 5. 3 a n d 5. 4. 3 re gar di n g a p pr o priate d osi n g of cis plati n f or 
me di u m ( 4. 5. 2) a n d hi g h -ris k ( 4. 5. 3) s u bjects d uri n g c o nc urre nt ra di ot hera p y  gi ve n after 
s ur ger y per sta n dar d of care.   
 
Eli gi bilit y c h a n ges  
1.  Re vise d e xcl usi o n criteri o n 3. 2. 2 0 t o ali g n wit h re q uire me nts f or males re gar di n g 
c o ntrace pti o n re q uire me nts a n d s per m d o nati o n, etc. f or na b -paclita xel a n d d ur val u ma b . 
 
 
 
 
 
T h e att ac he d versi o n d ate d J u ne 2 9 , 2 0 1 7 i nc or p or ates t he a b ove revisi o ns 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L                           
 Dece m ber 1, 2 0 2 1  
 
LI S T O F A B B R E VI A TI O N S   
5 -F U  
Fl u or o uracil  
A C T H  
A dre n oc ortic otr o pic h or m o ne  
A d E E R S  
A d verse E ve nt E x pe dite d Re p orti n g S yste m  
A E  
A d verse e ve nt  
AJ C C  
A merica n J oi nt C o m mittee o n Ca ncer  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n der c ur ve  
C B C  
C o m plete bl o o d c o u nt 
cc 
C u bic ce nti meter  
cC R R  
Cli nical c o m plete res p o nse rate  
C M P  
C o m pre he nsi ve meta b olic pa nel  
C P O  
Cli nical Pr ot oc ol Office  
C R  
C o m plete res p o nse  
Cr Cl  
Creati ni ne cleara nce  
c R R 
Cli nical res p o nse rate   
C T  
C o m p uter t o m o gra p h y  
C T V  
Cli nical Tar get V ol u me  
D L T  
D ose li miti n g t o xicit y  
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
D S M C  
Data safet y m o nit ori n g c o m mittee  
E C G  
Electr ocar di o gra p h y  
E C H O  
E c hocar di o gra p h y  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
Fcγ  
F ra g me nt cr ystalliza ble ga m ma rece pt or  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
FI S H  
Fl u oresce nce i n sit u h y bri dizati o n  
f x 
Fracti o n  
G C P  
G o o d cli nical practice  
G T V  
Gr oss T u m or V ol u me  
H B V  
He patitis B vir us  
H C V  
He patitis C vir us  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
HI V  
H u ma n i m m u n o deficie nc y vir us  
H P V  
H u ma n pa pill o ma vir us  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D S 
I n vesti gati o nal Dr u g Ser vice 
I g G 
I m m u n o gl o b uli n G 
I G R T 
I ma ge g ui da nce ra di ot hera p y 
I M R T 
I nte nsit y M o d ulate d Ra di ot hera p y Treat me nt 
I P 
I n vesti gati o nal pr o d uct 
ir A E 
Im m u ne relate d ad verse eve nts  
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
I ntra ve n o us 
m A b  
M o n ocl o nal a nti b o d y  
M RI  
Ma g netic res o na nce i ma gi n g  
N CI  
Nati o nal Ca ncer I nstit ute  

LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L                           
 Dece m ber 1, 2 0 2 1  
 
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute –  C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nts  
N S C L C  
N o n -s mall cell l u n g ca ncer 
O H R E  
Office of H u ma n Researc h Et hics  
O R R  
O bjecti ve res p o nse rate  
O S  
O verall s ur vi val  
p C R R  
Pat h ol o gic c o m plete res p o nse rate   
P D  
P har mac o d y na mic or Pr o gressi ve disease  
P D -L 1  
P r o gra m me d cell deat h li ga n d 1 
P E T  
P ositr o n e missi o n t o m o gra p h y  
P F S  
Pr o gressi o n free s ur vi val  
PI  
Pri nci pal i n vesti gat or  
P K  
P har mac o ki netic(s)  
P O  
Oral(l y)  
P R  
Partial res p o nse  
P R C  
Pr ot oc ol re vie w c o m mittee 
P R V  
Pla n ni n g ris k v ol u me  
P T V  
Pla n ni n g tar get v ol u me  
Q 2 W  
E ver y t w o wee ks  
Q 3 W  
E ver y t hree wee ks  
Q O L  
Q ualit y of life  
Q Tc  
C orrecte d Q T I nter val  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R T  
Ra diati o n t hera p y  
S A E  
Seri o us a d verse e ve nt  
S A R  
Seri o us a d verse reacti o n  
S C C H N  
S q ua m o us cell ca ncer of t he hea d a n d nec k  
S D  
Sta ble disease  
S O C  
Sta n dar d of care  
S q C C  
S q ua m o us cell carci n o ma  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
U L N  
U p per li mit of n or mal  
U N C  
U ni versit y of N ort h Car oli na  
U P  
U na ntici pate d pr o ble m  
W B C  
W hite bl o o d cell  
W O C B P  
W o ma n of c hil d beari n g p ote ntial  
 
 
 
 
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
i 
T A B L E O F C O N T E N T S  
LI S T O F A B B R E VI A TI O N S  .......................................................................................... ii 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  ................................................................. 1 
1. 1  
St u d y S y n o psis ..................................................................................................... 1  
1. 2  
A d va nces i n I n d ucti o n C he m ot hera p y ................................................................. 1  
1. 3  
St u d y Rati o nale .................................................................................................. 1 1  
1. 4  
C orrelati ve St u dies  ............................................................................................. 1 2 
2. 0  
S T U D Y O B J E C TI V E S  .......................................................................................... 0 
2. 1  
Pri mar y O bjecti ve  ................................................................................................ 0 
2. 2  
Sec o n dar y O bjecti ves  ........................................................................................... 0 
2. 3  
Tra nslati o nal/ E x pl orat or y O bjecti ves  .................................................................. 0 
2. 4  
E n d p oi nts ............................................................................................................. 1  
3. 0  
S U B J E C T E LI GI BI LI T Y  ..................................................................................... 2 
3. 1  
I ncl usi o n Criteria ................................................................................................. 2 
3. 2  
E x cl usi o n Criteria ................................................................................................ 4 
4. 0  
T R E A T M E N T P L A N  ............................................................................................ 7 
4. 1  
O ver vie w .............................................................................................................. 7  
4. 2  
Sc he ma  ................................................................................................................. 8 
4. 3  
I n d ucti o n C he m ot hera p y ...................................................................................... 9 
4. 4  
S ur ger y ............................................................................................................... 1 0  
4. 5  
P ost -O perati ve C o nc o mita nt C he m ora di ot hera p y ............................................. 1 0  
4. 6  
D osi n g Dela ys/ D ose M o dificati o ns f or I n d ucti o n C he m ot hera p y ..................... 1 4  
4. 7  
Treat me nt wit h A dj u va nt D ur val u ma b i n Part 3  ................................................ 1 9 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
ii 
4. 8  
Treat me nt Brea ks f or Ra diati o n d uri n g C o nc o mita nt C he m ora diati o n t hera p y 1 9  
4. 9  
D osi n g Dela ys/ D ose M o dificati o ns f or C he m ot hera p y d uri n g C o nc o mita nt 
C he m ora di ot hera p y (see Secti o n 4. 6)  ............................................................................. 1 9 
4. 1 0  
C o nc o mita nt Me dicati o ns/ Treat me nts  ............................................................... 2 0 
4. 1 1  
Pr o hi bite d Me dicati o ns  ...................................................................................... 2 0 
4. 1 2  
Me dicati o ns t o be use d wit h Ca uti o n ................................................................. 2 1  
4. 1 3  
C o ntrace pti o n ..................................................................................................... 2 2  
4. 1 4  
D urat i o n of T hera p y ........................................................................................... 2 3 
4. 1 5  
D urati o n of F oll o w U p ....................................................................................... 2 4  
4. 1 6  
Re m o val of S u bjects fr o m Pr ot oc ol T hera p y  ..................................................... 2 4 
5. 0  
D R U G I N F O R M A TI O N  ..................................................................................... 2 5 
5. 1  
D ur val u ma b........................................................................................................ 2 5  
5. 2  
Car b o plati n ......................................................................................................... 3 1  
5. 3  
Na b -Pacl ita xel .................................................................................................... 3 2 
5. 4  
Cis plati n  ............................................................................................................. 3 4 
6. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  ........................................................... 3 6 
6. 1  
Ti me a n d E ve nts Ta ble ...................................................................................... 3 6  
6. 2  
F oll o w- u p Assess me nts  ..................................................................................... 3 9 
6. 3  
C orrelati ve St u dies  ............................................................................................. 3 9 
6. 4  
Assess me nt of Safet y  ......................................................................................... 4 0 
6. 5  
Assess me nt of Efficac y  ...................................................................................... 4 3 
7. 0  
A D V E R S E E V E N T S  ........................................................................................... 4 7 
7. 1  
Defi niti o ns .......................................................................................................... 4 7 
7. 2  
D oc u me ntati o n of n o n- seri o us A Es or S A Rs .................................................... 5 0 
7. 3  
S A Es or Seri o us S A Rs  ....................................................................................... 5 1 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
iii 
7. 4  
A d verse E ve nt Re p orti n g ................................................................................... 5 1  
7. 5  
Data a n d Safet y M o nit ori n g Pla n  ....................................................................... 6 1 
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................... 6 2 
8. 1  
St u d y Desi g n/ St u d y E n d p oi nts .......................................................................... 6 2  
8. 2  
Sa m ple Size a n d Accr ual  ................................................................................... 6 2 
8. 3  
Data A nal ysis Pla ns  ........................................................................................... 6 3 
9. 0  
S T U D Y M A N A G E M E N T  ................................................................................... 6 5 
9. 1  
I nstit uti o nal Re vie w B oar d (I R B) A p pr o val a n d C o nse nt ................................. 6 5 
9. 2  
Re q uire d D oc u me ntati o n ................................................................................... 6 5  
9. 3  
Re gistrati o n Pr oce d ures  ..................................................................................... 6 5 
9. 4  
Data Ma na ge me nt a n d M o nit ori n g/ A u diti n g  ..................................................... 6 6 
9. 5  
A d here nce t o t he Pr ot oc ol .................................................................................. 6 6  
9. 6  
Rec or d Rete nti o n ............................................................................................... 6 9  
9. 7  
O bli gati o ns of I n vesti gat ors  ............................................................................... 6 9 
1 0. 0  
R E F E R E N C E S  ..................................................................................................... 7 0 
1 1. 0  
A P P E N DI C E S  ...................................................................................................... 7 3 
1 1. 1  
A p pe n di x A: E C O G Perf or ma nce Stat us  ........................................................... 7 3 
1 1. 2  
A p pe n di x B:  S u bject Ha n d o ut re gar di n g Dr u g I nteracti o ns ............................. 7 4  
1 1. 3  
A p pe n di x C: D ose M o dificati o ns/ T o xicit y Ma na ge me nt f or D ur val u ma b ( N o n-
i m m u ne-me diate d)  .......................................................................................................... 7 5 
1 1. 4  
A p pe n di x D: D ose M o dificati o ns/ T o xicit y Ma na ge me nt f or D ur val u ma b 
(I m m u ne-relate d) ............................................................................................................ 7 6 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
St u d y S y n o psis  
T his is a si n gle -ar m, n o n-ra n d o mize d, p hase II trial i n pre vi o usl y u ntreate d 
s u bjects wit h s q ua m o us cell carci n o ma of t he hea d a n d nec k ( S C C H N) t hat is 
l ocall y a d va nce d a n d a me na ble t o s ur gical resecti o n. Treat me nt will c o nsist of 3 
parts: ne oa dj u va nt i n d ucti o n wit h wee kl y car b o plati n a n d na b- paclita xel i n 
c o m bi nati o n wit h e ver y ot her wee k d ur val u ma b  ( part 1) pri or t o s ur ger y ( part 2).  
P ost -o perati ve treat me nt ( part 3) will var y de pe n di n g o n t he ris k cate g or y 
assi g ne d t o t he s u bject f oll o wi n g s ur ger y as f oll o ws: d ur val u ma b a d mi nistere d 
e ver y 2 wee ks f or 3 c ycles (l o w ris k), i psilateral ra diati o n c o nc urre nt wit h wee kl y 
cis plati n f oll o we d b y d ur val u ma b o nce e ver y 2 wee ks f or 3 c ycles  ( me di u m ris k), 
or sta n dar d of care a dj u va nt c he m ora di ot hera p y f or hi g h ris k f oll o we d b y 3 c ycl es 
of d ur val u ma b gi ve n e ver y t w o wee ks.    
 
We pla n t o e nr oll a t otal of u p t o 3 9 u ntreate d S C C H N s u bjects t o e ns ure t hat 3 7 
are e val ua ble. T he pri mar y o bjecti ve of t his st u d y is t o esti mate t he  pat h ol o gic 
c o m plete res p o nse rate ( p CR R) after i n d ucti o n c he m ot hera p y. Sec o n dar y 
o bjecti ves i ncl u de  esti mati n g cli nical res p o nse rate (c R R),  cli nical c o m plete 
res p o nse rate (c C R R), o verall s ur vi val ( O S), pr o gressi o n -free s ur vi val ( P F S), t he 
perce nt of s u bjects w h o ac hie ve a re d ucti o n i n ris k le vel p ost-i n d ucti o n 
c he m ot hera p y wit h t he use of pat h ol o gic e val uati o n (c o m pare d t o ris k le vel 
assi g ne d base d o n p h ysical e xa mi nati o n a n d i ma gi n g pri or t o i n d ucti o n 
c he m ot hera p y a n d s ur ger y), a n d c orrelati ve st u dies.  
1. 2  
A d v a nces i n I n d ucti o n C he m ot her a p y  
C he m ot hera p y i nitiall y f o u n d a r ole i n t he treat me nt of hea d a n d nec k ca ncers as 
i n d ucti o n ( ne oa dj u va nt) t hera p y gi ve n pri or t o defi niti ve ra diati o n.  F oll o wi n g t his 
a d va nce, t he R T O G 9 1- 1 1 trial c o m pare d se q ue ntial t o c o nc urre nt t hera p y a n d 
s h o we d a l ocal-c o ntr ol a d va nta ge f or c o nc urre nt t hera p y [1 ]. C o nc urre nt t hera p y 
wit h c he m ot hera p y a n d ra diati o n t heref ore re place d i n d ucti o n c he m ot hera p y 
f oll o we d b y ra diati o n as t he ne w sta n dar d of care w he n c he m ot hera p y a n d 
ra diati o n are c h ose n f or defi niti ve t hera p y. M ore rece ntl y, m u lti ple trials ha ve 
e x pl ore d t he use of i n d ucti o n c he m ot hera p y pri or t o defi niti ve t hera p y.  W hile 
earl y eff orts f oc use d o n t he t hree- dr u g re gi me n of cis plati n, 5- F U a n d d oceta xel, 
t hese eff orts ha ve n ot i m pr o ve d o utc o mes. W hile s o me patie nts ma y ha ve 
be nefite d, t he t o xicit y of t he re gi me n ma y c o u nter bala nce t hese be nefits.  
Alter nati ve a p pr oac hes b uilt o n a platf or m  of car b o plati n, a ta xa ne a n d a tar gete d 
t hera p y c o nti n ue.  
1. 2. 1  
D ocet a xel/ Cis pl ati n/ 5 F U ( T P F) as I n d ucti o n  
T he T A X 3 2 3 st u d y ra n d o mize d patie nts wit h sta ge III/I V u nresecta ble S C C H N t o 
f o ur c ycles of eit her T P F ( d oceta xel 7 5 m g/ m2, cis plati n 7 5 m g/ m2 a n d 5 F U 
7 5 0 m g/ m 2 da ys 1 -5) or P F (cis plati n 1 0 0 m g/ m 2 a n d 5 F U 1 0 0 0 m g/ m2 da ys 1 - 5) 
a d mi nistere d e ver y 3 wee ks; b ot h gr o u ps recei ve d s u bse q ue nt ra diati o n t o 7 0 G y 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 
[ 3].  T he a d diti o n of d oceta xel i m pr o ve d t he p ost i n d ucti o n res p o nse rate fr o m 
4 7 % t o 5 9 %, pr o gressi o n free s ur vi val ( P F S) fr o m 8 m o nt hs t o 1 1. 2 m o nt hs a n d 
me dia n s ur vi val fr o m 1 4. 5 m o nt hs t o 1 8. 8 m o nt hs [ 3]. T he T A X 3 2 4 st u d y 
ra n d o mize d patie nts wit h sta ge III/I V u nresecta ble disease or patie nts c o nsi dere d 
ca n di dates f or or ga n preser vati o n t o t hree c ycles of T P F ( d oceta xel 7 5 m g/ m 2, 
cis plati n 1 0 0 m g/ m 2 a n d 5 F U 1 0 0 0 m g/ m 2 da ys 1 -4 e ver y 3 wee ks) or P F (cis plati n 
1 0 0 m g/ m 2 a n d 5 F U 1 0 0 0 m g/ m2 da ys 1 - 5 e ver y 3 wee ks); b ot h gr o u ps 
s u bse q ue ntl y recei ve d c he m ora diati o n t o 7 0 G y c o nc urre nt wit h wee kl y 
car b o plati n d ose d t o a n A U C of 1. 5. Patie nts were re q uire d t o u n der g o nec k 
dissecti o n 6- 1 2 wee ks f oll o wi n g c he m ora diati o n f or N 2 disease wit h P R, a n y N 3 
disease or resi d ual disease.  F or patie nts o n t he T P F ar m, p ost i n d ucti o n res p o nse 
rates tre n de d t o war ds i m pr o ve me nt ( 6 4 % t o 7 2 %) [2 ] a n d me dia n s ur vi val 
i ncrease d fr o m 3 5 m o nt hs t o 7 1 m o nt hs as c o m pare d t o t he P F arm [3 ].   
 
Pri or t o t hese st u dies, i n d ucti o n c he m ot hera p y was c o nsi dere d a c o ntr o ve rsial, b ut 
reas o na ble sta n dar d of care f or i n o pera ble patie nts or patie nts wit h a d va nce d 
n o dal stat us.  Si nce prese ntati o n a n d p u blicati o n of t hese trials, t he p o p ularit y of 
i n d ucti o n c he m ot hera p y has i ncrease d s u bsta ntiall y, a n d d oceta xel has recei ve d 
F o o d a n d Dr u g A d mi nistrati o n ( F D A ) a p pr o val, i n c o m bi nati o n wit h cis plati n a n d 
fl u or o uracil, f or i n d ucti o n treat me nt of patie nts wit h i n o pera ble, l ocall y a d va nce d 
S C C H N.   
 
M ulti ple rece nt cli nical trials utilizi n g t he T P F re gi me n ha ve faile d t o i m pr o ve 
o u tc o mes as s u m marize d i n t he  Ta ble 1 . 
 
T a ble 1 . Cli nic al tri als utilizi n g t he T P F re gi me n  
Re gi me n  
C o ntr ol Ar m  
E x peri me ntal Ar m  
R es ult 
De CI D E  
D oceta xel/ h y dr o x y urea/
5 F U/ BI D X R T  
T P F x 2 t he n 
d oceta xel/ h yr o x y urea/ 5 F U/ B
I D X R T 
N o differe nce i n O S or 
D F S.  M ore t o xicit y i n 
T P F ar m.  
U n der p o were d  
Para di g m  
Cis plati n x 2 c o nc urre nt 
wit h X R T  
T P F x 3 t he n X R T wit h 
eit her d oceta xel or 
car b o plati n  
N o i m pr o ve me nt i n 3 -
year  s ur vi val.  
U n der p o were d  
G O R T E C 
2 0 0 7 -0 0 2  
Car b o plati n a n d 5 F U 
c o nc urre nt wit h X R T  
T P F x 3 t he n X R T wit h 
cet u xi ma b 
N o i m pr o ve me nt i n 
P F S or O S.  
Z h o n g et 
al. – oral 
ca vit y 
o nl y  
Ra dical s ur ger y t he n 
a dj u va nt ra di ot hera p y  
T P F x 2 t he n ra dical s ur ger y 
t he n a dj u va nt ra di ot hera p y 
N o i m pr o ve me nt i n 
D F S or O S.  Pts wit h 
< 1 0 % via ble t u m or 
cells ha d s u peri or O S 
a n d disease  c o ntr ol. 
 
T a ble 2 . Gr a de 3 or 4 T o xicities Ass oci ate d wit h T P F I n d ucti o n C he m ot her a p y f or S C C H N 
Gr a de 3/ 4 T o xicit y  
T A X 3 2 3 [ 3]  
( % of p atie nts) 
T A X 3 2 4 [ 2, 5] 
( % of p atie nts) 
Ne utr o pe nia  
7 6. 9 %  
8 3 %  
Fe brile ne utr o pe nia  
5. 2 %  
1 2 %  
Ne utr o pe nic i nfecti o n  
N ot re p orte d  
1 2 %  
Le u k o pe nia  
4 1. 6 %  
N ot re p orte d  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 
A ne mia  
9. 2 %  
1 2 %  
T hr o m b oc yt o pe nia  
5. 2 %  
4 %  
St o matitis  
4. 6 %  
2 1 %  
Al o pecia  
1 1. 6 %  
N ot re p orte d  
Na usea  
0. 6 %  
1 4 %  
Es o p ha gitis/ D ys p ha gia/ O d y n o p ha gia  
0. 6 %  
1 3 %  
V o miti n g  
0. 6 %  
8 %  
A n ore xia  
0. 6 %  
1 2 %  
Diarr hea  
2. 9 %  
7 %  
I nfecti o n 
6. 9 %  
6 %  
Let har g y  
2. 9 %  
5 %  
Ne ur ot o xicit y  
0. 6 %  
N ot re p orte d 
L ocal t o xic effect  
0. 6 %  
N ot re p orte d  
 
I n a d diti o n t o lac k of defi niti ve efficac y data (c o m pare d t o c he m ora di ot hera p y 
al o ne), T P F has a n u m ber of a d diti o nal s h ortc o mi n gs.  T hese i ncl u de t he 
re q uire me nt of a p ort f or c o nti n u o us i nf usi o n of 5 F U, a n d, i n ma n y c o m m u nities 
t he nee d f or i n patie nt h ospitalizati o n f or t hera p y a d mi nistrati o n. Gra de 3 a n d 4 
t o xicities fr o m t he T A X 3 2 3 a n d T A X 3 2 4 st u dies are s u m marize d a b o ve, alt h o u g h 
t he re p orte d res ults d o n ot be gi n t o d o j ustice t o t he de gree of t o xicit y a n d 
se q uelae ofte n e x perie nce d i n cli nical practice.  F urt her, t he t o xicit y is n ot si m pl y 
a matter of s h ort -ter m s ufferi n g wit h p ote ntial l o n g-ter m re war d; i n T A X 3 2 4, 
2 1 % of patie nts di d n ot pr ocee d t o p ote ntiall y c urati ve pr ot oc ol- defi ne d 
c he m ora diati o n [ 4 ] beca use of t o xicit y d uri n g t he i n d ucti o n p hase of treat me nt.  
T his hi g h le vel of gra de 3 a n d 4 t o xicit y wit h res ulta nt fail ure t o pr ocee d t o 
defi nit i ve t hera p y has le d ma n y i nstit uti o ns, i ncl u di n g U N C, t o see k alter nati ve 
i n d ucti o n re gi me ns.  We h y p ot hesize t hat re gi me ns wit h less t o xicit y t ha n T P F 
a n d greater efficac y c o ul d i m pr o ve o utc o mes w here T P F has faile d.  
1. 2. 2  Wee kl y re gi me ns  
Haraf et al. [5 ] treate d a p o p ulati o n c o nsisti n g pri maril y ( 9 7 %) of sta ge I V l ocal l y 
a d va nce d patie nts wit h car b o plati n A U C 2 a n d paclita xel 1 3 5 m g/ m 2 wee kl y f or si x 
c ycles.  T his t hera p y was f oll o we d b y t wice dail y ra diati o n c o nsisti n g of 1. 5 G y 
dail y i n a s plit c o urse.  Treat me nt res ults fr o m t his p hase II trial of 6 4 patie nts 
were pr o misi n g wit h 1 0 0 % c o m plete res p o nse ( C R)  after t otal treat me nt,  a 3- year  
o verall s ur vi val ( O S) of 7 0 % a n d 3- year  pr o gressi o n free s ur vi val ( P F S) of 9 0 % 
(all deter mi ne d after t he c o m pleti o n of ra diati o n t hera p y).   
 
Beca use E G F R is o vere x presse d i n m ost ca ncers of t he e pit heli u m, i ncl u di n g 
S C C H N, Ki es [6 ] a n d Wa ne b o [7 ] s o u g ht t o i m pr o ve u p o n t he res ults see n wit h 
paclita xel/ car b o plati n wit h  t he a d diti o n of cet u xi ma b. Kies a n d ass ociates treate d 
4 7 patie nts wit h N 2 b or greater disease wit h car b o plati n A U C 2, paclita xel 1 3 5 
m g/ m 2 a n d cet u xi ma b 4 0 0 m g/ m 2 l oa di n g f oll o we d b y 2 5 0 m g/ m 2 wee kl y f or si x 
wee ks.  P ost i n d ucti o n t hera p y, patie nts recei v e d ra diati o n t hera p y al o ne ( n = 2 3), 
c he m ora diati o n ( n = 2 3), or s ur ger y al o ne ( n = 1) de pe n di n g o n t heir sta ge a n d 
q ualit y of res p o nse t o i n d ucti o n. T he o verall res p o nse rate ( C R + P R) at t he e n d 
of ra diati o n t hera p y ( wit h or wit h o ut c he m ot hera p y) was 9 6 % wit h a C R of 7 0 %. 
T he m ost c o m m o n n o n- he mat ol o gic t o xicit y d uri n g i n d ucti o n t hera p y was 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 
ras h/f ollic ulitis ( gra des 2 a n d 3 i n 3 8 % a n d 4 5 % of patie nts, res pecti vel y), 
f oll o we d b y fati g ue ( 4 0 % gra de 2 a n d 2 % gra de 3), diarr hea ( 9 % gra de 2 a n d 9 % 
gra de 3) a n d se ns o r y ne ur o pat h y ( 1 5 % gra de 2 a n d 2 % gra de 3). T he m ost 
c o m m o n gra de 2 t o 4 he mat ol o gic t o xicit y was ne utr o pe nia ( gra des 2, 3, a n d 4 i n 
2 3 %, 1 9 %, a n d 2 % of patie nts, res pecti vel y). T here were n o i nsta nces of fe brile 
ne utr o pe nia. D ose re d ucti o ns were nee de d i n o ne patie nt f or cet u xi ma b a n d i n 
f o ur a n d t w o patie nts f or paclita xel a n d car b o plati n, res pecti vel y. Treat me nt 
dela ys of 7 da ys occ urre d i n 6 0 % of patie nts. 
 
Wa ne b o et al, u n der t he ae gis of t he E C O G, treate d o pera ble patie nts wit h sta ge 
III or I V disease wit h wee kl y car b o plati n A U C 2, paclita xel 9 0 m g/ m2 a n d 
cet u xi ma b 4 0 0 m g/ m 2 l oa di n g f oll o we d b y cet u xi ma b 2 5 0 m g/ m2 wee kl y f or  si x 
wee ks.  D uri n g t hera p y, patie nts u n der we nt t u m or sta gi n g bi o psies at t he pri mar y 
site u ntil bi o ps y ne gati vit y. F ort y of 6 7 e val uable patie nts ha d a cli nical res p o nse 
t o i n d ucti o n c he m ot hera p y a n d 2 6 of 4 0 ( 6 5 %) ha d a bi o ps y- pr o ve n C R. After 5 0 
G y ra diati o n (c o nc urre nt wit h car b o plati n A U C 1, paclita xel 3 0 m g/ m 2 a n d 
cet u xi ma b 2 5 0 m g/ m 2) all patie nts w h o ha d n ot yet ha d a ne gati ve bi o ps y were 
bi o psie d —all were ne gati ve. T o get her, t he Kies a n d Wa ne b o re p orts pr o vi de ver y 
str o n g s u p p ort f or i n d ucti o n re gi me ns t hat i ncl u de a ta xa ne, car b o plati n, a n d 
cet u xi ma b. 
 
Base d o n pr o misi n g res ults wit h na b- paclita xel i n S C C H N a n d S q C C l u n g, o ur 
gr o u p st u die d car b o plati n A U C 2, na b- paclita xel 1 0 0 m g/ m 2 a n d cet u xi ma b wee kl y 
f or si x wee ks pri or t o sta n dar d of care c he m ora di ot hera p y [8 ]. T he p o p ulati o n 
treate d was ver y hi g h ris k b ot h a nat o micall y a n d bi ol o gicall y. 
 
R es p o nse rate  was  7 7 % a n d was  a g n ostic t o H P V stat us:  
 
 
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
5 
 
P F S a n d O S data are fa v ora ble, es peciall y f or t his ver y hi g h- ris k p o p ulati o n:  
 
We als o st u die d t he c o m bi nati o n of car b o plati n A U C 2, paclita xel 1 3 5 m g/ m
2 a n d 
la pati ni b dail y f or si x wee ks pri or t o tra ns oral s ur ger y ( N C T 0 1 6 1 2 3 5 1).  I n 
preli mi nar y data o n t he first 3 6 patie nt s ( of 4 0 pla n ne d) p C R R was 3 3 % .  O nl y 
o ne patie nt has rec urre d or die d; t his patie nt ha d a res p o nse t o i n d ucti o n 
c he m ot hera p y a n d t he n decli ne d st u d y- ma n date s ur gical resecti o n a n d re m o ve d 
hi mself fr o m t he st u d y. Ot her c o nc urre nt data ha ve de m o nstrate d a n a bse nce of 
acti vit y of la pati ni b i n S C C H N  [9 ], s u g gesti n g t hat t hese res ults si m pl y 
de m o nstrate d t he hi g h acti vit y of wee kl y plati n u m a n d ta xa ne. A m ore acti ve 
tar gete d t hera p y, s uc h as d ur val u ma b, c o ul d f urt her i m pr o ve res ults.  
1. 2. 3  
D ur v al u m a b 
D ur val u ma b is bei n g de vel o pe d as a p ote ntial a ntica ncer t hera p y f or patie nts wit h 
a d va nce d s oli d t u m ors. D ur val u ma b is a h u ma n m o n ocl o nal a nti b o d y ( M A b) of 
t he i m m u n o gl o b uli n G 1 ka p pa (I g G 1 κ) s u bclass t hat i n hi bits bi n di n g of 
pr o gra m me d cell deat h li ga n d 1 ( P D- L 1) ( B 7 h o m ol o g 1 [ B 7- H 1], cl uster of 
differe ntiati o n [ C D] 2 7 4) t o pr o gra m me d cell deat h 1 ( P D - 1; C D 2 7 9) a n d C D 8 0 
( B 7- 1). D ur val u ma b is c o m p ose d of 2 i de ntical hea v y c hai ns a n d 2 i de ntical li g ht 
c hai ns, wit h a n o verall m olec ular wei g ht of a p pr o xi matel y 1 4 9 k Da. D ur val u ma b 
c o ntai ns a tri ple m utati o n i n t he c o nsta nt d o mai n of t he i m m u n o gl o b uli n (I g) G 1 
hea v y c hai n t hat re d uces bi n di n g t o c o m ple me nt pr otei n C 1 q a n d t he fra g me nt 
cr ystalliza ble ga m ma ( Fcγ) re ce pt ors i n v ol ve d i n tri g geri n g effect or f u ncti o n.  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 
 
A P hase I e x pa nsi o n st u d y of d ur val u ma b i n metastatic/rec urre nt S C C H N s h o we d 
a R R of 1 2 % i n hea vil y pretreate d patie nts wit h g o o d t olera bilit y [1 0 ]. I n N S C L C, 
P D 1 - a n d P D L 1 -tar geti n g a ge nts ha ve bee n st u die d t o get her wit h c he m ot hera p y 
w here t he y ha ve de m o nstrate d g o o d preli mi nar y efficac y a n d t olera bilit y, 
i ncl u di n g t he s pecific c o m bi nati o n wit h car b o plati n a n d na b-paclita xel [1 1 ]. 
 
Precli nical a n d Cli nical e x perie nce wit h d ur val u ma b is f ull y descri be d i n t he 
c urre nt versi o n of t he d ur val u ma b I n vesti gat or’s Br oc h ure (E diti o n  1 2). T he  
safet y of d ur val u ma b m o n ot hera p y i n o n g oi n g cli nical trials is briefl y s u m marize d 
i n secti o n 5. 1. 8 .  
 
Fixe d D osi n g  
A p o p ulati o n p har mac o ki netic ( P K ) m o del was de vel o pe d f or d ur val u ma b usi n g 
m o n ot hera p y data fr o m a P hase 1 st u d y ( st u dy 1 1 0 8; N = 2 9 2; d oses = 0. 1 t o 
1 0 m g/k g Q 2 W or 1 5 m g/k g Q 3 W; s oli d t u m ors ). P o p ulati o n P K a nal ysis 
i n dicate d o nl y mi n or i m pact of b o d y wei g ht ( W T) o n P K of d ur val u ma b 
(c oefficie nt of ≤ 0. 5). T he i m pact of b o d y W T- base d ( 1 0 m g/ k g Q 2 W) a n d fi xe d 
d osi n g ( 7 5 0 m g Q 2 W) of d ur val u ma b was e val uate d b y c o m pari n g pre dicte d 
stea d y state P K c o nce ntrati o ns ( 5 t h, me dia n a n d 9 5t h perce ntiles) usi n g t he 
p o p ulati o n P K m o del. A fi xe d d ose of 7 5 0 m g was selecte d t o a p pr o xi mate 1 0 
m g/ k g ( base d o n me dia n b o d y W T of ~ 7 5 k g). A t otal of 1 0 0 0 patie nts were 
si m ulate d usi n g b o d y W T distri b uti o n of 4 0 – 1 2 0 k g. Si m ulati o n res ults 
de m o nstrate t hat b o d y W T- base d a n d fi xe d d osi n g re gi me ns yiel d si milar me dia n 
stea d y state P K c o nce ntrati o ns wit h sli g htl y less o verall bet wee n-s u bject 
varia bilit y wit h fi xe d d osi n g re gi me n.   
 
Si milar fi n di n gs ha ve bee n re p orte d b y ot hers [ 1 2 - 1 5]. Wa n g a n d c ollea g ues 
i n vesti gate d 1 2 m o n ocl o nal a nti b o dies a n d f o u n d t hat fi xe d a n d b o d y size-base d 
d osi n g perf or m si milarl y, wit h fi xe d d osi n g bei n g better f or 7 of 1 2 a nti b o dies [ 3 ]. 
I n a d diti o n, t he y i n vesti gate d 1 8 t hera pe utic pr otei ns a n d pe pti des a n d s h o we d 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 
t hat fi xe d d osi n g perf or me d better f or 1 2 of 1 8 i n ter ms of re d uci n g t he bet wee n-
s u bject varia bilit y i n p har mac o ki netic/ p har mac o d y na mics para meters [1 5 ].  
 
A fi xe d d osi n g a p pr oac h is preferre d b y t he prescri bi n g c o m m u nit y d ue t o ease of 
use a n d re d uce d d osi n g err ors. Gi ve n e x pectati o n of si milar P K  e x p os ure a n d 
varia bilit y, we c o nsi dere d it feasi ble t o s witc h t o fi xe d d osi n g re gi me ns. Base d o n 
a vera ge b o d y we i g ht of 7 5 k g, a fi xe d d ose of 7 5 0 m g Q 2 W d ur val u ma b 
(e q ui vale nt t o 1 0 m g/ k g Q 2 W), is i ncl u de d i n t he c urre nt st u d y. Fi xe d d osi n g of 
d ur val u ma b is rec o m me n d e d o nl y f or s u bjects wit h > 3 0 k g ( 6 6 p o u n ds) b o d y 
wei g ht d ue t o e n d ot o xi n e x p os ure.   
1. 2. 4  S u m m ar y of A d v erse E ve nts Re p orte d i n Cli nic al Tri als of D ur v al u m a b: 
C D -O N - M E DI 4 7 3 6-1 1 0 8, A T L A N TI C a n d P A CI FI C  
Safet y data ha ve bee n p o ole d f or 3 d ur val u ma b m o n ot hera p y st u dies ( C D O N-
M E DI 4 7 3 6- 1 1 0 8, A T L A N TI C a n d P A CI FI C) f or patie nts w h o recei ve d a 
d ur val u ma b d ose of 1 0 m g/ k g Q 2 W; a t otal of 1 8 8 9 patie nts are i ncl u de d i n t his 
vali date d p o ole d data set. O verall, A Es re p orte d i n ≥1 0 % of patie nts were fati g ue 
( 3 1. 7 %), c o u g h ( 2 3. 1 %), decrease d a p petite ( 2 1. 4 %), d ys p nea ( 2 0. 8 %), na usea 
( 2 0. 2 %), c o nsti pati o n ( 1 7. 6 %), diarr hea ( 1 7. 4 %), p yre xia ( 1 5. 2 %), bac k pai n 
( 1 3. 8 %), a ne mia ( 1 3. 5 %), v o miti n g ( 1 3. 0 %), pr urit us ( 1 1. 8 %), art hral gia ( 1 1. 6 %), 
hea dac he ( 1 1. 0 %), ast he nia ( 1 0. 8 %), e de ma peri p heral ( 1 0. 5 %) a n d ras h ( 1 0. 2 %). 
A Es t hat were c o nsi dere d b y t he i n vesti gat or as relate d t o d ur val u ma b i n ≥5 % of  
patie nts were fati g ue ( 1 5. 8 %), diarr hea ( 8. 1 %), h y p ot h yr oi dis m ( 8. 0 %), na usea 
( 7. 2 %), pr urit us ( 6. 9 %), decrease d a p petite ( 6. 4 %) a n d ras h ( 6. 4 %). Ne w A Es of 
Gra de 3 m y ositis ( 1 s u bject; < 0. 1 %) a n d Gra de 3 of i ntesti nal perf orati o n ( 3 
s ubjects; 0. 3 %) i n t he c o m bi nati o n of d ur val u ma b wit h tre meli m u ma b were 
re p orte d. 
A t otal of 8 5 3 patie nts ( 4 5. 2 %) re p orte d A Es of C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E ve nts ( C T C A E) Gra de 3 or hi g her: 7 9 6 patie nts ( 4 2. 1 %) ha d e ve nts 
of Gra de 3, 1 2 6 patie nts ( 6. 7 %) ha d e ve nts of Gra de 4 a n d 1 0 1 patie nts ( 5. 3 %) 
ha d Gra de 5 (fatal) e ve nts. A Es of Gra de 3 or hi g her c o nsi dere d relate d t o 
d ur val u ma b were re p orte d i n 2 0 1 patie nts ( 1 0. 6 %): 1 7 7 patie nts ( 9. 4 %) ha d 
e ve nts of Gra de 3, 1 3 patie nts ( 0. 7 %) ha d e ve nts of Gra de 4 a n d 1 1 patie nts 
( 0. 6 %) ha d Gra de 5 (fatal) e ve nts. 
Gra de 3 or 4 e ve nts occ urri n g i n ≥1 % of patie nts we re a nae mia ( 5. 5 %); d ys p nea 
( 4. 6 %); h y p o natrae mia ( 3. 6 %); ga m ma-gl uta m yltra nsferase ( G G T) i ncrease d 
( 2. 6 %); p ne u m o nia ( 2. 5 %); fati g ue ( 2. 4 %); as partate a mi n otra nsferase ( A S T) 
i ncrease d ( 2. 1 %); bac k pai n ( 2. 0 %); a b d o mi nal pai n ( 1. 9 %); se psis ( 1. 8 %); 
h y perte nsi o n ( 1. 5 %); de h y drati o n ( 1. 4 %); decrease d a p petite a n d ge neral p h ysical 
healt h deteri orati o n ( 1. 3 % eac h); ala ni ne a mi n otra nsferase ( A L T) i ncrease d, 
ast he nia a n d h y p o kalae mia ( 1. 2 % eac h); bl o o d al kali ne p h os p hatase ( A L P) 
i ncrease d, ple ural eff usi o n, p ul m o nar y e m b olis m, uri nar y tract i nfecti o n a n d 
v o miti n g ( 1. 1 % eac h); a n d h y per gl yce mia a n d l u n g i nfecti o n ( 1. 0 % eac h). Gra de 
3 or 4 e ve nts c o nsi dere d relate d t o d ur val u ma b occ urri n g i n ≥0. 5 % patie nts  were 
fati g ue ( 1. 0 %); A S T i ncrease d ( 0. 8 %); G G T i ncrease d ( 0. 7 %); p ne u m o nitis 
( 0. 6 %); a n d A L T i ncrease d a n d diarr hea ( 0. 5 % eac h). T he m ost c o m m o n Gra de 5 
e ve nts were ge neral p h ysical healt h deteri orati o n ( 1 5 patie nts [ 0. 8 %]), res pirat or y 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 
fail ure ( 9 patie nts [ 0. 5 %]) a n d se psis ( 7 patie nts [ 0. 4 %]); Gra de 5 e ve nts of deat h, 
p ne u m o nia a n d p ne u m o nitis occ urre d i n 5 patie nts eac h ( 0. 3 %) wit h t he 
re mai n der of t he Gra de 5 e ve nts occ urri n g i n ≤3 patie nts f or each e ve nt. T he o nl y 
Gra de 5 e ve nt c o nsi dere d relate d t o d ur val u ma b occ urri n g i n ≥2 patie nts  was 
p ne u m o nitis ( 5 patie nts [ 0. 3 %]). 
A t otal of 1 7 8 patie nts ( 9. 4 %) disc o nti n ue d fr o m st u d y treat me nt d ue t o a n A E. 
T he m ost c o m m o n e ve nts lea di n g t o treat me nt disc o n ti n uati o n were p ne u m o nitis 
( 2 8 patie nts [ 1. 5 %]); p ne u m o nia ( 1 0 patie nts [ 0. 5 %]); d ys p nea a n d ge neral 
p h ysical healt h deteri orati o n ( 9 patie nts eac h [ 0. 5 %]); a n d ra diati o n p ne u m o nitis 
( 6 patie nts [ 0. 3 %]); all ot her disc o nti n uati o n e ve nts occ urre d i n ≤4 patie nts. A 
t otal of 1 0 8 patie nts ( 5. 7 %) ha d seri o us A Es ( S A Es) t hat were c o nsi dere d b y t he 
i n vesti gat or as relate d t o d ur val u ma b. T he m ost c o m m o n were: p ne u m o nitis ( 2 5 
patie nts [ 1. 3 %]); i nf usi o n relate d reacti o n ( 5 patie nts [ 0. 3 %]); c olitis, diarr hea, 
fati g ue, p ne u m o nia a n d ra diati o n p ne u m o nitis ( 4 patie nts eac h [ 0. 2 %]); ner v o us 
s yste m dis or der ( 3 patie nts [ 0. 2 %]); a b d o mi nal pai n, ac ute ki d ne y i nj ur y, a dre nal 
i ns ufficie nc y, a ne mia, A S T i ncrease d, a ut oi m m u ne he patitis, de h y drati o n, 
d ys p nea, her pes z oster, l u n g i nfecti o n, na usea, pericar dial eff usi o n, 
t hr o m b oc yt o pe nia a n d v o miti n g ( 2 patie nts eac h [ 0. 1 %]). 
A t otal of 1 0 6 3 patie nts ( 5 6. 3 %) e x perie nce d a n A E SI d uri n g t he st u d y. T he m ost 
c o m m o n gr o u pe d ter m A E SI was diarr hea ( 3 2 9 patie nts [ 1 7. 4 %]; of w h o m 1 4 
patie nt s [ 0. 7 %] ha d e ve nts of Gra de ≥3). Ot her c o m m o n A E SIs ( gr o u pe d ter m) 
were der matitis ( 2 9 9 patie nts [ 1 5. 8 %]; of w h o m 3 patie nts [ 0. 2 %] ha d e ve nts of 
Gra de ≥3); ras h ( 2 8 3 patie nts [ 1 5. 0 %]; of w h o m 1 1 patie nts [ 0. 6 %] ha d e ve nts of  
Gra de ≥3); select he patic e ve nts ( 2 2 7 patie nts [ 1 2. 0 %]; of w h o m 8 6 patie nts 
[ 4. 6 %] ha d e ve nts of Gra de ≥3); h y p ot h yr oi dis m ( 2 0 6 patie n ts [ 1 0. 9 %]; of w h o m 
2 patie nts [ 0. 1 %] ha d e ve nts of Gra de ≥3); h y pert h yr oi dis m ( 1 3 5 patie nts [ 7. 1 %]; 
of w h o m 1 patie nt [ < 0. 1 %] ha d e ve nts of Gra de ≥3);  select re nal e ve nts ( 1 1 9 
patie nts [ 6. 3 %];  of w h o m 2 3 patie nts [ 1. 2 %] ha d e ve nts of Gra de ≥3); a n d  
p ne u m o nitis ( 9 8 patie nts [ 5. 2 %]; of w h o m 2 0 patie nts [ 1. 1 %] ha d e ve nts of 
C T C A E Gra de ≥3). T here were  1 1 patie nts w h o ha d A E SIs of C T C A E Gra de 5 
(fatal e ve nts); 5 patie nts ha d p ne u m o nitis, 4 patie nts ha d he patic e ve nts 
(a ut oi m m u ne he patitis, he patic fail ure, h y per bilir u bi ne mia a n d tra nsa mi nases 
i ncrease d), 1 patie nt ha d ac ute ki d ne y i nj ur y a n d 1 patie nt ha d i m m u ne 
t hr o m b oc yt o pe nic p ur p ura. 
1. 2. 5  
 Li mit ati o ns of a dj u v a nt r a di ati o n t her a p y a n d 
c he m or a di ot her a p y  
I n a pre-a dj u va nt t hera p y era, l ocal a n d re gi o nal rec urre nce occ urre d i n 3 0 % of 
patie nts a n d dista nt rec urre nce i n 2 5 % [1 6 ]. Alt h o u g h a dj u va nt ra di ot hera p y 
i m pr o ves o utc o mes c o m pare d  wit h ra di ot hera p y al o ne, less t ha n half of patie nts 
are disease free at fi ve years. T w o maj or st u dies atte m pte d t o i m pr o ve o utc o mes 
f or hi g h-ris k p ost- o perati ve patie nts b y a d di n g cis plati n c he m ot hera p y t o a dj u va nt 
ra di ot hera p y. R T O G 9 5 0 1 [1 7 , 1 8 ] ra n d o mize d patie nts wit h hist ol o gic e vi de nce 
of i n vasi o n of t w o  or m ore re gi o nal l y m p h n o des, e xtraca ps ular e xte nsi o n of 
n o dal disease, or micr osc o picall y-i n v ol ve d m uc osal mar gi ns of resecti o n t o 
ra di ot hera p y al o ne or ra di ot hera p y pl us t hree c ycles of cis plati n at 1 0 0 m g/ m2. A 
sec o n d st u d y, E O R T C 2 2 9 3 1[1 9 ] ha d a si milar ra n d o mizati o n, b ut differe nt 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 
i ncl usi o n criteria – p T 3 or p T 4 a n d a n y n o dal sta ge (e xce pt T 3 N 0 of t he lar y n x, 
wit h ne gati ve resecti o n mar gi ns), or a t u m or sta ge of 1 or 2 wit h a n o dal sta ge of 
2 or 3 or sta ge T 1/ T- N 0/ 1 wit h u nfa v ora ble pat h ol o gical fi n di n gs (e xtra n o dal 
s prea d, p ositi ve resecti o n mar gi ns, peri ne ural i n v ol ve me nt, or vasc ular t u m or 
e m b olis m) or oral -ca vit y or or o p har y n geal t u m ors wit h i n v ol ve d l y m p h n o des at 
le vel I V or V. A c o m bi ne d a nal ysis of t hese t w o trials [2 0 ] s h o we d t hat be nefit 
see me d restricte d t o patie nts wit h e xtraca ps ular e xte nsi o n or p ositi ve mar gi ns 
(statisticall y si g nifica nt f or t his s u b gr o u p i n E O R T C wit h a str o n g tre n d i n 
R T O G).  Si milar res ults/tre n ds were see n i n l o n g ter m f oll o w u p of t he R T O G 
st ud y. 
 
T he R T O G st u d y pr o vi de d m ore detaile d data o n ac ute a n d c hr o nic t o xicit y as 
o utli ne d i n  t he Ta ble 3 . T he rate of ac ute G 3 -5 t o xicit y wit h ra di ot h era p y al o ne 
was 3 4. 4 %; wit h t he a d diti o n of cis plati n, t his r ose t o 7 7. 0 %. I n cli nical practice 
l o n g ter m ot o pat h y, ne p hr o pat h y a n d ne ur o pat h y are als o c o m m o nl y see n.   
 
 
 
T a ble 3 . Ac ute a n d c hr o nic t o xicit y t o c he m or a di ot her a p y ( R T O G 9 5 0 1)  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 0 
1. 2. 6  
S afet y of D ur v al u m a b a n d R a di ati o n 
T he L C C C 1 6 2 1 st u d y d oes n ot c o nc urre ntl y a d mi nister d ur val u ma b a n d ra diati o n, 
b ut data o n t he safet y of t his c o m bi nati o n are rele va nt t o t his st u d y. A si n gle 
ce nter e x pa nsi o n c o h ort of t he P h ase I/ 2 trial of d ur val u ma b e nr olle d 1 0 patie nts 
wit h s oli d t u m ors w h o als o recei ve d eit her c o nc urre nt 3 -di me nsi o nal ra di ot hera p y 
( R T) ( 7 9 %) or stere otactic R T ( 2 1 %) [2 1 ]. D ur val u ma b ( 1 0 m g/ k g Q 2 W) was 
gi ve n wit h R T at a me dia n bi ol o gicall y -effecti ve d ose of 2 8 G y i n a me dia n 
n u m ber of 5 fracti o ns o ver a me dia n d urati o n of 6 da ys.  Fi ve patie nts re p orte d 
irra diati o n-relate d A Es a n d t he m ost fre q ue ntl y re p orte d e ve nt was gra de 2 
m uc ositis. T here were n o gra de 3 or m ore R T- relate d A Es. T here are c urre ntl y 
o ver 2 0 pla n ne d, o n g oi n g or c o m plete d cli nical st u dies of d ur val u ma b liste d o n 
t he cli nical trials. g o v we bsite t hat i ncl u de a d mi nistrati o n of d ur val u ma b al o ne or 
wit h tre meli m u ma b i n c o m bi nati o n wit h ra di ot hera p y or c he m ora di ot hera p y i n 
m ulti ple s oli d t u m or t y pes. T he P A CI FI C/ D 4 1 9 1 C 0 0 0 0 1 st u d y w hic h is a 
ra n d o mize d P hase III trial i n s u bjects wit h l ocall y a d va nce d, u nresecta ble Sta ge 
III N S C L C p ost c o nc urre nt c he m ora di ot hera p y, has re p orte d o ut safet y data i n a 
t otal of 1 1 5 s u bjects [2 2 ]. S u bjects ha d recei ve d 1 t o 2 6 d oses of d ur val u ma b 
( 1 0 m g/ k g Q 2 W w hic h is c o m para ble t o 7 5 0 m g Q 2 W pr o p ose d i n L C C C 1 6 2 1) as 
re p orte d i n t he c urre nt i n vesti gat or’s br oc h ure f or d ur val u ma b. T his st u d y re mai ns 
bli n de d. Treat me nt e mer ge nt A Es of s pecial i nteres t i n t his o n g oi n g trial are 
pr o vi de d bel o w. F ull data are n ot yet a vaila ble b ut  press release has i n dicate d t hat 
t he trial was p ositi ve f or its pri mar y e n d p oi nt of P F S. 
 
T a ble 4 . Tre at me nt e mer ge nt A Es of s peci al i nterest i n t he P A CI FI C/ D 4 1 9 1 C 0 0 0 0 1 st u d y  
 
S pecific  A d verse  E ve nt  of  I nterest 
Preferre d Ter m ( Me d D RA V 1 8. 0)  
               T ot a l (N  = 1 1 5)  
                      n ( %) 
All  Gr a des  
≥ Gr a de  3  
H y pert h yr oi dis m  
2 ( 1. 7) 
0  
H y p ert h yr oi dis m  
1 ( 0. 9) 
0  
T h yr oi ditis  
1 ( 0. 9) 
0  
Ne p hritis/ Ac ute  Re n al  F ail ure  
2 ( 1. 7) 
0  
A c ute  ki d ne y  i nj ur y 
1 ( 0. 9) 
0  
Bl o o d  creati ni ne  i ncrease d 
1 ( 0. 9) 
0  
P a ncre atitis  
2 ( 1. 7) 
1 ( 0. 9) 
A m ylase  i ncrease d 
1 ( 0. 9) 
0  
Li pase  i ncrease d 
1 ( 0. 9) 
1 ( 0. 9) 
Pa ncreatitis  
1 ( 0. 9) 
0  
H y p ot h yr oi dis m  
1 ( 0. 9) 
0  
H y p ot h yr oi dis m  
1 ( 0. 9) 
0  
I nf usi o n Rel ate d/ H y perse nsiti vit y/ A n a p h yl actic  Re acti o ns  
1 ( 0. 9) 
0  
I nf usi o n relate d reacti o n 
1 ( 0. 9) 
0  
Select  He p atic  E ve nts  
1 ( 0. 9) 
0  
Ga m m a -gl uta m yltra nsferase  i ncrease d 
1 ( 0. 9) 
0  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 1 
 
A E SI  = a d verse e ve nt of  s pecial i nterest; Me d D R A  = Me dical  Dicti o nar y  f or Re g ulat or y  Acti vities.  
1. 3  
St u d y R ati o n ale  
Tra diti o nall y, i n d ucti o n c he m ot hera p y i n S C C H N has bee n st u die d pri or t o 
c he m ora di ot hera p y.  W he n ra diati o n t hera p y is deli vere d defi niti vel y ( u p -fr o nt as 
t he pri mar y m o dalit y f or c ure) t he ra diati o n fiel ds m ust be gi ve n wi del y t o a n y 
areas c o nsi dere d at r is k base d o n p h ysical e xa mi nati o n, i ma gi n g, a n d t he nat ural 
patter ns of disease s prea d. As C T i ma gi n g is li mite d i n its a bilit y t o defi ne t he tr ue 
e xte nt of disease, patie nts recei ve wi der fiel ds t ha n necessar y, i ncreasi n g l o n g -
ter m m or bi dit y.  T his pri ncipal of u ncertai nt y of t he e xte nt of disease o n C T 
i ma gi n g is e xacer bate d b y i n d ucti o n c he m ot hera p y a n d beca use of t his 
u nrelia bilit y, t he sta n dar d of care f or ra diati o n deli vere d after i n d ucti o n 
c he m ot hera p y is t o treat t he pre -i n d ucti o n fiel d, e ve n if t he t u m or has s hr u n k 
dra maticall y [2 3 ].   
 
T he rece ntl y c o m plete d L C C C 1 1 2 5 st u d y s o u g ht t o n ot o nl y i m pr o ve c ure rates, 
b ut t o i m pr o ve f u ncti o nal o utc o mes b y a v oi di n g ra diati o n f or patie nts wit h g o o d 
res p o nse a n d b y mi ni mizi n g it t o pat h ol o gicall y- pr o ve n i n v ol ve d fiel ds f or t h ose 
w h o re q uire d it. I n t hat st u d y, m ost patie nts were a ble t o a v oi d ra diati o n a n d 
q ualit y of life was preser ve d ( data n o p u blis he d, s u b mitte d t o A S C O 2 0 1 7).  
L C C C 1 1 2 5 ga ve i n d ucti o n c he m ot hera p y c o nsisti n g of car b o plati n, paclita xel a n d 
la pati ni b pri or t o s ur gical resecti o n. I n t his st u d y, s ur gical resecti o n has n ot o nl y 
all o we d f or e xtir pati o n of disease b ut has als o pr o vi de d clearer defi niti o n of t he 
a nat o mic e xte nt of disease. L o n g -ter m res ults are pe n di n g, b ut earl y res ults usi n g 
t his a p pr oac h are fa v ora ble a n d we p ost ulate t hat it will mi ni mize ra diati o n-
i n d uce d m or bi dit y, i ncl u di n g xer ost o mia. Xer ost o mia occ urs i n all irra diate d 
patie nts t o s o me de gree, re gar dless of ra diati o n met h o d (i ncl u di n g i nte nsit y 
m o d ulate d ra diati o n t hera p y (I M R T)). Xer ost o mia n ot o nl y alters q ualit y of life, 
b ut als o ca n lea d t o de ntal c o m pr o mise, a n d oste ora di o necr osis. K n o wi n g t he tr ue 
sta ge of a patie nt a n d b ur de n of disease base d o n t he g ol d sta n dar d of pat h ol o gical 
re vie w of s ur gical tiss ue all o ws o ne t o offer t he m ost a p pr o priate a dj u va nt t hera p y 
a n d c o u nseli n g o n pr o g n osis. F urt her m ore, t he m or bi dit y of a n electi ve nec k 
dissecti o n is mi ni mal, a n d pe o ple ca n ret ur n t o n or mal acti vit y wit hi n 3 -5 da ys, 
wit h a restricti o n o n lifti n g f or 2 wee ks.    
 
Wit h tra diti o nal s ur ger y (e xter nal a p pr oac hes) a n d tra diti o nal i n d ucti o n 
c he m ot hera p y ( T P F), o pti o ns f or f urt her t hera p y are li mite d d ue t o t he t o xic 
nat ure of t he t hera p y. We ha ve pre vi o usl y s h o w n hi g h R R t o car b o plati n, na b-
paclita xel a n d cet u xi ma b. Base d o n data fr o m t he metastatic setti n g, we 
h y p ot hesize t hat t he c o m bi nati o n wit h d ur val u ma b will be m ore acti ve. 
 
I n t he metastatic setti n g, treat me nt wit h cet u xi ma b res ulte d i n a R R of 1 3 %.  I n 
c o ntrast, t w o P D 1 i n hi bit ors a n d t he P D L 1 i n hi bit or d ur val u ma b ha ve s h o w n 
n u mericall y s u peri or R R, i ncl u di n g s o me d ura ble c o ntr ol.  Treat me nt wit h 
pe m br oliz u ma b res ulte d i n a n 1 8 % R R b ot h i n a st u d y restricte d t o patie nts w h ose 
t u m ors were P D L 1+  [2 4 ] a n d i n a st u d y of u nselecte d patie nts [2 5 ]. Ni v ol u ma b 
was rece ntl y c o m pare d t o 2 n d li ne c he m ot hera p y ( met h otre xate, d oceta xel or 

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C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 2 
cet u xi ma b) a n d s h o we d b ot h s u peri or s ur vi val a n d s u peri or q ualit y of life ; R R 
was 1 8 % i n u nselecte d patie nts  [2 6 ]. We h y p ot hesize t hat be y o n d its s u peri or 
si n gle-a ge nt acti vit y, t hat a nti ge n prese ntati o n fr o m c yt ot o xic cell deat h wit h 
c he m ot hera p y will s y ner gize  wit h  i m m u n ot hera p y a n d facilitate  efficac y. 
 
T h us, t hr o u g h t he se q ue nci n g of i n d ucti o n c he m ot hera p y, mi ni mall y i n vasi ve 
s ur ger y a n d ra diati o n i n L C C C 1 1 2 5 , we s o u g ht t o n ot o nl y e n ha nce  s ur vi val a n d 
ca ncer c o ntr ol be nefit, b ut als o si m ulta ne o usl y i m pr o ve a dj u va nt t hera p y 
decisi o ns t o mi ni m ize m or bi dit y. We pr o p ose t o b uil d o n t his a p pr oac h i n t he 
c urre nt st u d y L C C C 1 6 2 1 e val uati n g car b o plati n, na b- paclita xel a n d d ur val u ma b 
i n d ucti o n t hera p y f or l ocall y-a d va nce d a n d s ur gicall y resecta ble S C C H N.  
1. 4  
C orrel ati ve St u dies  
T he use of s ur ger y f or defi niti ve t hera p y als o all o ws f or paire d c o m paris o n of pre -
treat me nt a n d p ost-treat me nt s peci me ns. S u bjects will be c o nse nte d f or c ollecti o n 
of bl o o d a n d t u m or sa m ples pri or t o a n d after i n d ucti o n t hera p y  f or i m m u ne 
c orrelati ve st u dies.  D uri n g scree ni n g, a rc hi val t u m or tiss ue will be o btai ne d a n d 
o pti o nal fres h t u m or bi o psies will be re q ueste d a n d o btai ne d fr o m s u bjects w h o 
c o nse nt t o t his pr oce d ure. A pretreat me nt bl o o d sa m ple will be c ollecte d pri or t o 
i nitiati n g st u d y treat me nt.  F oll o wi n g i n d ucti o n t h era p y, t u m or a n d bl o o d sa m ples 
will als o be c ollecte d d uri n g t he sc he d ule d s ur gical resecti o n f or researc h 
p ur p oses. C ollecti o n a n d pr ocessi n g of s peci me ns will be descri be d  i n t he 
la b orat or y ma n ual. 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 
3. 0  
S U B J E C T  E LI GI BI LI T Y  
3. 1  
I ncl usi o n Criteri a 
S u bject m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o partici pate i n t his 
st u d y: 
3. 1. 1  Pre vi o usl y u ntreate d, hist ol o gicall y pr o ve n , s ur gicall y resecta ble pri mar y 
s q ua m o us cell carci n o ma of t he hea d a n d nec k, sta ge III or I V ( H P V 
p ositi ve or ne gati ve  n o n- metastatic disease)  acc or di n g t o t he AJ C C Ca ncer 
Sta gi n g Ma n ual, 7t h e diti o n. S C C H N of u n k n o w n pri mar y is e xcl u de d.   
S C C H N of t he oral ca vit y is all o we d *. U na m bi g u o usl y s q ua m o us E B V-
ne gati ve nas o p har y n x ca ncer will n ot be e xcl u de d n or will u na m bi g u o usl y 
s q ua m o us ca ncers of t he s k ull base t hat are clearl y s ur gicall y resecta ble a n d 
clearl y s q ua m o us. S q ua m o us s ki n ca ncer occ urri n g i n t he hea d/ nec k re gi o n 
will n ot be eli gi ble n or will E B V +  nas o p har y n x ca ncer (see fi g ure bel o w f or 
a nat o mic s u bsites of hea d a n d nec k ca ncer) . ( * I n d ucti o n c he m ot hera p y is n ot 
c o nsi dere d sta n dar d t hera p y f or S C C H N of t he oral ca vit y a n d partici pati o n o n t his trial 
will lea d t o a dela y i n ti me t o defi niti ve, p ote ntiall y c urati ve t hera p y , i.e. s ur ger y). 
 
A nat o mic sites a n d s u bsites of t he hea d a n d nec k.  T he a p pr o xi mate 
distri b uti o n of hea d a n d nec k ca ncer is oral ca vit y, 4 4 %, lar y n x, 
3 1 %, a n d p har y n x, 2 5 %.  
3. 1. 2  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of ≤1 
(see A p pe n di x A: E C O G Perf or m a nce St at us ). 

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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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3 
3. 1. 3  Meas ura ble disease as per R E CI S T 1. 1 . 
3. 1. 4  A ge ≥1 8 years  at ti me of st u d y e ntr y . 
3. 1. 5  A de q uate b o ne marr o w f u ncti o n as de m o nstrate d b y:  
•  A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1, 5 x 1 0 9/ L 
•  H g b > 1 0 g/ d L ( use of tra nsf usi o n t o reac h t his t hres h ol d pri or t o st u d y 
i nitiati o n is acce pta ble)  
•  Platelet c o u nt ≥ 1 0 0  x 1 0 9/ L  
3. 1. 6  A de q uate he patic a n d re nal f u ncti o n as de m o nstrate d b y: 
•  As partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤ 
2. 5 ×  u p per li mit of n or mal ( U L N);  
•  T otal ser u m bilir u bi n ≤1. 5 U L N  
•  Creati ni ne cleara nce ( Cr C L) > 4 0 m L/ mi n as meas ure d via C oc kcr oft-
Ga ult  
Males:  
 
 
Creati ni ne C L 
( m L/ mi n) 
= 
Wei g ht ( k g) x ( 1 4 0 – A ge)       .  
7 2 x ser u m creati ni ne ( m g/ d L)  
 
 
 
Fe mal es:  
 
 
C reati ni ne C L 
( m L/ mi n) 
= 
Wei g ht ( k g) x ( 1 4 0 – A ge)        x 0. 8 5  
7 2 x ser u m creati ni ne ( m g/ d L) 
3. 1. 7  Ne gati ve ser u m β -h C G pre g na nc y test wit hi n 7 2 h o urs of da y 1 of i n d ucti o n 
c he m ot hera p y i n w o me n of c hil d- beari n g p ote ntial. 
3. 1. 8  All males a n d fe males of c hil d beari n g p ote ntial m ust a gree t o use a de q uate 
c o ntrace pti o n d uri n g t he st u d y. A de q uate c o ntrace pti o n is defi ne d as a n y 
me dicall y rec o m me n de d met h o d ( or c o m bi nati o n of met h o ds) as per 
sta n dar d of care.  Fe males of n o n-c hil d beari n g p ote ntial are t h ose w h o are 
p ost me n o pa usal greater t ha n 1 year or w h o ha ve ha d a bilateral t u bal 
li gati o n or h ysterect o my or bilat eral o o p h orect o m y.  See secti o n 4. 1 3  f or list 
of acce pta ble met h o ds of c o ntrace pti o n.  
3. 1. 9  Si g ne d a n i nstit uti o nal  re vie w b oar d (I R B) a p pr o ve d i nf or me d c o nse nt a n d 
HI P A A a ut h orizati o n.   
3. 1. 1 0  S u bject is willi n g a n d a ble t o c o m pl y wit h t he pr ot oc ol f or t he d urati o n of 
t he st u d y i ncl u di n g u n der g oi n g treat me nt a n d sc he d ule d visits a n d 
e xa mi nati o ns i ncl u di n g f oll o w u p. 
3. 1. 1 1  S u bjects m ust a gree t o all o w  use of a n y pre-treat me nt tiss ue re mai ni n g after 
defi niti ve dia g n osis is ma de (i .e., arc hi val a n d or fres h tiss ue) f or researc h 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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4 
p ur p oses. I n a d diti o n, s u bjects m ust c o nse nt t o all o w use of t heir resi d ual 
p ost- o perati ve tiss ue f or researc h p ur p oses.  
 
3. 2  
E xcl usi o n Criteri a   
S u bjects w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria will be i neli gi ble t o 
partici pate i n t his st u d y: 
3. 2. 1  I n v ol ve me nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o staff at 
t he st u d y site) or pre vi o us e nr oll me nt i n t he prese nt st u d y.  
3. 2. 2  A n y metastatic disease.  
3. 2. 3  K n o w n hist or y of pre vi o us cli nical dia g n osis of t u berc ul osis. 
3. 2. 4  Hist or y a n d/ or c o nfir me d p ne u m o nitis. 
3. 2. 5  L o w -ris k H P V+  disease  of t he or o p har y n x, defi ne d as meeti n g all of t he 
f oll o wi n g criteria:  
 
•  
S u bjects wit h  k n o w n H P V +  b y FI S H a n d/ or p 1 6  
•  
s m o ki n g hist or y ≤1 0 pac k years  
•  
Sta ge T 1 -2 N 0 - 2 b, T 3 N 0  
3. 2. 6  N ot c o nsi dere d eli gi ble f or a n y of t he c he m ot hera p y a ge nts i ncl u de d i n t he 
i n d ucti o n re gi me n. 
3. 2. 7  C urre nt acti ve he patic or biliar y disease ( wit h e xce pti o n of s u bjects wit h 
Gil bert's s y n dr o me, as y m pt o matic gallst o nes, or sta ble c hr o nic li ver disease 
per i n vesti gat or assess me nt) . 
3. 2. 8  M aj or s ur ger y wit hi n 2 8 da ys pri or t o da y 1 of st u d y treat me nt fr o m w hic h 
t he s u bject has n ot c o m pletel y rec o vere d.  
3. 2. 9  Recei vi n g a n y i n vesti gati o nal a ge nt c urre ntl y or wit hi n 2 8 da ys or 5 half-
li ves of Da y 1 of treat me nt o n t his st u d y. 
3. 2. 1 0  Acti ve, seri o us i nfecti o n, me dical, or ps yc hiatric c o n diti o n t hat w o ul d 
re prese nt a n i na p pr o priate ris k t o t he s u bject or w o ul d li kel y c o m pr o mise 
ac hie ve me nt of t he pri mar y st u d y o bjecti ve, i ncl u di n g u nsta ble a n gi na, 
seri o us u nc o ntr olle d car diac arr h yt h mia, u nc o ntr olle d i nfecti o n, or 
m y ocar dial i nfarcti o n ≤ 6 m o nt hs pri or t o st u d y e ntr y . 
3. 2. 1 1  Acti ve or pri or d oc u me nte d a ut oi m m u ne or i nfla m mat or y dis or ders 
(i ncl u di n g i nfla m mat or y b o wel disease [e. g., c olitis, Cr o h n’s disease], 
di vertic ulitis wit h t he e xce pti o n of a pri or e pis o de t hat has res ol ve d or 
di vertic ul osis, celiac disease, irrita ble b o wel disease, or ot her seri o us 
gastr oi ntesti nal c hr o nic c o n diti o ns ass ociate d wit h diarr hea; s yste mic l u p us 

L C C C 1 6 2 1  
 
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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5 
er yt he mat os us; We ge ner’s s y n dr o me [ gra n ul o mat osis wit h p ol ya n giitis]; 
m yast he nia gra vis;; r he u mat oi d art hritis; h y p o p h ysitis, u veitis; etc .) wit hi n 
t he past 2 years pri or t o t he start of treat me nt. N O T E:  S u bjects wit h vitili g o, 
Gra ve’s disease, or ps oriasis n ot re q uiri n g s yste mic treat me nt ( wit hi n t he 
past 2 years) are n ot e xcl u de d  
3. 2. 1 2  K n o w n m ea n Q T i nter val c orrecte d f or heart rate ( Q Tc) ≥4 7 0 ms calc ulate d 
fr o m 3 electr ocar di o gra ms ( E C Gs) usi n g Fre diricia’s C orrecti o n. ( N ote t hat 
E C G is n ot re q uire d f or st u d y e ntr y a n d is n ot part of st u d y pr oce d ures). 
3. 2. 1 3  Ot her pri or or c o nc o mita nt mali g na ncies wit h t he e xce pti o n of : 
•  N o n -mela n o ma s ki n ca ncer  
•  I n-sit u mali g na nc y 
•  L o w -ris k pr ostate ca ncer after c urati ve t hera p y 
•  Ot her ca ncer f or w hic h t he s u bject has bee n disease free f or ≥ 5 years  
bef ore t he first d ose of st u d y dr u g a n d of l o w p ote ntial ris k f or 
rec urre nce.  
3. 2. 1 4  A n y c o nc urre nt c he m ot hera p y, i n vesti gati o nal treat me nt, bi ol o gic or 
h or m o nal t hera p y f or ca ncer treat me nt.  C o nc urre nt use of h or m o nal t hera p y 
f or n o n-ca ncer -relate d c o n diti o ns (e. g. h or m o ne re place me nt t hera p y) is 
acce pta ble. 
3. 2. 1 5  C urre nt or pri or use of i m m u n os u p pressi ve me dicati o n wit hi n 1 4 da ys pri or 
t o t he first d ose of d ur val u ma b.  T he f oll o wi n g are e xce pti o ns t o t his 
criteri o n: i ntra nasal, i n hale d, t o pical or l ocal ster oi d i njecti o ns (e g. i ntra -
artic ular i njecti o n); ster oi ds as pre me dicati o n f or h y perse nsiti vit y reacti o ns; 
s yste mic c ortic oster oi d at p h ysi ol o gic d oses n ot t o e xcee d 1 0 m g/ da y of 
pre d nis o ne or e q ui vale nt.  [ N O T E:  If s yste mic c ortic oster oi ds are part of t he 
treat me nt re gi me n f or t he i n dicati o n u n der st u d y, t he s ystemic c ortic oster oi d 
is per mitte d]. 
3. 2. 1 6  K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V), he patitis C vir us ( H C V) or 
e vi de nce of acti ve he patitis B vir us ( H B V).  
3. 2. 1 7  Hist or y of h y perse nsiti vit y t o d ur val u ma b or a n y e xci pie nt. 
3. 2. 1 8  Recei pt of li ve atte n uate d vacci nati o n wit hi n 3 0  da ys pri or t he first d ose of 
d ur val u ma b [ N O T E: If a vacci ne is part of t he treat me nt re gi me n f or t he 
i n dicati o n u n der st u d y, t he vacci ne is per mitte d]. 
3. 2. 1 9  Fe male s u bjects w h o are pre g na nt, breast -fee di n g or fe male s u bjects of 
re pr o d ucti ve p ote ntial w h o are not e m pl o yi n g a n effecti ve met h o d of birt h 
c o ntr ol fr o m starti n g d ose of st u d y me dicati o ns ( C ycle 1 Da y 1), i ncl u di n g 
d osi n g i nterr u pti o ns t hr o u g h 9 0 da ys after recei pt of t he last d ose of 
d ur val u ma b. S u bjects m ust r efrai n fr o m e g g cell d o nati o n w hile ta ki n g 
d ur val u ma b a n d f or at least 9 0 da ys after t he last d ose of d ur val u ma b. 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 
3. 2. 2 0  Male s u bjects w h o are n ot e m pl o yi n g a n effecti ve met h o d of birt h c o ntr ol 
fr o m starti n g d ose of st u d y me dicati o ns ( C ycle 1 Da y 1), i ncl u di n g d osi n g 
i nterr u pti o ns t hr o u g h 6 m o nt hs  after recei pt of st u d y treat me nt.  Male 
s u bjects s h o ul d a gree t o refrai n fr o m s per m d o nati o n w hile ta ki n g st u d y 
treat me nt a n d f or at least 6 m o nt hs after t he last d ose of na b- paclita xel a n d 
at least 9 0 da ys after t he last d ose of d ur val u ma b . S h o ul d a fe male part ner of 
a male s u bject bec o me pre g na nt or s us pect s he is pre g na nt w hile 
partici pati n g i n t he st u d y, he s h o ul d i nf or m his treati n g p h ysicia n a n d t he 
fe male part ner s h o ul d call her p h ysicia n i m me diatel y.   
3. 2. 2 1  A n y pre vi o us treat me nt wit h a P D 1 or P D- L 1 i n hi bit or, i ncl u di n g 
d ur val u ma b. 
3. 2. 2 2  Hist or y of pri mar y i m m u n o deficie nc y.  
3. 2. 2 3  Hist or y of or ga n tra ns pla nt.  
3. 2. 2 4  A n y c o n diti o n t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d i nterfere wit h  
e val uati o n of st u d y treat me nt or i nter pretati o n of s u bject safet y or st u d y 
res ults (e. g., u nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, 
o n g oi n g or acti ve i nfecti o n, s y m pt o matic c o n gesti ve heart fail ure, 
u nc o ntr olle d h y perte nsi o n, u nsta ble a n gi na pect oris, car diac arr h yt h mia, 
acti ve pe ptic ulcer disease or gastritis, acti ve blee di n g diat heses or 
ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y 
re q uire me nts or c o m pr o mise t he a bilit y of t he s u bject t o gi ve writte n 
i nf or me d c o nse nt). 
3. 2. 2 5  S u bjects wit h k n o w n c o ntrai n dicati o ns t o ra di ot hera p y i ncl u di n g i n herite d 
s y n dr o mes ass ociate d wit h h y perse nsiti vit y t o i o nizi n g ra diati o n (e. g., 
Ata xia Tela n giectasia, Nij me ge n Brea ka ge S y n dr o me).  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 
4. 0  
T R E A T M E N T P L A N  
4. 1  
O ver vie w  
T he treat me nt pla n f or t his st u d y is c o m prise d of t hree parts. Pri or t o s ur ger y, 
s u bjects will be treate d wit h i n d ucti o n c he m ot hera p y ( Part 1) c o m prise d of 
wee kl y car b o plati n a n d na b- paclita xel  f or 6 wee ks i n c o m bi nati o n wit h e ver y 
ot her wee k d ur val u ma b  a d mi nistere d f or 5 c ycles ( See sc he ma i n secti o n 4. 2 ). 
 
P art 2 will c o nsist of s ur gical resecti o n.  T he res ults of pat h ol o g y fr o m t his 
s ur ger y will stratif y s u bjects i nt o o ne of t hree ris k cate g ories. S ur ger y will als o 
all o w i n vesti gat ors t o pat h ol o gicall y defi ne t he e xte nt of res p o nse t o i n d ucti o n 
c he m ot hera p y. After s ur ger y, s u bjects will be assi g ne d a treat me nt gr o u p base d 
o n t heir ris k a n d treate d wit h a dj u va nt t hera p y i n P art 3.  
 
S o me s u bjects will be l o w ris k at st u d y e ntr y, w hile ot hers will bec o me l o w ris k 
as a c o nse q ue nce of t he s uccess of i n d ucti o n c he m ot hera p y. N ota bl y, t his l o w ris k 
gr o u p i n here ntl y i ncl u des s u bjects w h o ha ve a c o m plete res p o nse ( C R) t o 
i n d ucti o n c he m ot hera p y. After s ur ger y, s u bjects i n t he l o w ris k cate g or y will be 
gi ve n d ur val u ma b o nce e ver y t w o wee ks f or 3 c ycles as a dj u va nt t hera p y.  
 
T he me di u m ris k s u bjects will re q uire a d diti o nal ra diati o n t o i m pr o ve t he c ure 
rate f oll o wi n g s ur gical resecti o n.  H o we ver, e ve n here t he m or bi dit y of t hera p y 
ma y  be decrease d.  First, t he res ults of s ur gical resecti o n will defi ne t he e xte nt of 
t he fiel d of ra diati o n.  B y ha vi n g pat h ol o gic data re gar di n g w here t here is resi d ual 
disease, a d diti o nal n or mal tiss ue ma y be s pare d. Sec o n d, as a c o nse q ue nce of t he 
use of i n d ucti o n c he m ot hera p y, hi g h- d ose cis plati n ma y be a v oi de d. As s uc h 
me di u m ris k s u bjects will be treate d c o nc urre ntl y wit h ra diati o n a n d wee kl y 
cis plati n per sta n dar d of care (S O C ) f oll o we d b y d ur val u ma b gi ve n o nce e ver y 
t w o wee ks f or 3 c ycles as a dj u va nt t hera p y.  
 
T he s u bject w h o re mai ns hi g h ris k des pite i n d ucti o n c he m ot hera p y will re q uire 
ma xi mal t hera p y t o elicit c ure. N ota bl y, t hese s u bjects are c urre ntl y treate d 
pri maril y wit h ra diati o n c o nc urre nt wit h cis plati n. H o we ver, ma n y E N T 
o nc ol o gists, b ot h s ur gical a n d me dical, ar g ue t hat t he a d diti o n of s ur ger y mi g ht 
i m pr o ve c ure rates. Here s uc h s u bjects w o ul d be treate d wit h tri m o dalit y t hera p y 
(i n d ucti o n c he m ot hera p y i nc or p orati n g d ur val u ma b t he n s ur ger y t he n 
c he m ora di ot hera p y). As s uc h treat me nt is m ore i nte nse t ha n t he c urre nt sta n dar d 
of care, we h o pe t hat t his a p pr oac h will i m pr o ve t he c u re rate f or t hese hi g h- ris k 
s u bjects. As s uc h hi g h- ris k s u bjects will be treate d c o nc urre ntl y wit h bilateral 
ra diati o n a n d cis plati n e ver y t hree wee ks  per S O C f oll o we d b y d ur val u ma b gi ve n 
o nce e ver y t w o wee ks f or 3 c ycles as a dj u va nt t hera p y.  A gai n, t he h y p ot hesis f or 
b ot h i ncrease d efficac y wit h o ut i ncrease d t o xicit y is deri ve d fr o m pri or 
e x perie nce  [2 7 ]. 
 
O perati ve dela ys a n d c o m plicati o ns t hat ma y be relate d t o i n d ucti o n t hera p y will 
als o be d oc u me nte d. S pecificall y, we will d oc u me nt w het her t he i n d ucti o n 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 
re gi me n res ulte d i n bl o o d c he mistr y i m bala nce, a d verse reacti o ns or var yi n g 
de grees of pa nc yt o pe nia, l ea di n g t o a dela y i n s ur gical t hera p y. A d verse reacti o ns 
c o ul d i ncl u de de h y drati o n, fail ure t o t hri ve, na usea, p o or n utriti o nal i nta ke, etc. 
4. 2  
Sc he m a  
 
St u d y P o p ul ati o n : U p t o 3 9 treat me nt - naï ve s u bjects wit h S C C H N  ma y be 
e nr olle d t o e ns ure 3 7 are e val ua ble. Ris k le vel pre-i n d ucti o n will be base d o n 
p h ysical e xa mi nati o n a n d i ma gi n g a n d will be defi ne d a n d d oc u me nte d i n e C R Fs 
pri or t o t he i nitiati o n of i n d ucti o n t hera p y.  P ost- i n d ucti o n ris k le vel will be 
deter mi ne d base d o n pat h ol o gic e val uati o n of t he s ur gical s peci me n.  
 
T his is a si n gle -ar m, n o nra n d o mize d p hase II trial c o nsisti n g of 3 parts. After 
i nf or me d c o nse nt a n d scree ni n g, pre -i n d ucti o n, ris k le vels will be assesse d 
cli nicall y, b y a c o m bi nati o n of p h ysical e xa m a n d i ma gi n g. A ll s u bjects will t he n 
recei ve 6 wee ks of i n d ucti o n c he m ot hera p y i n Part 1 c o m prise d of wee kl y c ycles 
of car b o plati n a n d na b- paclita xel  X 6 c ycles i n c o m bi nati o n wit h d ur val u ma b 
a d mi nistere d o nce e ver y t w o wee ks f or 5 c ycles  ( D 1 of wee ks 1, 3, 5, 7, a n d 9).   
 
Wit hi n a 1 t o 4 wee k wi n d o w p ost i n d ucti o n, t u m or i ma gi n g will be f oll o we d b y 
s ur gical resecti o n ( Part 2) . After s ur ger y, s u bjects will be stratifie d i nt o o ne of 3 
ris k cate g ories base d o n t heir disease pat h ol o g y, assi gne d a treat me nt gr o u p base d 
o n t heir ris k, a n d treate d acc or di n gl y ( P art 3)  as o utli ne d a b o ve. L o w ris k s u bjects 
wit h recei ve d ur val u ma b o nce e ver y t w o wee ks x 3 c ycles, w hile me di u m ris k or 
hi g h ris ks gr o u ps will recei ve c o nc urre nt c he m ora diati o n t hera p y f oll o we d b y 
d ur val u ma b o nce e ver y t w o wee ks x 3 c ycles. After  c o m pleti o n of st u d y t hera p y 
( w hic h will var y b y st u d y ar m) s u bjects will be e val uate d e ver y t hree m o nt hs 
d uri n g f oll o w u p f or pr o gressi o n o ver a peri o d of 1 8 m o nt hs. Eac h f oll o w u p visit 
will i n cl u de p h ysical e xa mi nati o n, C T or M RI i ma gi n g of t he nec k. C hest 
i ma gi n g will be o btai ne d ( or n ot) as i n dicate d b y S O C. After t he first 1 8 m o nt hs, 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 
s u bjects will be f oll o we d - u p per S O C, wit h d oc u me ntati o n i n t he electr o nic case 
re p ort f or m (eC R F) li mite d t o  pr o gressi o n a n d s ur vi val n ote d at t heir S O C visits.  
If a s u bject  s h o ul d m o ve a wa y or ot her wise be l ost t o i n- pers o n f oll o w u p b ut is 
a me na ble t o tele p h o ne f oll o w  u p, t his will be per mitte d d uri n g t he S O C f oll o w u p 
peri o d. 
4. 3  
I n d ucti o n C he m ot her a p y 
I n d ucti o n c he m ot hera p y will i ncl u de wee kl y car b o plati n d ose d t o a n A U C 2, 
wee kl y na b- paclita xel 1 0 0  m g/ m 2 a d mi nistere d f or 6 wee ks al o n g wit h 
d ur val u ma b ( 7 5 0 m g gi ve n o nce e ver y 2 wee ks f or 5 c ycles) .  I n d ucti o n t hera p y 
will c o nti n ue f or a t ota l of 9 wee ks.  
4. 3. 1  Pre me dic ati o ns f or I n d ucti o n C he m ot her a p y  
Pre me dicati o n s h o ul d i ncl u de a 5 H T- 3 a nta g o nist s uc h as o n da nsetr o n 2 4 m g P O 
( or 8 m g I V). Ster oi ds s h o ul d be a v oi de d as first-c ycle pri mar y pr o p h yla xis a gai nst 
e mesis, b ut de xa met has o ne 4 m g P O or I V or e q ui vale nt ma y be a d de d as nee de d. 
A pre pita nt, f osa pre pita nt, c o m pazi ne, a n d ola nza pi ne are per mitte d . 
4. 3. 2  N a b -P aclit a xel   
Na b - paclita xel 10 0 m g/ m 2 will be dil ute d as per i nstit uti o nal sta n dar d a n d i nf use d 
o ver 3 0 mi n utes.  Act ual b o d y wei g ht will be use d f or t he calc ulati o n, a n d d oses 
will be recalc ulate d w he ne ver b o d y wei g ht c ha n ges b y ≥1 0 %.  Na b - paclita xel 
m ust be a d mi nistere d pri or t o car b o plati n.   
4. 3. 3  C ar b o pl ati n 
Car b o plati n will be i nf use d at a n A U C of 2, wit h t he d ose calc ulate d usi n g t he 
Cal vert e q uati o n (t otal d ose ( m g) = 2 X ( G F R + 2 5).  T he d ose will be re -
calc ulate d pri or t o every cycle  i n or der t o a dj ust f or a n y p ote ntial c ha n ge i n re nal 
f u ncti o n as assesse d via ser u m creati ni ne (als o c hec ke d eac h c ycle). T he s u bject’s 
gl o mer ular filtrati o n rate ( G F R) as creati ni ne cleara nce ( Cr C L) i n m L/ mi n will be 
calc ulate d usi n g t he C oc kcr oft - Ga ult f or m ula, wit h wei g ht defi ne d as act ual b o d y 
wei g ht: 
 
F or males:  Creati ni ne cleara nce ( m L/ mi n) = ( 1 4 0 – a ge) x wei g ht i n kil o gra ms 
                                                                                       7 2 x ser u m creati ni ne i n m g/ dl  
 
F or fe males: use sa me f or m ula b ut m ulti pl y b y 0. 8 5 f or creati ni ne cleara nce  
 
A ma xi m u m G F R of 1 2 5 m L/ mi n will be use d.  T heref ore, t he ma x i m u m d ose of 
car b o plati n p ossi ble i n t his st u d y will be 3 0 0 m g.  T he car b o plati n will be i nf use d 
o ver 3 0 mi n utes.  Car b o plati n s h o ul d be a d mi nistere d after Na b -paclita xel.  
4. 3. 4  D ur v al u m a b 
D u r val u ma b 7 5 0 m g will be a d mi nistere d e ver y t w o wee ks f or 5 c ycles o n D 1 of 
wee ks 1, 3, 5, 7, a n d 9 of i n d ucti o n t hera p y i n Part 1. 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 0 
D ur val u ma b 7 5 0 m g will be a d mi nistere d e ver y 2 wee ks f or 3 c ycles eit her al o ne 
f oll o wi n g s ur gical resecti o n i n l o w ris k s u bjects or after s ur ger y a n d f oll o wi n g t he 
c o m pleti o n of a dj u va nt c he m ora di ot hera p y i n s u bjects wit h me di u m or hi g h -ris k 
disease i n Part 3 .   
4. 4  
S ur ger y  
S ur gical t hera p y will be at t he discreti o n of t he treati n g s ur ge o n per sta n dar d of 
care. S ur ger y will be d o ne at 1- 4 wee ks after t he c o m pleti o n of i n d ucti o n t hera p y; 
a n i nter val of > 5 0 da ys will be c o nsi dere d a d ose li miti n g t o xicit y. T he s u bject 
will u n der g o gr oss t otal resecti o n of t he pretreat me nt pri mar y site ca ncer v ol u me 
(as deter mi ne d b y a c o m bi nati o n pre o perati ve ra di o gra p h a n d eit her pre o perati ve 
p h ot o d oc u me ntati o n or tatt o oi n g), i ncl u di n g fr oze n secti o n mar gi ns fr o m t he 
peri p her y a n d dee p tiss ue pla nes. Rec o nstr ucti o n of t he defect will be at t he 
discreti o n of t he s ur ge o n. Pri mar y site a n d nec k s ur ger y ma y be perf or me d 
si m ulta ne o usl y or se q ue ntiall y, b ut i n t he case of se q ue ntial s ur ger y, b ot h sites 
m ust be c o m plete d wit hi n 1 4 da ys fr o m eac h ot her. 
 
Bilateral nec k dissecti o ns will be perf or me d o n all s u bjects at ris k f or c o ntralateral 
metastasis per sta n dar d of care.  
 
S peci me ns will be caref ull y orie nte d a n d a nat o mic l ocati o n caref ull y a n n otate d t o 
all o w f or tail ori n g of ra diati o n t o t he pat h ol o gicall y pr o ve n t u m or area pl us a 
mar gi n.  
4. 5  
P ost -O per ati ve C o nc o mit a nt C he m or a di ot her a p y  
4. 5. 1  L o w Ris k  
S u bjects i n t his cate g or y will recei ve d ur val u ma b ( 7 5 0 m g ) a d mi nistere d e ver y 
t w o wee ks f or 3 c ycles. T he c o m ple xit y or ris k assess me nt i n hea d/ nec k ca ncer is 
t o o great t o e ns ure t hat all s u bjects dee me d l o w ris k b y L C C C 1 6 2 1 criteria tr ul y 
w o ul d n ot be nefit fr o m a dj u va nt ra di ot hera p y. T heref or e, t o e ns ure o pti mal 
treat me nt of all s u bjects, i n t he case w here a m ulti disci pli nar y t u m or b oar d 
rec o m me n ds a dj u va nt ra di ot hera p y or c he m ora di ot hera p y f or a s u bject meeti n g 
L C C C 1 6 2 1 criteria f or l o w ris k, t his will be all o we d  a n d will n ot be c o nsi dere d a 
pr ot oc ol de viati o n or vi olati o n.  Of n ote, t his s h o ul d a p pl y t o eit her n o s u bjects or 
t o a ver y s mall n u m ber of s u bjects —r o uti ne e xce pti o ns f or i nstit uti o nal or 
pr o vi der prefere nce t o r o uti nel y a d mi nister a dj u va nt t hera p y will n ot be all o we d. 
4. 5. 2  Me di u m ris k  
S u bjects dee me d me di u m ris k  as per s ur gical pat h ol o g y will recei ve i psilateral 
i n v ol ve d fiel d ra diati o n c o nc urre nt wit h wee kl y cis plati n 3 0 m g/ m 2 wee kl y 
c o nc urre nt wit h ra diati o n f or u p t o  6 c ycles . F or t he p ur p oses of t his st u d y, 
“i n v ol ve d fiel d ra diati o n” will refer t o areas de m o nstrate d t o har b or disease o n 
pat h ol o g y, a n d n ot electi ve areas. All s u bjects will be treate d wit h I M R T. 
Ra diati o n will c o m me nce o nce t he s u bject has a de q uatel y heale d fr o m s ur ger y; 
t his will t y picall y ta ke place t w o t o si x wee ks f oll o wi n g s ur ger y b ut will var y b y 
s u bject. W he n s ur gical pat h ol o g y res ults are s ufficie ntl y detaile d t o all o w f or 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 1 
defi nite e val uati o n, t he p osti n d ucti o n pri mar y site a n d n o dal gr oss t u m or v ol u mes 
( G T Vs) s h o ul d be use d f or ra diati o n t hera p y ( R T) pla n ni n g.  
 
L oc aliz ati o n, Si m ul ati o n, a n d I m m o biliz ati o n  
S u bjects m ust ha ve a n i m m o bilizati o n de vice f or t he hea d a n d nec k (s h o ul ders 
o pti o nal) (e. g., a q ua plast mas k) ma de pri or t o t he treat me nt pla n ni n g C T sca n t hat 
is re q uire d f or all s u bjects. T he treat me nt pla n ni n g C T sca n ca n be perf or me d 
wit h or wit h o ut I V c o ntrast ( prefera ble) . T he treat me nt pla n ni n g C T sca n m ust be 
perf or me d wit h t he i m m o bilizati o n de vice a n d i n t he treat me nt p ositi o n. Slice 
t hic k ness s h o ul d be ma xi m u m 3 m m. 
 
D ail y i m a ge g ui d a nce (I G R T)  is rec o m me n de d b ut n ot re q uire d. Wee kl y 
verificati o n i ma gi n g is re q uire d.  
 
Tre at me nt Pl a n ni n g/ T ar get V ol u mes  
•  C T V 6 0: T his v ol u me will recei ve 2 G y per da y. C T V 6 0 will i ncl u de t he pri mar y 
t u m or be d ( base d o n o perati ve fi n di n gs a n d p ost- o perati ve pat h ol o g y) pl us 
re gi o ns of pat h ol o gicall y i n v ol ve d l y m p ha de n o pat h y. C T V 6 0 ma y i ncl u de t he 
br oa der o perati ve resecti o n be d i n t he re gi o n of gr oss pri mar y a n d n o dal disease 
as well as t he e ntire n o dal re gi o ns i n t he  i n v ol ve d nec k at t he discreti o n of t he 
i n vesti gat or f or percei ve d hi g her-ris k ca ncers.  
•  C T V 5 4: T his will i ncl u de all ot her lesser ris k re gi o ns wit h o ut via ble resi d ual 
ca ncer i n t he pat h ol o g y s peci me n b ut i n t he o perati ve be d a n d felt t o be at ris k f or 
har b ori n g micr osc o pic ca ncer t hat d o n ot meet t he criteria f or C T V 6 0. T his 
v ol u me will recei ve 1. 8 G y per da y.  C T V 6 0 a n d C T V 5 4 will be i n o ne I M R T 
pla n wit h t he d ose pai nte d.  
•  Pla n ni n g Tar get V ol u mes ( P T Vs): I n ge neral, t he P T V s h o ul d n ot e xte n d be y o n d 
t he s ki n s urface, e xce pt if t he s ki n was i n v ol ve d wit h t u m or. If it d oes e xte n d 
be y o n d t he s ki n s urface, t he a p plicati o n of b ol us material o ver t his p orti o n of t he 
P T V ma y be c o nsi dere d. C T V t o P T V e x pa nsi o n will be 3 t o 5 m m. 
 
I M R T D ose Prescri pti o n t o P T Vs:  D ose will be prescri be d t o t he P T V’s s o t hat 
9 5 % of t he d ose c o vers 1 0 0 % of t he v ol u me.  
D ose C o nstr ai nts  
 P T V 6 6, P T V 6 0, P T V 5 4  
o  1 0 0 % of t he prescri pti o n s h o ul d c o ver 9 5 % of t he P T V 
o  N o m ore t ha n 1 0 % of t he P T V s h o ul d recei ve ≥ 1 1 0 % of t he prescri be d 
d ose 
o  N o m ore t ha n 1 % of t he P T V s h o ul d recei ve ≤ 9 3 % of t he prescri be d d ose  
 N o n -tar get Tiss ue 
o  N o m ore t ha n 1 % of t he tiss ue o utsi de t he P T V s h o ul d recei ve ≥ 1 1 0 % of 
t he prescri be d d ose 
 P R V  
o  S pi nal C or d:  0. 1cc ≤ 5 0 G y  
o  Brai nste m: 0. 1cc ≤ 5 4 G y  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 2 
o  Par oti d:  Mea n d ose < 2 6 G y a n d/ or 5 0 % < 3 0 G y 
o  C oc hlea:  Mea n d ose < 4 5 G y  
o  Lar y n x:  Mea n d ose < 4 1 G y a n d/ or 6 0 G y t o < 2 0 % 
o  O ptic str uct ures:  . 1cc < 5 4 G y 
 
P T V c o vera ge s h o ul d n ot be c o m pr o mise d t o meet t he d ose c o nstrai nts of t he 
par oti d, c oc hlea, or lar y n x. S pari n g of t hese str uct ures is left at t he discreti o n of 
t he treati n g ra diati o n o nc ol o gists. T he d ose c o nstrai nts f or t he s pi nal c or d a n d 
brai nste m m ust  be satisfie d. T his ma y be d o ne at t he c ost of alteri n g t he P T V.   
 
N O T E:  Alter nati ve re gi me ns ma y be s u bstit ute d f or cis plati n i n s u bjects w h o are 
n ot ca n di dates f or cis plati n at t he discreti o n of t he i n vesti gat or.  If car b o plati n is 
use d, a creati ni ne cleara nce ca p of 1 2 5 m L/ mi n m ust be use d, as per sta n dar d of 
care.  Re gi me ns t hat ma y be use d i ncl u de: 
•  Wee kl y car b o plati n at a d ose of A U C of 1. 5 [ 2 ].  
•  Wee kl y car b o plati n at a d ose of A U C of 1 c o m bi ne d wit h paclita xel at a 
d ose of 4 5 m g / m2 [2 8 ]. 
•  Wee kl y cet u xi ma b [2 9 , 3 0 ], a d mi nistere d at a l oa di n g d ose of 4 0 0 m g/ m 2 
f oll o we d b y wee kl y t hera p y at a d ose of 2 5 0 m g/ m 2. T he l oa di n g d ose 
ma y be a d mi nistere d eit her t he wee k prece di n g c he m ora di ot hera p y or 
c o nc urre nt wit h t he first wee k of t hera p y. 
•  Wee kl y cet u xi ma b, a d mi nistere d at a l oa di n g d ose of 4 0 0 m g/ m 2 f oll o we d 
b y wee kl y t hera p y at a d ose of 2 5 0 m g/ m 2.  T he l oa di n g d ose ma y be 
a d mi nistere d eit her t he wee k prece di n g c he m ora di ot hera p y or c o nc urre nt 
wit h t he first wee k of t hera p y.  T his will be a d mi nistere d wit h wee kl y 
d oceta xel at 1 5 m g/ m 2, starti n g c o nc urre nt wit h t he first wee k of ra diati o n 
t hera p y [3 1 ]. 
 
Ra diati o n treat me nt brea ks s h o ul d be mi ni mize d as p ossi ble.  
 
O nce c he m ora di ot hera p y is c o m plete t hese s u bjects will recei ve d ur val u ma b 
7 5 0 m g e ver y t w o wee ks f or 3 c ycles. 
4. 5. 3  Hi g h -ris k 
We d o n ot a ntici pate a n y hi g h- ris k s u bjects. Base d o n e xisti n g data alrea d y 
descri be d , we a ntici pate t his re gi me n t o be m ore effecti ve t ha n t he L C C C 1 1 2 5 
re gi me n a n d n o s u bjects i n t hat st u d y were hi g h ris k. N o net heless, i n or der t o 
a d dress o pti mal care of s uc h a t he oretical s u bject, t hera p y is disc usse d herei n.   
Ra diati o n will c o m me nce o nc e t he s u bject has a de q uatel y heale d fr o m s ur ger y; 
t his will t y picall y ta ke place t w o t o si x wee ks f oll o wi n g s ur ger y b ut will var y b y 
s u bject. All s u bjects will be treate d wit h I M R T.  
 
L oc aliz ati o n, Si m ul ati o n, a n d I m m o biliz ati o n  
S u bjects m ust ha ve a n i m m o bilizati o n de vice f or t he hea d a n d nec k (s h o ul ders 
o pti o nal) (e. g., a q ua plast mas k) ma de pri or t o t he treat me nt pla n ni n g C T sca n t hat 
is re q uire d f or all s u bjects. T he treat me nt pla n ni n g C T sca n ca n be perf or me d 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 3 
wit h or wit h o ut I V c o ntrast ( prefera ble) T he treat me nt pla n ni n g C T sca n m ust be 
perf or me d wit h t he i m m o bilizati o n de vice a n d i n t he treat me nt p ositi o n. Slice 
t hic k ness s h o ul d be ma xi m u m 3 m m. 
D ail y i m a ge g ui d a nce (I G R T)  is rec o m me n de d b ut n ot re q uire d. Wee kl y 
verificati o n i ma gi n g is re q uire d.  
Tre at m e nt Pl a n ni n g/ T ar get V ol u mes  
•  C T V 6 0: T his v ol u me will recei ve 2 G y per da y. C T V 6 0 will i ncl u de t he pri mar y 
t u m or be d ( base d o n pre o perati ve i ma gi n g, pre o perati ve p h ysical 
e xa m/e n d osc o p y, o perati ve fi n di n gs, pat h ol o gic fi n di n gs) pl us re gi o ns of gr ossl y 
i n v ol ve d l y m p ha de n o pat h y. C T V 6 0 ma y i ncl u de t he br oa der o perati ve resecti o n 
be d i n t he re gi o n of gr oss pri mar y a n d n o dal disease. T he e ntire n o dal re gi o ns i n 
t he i n v ol ve d he mi- nec k ma y be i ncl u de d i n C T V 6 0 at t he discreti o n of t he 
i n vesti gat or f or percei ve d hi g her-ris k ca ncers. C T V 6 0 will i ncl u de t he i psilateral 
pat h ol o gicall y p ositi ve he mi nec k (if b ot h si des of t he nec k are pr o ve n 
pat h ol o gicall y p ositi ve, C T V 6 0 will i ncl u de b ot h si des).  
•  C T V 5 4: T his will i ncl u de all ot her lesser ris k re gi o ns i n t he o perati ve be d  (t hat 
were i n v ol ve d wit h s ur ger y i n a n y wa y) b ut felt t o be at ris k f or har b ori n g 
micr osc o pic ca ncer t hat d o n ot meet t he criteria f or C T V 6 0. T his v ol u me will 
recei ve 1. 8 G y per da y.  C T V 6 0 a n d C T V 5 4 will be i n o ne I M R T pla n wit h t he 
d ose pai nte d.  
•  C T V 6 6 O pti o nal: T his v ol u me ma y be defi ne d at t he discreti o n of t he treati n g 
ra diati o n o nc ol o gist. T his w o ul d i ncl u de re gi o ns felt t o be at partic ularl y hi g h ris k 
f or rec urre nce (e. g., a n area of t he E C S or p ositi ve mar gi n of resecti o n). N ote: A 
se parate bo ost pla n will be create d ( 2 G y/f x f or 3 fracti o ns f or a t otal d ose of 6 
G y.  
•  Pla n ni n g Tar get V ol u mes ( P T Vs): I n ge neral, t he P T V s h o ul d n ot e xte n d be y o n d 
t he s ki n s urface, e xce pt if t he s ki n was i n v ol ve d wit h t u m or. If it d oes e xte n d 
be y o n d t he s ki n s urface, t he a p plicati o n of b ol us material o ver t his p orti o n of t he 
P T V ma y be c o nsi dere d. C T V t o P T V e x pa nsi o n will be 3 t o 5 m m. 
 
I M R T D ose Prescri pti o n t o P T Vs:  D ose will be prescri be d t o t he P T V’s s o t hat 
9 5 % of t he d ose c o vers 1 0 0 % of t he v ol u me.  
D ose C o nstr ai nts  
 P T V 6 6, P T V 6 0, P T V 5 4  
o  1 0 0 % of t he prescri pti o n s h o ul d c o ver 9 5 % of t he P T V 
o  N o m ore t ha n 1 0 % of t he P T V s h o ul d recei ve ≥ 1 1 0 % of t he prescri be d 
d ose 
o  N o m ore t ha n 1 % of t he P T V s h o ul d recei ve ≤ 9 3 % of t he prescri be d d ose  
 N o n -tar get Tiss ue 
o  N o m ore t h a n 1 % of t he tiss ue o utsi de t he P T V s h o ul d recei ve ≥ 1 1 0 % of 
t he prescri be d d ose 
 P R V  
o  S pi nal C or d:  0. 1cc ≤ 5 0 G y  
o  Brai nste m: 0. 1cc ≤ 5 4 G y  
o  Par oti d: mea n d ose < 2 6 G y a n d/ or 5 0 % < 3 0 G y 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 4 
o  C oc hlea: mea n d ose < 4 5 G y 
o  Lar y n x: mea n d ose < 4 1 G y a n d/ or 6 0 G y t o < 2 0 % 
o  O ptic str uct ures: . 1cc < 5 4 G y 
 
P T V c o vera ge s h o ul d n ot be c o m pr o mise d t o meet t he d ose c o nstrai nts of t he 
par oti d, c oc hlea, or lar y n x. S pari n g of t hese str uct ures is left at t he discreti o n of 
t he treati n g ra diati o n o nc ol o gists. T he d ose c o nstrai nts f or t he s pi nal c or d a n d 
brai nste m m ust  be satisfie d. T his ma y be d o ne at t he c ost of alteri n g t he P T V.   
 
Sta n dar d treat me nt i n t his ar m will be defi ne d as b ol us cis plati n  ( 1 0 0 m g/ m2 e ver y 
3 wee ks f or 3 c ycles c o nc urre nt wit h ra diati o n). F or s u bjects n ot c o nsi dere d 
a p pr o priate ca n di dates f or hi g h d ose b ol us cis plati n (i.e., 1 0 0 m g/ m 2 e ver y 3 
wee ks f or 3 c ycles)  i n c o m bi nati o n wit h  ra di ot hera p y, o ne of t he c h oices bel o w 
ma y be per mitte d . If car b o plati n is use d, a ma xi m u m of 1 2 5 m L/ mi n m ust be use d 
(see secti o n 4. 3. 3 ), as per sta n dar d of care.   
 
•  Wee kl y cis plati n at a d ose of 3 0 - 4 0 m g/ m 2 [3 2 ]. 
•  Wee kl y cis plati n at a d ose of 2 0  m g/ m 2 c o m bi ne d wit h paclita xel at a d ose 
of 3 0 m g/ m 2 [3 3 ]. 
•  Wee kl y car b o plati n at a d ose of A U C of 1. 5 [ 2 ]. 
•  Wee kl y car b o plati n at a d ose of A U C of 1 c o m bi ne d wit h paclita xel at a 
d ose of 4 5 m g/ m 2 [2 8 ]. 
•  Wee kl y cet u xi ma b [2 9 , 3 0 ], a d mi nistere d at a l oa di n g d ose of 4 0 0 m g/ m 2 
f oll o we d b y wee kl y t hera p y at a d ose of 2 5 0 m g/ m 2. T he l oa di n g d ose 
ma y be a d mi nistere d eit her t he wee k prece di n g  c he m ora di ot hera p y or 
c o nc urre nt wit h t he first wee k of t hera p y. 
•  Wee kl y cet u xi ma b, a d mi nistere d at a l oa di n g d ose of 4 0 0 m g/ m 2 f oll o we d 
b y wee kl y t hera p y at a d ose of 2 5 0 m g/ m 2. T he l oa di n g d ose ma y be 
a d mi nistere d eit her t he wee k prece di n g c he m ora di ot hera p y or c o nc urre nt 
wit h t he first wee k of t hera p y. T his will be a d mi nistere d wit h wee kl y 
d oceta xel at 1 5 m g/ m 2, starti n g c o nc urre nt wit h t he first wee k of ra diati o n 
t hera p y [3 1 ]. 
 
Ot her re gi me ns ma y be o pti mal f or t he care of i n di vi d ual s u bjects. T o e ns ure 
a d here nce t o sta n dar d of care, ot her re gi me ns will re q uire t he a p pr o val of t he 
i nstit uti o nal (site) PI.  
 
O nce c he m ora di ot hera p y is c o m plete t hese s u bjects  will recei ve d ur val u ma b 
7 5 0 m g e ver y t w o wee ks f or 3 c ycles. 
4. 6  
D osi n g Del a ys/ D ose M o dific ati o ns f or I n d ucti o n C he m ot her a p y  
A n y s u bject w h o recei ves a n y treat me nt o n t his pr ot oc ol will be e val ua ble f or 
t o xicit y. Eac h s u bject will be assesse d peri o dicall y f or t he de vel o p me nt of a n y 
t o xicit y acc or di n g t o t he Ti me a n d E ve nts ta ble . T o xicit y will be assesse d 
acc or di n g t o t he N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 5 
( C T C A E), versi o n 4. 0 3. D ose a dj ust me nts s h o ul d be ma de acc or di n g t o t he 
s yste m s h o wi n g t he greatest de gree of t o xicit y.   
 
A m a xi m u m of t w o re d ucti o ns of e ac h dr u g will be all o we d per s u bject.   If 
> 2 d ose re d ucti o ns of na b -paclita xel  a n d car b o plati n are re q uire d, pr ot oc ol 
t hera p y is t o be disc o nti n ue d, res p o nse assesse d, a n d t he s u bject s h o ul d pr ocee d t o 
o pti mal defi niti ve t hera p y o utsi de t he cli nical trial ( as per sta n dar d of care). O nce 
a s u bject’s d ose has bee n re d uce d, t he d ose re d ucti o n will be per ma ne nt — d ose re-
escalati o n will n ot be per mitte d.  
  
F or A Es t hat re q uire d ose re d ucti o ns of na b- paclita xel  or car b o plati n, please refer 
t o t he d ose le vels i n t he f oll o wi n g ta ble: 
 
D ose Le vel  
N a b -P aclit a xel ( m g/ m 2) C ar b o pl ati n ( A U C)  
0 (starti n g d ose) 
1 0 0 
2 
-1  
7 5  
1. 6  
-2  
5 0  
1. 2  
 
D ose re d ucti o ns f or A Es relate d t o D ur val u ma b  are n ot all o we d as n ote d i n t he ta ble: 
 
D ose Le vel  
D ur v al u m a b  ( m g) 
0 (starti n g d ose)  
7 5 0  
N o d ose re d ucti o ns are all o we d. O pti o ns are t o wit h h ol d t he d ose or disc o nti n ue d ur val u ma b.  
G ui deli nes f or d osi n g a n d ma na ge me nt of n o n -i m m u ne a n d i m m u ne-relate d A Es are 
pr o vi de d i n  A p pe n di x C  a n d A p pe n di x D . 
G ui deli nes f or I nf usi o n -relate d reacti o ns are pr o vi de d i n Ta ble 8  i n secti o n 5. 1. 6. 1 . 
 
4. 6. 1  S u g geste d D ose del a ys/ D ose M o dific ati o ns f or N a b - P aclit a xel a n d 
C ar b o pl ati n D uri n g I n d ucti o n  
B ot h car b o plati n a n d na b - paclita xel are F D A a p pr o ve d c he m ot hera p y a ge nts 
w hic h are r o uti nel y d ose-a dj uste d b y o nc ol o gists o utsi de of pr ot oc ol setti n gs.  
Gi ve n t he hi g h le vel of cli nical e x perie nce wit h t hese me dicati o ns, cli nicia ns ca n 
better i n di vi d ualize d ose-re d ucti o ns t ha n ri gi d g ui deli nes. T heref ore, w he n d ose 
a dj ust me nt is s u g geste d per Ta ble 5 , t he treati n g cli nicia n s hall deci de w het her t o 
d ose-re d uce o ne or b ot h a ge nts. T he ma g nit u de of decre me nt s hall f oll o w t he 
ta ble a b o ve. T he treati n g p h ysicia n ma y als o c h o ose n ot t o d o a n y d ose 
a dj ust me nt base d o n cli nical j u d ge me nt. S u g geste d d ose dela y s a n d m o dificati o ns 
f or s pecific t o xicities are pr o vi de d i n Ta ble 5  bel o w . 
 
If h y perse nsiti vit y reacti o ns t o na b- paclita xel occ ur, mi n or s y m pt o ms s uc h as 
fl us hi n g, s ki n reacti o ns, d ys p nea, l o wer bac k pai n, h y p ote nsi o n, or tac h ycar dia 
ma y re q uire te m p orar y i nterr u pti o n of t he i nf usi o n.  H o we ver, se vere reacti o ns, 
s uc h as h y p ote nsi o n re q uiri n g treat me nt, d ys p nea re q uiri n g br o nc h o dilat ors, 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 8 
of care).  T he n u m ber of da ys of G C S F is u p t o t he discreti o n of t he treati n g 
p h ysicia n; h o we ver, t he s u bject m ust start  G-C S F  at least 2 4 h o urs after t he d ose 
of c he m ot hera p y a n d G- C S F m ust be hel d at least 4 8 h o urs pri or t o t he ne xt d ose 
of i n d ucti o n c he m ot hera p y. T he d ose of t he G- C S F ca n be a dj uste d base d o n t he 
i n vesti gat or’s discreti o n. E S As, fil grasti m ( G- C S F) a n d pe g-fil grasti m will  n ot be 
per mitte d d uri n g c he m ora di ot hera p y.  
4. 6. 2  S u g geste d D ose del a ys/ D ose M o dific ati o ns f or D u r v al u m a b D uri n g 
I n d ucti o n 
F or a d verse e ve nts ( A Es) t hat are c o nsi dere d p ossi bl y d ue t o a d mi nistrati o n of 
d ur val u ma b, t he f oll o wi n g d ose a dj ust me nt g ui da nce ma y be a p plie d: 
 
•  
Treat eac h of t he t o xicities wit h ma xi m u m s u p p orti ve care (i ncl u di n g 
h ol di n g t he a ge nt s us pecte d of ca usi n g t he t o xicit y w here re q uire d). 
 
•  
If t he s y m pt o ms pr o m ptl y res ol ve wit h s u p p orti ve care, c o nsi derati o n 
s h o ul d be gi ve n t o c o nti n ui n g t he sa me d ose of d ur val u ma b al o n g wit h 
a p pr o priate c o nti n ui n g s u p p orti ve care.  
 
•  
 All d ose m o dificati o ns s h o ul d be d oc u me nte d wit h clear reas o ni n g a n d 
d oc u me ntati o n of t he a p pr oac h ta ke n. 
 
I n a d diti o n, t here are certai n circ u msta nces i n w hic h d ur val u ma b s h o ul d be 
per ma ne ntl y disc o nti n ue d. 
 
Base d o n t he mec ha nis m of acti o n of d ur val u ma b lea di n g t o T- cell acti vati o n a n d 
pr oliferati o n, t here is t he p ossi bilit y of o bser vi n g i m m u ne -relate d A d verse E ve nts 
(ir A Es) d uri n g t he c o n d uct of t his st u d y.  P ote ntial ir A Es i ncl u de i m m u ne 
me diate d e nter oc olitis, der matitis, he patitis, a n d e n d ocri n o pat hies. S u bjects 
s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of ir A Es. I n t he a bse nce of a n 
alter nate eti ol o g y (e. g., i nfecti o n or P D) si g ns or s y m pt o ms of e nter oc olitis, 
der matitis, he patitis, a n d e n d ocri n o pat h y s h o ul d be c o nsi dere d t o be i m m u ne-
relate d.   
 
 D ur val u ma b d ose m o dificati o n rec o m me n dati o ns a n d t o xicit y 
ma na ge me nt g ui deli nes f or i nf usi o n- relate d reacti o ns are pr o vi de d i n 
Ta ble 8  l ocate d i n secti o n 5. 1. 6. 1  
 
 D ur val u ma b d ose m o dificati o n rec o m me n dati o ns a n d t o xicit y 
ma na ge me nt g ui deli nes f or n o n- i m m u ne-me diate d reacti o ns are detaile d 
i n A p pe n di x C . 
 
 D ur val u ma b d ose m o dificati o n rec o m me n dati o ns a n d t o xicit y 
ma na ge me nt g ui deli nes f or i m m u ne-me diate d reacti o ns are detaile d i n 
A p pe n di x D .  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
1 9 
I n a d diti o n, ma na ge me nt g ui deli nes f or a d verse e ve nts of s pecial i nterest ( A E SIs) 
f or d ur val u ma b are detaile d i n Secti o n  7. 4. 2 . All t o xicities will be gra de d 
acc or di n g t o N CI C T C A E v 4. 0 3 
4. 7  
Tre at me nt wit h A dj u v a nt D ur v al u m a b  i n P art 3  
S u bjects cate g orize d as l o w ris k f oll o wi n g i n d ucti o n t hera p y a n d s ur ger y will be 
treate d wit h a dj u va nt d ur val u ma b (7 5 0 m g ) a d mi nistere d e ver y 2 wee ks f or 3 
c ycles.  T he d ur val u ma b treat me nt will c o m me nce o nce t he s u bject has 
a de q uatel y heale d fr o m s ur ger y; t his will t y picall y ta ke place t w o t o si x wee ks 
f oll o wi n g s ur ger y, b ut will var y b y s u bject.   
 
S u bjects cate g orize d as me di u m or hi g h ris k f oll o wi n g i n d ucti o n t hera p y a n d 
s ur ger y will be treate d wit h a dj u va nt d ur val u ma b (7 5 0 m g ) a d mi nistere d e ver y 2 
wee ks f or 3 c ycles after t he y ha ve c o m plete d c he m ora di ot hera p y.  T he 
d ur val u ma b treat me nt will c o m me nce o nce t he s u bject has a d e q uatel y heale d 
fr o m s ur ger y; t his will t y picall y ta ke place t w o t o si x wee ks f oll o wi n g c o m pleti o n 
of c he m ora di ot hera p y b ut will var y b y s u bject.   
4. 8  
Tre at me nt Bre a ks f or R a di ati o n d uri n g C o nc o mit a nt C he m or a di ati o n 
t her a p y 
T hera p y i nterr u pti o ns will ge nerall y n ot be necessar y  a n d will be a d dresse d per 
sta n dar d of care b y t he treati n g Ra diati o n O nc ol o gist.   
 
Treat me nt brea ks m ust be clearl y i n dicate d i n t he treat me nt rec or d.   
 
If ra diati o n t hera p y is dela ye d, t he n c he m ot hera p y s h o ul d als o be dela ye d t o 
re mai n i n s y nc hr o nizati o n wit h ra diati o n per sta n dar d of care.   
4. 9  
D osi n g Del a ys/ D ose M o dific ati o ns f or C he m ot her a p y d uri n g C o nc o mit a nt 
C he m or a di ot her a p y (see Secti o n  4. 6 ) 
S u bjects ma y be gi n Part 3 c he m ora di ot hera p y ( me di u m a n d hi g h -ris k s u bjects, 
see Sc he ma i n secti o n 4. 2 ) pr o vi de d t he y are still c o nsi dere d a p pr o priate 
ca n di dates f or t his t h era p y as per sta n dar d of care as deter mi ne d b y a gree me nt 
bet wee n t he s ur gical, me dical a n d ra diati o n o nc ol o gists. If t he s u bject n o l o n ger 
meets t he sta n dar d of care criteria f or a partic ular a ge nt (e. g. hi g h d ose cis plati n), 
t he n care ma y be o pti mize d f or t he i n di vi d ual s u bject.   
 
F or d ur val u ma b , please refer t o t he d ose m o dificati o ns/ s u p p orti ve g ui deli nes 
l ocate d i n A p pe n di ces C  a n d D  of t his pr ot oc ol. F or car b o plati n (if t his is 
s u bstit ute d f or cis plati n i n me di u m ris k s u bjects), t he t o xicities of car b o plati n are 
well esta blis he d a n d i ncl u de m yel os u p pressi o n, na usea a n d v o miti n g, peri p heral 
ne ur o pat h y, a n d ele vati o ns i n li ver f u ncti o n tes ts.  T he t o xicities are well 
d oc u me nte d a n d t olera ble.  I n vesti gat ors will d ose m o dif y car b o plati n d uri n g 
c o nc o mita nt c he m ora di ot hera p y as per sta n dar d of care.    
 
F or hi g h- ris k s u bjects, please refer t o t he d ose m o dificati o ns/ s u p p orti ve 
g ui deli nes l ocate d i n A p pe n di x C  a n d A p pe n di x D  f or d ur val u ma b i n t his 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 0 
pr ot oc ol. F or cis plati n  t he t o xicities of cis plati n are well esta blis he d, a n d i ncl u de 
na usea a n d v o miti n g, ris k of ki d ne y fail ure, peri p heral ne ur o pat h y, heari n g l oss 
a n d fe brile ne utr o pe nia.  T he cis plati n d ose of 1 0 0 m g/ m 2 has bee n e xte nsi vel y 
st u die d i n l u n g ca ncer a n d hea d a n d nec k ca ncer, wit h a n d wit h o ut ra di ot hera p y.  
T he t o xicities, i ncl u di n g t he pre dicta ble i ncrease s of t he ra di ot hera p y l ocal 
t o xicities, are well d oc u me nte d a n d t olera ble. I n vesti gat ors will d ose m o dif y 
cis plati n d uri n g c o nc o mita nt c he m ora di ot hera p y as per sta n dar d of care.   
4. 1 0  
C o nc o mit a nt Me dic ati o ns/ Tre at me nts  
S u bjects will be i nstr ucte d n ot t o ta ke a n y a d diti o nal me dicati o ns (i ncl u di n g o ver-
t he-c o u nter pr o d ucts) d uri n g t he c o urse of t he st u d y wit h o ut pri or c o ns ultati o n 
wit h t he i n ve sti gat or.  At eac h visit, t he i n vesti gat or will as k t he s u bject a b o ut a n y 
ne w me dicati o ns he/s he is or has ta ke n after t he start of t he st u d y dr u g.  
 
I n vesti gat ors ma y prescri be c o nc o mita nt me dicati o ns or treat me nts (e. g., 
aceta mi n o p he n, di p he n h y dra mi ne) d ee me d necessar y t o pr o vi de a de q uate 
pr o p h ylactic or s u p p orti ve care (i ncl u di n g a nti bi otics, n utriti o nal s u p p ort, gr o wt h 
fact or s u p p ort (see secti o n 4. 6. 1. 1  a b o ve), meta b olic dis or der c orrecti o ns, o pti mal 
s y m pt o m c o ntr ol, a n d pai n ma na ge me nt). 
4. 1 1  
Pr o hi bite d Me dic ati o ns  
T he f oll o wi n g me dicati o ns are c o nsi dere d e xcl usi o nar y d uri n g t he st u d y: 
 
•  
T he use of a n y ot her i n vesti gati o nal a ge nt(s) or ot her a nti -ca ncer a ge nts 
ot her t ha n t h ose o utli ne d i n t he pr ot oc ol is pr o hi bite d f or s u bjects w hile o n 
st u d y.  
 
•  
A n y c o nc urre nt c he m ot hera p y, ra di ot hera p y (e xce pt palliati ve 
ra di ot hera p y), i m m u n ot hera p y, bi ol o gic or h or m o nal t hera p y f or ca ncer 
treat me nt, ot her t ha n a n y state d c o m parat or or c o m bi nati o n re gi me ns 
C o nc urre nt use of h or m o nes f or n o nca ncer-relate d c o n diti o ns (e. g., i ns uli n 
f or dia betes a n d h or m o ne re place me nt t hera p y) is acce pta ble.  
 
•  
 I m m u n os u p pressi ve me dicati o ns i ncl u di n g, b ut n ot li mite d t o s yste mic 
c ortic oster oi ds at d oses e xcee di n g 1 0 m g/ da y of pre d nis o ne or e q ui vale nt, 
met h otre xate, azat hi o pri ne, a n d T N F- α bl oc kers. Use of 
i m m u n os u p pressi ve me dicati o ns f or t he ma na ge me nt of i n vesti gati o nal 
pr o d uct- relate d A Es or i n s u bjects wit h c o ntrast aller gies is acce pta ble. I n 
a d diti o n, use of i n hale d a n d i ntra nasal c ortic oster oi ds is per mitte d. A 
te m p orar y peri o d of ster oi ds will be all o we d f or differe nt i n dicati o ns, at 
t he discreti o n of t he pri nci pal i n vesti gat or (e. g., c hr o nic o bstr ucti ve 
p ul m o nar y disease, ra diati o n, na usea, etc).    
 
•  
Li ve atte n uate d vacci nes wit hi n 3 0 da ys of d ur val u ma b d osi n g (ie, 3 0 da ys 
pri or t o t he first d ose, d uri n g treat me nt wit h d ur val u ma b a n d f or 3 0 da ys 
p ost disc o nti n uati o n of d ur val u ma b.  I nacti vate d vacci nes, s uc h as t he 
i njecta ble i nfl ue nza vacci ne, are per mitte d. [ N O T E:  If a vacci ne is part of 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 1 
t he treat me nt re gi me n f or t he i n dicati o n u n der st u d y, t he vacci ne is 
per mitte d].  
 
•  
Her bal a n d nat ural re me dies s h o ul d be a v oi de d d uri n g t he st u d y. 
 
4. 1 2  
Me dic ati o ns t o be use d wit h C a uti o n  
I n vesti gat ors, at t heir discreti o n, ma y a d mi nister c o nc o mita nt me dicati o ns fr o m 
t he cate g ories bel o w (see A p pe n di x B:  S u bject Ha n d o ut re gar di n g Dr u g 
I nteracti o ns) t o s u bjects e nr olle d i n L C C C 1 6 2 1. S u bjects recei vi n g s uc h 
me dicati o ns m ust be caref ull y m o nit ore d f or p ote ntiati o n of t o xicit y d ue t o a n y 
i n di vi d ual c o nc o mita nt me dicati o n a n d ma y re q uire d ose m o dificati o ns.   
 
Use ca uti o n w he n c o nc o mita ntl y a d mi nisteri n g na b -paclita xel wit h i n hi bit ors (e. g. 
ket oc o naz ole a n d ot her i mi daz ole a ntif u n gals, er yt hr o m yci n, fl u o xeti ne, 
ge mfi br ozil, ci meti di ne, rita n o vir, sa q ui na vir, i n di na vir, a n d nelfi na vir) or 
i n d ucers (e. g. rifa m pici n, car ba maze pi ne, p he n yt oi n, efa vire nz, a n d ne vira pi ne) of 
eit her C Y P 2 C 8 or C Y P 3 A 4. A c o m plete list is a vaila ble at 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n- ta ble 
 
T he re nal effects of ne p hr ot o xic c o m p o u n ds ma y be p ote ntiate d b y car b o plati n. 
Cis plati n pr o d uces c u m ulati ve ne p hr ot o xicit y w hic h is p ote ntiate d b y 
a mi n o gl yc osi de a nti bi otics. T he ser u m creati ni ne, bl o o d urea nitr o ge n ( B U N), 
creati ni ne cleara nce, a n d ma g nesi u m, s o di u m, p otassi u m, a n d calci u m le vels 
s h o ul d be meas ure d pri or t o i nitiati n g t hera p y a n d pri or t o eac h s u bse q ue nt 
c o urse.  Dr u gs t hat ca n i n d uce ne p hr ot o xicit y s h o ul d be a v oi de d or use d wit h 
ca uti o n i n c o m bi nati o n wit h cis plati n. A list of dr u gs t hat ca use ne p hr ot o xicit y 
ca n be f o u n d i n Na u g ht o n C A, et al., A m Fa m P h ysicia n, 2 0 0 8; 7 8( 6): 7 4 3- 7 5 0 
[3 4 ]. 
 
Peri p heral bl o o d c o u nts s h o ul d be m o nit ore d wee kl y. Li ver f u ncti o n s h o ul d be 
m o nit ore d peri o dicall y. Ne ur ol o gic e xa ms s h o ul d be perf or me d o n a re g ular basis. 
 
Plas ma le vels of a ntic o n v ulsa nt a ge nts ma y bec o me s u b -t hera pe utic d uri n g 
cis plati n t hera p y. I n a ra n d o mize d trial i n a d va nce d o varia n ca ncer, res p o nse 
d urati o n was a d versel y affecte d w he n p yri d o xi ne was use d i n c o m bi nati o n wit h 
altreta mi ne ( he xa met h yl mela mi ne) a n d cis plati n.  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 2 
4. 1 3  
C o ntr ace pti o n 
T he f oll o wi n g restricti o ns a p pl y w hile t he s u bject is recei vi n g st u d y treat me nt a n d 
f or t he s pecifie d ti mes bef ore a n d after: 
 
1.  Fe male s u bjects of c hil d beari n g p ote ntial w h o are se x uall y acti ve wit h a 
n o n- sterilize d male part ner m ust use at least o ne hi g hl y effecti ve met h o d of 
c o ntrace pti o n ( Ta ble 6 ) fr o m t he ti me of scree ni n g a n d m ust a gree t o c o nti n ue 
usi n g s uc h preca uti o ns f or 9 0 da ys after t he last d ose of i n vesti gati o nal 
pr o d uct. Male part ners of a fe male s u bject m ust use male c o n d o m pl us 
s per mici de t hr o u g h o ut t his peri o d. Cessati o n of birt h c o ntr ol after t his p oi nt 
s h o ul d be disc usse d wit h a res p o nsi ble p h ysicia n. N ot e n ga gi n g i n se x ual 
acti vit y f or t he t otal d urati o n of t he trial a n d t he dr u g was h o ut peri o d is a n 
acce pta ble practice; h o we ver, occasi o nal a bsti ne nce, t he r h yt h m met h o d, a n d 
t he wit h dra wal met h o d are n ot acce pta ble met h o ds of c o ntrace pti on. Fe male 
s u bjects s h o ul d refrai n fr o m breastfee di n g t hr o u g h o ut t his peri o d.   
2.  N o n -sterilize d male s u bjects w h o are se x uall y acti ve wit h a fe male part ner of 
c hil d beari n g p ote ntial m ust use male c o n d o m pl us s per mici de fr o m scree ni n g 
t hr o u g h 6 m o nt hs after t he last d ose of i n vesti gati o nal pr o d uct. N ot e n ga gi n g i n 
se x ual acti vit y f or t he t otal d urati o n of t he trial a n d t he dr u g was h o ut peri o d is 
a n acce pta ble practice; h o we ver, occasi o nal a bsti ne nce, t he r h yt h m met h o d, 
a n d t he wit h dra wal met h o d are n ot acce pta ble met h o ds of c o ntrace pti o n. Male 
s u bjects s h o ul d refrai n fr o m s per m d o nati o n t hr o u g h o ut t his peri o d. Fe male 
part ners of a male s u bject m ust use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
t hr o u g h o ut t his peri o d. 
3.  Fe males of c hil d beari n g p ote ntial are defi ne d as t h ose w h o are n ot s ur gicall y 
sterile (i.e., bilateral t u bal li gati o n, bilateral o o p h orect o m y, or c o m plete 
h ysterect o m y) or p ost- me n o pa usal ( defi ne d as 1 2 m o nt hs wit h n o me nses 
wit h o ut a n alter nati ve me dical ca use).  
4.  Hi g hl y effecti ve met h o ds of c o ntrace pti o n are descri be d i n Ta ble 6 . A hi g hl y 
effecti ve met h o d of c o ntrace pti o n is defi ne d as o ne t hat res ults i n a l o w fail ure 
rate (i.e. less t ha n 1 % per year) w he n use d c o nsiste ntl y a n d c orrectl y. N ote t hat 
s o me c o ntrace pti o n met ho ds are n ot c o nsi dere d hi g hl y effecti ve (e. g. male or 
fe male c o n d o m wit h or wit h o ut s per mici de; fe male ca p, dia p hra g m, or s p o n ge 
wit h or wit h o ut s per mici de; n o n-c o p per c o ntai ni n g i ntra uteri ne de vice; 
pr o gest o ge n- o nl y oral h or m o nal c o ntrace pti ve pills w here  i n hi biti o n of 
o v ulati o n is n ot t he pri mar y m o de of acti o n [e xcl u di n g Cerazette/ des o gestrel 
w hic h is c o nsi dere d hi g hl y effecti ve]; a n d tri p hasic c o m bi ne d oral 
c o ntrace pti ve pills).  
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 3 
T a ble 6 . Hi g hl y Effecti vea Met h o ds of C o ntr ace pti o n  
B arrier/I ntr a uteri ne 
Met h o ds  
H or m o n al Met h o ds  
•  
C o p per T 
i ntra uteri ne 
de vice  
•  
Le v o n or gesterel -
releasi n g 
i ntra uteri ne 
s yste m (e g, 
Mire na
® )b 
• 
“I m pla nts”: Et o n o gestrel -releasi n g i m pla nts: e. g. 
I m pla n o n®  or N or pla n ®  
• 
“I ntra va gi nal De vices”: 
Et hi n ylestra di ol/et o n o gestrel -releasi n g 
i ntra va gi nal de vices: e. g. N u va Ri n g®    
• 
“I njecti o n”: Me dr o x y pr o gester o ne i njecti o n: e. g. 
De p o -Pr o vera ®   
• 
“ C o m bi ne d Pill”: N or mal a n d l o w d ose 
c o m bi ne d oral c o ntrace pti ve pill  
• 
“ Patc h”: N orel gest r o mi n/et hi n ylestra di ol-
releasi n g tra ns der mal s yste m: e. g. Ort h o E vra®    
• 
“ Mi ni pill c”: Pr o gester o ne base d oral 
c o ntrace pti ve pill usi n g des o gestrel   e. g. 
Cerazette ®   
a 
Hi g hl y effecti ve (i.e. fail ure rate of < 1 % per year)  
b 
T his is als o c o nsi dere d a h or m o nal met h o d  
c 
Cerazette ®  is c urre ntl y t he o nl y hi g hl y effecti ve pr o gester o ne base d pill 
Bl o o d d o n ati o n 
S u bjects s h o ul d n ot d o nate bl o o d w hil e partici pati n g i n t his st u d y, or f or at least 
9 0 da ys f oll o wi n g t h e last i nf usi o n of d ur val u ma b . 
4. 1 4  
D ur ati o n of T her a p y  
I n t he a bse nce of treat me nt dela ys d ue t o a d verse e ve nts, i n d ucti o n t hera p y will 
c o nti n ue f or a peri o d of 9 wee ks c o ncl u di n g wit h t he fi nal d ose of d ur val u ma b 
a d mi nistere d o n D 1 of wee k 9 of i n d ucti o n t hera p y, f oll o we d b y s ur ger y.  T he 
a d diti o n of p ost- o perati ve c he m ora diati o n will de pe n d o n t he ris k cate g or y, wit h a 
d urati o n var yi n g fr o m 0 t o a p pr o xi matel y 7 wee ks ( or per sta n dar d of care) 
f oll o we d b y d ur val u ma b ad mi nistere d e ver y 2 wee ks f or 3 c ycles ( 6 wee ks) 
u nless t he f oll o wi n g occ urs t hat w o ul d lea d t o per ma ne n t disc o nti n uati o n fr o m t he 
st u d y me dicati o n: 
•  Wit h dra wal of c o nse nt or l ost t o f oll o w u p  
•  I nter-c urre nt ill ness t hat pre ve nts f urt her a d mi nistrati o n of tr eat me nt 
•  U nacce pta ble a d verse e ve nt(s)  or a d verse e ve nt t hat i n t he o pi ni o n of 
t he i n vesti gat or or s p o ns or, c o ntrai n dicates f urt her d osi n g 
•  S u bject deci des t o wit h dra w fr o m t he st u d y, or  
•  Ge neral or s pecific c ha n ges i n t he s u bject’s  c o n diti o n re n der t he 
s u bject u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he 
i n vesti gat or. 
•  N o n- c o m plia nce b y t he s u bject t o pr ot oc ol ma n date d pr oce d ures i n a 
ma n ner t hat c o m pr o mises data i nte grit y or s u bject safet y  
•  Pre g na nc y  
•  Gra de ≥3 i nf usi o n reacti o n 
•  I nitiati o n of alternati ve a ntica ncer t hera p y n ot all o we d b y t his pr ot oc ol 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 4 
•  Re m o val fr o m st u d y b y i n vesti gat or deter mi nati o n t hat s u bject is n o 
l o n ger be nefitti n g fr o m st u d y t hera p y 
4. 1 5  
D ur ati o n of F oll o w U p 
S u bjects will be f oll o we d i n cli nic 8- 1 2 wee ks after treat me nt disc o nti n uati o n, 
wit h s u bse q ue nt f oll o w- u p visits e ver y 3 m o nt hs t hereafter per sta n dar d of care 
( S O C). S O C t y picall y i ncl u des p h ysical e xa m of nec k a n d pri mar y site a n d/ or 
i ma gi n g of t hese areas e ver y 3 m o nt hs f or at least 2 years wit h d oc u me ntati o n i n 
t he case re p ort f or m ( C R F) li mite d t o pr o gressi o n a n d s ur vi val n ote d at t heir S O C 
M D visits  f or at least 5 years. S u bjects re m o ve d fr o m st u d y treat me nt f or 
u nacce pta ble A Es will be f oll o we d u ntil res ol uti o n or sta bilizati o n of  t he A E.    
4. 1 6  
Re m o v al of S u bjects  fr o m Pr ot oc ol T her a p y 
S u bjects will be re m o ve d fr o m st u d y w he n a n y of t he criteria liste d i n Secti o n 
4. 1 4  a p pl y. N otif y t he Pri nci pal I n vesti gat or a n d d oc u me nt t he reas o n f or st u d y 
re m o val a n d t he date t he s u bject was re m o ve d o n t he electr o nic case re p ort for m 
(e C R F). T he s u bject s h o ul d be f oll o we d u p per pr ot oc ol.     
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 5 
5. 0  
D R U G I N F O R M A TI O N  
5. 1  
D ur v al u m a b 
5. 1. 1  S u p plier/ H o w S u p plie d  
D ur val u ma b will be s u p plie d b y Astra Ze neca i n si n gle- use vials. Eac h vial will be 
s u p plie d t o t he i n vesti gat or as a li q ui d s ol uti o n c o ntai ni n g 5 0 0 m g ( n o mi nal) of 
d ur val u ma b at a c o nce ntrati o n of 5 0 m g/ m L a n d will als o i ncl u de 2 6 m M 
histi di ne/ histi di ne h y d r oc hl ori de, 2 7 5 m M tre hal ose di h y drate, a n d 0. 0 2 % 
( wei g ht/ v ol u me) p ol ys or bate 8 0; it has a p H of 6. 0. T he n o mi nal fill v ol u me is 1 0 
m L.  
T he i n vesti gat or or desi g nee is res p o nsi ble f or ta ki n g a n i n ve nt or y of eac h s hi p me nt 
of d ur val u ma b recei ve d a n d c o m pari n g it wit h t he c orres p o n di n g pac ki n g list. T he 
i n vesti gat or or desi g nee will verif y t he acc urac y of t he i nf or mati o n a n d c o nfir m 
s hi p me nt recei pt or n ote l ost or da ma ge d s hi p me nt. 
5. 1. 2  Pre p ar ati o n of I nf usi o n S ol uti o n  
T he d ose of d ur val u ma b f or a d mi nistrati o n m ust be pre pare d b y trai ne d pers o n nel 
u n der ase ptic c o n diti o ns. Vials m ust be use d f or s pecific s u bjects a n d m ust n ot be 
s hare d bet wee n s u bjects.  
1.  2 vials are nee de d t o ac hie ve 7 5 0 m g d ose ( 5 0 0 m g/ vial, 5 0 m L).  
2.  I ns pect vis uall y f or a n y partic ulate matter a nd disc ol orati o n pri or t o d ose 
pre parati o n.  
3.  D ur val u ma b vials ma y be ge ntl y i n verte d f or mi xi n g b ut m ust n ot be s ha ke n  
4.  1 5 m L d ur val u ma b ( 7 5 0 m g d ur val u ma b) will be a d de d t o I V i nf usi o n ba gs of n or mal 
sali ne ( 0. 9 % [ w/ v] s o di u m c hl ori de i njecti o n, 2 5 0 m L size or 5 % ( w/ v) de xtr ose , 2 5 0 
m L size,  f oll o we d b y mi xi n g b y ge ntle i n versi o n t o e ns ure h o m o ge neit y of t he 
s ol uti o n. Fi nal i n- ba g c o nce ntrati o n s h o ul d be wit hi n 1 – 2 0 m g/ m L. Sali ne ba gs 
m ust be late x -free a n d ca n be ma de of p ol y pr o p yle ne, p ol yet h yle ne, p ol y olefi n 
c o p ol y mers, or p ol y vi n yl c hl ori de.  
5.  F oll o wi n g pre parati o n of t he d ose, t he e ntire c o nte nts of t he I V ba g m ust be 
a d mi nistere d.  
6.  Fl us h t he I V li ne wit h a v ol u me of dil ue nt e q ual t o t he pri mi n g v ol u me of t he 
i nf usi o n set use d after t he c o nte nts of t he I V ba g are f ull y a d mi nistere d or c o m plete 
t he i nf usi o n acc or di n g t o t he i nstit uti o nal p olic y t o e ns ure t he f ull d ose is 
a d mi nistere d. If t he li ne was n ot fl us he d, t his m ust be d oc u me nte d.  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 6 
5. 1. 3  St or a ge a n d H a n dli n g  
At t he st u d y site, all d ur val u ma b recei ve d will be st ore d acc or di n g t o t he st ora ge 
c o n diti o ns descri be d o n t he pac ka gi n g la bel. I n vesti gati o nal pr o d uct m ust be 
st ore d at c o ntr olle d te m perat ure a n d a te m perat ure l o g m ust be mai ntai ne d at t he 
site. I n case of a te m perat ure e xc ursio n, s uc h a n e xc ursi o n m ust be d oc u me nte d 
o n t he te m perat ure e xc ursi o n l o g a n d t he site m ust n otif y Astra Ze neca 
i m me diatel y. I n a d diti o n, all I Ps m ust be st ore d i n a sec ure d/l oc ke d area t o 
pre ve nt u na ut h orize d access. If a site is partici pati n g i n m ore t ha n o ne 
Astra Ze neca st u d y, clearl y se parate/ i de ntif y s u p plies fr o m ot her st u dies.  
Sites s h o ul d f oll o w sta n dar d a n d l ocal ase ptic pr oce d ures a n d i nstr ucti o ns f or all 
acti vities. All dis pe nsi n g acti vities s h o ul d be d oc u me nte d acc or di n g t o l ocal 
pr oce d ures. 
D ur val u ma b m ust be use d wit hi n t he i n di vi d uall y assi g ne d e x pir y date o n t he 
pr o d uct la bel.  
5. 1. 4  St a bilit y  
T otal i n -use st ora ge ti me fr o m nee dle p u nct ure of t he d ur val u ma b vial t o start of 
a d mi nistrati o n m ust n ot e xcee d 4 h o urs at r o o m te m perat ure or 2 4 h o urs at 2° C t o 
8° C ( 3 6° F t o 4 6° F) as s h o w n i n Ta ble 5 . If i n-use st ora ge ti me e xcee ds t hese 
li mits, a ne w d ose m ust be pre pare d fr o m ne w vials. I nf usi o n s ol uti o ns m ust be 
all o we d t o e q uili brate t o r o o m te m perat ure pri or t o c o m me nce me nt of 
a d mi nistrati o n. D ur val u ma b d oes n ot c o ntai n preser vati ves, t heref ore, a n y u n use d 
p orti o n m ust be discar de d. 
T he s helf li ves state d i n t his d oc u me nt are base d o n c he mical a n d p h ysical 
sta bilit y. Assi g n me nt of micr o bial s helf life is t he res p o nsi bilit y of t he cli nical site 
a n d m ust be ali g ne d wit h l ocal pr oce d ures f or ma na gi n g micr o bial ris k as l o n g as 
t he ti mes s pecifie d i n Ta b le 5 are n ot e xcee de d.  
T a ble 7 . I n-use st a bilit y of dr u g – D ur v al u m a b  
 
 
St or a ge 
Te m p er at ure  
D ur ati o n  
D ur val u ma b 
f or I V 
i nf usi o n 
Vial c o ntai ns 5 0 0 
m g/ vial  
2° C - 8° C ( 3 6° F - 
4 6° F)  
Wit hi n t he 
i n di vi d uall y assi g ne d 
e x pirati o n date o n 
t he la bel 
Pre pare d I V Ba g 
( nee dle p u nct ure of 
vial t o start of 
a d mi nistrati o n)  
R o o m Te m perat ure  
≤ 4 h o urs  
2° C - 8° C ( 3 6° F - 
4 6° F)  
≤ 2 4 h o urs  
 
Pre pare d I V 
Ba g 
( ma xi m u m 
R o o m Te m perat ure  
≤ 8 h o urs  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 7 
ti me f or I V 
ba g i nf usi o n, 
i ncl u di n g 
i nterr u pti o ns) 
I n t he e ve nt t hat eit her pre parati o n ti me or i nf usi o n ti me e xcee ds t he ti me li mits 
o utli ne d a b o ve, a ne w d ose m ust be pre pare d fr o m ne w vials. D ur val u ma b d oes 
n ot c o ntai n preser vati ves, a n d a n y u n use d p orti o n m ust be discar de d.  
5. 1. 5  Met h o d of A d mi nistr ati o n  
Site pers o n nel will re vie w t he d osi n g i nf or mati o n wit h t he s u bject ( or le gall y 
a ut h orize d re prese ntati ve) o n sc he d ule d cli nic visit da ys. Site pers o n nel will 
perf or m a n I P a d mi nistrati o n c o m plia nce c hec k a n d rec or d t his i nf or mati o n i n t he 
s u bject’s s o urce d oc u me ntati o n. A d mi nistrati o n of all I P will be rec or de d 
i ncl u di n g dis pe nsi n g, d osi n g, a n d a n y c ha n ges i n d osa ge a d mi nistrati o n s uc h as 
i nterr upti o n or re d ucti o n i n d osi n g d ue t o a n a d verse e ve nt ( A E). 
S u bjects will recei ve d ur val u ma b, 7 5 0 m g e ver y 2 wee ks ( 1 c ycle = 2 wee ks) b y 
I V i nf usi o n o ver a p pr o xi matel y 1 h o ur ( ± 5 mi n utes). 
•  D ur val u ma b will be gi ve n o n D 1 of Wee ks , 1, 3, 5, 7 a n d 9 as a c o m p o ne nt of 
i n d ucti o n t hera p y  
•  D ur val u ma b will be gi ve n e ver y 2 wee ks X 3 as a dj u va nt t hera p y after s ur gical 
resecti o n.  
o  L o w ris k s u bjects will recei ve d ur val u ma b al o ne 
o  Me di u m a n d hi g h -ris k s u bjects will recei ve t his re gi me n after a dj u va nt 
c he m ora di o t hera p y is c o m plete  
F oll o wi n g pre parati o n of d ur val u ma b, t he e ntire c o nte nts of t he I V ba g s h o ul d be 
a d mi nistere d at r o o m te m perat ure b y c o ntr olle d i nf usi o n via a n i nf usi o n p u m p i nt o a 
peri p heral or ce ntral vei n  o ver a p pr o xi matel y 6 0 mi n utes ( ± 5 mi n utes), usi n g a 0. 2, 
or 0. 2 2- μ m i n -li ne filter. S u bjects will be m o nit ore d d uri n g a n d after t he i nf usi o n at 
t he ti mes s pecifie d i n t he St u d y Pr ot oc ol. I nf usi o ns of d ur val u ma b ma y be 
i nterr u pte d, sl o we d, or disc o nti n ue d i n or der t o a d dress t o xicit y. If t here are 
i nterr u pti o ns d uri n g i nf usi o n, t he t otal all o we d ti me fr o m t he start of i nf usi o n 
u ntil t he e n d of i nf usi o n s h o ul d n ot e xcee d 8 h o urs at r o o m te m perat ure as s h o w n 
i n t he Ta ble 5 . 
A n aller gic reacti o n f oll o wi n g d ose a d mi nistrati o n ma y occ ur. A p pr o priate dr u gs 
a n d me dical e q ui p me nt t o treat ac ute a na p h ylactic reacti o ns m ust be i m me diatel y 
a vaila ble, a n d st u d y pers o n nel m ust be trai ne d t o rec o g nize a n d treat a na p h yla xis. 
T he st u d y sit e m ust ha ve i m me diate access t o e mer ge nc y res uscitati o n tea ms a n d 
e q ui p me nt. T he st u d y site m ust als o ha ve t he a bilit y t o a d mit s u bjects t o a n 
i nte nsi ve care u nit if necessar y.   

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 8 
5. 1. 6  Dr u g Acc o u nt a bilit y  
T he i n vesti gat or is res p o nsi ble f or kee pi n g acc urate rec o r ds of t he cli nical 
s u p plies recei ve d fr o m Astra Ze neca or desi g nee, t he a m o u nt dis pe nse d t o t he 
s u bjects a n d t he a m o u nt re mai ni n g at t he c o ncl usi o n of t he trial.  
Fi nal acc o u nta bilit y ma y be c o n d ucte d pri or t o t he cl ose- o ut visit o nce all s u bjects are 
n o l o n ger usi n g I P. T he i n vesti gat or will e ns ure t hat a fi nal re p ort of dr u g 
acc o u nta bilit y t o t he u nit d ose le vel, ( vial f or d ur val u ma b) is pre pare d a n d place d i n 
b ot h t he i n vesti gat or st u d y file a n d t he ce ntral cli nical st u d y file. 
U p o n c o m pleti o n or ter mi nati o n of t he st u d y, all u n use d a n d/ or partiall y use d 
i n vesti gati o nal pr o d uct will be destr o ye d at t he site per U N C I D S dr u g destr ucti o n 
p olic y ( or ot her site i nstit uti o nal p olic y as a p plica ble). It is t he I n vesti gat or’s 
res p o nsi bilit y t o arra n ge f or dis p osal of all e m pt y c o ntai ners, pr o vi de d t hat 
pr oce d ures f or pr o per dis p osal ha ve bee n esta blis he d acc or di n g t o a p plica ble 
fe deral, state, l ocal a n d i nstit uti o nal g ui deli nes a n d pr oce d ures, a n d pr o vi de d t hat 
a p pr o priate rec or ds of dis p osal are ke pt.  
5. 1. 6. 1  M o nit ori n g of d ose a d mi nistr ati o n f or i nf usi o n -rel ate d re acti o ns  
S u bjects will be m o nit ore d bef ore, d uri n g a n d after t he i nf usi o n wit h assess me nt 
of vital si g ns. S u bjects are m o nit ore d ( p ulse rate, bl o o d press ure) e ver y 3 0 
mi n utes d uri n g t he i nf usi o n peri o d (i ncl u di n g ti mes w here i nf usi o n rate is sl o we d 
or te m p oraril y st o p pe d).  
 
•  
I n t he e ve nt of a Gra de ≤2 i nf usi o n -relate d reacti o n, t he i nf usi o n rate of 
st u d y dr u g ma y be decrease d b y 5 0 % or i nterr u pte d u ntil res ol uti o n of t he 
e ve nt ( u p t o 4 h o urs) a n d re- i nitiate d at 50 % of t he i nitial rate u ntil 
c o m pleti o n of t he i nf usi o n.    
•  
F or s u bjects wit h a Gra de ≤2 i nf usi o n- relate d reacti o n, s u bse q ue nt 
i nf usi o ns ma y be a d mi nistere d at 5 0 % of t he i nitial rate. Aceta mi n o p he n 
a n d/ or a n a nti hista mi ne (e. g., di p he n h y dra mi ne) or e q ui val e nt me dicati o ns 
per i nstit uti o nal sta n dar d ma y be a d mi nistere d at t he discreti o n of t he 
i n vesti gat or.  
•  
 If t he i nf usi o n-relate d reacti o n is Gra de 3 or hi g her i n se verit y, st u d y dr u g 
will be disc o nti n ue d.   
•  
T he sta n dar d i nf usi o n ti me is o ne h o ur, h o we ver if t here are i nterr u pti o ns 
d uri n g i nf usi o n, t he t otal all o we d ti me fr o m i nf usi o n start t o c o m pleti o n of 
i nf usi o n s h o ul d n ot e xcee d 8 h o urs at r o o m te m perat ure ( ot her wise 
re q uires ne w i nf usi o n pre parati o n).   
 
As wit h a n y a nti b o d y, aller gic reacti o ns t o d ose a d mi nistrati o n are 
p ossi ble. A p pr o priate dr u gs a n d me dical e q ui p me nt t o treat ac ute a na p h ylactic 
reacti o ns m ust be i m me diatel y a vaila ble, a n d st u d y pers o n nel m ust be trai ne d t o 
rec o g nize a n d treat a na p h yla xis. T he st u d y site m ust ha ve i m me diate access t o 
e mer ge nc y res uscitati o n tea ms a n d e q ui p me nt i n a d diti o n t o t he a bilit y t o a d mit 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
2 9 
s u bjects t o a n i nte nsi ve care u nit if necessar y. See Ta ble 6  bel o w f or ma na ge me nt 
g ui deli nes f or i nf usi o n- relate d reacti o ns. 
 
T a ble 8. G ui deli ne f or M a n a ge me nt of I nf usi o n -rel ate d Re acti o ns  ( D ur v al u m a b) 
Se verit y 
Gr a de of t he 
E ve nt ( N CI 
C T C A E 
versi o n  4. 0 3)  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
A n y Gr a de  
Ge neral G ui da nce  
F or A n y Gr a de:  
− 
Ma na ge per i nstit uti o nal sta n dar d at 
t he discreti o n of i n vesti gat or. 
− 
M o nit or s u bjects f or si g ns a n d 
s y m pt o ms of i nf usi o n-relate d 
reacti o ns (e. g., fe ver a n d/ or s ha ki n g 
c hills, fl us hi n g a n d/ or itc hi n g, 
alterati o ns i n heart rate a n d bl o o d 
press ure, d ys p nea or c hest 
disc o mf ort, or s ki n ras hes) a n d 
a na p h yla xis (e g,  ge neralize d 
urticaria, a n gi oe de ma, w heezi n g, 
h y p ote nsi o n, or tac h ycar dia).  
Gr a de 1 or 2  
F or Gr a de 1:  
T he i nf usi o n rate of st u d y 
dr u g/st u d y re gi me n ma y be 
decrease d b y 5 0 % or te m p oraril y 
i nterr u pte d u ntil res ol uti o n of t he 
e ve nt. 
 
F or Gr a de 2:  
T he i nf usi o n rate of st u d y 
dr u g/st u d y re gi me n ma y be 
decrease d 5 0 % or te m p oraril y 
i nterr u pte d u ntil res ol uti o n of t he 
e ve nt. 
S u bse q ue nt i nf us i o ns ma y be 
gi ve n at 5 0 % of t he i nitial 
i nf usi o n rate. 
F or Gr a de 1 or 2:  
− 
Aceta mi n o p he n a n d/ or 
a nti hista mi nes ma y be a d mi nistere d 
per i nstit uti o nal sta n dar d at t he 
discreti o n of t he i n vesti gat or.  
− 
C o nsi der pre me dicati o n per 
i nstit uti o nal sta n dar d pri or t o 
s ubse q ue nt d oses.  
− 
Ster oi ds s h o ul d n ot be use d f or 
r o uti ne pre me dicati o n of Gra de ≤2 
i nf usi o n reacti o ns. 
Gr a de 3 or 4  
F or Gr a de 3 or 4:  
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n.  
F or Gr a de 3 or 4:  
− 
Ma na ge se vere i nf usi o n -relate d 
reacti o ns per i nstit uti o nal sta n dar ds 
(e g, I M e pi ne p hri ne, f oll o we d b y 
I V di p he n h y dra mi ne a n d ra niti di ne, 
a n d I V gl uc oc ortic oi d).  
 
5. 1. 7  A d verse E ve nts Ass oci ate d wit h D ur v al u m a b 
F or a d verse e ve nts ( A Es) t hat are c o nsi dere d p ossi bl y d ue t o a d mi nistrati o n of 
d ur val u ma b, t he f oll o wi n g d ose a dj ust me nt g ui da nce ma y be a p plie d: 
 
• 
Treat eac h of t he t o xicities wit h ma xi m u m s u p p orti ve care (i ncl u di n g 
h ol di n g t he a ge nt s us pecte d of ca usi n g t he t o xicit y w here re q uire d) 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 0 
•  
If t he s y m pt o ms pr o m ptl y res ol ve wit h s u p p ortive care, c o nsi derati o n 
s h o ul d be gi ve n t o c o nti n ui n g t he sa me d ose of d ur val u ma b al o n g wit h 
a p pr o priate c o nti n ui n g s u p p orti ve care  
 
•  
 All d ose m o dificati o ns s h o ul d be d oc u me nte d wit h clear reas o ni n g a n d 
d oc u me ntati o n of t he a p pr oac h ta ke n 
 
 
A E SIs o bser ve d wit h d ur val u ma b i ncl u de: 
• 
Diarr hea / C olitis a n d i ntesti nal perf orati o n  
• 
P ne u m o nitis / I L D  
• 
he patitis / tra nsa mi nase i ncreases  
•  
E n d ocri n o pat hies (i.e. e ve nts of h y p o p h ysitis/ h y p o pit uitaris m, t h yr oi ditis, 
a dre nal i ns ufficie nc y, h y per- a n d h y p ot h yr oi di s m a n d t y pe I dia betes mellit us) 
• 
Ras h / Der matitis  
• 
Ne p hritis / Bl o o d creati ni ne i ncreases  
• 
Pa ncreatitis / ser u m li pase a n d a m ylase i ncreases   
•  
M y ocar ditis 
•  
M y ositis / P ol y m y ositis 
Ot her i nfla m mat or y res p o nses t hat are rare/less fre q ue nt wit h a p ote ntial i m m u ne -
me diate d eti ol o g y i ncl u de, b ut are n ot li mite d t o: 
• 
Pericar ditis  
• 
Ne ur o m usc ular t o xicities (s uc h as G uillai n -Barre s y n dr o me a n d 
m yast he nia gra vis)  
•  
Sarc oi d osis 
• 
U veitis  
•  
Ot her e ve nts i n v ol vi n g t he e ye a n d s ki n 
• 
He mat ol o gical e ve nts  
• 
R he u mat ol o gical e ve nts  
• 
Vasc ulitis  
• 
N o n -i nfecti o us me ni n gitis 
• 
N o n -i nfecti o us e nce p halitis.  
 
It is p ossi ble t hat e ve nts wit h a n i nfla m mat or y or i m m u ne me diate d mec ha nis m 
c o ul d occ ur i n nearl y all or ga ns. 
 
I n a d diti o n, i nf usi o n-relate d reacti o ns a n d h y perse nsiti vit y/a na p h ylactic reacti o ns 
wit h a differe nt u n derl yi n g p har mac ol o gical eti ol o g y are als o c o nsi dere d A E SIs. 
F urt her i nf or mati o n o n t hese ris ks (e. g. prese nti n g s y m pt o ms) ca n be f o u n d i n t he 
c urre nt versi o n of t he d ur val u ma b I n vesti gat or’s Br oc h ure.  
 
M ore s pecific g ui deli nes f or t heir e val uati o n a n d treat me nt are descri be d i n detail 
i n t he A p pe n di x C: D ose M o dificati o ns/ T o xicit y Ma na ge me nt f or D ur val u ma b 
( N o n-i m m u ne-me diate d)   a n d A p pe n di x  D:  D ose  M o dificati o ns/ T o xicit y  
Ma na ge me nt  f or  D ur val u ma b  (I m m u ne -relate d).  T hese  g ui deli nes  ha ve  bee n  
pre pare d b y t he S p o ns or t o assist t he I n vesti gat or i n t he e xercise of his/ her cli nical 
j u d g me nt  i n treati n g t hese t y pes of  t o xicities.  T hese g ui deli nes a p pl y t o Aes 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 1 
c o nsi dere d  ca usall y  relate d  t o  t he  st u d y  dr u g/st u d y  re gi me n  b y  t he  re p orti n g  
i n vesti gat or. 
 
I n a d diti o n, t here are certai n circ u msta nces i n w hic h d ur val u ma b s h o ul d be 
per ma ne ntl y disc o nti n ue d. 
 
Base d o n t he mec ha nis m of acti o n of d ur val u ma b lea di n g t o T- cell acti vati o n a n d 
pr oliferati o n, t here is t he p ossi bilit y of o bser vi n g i m m u ne relate d A d verse E ve nts 
(ir A Es) d uri n g t he c o n d uct of t his st u d y.  P ote ntial ir A Es i ncl u de i m m u ne-
me diate d e nter oc olitis, der matitis, he patitis, a n d e n d ocri n o pat hies. S u bjects 
s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of ir A Es. I n t he a bse nce of a n 
alter nate eti ol o g y (e. g., i nfecti o n or P D) si g ns or s y m pt o ms of e nter oc olitis, 
der matitis, he patitis, a n d e n d ocri n o pat h y s h o ul d be c o nsi dere d t o be i m m u ne-
relate d.  F oll o wi n g t he first d ose of d ur val u ma b, s u bse q ue nt a d mi nistrati o n of 
d ur val u ma b ca n be m o difie d base d o n t o xicities o bser ve d. 
 
D ose m o dificati o n rec o m me n dati o ns a n d t o xicit y ma na ge me nt g ui deli nes f or 
i nf usi o n-relate d reacti o ns are pr o vi de d i n secti o n 5. 1. 6. 1  a b o ve i n Ta ble 8 . 
 
D ose m o dificati o n rec o m me n dati o ns a n d t o xicit y ma na ge me nt g ui deli nes f or n o n-
i m m u ne-me diate d reacti o ns are detaile d i n A p pe n di x C . 
 
D ose m o dificati o n rec o m me n dati o ns a n d t o xicit y ma na ge me nt g ui deli nes f or 
i m m u ne-me diate d reacti o ns are detaile d i n A p pe n di x D .  
 
5. 2  
C ar b o pl ati n  
5. 2. 1  S u p plier  
C o m mercial s u p plies of car b o plati n wil l be use d f or t his st u d y a n d bille d t o 
s u bjects a n d/ or t heir i ns ura nce c o m pa n y. See t he pac ka ge i nsert f or c o m plete 
prescri bi n g i nf or mati o n a vaila ble at f oll o wi n g li n k:  
 htt p:// w w w.sa ge nt p har ma.c o m/ w p-c o nte nt/ u pl oa ds/ 2 0 1 4/ 1 1/ Car b o plati n PI. p df  
5. 2. 2  St or a ge, H a n dli n g a n d Dis p os al 
Car b o plati n s h o ul d be st ore d, ha n dle d a n d dis p ose d per i nstit uti o nal g ui deli nes. 
5. 2. 3  Pre p ar ati o n  
Car b o plati n s h o ul d be pre pare d per i nstit uti o nal g ui deli nes a n d as o utli ne d i n 
secti o n 4. 3. 3 . 
5. 2. 4  A d verse E ve nts Ass oci ate d wit h  C ar b o pl ati n 
I nci de nce rates of a d verse e ve nts ass ociate d wit h car b o plati n are pr o vi de d i n t he 
pr o d uct’s prescri bi n g i nf or mati o n. S o me of t he a d verse e ve nts e x pecte d wit h 
car b o plati n treat me nt are liste d bel o w.  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 2 
He mat ol o gic: M yel os u p pressi o n is t he maj or d ose- li miti n g t o xicit y. 
T hr o m b oc yt o pe nia, ne utr o pe nia, le u k o pe nia, a n d a ne mia are c o m m o n, b ut 
t y picall y res ol ve b y Da y 2 8 w he n car b o plati n is gi ve n as a si n gle a ge nt. 
 
Aller gic reacti o ns : H y perse nsiti vit y t o car b o plati n has bee n re p orte d i n 2 % of 
patie nts recei vi n g t he dr u g. S y m pt o ms i ncl u de ras h, urticaria, er yt he ma, pr urit us, 
a n d rarel y a na p h yla xis wit h br o nc h os pas m a n d h y p ote nsi o n. T he reacti o ns ca n be 
s uccessf ull y ma na ge d wit h sta n dar d e pi ne p hri ne, c ortic oster oi d, a n d a nti hista mi ne 
t hera p y. 
 
Ne ur ol o gic : Peri p heral ne ur o pat hies ha ve bee n o bser ve d i n 4 % of patie nts 
recei vi n g car b o plati n wit h mil d parest hesia bei n g t he m ost c o m m o n. 
 
Gastr oi ntesti nal: Na usea a n d v o miti n g are t he m ost c o m m o n gastr oi ntesti nal  
e ve nts; b ot h us uall y r es ol ve wit hi n 2 4 h o urs a n d res p o n d t o a ntie metics. Ot her 
gastr oi ntesti nal  e ve nts i ncl u de diarr hea, wei g ht l oss, c o nsti pati o n, a n d 
gastr oi ntesti nal pai n.  
 
He patic t o xicit y : Elevate d al kali ne p h os p hatase, t otal bilir u bi n, a n d A S T ha ve 
bee n o bser ve d. 
 
Ot her:  Pai n a n d ast he nia are t he m ost c o m m o n miscella ne o us a d verse e ve nts. 
Al o pecia has bee n re p orte d i n 3 % of t he patie nts ta ki n g car b o plati n. 
 
5. 3  
N a b -P a clit a xel 
5. 3. 1  Dr u g s u p pl y  
Na b - paclita xel will be s u p plie d b y Cel ge ne C or p orati o n a n d la bele d a p pr o priatel y 
as i n vestigati o nal material f or t his st u d y. La bels will bear Cel ge ne’s na me a n d 
a d dress, t he pr ot oc ol n u m ber L C C C 1 6 2 1, pr o d uct na me, d osa ge f or m a n d 
stre n gt h, me dicati o n i de ntificati o n/ kit n u m ber, l ot n u m ber, e x pir y date, d osi n g 
i nstr ucti o ns, st ora ge c o n diti o ns, t he q ua ntit y of I P c o ntai ne d, a n d re q uire d ca uti o n 
state me nts a n d/ or re g ulat or y state me nts as a p plica ble. N o s u p plies will be s hi p pe d 
t o a n y site u ntil re g ulat or y a p pr o val has bee n o btai ne d. I n vesti gati o nal sites will 
be s u p plie d wit h Na b- paclita xel u p o n i de ntificati o n a n d scree ni n g of a p ote ntial 
trial s u bject.  
Eac h si n gle- use vial c o ntai ns 1 0 0 m g of paclita xel a n d a p pr o xi matel y 9 0 0 m g of 
h u ma n al b u mi n. Eac h milliliter ( m L) of rec o nstit ute d s us pe nsi o n c o ntai ns 5 m g 
paclita xel.  
5. 3. 2  Pre p ar ati o n of I nf usi o n S ol uti o n  
Please see l ocal prescri bi n g i nf or mati o n f or na b -paclita xel ( 1 0 0 m g/ m 2) f or 
detaile d i nstr ucti o ns o n t he rec o nstit uti o n a n d a d mi nistrati o n.  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 3 
5. 3. 3  S peci al H a n dli n g I nstr ucti o ns  
Na b -Paclita xel is a c yt ot o xic a ntica ncer dr u g a n d, as wit h ot her p ote ntiall y t o xic 
paclita xel c o m p o u n ds, ca uti o n s h o ul d be e xercise d i n ha n dli n g na b- paclita xel.  
T he use of gl o ves is rec o m me n de d. If na b - paclita xel (l y o p hilize d ca ke or 
rec o nstit ute d s us pe nsi o n) c o ntacts t he s ki n, was h t he s ki n i m me diatel y a n d 
t h or o u g hl y wit h s oa p a n d water. F oll o wi n g t o pical e x p os ure t o na b- paclita xel, 
e ve nts ma y i ncl u de ti n gli n g, b ur ni n g a n d re d ness. If na b- paclita xel c o ntacts 
m uc o us me m bra nes, t he me m bra nes s h o ul d be fl us he d t h or o u g hl y wit h water.  
5. 3. 4  St or a ge a n d H a n dli n g  
At t he st u d y site, all na b -paclita xel recei ve d will be st ore d acc or di n g t o t he 
st ora ge c o n diti o ns descri be d o n t he pac ka gi n g la bel. I n vesti gati o nal pr o d uct m ust 
be st ore d at c o ntr olle d te m perat ure a n d a te m pe rat ure l o g m ust be mai ntai ne d at 
t he site. I n case of a te m perat ure e xc ursi o n, s uc h a n e xc ursi o n m ust be 
d oc u me nte d o n t he te m perat ure e xc ursi o n l o g a n d t he site m ust n otif y Cel ge ne 
i m me diatel y. I n a d diti o n, all I Ps m ust be st ore d i n a sec ure d/l oc ke d area t o 
pre ve nt u na ut h orize d access. If a site is partici pati n g i n m ore t ha n o ne Cel ge ne 
st u d y, clearl y se parate/ i de ntif y s u p plies fr o m ot her st u dies. 
5. 3. 5  Met h o d of A d mi nistr ati o n  
Na b -paclita xel is i njecte d i nt o a vei n via i ntra ve n o us (I. V.) i nf usi o n o ver 3 0 
mi n ut es. T he use of a n i n -li ne filter is n ot rec o m me n de d. F oll o wi n g 
a d mi nistrati o n, t he i ntra ve n o us li ne s h o ul d be fl us he d wit h s o di u m c hl ori de 9 
m g/ ml ( 0. 9 %) s ol uti o n f or i njecti o n t o e ns ure c o m plete a d mi nistrati o n of t he 
c o m plete d ose, acc or di n g t o l ocal prac tice. 
5. 3. 6  Dr u g Or deri n g a n d Acc o u nt a bilit y  
U p o n i de ntificati o n of a p ote ntial s u bject, sites m ust or der na b- paclita xel. T he site 
s h o ul d or der na b- paclita xel t hr o u g h t he E n d p oi nt (I D O S) o nli ne dr u g or deri n g 
s yste m. All o w 5 w or ki n g da ys f or dr u g s hi p me nt a n d n ote t here are n o dr u g 
s hi p me nts o n Fri da ys a n d h oli da ys. 
T he I n vesti gat or or desi g nee is res p o nsi ble f or ta ki n g a n i n ve nt or y of eac h 
s hi p me nt of st u d y dr u g recei ve d a n d c o m pari n g it wit h t he acc o m pa n yi n g st u d y 
dr u g acc o u nta bilit y f or m. T he I n vesti gat or will verif y t he acc urac y of t he 
i nf or mati o n o n t he f or m, si g n a n d date it, retai n a c o p y i n t he st u d y file, a n d ret ur n 
a c o p y t o Cel ge ne or its re prese ntati ve.   
5. 3. 7  Ret ur n a n d Rete nti o n of St u d y Dr u g  
Cel ge ne will i nstr uct t he I n vesti gat or o n t he ret ur n or destr uc ti o n of u n use d st u d y 
dr u g. If a n y st u d y dr u g is l ost or da ma ge d, its dis p ositi o n s h o ul d be d oc u me nte d 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 4 
i n t he s o urce d oc u me nts. St u d y dr u g s u p plies will be retai ne d at t he cli nical site 
pe n di n g i nstr ucti o ns f or dis p ositi o n b y Cel ge ne. 
5. 3. 8  A d verse E ve nts Ass oci a te d wit h N a b - paclit a xel  
T he m ost c o m m o n t o xicities ass ociate d wit h na b- paclita xel f or metastatic breast 
ca ncer ( ≥ 2 0 %) i ncl u de al o pecia, ne utr o pe nia, se ns or y ne ur o pat h y, a b n or mal 
E C G, fati g ue/ast he nia, m yal gia/art hral gia, A S T ele vati o n, al kali ne ele vati o n, 
a ne mia, na usea, i nfec ti o ns, a n d diarr hea. 
 
T he m ost c o m m o n A Es ( ≥ 2 0 %) f or na b-paclita xel  i n N S C L C are a ne mia, 
ne utr o pe nia, t hr o m b oc yt o pe nia, al o pecia, peri p heral ne ur o pat h y, na usea, a n d 
fati g ue. 
 
T he m ost c o m m o n t o xicities ( ≥ 2 0 %) of na b -paclita xel i n a de n ocarci n o ma of t he 
pa ncreas are ne utr o pe nia, fati g ue, peri p heral ne ur o pat h y, na usea, al o pecia, 
peri p heral e de ma, diarr hea, p yre xia, v o miti n g, decrease d a p petite, ras h a n d 
de h y drati o n.  
5. 4  
Cis pl ati n  
5. 4. 1  S u p plier  
Cis plati n is c o m merciall y a vaila ble a n d a p pr o ve d b y t he U S F o o d a n d Dr u g 
A d mi nistrati o n ( F D A) f or t he treat me nt of a d va nce d bla d der, o varia n a n d 
testic ular ca ncer.  It has bee n wi del y st u die d i n a variet y of s oli d t u m or t y pes.   
C o m mercial s u p plies of cis p lati n will be use d f or t his st u d y a n d bille d t o s u bjects 
a n d/ or t heir i ns ura nce c o m pa n y.  See pac ka ge i nsert f or c o m plete prescri bi n g 
i nf or mati o n a vaila ble at t he f oll o wi n g li n k: 
  htt p:// w w w.access data.f da. g o v/ dr u gsatf da d ocs/la bel/ 2 0 1 5/ 0 1 8 0 5 7s 0 8 3l bl. p df  
5. 4. 2  St or a ge, H a n dli n g a n d Dis p os al 
Cis plati n s h o ul d be st ore d, ha n dle d a n d dis p ose d per i nstit uti o nal g ui deli nes. 
5. 4. 3  Pre p ar ati o n  
Cis plati n s h o ul d be pre pare d per i nstit uti o nal g ui deli nes. As state d i n secti o n 
4. 5. 2 , p ost- o perati ve ra diati o n a n d c o nc o mita nt wee kl y cis plati n ( 3 0 m g/ m2) ma y 
be a d mi nistere d t o  me di u m -ris k s u bjects f or u p t o 6 c ycles. 
 
As state d i n secti o n 4. 5. 3  p ost- o perati ve ra diati o n a n d c o nc o mita nt hi g h d ose 
b ol us cis plati n ( 1 0 0 m g/ m 2) ma y  be a d mi nistere d t o hi g h -ris k s u bjects e ver y 3 
wee ks f or u p t o 3 c ycles. 
5. 4. 4  A d verse E ve nts Ass oci ate d wit h Cis pl ati n  
T he t o xicities of cis plati n are well esta blis he d, a n d i ncl u de na usea a n d v o miti n g, 
ris k of ki d ne y fail ure, peri p heral ne ur o pat h y, heari n g l oss a n d fe brile ne utr o pe nia.  
T he cis plati n d ose of 1 0 0 m g/ m 2 has bee n e xte nsi vel y st u die d i n l u n g ca ncer a n d 
hea d a n d nec k ca ncer, wit h a n d wit h o ut ra di ot hera p y.  T he t o xicities, i ncl u di n g 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 5 
t he pre dicta ble i ncrease of t he ra di ot hera p y l ocal t o xicities, are well d oc u me nte d 
a n d t olera ble. 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 6 
6. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  
6. 1  
Ti me a n d E ve nts T a ble  
Pr oce d ure  
Scree n
i n g1 
D 1  
Wee kl y  
visits  
( 1-6) 2 a 
D 1  
Wee k 7  
D 1  
Wee k 9  
1 -4 wee ks 
p ost 
i n d ucti o n3 
S ur gic al 
resecti o n 4 
S O C A dj u v a nt  T X T  
D a y 1 ( +/ -1 d a y) of 
e ac h 
c he m or a di ot her a p y 
c ycle ( or e ver y t hree 
wee ks f or wee kl y 
re gi me ns) 4 
A dj u v a nt 
D ur v al u m a b  
Q 2 wee ks x 3  
Tre at me nt 
Disc o nti n u ati o n 5 
F oll o w -
u p 6 
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X 7 
X 7 
X  
 
X  
 
X 7 
X  
X  
X  
P h ysical E xa m  
X 8 
X  
X  
 
X  
 
X  
X  
X  
X  
E C O G Perf or ma nce stat us  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
Wei g ht  
X  
X  
X  
 
X  
 
X  
X  
X  
X  
C B C w it h differe ntial  
X  
X  
 
X  
 
 
X  
 
X  
 
Ser u m c he mistries 9 
X  
X  
X  
X  
 
 
X 8 
X  
X  
 
Calc ulate d Cr Cl 1 1 
X  
X  
 
 
 
 
X 1 1 
X  
 
 
T S H  
 
X 1 5  
 
X  
 
 
 
X 1 6  
 
 
Ser u m pre g na nc y test  
X 1 2 
 
 
 
 
 
 
 
 
 
T u m or e val uati o n 1 3 
X  
 
 
 
X  
 
 
 
X  
X  
Bl o o d dra w f or c orrelati ve s1 8  
 
X 1 9  
 
 
X  
 
 
 
X  
 
Arc hi ve d or fres h tiss ue  
X 1, 1 4 
 
 
 
 
X 1 4 
 
 
 
 
T o xicit y assess me nt  
X  
X  
M o nit or t hr o u g h o ut st u d y at eac h cli nic visit  
X 1 7 
X 1 7 
Car b o plati n  
 
X 2 b  
 
 
 
 
 
 
 
 
Na b -p aclita xel 
 
X 2 b  
 
 
 
 
 
 
 
 
D ur val u ma b (p ulse a n d B P) 2 d 
 
X 2 b , d 
X  
X  
 
 
 
X 2 c, d 
 
 
Ra diati o n  
 
 
 
 
 
 
X 4 
 
 
 
Cis plati n  
 
 
 
 
 
 
X 4 , 
 
 
 
C o nc o mita nt Me ds  
X  
X  
X  
X  
X  
 
X  
X  
 
 
Ris k stratificati o n  
 
 
 
 
 
X 4 
 
 
 
 
E ns ure s u bject has o perati ve 
a p p oi nt me nt 
 
 
X  
 
 
 
 
 
 
 
Q O L ( F A C T-H N )2 0 
X  
 
 
 
X  
 
 
 
X  
 
S ur vi val assess me nt  
 
 
 
 
 
 
 
 
 
X  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 7 
 
Ke y t o Ti me a n d E ve nts T a ble F o ot n otes  
 
1.  U nless ot her wise n ote d, scree ni n g e val uati o ns t o ta ke place wit hi n 2 wee ks pri or t o da y 1 of st u d y 
treat me nt.  F or D 1 of wee k 1, if scree ni n g ( baseli ne) e val uati o ns were perf or me d wit hi n 7 da ys of D 1 
of treat me nt, t hese d o n ot nee d t o be re peate d.   
 
2.  A ) Da y 1 ( +/-) 1 da y; paclita xel a n d car b o plati n a d mi nistere d wee kl y f or 6 wee ks, c o nc o mita nt wit h 
d ur val u ma b ( See 2 B).  La b orat or y e val uati o ns o n da y 1 of c ycle 1 nee d be re peate d o nl y if > 7 da ys 
ha ve ela pse d bet wee n scree ni n g la b orat or y tests a n d da y 1.    
 
2.  B)  Na b -Paclita xel ( 1 0 0 m g/ m 2), car b o plati n ( A U C 2) a d mi nistere d wee kl y f or 6 wee ks + D ur val u ma b 
(7 5 0 m g ) a d mi nistere d e ver y 2 wee ks X 5 (i.e., wee k  1, wee k  3, wee k  5, wee k  7, wee k  9).  
 
2.  C) A dj u va nt D ur val u ma b ( 7 5 0 m g ) a d mi nistere d e ver y 2 wee ks X 3 (i.e., wee k  1, wee k  3, wee k  5)  
 
2.  D) S u bjects will be m o nit ore d bef ore, d uri n g a n d after t he i nf usi o n of d ur val u ma b wit h assess me nt of 
vital si g ns. S u bjects are m o nit ore d ( p ulse rate, bl o o d press ure) e ver y 3 0 mi n utes d uri n g t he i nf usi o n 
peri o d (i ncl u di n g ti mes w here i nf usi o n rate is sl o we d or te m p oraril y st o p pe d) 
 
3.  T his cli nic visit s h o ul d ta ke place 1- 4 wee ks after s u bject c o m pletes  i n d ucti o n treat me nt or ceases 
t hera p y f or ot her reas o ns (i ncl u di n g earl y disc o nti n uati o n).  S ur ger y ma y f oll o w i m me diatel y after.  
 
4.  S ur gical resecti o n s h o ul d occ ur 1- 4 wee ks f oll o wi n g c o m pleti o n of i n d ucti o n t hera p y. S u bjects  
dee me d l o w ris k will recei ve 3 c ycles of d ur val u ma b at a d ose of 7 5 0 m g  a d mi nistere d e ver y t w o 
wee ks after s ur ger y (see e xce pti o ns n ote d f or i n v ol ve d fiel d ra diati o n i n secti o n 4. 5. 1 ).  T h ose i n t he 
me di u m ris k gr o u p will recei ve ra diati o n as per sta n dar d of care wit h c o nc urre nt wee kl y cis plati n 
c he m ot hera p y (see se cti o n  4. 5. 2  f or alter nati ve o pti o ns); c ycles will be defi ne d as e ver y 3 wee ks. 
S u bjects  i n t he hi g h -ris k gr o u p will recei ve p ost -o perati ve ra diati o n a n d c o nc o mita nt hi g h d ose b ol us 
cis plati n 1 0 0 m g/ m 2 e ver y 3 wee ks f or u p t o 3 c ycles  (see secti o n 4. 5. 3  f or p ossi ble e xce pti o ns t o t his 
re gi me n i n hi g h-ris k gr o u p). S o me cli nicia ns ma y c h o ose t o see s o me s u bjects wee kl y d uri n g wee kl y 
c he m ora diati o n re gi me ns. T his w ill be left t o cli nicia n discreti o n. F oll o wi n g c he m ora di ot hera p y, 
s u bjects i n t he me di u m a n d hi g h -ris k gr o u ps will recei ve 3 c ycles of d ur val u ma b ( 7 5 0 m g)  
a d mi nistere d  e ver y t w o wee ks . Visits will be d oc u me nte d f or st u d y p ur p oses o nl y  at t he e ver y t hree 
wee ks  visits per t he T a n d  E ta ble.  
 
5.  T his visit s h o ul d ta ke place w he n s u bject st o ps treat me nt d ue t o d oc u me nte d ra di o gra p hic or cli nical 
disease pr o gressi o n, u n ma na gea ble t o xicit y, or w he n st u d y treat me nt is c o m plete.   I n t he case of 
s u bjects w h o reac h t his milest o ne d ue t o c o m pleti o n of st u d y t hera p y, t his visit s h o ul d occ ur 8 -1 2 
wee ks f oll o wi n g t he c o ncl usi o n of a dj u va nt d ur val u ma b. S u bjects  w h o e x perie nce a gra de 4 t o xicit y or 
S A E will be c o ntacte d e ver y 2 wee ks u ntil t he e ve nt is res ol ve d, deter mi ne d t o be irre versi ble b y t he 
i n vesti gat or, or u ntil t he s u bject be gi ns a n alter nate f or m of treat me nt.   
 
6.  T he first f oll o w u p, descri be d as “treat me nt disc o nti n uati o n a b o ve,” c o ntai ns st u d y -ma n date d f oll o w  
u p i ncl u di n g i ma gi n g. S u bse q ue nt f oll o w -u p visits will ta ke place per sta n dar d of care  ( S O C). S O C 
t y picall y i ncl u des p h ysical e xa m of nec k a n d pri mar y site a n d/ or i ma gi n g of t hese areas e ver y 3 
m o nt hs f or at least 2 years wit h d oc u me ntati o n i n t he electr o nic case re p ort f or m ( eC R F) li mite d t o 
pr o gressi o n a n d s ur vi val n ote d at t heir S O C M D visits f or at least 5 years.  
 
7.  C o m plete me dical hist or y at baseli ne t o i ncl u de de m o gra p hics, H P V stat us a n d s m o ki n g hist or y.  
 
8.  P h ysical e xa mi nati o n t o i ncl u de hei g ht at baseli ne o nl y, a n d c o m plete e xa mi nati o n of hea d a n d nec k.  
 
9.  Ser u m c he mistries t o i ncl u de s o di u m, p otassi u m, c hl ori de, C O 2, B U N, creati ni ne, gl uc ose, calci u m, 
al b u mi n, total p r otei n, total b ilir u bi n, A S T, A L T, a m ylase, li pase a n d al kali ne p h os p hatase . 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 8 
 
1 0.  Li ver f u ncti o n tests t o i ncl u de t otal bilir u bi n,  al kali ne p h os p hatase, A S T, A L T.  
 
1 1.  Usi n g C oc kr oft & Ga ult f or m ula (see secti o n 4. 3. 3 ).  T his s h o ul d be calc ulate d pri or t o eac h d ose of 
car b o plati n  
 
1 2.  T o be d o ne wit hi n 7 2 h o urs  pri or t o da y 1 of treat me nt i n w o me n of c hil d beari n g p ote ntial.  
 
1 3.  T he sa me met h o d of e val uati o n s h o ul d be use d t hr o u g h o ut st u d y a n d ma y i ncl u de C T or M RI of t he 
nec k, a n d c hest i ma gi n g ( X- ra y or C T sca n at discreti o n of p h ysicia n). C T of t he nec k s h o ul d ha ve I V 
c o ntrast u nless c o ntrai n dicate d (aller g y or a d verse reacti o n or re nal iss ues).  Scree ni n g ra di o l o gic 
e val uati o n ma y ta ke place wit hi n 4 wee ks of treat me nt i nitiati o n.  If P E T/ C T or P E T/ M RI was use d f or 
baseli ne i ma gi n g, it is acce pta ble t o o btai n C T or M RI (res pecti vel y) al o ne f or f oll o w  u p i ma gi n g.  See 
secti o n 6. 2. 2  f or fre q ue nc y t o t u m or e val uati o n d uri n g  f oll o w u p (i.e., e ver y 3 m o nt hs). 
 
1 4.  At scree ni n g arc hi val t u m or tiss ue s h o ul d be o btai ne d. C ollect a fres h bi o ps y fr o m s u bjects w h o a gree 
t o t his pr oce d ure via c o nse nt. C ollect tiss ue d uri n g s ur ger y f or c orrelati ve st u dies. 
 
1 5.  Wee ks 1, 5 a n d 9.   T h yr oi d pa nel i ncl u des T S H, T 3 a n d free T 4. If c o nsiste nt wit h i nstit uti o nal sta n dar d 
of care, it is acce pta ble t o o btai n T S H al o ne a n d o nl y o btai n T 3 a n d free T 4 if cli nicall y usef ul. 
 
1 6.  Bef ore 1st a n d 3r d c ycle o nl y.  
 
1 7.  S u bjects  w h o ha ve a n o n g oi n g Gra de 4 t o xicit y at t he ti me of disc o nti n uati o n fr o m treat me nt will 
c o nti n ue t o be f oll o we d u ntil t he e ve nt is res ol ve d or dee me d irre versi ble b y t he i n vesti ga t or. 
 
1 8.  Bl o o d dra w  - 3 x 8 m Ls w h ole bl o o d i n A C D t u bes will be t o e val uate f or cl o nall y restricte d circ ulati n g 
B a n d T cells.   
 
1 9.  C ycle 1, da y 1 o nl y.  C ollect s peci me n pri or t o treat me nt .  
 
2 0.  F u ncti o nal Assess me nt of Ca ncer T hera p y -Hea d a n d Nec k , Versi o n 4 . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
3 9 
6. 2  
F oll o w- u p Assess me nts  
S u bjects w h o wit h dra w c o nse nt fr o m st u d y dr u g treat me nt s h o ul d e nter t he f oll o w 
u p peri o d ( u nless c o nse nt t o f oll o w- u p is s pecificall y wit h dra w n). After st u d y 
dr u g treat me nt e n ds, s u bse q ue nt a nti- ca ncer me dicati o ns ta ke n b y t he s u bject  
s h o ul d be d oc u me nte d i n t he e C R F if t his i nf or mati o n is a vaila ble d uri n g f oll o w-
u p.  
6. 2. 1  I niti al F oll o w-u p Visit  
F oll o wi n g c o m pleti o n of all treat me nt, t he first f oll o w -u p visit will occ ur at 8 t o 
1 2 wee ks after treat me nt disc o nti n uati o n.  T his visit will i ncl u de: 
 
P h ysical e xa mi nati o n (i ncl u d i n g wei g ht), a n d s y m pt o m directe d me dical hist or y  
E C O G Perf or ma nce Stat us (see A p pe n di x A ) 
La b orat or y e val uati o ns:  
•  C B C wit h differe ntial  
•  Ser u m c he mistries ( s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, ser u m 
creati ni ne, gl uc ose, calci u m, ma g nesi u m, al b u mi n) 
•  Li ver f u ncti o n tests  
•  T S H   
T o xicit y Assess me nt:  As p er N CI C T C A E v 4. 0 3. S u bjects w h o e x perie nce d a 
gra de 4 or S A E d uri n g t he treat me nt p hase will be c o ntacte d e ver y 2 wee ks u ntil 
t he e ve nt is res ol ve d or dee me d irre versi ble b y t he i n vesti gat or. 
Q ualit y of life:  F A C T -H N  
 
6. 2. 2  S u bse q ue nt F oll o w -u p t hr o u g h 5 ye ars 
S u bse q ue nt f oll o w -u p visits will ta ke place per sta n dar d of care ( S O C). S O C 
t y picall y i ncl u des p h ysical e xa m of nec k a n d pri mar y site a n d/ or i ma gi n g of t hese 
areas e ver y 3 m o nt hs f or at least 2 years wit h d oc u me ntati o n i n t he electr o nic case 
re p ort f or m (eC R F) li mite d t o pr o gressi o n a n d s ur vi val n ote d at t heir S O C M D 
visits f or at least 5 years.  
6. 3  
C orrel ati ve St u dies  
T he state of t he art f or bi o mar ker testi n g i n i m m u n ot hera p y is ra pi dl y e v ol vi n g at 
t he ti mi n g of pr ot oc ol ge nerati o n.  We s us pect t hat bi o mar kers of rele va nce f or 
pre dicti n g treat me nt efficac y a n d f or f ut ure st u d y de vel o p me nt will be 
s u bsta ntiall y differe nt at t he ti me of st u d y c o ncl usi o n t ha n t he y are at t he ti me of 
st u d y i nitiati o n.  S u bjects will be c o nse nte d f or bi o mar ker testi n g of bl o o d a n d 
tiss ue sa m ples c ollecte d. N o s u bject will be ref use d st u d y e ntr y f or lac k of tiss ue, 
b ut s u bjects will be re q uire d t o all o w use of a n y pre- treat me nt tiss ue re mai ni n g 
after defi niti ve dia g n osis is ma de  (i.e., arc hi val a n d or fres h tiss ue) f or researc h 
p ur p oses.  I n a d diti o n, s u bjects will be re q uire d t o all o w use of t heir resi d ual 
o perati ve tiss ue f or researc h p ur p oses.  
 
H a n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Rese arc h  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 0 
Bi os peci me ns c ollecte d f or t his st u d y will be st ore d i n t he Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter ( L C C C) Tiss ue Pr oc ure me nt Facilit y ( T P F), or if 
nee de d, i n a sec ure off -site st ora ge facilit y. All bi os peci me n sa m ples will be 
o btai ne d i n acc or da nce wit h pr oce d ures o utli ne d i n t he L C C C 1 6 2 1 St u d y 
La b orat or y Ma n ual a n d st ore d i n c o ntai ners wit h c o ntr olle d access. Eac h sa m ple 
will be assi g ne d a u ni q ue c o de n u m ber a n d n o i de ntifia ble pers o nal healt h 
i nf or mati o n ( P HI) will be o n t he s peci me n la bel.  I nf or mati o n a b o ut t he s u bject’s 
disease will be li n ke d t o t he s peci me ns st ore d i n t he re p osit or y data base. T P F -
ass ociate d researc h staff, L C C C Bi oi nf or matics staff w h o s u p p ort t he T P F 
data base a n d t he L C C C Data Ware h o use, a n d researc hers wit h I R B -a p pr o val f or 
access t o P HI f or eac h s u bject i n t his st u d y will be a ble t o li n k s peci me ns t o 
rele va nt me dical i nf or mati o n. S o me res ults fr o m la b orat or y a nal yses t hat occ urre d 
d uri n g t he s u bject’s partici pati o n i n t he cli nical st u d y ma y als o be i ncl u de d. T his 
i nf or mati o n ma y be i m p orta nt f or u n dersta n di n g h o w t he s u bject’s ca ncer 
de vel o pe d a n d res p o n de d t o treat me nt. 
 
St or a ge Ti me: 
•  
T he bi os peci me n will be use d first a n d f ore m ost f or researc h p ur p oses 
o utli ne d wit hi n t he c o nfi nes of t his pr ot oc ol. Sa m ples will be st ore d f or at 
least 5 years f or t his st u d y a n d u p t o 1 5 years, if c o nse nt was o btai ne d fr o m 
t he s u bject t o use tiss ue f or ot her researc h p ur p oses (e. g., T P F c o nse nt f or m 
was si g ne d b y t he s u bject).   
o  T he i n vesti gat or a gree s t o a bi de b y p olicies a n d pr oce d ures of t he T P F 
facilit y a n d will si g n a letter of researc h a gree me nt f or et hical a n d 
a p pr o priate c o n d uct of t heir researc h t hat utilizes s peci me ns o btai ne d fr o m 
t he T P F facilit y. 
 
C o m pli a nce St ate me nt  
Bi os peci me n c ollecti o n f or t his st u d y will be c o n d ucte d i n f ull acc or da nce t o all 
a p plica ble U ni versit y of N ort h Car oli na ( U N C) Researc h P olicies a n d Pr oce d ures 
a n d all a p plica bl e Fe deral a n d state la ws a n d re g ulati o ns i ncl u di n g 4 5 C F R 4 6, 
a n d t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) Pri vac y 
R ule. A n y e pis o de of n o nc o m plia nce will be d oc u me nte d. 
 
T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t h is pr ot oc ol, will 
o btai n c o nse nt, a n d will re p ort u ne x pecte d pr o ble ms i n acc or da nce wit h T he U N C 
I R B P olicies a n d Pr oce d ures a n d all fe deral re q uire me nts. C ollecti o n, rec or di n g, 
a n d re p orti n g of data will be acc urate a n d will e ns ure t he pri vac y, healt h, a n d 
welfare of researc h s u bjects d uri n g a n d after t he st u d y.  
6. 4  
Assess me nt of S afet y  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he 
st u d y is fa miliar wit h t he c o nte nt of t his secti o n. 
 
A n y s u bject w h o recei ves treat me nt o n t his pr ot oc ol will be e val ua ble f or t o xicit y.  
Eac h s u bject will be assesse d peri o dicall y f or t he de vel o p me nt of a n y t o xicit y 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 1 
acc or di n g t o t he Ti me a n d E ve nts ta ble.  T o xicit y will be assesse d acc or di n g t o 
t he N CI C T C A E v 4. 03. 
6. 4. 1  D ur v al u m a b S afet y  
T he saf et y pr ofile of d ur val u ma b is c o nsiste nt wit h t he p har mac ol o g y of t he tar get 
a n d ot her a ge nts i n t he i m m u ne c hec k p oi nt i n hi bit or class. N o t u m or t y pes 
a p peare d t o be ass ociate d wit h u ni q ue A Es. I m m u ne- relate d A Es (ir A Es), w hic h 
are i m p orta nt ris ks of i m m u ne  c hec k p oi nt i n hi bit ors, ha ve bee n o bser ve d wit h 
d ur val u ma b a n d i ncl u de c olitis, p ne u m o nitis, he patitis/ he pat ot o xicit y, 
ne ur o pat h y/ ne ur o m usc ular t o xicit y, e n d ocri n o pat h y, der matitis, a n d ne p hritis. I n 
a d diti o n, pa ncreatitis is a n i m p orta nt p ote ntial ris k partic ularl y wit h d ur val u ma b 
a n d tre meli m u ma b c o m bi nati o n t hera p y; T his st u d y c o nsi ders o nl y D ur val u ma b 
a n d n ot Tre meli m u ma b. T hese e ve nts are ma na gea ble b y a vaila ble/esta blis he d 
treat me nt g ui deli nes as descri be d i n t he st u d y pr ot oc ol. 
6. 4. 2  Assess me nt of S afet y P ar a meters  
Assess me nt of Se verit y  
F or b ot h A Es a n d S A Es, t he I n vesti gat or m ust assess t he se verit y / i nte nsit y of t he 
e ve nt.  
T he se verit y/i nte nsit y of A Es will be gra de d base d u p o n t he s u bject’s s y m pt o ms 
acc or di n g t o t he c urre nt acti ve mi n or versi o n of t he C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E, Versi o n 4. 0 3); 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plica ti o ns/ctc. ht m #ctc
4 0  
A Es t hat are n ot defi ne d i n t he C T C A E s h o ul d be e val uate d f or se verit y/i nte nsit y 
acc or di n g t o t he f oll o wi n g scale:  
•  Gra de 1 = Mil d – tra nsie nt or mil d disc o mf ort; n o li mitati o n i n acti vit y; n o 
me dical i nter ve nti o n/t hera p y re q uire d  
•  Gra de 2 = M o derate – mil d t o m o derate li mitati o n i n acti vit y, s o me assista nce 
ma y be nee de d; n o or mi ni mal me dical i nter ve nti o n/t hera p y re q uire d  
•  Gra de 3 = Se vere – mar ke d li mit ati o n i n acti vit y, s o me assista nce us uall y 
re q uire d; me dical i nter ve nti o n/t hera p y re q uire d, h os pitalizati o n is p ossi ble 
•  Gra de  4 = Life -t hreate ni n g – e xtre me li mitati o n i n acti vit y, si g nifica nt 
assista nce re q uire d; si g nifica nt me dical i nter ve nti o n/t hera p y r e q uire d, 
h os pitalizati o n or h os pice care pr o ba ble 
•  Gra de  5 = Deat h - t he e ve nt res ults i n deat h 
T he ter m “se vere” is ofte n use d t o descri be t he i nte nsit y of a s pecific e ve nt (as i n 
mil d, m o derate or se vere m y ocar dial i nfarcti o n); t he e ve nt itself, h o we ver, ma y be 
of relati vel y mi n or me dical si g nifica nce (s uc h as se vere hea dac he).  T his criteri o n 
is n ot t he sa me as “seri o us” w hic h is base d o n s u bject/e ve nt o utc o me or acti o n 
criteria ass ociate d wit h e ve nts t hat p ose a t hreat t o a s u bject’s life or f u ncti o ni n g.   

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 2 
Seri o us ness, n ot se verit y, ser ves as a g ui de f or defi ni n g re g ulat or y o bli gati o ns. 
C a us alit y  
T he I n vesti gat or m ust deter mi ne t he relati o ns hi p bet wee n t he a d mi nistrati o n of I P 
a n d t he occ urre nce of a n A E/ S A E as N ot S us pecte d or S us pecte d as defi ne d 
bel o w: 
N ot s us pecte d: A ca usal relati o ns hi p of t he a d verse e ve nt t o I P a d mi nistrati o n is 
u nli kel y or re m ote , or ot her me dicati o ns, t hera pe utic i nter ve nti o ns, or u n derl yi n g 
c o n diti o ns pr o vi de a s ufficie nt e x pla nati o n f or t he o bser ve d e ve nt. 
S us pecte d: T here is a re as o n a ble p ossi bilit y  t hat t he a d mi nistrati o n of I P ca use d 
t he a d verse e ve nt. ‘ Reas o na ble p ossi bilit y’ mea ns t here is e vi de nce t o s u g gest a 
ca usal relati o ns hi p bet wee n t he I P a n d t he a d verse e ve nt.  
Ca usalit y s h o ul d be assesse d a n d pr o vi de d f or e ver y A E/ S A E base d o n c urre ntl y 
a vaila ble i nf or mati o n. Ca usalit y is t o be reassesse d a n d pr o vi de d as a d diti o nal 
i nf or mati o n bec o mes a vaila ble. 
If a n e ve nt is assesse d as s us pecte d of bei n g relate d t o a c o m parat or, a ncillar y or 
a d diti o nal I P t hat has n ot bee n ma n ufact ure d or pr o vi de d b y Cel ge ne, please 
pr o vi de t he na me of t he ma n ufact urer w he n re p orti n g t he e ve nt. 
D ur ati o n 
F or b ot h A Es a n d S A Es, t he I n vesti gat or will pr o vi de a rec or d of t he start a n d 
st o p dates of t he e ve nt. 
Acti o n T a ke n  
T he I n vesti gat or will re p ort t he  acti o n ta ke n wit h I P as a res ult of a n A E or S A E, 
as a p plica ble (e. g., disc o nti n uati o n, i nterr u pti o n of I P, as a p pr o priate) a n d re p ort if 
c o nc o mita nt a n d/ or a d diti o nal treat me nts were gi ve n f or t he e ve nt. 
O utc o me  
T he I n vesti gat or will re p ort t he o utc o me o f t he e ve nt f or b ot h A Es a n d S A Es.  All 
S A Es t hat ha ve n ot res ol ve d u p o n disc o nti n uati o n of t he s u bject’s partici pati o n i n 
t he st u d y m ust be f oll o we d u ntil rec o vere d (ret ur ne d t o baseli ne), rec o vere d wit h 
se q uelae, or deat h ( d ue t o t he S A E). 
6. 4. 3  A d verse  Eve nt R e p orti n g 
A d verse E ve nt i nte nsit y a n d/ or se verit y will be gra de d usi n g C T C A E Versi o n 
4. 0 3 f or t o xicit y a n d a d verse e ve nt re p orti n g.  A c o p y of t he C T C A E Versi o n 4. 0 3 
ca n be d o w nl oa de d fr o m C T E P 
(htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/ electr o nic a p plicati o ns/ctc. ht m #ctc
4 0 ). All a p pr opriate 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. 0 3.  All a d verse cli nical e x perie nces, w het her  o bser ve d b y t he 
i n vesti gat or or re p orte d b y t he s u bject, m ust be rec or de d, wit h details a b o ut t he 
d urati o n a n d i nte nsit y of eac h e pis o de, t he acti o n ta ke n wit h res pect t o t he test 
dr u g, a n d t he e ve nt’s o utc o me, i ncl u di n g la b a b n or malities.  T he i n vesti gat or m ust 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 3 
e val uate eac h a d verse e x perie nce f or its relati o ns hi p t o t he test dr u g a n d f or its 
seri o us ness. 
T he i n vesti gat or m ust a p praise all a b n or mal la b orat or y res ults f or t heir cli nical 
si g nifica nce.  If a n y a b n or mal la b orat or y res ult is c o nsi dere d cli nicall y si g nifica nt, 
t he i n vesti gat or m ust pr o vi de details a b o ut t he acti o n ta ke n wit h res pect t o t he test 
dr u g a n d a b o ut t he e ve nt’s o utc o me or la b a b n or malit y. 
M o nit ori n g, rec or di n g a n d re p orti n g a d verse e ve nts  
A n A E is a n y n o xi o us, u ni nte n de d, or u nt o war d me dical occ urre nce t hat ma y 
a p pear or w orse n i n a s u bject d uri n g t he c o urse of a st u d y. It ma y be a ne w 
i nterc urre nt ill ness, a w orse ni n g c o nc o mita nt ill ness, a n i nj ur y, or a n y 
c o nc o mita nt i m pair me nt of t he s u bject’s healt h, i ncl u di n g la b orat or y test val ues, 
re gar dless of eti ol o g y.  A n y w orse ni n g (i.e., a n y cli nicall y si g nifica nt a d verse 
c ha n ge i n t he fre q ue nc y or i nte nsit y of a pre-e xisti n g c o n diti o n) s h o ul d be 
c o nsi dere d a n A E. A dia g n osis or s y n dr o me s h o ul d be rec or de d rat her t ha n t he 
i n di vi d ual si g ns or s y m pt o ms of t he dia g n osis or s y n dr o me.   
 
A b use, wit h dra wal, se nsiti vit y or t o xicit y  t o a n i n vesti gati o nal pr o d uct s h o ul d be 
re p orte d as a n A E.  A n o ver d ose, acci de ntal or i nte nti o nal, w het her or n ot it is 
ass ociate d wit h a n A E, s h o ul d be re p orte d. A n y se q uela of a n acci de ntal or 
i nte nti o nal o ver d ose of a n i n vesti gati o nal pr o d uct s h o ul d be re p orte d as a n A E.   If 
t he se q uela of a n o ver d ose is a n S A E, t he n t he se q uela m ust be re p orte d o n a n 
S A E re p ort f or m a n d as a n A E.   
 
All s u bjects will be m o nit ore d f or A Es d uri n g t he st u d y. Assess me nts ma y 
i ncl u de m o nit ori n g of a n y or all of t he f oll o win g para meters: t he s u bject’s cli nical 
s y m pt o ms, la b orat or y, pat h ol o gical, ra di ol o gical or s ur gical fi n di n gs, p h ysical 
e xa mi nati o n fi n di n gs, or fi n di n gs fr o m ot her tests a n d/ or pr oce d ures.  
All A Es will be rec or de d b y t he I n vesti gat or fr o m t he ti me t he s u bject si g ns 
i nf or me d c o nse nt u ntil 9 0 da ys after t he last d ose of I P a n d t h ose S A Es ma de 
k n o w n t o t he i n vesti gat or at a n y ti me t hereafter t hat are s us pecte d of bei n g relate d 
t o I P.  A Es a n d seri o us a d verse e ve nts ( S A Es) will be rec or de d i n t he s u bject’s 
s o urce d oc u me nts.  All S A Es m ust be re p orte d t o Cel ge ne Dr u g Safet y wit hi n 2 4 
h o urs of t he I n vesti gat or’s k n o wle d ge of t he e ve nt b y facsi mile, or ot her 
a p pr o priate met h o d, usi n g t he S A E Re p ort F or m, or a p pr o ve d e q ui vale nt f or m. 
6. 5  
Assess me nt of Effic ac y  
T he pri mar y e n d p oi nt of pat h ol o gic c o m plete res p o nse rate (p C R R ) will be 
defi ne d as per R E CI S T 1. 1. [ 3 5 ]  A n i nte nt-t o-treat a p pr oac h will be f oll o we d i n 
all data s u m maries usi n g all a vaila ble data i n t he a nal y ses. Eac h s u bject e nr olle d 
will be i n t he pri mar y I T T a nal ysis set. C o nse q ue ntl y, n o s pecial a dj ust me nts t o 
t he data are i nte n de d f or deali n g wit h missi n g val ues or s u bjects w h o wit h dra w 
pri or t o c o m pleti n g st u d y. I n t he case of n o t u m or assess me nt, t he s u bject will 
c o u nt as a n o n- res p o n der if fail ure t o ac q uire t u m or assess me nt was e ve n p ossi bl y 
relate d t o st u d y pr oce d ures (f or e xa m ple, disc o nti n uati o n d ue t o t o xicit y); i n t he 
case t hat fail ure t o ac q uire t u m or assess me nt is clearl y n ot d ue t o st u d y 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 4 
pr oce d ures (f or e xa m ple, s u bject c h oice u nrelate d t o t o xicit y or fail ure o f 
efficac y) t he n s uc h a s u bject  will be e xcl u de d fr o m t he a nal ysis.   
6. 5. 1  T u m or Me as ure me nt  
T u m or lesi o ns will be e val uate d via C T sca n of t he nec k a n d c hest i ma gi n g ( X-ra y 
or C T sca n at discreti o n of p h ysicia n). Meas ura ble disease will be defi ne d as t he 
prese nce of at least o ne meas ura ble lesi o n t hat ca n be acc uratel y meas ure d i n at 
least o ne di me nsi o n wit h t he l o n gest dia meter a mi ni m u m size of: 
•  ≥1 0 m m b y C T sca n ( C T sca n slice t hic k ness n o greater t ha n 5 m m)  
•  1 0 m m cali per meas ure me nt b y cli nical e xa m (lesi o n s w hic h ca n n ot be 
acc uratel y meas ure d wit h cali pers s h o ul d be rec or de d as n o n-
meas ura ble)  
•  2 0 m m b y c hest X- ra y 
 
F or mali g na nt l y m p h n o des t o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d 
meas ura ble, a l y m p h n o de m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y C T  
sca n ( C T sca n slice t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m).  At 
baseli ne a n d i n f oll o w- u p, o nl y t he s h ort a xis will be meas ure d a n d f oll o we d.   
 
All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or 
pat h ol o gical l y m p h n o des wit h ≥1 0 t o < 1 5 m m s h ort a xis) as well as tr ul y n o n -
meas ura ble lesi o ns, will be c o nsi dere d n o n- meas ura ble.  Lesi o ns c o nsi dere d tr ul y 
n o n- meas ura ble i ncl u de: le pt o me ni n geal disease; ascites; ple ural/ pericar dial 
eff usi o n; i nfla m mat or y breast disease; l y m p ha n git ic i n v ol ve me nt of s ki n or l u n g; 
a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysical e xa m t hat is 
n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues. 
 
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if 
cli nicall y assesse d.  All baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as 
p ossi ble t o t he treat me nt start a n d ne ver m ore t ha n 4 wee ks bef ore t he be gi n ni n g 
of t he treat me nt.  T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d 
be use d t o c haracterize eac h i de ntifie d  a n d re p orte d lesi o n at baseli ne a n d d uri n g 
f oll o w- u p.  I ma gi n g base d e val uati o n s h o ul d al wa ys be d o ne rat her t ha n cli nical 
e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot be i ma ge d b ut are 
assessa ble b y cli nical e xa m.  Cli nical lesi o ns will o nl y be  c o nsi dere d meas ura ble 
w he n t he y are s u perficial a n d ≥1 0 m m dia meter as assesse d usi n g cali pers (e. g., 
s ki n n o d ules).  F or t he case of s ki n lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y 
i ncl u di n g a r uler t o esti mate t he size of t he lesi o ns is rec o m me n de d. 
6. 5. 2  B a seli ne D oc u me nt ati o n of T ar get a n d N o n-T ar get Lesi o ns  
All meas ura ble lesi o ns u p t o a ma xi m u m of 5 lesi o ns t otal (a n d a ma xi m u m of 2 lesi o ns 
per or ga n) re prese ntati ve of all i n v ol ve d or ga ns s h o ul d be i de ntifie d as tar get lesi o ns 
a n d will be rec or de d a n d mea s ure d at baseli ne.   
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 5 
Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n ger 
dia meter), be re prese ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat 
le n d t he msel ves t o re pr o d uci ble re peate d meas ure me nts.  
 
A s u m of t he dia meters (l o n gest f or n o n- n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or 
all tar get lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m dia meters.  If 
l y m p h n o des are t o be i ncl u de d i n t he s u m, o nl y t he s h ort a xis is a d de d i nt o t he su m.  
T he baseli ne s u m dia meters will be use d as refere nce t o f urt her c haracterize t he 
o bjecti ve t u m or res p o nse of t he meas ura ble di me nsi o n of t he disease.  
 
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l y m p h n o des s h o ul d be 
i de ntifie d as n o n-tar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne. Meas ure me nts 
are n ot re q uire d a n d t hese lesi o ns s h o ul d be f oll o we d as “ prese nt” or “a bse nt”, or i n 
rare cases “ u ne q ui v ocal pr o gressi o n”.   
6. 5. 3  E v al u ati o n of T ar get Lesi o ns  
C o m plete res p o nse ( C R ) − Dis ap peara nce of all tar get lesi o ns.  A n y pat h ol o gical l y m p h 
n o de ( L N) tar get or n ot m ust ha ve decrease d i n s h ort a xis t o < 1 0 m m.  
 
Pat h ol o gic c o m plete res p o nse ( p C R) – T he a bse nce of a n y resi d ual ca ncer cells wit hi n 
t he resecte d s ur gical s peci me n 
 
Partial res p o nse ( P R ) − At least a 3 0 % decrease i n t he s u m of t he L D of t he tar get 
lesi o ns ta ki n g as refere nce t he baseli ne s u m L D. 
 
Pr o gressi ve Disease ( P D ) − At least a 2 0 % i ncrease i n t he s u m of t he L D of t he tar get 
lesi o ns ta ki n g as refere nce t he s mallest s u m L D rec or de d si nce t he treat me nt starte d 
i ncl u di n g baseli ne if t hat is t he s mallest o n st u d y.  I n a d diti o n t o t he relati ve i ncrease of 
2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 5 m m.  T he 
a p peara nce of o ne or m ore ne w lesi o ns als o c o nstit utes P D.  
 
Sta ble disease ( S D ) − Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt 
i ncrease t o q ualif y f or P D ta ki n g as refere nces t he s mallest s u m L D si nce t he treat me nt 
starte d.  I n t he case of S D, meas ure me nts m ust ha ve met t he S D criteria at least o nce 
after st u d y e ntr y at a mi ni m u m i nter val of 8 wee ks fr o m i nitiati o n of treat me nt.   
6. 5. 4  E v al u ati o n of N o n- T ar g et Lesi o ns  
C o m plete res p o nse ( C R ) − Di sa p peara nce of all n o n-tar get lesi o ns.  All L N m ust be 
n o n- pat h ol o gical i n size ( < 1 0 m m s h ort a xis).   
 
N o n -c o m plete res p o nse ( n o n-C R)/ n o n - pr o gressi o n ( n o n-P D ) − Persiste nce of o ne or 
m ore n o n- tar get lesi o n(s) or/a n d mai nte na nce of t u m or mar ker le vel a b o ve t he n or mal 
li mits. 
 
Pr o gressi ve disease ( P D ) − A p peara nce of o ne or m ore ne w lesi o ns  a n d/ or u ne q ui v ocal 
pr o gressi o n of e xisti n g n o n- tar get lesi o ns. 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 6 
6. 5. 5  E v al u ati o n of Best O ver all Res p o nse   
T he best o verall res p o nse is defi ne d as t he best res p o nse ac hie ve d acr oss all ti me 
p oi nts pri or t o pr o gressi o n (f or e xa m ple, a s u bject w h o has S D at first assess me nt, 
P R at sec o n d assess me nt, a n d P D o n last assess me nt has a best o verall res p o nse of 
P R).  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 7 
7. 0  
A D V E R S E E V E N T S  
7. 1  
Defi niti o ns  
7. 1. 1  A d verse E ve nt ( A E)  
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce (e. g., a n a b n or mal 
lab orat or y fi n di n g, s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
dr u g) i n a s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot 
necessaril y ha ve a ca usal relati o ns hi p wit h t his treat me nt.  A n A E ca n t heref ore 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 te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, 
w het her or n ot relate d t o t he me dici nal pr o d uct.  
 
A n A E i ncl u des b ut is n ot li mite d t o a n y cli nicall y si g nifica nt w orse ni n g of a 
s u bject’s pre-e xisti n g c o n diti o n. A n a b n or mal la b orat or y fi n di n g (i ncl u di n g E C G 
fi n di n g) t hat re q uires a n acti o n or i nter ve nti o n b y t he i n vesti gat or, or a fi n di n g 
j u d ge d b y t he i n vesti gat or t o re prese nt a c ha n ge be y o n d t he ra n ge of n or mal 
p h y si ol o gic fl uct uati o n, s h o ul d be re p orte d as a n A E. 
 
H os pitalizati o n f or electi ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he 
res ult of a n A E (e. g., s ur gical i nserti o n of ce ntral li ne) nee d n ot be c o nsi dere d 
A Es a n d s h o ul d n ot be rec or de d as a n A E. Disease pr o gressi o n s h o ul d n ot be 
rec or de d as a n A E, u nless it is attri b uta ble b y t he i n vesti gat or t o t he st u d y t hera p y. 
7. 1. 2  S us pecte d A d verse Re acti o n ( S A R)  
A s us pecte d a d verse reacti o n ( S A R) is a n y A E f or w hic h t here is a re as o n a ble 
p ossi bility  t hat t he dr u g is t he ca use. Re as o n a ble p ossi bility  mea ns t hat t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E.  A 
s us pecte d a d verse reacti o n i m plies a lesser de gree of certai nt y a b o ut ca usalit y 
t ha n a d verse reacti o n, w hic h mea ns a n y a d verse e ve nt ca use d b y a dr u g.   
 
Ca usalit y assess me nt t o a st u d y dr u g is a me dical j u d g me nt ma de i n c o nsi derati o n 
of t he f oll o wi n g fact ors: te m p oral relati o n s hi p of t he A E t o st u d y dr u g e x p os ure, 
k n o w n mec ha nis m of acti o n or si de effect pr ofile of st u d y treat me nt, ot her rece nt 
or c o nc o mita nt dr u g e x p os ures, n or mal cli nical c o urse of t he disease u n der 
i n vesti gati o n, a n d a n y ot her u n derl yi n g or c o nc urre nt me dical c o n diti o ns.  Ot her 
fact ors t o c o nsi der i n c o nsi deri n g dr u g as t he ca use of t he A E: 
•  Si n gle occ urre nce of a n u nc o m m o n e ve nt k n o w n t o be str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, Ste ve ns-J o h ns o n 
S y n dr o me) 
•  O ne or m ore occ urre nces of a n e ve nt n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os ure, b ut ot her wise u nc o m m o n i n t he p o p ulati o n (e. g., te n d o n 
r u pt ure); ofte n m ore t ha n o nce occ urre nce fr o m o ne or m ulti ple st u dies 
w o ul d be nee de d bef ore t he s p o ns or c o ul d deter mi ne t hat t here is 
re as on a ble p ossi bility  t hat t he dr u g ca use d t he e ve nt.   

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 8 
•  A n a g gre gate a nal ysis of s pecific e ve nts o bser ve d i n a cli nical trial t hat 
i n dicates t he e ve nts occ ur m ore fre q ue ntl y i n t he dr u g treat me nt gr o u p 
t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p 
7. 1. 3  U ne x pecte d A E or S A R  
A n A E or S A R is c o nsi dere d u ne x pecte d if t he s pecificit y or se verit y of it is n ot 
c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n (e. g., I n vesti gat or’s Br oc h ure 
(I B) f or a n u na p pr o ve d i n vesti gati o nal pr o d uct or pac ka ge i nsert/s u m mar y of 
pr o d uct c haracteristics f or a n a p pr o ve d pr o d uct). U ne x pecte d als o refers t o A Es or 
S A Rs t hat are me nti o ne d i n t he I B as occ urri n g wit h a class of dr u gs or as 
a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g b ut are n ot 
s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.   
7. 1. 4  Seri o us A E or S A R  
A n A E or S A R is c o nsi dere d seri o us if, i n t he vie w of eit her t he i n vesti gat or or 
s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h;  
•  Is life-t hreate ni n g ( places t he s u bject at i m me diate ris k of deat h fr o m 
t he e ve nt as it occ urre d); 
•  Re q uires i n patie nt h os pitalizati o n ( > 2 4 h o urs) or pr ol o n gati o n of 
e xisti n g h os pitalizati o n; *  
•  Res ults i n c o n ge nital a n o mal y/ birt h defect;  
•  Res ults i n a persiste nt or si g nifica nt i nca pacit y or s u bsta nt ial 
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;  
•  I m p orta nt me dical e ve nts 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 a seri o us 
a d verse dr u g e x perie nce w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t he 
defi niti o n.  
•  Pre g na ncies will als o be re p orte d pr o m ptl y t o 
Astraze neca / Me dI m m u ne a n d Cel ge ne i n a si milar ma n ner t o S A Es  
 
* H os pitalizati o n f or a ntici pate d or pr ot oc ol s pecifie d pr oce d ures s uc h as a d mi nistrati o n of 
c he m ot hera p y, ce ntral li ne i nserti o n, metastasis i nter ve nti o nal t hera p y, resecti o n of pri mar y 
t u m or, or electi ve s ur ger y, will n ot be c o nsi dere d seri o us a d verse e ve nts. 
 
I m p orta nt me dical e ve nts are defi ne d as t h ose occ urre nces t hat ma y n ot be 
i m me diatel y life t hreate ni n g or res ult i n deat h, h os pitalizati o n, or disa bilit y, b ut 
ma y je o par dize t he s u bject or 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 ot her o utc o mes liste d a b o ve.  Me dical a n d scie ntific j u d g me nt s h o ul d 
be e xercise d i n deci di n g w het her s uc h a n A E s h o ul d be c o nsi dere d seri o us. 
E xa m ples of me dicall y i m p orta nt e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y 
r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias, or c o n v ulsi o ns t hat 
d o n ot res ult i n h os pitalizati o ns; or de vel o p me nt of dr u g de pe n de nc y or dr u g 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
4 9 
a b use. Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her 
e x pe dite d re p orti n g is a p pr o priate i n t his sit u ati o n. 
 
T he ca usalit y of S A Es (t heir relati o ns hi p t o all st u d y treat me nt/ pr oce d ures) will 
be assesse d b y t he i n vesti gat or a n d c o m m u nicate d t o Astra Ze neca.  
 
E ve nts n ot c o nsi dere d t o be S A Es are h os pit aliz ati o ns f or:  
•  A sta n dar d pr oce d ure f or pr ot oc ol t hera p y a d mi nistrati o n. H o we ver, 
h os pitalizati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n of t hera p y 
a d mi nistrati o n will be re p orte d as a n S A E.  
•  R o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n n ot ass ociate d wit h 
a n y deteri orati o n i n c o n diti o n. 
•  T he a d mi nistrati o n of bl o o d or platelet tra nsf usi o n as r o uti ne treat me nt of 
st u die d I n dicati o n.  H o we ver, h os pitalizati o n or pr ol o n ge d h os pitalizati o n f or 
a c o m plicati o n of s uc h tra nsf usi o n re mai ns a re p orta ble S A E.  
•  A pr oce d ure f or pr ot oc ol/ disease- relate d i n vesti gati o ns (e. g., s ur ger y, sca ns, 
e n d osc o p y, sa m pli n g f or la b orat or y tests, b o ne marr o w sa m pli n g).  H o we ver, 
h os pitalizati o n or pr ol o n ge d h os pitalizati o n f or a c o m plicati o n of s uc h 
pr oce d ures re mai ns a re p orta ble S A E.  
•  H os pitalizati o n or pr ol o n gat i o n of h os pitalizati o n f or tec h nical, practical, or 
s ocial reas o ns, i n a bse nce of a n A E. 
•  A pr oce d ure t hat is pla n ne d (i.e., pla n ne d pri or t o starti n g of treat me nt o n 
st u d y); m ust be d oc u me nte d i n t he s o urce d oc u me nt a n d t he C R F.  
H os pitalizati o n or pr ol o n g e d h os pitalizati o n f or a c o m plicati o n re mai ns a 
re p orta ble S A E. 
•  A n electi ve treat me nt of or a n electi ve pr oce d ure f or a pre -e xisti n g c o n diti o n 
u nrelate d t o t he st u die d i n dicati o n. 
•  E mer ge nc y o ut patie nt treat me nt or o bser vati o n t hat d oes n ot res ult i n 
a d missi o n, u nless f ulfilli n g ot her seri o us ness criteria a b o ve. 
If a n A E is c o nsi dere d seri o us, b ot h t he A E pa ge/scree n of t he C R F a n d t he S A E 
Re p ort F or m m ust be c o m plete d.  F or eac h S A E, t he I n vesti gat or will pr o vi de 
i nf or mati o n o n se verit y, start a n d st o p dates, relati o ns hi p t o I P, acti o n ta ke n 
re gar di n g I P, a n d o utc o me. 
I n a d diti o n, t he f oll o wi n g varia bles will be c ollecte d f or S A Es as a p plica ble: 
•  
Date A E met criteria f or seri o us A E  
•  
Date I n vesti gat or beca me a ware of seri o us A E  
•  
Criteria f or A E t o be c o nsi dere d seri o us 
•  
Date of h os pitalizati o n  
•  
Date of disc har ge 
•  
Pr o ba ble ca use of deat h 
•  
Date of deat h  

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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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5 0 
•  
A ut o ps y perf or me d 
•  
Descri pti o n of A E  
•  
Ca usalit y assess me nt i n relati o n t o St u d y pr oce d ure(s)  
 
7. 2  
D oc u me nt ati o n of n o n- seri o us A Es or S A Rs 
A d verse e ve nts will be rec or de d i n t he e C R F usi n g a rec o g nize d me dical ter m or 
dia g n osis t hat acc uratel y reflects t he e ve nt. A d verse e ve nts will be assesse d b y t he 
i n vesti gat or f or se verit y, relati o ns hi p t o t he i n vesti gati o nal pr o d uct, p ossi ble 
eti ol o gies, a n d w het her t he e ve nt meets criteria of a n S A E a n d t heref ore re q uires 
i m me diate n otificati o n t o Astra Ze neca/ Me dI m m u ne Patie nt Safet y.  
T he f oll o wi n g varia bles will be c ollecte d f or eac h A E:  
•  A E ( ver bati m)  
•  T he date a n d ti me w he n t he A E starte d a n d st o p pe d 
•  C ha n ges i n N CI C T C A E gra de a n d t he ma xi m u m C T C gra de attai ne d 
•  W h et her t he A E is seri o us or n ot  
•  I n vesti gat or ca usalit y rati n g a gai nst d ur val u ma b a n d/ or 
c o m parat or/c o m bi nati o n dr u g  
•  Acti o n ta ke n wit h re gar d t o d ur val u ma b /c o m parat or/c o m bi nati o n 
a ge nt 
•  O utc o me 
I n a d diti o n, t he f oll o wi n g varia bles will be c ollecte d f or S A Es as a p plica ble: 
•  Date A E met criteria f or seri o us A E  
•  Date I n vesti gat or beca me a ware of seri o us A E  
•  A E is seri o us d ue t o t he f oll o wi n g i.e., s pecif y criteria  
•  Date of h os pitalizati o n  
•  Date of disc har ge 
•  Pr o ba ble ca use of deat h  
•  Date of deat h  
•  A ut o ps y perf or me d 
•  Descri pti o n of A E  
•  Ca usalit y assess me nt i n relati o n t o St u d y pr oce d ure(s)  
•  Ca usalit y assess me nt i n relati o n t o A d diti o nal St u d y Dr u g  
 
D uri n g t he c o urse of t he st u d y all A Es a n d S A Es s h o ul d be pr oacti vel y f oll o we d 
u p f or eac h s u bject. E ver y eff ort s h o ul d be ma de t o o btai n a res ol uti o n f or all 
e ve nts, e ve n if t he e ve nts c o nti n ue after disc o nti n uati o n/st u d y c o m pleti o n. 
If a s u bject disc o nti n ues fr o m treat me nt f or reas o ns ot her t ha n disease 
pr o gressi o n, a n d t heref ore c o nti n ues t o ha ve t u m or assess me nts, dr u g or 
pr oce d ure- relate d S A Es m ust be ca pt ure d u ntil t he s u bject is c o nsi dere d t o ha ve 
c o nfir me d P D a n d will ha ve n o f u rt her t u m or assess me nts. 

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C O N FI D E N TI A L  
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5 1 
T he i n vesti gat or is res p o nsi ble f or f oll o wi n g all S A Es u ntil res ol uti o n, u ntil t he 
s u bject ret ur ns t o baseli ne stat us, or u ntil t he c o n diti o n has sta bilize d wit h t he 
e x pectati o n t hat it will  re mai n c hr o nic, e ve n if t his e xte n ds be yo n d st u d y 
partici pati o n.  
 
F or n o n-seri o us A Es or S A Rs, d oc u me ntati o n m ust be gi n fr o m da y 1 of st u d y 
treat me nt a n d c o nti n ue t hr o u g h t he 9 0 - da y f oll o w- u p peri o d f or d ur val u ma b or 2 8 
da ys after ot her st u d y treat me nt is disc o nti n ue d.   
 
C ollecte d i nf or mati o n s h o ul d be rec or de d i n t he electr o nic c ase re p ort for ms 
(eC R F) f or t hat s u bject.  Please i ncl u de a descri pti o n of t he e ve nt, its se verit y or 
t o xicit y gra de, o nset a n d res ol ve d dates (if a p plica ble), a n d t he relati o ns hi p t o t he 
st u d y dr u g.  D oc u me ntati o n s h o ul d occ ur at least m o nt hl y.  
7. 3  
S A Es or Seri o us S A Rs  
7. 3. 1  Ti mi n g  
After i nf or me d c o nse nt b ut pri or t o i nitiati o n of st u d y me dicati o ns, o nl y S A Es 
ca use d b y a pr ot oc ol- ma n date d i nter ve nti o n will be c ollecte d (e. g. S A Es relate d t o 
i n vasi ve pr oce d ures s uc h as bi o psies, me dicati o n was h o ut).  
 
F or a n y ot her e x perie nce or c o n diti o n t hat meets t he defi niti o n of a n S A E or a 
seri o us S A R, rec or di n g of t he e ve nt m ust be gi n fr o m da y 1 of st u d y treat me nt a n d 
c o nti n ue t hr o u g h t he 3 0 da y s after st u d y treat me nt disc o nti n uati o n. 
7. 3. 2  D oc u me nt ati o n a n d N otific ati o n  
S A Es or Seri o us S A Rs m ust be rec or de d i n t he S A E c o ns ole wit hi n O n C ore ®  f or 
t hat s u bject wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. A d diti o nall y, t he N C C N 
Pr oject Ma na ger m ust als o be n otifie d via e mail of all S A Es wit hi n  2 4 h o urs of 
lear ni n g of its occ urre nce.  
7. 4  
A d verse E ve nt Re p orti n g  
7. 4. 1  I R B Re p orti n g Re q uire me nts: 
U N C : 
•  T he U N C -I R B will be n otifie d of all S A Es t hat q ualif y as a n 
U na ntici pate d Pr o ble m as per t he U N C I R B P olicies usi n g t he I R B’s we b -
base d re p orti n g s yste m wit hi n 7 da ys of t he I n vesti gat or bec o mi n g a ware 
of t he pr o ble m.  Please n ote, t hese e ve nts m ust be re p orte d t o t he s p o ns or 
wit hi n 2 4 h o urs of lear ni n g of t he occ urre nce. 
 
Pre g na nc y 
Pre g na ncies a n d s us pecte d pre g na ncies (i ncl u di n g a p ositi ve pre g na nc y test 
regar dless of a ge or disease state) of a fe male s u bject occ urri n g w hile t he s u bject 
is o n st u d y, or wit hi n 2 8 da ys of t he s u bject’s last d ose of st u d y s h o ul d be 
rec or de d as S A Es. T he s u bject is t o be disc o nti n ue d i m me diatel y fr o m t he st u d y.  

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C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
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5 2 
 
T he fe male s u bj ect s h o ul d be referre d t o a n o bstetricia n- g y nec ol o gist, prefera bl y 
o ne e x perie nce d i n re pr o d ucti ve t o xicit y f or f urt her e val uati o n a n d c o u nseli n g. 
 
T he I n vesti gat or will f oll o w t he fe male s u bject u ntil c o m pleti o n of t he pre g na nc y, 
a n d m ust d oc u me nt t he o ut c o me of t he pre g na nc y (eit her n or mal or a b n or mal 
o utc o me) a n d re p ort t he c o n diti o n of t he fet us or ne w b or n t o t he U N C St u d y 
C o or di nat or. If t he o utc o me of t he pre g na nc y was a b n or mal (e. g., s p o nta ne o us or 
t hera pe utic a b orti o n), t he I n vesti gat or s h o ul d re p ort t he a b n or mal o utc o me as a n 
A E. If t he a b n or mal o utc o me meets a n y of t he seri o us criteria, it m ust be re p orte d 
as a n S A E.  
7. 4. 1. 1  Astr a Ze nec a Re p orti n g  Re q uire me nts:  
All S A Es will be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he 
i n vesti gati o nal pr o d uct, or t o t he st u d y pr oce d ure(s). T he re p orti n g peri o d f or 
S A Es is t he peri o d i m me diatel y f oll o wi n g t he ti me t hat writte n i nf or me d c o nse nt 
is o btai ne d t hr o u g h 9 0 da ys after t he last d ose of d ur val u ma b (or at lea st 5 half-
li ves of ot her st u d y me dicati o ns) or u ntil t he i nitiati o n of alter nati ve a ntica ncer 
t hera p y.  T he i n vesti gat or a n d/ or S p o ns or are res p o nsi ble f or i nf or mi n g t he Et hics 
C o m mittee a n d/ or t he Re g ulat or y A ut h orit y of t he S A E as per l ocal re q uire me nts.  
 
T he i n vesti gat or a n d/ or s p o ns or m ust i nf o r m t he F D A, via a Me d Watc h/ A d E E RS 
f or m, of a n y seri o us or u ne x pecte d a d verse e ve nts t hat occ ur i n acc or da nce wit h 
t he re p orti n g o bli gati o ns of 2 1 C F R 3 1 2. 3 2, a n d will c o nc urre ntl y f or war d all 
s uc h re p orts t o Astra Ze neca.  A c o p y of t he Me d Watc h/ A d E E RS re p o rt m ust be 
fa xe d t o Astra Ze neca at t he ti me t he e ve nt is re p orte d t o t he F D A.  It is t he 
res p o nsi bilit y of t he s p o ns or t o c o m pile all necessar y i nf or mati o n a n d e ns ure t hat 
t he F D A recei ves a re p ort acc or di n g t o t he F D A re p orti n g re q uire me nt ti meli nes 
a n d to e ns ure t hat t hese re p orts are als o s u b mitte d t o Astra Ze neca at t he sa me 
ti me. 
* A c o ver pa ge s h o ul d acc o m pa n y t he Me d Watc h/ A d E E R S f or m i n dicati n g t he 
f oll o wi n g: 
•  “ N otificati o n fr o m a n I n vesti gat or S p o ns ore d St u d y” 
•  T he i n vesti gat or I N D n u m ber assi g ne d b y t he F D A  
•  T he i n vesti gat or’s na me a n d a d dress  
•  T he trial na me/title a n d Astra Ze neca I S S refere nce n u m ber ( E S R - 1 6- 1 2 0 6 8) 
* S p o ns or m ust als o i n dicate, eit her i n t he S A E re p ort or t he c o ver pa ge, t he 
ca usalit y of e ve nts i n relati o n t o all st u d y me dicati o ns a n d if t he S A E is relate d t o 
disease pr o gressi o n , as deter mi ne d b y t he pri nci pal i n vesti gat or. 
* Se n d S A E re p ort a n d acc o m pa n yi n g c o ver pa ge b y wa y of e mail t o 
Astra Z e neca’s desi g nate d mail b o x:     
A E Mail b o x Cli nical Trial T C S @astraze neca.c o m  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
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5 3 
If a n o n-seri o us A E bec o mes seri o us, t his a n d ot her rele va nt f oll o w- u p 
i nf or mati o n m ust als o be pr o vi de d t o Astra Ze neca a n d t he F D A. 
 
Seri o us a d verse e ve nts  t hat d o n ot re q uire e x pe dite d re p orti n g t o t he F D A still 
nee d t o be re p orte d t o Astra Ze neca prefera bl y usi n g t he Me d D R A c o di n g 
la n g ua ge f or seri o us a d verse e ve nts.  T his i nf or mati o n s h o ul d be re p orte d o n a 
m o nt hl y basis a n d u n der n o circ u msta nce less fre q ue ntl y t ha n q uarterl y.   
Astra Ze neca/ Me dI m m u ne retai n s t he ri g ht t o re q uest a d diti o nal i nf or mati o n f or 
a n y s u bject wit h o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if j u d ge d 
necessar y.  
7. 4. 1. 2  E x pe dite d Re p orti n g b y I n vesti g at or t o Cel ge ne  
Seri o us a d verse e ve nts ( S A E) are defi ne d a b o ve. T he i n vesti gat or m ust i nf orm 
Cel ge ne i n writi n g usi n g a S A E f or m or M e dW atc h 3 5 0 0 A f or m of a n y S A E 
wit hi n 2 4 h o urs of bei n g a ware of t he e ve nt. T he writte n re p ort m ust be 
c o m plete d a n d s u p plie d t o Cel ge ne b y facsi mile wit hi n 2 4 h o urs. T he i nitial 
re p ort m ust be as c o m plete as p ossi ble, i ncl u di n g a n assess me nt of t he ca usal 
relati o ns hi p bet wee n t he e ve nt a n d t he i n vesti gati o nal pr o d uct(s).  I nf or mati o n n ot 
a vaila ble at t he ti me of t he i nitial re p ort (e. g., a n e n d date f or t he a d verse e ve nt or 
la b orat or y val ues recei ve d after t he re p ort) m ust be d oc u me nte d o n a f oll o w- u p 
re p ort.  A fi nal re p ort t o d oc u me nt res ol uti o n of t he S A E is re q uire d. T he Cel ge ne 
trac ki n g n u m ber a n d t he i nstit uti o nal pr ot oc ol n u m ber s h o ul d be i ncl u de d o n S A E 
re p orts ( or o n t he fa x c o ver letter) se nt t o Cel ge ne. A c o p y of t he fa x tra ns missi o n 
c o nfir mati o n of t he S A E re p ort t o Cel ge ne s h o ul d be attac he d t o t he S A E a n d 
retai ne d wit h t he s u bject rec or ds. 
  
Dr u g S afet y C o nt act I nf or m ati o n: 
 
Cel ge ne C or p orati o n      
Gl o bal Dr u g Safet y a n d Ris k Ma na ge me nt     
5 5 6 M orris A ve n ue, B uil di n g S 1 2 
S u m mit, Ne w Jerse y 0 7 9 0 1 
Fa x: ( 9 0 8) 6 7 3- 9 1 1 5 
E- mail: dr u gsafet y @cel ge ne.c o m  
Tele p h o ne: 1 - 9 0 8- 6 7 3- 9 6 6 7 
T oll Free:    1 - 8 0 0- 6 4 0- 7 8 5 4                                                                                                         
7. 4. 1. 3  F D A E x pe dite d Re p orti n g re q uire me nts  u n der 2 1 C F R 3 1 2. 3 2 f or st u dies 
c o n d ucte d u n der a n I N D  
A s p o ns or m ust re p ort a n y s us pecte d a d verse reacti o n t hat is b ot h seri o us a n d 
u ne x pecte d t o t he F D A. T he s p o ns or m ust re p ort a n a d verse e ve nt as a s us pecte d 
a d verse reacti o n o nl y if t here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n 
t he dr u g a n d t he a d verse e ve nt, s uc h as: 
•  A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be 
str o n gl y ass ociate d wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, 
Ste ve ns-J o h ns o n S y n dr o me); 

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•  O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d 
wit h dr u g e x p os ure, b ut is ot her wise u nc o m m o n i n t he p o p ulati o n 
e x p ose d t o t he dr u g (e. g. te n d o n r u pt ure); 
•  A n a g gre gate a nal ysis of s pecific e ve nts o bser ve d i n a cli nical trial (s uc h 
as k n o w n c o nse q ue nces of u n derl yi n g disease or c o n diti o n u n der 
i n vesti gati o n or ot her e ve nts t hat c o m m o nl y occ ur i n t he st u d y p o p ulati o n 
i n de pe n de nt of dr u g t hera p y) t hat i n dicates t h ose e ve nts occ ur m ore 
fre q ue ntl y i n t he dr u g treat me nt gr o u p t ha n i n a c o nc urre nt or hist orical 
c o ntr ol gr o u p. 
 
T he s p o ns or m ust s u b mit eac h I N D safet y re p ort o n F D A F or m 3 5 0 0 A. Eac h 
n otificati o n t o F D A m ust bear pr o mi ne nt i de ntificati o n of its c o nte nts, i.e., “I N D 
Safet y Re p ort,” a n d m us t be tra ns mitte d t o t he re vie w di visi o n t hat has t he 
res p o nsi bilit y f or re vie w of t he I N D.  
If t he s p o ns or dee ms t hat a n e ve nt is b ot h a seri o us S A R A N D u ne x pecte d, it m ust 
als o (i n a d diti o n t o O nc ore) be rec or de d o n t he Me d Watc h F or m 3 5 0 0 A as per 2 1 
C F R 3 1 2. 3 2.  U ne x pecte d a d verse e ve nts or a d verse reacti o n refers t o a n e ve nt or 
reacti o n t hat is n ot liste d i n t he i n vesti gat or’s br oc h ure or is n ot liste d at t he 
s pecificit y or se verit y t hat has bee n o bser ve d; or if a n i n vesti gat or’s br oc h ure is n ot 
re q uire d or a vaila ble, is n ot c o nsiste nt wit h t he ris k i nf or mati o n descri be d i n t he 
ge neral i n vesti gati o n pla n or else w here i n t he c urre nt I N D a p plicati o n.   
T he Me d Watc h f or m s h o ul d be fa xe d t o t he U N C M ultice nter  Pr oject Ma na ger at 
9 1 9- 9 6 6- 4 3 0 0 ( or e maile d at C P O M ulti Ce nter @ me d. u nc.e d u ) al o n g wit h 
s u p p orti n g d oc u me ntati o n defi ni n g t he e ve nt a n d ca usalit y.  T he U N C M ultice nter  
Pr oject Ma na ger will t he n se n d t he re p ort t o t he F u n di n g S o urce. T he Me d Watc h 
3 5 0 0a f or m ca n be accesse d at: 
htt p:// w w w.f da. g o v/ Safet y/ Me d Watc h/ H o w T o Re p ort/ D o w nl oa d F or ms/ defa ult. ht m .  
 
( Please be s ure a n d access f or m 3 5 0 0 A, a n d n ot f or m 3 5 0 0).  
 
O nce t he s p o ns or deter mi nes a n e ve nt is a seri o us S A R A N D u ne x pecte d, t he 
Me d Watc h 3 5 0 0 A f or m will be s u b mitte d t o t he F D A.  If t he e ve nt is seri o us, 
u ne x pecte d a n d c o nsi dere d t o be p ossi bl y-, pr o ba bl y- or defi nitel y -relate d t o t he 
st u d y treat me nt, t he UN C M ultice nter  Pr oj ect Ma na ger will i nf or m t he Re g ulat or y 
Ass ociate at U N C w h o will be res p o nsi ble f or s u b mitti n g t he S A R  via serial 
s u b missi o n t o t he I N D. T he Me d Watc h f or m s h o ul d als o be se nt t o t he Re g ulat or y 
Ass ociate a n d t he I N D S pecialist wit hi n 4 8 h o urs of t he s p o ns or bei n g a ware of t he 
e ve nt.  T he Re g ulat or y Ass ociate wit h t he ai d of t he I N D S pecialist will s u b mit t he 
I N D Safet y Re p ort via I N D serial s u b missi o n t o t he F D A re vie w di visi o n. All I N D 
safet y re p orts m ust be s u b mitte d o n F or m 3 5 0 0 A a n d be acc o m pa nie d b y F orm 
1 5 7 1. T he F D A m ust be n otifie d or a n y u ne x pecte d or life- t hreate ni n g s us pecte d 
a d verse reacti o ns as s o o n as p ossi ble, b ut n o later t ha n 7 cale n dar da ys of lear ni n g 
of t he e ve nt. If t he e ve nt is seri o us, b ut n ot life-t hreate ni n g, F D A m ust be n otifie d 
as so o n as p ossi ble, b ut i n n o case later t ha n 1 5 cale n dar da ys after t he s p o ns or 
deter mi nes t hat t he i nf or mati o n q ualifies f or re p orti n g.  
 

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C O N FI D E N TI A L  
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Dece m ber 1, 2 0 2 1  
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5 5 
T he U N C  M ultice nter  Pr oject Ma na ger will als o be res p o nsi ble f or i nf or mi n g eac h 
Affiliate site of all seri o us a n d u ne x pecte d S A Rs re p orte d t o t he F D A via fa x as 
s o o n as p ossi ble, b ut i n n o case later t ha n 1 5 cale n dar da ys after t he s p o ns or 
deter mi nes t hat t he i nf or mati o n q ualifies f or re p orti n g.    
 
A d diti o n al G ui d a nce  
Please refer t o 2 1 C F R 3 1 2. 3 2 a n d “ G ui da nce f or I n d ustr y a n d I n vesti gat ors: 
Safet y Re p orti n g Re q uire me nts f or I N Ds a n d B A/ B E St u dies” f or a d diti o nal 
i nf or mati o n a n d re p orti n g re q uire me nts. All I N D Safet y Re p orts will be s u b mitte d 
i n acc or da nce wit h t hese re g ulati o ns/ g ui da nces.  
 
O ver d ose  
A n o ver d ose is defi ne d a s a s u bject recei vi n g a d ose of d ur val u ma b i n e xcess of 
t hat s pecifie d i n t he I n vesti gat or’s Br oc h ure, u nless ot her wise specifie d i n t his 
pr ot oc ol. 
 
A n y o ver d ose of a st u d y s u bject wit h d ur val u ma b, wit h or wit h o ut ass ociate d 
A Es/ S A Es, is re q uire d t o be re p orte d wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt 
t o t he s p o ns or a n d Astra Ze neca/ Me dI m m u ne Patie nt Safet y or desi g nee usi n g t he 
desi g nate d Safet y e -mail b o x (see Secti o n  7. 4. 1. 1  f or c o ntact i nf or mati o n). If t he 
o ver d ose res ults i n a n A E, t he A E m ust als o be rec or de d as a n A E. O ver d ose d oes 
n ot a ut o maticall y ma ke a n A E seri o us, b ut if t he c o nse q ue nces of t he o ver d ose are 
seri o us, f or e xa m ple deat h or h os pitalizati o n, t he e ve nt is seri o us a n d m ust be 
rec or de d a n d re p orte d as an S A E. T here is c urre ntl y n o s pecific treat me nt i n t he 
e ve nt of a n o ver d ose of d ur val u ma b.  
A n o ver d ose of na b- paclita xel is defi ne d, o n a per d ose basis, as t he f oll o wi n g 
a m o u nt o ver t he pr ot oc ol- s pecifie d d ose of na b-paclita xel assi g ne d t o a gi ve n 
s u bject, re gar dless of a n y ass ociate d a d verse e ve nts or se q uelae. 
o  I V  
1 0 % o ver t he pr ot oc ol-s pecifie d d ose   
 
O n a sc he d ule or fre q ue nc y basis, a n o ver d ose is defi ne d as a n yt hi n g m ore 
fre q ue nt t ha n t he pr ot oc ol re q uire d sc he d ule or fre q ue nc y.   
 
O n a n i nf usi o n rate basis, a n o ver d ose is defi ne d as a n y rate faster t ha n t he 
pr ot oc ol- s pecifie d rate.  F or na b- paclita x el, a n i nf usi o n c o m plete d i n less t ha n 2 5 
mi n utes ma y i ncrease C ma x b y a p pr o xi matel y 2 0 %, t heref ore a na b- paclita xel 
i nf usi o n c o m plete d i n less t ha n 2 5 mi n utes will meet t he i nf usi o n rate criteri o n f or 
a n o ver d ose. 
 
C o m plete data a b o ut dr u g a d mi nistrati o n,  i ncl u di n g a n y o ver d ose, re gar dless of 
w het her t he o ver d ose was acci de ntal or i nte nti o nal, s h o ul d be re p orte d i n t he case 
re p ort f or m. 
 
T he i n vesti gat or will use cli nical j u d g me nt t o treat a n y o ver d ose.  

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He p atic F u ncti o n A b n or m alit y  
He patic  f u ncti o n a b n or malit y i n a st u d y s u bject, wit h or wit h o ut ass ociate d 
cli nical ma nifestati o ns, is re q uire d t o be re p orte d as “ he patic f u ncti o n a b n or mal” 
wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt  t o t he s p o ns or a n d 
Astra Ze neca/ Me dI m m u ne Patie nt Safet y usi n g t he desi g nate d Safet y e - mail b o x 
pr o vi de d i n secti o n 7. 4. 1. 1 , u nless a defi niti ve u n derl yi n g dia g n osis f or t he 
a b n or malit y (e. g., c h olelit hiasis or bile d uct o bstr u cti o n) t hat is u nrelate d t o t he 
st u d y me dicati o ns has bee n c o nfir me d. 
•  If t he defi niti ve u n derl yi n g dia g n osis f or t he a b n or malit y has bee n esta blis he d 
a n d is u nrelate d t o i n vesti gati o nal pr o d uct, t he decisi o n t o c o nti n ue d osi n g of 
t he st u d y s u bject will be base d o n t he cli nical j u d g me nt of t he i n vesti gat or.  
•  If n o defi niti ve u n derl yi n g dia g n osis f or t he a b n or malit y is esta blis he d, d osi n g 
of t he st u d y s u bject m ust be i nterr u pte d i m me diatel y. F oll o w- u p i n vesti gati o ns 
a n d i n q uiries m ust be i nitiate d b y t he i n ves ti gati o nal site wit h o ut dela y. 
Eac h re p orte d e ve nt of he patic f u ncti o n a b n or malit y will be f oll o we d b y t he 
i n vesti gat or a n d e val uate d b y t he s p o ns or a n d Astra Ze neca/ Me dI m m u ne.  
 
Pre g n a nc y  
Pre g na nc y itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t he st u d y 
me dicati o ns u n der st u d y ma y ha ve i nterfere d wit h t he effecti ve ness of a 
c o ntrace pti ve me dicati o n.  Pre g na ncies a n d s us pecte d pre g na ncies (i ncl u di n g a 
p ositi ve pre g na nc y te st re gar dless of a ge or disease state) of a fe male s u bject 
occ urri n g w hile t he s u bject is o n d ur val u ma b or ot her st u d y me dicati o ns , or 
wit hi n at least 9 0 da ys of t he s u bject’s last d ose of  d ur val u ma b, are c o nsi dere d 
i m me diatel y re p orta ble e ve nts. St u d y me d icati o ns are t o be disc o nti n ue d 
i m me diatel y. T he pre g na nc y, s us pecte d pre g na nc y, or p ositi ve pre g na nc y test 
m ust be re p orte d t o Astra Ze neca/ Cel ge ne Dr u g Safet y i m me diatel y b y facsi mile, 
or ot her a p pr o priate met h o d, usi n g t he Pre g na nc y I nitial Re p ort F or m, or 
a p pr o ve d e q ui vale nt f or m n o later t ha n 2 4 h o urs of w he n he or s he bec o mes 
a ware of it. T he desi g nate d Astra Ze neca re prese ntati ve will w or k wit h t he 
I n vesti gat or t o e ns ure t hat all rele va nt i nf or mati o n is pr o vi de d t o t he Astra Ze neca 
Patie nt Safet y data e ntr y site wit hi n 1 t o 5  cale n dar da ys f or S A Es a n d wit hi n 3 0 
da ys f or all ot her pre g na ncies. T he fe male s u bject ma y be referre d t o a n 
o bstetricia n - g y nec ol o gist ( n ot necessaril y o ne wit h re pr o d ucti ve t o xicit y 
e x perie nce) or a n ot her a p pr o priate healt hcare pr ofessi o nal f or f urt her e val uati o n  
a n d c o u nseli n g. T he sa me ti meli nes a p pl y w he n o utc o me i nf or mati o n is a vaila ble.   
 
T he I n vesti gat or will f oll o w t he fe male s u bject u ntil c o m pleti o n of t he pre g na nc y 
a n d m ust n otif y Astra Ze neca/ Cel ge ne Dr u g Safet y i m me diatel y a b o ut t he 
o utc o me of t he pre g na nc y (eit her n or mal or a b n or mal o utc o me) usi n g t he 
Pre g na nc y F oll o w- u p Re p ort F or m, or a p pr o ve d e q ui vale nt f or m. If t he o utc o me 
of t he pre g na nc y was a b n or mal (e. g., s p o nta ne o us or t hera pe utic a b orti o n), t he 
I n vesti gat or s h o ul d re p ort t he a b n or mal o utc o me as a n A E.  If t he a b n or mal 

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o utc o me meets a n y of t he seri o us criteria, it m ust be re p o rte d as a n S A E t o 
Astra Ze neca/ Cel ge ne Dr u g Safet y i m me diatel y b y facsi mile, or ot her a p pr o priate 
met h o d, wit hi n 2 4 h o urs of t he I n vesti gat or’s k n o wle d ge of t he e ve nt usi n g t he 
S A E Re p ort F or m, or a p pr o ve d e q ui vale nt f or m. C o n ge nital a b n or malities or birt h 
defects a n d s p o nta ne o us miscarria ges s h o ul d be re p orte d a n d ha n dle d as S A Es.  
Electi ve a b orti o ns wit h o ut c o m plicati o ns s h o ul d n ot be ha n dle d as A Es.   T he 
o utc o me of all pre g na ncies (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, 
ect o pic pre g na nc y, n or mal birt h, or c o n ge nital a b n or malit y) s h o ul d be f oll o we d 
u p a n d d oc u me nte d e ve n if t he s u bject was disc o nti n ue d fr o m t he st u d y.   
All ne o natal deat hs t hat occ ur wit hi n 2 8 da ys of birt h s h o ul d be re p orte d, wit h o ut 
re gar d t o ca usalit y, as S A Es. I n a d diti o n, a n y i nfa nt deat h after 2 8 da ys t hat t he 
I n vesti gat or s us pects is relate d t o t he i n uter o e x p os ure t o t he st u d y me dicati o ns 
s h o ul d als o be re p orte d t o Astra Ze neca/ Cel ge ne Dr u g Safet y i m me diatel y b y 
facsi mile, or ot her a p pr o priate met h o d, wit hi n 2 4 h o urs of t he I n vesti gat or’s 
k n o wle d ge of t he e ve nt usi n g t he S A E Re p ort F or m, or a p pr o ve d e q ui vale nt f or m. 
 
M ale S u bjects  
D ur val u ma b : Male su bjects s h o ul d refrai n fr o m fat heri n g a c hil d or d o nati n g 
s per m d uri n g t he st u d y a n d f or 9 0 da ys after t he last d ose of d ur val u ma b 
m o n ot hera p y.   
If a fe male part ner of a male s u bject ta ki n g st u d y me dicati o ns bec o m es pre g na nt, 
t he male s u bject ta ki n g t he st u d y me dicati o ns s h o ul d n otif y t he I n vesti gat or, a n d 
t he pre g na nt fe male part ner s h o ul d be a d vise d t o call t heir healt hcare pr o vi der 
i m me diatel y. 
 
Na b -paclita xel : If a fe male part ner of a male s u bject recei vi n g na b-paclita xel 
bec o mes pre g na nt, t he male s u bject o n na b -paclita xel s h o ul d n otif y t he 
I n vesti gat or, a n d t he pre g na nt fe male part ner s h o ul d be a d vise d t o call t heir 
healt hcare pr o vi der i m me diatel y. Male s u bjects  treate d wit h na b-paclita xel are 
a d vise d n ot t o fat her a c hil d d uri n g a n d u p t o 6 m o nt hs a fter treat me nt wit h na b-
paclita xel.  
 
Pre g na nc y of t he s u bject’s part ner is n ot c o nsi dere d t o be a n A E. H o we ver, t he 
o utc o me of all pre g na ncies (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, 
ect o pic pre g na nc y, n or mal birt h, or c o n ge nital a b n or malit y) occ ur ri n g fr o m t he 
date of t he first d ose of st u d y me dicati o ns u ntil 9 0 da ys after t he last d ose s h o ul d, 
if p ossi ble, be f oll o we d u p a n d d oc u me nte d.   
 
W here a re p ort of pre g na nc y is recei ve d, pri or t o o btai ni n g i nf or mati o n a b o ut t he 
pre g na nc y, t he I n vesti gat or  m ust o btai n t he c o nse nt of t he s u bject’s part ner.  
T heref ore, t he l ocal st u d y tea m s h o ul d a d o pt t he ge neric I C F te m plate i n li ne wit h 
l ocal pr oce d ures a n d s u b mit it t o t he rele va nt Et hics C o m mittees 
( E Cs)/I nstit uti o nal Re vie w B oar ds (I R Bs) pri or t o use.   
 

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7. 4. 2  Defi niti o n of A d verse E ve nts of S peci al I nterest ( A E SI)    
A n a d verse e ve nt of s pecial i nterest ( A E SI) is o ne of scie ntific a n d me dical 
i nterest s pecific t o u n dersta n di n g of t he I n vesti gati o nal Pr o d uct a n d ma y re q uire 
cl ose m o nit ori n g a n d ra pi d c o m m u nicati o n b y t he i n vesti gat or t o t he s p o ns or. A n 
A E SI ma y be seri o us or n o n-seri o us. T he ra pi d re p orti n g of A E SIs all o ws 
o n g oi n g s ur veilla nce of t hese e ve nts i n or der t o c haracterize a n d u n dersta n d t he m 
i n ass ociati o n wit h t he use of t his i n vesti gati o nal pr o d uct. 
A E SIs f or d ur val u ma b i ncl u de b ut are n ot li mite d t o e ve nts wit h a p ote ntial 
i nfla m mat or y or i m m u ne-me diate d mec ha nis m a n d w hic h ma y re q uire m ore 
fre q ue nt m o nit ori n g a n d/ or i nter ve nti o ns s uc h as ster oi ds, i m m u n os u p pressa nts 
a n d/ or h or m o ne re place me nt t hera p y. T hese A E SIs are bei n g cl osel y m o nit ore d i n 
cli nical st u dies wit h d ur val u ma b m o n ot hera p y a n d c o m bi nati o n t hera p y. A n 
i m m u ne-relate d a d verse e ve nt (ir A E) is defi ne d as a n a d verse e ve nt t hat is 
ass ociate d wit h dr u g e x p os ure a n d is c o nsiste nt wit h a n i m m u ne- me diate d 
mec ha nis m of acti o n a n d w here t here is n o clear alter nate eti ol o g y. Ser ol o gic, 
i m m u n ol o gic, a n d hist ol o gic ( bi o ps y) data, as a p pr o priate, s h o ul d be use d t o 
s u p p ort a n ir A E dia g n osis. A p pr o priate eff orts s h o ul d be ma de t o r ule o ut 
ne o plastic, i n fecti o us, meta b olic, t o xi n, or ot her eti ol o gic ca uses of t he ir A E. 
If t he I n vesti gat or has a n y q uesti o ns i n re gar ds t o a n a d verse e ve nt ( A E) bei n g a n 
ir A E, t he I n vesti gat or s h o ul d pr o m ptl y c o ntact t he St u d y P h ysicia n. 
A E SIs o bser ve d wit h d ur val u ma b i ncl u de: 
•  C olitis  
•  P ne u m o nitis 
•  A L T/ A S T i ncreases / he patitis / he pat ot o xicit y  
•  Ne ur o pat h y / ne ur o m usc ular t o xicit y (i.e. e ve nts of e nce p halitis, peri p heral 
m ot or a n d se ns or y ne ur o pat hies, G uillai n- Barré, a n d m yast he nia gra vis) 
•  E n d ocri n o pat h y (i.e. e ve nts of h y p o p h ysitis, a dre nal i ns ufficie nc y, a n d 
h y per- a n d h y p ot h yr oi dis m) 
•  Der matitis  
•  Ne p hritis  
•  Pa ncreatitis ( or la b orat or y para meter s s u g gesti ve of pa ncreatitis - i ncrease d 
ser u m li pase , i ncrease d ser u m a m ylase)   
F urt her i nf or mati o n o n t hese ris ks (e. g. prese nti n g s y m pt o ms) ca n be f o u n d i n t he 
c urre nt versi o n of t he D ur val u ma b I n vesti gat or’s  Br oc h ure. 
7. 4. 2. 1  P ne u m o nitis  
A d verse e ve nts of p ne u m o nitis are of i nterest f or Astra Ze neca/ Me d I m m u ne, as 
p ne u m o nitis has bee n re p orte d wit h a nti- P D - 1 M A bs [3 6 ].  I nitial w or k- u p s h o ul d 
i ncl u de hi g h-res ol uti o n C T sca n, r uli n g o ut i nfecti o n, a n d p ulse o xi metr y. 
P ul m o nar y c o ns ultati o n is hi g hl y rec o m me n de d.  

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G ui deli nes f or t he ma na ge me nt of s u bjects wit h i m m u ne -me diate d e ve nts 
i ncl u di n g p ne u m o nitis are o utli ne d i n A p pe n di x D . 
7. 4. 2. 2  H y perse nsiti vit y Re acti o ns  
H y perse nsiti vit y reacti o ns as well as i nf usi o n -relate d reacti o ns ha ve bee n re p orte d 
wit h a nti- P D - L 1 a n d a nti-P D - 1 t hera p y. As wit h t he a d mi nistrati o n of a n y f orei g n 
pr otei n a n d/ or ot her bi ol o gic a ge nts, reacti o ns f oll o wi n g t he i nf usi o n of m A bs ca n 
be ca use d b y vari o us mec ha nis ms, i ncl u di n g ac ute a na p h ylactic (i m m u n o gl o b uli n 
E- me diate d) a n d a na p h ylact oi d reacti o ns a gai nst t he m A b , a n d ser u m sic k ness. 
Ac ute aller gic reacti o ns ma y occ ur, ma y be se vere, a n d ma y res ult i n deat h. Ac ute 
aller gic reacti o ns ma y i ncl u de h y p ote nsi o n, d ys p nea, c ya n osis, res pirat or y fail ure, 
urticaria, pr urit us, a n gi oe de ma, h y p ot o nia, art hral gia, br o nc h os pas m, w heeze, 
c o u g h, dizzi ness, fati g ue, hea dac he, h y perte nsi o n, m yal gia, v o miti n g a n d 
u nres p o nsi ve ness.  
G ui deli nes f or ma na ge me nt of s u bjects  wit h h y perse nsiti vit y (i ncl u di n g 
a na p h ylactic reacti o n) a n d i nf usi o n- relate d reacti o ns are o utli ne d i n Secti o n 
5. 1. 2. 2 . 
7. 4. 2. 3  He p atic f u ncti o n a b n or m alities ( he p at ot o xicit y)  
I ncrease d tra nsa mi nases ha ve bee n re p orte d d uri n g treat me nt wit h a nti-P D -
L 1/a nti- P D - 1 a nti b o dies [3 7 ]. I nfla m mat or y he patitis has bee n re p orte d i n 3 % t o 
9 % of s u bjects treate d wit h a nti -C T L A - 4 m o n ocl o nal a nti b o dies (e. g., 
i pili m u ma b).  T he cli nical ma nifestati o ns of i pili m u ma b-treate d s u bjects i ncl u de d 
ge neral wea k ness, fati g ue, na usea a n d/ or mil d fe ver a n d i ncrease d li ver f u ncti o n 
tests s uc h as A S T, A L T, al kali ne p h os p hatase, a n d/ or t otal bilir u bi n. 
He patic f u ncti o n a b n or malit y is defi ne d as a n y i ncrease i n A L T or A S T t o greater 
t ha n 3 × U L N a n d c o nc urre nt  i ncrease i n t otal bilir u bi n t o be greater t ha n 2 × 
U L N. C o nc urre nt fi n di n gs are t h ose t hat deri ve fr o m a si n gle bl o o d dra w or fr o m 
se parate bl o o d dra ws ta ke n wit hi n 8 da ys of eac h ot her. F oll o w- u p i n vesti gati o ns 
a n d i n q uiries will be i nitiate d pr o m ptl y b y t he i n vesti gati o nal site t o deter mi ne 
w het her t he fi n di n gs are re pr o d uci ble a n d/ or w het her t here is o bjecti ve e vi de nce 
t hat clearl y s u p p orts ca usati o n b y a disease (e. g., c h olelit hiasis a n d bile d uct 
o bstr ucti o n wit h diste n de d gall bla d der) or a n a ge nt ot her t ha n t he i n vesti gati o nal 
pr o d uct. G ui deli nes f or ma na ge me nt of s u bjects wit h he patic f u ncti o n 
a b n or malit y are o utli ne d i n Secti o n  4. 6. 2  . 
Cases w here a s u bject s h o ws a n A S T or  A L T ≥3 x U L N or  t otal bilir u bi n ≥ 
2 x U L N ma y nee d t o be re p orte d as S A Es. T hese cases s h o ul d be re p orte d as 
S A Es  if, after e val uati o n t he y meet t he criteria f or a H y’s La w case or if a n y of 
t he i n di vi d ual li ver test para meters f ulfill a n y of t he S A E criteria. 
Criteri a f or H y’s L a w ( F D A G ui d a nce 2 0 0 9) 
•  T he dr u g ca uses he pat ocell ular i nj ur y, ge nerall y s h o w n b y a hi g her i nci de nce 
of 3-f ol d or greater ele vati o ns a b o ve t he U L N of A L T or A S T t ha n t he 
( n o n- he pat ot o xic) c o ntr ol dr u g or place b o  

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•  A m o n g trial s u bjects s h o wi n g s uc h a mi n otra nsferase ele vati o ns, ofte n wit h 
a mi n otra nsferases m uc h greater t ha n 3 x U L N, o ne or m ore al s o s h o w 
ele vati o n of ser u m t otal bilir u bi n t o > 2 x U L N, wit h o ut i nitial fi n di n gs of 
c h olestasis (ele vate d ser u m al kali ne p h os p hatase)  
•  N o ot her reas o n ca n be f o u n d t o e x plai n t he c o m bi nati o n of i ncrease d 
a mi n otra nsferases a n d t otal bilir u bi n, s uc h as viral  he patitis A, B, or C; pre -
e xisti n g or ac ute li ver disease; or a n ot her dr u g ca pa ble of ca usi n g t he 
o bser ve d i nj ur y. 
7. 4. 2. 4  G astr oi ntesti n al dis or ders  
Diarr hea/c olitis is t he m ost c o m m o nl y o bser ve d treat me nt e mer ge nt S A E w he n 
tre meli m u ma b is use d as m o n ot hera p y.  I n rare cases, c ol o n perf orati o n ma y 
occ ur t hat re q uires s ur ger y (c olect o m y) or ca n lea d t o a fatal o utc o me if n ot 
pr o perl y ma na ge d.  G ui deli nes o n ma na ge me nt of diarr hea a n d c olitis i n patie nts 
recei vi n g d ur val u ma b are pr o vi de d i n A p pe n di x D . 
7. 4. 2. 5  E n d ocri ne dis or ders  
I m m u ne- me diate d e n d ocri n o pat hies i ncl u de h y p o p h ysitis, a dre nal i ns ufficie nc y, 
a n d h y per- a n d h y p ot h yr oi dis m.  G ui deli nes f or t he ma na ge me nt of patie nts wit h 
i m m u ne- me diate d e n d ocri ne e ve nts are pr o vi de d i n A p pe n di x D . 
7. 4. 2. 6  P a ncre atic dis or ders  
I m m u ne-me diate d pa ncreatitis i ncl u des a ut oi m m u ne pa ncreatitis, a n d li pase a n d 
a m ylase ele vati o n.  G ui deli nes f or t he ma na ge me nt of patie nts wit h i m m u ne-
me diate d pa ncreatic dis or ders are pr o vi de d i n A p pe n di x D . 
7. 4. 2. 7  Ne ur ot o xicit y 
I m m u ne-me diate d ner v o us s yste m e ve nts i ncl u de e nce p halitis, peri p heral m ot or 
a n d se ns or y ne ur o pat hies, G uillai n- Barré, a n d m yast he nia gra vis.  G ui deli nes f or 
t he ma na ge me nt of patie nts wit h i m m u ne-me diate d ne ur ot o xic e ve nts are 
pr o vi de d i n A p pe n di x D .   
7. 4. 2. 8  Ne p hritis  
C o ns ult wit h Ne p hr ol o gist.  M o nit or f or si g ns a n d s y m pt o ms t hat ma y be relat e d 
t o c ha n ges i n re nal f u ncti o n (e. g. r o uti ne uri nal ysis, ele vate d ser u m B U N a n d 
creati ni ne, decrease d creati ni ne cleara nce, electr ol yte i m bala nce, decrease i n uri ne 
o ut p ut, pr otei n uria, etc. )  
Patie nts s h o ul d be t h or o u g hl y e val uate d t o r ule o ut a n y alter n ati ve eti ol o g y (e. g., 
disease pr o gressi o n, i nfecti o ns etc.)  
Ster oi ds s h o ul d be c o nsi dere d i n t he a bse nce of clear alter nati ve eti ol o g y e ve n f or 
l o w gra de e ve nts ( Gra de 2), i n or der t o pre ve nt p ote ntial pr o gressi o n t o hi g her 
gra de e ve nt. G ui deli nes f or t he ma na ge me nt of patie nts wit h i m m u ne - me diate d 
ne ur ot o xic e ve nts are pr o vi de d i n A p pe n di x D . 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 1 
 
7. 4. 3  Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes N ot 
Q u al if yi n g as S A Es:  
A n e ve nt w hic h is part of t he nat ural c o urse of t he disease u n der st u d y (i.e., 
disease pr o gressi o n) d oes n ot nee d t o be re p orte d as a n S A E. Pr o gressi o n of t he 
s u bject's ne o plasia will be rec or de d i n t he cli nical assess me nts i n t he C R F. Deat h 
d ue t o pr o gressi ve disease is t o be rec or de d o n t he ' Rec or d of Deat h' C R F pa ge 
a n d n ot as a n S A E. H o we ver, if t he pr o gressi o n of t he u n derl yi n g disease is 
greater t ha n t hat w hic h w o ul d n or mall y be e x pecte d f or t he s u bject, or if t he  
i n vesti gat or c o nsi ders t hat t here was a ca usal relati o ns hi p bet wee n st u d y treat me nt 
or pr ot oc ol desi g n/ pr oce d ures a n d t he disease pr o gressi o n, t he n t his m ust be 
re p orte d as a n S A E. A n y ne w pri mar y ca ncer m ust be re p orte d as a n S A E. 
7. 5  
D at a a n d S afet y M o nit ori n g Pl a n 
T he Pri nci pal I n vesti gat or will pr o vi de c o nti n u o us m o nit ori n g of s u bject safet y i n 
t his trial wit h peri o dic re p orti n g t o t he Data a n d Safet y M o nit ori n g C o m mittee 
( D S M C).  
 
Meeti n gs/telec o nfere nces will be hel d at a fre q ue nc y de pe n de nt o n st u d y accr ual, 
a n d i n c o ns ultati o n wit h t he st u d y Bi ostatisticia n.  T hese meeti n gs will i ncl u de t he 
i n vesti gat ors as well as pr ot oc ol n urses, cli nical researc h ass ociates, re g ulat or y 
ass ociates, data ma na gers, bi ostatisticia ns, a n d a n y ot her rele va nt pers o n nel t he 
pri nci pal i n vesti gat ors ma y dee m a p pr o priate.  At t hese meeti n gs, t he researc h 
tea m will disc uss all iss ues rele va nt t o st u d y pr o gress, i ncl u di n g e nr oll me nt, 
safet y, re g ulat or y, data c ollecti o n, etc.” 
 
T he tea m will pr o d uce s u m maries or mi n utes of t hese meeti n gs. T hese s u m maries 
will be a vaila ble f or i ns pecti o n w he n re q ueste d b y a n y of t he re g ulat or y b o dies 
c har ge d wit h t he safet y of h u ma n s u bjects a n d t he i nte grit y of data i ncl u di n g, b ut 
n ot li mite d t o, t he o versi g ht ( Office of H u ma n Researc h Et hics ( O H R E) 
Bi o me dical I R B, t he  O nc ol o g y Pr ot oc ol Re vie w C o m mittee ( P R C) or t he N ort h 
Car oli na Tra C S I nstit ute Data a n d Safet y M o nit ori n g B oar d ( D S M B).   
 
T he U N C L C C C Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) will re vie w t he 
st u d y o n a re g ular ( q uarterl y t o a n n uall y) basis, wit h t he fre q ue nc y of re vie w 
base d o n ris k a n d c o m ple xit y as deter mi ne d b y t he U N C Pr ot oc ol Re vie w 
C o m mittee.  T he U N C PI will be res p o nsi ble f or s u b mitti n g t he f oll o wi n g 
i nf or mati o n f or re vie w: 1) safet y a n d accr ual data i ncl u di n g t he n u m ber of 
s u bjects treate d; 2) si g nifica nt de vel o p me nts re p orte d i n t he literat ure t hat ma y 
affect t he safet y of partici pa nts or t he et hics of t he st u d y; 3) preli mi nar y res p o n se 
data; a n d 4) s u m maries of tea m meeti n gs t hat ha ve occ urre d si nce t he last re p ort.  
Fi n di n gs of t he D S M C re vie w will be disse mi nate d b y me m o t o t he U N C PI, 
P R C, a n d t he U N C I R B a n d D S M B.   
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 2 
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1  
St u d y Desi g n/ St u d y E n d p oi n ts 
T his is a si n gle -ar m n o n-ra n d o mize d p hase II trial i n pre vi o usl y u ntreate d s u bjects 
wit h S C C H N. Treat me nt will c o nsist of 3 parts: ne oa dj u va nt i n d ucti o n wit h 
wee kl y car b o plati n, na b- paclita xel f or si x wee ks i n c o m bi nati o n wit h e ver y ot her 
wee k d ur val u ma b f or fi ve d oses ( 9 wee ks) ( P art 1) pri or t o sta n dar d of care 
s ur ger y ( Part 2).  P ost-o perati ve treat me nt ( P art 3) will var y de pe n di n g o n t he ris k 
cate g or y assi g ne d t o t he s u bject d uri n g s ur ger y.  
 
T he pri mar y o bjecti ve of t his st u d y is t o esti mate t he pat h ol o gic c o m plete 
res p o nse rate after i n d ucti o n c he m ot hera p y. 
8. 2  
S a m ple Size a n d Accr u al  
Base d o n preli mi nar y data fr o m L C C C 1 1 2 5, w hic h ha d l o wer ris k s u bsites (t he 
s u bjects m ostl y ha d or o p har y n x ca ncer d ue t o t he re q uire me nt f or tra ns oral 
resecta bilit y) a n d use d la pata ni b i nstea d of d ur val u ma b, we ha ve set t he n ull 
h y p ot hesis pat h ol o gic c o m plete res p o nse rate ( p C R R) at 3 0 %. T his n ull 
h y p ot hesis will be teste d a gai nst a o ne-si de d alter nati ve. A o ne sa m ple bi n o mial 
test wit h a 0. 0 5 0 o ne-si de d si g nifica nce level will ha ve 8 0 % p o wer t o detect t he 
differe nce bet wee n t he n ull h y p ot hesis pr o p orti o n of 0. 3 a n d t he alter nati ve 
pr o p orti o n of 0. 5 w he n t he sa m ple size is 3 7. If 1 7/ 3 7 or m ore ha ve a p C R, we 
will reject t he n ull h y p ot hesis. Of n ote, we all o w f or a t otal of u p t o 2 u ne val ua ble 
s u bjects, t h us t he t otal n of u p t o 3 9 s u bjects .  T his sa m ple size was calc ulate d 
usi n g S W O G Stat o nli ne calc ulat or.    
 
Se q ue ntial b o u n daries will be use d t o s us pe n d t he trial if e xcessi ve t o xicit y is 
see n. If t he st u d y reac hes a st op pi n g b o u n dar y, it ma y be ter mi nate d b y t he PI, or 
s u b mitte d t o t he Data a n d Safet y M o nit ori n g C o m mittee wit h a descri pti o n of t he 
fail ures t o date a n d a rati o nale f or w h y t he st u d y s h o ul d be c o nti n ue d. A d ose-
li miti n g t o xicit y ( D L T) is defi ne d as a n y gra de 4 a d verse e ve nt attri b ute d t o 
i n d ucti o n t hera p y or a n y  dela y t o s ur ger y greater t ha n 5 0 da ys f oll o wi n g t he last 
d ose of i n d ucti o n t hera p y . T he accr ual will be halte d if t he n u m ber of D L Ts is 
e q ual t o or e xcee ds b n o ut of n s u bjects wit h f ull t o xicit y f oll o w -u p (see ta ble 
bel o w). T his is a P oc oc k t y pe st o p pi n g b o u n dar y [ 3 8 ] t hat ass u mes t hat a D L T 
rate of 0.1 5 is acce pta ble. If t he tr ue D L T rate is e q ual t o 0.1 5 , t he pr o ba bilit y of 
cr ossi n g t he b o u n dar y is 0. 0 5  [3 9 ]. St o p pi n g r ule f or D L T. T he trial is st o p pe d if 
t here are  
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 4 
 
All perce nta ges will be re p orte d wit h e xact 9 5 % c o nfi de nce i nter vals.  A ka p pa 
statistic will be use d t o see h o w well t he pre dicte d ris k gr o u p a grees wit h t he 
act ual assi g ne d ris k gr o u p f or Part 3.  Ti me t o e ve nt a nal yses will be d o ne usi n g 
t he Ka pla n Meier met h o d a n d me dia n ti mes will be re p orte d wit h 9 5 % c o nfi de nce 
i nter vals.   
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 5 
9. 0  
S T U D Y M A N A G E M E N T  
9. 1  
I nstit uti o n al Re vie w B o ar d (I R B) A p pr o v al a n d C o nse nt 
It is e x pecte d t hat t he I R B will ha ve t he pr o per re prese ntati o n a n d f u ncti o n i n 
acc or da nce wit h fe derall y ma n date d re g ulati o ns.  T he I R B s h o ul d a p pr o ve t he 
c o nse nt f or m a n d pr ot oc ol. 
 
I n o btai ni n g a n d d oc u me nti n g i nf or me d c o nse nt, t he i n vesti gat or s h o ul d c o m pl y 
wit h t he a p plica ble re g ulat or y re q uire me nt(s), a n d s h o ul d a d here t o G o o d Cli nical 
Practice ( G C P) a n d t o et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n 
of Helsi n ki.  
  
  
 
Bef ore recr uit me nt a n d e nr oll me nt o nt o t his st u d y, t he s u bject will be gi ve n a f ull 
e x pla nati o n of t he st u d y a n d will be gi ve n t he o p p ort u nit y t o re vie w t he c o nse nt 
f or m. Eac h c o nse nt f or m m ust i ncl u de all t he rele va nt ele me nts c urre ntl y re q uire d 
b y t he F D A Re g ulati o ns a n d l ocal or state re g ulati o ns. O nce t his esse ntial 
i nf or mati o n has bee n pr o vi de d t o t he s u bject a n d t he i n vesti gat or is ass ure d t hat 
t he s u bject u n dersta n ds t he i m plicati o ns of partici pati n g i n t he st u d y, t he s u bject 
will be as ke d t o gi ve c o nse nt t o partici pate i n t he st u d y b y si g ni n g a n 
I R B-a p pr o ve d c onse nt f or m.  
 
Pri or t o a s u bject’s partici pati o n i n t he trial, t he writte n i nf or me d c o nse nt f or m 
s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject a n d b y t he pers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt disc ussi o n.  
9. 2  
Re q uire d D oc u me nt ati o n  
Bef ore t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g d oc u me ntati o n m ust be 
pr o vi de d t o t he Cli nical Pr ot oc ol Office ( C P O) at t he U ni versit y of N ort h 
Car oli na.  
 
•  A c o p y of t he official I R B a p pr o val letter f or t he pr ot oc ol a n d 
i nf or me d c o nse nt 
•  I R B me m bers hi p list 
•  C Vs a n d me dical lice ns ure f or t he pri nci pal i n vesti gat or a n d a n y s u b -
i n vesti gat ors w h o will be i n v ol ve d i n t he st u d y. 
•  F or m F D A 1 5 7 2 a p pr o priatel y fille d o ut a n d si g ne d wit h a p pr o priate 
d oc u me ntati o n  
•  C A P a n d C LI A La b orat or y certificati o n n u m bers a n d i nstit uti o n la b 
n or mal val ues  
•  E xec ute d cli nical researc h c o ntract  
 
9. 3  
Re gistr ati o n Pr oce d ures  
All s u bjects m ust be re gistere d wit h t he L C C C C P O M ultice nter Office at t he 
U ni versit y of N ort h Car oli na bef ore e nr oll me nt t o st u d y.  T o re gister a s u bject,  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 6 
call t he M ultice nter  office  at 9 1 9- 9 6 6- 7 3 5 9  M o n da y- F ri da y 8: 3 0  a m – 5: 0 0 p m 
E S T .  Sca n a n d e mail t he U N C Pr oject Ma na ger 
( C P O M ulti Ce nter @ me d. u nc.e d u; preferre d) or fa x ( 9 1 9-9 6 6 - 4 3 0 0) t he 
re gistrati o n f or m, si g ne d i nf or me d c o nse nts , si g ne d eli gi bilit y f or m a n d all s o urce 
d oc u me nts  t o c o nfir m eli gi bilit y. Eli gi bilit y ma y be c o nfir me d b y t he U N C St u d y 
C o or di nat or f or s u bjects treate d at U N C. W he n se n di n g re gistrati o n re q uest wit h 
eli gi bilit y d oc u me ntati o n, please all o w 2 4 h o ur s f or s o urce t o be re vie we d. 
9. 4  
D at a M a n a ge me nt a n d M o nit ori n g/ A u diti n g  
T he  C P O M ultice nter Office of t he U N C L C C C will ser ve as t he c o or di nati n g 
ce nter f or t his trial. Data will be c ollecte d t hr o u g h a we b base d cli nical researc h 
platf or m, O n C ore ® . Ot her st u d y i nstit uti o ns will be gi ve n a pass w or d t o directl y 
e nter t heir o w n data o nt o t he we b site via electr o nic case re p ort f or ms (e C R Fs).  
M ultice nter  pers o n nel will c o or di nate a n d ma na ge data f or q ualit y c o ntr ol 
ass ura nce a n d i nte grit y.  
 
All data will be c olle cte d a n d e ntere d i nt o O n C ore ® b y t he affiliate st u d y tea ms at 
partici pati n g i nstit uti o ns. T he i n vesti gat ors at eac h site will all o w m o nit ors t o 
re vie w all s o urce d oc u me nts s u p p orti n g data e ntere d i nt o O n C ore® . T he 
M ultice nter  Data C o or di nat or ca n be reac hed at 9 1 9 - 8 4 3- 2 7 4 2 or 1- 8 7 7-6 6 8 -
0 6 8 3. 
 
All data will be m o nit ore d, a n d s o urce data will be verifie d o n selecte d 
s u bjects.  Q ueries will be iss ue d o n a n o n g oi n g basis o n all s u bjects. Partici pati n g 
sites s h o ul d res p o n d t o data q ueries wit hi n 1 4 da ys of receipt. T he L C C C 
c o m plia nce c o m mittee or t heir desi g nee will a u dit trial sites e ver y t wel ve m o nt hs 
w hile still e nr olli n g or s u bjects are still o n treat me nt. Partici pati n g sites m ust se n d 
s o urce a n d re g ulat or y d oc u me nts t o L C C C u p o n re q uest, f or re m ote m o nit ori n g 
a n d/ or a u dit re vie w.  
9. 5  
A d here nce t o t he Pr ot oc ol  
E xce pt f or a n e mer ge nc y sit uati o n i n w hic h pr o per care f or t he pr otecti o n, safet y, 
a n d well- bei n g of t he st u d y s u bject re q uires alter nati ve treat me nt, t he st u d y s hall 
be c o n d ucte d e xactl y as descri be d i n t h e a p pr o ve d pr ot oc ol.   
9. 5. 1  E mer ge nc y M o dific ati o ns  
U N C a n d Affiliate i n vesti gat ors ma y i m ple me nt a de viati o n fr o m, or a c ha n ge of, 
t he pr ot oc ol t o eli mi nate a n i m me diate hazar d(s) t o trial s u bjects wit h o ut pri or 
U N C or t heir res pecti ve i nstit uti o n’s I R B/I E C a p pr o val/fa v ora ble o pi ni o n.   
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B: 
F or a n y s uc h e mer ge nc y m o dificati o n i m ple me nte d, a U N C I R B m o dificati o n 
f or m m ust be c o m plete d b y U N C Researc h Pers o n nel wit hi n fi ve ( 5) b usi ness 
da ys of ma ki n g t he c ha n ge.   
 
F or I nstit uti o ns Rel yi n g o n T heir O w n I R B: 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 7 
F or Affiliate i n vesti gat ors rel yi n g o n t heir o w n i nstit uti o n’s I R B, as s o o n as 
p ossi ble after t he m o dificati o n has bee n ma de, t he i m ple me nte d de viati o n or 
c ha n ge a n d t he reas o ns f or it s h o ul d be s u b mitte d t o: 
 
•  T o U N C Pri nci pal I n vesti gat or f or a gree me nt  
•  T he Affiliate i nstit uti o n’s I R B f or re vie w a n d a p pr o val. ( O nce 
I R B’s res p o nse is recei ve d, t his s h o ul d be f or war de d t o t he 
M ultice nter  Re g ulat or y Ass ociate).  
9. 5. 2  Si n gle S u bject E xce pti o ns  
Eli gi bilit y si n gle s u bject e xce pti o ns are n ot per mitte d f or Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter I n vesti gat or I nitiate d Trials u n der a n y 
circ u msta nces. Ot her t y pes of si n gle s u bject e xce pti o ns ma y be all o we d if pr o per 
re g ulat or y re vie w has bee n c o m plete d i n acc or da nce wit h Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter’s Si n gle S u bject E xce pti o ns P olic y.  
9. 5. 3  Ot her Pr ot oc ol De vi ati o ns Vi ol ati o ns  
Acc or di n g t o U N C’s I R B, a pr ot oc ol de viati o n is a n y u n pla n ne d varia nce fr o m a n 
I R B a p pr o ve d pr ot oc ol t hat:  
•  Is ge nerall y n ote d or rec o g nize d after it occ urs 
•  Has n o s u bsta nti ve effect o n t he ris ks t o researc h partici pa nts  
•  Has n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n 
or t he val ue of t he data c ollecte d  
•  Di d n ot res ult fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot oc ol varia nce is c o nsi dere d a vi olati o n  if t he varia nce meets 
a n y of t he f oll o wi n g criteria:  
•  Has har me d or i ncrease d t he ris k of har m t o o ne or m ore researc h 
partici pa nts.  
•  Has da ma ge d t he scie ntific i nte grit y of t he data c ollecte d f or t he st u d y.  
•  Res ults fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
in vesti gat or(s).  
•  De m o nstrates seri o us or c o nti n ui n g n o nc o m plia nce wit h fe deral 
re g ulati o ns, State la ws, or U ni versit y p olicies. 
 
If a de viati o n or vi olati o n occ urs, please f oll o w t he g ui deli nes bel o w: 
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B: 
Pr ot oc ol De vi ati o ns: U N C or Affiliate pers o n nel will rec or d t he de viati o n i n 
O n C ore ® , a n d re p ort t o a n y s p o ns or or data a n d safet y m o nit ori n g c o m mittee i n 
acc or da nce wit h t heir p olicies.  De viati o ns s h o ul d be s u m marize d a n d re p orte d t o 
t he I R B at t he ti me of c o nti n ui n g re vie w.  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 8 
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p orte d b y U N C pers o n nel wit hi n o ne 
( 1) wee k of t he i n vesti gat or bec o mi n g a ware of t he e ve nt usi n g t he sa me I R B 
o nli ne mec ha nis m use d t o re p ort U na ntici pate d Pr o ble ms.   
 
F or I nstit uti o ns Re l yi n g o n Their O w n I R B: 
I n a d diti o n t o a d heri n g t o t he p olicies re gar di n g pr ot oc ol c o m plia nce set f ort h b y 
y o ur i nstit uti o n’s I R B, t he f oll o wi n g is als o re q uire d: 
 
Pr ot oc ol De vi ati o ns: I n t he e ve nt a de viati o n fr o m pr ot oc ol pr oce d ures is 
i de ntifie d, rec or d t he de viati o n i n O n C ore® . 
 
Pr ot oc ol Vi ol ati o ns: A n y pr ot oc ol vi olati o n t hat occ urs m ust be re p orte d t o y o ur 
I R B per i nstit uti o nal p olicies a n d re p orte d t o t he U N C M ultice nter Pr oject 
Ma na ger  wit hi n 5 da ys. U N C-C H will deter mi ne if t he vi olati o n affects t h e safet y 
of t he s u bject a n d i nte grit y of t he data.  O nce y o ur i nstit uti o n’s I R B res p o nse is 
recei ve d, please f or war d t o t he M ultice nter  Re g ulat or y Ass ociate.  
 
U n a ntici p ate d Pr o ble ms:  
Affiliate Sites:  
A n y e ve nts t hat meet t he criteria f or “ U na ntici pate d Pr o ble ms ( U Ps)” as defi ne d 
b y U N C’s I R B m ust als o be re p orte d t o t he U N C M ultice nter Pr ojec Ma na ger .   
T he U N C M ultice nter Re g ulat or y Ass ociate  will re p ort t he e ve nt t o t he U N C I R B 
usi n g t he I R B’s we b- base d re p orti n g s yste m.  E xa m ples of s uc h U Ps i ncl u de a 
l ost or st ole n la pt o p c o m p uter t hat c o ntai ns se nsiti ve st u d y i nf or mati o n. 
 
U N C  
A n y e ve nts t hat meet t he criteria f or “ U na ntici pate d Pr o ble ms” as defi ne d b y 
U N C’s I R B m ust be re p orte d b y t he St u d y C o or di nat or usi n g t he I R B’s we b -
base d re p orti n g s yste m.  
 
A me n d me nts t o t he Pr ot oc ol 
S h o ul d a me n d me nts t o t he pr ot oc ol be re q uire d, t he a me n d me nts will be 
ori gi nate d a n d d oc u me nte d b y t he Pri nci pal I n vesti gat or at U N C.  It s h o ul d als o 
be n ote d t hat w he n a n a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y 
desi g n or t he p ote ntial ris k t o t he s u bject, a re vise d c o nse nt f or m mi g ht be 
re q uire d.   
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B: 
T he writte n a me n d me nt, a n d if re q uire d t he a me n de d c o nse nt f or m, m ust be se nt 
t o U N C’s I R B f or a p pr o val pri or t o i m ple me ntati o n.   
 
F or I nstit uti o ns Rel yi n g o n T heir O w n I R B: 
I n vesti gat ors m ust s u b mit t he U N C I R B a p pr o ve d a me n d me nt t o t heir 
i nstit uti o n’s IR B f or a p pr o val.  F or m ulti- ce nter st u dies, a n y affiliate site m ust 
s u b mit t heir i nf or me d c o nse nt re visi o ns t o t he M ultice nter  Re g ulat or y Ass ociate 
pri or t o s u b missi o n t o t heir I R B.   

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
6 9 
9. 6  
Rec or d Rete nti o n  
St u d y d oc u me ntati o n i ncl u des all e C R Fs, data c orrecti o n f or ms or q ueries, s o urce 
d oc u me nts, S p o ns or -I n vesti gat or c orres p o n de nce, m o nit ori n g l o gs/letters, a n d 
re g ulat or y d oc u me nts (e. g., pr ot oc ol a n d a me n d me nts, I R B c orres p o n de nce a n d 
a p pr o val, si g ne d s u bject c o nse nt f or ms). 
 
S o urce d oc u me nts i ncl u de all rec or d i n gs of o bser vati o ns or n otati o ns of cli nical 
acti vities a n d all re p orts a n d rec or ds necessar y f or t he e val uati o n a n d 
rec o nstr ucti o n of t he cli nical researc h st u d y. 
 
G o ver n me nt a ge nc y re g ulati o ns a n d directi ves re q uire t hat all st u d y 
d oc u me ntati o n pertai ni n g t o t he c o n d uct of a cli nical trial m ust be retai ne d b y t he 
st u d y i n vesti gat or.  I n t he case of a st u d y wit h a dr u g see ki n g re g ulat or y a p pr o val 
a n d mar keti n g, t hese d oc u me nts s hall be retai ne d f or at least t w o years after t he 
last a p pr o val of mar keti n g a p plicati o n i n a n I nter nati o nal C o nfere nce o n 
Har m o nizati o n (I C H) re gi o n.  I n all ot her cases, st u d y d oc u me nts s h o ul d be ke pt 
o n file u ntil t hree years after t he c o m pleti o n a n d fi nal st u d y re p ort of t his 
i n vesti gati o nal st u d y. 
9. 7  
O bli g ati o ns of I n vesti g at ors 
T he Pri nci pal I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he cli nical trial at t he 
site i n acc or da nce wit h Title 2 1 of t he C o de of Fe deral Re g ulati o ns a n d/ or t he 
Declarati o n of Helsi n ki. T he Pri nci pal I n vesti gat or is res p o nsi ble f or pers o nall y 
o verseei n g t he treat me nt of all st u d y s u bjects .  T he Pri nci pal I n vesti gat or m ust 
ass ure t hat all st u d y site pers o n nel, i ncl u di n g s u b -i n vesti gat ors a n d ot her st u d y 
staff me m bers, a d here t o t he st u d y pr ot oc ol a n d all F D A/ G C P/ N CI re g ulati o ns 
a n d g ui deli nes re gar di n g c li nical trials b ot h d uri n g a n d after st u d y c o m pleti o n. 
 
T he Pri nci pal I n vesti gat or at eac h i nstit uti o n or site will be res p o nsi ble f or 
ass uri n g t hat all t he re q uire d data will be c ollecte d a n d e ntere d i nt o t he e C R Fs. 
Peri o dicall y, m o nit ori n g visits will be  c o n d ucte d, a n d t he Pri nci pal I n vesti gat or 
will pr o vi de access t o his/ her ori gi nal rec or ds t o per mit verificati o n of pr o per 
e ntr y of data. At t he c o m pleti o n of t he st u d y, all e C R Fs will be re vie we d b y t he 
Pri nci pal I n vesti gat or a n d will re q uire his/ her fi nal si g nat ure t o verif y t he 
acc urac y of t he data.  
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 0 
1 0. 0  R E F E R E N C E S  
 
1.  
F orastiere, A. A., et al., C o nc urre nt c he m ot her a py a n d r a di ot her a py f or or g a n 
preserv ati o n i n a dv a nce d l ary n ge al c a ncer.  N E n gl J Me d, 2 0 0 3. 3 4 9 ( 2 2): p. 
2 0 9 1- 8. 
2.  
P os ner, M. R., et al., Cis pl ati n a n d fl u or o ur acil al o ne or wit h d ocet axel i n he a d 
a n d neck c a ncer.  N E n gl J Me d, 2 0 0 7. 3 5 7 ( 1 7): p. 1 7 0 5- 1 5. 
3.  
J. H. L orc h, M. R. P., O. G ol o u be va, K. J. C ulle n, N. J. Sarlis, R. B. Tis hler, R. I. 
Ha d da d, T A X 3 2 4 St u d y Gr o u p, L o n g- ter m res ults fr o m T A X 3 2 4: A p h ase III 
tri al of se q ue nti al t her a py c o m p ari n g T P F t o P F i n l oc ally a dv a nce d ( L A) 
s q u a m o us cell c a ncer of t he he a d a n d neck ( H N C), i n J Cli n O nc ol 2 8: 1 5s, 2 0 1 0 
(s u p pl; a bstr 5 5 1 2). 2 0 1 0: C hica g o, I L. 
4.  
Ha d da d, R.I. a n d M. R. P os ner, I n d ucti o n c he m ot her a py i n he a d a n d neck c a ncer. 
J Cli n O nc ol, 2 0 0 9. 2 7 ( 2 3): p. e 5 2- 3; a ut h or re pl y e 5 4. 
5.  
Haraf, D.J., et al., I n d ucti o n c he m ot her a py f oll o we d by c o nc o mit a nt T F H X 
c he m or a di ot her a py wit h re d uce d d ose r a di ati o n i n a dv a nce d he a d a n d neck 
c a ncer. Cli n Ca ncer Res, 2 0 0 3. 9 ( 1 6 Pt 1): p. 5 9 3 6- 4 3. 
6.  
Kies, M. S., et al., I n d ucti o n c he m ot her a py a n d cet uxi m a b f or l oc ally a dv a nce d 
s q u a m o us cell c arci n o m a of t he he a d a n d neck: res ults fr o m a p h ase II 
pr os pective tri al.  J Cli n O nc ol, 2 0 1 0. 2 8 ( 1): p. 8- 1 4. 
7.  
H. J. Wa ne b o, M. G., B. B urt ness, S. S pe ncer, J. Ri d ge, A. F orastiere, M. 
G he bre mic hael, P h ase II ev al u ati o n of cet uxi m a b ( C 2 2 5) c o m bi ne d wit h 
i n d ucti o n p aclit axel a n d c ar b o pl ati n f oll o we d by C 2 2 5, p aclit axel, c ar b o pl ati n, 
a n d r a di ati o n f or st a ge III/I V o per a ble s q u a m o us c a ncer of t he he a d a n d neck 
( E C O G, E 2 3 0 3). J o ur nal of Cli nical O nc ol o g y, 2 0 0 7 A S C O A n n ual Meeti n g 
Pr ocee di n gs Part I. V ol 2 5, N o. 1 8 S (J u ne 2 0 S u p ple me nt), 2 0 0 7: 6 0 1 5. 
8. 
Weiss J, H. D., Deal A M, C hera B S, Weissler M C, M ur p h y B A, Lia o JJ, Grille y -
Ols o n J E, Gil bert J, Ne o a dj uv a nt c ar b o pl ati n, n a b- p aclit axel a n d cet uxi m a b pri or 
t o st a n d ar d of c are c he m or a di ot her a py f or N 2 b or u nresect a ble s q u a m o us he a d 
a n d neck c a ncer.  J Cli n O nc ol 3 4, 2 0 1 6 (s u p pl; a bstr 6 0 7 5). 
9. 
Weiss, J. M., et al., C a pecit a bi ne a n d l a p ati ni b f or t he first- li ne tre at me nt of 
met ast atic/rec urre nt he a d a n d neck s q u a m o us cell c arci n o m a.  Ca ncer, 2 0 1 6. 
1 2 2 ( 1 5): p. 2 3 5 0- 5. 
1 0. 
Se gal N H, O. S. - H., Bal ma n o u kia n A S, F ury M G, Massarellia E, Bra h mer J R, 
Weiss J, Sc h offs ki P, A nt o nia SJ, Massar d C, Za n d ber g D P, K hleif S N, Re belatt o 
M C, Steele K E, R o b bi ns P B, Bla ke- Has ki ns J A, B utler M O, S afety a n d effic acy 
of M E DI 4 7 3 6, a n a nti- P D - L 1 a nti b o dy, i n p atie nts fr o m a s q u a m o us cell 
c arci n o m a of t he he a d a n d neck ( S C C H N) ex p a nsi o n c o h ort.  J Cli n O nc ol 3 3, 
2 0 1 5 (s u p pl; a bstr 3 0 1 1). 
1 1.  
Ca mi d ge R, L. S., P o w derl y J, Rea d y N, H o di S, Getti n ger G, Giacc o ne G, Li u B, 
Walli n J, F u n ke R, Water ka m p D, Heist R, Atez oliz u m a b ( M P D L 3 2 8 0 A) 
C o m bi n e d wit h Pl ati n u m- B ase d C he m ot her a py i n N o n- S m all Cell L u n g C a ncer 
( N S C L C): A P h ase I b S afety a n d Effic acy U p d ate. W orl d L u n g C o nferece, 2 0 1 5. 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 1 
1 2.  
Nar wal, R., L. K. R os k os, a n d G.J. R o b bie, P o p ul ati o n p h ar m ac oki netics of 
sif ali m u m a b, a n i nvesti g ati o n al a nti-i nterfer o n- al p h a m o n ocl o n al a nti b o dy, i n 
syste mic l u p us eryt he m at os us. Cli n P har mac o ki net, 2 0 1 3. 5 2 ( 1 1): p. 1 0 1 7- 2 7. 
1 3.  
N g, C. M., et al., R ati o n ale f or fixe d d osi n g of pert uz u m a b i n c a ncer p atie nts 
b ase d o n p o p ul ati o n p h ar m ac oki netic a n alysis.  P har m Res, 2 0 0 6. 2 3 ( 6): p. 1 2 7 5-
8 4. 
1 4.  
Wa n g, D. D., et al., Fixe d d osi n g vers us b o dy size - b ase d d osi n g of m o n ocl o n al 
a nti b o dies i n a d ult cli nic al tri als.  J Cli n P har mac ol, 2 0 0 9. 4 9 ( 9): p. 1 0 1 2- 2 4. 
1 5.  
Z ha n g, S., et al., Fixe d d osi n g vers us b o dy size - b ase d d osi n g of ther a pe utic 
pe pti des a n d pr otei ns i n a d ults.  J Cli n P har mac ol, 2 0 1 2. 5 2 ( 1): p. 1 8- 2 8. 
1 6.  
Lara m ore, G. E., et al., A dj uv a nt c he m ot her a py f or resect a ble s q u a m o us cell 
c arci n o m as of t he he a d a n d neck: re p ort o n I nter gr o u p St u dy 0 0 3 4.  I nt J Ra diat 
O nc ol Bi ol P h ys, 1 9 9 2. 2 3 ( 4): p. 7 0 5- 1 3. 
1 7.  
C o o per, J. S., et al., P ost o per ative c o nc urre nt r a di ot her a py a n d c he m ot her a py f or 
hi g h-risk s q u a m o us-cell c arci n o m a of t he he a d a n d neck.  N E n gl J Me d, 2 0 0 4. 
3 5 0 ( 1 9): p. 1 9 3 7- 4 4. 
1 8.  
C o o per, J. S., et al., L o n g- ter m f oll o w- u p of t he R T O G 9 5 0 1/i nter gr o u p p h ase III 
tri al: p ost o per ative c o nc urre nt r a di ati o n t her a py a n d c he m ot her a py i n hi g h-risk 
s q u a m o us cell c arci n o m a of t he he a d a n d neck. I nt J Ra diat O nc ol Bi ol P h ys, 
2 0 1 2. 8 4 ( 5): p. 1 1 9 8- 2 0 5. 
1 9.  
Ber nier, J., et al., P ost o per ative irr a di ati o n wit h or wit h o ut c o nc o mit a nt 
c he m ot her a py f or l oc ally a dv a nce d he a d a n d neck c a ncer.  N E n gl J Me d, 2 0 0 4. 
3 5 0 ( 1 9): p. 1 9 4 5- 5 2. 
2 0.  
Ber nier, J., et al., Defi ni n g risk levels i n l oc ally a dv a nce d he a d a n d  neck c a ncers: 
a c o m p ar ative a n alysis of c o nc urre nt p ost o per ative r a di ati o n pl us c he m ot her a py 
tri als of t he E O R T C ( # 2 2 9 3 1) a n d R T O G ( # 9 5 0 1). Hea d Nec k, 2 0 0 5. 2 7 ( 1 0): p. 
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2 1.  
Le v y, A., et al., C o nc urre nt irr a di ati o n wit h t he a nti- pr o gr a m me d cell de a t h 
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fr o m a p h ase 1/ 2 tri al. E ur J Ca ncer, 2 0 1 6. 6 8 : p. 1 5 6- 1 6 2. 
2 2.  
Me dI m m u ne, I nvesti g at or's Br oc h ure ( D urv al u m a b). 2 0 1 6. 
2 3.  
Sala ma, J. K., et al., Cli nic al pr actice g ui d a nce f or r a di ot her a py pl a n ni n g after 
i n d ucti o n c he m ot her a py i n l oc ore gi o n ally a dv a nce d he a d-a n d -neck c a ncer.  I nt J 
Ra diat O nc ol Bi ol P h ys, 2 0 0 9. 7 5 ( 3): p. 7 2 5- 3 3. 
2 4.  
Sei wert, T. Y., et al., S afety a n d cli nic al activity of pe m br oliz u m a b f or tre at me nt of 
rec urre nt or met ast atic s q u a m o us cell c arci n o m a of t he he a d a n d neck 
( K E Y N O T E- 0 1 2): a n o pe n-l a bel, m ultice ntre, p h ase 1 b tri al. La ncet O nc ol, 2 0 1 6. 
1 7 ( 7): p. 9 5 6- 6 5. 
2 5.  
C h o w, L. Q., et al., A ntit u m or Activity of Pe m br oliz u m a b i n Bi o m arker- U nselecte d 
P atie nts Wit h Rec u rre nt a n d/ or Met ast atic He a d a n d Neck S q u a m o us Cell 
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O nc ol, 2 0 1 6. 
2 6.  
Ferris r L, B. G., Fa yette J, G ui ga y J, C ole vas D, Licitra L F, Harri n gt o n KJ, Kas per 
S, V o kes E E, E ve n C, W or de n F P, Ha d da d RI, Ki y ota N, Ta hara M, M o n ga M, 
L y nc h MJ, Geese WJ, K o pit J, S ha w J W a n d Gillis o n M L, F urt her ev al u ati o ns of 
niv ol u m a b ( niv o) vers us i nvesti g at or’s c h oice (I C) c he m ot her a py f or rec urre nt or 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 2 
met ast atic ( R/ M) s q u a m o us cell c arci n o m a of t he he a d a n d neck ( S C C H N): 
C heck M ate 1 4 1.  J Cli n O nc ol 3 4, 2 0 1 6 (s u p pl; a bstr 6 0 0 9). 
2 7.  
Harri n gt o n KJ, B. A., R o bi ns o n M, et al., P h ase II St u dy of or al l a p ati ni b, a d u al-
tyr osi ne ki n ase i n hi bit or, c o m bi ne d wit h c he m or a di ot her a py ( C R T) i n p atie nts 
( pts) wit h l oc ally adv a nce d, u nresecte d s q u a m o us cell c arci n o m a of t he he a d a n d 
neck ( S C C H N).  A merica n S ociet y of Cli nical O nc ol o g y, 2 0 1 0. 2 8 ( 1 5s): p. 
a bstract 5 5 0 5. 
2 8.  
Ha d da d, R., et al., R a n d o mize d p h ase 2 st u dy of c o nc o mit a nt c he m or a di ot her a py 
usi n g weekly c ar b o pl ati n/ p aclit axel wit h or wit h o ut d aily s u bc ut a ne o us a mif osti ne 
i n p atie nts wit h l oc ally a dv a nce d he a d a n d neck c a ncer. Ca ncer, 2 0 0 9. 1 1 5 ( 1 9): p. 
4 5 1 4- 2 3. 
2 9.  
B o n ner, J. A., et al., R a di ot her a py pl us cet uxi m a b f or l oc ore gi o n ally a dv a nce d 
he a d a n d neck c a ncer: 5- ye ar s urviv al d at a fr o m a p h ase 3 r a n d o mise d tri al, a n d 
rel ati o n bet wee n cet uxi m a b-i n d uce d r as h a n d s urviv al. La ncet O nc ol, 2 0 1 0. 
1 1 ( 1): p. 2 1- 8. 
3 0.  
B o n ner, J. A., et al., R a di ot her a py pl us cet uxi m a b f or s q u a m o us-cell c arci n o m a of 
t he he a d a n d neck. N E n gl J Me d, 2 0 0 6. 3 5 4 ( 6): p. 5 6 7- 7 8. 
3 1.  
Kies, M., J Harris, M Z R ot ma n, J N Me yers, R L F o ote, M Mac hta y, D K h u ntia, 
W L Stra u be, K K A n g, P M Harris., P h ase II R a n d o mize d Tri al of P ost o per ative 
C he m or a di ati o n Pl us Cet uxi m a b f or Hi g h-risk S q u a m o us Cell C arci n o m a of t he 
He a d a n d Neck ( R T O G 0 2 3 4).  I. J. Ra diati o n O nc ol, 2 0 0 9. 7 5 ( 3): p. S u p ple me nt. 
3 2.  
Tra y n or, A. M., et al., C o m pre he nsive I M R T pl us weekly cis pl ati n f or a dv a nce d 
he a d a n d neck c a ncer: t he U niversity of Wisc o nsi n ex perie nce.  Hea d Nec k, 2 0 1 0. 
3 2 ( 5): p. 5 9 9 - 6 0 6. 
3 3.  
Gar de n, A. S., et al., Preli mi n ary res ults of R a di ati o n T her a py O nc ol o gy Gr o u p 
9 7- 0 3: a r a n d o mize d p h ase ii tri al of c o nc urre nt r a di ati o n a n d c he m ot her a py f or 
a dv a nce d s q u a m o us cell c arci n o m as of t he he a d a n d neck.  J Cli n O nc ol, 2 0 0 4. 
2 2 ( 1 4): p. 2 8 5 6- 6 4. 
3 4.  
Na u g ht o n, C. A., Dr u g -i n d uce d ne p hr ot oxicity. A m Fa m P h ysicia n, 2 0 0 8. 7 8 ( 6): 
p. 7 4 3- 5 0. 
3 5.  
Eise n ha uer, E. A., et al., Ne w res p o nse ev al u ati o n criteri a i n s oli d t u m o urs: 
revise d R E CI S T g ui deli ne (versi o n 1. 1). E ur J Ca ncer, 2 0 0 9. 4 5 ( 2): p. 2 2 8- 4 7. 
3 6.  
T o palia n, S. L., et al., S afety, activity, a n d i m m u ne c orrel ates of a nti- P D - 1 
a nti b o dy i n c a ncer.  N E n gl J Me d., 2 0 1 2. 3 6 6 ( 2 6): p. 2 4 4 3- 5 4. d oi: 
1 0. 1 0 5 6/ N EJ M oa 1 2 0 0 6 9 0. E p u b 2 0 1 2 J u n 2. 
3 7.  
Bra h mer, J. R., et al., S afety a n d activity of a nti- P D - L 1 a nti b o dy i n p atie nts wit h 
a dv a nce d c a ncer.  N E n gl J Me d, 2 0 1 2. 3 6 6 ( 2 6): p. 2 4 5 5- 6 5. 
3 8.
 
htt p://ca ncer. u nc.e d u/ bi ostatistics / pr o gram/i va n o va/ C o nti n u os M o nit ori n g F
or T o xicit y.as p x . 
3 9.  
I va n o va, A., B. F. Qa qis h, a n d M.J. Sc hell, C o nti n u o us t oxicity m o nit ori n g i n 
p h ase II tri als i n o nc ol o gy.  Bi o metrics, 2 0 0 5. 6 1 ( 2): p. 5 4 0-5.  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 3 
1 1. 0  A P P E N DI C E S  
1 1. 1  
A p pe n di x A : E C O G Perf or m a nce St at us 
 
Sc ore  
Defi niti o n  
0  
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut 
restricti o n 
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble 
t o carr y o ut w or k of a li g ht or se de ntar y nat ure, e. g., li g ht h o urs 
w or k, office w or k  
2  
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut 
a n y w or k acti vities.  U p a n d a b o ut m ore t ha n 5 0 % of wa ki n g 
h o urs.  
3  
I n be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs 
4  
T otall y c o nfi ne d t o be d or c hair –  ca n n ot carr y o n a n y self -care. 
5  
Dea d  
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 4 
1 1. 2  
A p pe n di x B :  S u bject  H a n d o ut re g ar di n g Dr u g I nter acti o ns  
 
•  Dr u gs s uc h as na b-paclita xel t hat y o u will be gi ve n  are pr ocesse d b y a certai n 
e nz y me i n t he li ver calle d C Y P 3 A 4 or C Y P 2 C 8 .  Dr u gs t hat i ncrease t he acti vit y 
of t his e nz y me are calle d “i n d uc ers”, a n d dr u gs t hat decrease t he acti vit y of t his 
e nz y me are calle d “i n hi bit ors”.  Na b -paclita xel  m ust be use d ver y caref ull y wit h 
ot her me dici nes t hat are i n d ucers or i n hi bit ors of C Y P 3 A 4  or C Y P 2 C 8 .   
•  Y o u a n d healt hcare pr o vi ders w h o prescri be dr u gs f or y o u m ust be caref ul a b o ut 
a d di n g or re m o vi n g a n y dr u g i n t his cate g or y 
•  Bef ore y o u start t he st u d y, y o ur st u d y d oct or will w or k wit h y o ur re g ular 
prescri ber t o s witc h t he f oll o wi n g me dicati o ns if y o u are ta ki n g t he m: i n hi bit ors 
s uc h as ket oc o naz ole a n d ot her i mi daz ole a ntif u n gals, er yt hr o m yci n, fl u o xeti ne, 
ge mfi br ozil, ci meti di ne, rita n o vir, sa q ui na vir, i n di na vir, a n d nelfi na vir or i n d ucers 
s uc h as rifa m pici n, car ba maze pi ne, p he n yt oi n, efa vire nz, a n d ne vira pi ne.  Y o u 
s h o ul d als o a v oi d gr a pefr uit j uice w hile y o u are o n t his st u d y.   
•  Y o ur re g ular prescri bers s h o ul d l o o k at t his we b site: 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ta ble.as p  t o see if a n y me dici ne t he y 
wa nt t o prescri be is o n  a list of dr u gs t o a v oi d (t hat is, a n y str o n g i n hi bit or of t he 
li ver e nz y me C Y P 3 A 4.  Y o ur st u d y d oct or ma y als o ha ve a list of me dicati o ns f or 
y o u t o s h o w y o ur re g ular prescri bers i nstea d of, or i n a d diti o n t o, t his we bsite.   
•  If y o u dri n k gra pefr uit j uice or eat gra pefr uit, y o u s h o ul d a v oi d t hese u ntil t he 
st u d y is o ver.  
•  Ot her me dici nes  s uc h as a mi n o gl yc osi de a nti bi otics s h o ul d n ot be prescri be d or 
gi ve n wit h y o ur st u d y dr u gs. 
o  Y o u s h o ul d c hec k wit h y o ur d oct or or p har macist w he ne ver y o u nee d t o use a n 
o ver- t he-c o u nter me dici ne or her bal s u p ple me nt.  
o  Y o ur re g ular prescri ber s h o ul d c hec k a me dical refere nce or call y o ur st u d y 
d oct or bef ore prescri bi n g a n y ne w me dici ne f or y o u. Y o ur st u d y d oct or’s na me is 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ a n d he or s he ca n be c o ntacte d at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _. 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 5 
1 1. 3  
A p pe n di x C: D ose M o dific ati o ns/ T o xicit y M a n a ge me nt f or D ur v al u m a b  ( N o n-i m m u ne-
me di ate d)   
N o n -i m m u ne-me di ate d Re acti o ns  
Se verit y 
Gr a de of t he 
E ve nt ( N CI 
C T C A E 
versi o n  4. 0 3)  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
A n y Gr a de  
N ote: D ose m o dificati o ns are n ot 
re q uire d f or A Es n ot dee me d t o 
be relate d t o st u d y treat me nt 
(ie, e ve nts d ue t o u n derl yi n g 
disease) or f or la b orat or y 
a b n or malities n ot dee me d t o be 
cli nicall y si g nifica nt. 
Treat acc or di n gl y, as per 
i nstit uti o nal sta ndar d. 
Gr a de 1  
N o d ose m o dificati o ns.  
Treat acc or di n gl y, as per 
i nstit uti o nal sta n dar d. 
Gr a de 2  
H ol d st u d y dr u g/st u d y re gi me n 
u ntil res ol uti o n t o ≤Gra de 1 or 
baseli ne.  
Treat acc or di n gl y, as per 
i nstit uti o nal sta n dar d. 
Gr a de 3  
H ol d st u d y dr u g/st u d y re gi me n 
u ntil res ol uti o n t o ≤Gra de 1 or 
baseli ne.  
F or A Es t hat d o w n gra de t o 
≤Gra de 2 wit hi n 7 da ys or 
res ol ve t o ≤Gra de 1 or baseli ne 
wit hi n 1 4 da ys, res u me st u d y 
dr u g/st u d y re gi me n 
a d mi nistrati o n.  Ot her wise, 
disc o nti n ue st u d y dr u g/st u d y 
re gi men.  
Treat acc or di n gl y, as per 
i nstit uti o nal sta n dar d. 
Gr a de 4  
 
Disc o nti n ue st u d y dr u g/st u d y 
re gi me n ( N ote: F or Gra de 4 la bs, 
decisi o n t o disc o nti n ue s h o ul d be 
base d o n acc o m pa n yi n g cli nical 
si g ns/s y m pt o ms, t he 
I n vesti gat or’s cli nical j u d g me nt, 
a n d c o ns ultati o n wit h t he 
S p o ns or.).  
Treat acc or di n gl y, as per 
i nstit uti o nal sta n dar d. 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 6 
1 1. 4  
A p pe n di x D: D ose M o dific ati o ns/ T o xicit y M a n a ge me nt f or D ur v al u m a b (I m m u ne -rel ate d) 
 
D osi n g M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes ( T M Gs) f or D ur v al u m a b 
M o n ot her a p y, D ur v al u m a b  i n C o m bi n ati o n wit h ot her Pr o d ucts, or Tre meli m u m a b 
M o n ot her a p y –  2 8 Oct o ber 2 0 2 1  
Ge ner al C o nsi der ati o ns  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
Dr u g a d mi nistrati o n m o dificati o ns of st u d y dr u g/st u d y re gi me n will 
be ma de t o ma na ge p ote ntial i m m u ne -relate d A Es base d o n se verit y 
of treat me nt -e mer ge nt t o xicities gra de d per N CI C T C A E v 4. 0 3.  
I n a d diti o n t o t he criteria f or per ma ne nt disc o nti n uati o n of st u d y 
dr u g/st u d y re gi me n base d o n C T C gra de/se verit y (ta ble bel o w), 
per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y re gi me n f or t he f oll o wi n g 
c o n diti o ns: 
•  
I na bilit y t o re d uce c ortic oster oi d t o a d ose of ≤1 0 m g of 
pre d nis o ne per da y ( or e q ui vale nt) wit hi n 1 2 wee ks  after 
last d ose of st u d y dr u g/st u d y re gi me n 
•  
Rec urre nce of a pre vi o usl y e x perie nce d Gra d e 3 treat me nt -
relate d A E f oll o wi n g res u m pti o n of d osi n g 
Gr a de 1  
N o d ose m o dificati o n  
Gr a de 2  
H ol d st u d y dr u g/st u d y re gi me n d ose u ntil Gra de 2 
res ol uti o n t o Gra de ≤1. 
If t o xicit y w orse ns, t he n treat as Gra de 3 or Gra de 4. 
St u d y dr u g/st u d y re gi me n ca n be res u me d o nce e ve nt 
sta bilizes t o Gra de ≤1 after c o m pleti o n of ster oi d ta per. 
S u bjects wit h e n d ocri n o pat hies w h o ma y re q uire 
pr ol o n ge d or c o nti n ue d ster oi d re place me nt ca n be 
retreate d wit h st u d y dr u g/st u d y re gi me n o n t he 
f oll o wi n g c o n diti o ns: 
1.  
T he e ve nt sta bilizes a n d is c o ntr olle d.  
2.  
T he s u bject is cli nicall y sta ble as per I n vesti gat or 
or treati n g p h ysicia n’s cli nical j u d ge me nt.  
3.  
D oses of pre d nis o ne are at ≤1 0  m g/ da y or 
e q ui vale nt. 
Gr a de 3  
De pe n di n g o n t he i n di vi d ual t o xicit y, st u d y dr u g/st u d y 
re gi me n ma y be per ma ne ntl y disc o nti n ue d. Please refer 
t o g ui deli nes bel o w. 
Gr a de 4  
Per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y re gi me n.  
N ote: F or Gra de ≥3 as y m pt o matic a m ylase or li pase le vels, h ol d st u d y 
dr u g/st u d y re gi me n, a n d if c o m plete w or k u p s h o ws n o e vi de nce of 
pa ncr eatitis, st u d y dr u g/st u d y re gi me n ma y be c o nti n ue d or res u me d.  
N ote: St u d y dr u g/st u d y re gi me n s h o ul d be per ma ne ntl y disc o nti n ue d 
i n Gra de 3 e ve nts wit h hi g h li keli h o o d f or m or bi dit y a n d/ or m ortalit y 
– e. g., m y ocar ditis, or ot her si milar e ve nts e ve n if t he y  are n ot 
c urre ntl y n ote d i n t he g ui deli nes. Si milarl y, c o nsi der w het her st u d y 
dr u g/st u d y re gi me n s h o ul d be per ma ne ntl y disc o nti n ue d i n Gra de 2 
e ve nts wit h hi g h li keli h o o d f or m or bi dit y a n d/ or m ortalit y – e. g., 
m y ocar ditis, or ot her si milar e ve nts e ve n if t he y are n ot c urre ntl y 
n ote d i n t he g ui deli nes – w he n t he y d o n ot ra pi dl y i m pr o ve t o Gra de 
< 1 u p o n treat me nt wit h s yste mic ster oi ds a n d f oll o wi n g f ull ta per  
N ote: T here are s o me e xce pti o ns t o per ma ne nt disc o nti n uati o n of 
st u d y dr u g f or Gra de 4 e ve nts (i.e., h y pert h yr oi dis m, h y p ot h yr oi dis m, 
T y pe 1 dia betes mellit us).  
 
It is rec o m me n de d t hat ma na ge me nt of i m m u ne-me diate d a d verse e ve nts 
(i m A Es) f oll o ws t he g ui deli nes prese nte d i n t his ta ble: 
− 
It is p ossi ble t hat e ve nts wit h a n i nfla m mat or y or i m m u ne 
me diate d me c ha nis m c o ul d occ ur i n nearl y all or ga ns, s o me of 
t he m n ot n ote d s pecificall y i n t hese g ui deli nes. 
− 
W het her s pecific i m m u ne -me diate d e ve nts (a n d/ or la b orat or y 
i n dicat ors of s uc h e ve nts) are n ote d i n t hese g ui deli nes or n ot, 
s u bjects s h o ul d be t h or o u g hl y e val uate d t o r ule o ut a n y 
alter nati ve eti ol o g y (e. g., disease pr o gressi o n, c o nc o mita nt 
me dicati o ns, a n d i nfecti o ns) t o a p ossi ble i m m u ne -me diate d 
e ve nt. I n t he a bse nce of a clear alter nati ve eti ol o g y, all s uc h 
e ve nts s h o ul d be ma na ge d as if t he y were i m m u ne relate d. 
Ge neral rec o m me n dati o ns f oll o w.  
− 
S y m pt o matic a n d t o pical t hera p y s h o ul d be c o nsi dere d f or 
l ow- gra de ( Gra de 1 or 2, u nless ot her wise s pecifie d) e ve nts.  
− 
F or persiste nt ( > 3 t o 5 da ys) l o w -gra de ( Gra de 2) or se vere 
( Gra de ≥3) e ve nts, pr o m ptl y start pre d nis o ne 1 t o 2 m g/ k g/ da y 
P O or I V e q ui vale nt.  
− 
S o me e ve nts wit h hi g h li keli h o o d f or m or bi dit y a n d/ or  
m ortalit y – e. g., m y o-car ditis, or ot her si milar e ve nts e ve n if 
t he y are n ot c urre ntl y n ote d i n t he g ui deli nes – s h o ul d pr o gress 
ra pi dl y t o hi g h d ose I V c ortic oster oi ds ( met h yl pre d nis ol o ne at 
2 t o 4  m g/ k g/ da y) e ve n if t he e ve nt is Gra de 2, a n d if cli nical  
s us pici o n is hi g h a n d/ or t here has bee n cli nical c o nfir mati o n. 
C o nsi der, as necessar y, disc ussi n g wit h t he st u d y p h ysicia n, 
a n d pr o m ptl y p urs ue s pecialist c o ns ultati o n.  
− 
If s y m pt o ms rec ur or w orse n d uri n g c ortic oster oi d ta peri n g 
( 2 8 da ys of ta per), i ncreas e t he c ortic oster oi d d ose ( pre d nis o ne 
d ose [e. g., u p t o 2 t o 4  m g/ k g/ da y P O or I V e q ui vale nt]) u ntil 
sta bilizati o n or i m pr o ve me nt of s y m pt o ms, t he n res u me 
c ortic oster oi d ta peri n g at a sl o wer rate ( > 2 8  da ys of ta per).  
− 
M ore p ote nt i m m u n os u p pressi ves s uc h as T N F i n hi bit ors 
(e. g., i nfli xi ma b) (als o refer t o t he i n di vi d ual secti o ns of t he 
i m A Es f or s pecific t y pe of i m m u n os u p pressi ve) s h o ul d be 
c o nsi dere d f or e ve nts n ot res p o n di n g t o s yste mic ster oi ds. 
Pr o gressi o n t o use of m ore p ote nt i m m u n os u p pressi ves s h o ul d 
p r ocee d m ore ra pi dl y i n e ve nts wit h hi g h li keli h o o d f or 
m or bi dit y a n d/ or m ortalit y – e. g., m y ocar ditis, or ot her si milar 
e ve nts e ve n if t he y are n ot c urre ntl y n ote d i n t he g ui deli nes – 
w he n t hese e ve nts are n ot res p o n di n g t o s yste mic ster oi ds.  
− 
Wit h l o n g -term ster oi d a n d ot her i m m u n os u p pressi ve use, 
c o nsi der nee d f or P ne u m ocystis jir ovecii  p ne u m o nia ( PJ P, 
f or merl y k n o w n as P ne u m ocystis c ari nii  p ne u m o nia) 
pr o p h yla xis, gastr oi ntesti nal pr otecti o n, a n d gl uc ose 
m o nit ori n g. 
− 
Disc o nti n uati o n of st u d y dr u g/st u d y re gi me n is n ot ma n date d 
f or Gra de 3/ Gra de 4 i nfla m mat or y reacti o ns attri b ute d t o l ocal 
t u m or res p o nse (e. g., i nfla m mat or y reacti o n at sites of 
metastatic disease a n d l y m p h n o des). C o nti n uati o n of st u d y 
dr u g/st u d y re gi me n i n t his sit uati o n s h o ul d be base d u p o n a 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 7 
D osi n g M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes ( T M Gs) f or D ur v al u m a b 
M o n ot her a p y, D ur v al u m a b  i n C o m bi n ati o n wit h ot her Pr o d ucts, or Tre meli m u m a b 
M o n ot her a p y –  2 8 Oct o ber 2 0 2 1  
Ge ner al C o nsi der ati o ns  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
be nefit -ris k a nal ysis f or t hat s u bject. 
A E A d verse e ve nt; C T C C o m m o n T o xicit y Criteria; C T C A E C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; i m A E i m m u ne -me diate d a d verse 
e ve nt; I V i ntra ve n o us; N CI Nati o nal Ca ncer I nstit ute; P O B y m o ut h.  
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 8 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
P ne u m o nitis/I nterstiti al 
L u n g Dise ase (I L D)  
A n y Gr a de  
 
( Refer t o N CI C T C A E 
a p plica ble versi o n i n  
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E 
gra de/se verit y)  
Ge ner al G ui d a nce  
F or A n y Gr a de:  
− 
Patie nts s h o ul d be t h or o u g hl y e val uate d t o  
− 
r ule o ut a n y alter nati ve eti ol o g y (e. g. 
− 
i nfecti o n, pr o gressi ve disease) 
− 
− M o nit or patie nts f or si g ns a n d s y m pt o ms 
of 
− 
p ne u m o nitis or I L D ( ne w o nset or w orse ni n g 
− 
s h ort ness of breat h or c o u g h). E val uate 
− 
patie nts wit h i ma gi n g a n d p ul m o nar y  
− 
f u ncti o n tests, i ncl u di n g ot her dia g n ostic 
− 
pr oce d ures as descri be d bel o w.  
− 
− S us pecte d p ne u m o nitis s h o ul d be 
c o nfir me d 
− 
wit h ra di o gra p hic i ma gi n g a n d ot her  
− 
i nfecti o us a n d disease-relate d aeti ol o gies 
− 
e xcl u de d, a n d ma na ge d as descri be d bel o w.  
− 
− I nitial w or k -u p ma y i ncl u de cli nical  
− 
e val uati o n, m o nit ori n g of o x y ge nati o n via  
− 
p ulse o xi metr y (resti n g a n d e xerti o n),  
− 
la b orat or y w or k-u p, a n d hi g h - res ol uti o n 
− 
c o m p ute d t o m o gra p h y ( C T) s ca n. 
− 
− C o nsi der P ul m o nar y a n d I nfecti o us 
Diseases  
− 
c o ns ults. 
Gr a de 1  
 
N o d ose m o dificati o ns re q uire d. 
H o we ver, c o nsi der h ol di n g 
st u d y dr u g/st u d y re gi me n d ose 
as cli nicall y a p pr o priate a n d 
d uri n g dia g n ostic w or k -u p f or 
ot her eti ol o gies.  
F or Gr a de 1  
− 
M o nit or a n d cl osel y f oll o w u p i n 2 t o 4 da ys 
f or cli nical s y m pt o ms, p ulse o xi metr y 
(resti n g a n d e xerti o n), a n d la b orat or y w or k-
u p a n d t he n as cli nicall y i n dicate d.  
Gr a de 2  
 
H ol d st u d y dr u g/st u d y re gi me n 
d ose u ntil Gra de 2 res ol uti o n t o 
Gra de ≤1.  
•  
If t o xicit y i m pr o ves t o 
Gra de ≤1, t he n t he 
decisi o n t o rei nitiate st u d y 
dr u g/st u d y re gi me n will be 
base d u p o n treati n g 
p h ysicia n’s cli nical 
j u d g me nt a n d after 
c o m pleti o n of ster oi d 
ta per. 
F or Gr a de 2  
− M o nit or s y m pt o ms dail y a n d c o nsi der 
h os pitalizati o n. 
− O btai n P ul m o nar y a n d I nfecti o us Diseases  
C o ns ults; c o nsi der disc ussi n g wit h Cli nical  
St u d y Lea d, as nee de d.  
- Pr o m ptl y start s yste mic ster oi ds (e. g.,  
pre d nis o ne 1 t o 2 m g/ k g/ da y P O or I V  
e q ui vale nt). 
− Rei ma ge as cli nicall y i n dicate d, c o nsi der  
c hest C T wit h c o ntrast a n d re peat i n 3 - 4 
wee ks.  
− If n o i m pr o ve me nt wit hi n 2 t o 3 da ys, 
a d diti o nal w or k u p s h o ul d be c o nsi dere d a n d  
pr o m pt treat me nt wit h I V  
met h yl pre d nis ol o ne 2 t o 4 m g/ k g/ da y  
starte d. 
− If n o i m pr o ve me nt wit hi n 2 t o 3 da ys des pite 
I V met h yl pre d nis ol o ne at 2 t o 4 m g/ k g/ da y, 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
7 9 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
pr o m ptl y start i m m u n os u p pressi ve t hera p y.  
s uc h as t u m or necr osis fact or ( T N F) 
i n hi bit ors (e. g., i nfli xi ma b at 5 m g/ k g I V 
o nce, ma y be re peate d at 2 a n d 6 wee ks after  
i nitial d ose at t he discreti o n of t he treati n g 
pr o vi der or rele va nt practice g ui deli nes).  
Ca uti o n: It is i m p orta nt t o r ule o ut se psis a n d  
refer t o i nfli xi ma b la bel f or ge neral g ui da nce 
bef ore usi n g i nfli xi ma b. C o nsi der, as  
necessar y, disc ussi n g wit h Cli nical St u d y  
Lea d . 
Gr a de 3 or 4  
 
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n.  
F or Gr a de 3 or 4  
− 
Pr o m ptl y i nitiate e m piric I V 
met h yl pre d nis ol o ne 1 t o 4  m g/ k g/ da y or 
e q ui vale nt. 
− 
O btai n P ul m o nar y a n d I nfecti o us disease 
c o ns ult; c o nsi der, as necessar y, disc ussi n g 
wit h st u d y p h ysicia n. 
− 
H os pitalize t he s u bject. 
− 
S u p p orti ve care (e. g., o x y ge n).  
− 
If n o i m pr o ve me nt wit hi n 2  da ys, a d diti o nal 
w or k u p s h o ul d be c o nsi dere d a n d pr o m pt 
treat me nt wit h a d diti o nal 
i m m u n os u p pressi ve t hera p y s uc h as T N F 
i n hi bit ors (e. g., i nfli xi ma b at 5 m g/ k g I V, 
ma y be re peate d at 2 a n d 6 wee ks after 
i nitial d ose at t he discreti o n of t he treati n g 
pr o vi der or rele va nt practice g ui deli nes).  
Ca uti o n: r ule o ut se psis a n d refer t o 
i nfli xi ma b la bel f or ge neral g ui da nce bef ore 
usi n g i nfli xi ma b.  
Di arr he a/ C olitis 
A n y Gr a de  
 
( Refer t o N CI C T C A E 
a p plica ble versi o n i n  
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E  
gra de/se verit y)  
Ge ner al G ui d a nce  
F or A n y Gr a de:  
−     Patie nts  s h o ul d be t h or o u g hl y e val uate d t o 
r ule o ut a n y alter nati ve  eti ol o g y (e. g., 
disease  pr o gressi o n, ot her me dicati o ns,  or 
i nfecti o ns), i ncl u di n g testi n g f or 
Cl ostri di u m difficile  t o xi n, etc. 
−      M o nit or f or s y m pt o ms t hat ma y  be relate d 
t o diarr hea/e nter oc olitis (a b d o mi nal pai n, 
cra m pi n g, or c ha n ges i n b o wel ha bits  s uc h 
as i ncrease d fre q ue nc y o ver baseli ne or 
bl o o d i n st o ol) or  relate d t o b o wel 
perf orati o n  (s uc h as se psis, perit o neal 
si g ns, a n d ile us). 
−     W H E N  S Y M P T O M S  O R  
E V A L U A TI O N  I N DI C A T E A N  
I N T E S TI N A L P E R F O R A TI O N  I S 
S U S P E C T E D,  C O N S U L T  A S U R G E O N  
E X P E RI E N C E D  I N A B D O MI N A L  
S U R G E R Y  I M M E DI A T E L Y 
WI T H O U T  A N Y  D E L A Y.  
−     P E R M A N E N T L Y  DI S C O N TI N U E  
S T U D Y  D R U G  F O R  A N Y  G R A D E  O F  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 0 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
I N T E S TI N A L P E R F O R A TI O N.  
−      Ster oi ds s h o ul d be c o nsi dere d i n t he a bse nce of 
clear alter nati ve  eti ol o g y, e ve n f or l o w- gra de 
e ve nts, i n or der t o pre ve nt p ote ntial pr o gressi o n  
t o hi g her gra de e ve nts, i ncl u di n g i ntesti nal 
perf orati o n. 
−     Use  a nal gesics caref ull y; t he y ca n mas k  
s y m pt o ms of  perf orati o n  a n d perit o nitis.  
Gr a de 1  
 
N o d ose m o dificati o ns.  
F or Gr a de 1:  
− 
M o nit or cl osel y f or w orse ni n g s y m pt o ms.  
− 
C o nsi der s y m pt o matic treat me nt, i ncl u di n g 
h y drati o n, electr ol yte re place me nt, dietar y 
c ha n ges (e. g., A merica n Dietetic Ass ociati o n 
c olitis diet), a n d l o pera mi de , a n d ot her 
s u p p orti ve care meas ures.  
− 
If s y m pt o ms persist, c o nsi der c hec ki ng 
lact oferri n; if p ositi ve, treat as Gra de 2.  
Gr a de 2  
 
H ol d st u d y dr u g/st u d y re gi me n 
u ntil res ol uti o n t o Gra de ≤1  
•  
If t o xicit y i m pr o ves t o 
Gra de ≤1, t he n st u d y 
dr u g/st u d y re gi me n ca n be 
res u me d after c o m pleti o n 
of ster oi d ta per  ( < 1 0 m g 
pre d nis o ne, or e q ui vale nt) . 
F or Gr a de 2:  
− 
C o nsi der s y m pt o matic treat me nt, i ncl u di n g 
h y drati o n, electr ol yte re place me nt, dietar y 
c ha n ges (e. g., A merica n Dietetic Ass ociati o n 
c olitis diet), a n d l o pera mi de a n d/ or 
b u des o ni de. 
− 
Pr o m ptl y start pre d nis o ne 1  t o 2 m g/ k g/ da y 
P O or I V e q ui vale nt.  
− 
If e ve nt is n ot res p o nsi ve wit hi n 2 t o 3 da ys 
or w orse ns des pite pre d nis o ne at 1 t o 2 
m g/ k g/ da y P O or I V e q ui vale nt, c o ns ult a 
gastr oi ntersti nal ( GI ) s pecialist f or 
c o nsi derati o n of f urt her w or k u p, s uc h as 
i ma gi n g a n d/ or c ol o n osc o p y, t o c o nfir m 
c olitis a n d r ule o ut perf orati o n . 
− 
If still n o i m pr o ve me nt wit hi n 2 t o 3 da ys 
des pite 1 t o 2 m g/ k g I V met h yl pre d nis ol o ne, 
pr o m ptl y start i m m u n os u p pressi ves s uc h as 
i nfli xi ma b at 5 m g/ k g I V, ma y be re peate d at 
2 a n d 6 wee ks after i nitial d ose at t he 
discreti o n of t he treati n g pr o vi der or rele va nt 
practice g ui deli nes. C a uti o n:  it is i m p orta nt 
t o r ule o ut b o wel perf orati o n a n d refer t o 
i nfli xi ma b la bel f or ge neral g ui da nce bef ore 
usi n g i nfli xi ma b.  
− 
If perf or ati o n is s us pecte d, c o ns ult a 
s ur ge o n e x perie nce d i n a b d o mi n al 
s ur ger y i m me di atel y wit h o ut a n y del a y. 
− 
 C o nsi der, as necessar y, disc ussi n g wit h 
Cli n ical St u d y Lea d if n o res ol uti o n t o Gra de 
− 
≤1 i n 3 t o 4 da ys.  
Gr a de 3 or 4  
 
Gr a de 3  
- F or patie nts treate d wit h 
d ur val u ma b m o n ot hera p y, h ol d 
st u d y dr u g/st u d y re gi me n u ntil 
F or Gr a de 3 or 4:  
− 
Pr o m ptl y i nitiate e m piric I V 
met h yl pre d nis ol o ne 1 t o 2 m g/ k g/ da y or 
e q ui vale nt. 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 6 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
If e ve nt is n ot res p o nsi ve wit hi n 3 t o 5 da ys or w orse ns 
des pite pre d nis o ne at 1 t o 2 m g/ k g/ da y P O or I V 
e q ui vale nt, c o nsi der a d diti o nal w or k u p . s h o ul d be 
c o nsi dere d a n d pr o m pt treat me nt wit  
W he n e ve nt ret ur ns t o baseli ne, res u me st u d y 
dr u g/st u d y re gi me n a n d r o uti ne ser u m creati ni ne 
m o nit ori n g per st u d y pr ot oc ol.  
Gr a de 3 or 4  
 
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n.  
F or Gr a de 3 or 4:  
− 
Caref ull y m o nit or ser u m creati ni ne o n dail y 
basis.  
− 
C o ns ult ne p hr ol o gist a n d c o nsi der re nal 
bi o ps y if cli nicall y i n dicate d.  
− 
Pr o m ptl y start pre d nis o ne 1 t o 2 m g/ k g/ da y 
P O or I V e q ui vale nt.  
− 
If e ve nt is n ot res p o nsi ve wit hi n 3 t o 5 da ys 
or w orse ns des pite pre d nis o ne at 1 t o 2 
m g/ k g/ da y P O or I V e q ui vale nt, c o nsi dere d 
a d diti o nal w or k u p a n d pr o m pt treat me nt 
wit h i m m u n os u p pressa nt i n c o ns ultati o n 
wit h a ne p hr ol o gist.  
 
 
R as h  or Der m atitis  
(I ncl u di n g Pe m p hi g ol d) 
A n y Gr a de  
( Refer t o N CI C T C A E 
a p plica ble versi o n i n 
st u d y pr ot oc ol f or 
defi niti o n of 
se verit y/ gra de 
de pe n di n g o n t y pe of  
s ki n ras h) 
 
Ge ner al G ui d a nce  
F or A n y Gr a de:  
− 
 Patie nts s h o ul d be t h or o u g hl y e val uate d t o 
r ule o ut a n y alter nati ve eti ol o g y. 
− 
M o nit or f or si g ns a n d s y m pt o ms of 
der matitis (ras h a n d pr urit us).  
− 
H O L D S T U D Y D R U G I F S T E V E N S - 
J O H N S O N S Y N D R O M E ( S J S), T O XI C 
E PI D E R M A L N E C R O L Y SI S ( T E N),  O R  
O T H E R  S E V E R E C U T A N E O U S 
A D V E R S E R E A C TI O N ( S C A R) I S 
S U S P E C T E D.  
− 
P E R M A N E N T L Y  DI S C O N TI N U E 
S T U D Y D R U G I F S J S, T E N, O R S C A R 
I S C O N FI R M E D. 
Gr a de 1  
N o d ose m o dificati o ns.  
F or Gr a de 1:  
− 
C o nsi der s y m pt o matic treat me nt, i ncl u di n g 
oral a nti pr uritics (e. g., di p he n h y dra mi ne or 
h y dr o x yzi ne) a n d t o pical t hera p y 
(e. g., e m ollie nt, l oti o n, or i nstit uti o nal 
sta n dar d). 
Gr a de 2  
F or persiste nt ( > 1 wee k) 
Gra de 2 e ve nts, h ol d sc he d ule d 
st u d y dr u g/st u d y re gi me n u ntil 
res ol uti o n t o Gra de ≤1 or 
baseli ne.  
•  
If t o xicit y i m pr o ves t o 
Gra de ≤1 or baseli ne, t he n 
res u me dr u g/st u d y 
re gi me n after c o m pleti o n 
F or Gr a de 2:  
− 
O btai n der mat ol o g y c o ns ult.  
− 
C o nsi der s y m pt o matic treat me nt, i ncl u di n g 
oral a nti pr uritics (e. g., di p he n h y dra mi ne or 
h y dr o x yzi ne) a n d t o pical t hera p y.  
− 
C o nsi der m o derate -stre n gt h t o pical ster oi d. 
− 
If n o i m pr o ve me nt of ras h/s ki n lesi o ns 
occ urs wit hi n 3 da ys or is w orse ni n g des pite  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 7 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
of ster oi d ta per  ( < 1 0 m g 
pre d nis o ne, or 
e q ui vale nt). 
− 
s y m pt o matic treat me nt a n d/ or use of 
m o derate stre n gt h t o pical ster oi d, c o nsi der 
disc ussi n g wit h Cli nical St u d y Lea d, as 
nee de d, a n d pr o m ptl y start s yste mic ster oi ds 
s uc h as pre d nis o ne 1 t o 2 m g/ k g/ da y P O or 
I V e q ui vale nt. 
− 
C o nsi der s ki n bi o ps y if t he e ve nt persists f or  
> 1 wee k or rec urs.   
 
Gr a de 3 or 4  
F or Gr a de 3:  
H ol d st u d y dr u g/st u d y re gi me n 
u ntil res ol uti o n t o Gra de ≤1 or 
baseli ne.  
 
If t o xicit y i m pr o ves t o Gra de 
≤1 or baseli ne, t he n res u me 
dr u g/st u d y re gi me n after 
c o m pleti o n of  
ster oi d ta per ( < 1 0 
m g pre d nis o ne, or e q ui vale nt).  
 
F or Gr a de 4:  
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n.  
 
F or Gr a de 3 or 4:  
− 
C o ns ult der mat ol o g y.  
− 
Pr o m ptl y i nitiate e m piric I V 
met h yl pre d nis ol o ne 1 t o 2 m g/ k g/ da y or 
e q ui vale nt. 
− 
C o nsi der h os pitalizati o n.  
− 
M o nit or e xte nt of ras h [ R ule of Ni nes].  
− 
C o nsi der s ki n bi o ps y ( prefera bl y m ore t ha n 
1) as cli nicall y feasi ble.  C o nsi der, as 
necessar y, disc ussi n g wit h Cli nical St u d y 
Lea d . 
E n d ocri n o p at h y 
(e. g., h y pert h yr oi dis m, 
h y p ot h yr oi dis m,  T y pe 1 
dia betes mellit us, 
h y p o p h ysitis, 
h y p o pit uitaris m, a n d 
a dre nal i ns ufficie nc y)  
 
A n y Gr a de  
( De pe n di n g o n t he 
t y pe of e n d ocri n o pat h y, 
refer t o N CI C T C A E 
a p plica ble versi o n i n 
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E  
gra de/se verit y) 
 
Ge ner al G ui d a nce  
F or A n y Gr a de:  
−     Patie nts s h o ul d be t h or o u g hl y e val uate d t o r ule 
o ut a n y alter nati ve eti ol o g y (e. g., disease pr o gressi o n 
i ncl u di n g brai n metastases, or i nfecti o ns). 
−     C o nsi der c o ns ulti n g a n e n d ocri n ol o gist f or 
e n d ocri ne e ve nts.  
−     C o nsi der disc ussi n g wit h Cli nical St u d y Lea d, as 
nee de d.  
−     M o nit or patie nts f or si g ns a n d s y m pt o ms of 
e n d ocri n o pat hies. ( N o n -s pecific s y m pt o ms i ncl u de 
hea dac he, fati g ue, be ha vi o ur c ha n ges, me ntal stat us 
c ha n ges, p h ot o p h o bia, vis ual fiel d c uts, verti g o, 
a b d o mi nal pai n, u n us ual b o wel ha bits,  di psia, 
p ol y uria, h y p ote nsi o n, a n d wea k ness.)  
−     De pe n di n g o n t he s us pecte d e n d ocri n o pat h y, 
m o nit or a n d e val uate t h yr oi d f u ncti o n tests: t h yr oi d 
sti m ulati n g h or m o ne ( T S H), free T 3 a n d free T 4 a n d 
ot her rele va nt e n d ocri ne a n d relate d la bs (e. g., bl o o d 
gl uc ose a n d ket o ne le vels, he m o gl o bi n A 1c 
( H g A 1c)).If a patie nt e x perie nces a n A E t hat is 
t h o u g ht t o be p ossi bl y of a ut oi m m u ne nat ure (e. g., 
t h yr oi ditis, pa ncreatitis, h y p o p h ysitis, or dia betes 
i nsi pi d us), t he i n vesti gat or s h o ul d se n d a bl o o d sa m ple 
f or a p pr o priate a ut oi m m u ne a nti b o d y testi n g. 
−     I n vesti gat ors s h o ul d as k s u bjects wit h 
e n d ocri n o pat hies w h o ma y re q uire  pr ol o n ge d or 
co nti n ue d h or m o nal re place me nt, t o c o ns ult t heir 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 8 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
pri mar y care p h ysicia ns or e n d ocri n ol o gists a b o ut 
f urt her m o nit ori n g a n d treat me nt after c o m pleti o n of 
t he st u d y. 
          
 
 
Gr a de 1  
N o d ose m o dificati o ns.  
F or Gr a de 1  
− 
M o nit or s u bject wit h a p pr o priate e n d ocri ne 
f u ncti o n tests. 
− 
F or s us pecte d h y p o p h ysitis/ h y p o pit uitaris m, 
c o nsi der c o ns ultati o n of a n e n d ocri n ol o gist 
t o g ui de assess me nt of earl y- m or ni n g 
A C T H, c ortis ol, T S H a n d free T 4; als o 
c o nsi der g o na d otr o pi ns, se x h or m o nes, a n d 
pr olacti n le vels, as well as c os y ntr o pi n 
sti m ulati o n test (t h o u g h it ma y n ot be usef ul 
i n dia g n osi n g earl y sec o n dar y a dre nal 
i ns ufficie nc y). 
− 
If T S H < 0. 5 × L L N, or T S H > 2 × U L N, or 
c o nsiste ntl y o ut of ra n ge i n 2 s u bse q ue nt 
meas ure me nts, i ncl u de free T 4 at s u bse q ue nt 
c ycles as cli nicall y i n dicate d a n d c o nsi der 
c o ns ultati o n of a n e n d ocri n ol o gist.  
Gr a de 2, 3, or 4  
F or Gra de 2 - 4 e n d ocri n o pat h y 
ot her t ha n h y p ot h yr oi dis m a n d 
T y pe 1 dia betes mellit us , 
c o nsi der h ol d i n g st u d y 
dr u g/st u d y re gi me n d ose u ntil 
s u bject is cli nicall y sta ble. 
St u d y dr u g/st u d y re gi me n ca n 
be res u m e d o nce patie nt 
sta bilizes a n d after c o m pleti o n 
of ster oi d ta per  ( < 1 0 m g 
pre d nis o ne or e q ui vale nt).  
Patie nts  wit h e n d ocri n o pat hies 
w h o ma y re q uire pr ol o n ge d or 
c o nti n ue d ster oi d re place me nt 
(e. g., a dre nal i ns ufficie nc y) ca n 
be retreate d wit h st u d y 
dr u g/st u d y if t he patie nt is 
cli nicall y sta ble as per 
i n vesti gat or or treati n g 
p h ysicia n’s cli nical j u d ge me nt.  
 
F or G r a de 2, 3, or 4  
− 
C o ns ult e n d ocri n ol o gist t o g ui de e val uati o n 
of e n d ocri ne f u ncti o n a n d, as i n dicate d b y 
s us pecte d e n d ocri n o pat h y a n d as cli nicall y 
i n dicate d, c o nsi der pit uitar y sca n. 
− 
F or all s u bjects wit h a b n or mal e n d ocri ne 
w or k u p, e xce pt t h ose wit h is ola te d 
h y p ot h yr oi dis m or T 1 D M, a n d as g ui de d b y 
a n e n d ocri n ol o gist, c o nsi der s h ort -ter m 
c ortic oster oi ds (e. g., 1 t o 2  m g/ k g/ da y 
met h yl pre d nis ol o ne or I V e q ui vale nt) a n d 
pr o m pt i nitiati o n of treat me nt wit h rele va nt 
h or m o ne re place me nt.  
− 
Is olate d h y p ot h yr oi dis m ma y be treate d wit h 
re place me nt t hera p y, wit h o ut st u d y 
dr u g/st u d y re gi me n i nterr u pti o n, a n d wit h o ut 
c ortic oster oi ds. 
− 
Is olate d T 1 D M ma y be treate d wit h 
a p pr o priate dia betic t hera p y, a n d wit h o ut 
c ortic oster oi ds. O nl y h ol d st u d y 
dr u g/st u d y re gi me n i n setti n g of 
h y per gl yce mi a w he n di a g n osti c w or k u p is 
p ositi ve f or di a betic ket o aci d osis.  
− 
F or s u bjects wit h n or mal e n d ocri ne w or k u p 
(la b orat or y assess me nt or M RI sca ns), re peat 
la b orat or y assess me nts/ M RI as cli nicall y 
i n dicate d. 
 
 
 
Ne ur ot o xicit y 
A n y Gr a de  
Ge ner al G ui d a nce  
F or A n y Gr a de:  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
8 9 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
(t o i ncl u de b ut n ot 
li mite d t o n o n-i nfecti o us 
me ni n gitis, n o n - 
i nfecti o us e nce p halitis, 
a n d a ut o n o mic 
ne ur o pat h y, e xcl u di n g 
M yast he nia Gra vis a n d  
G uillai n - Barre) 
 
( De pe n di n g o n t he 
t y pe of ne ur ot o xicit y, 
refer t o N CI C T C A E 
a p plica ble versi o n i n 
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E  
gra de/se verit y) 
 
− 
Patie nts  s h o ul d be e val uate d t o r ule o ut a n y 
alter nati ve eti ol o g y (e. g., disease 
pr o gressi o n, i nfecti o ns, meta b olic 
s y n dr o mes, or me dicati o ns). 
− 
M o n it or s u bject f or ge neral s y m pt o ms 
( hea dac he, na usea, verti g o, be ha vi or c ha n ge, 
or wea k ness).  
− 
C o nsi der a p pr o priate dia g n ostic testi n g 
(e. g., electr o m y o gra m a n d ner ve c o n d ucti o n 
i n vesti gati o ns). 
− 
Perf or m s y m pt o matic treat me nt wit h 
ne ur ol o gical c o ns ult as a p pr o priate. 
Gr a de 1  
N o d ose m o dificati o ns.  
F or Gr a de 1:  
− 
See “ A n y Gra de” rec o m me n dati o ns a b o ve.  
Gr a de 2  
F or ac ute m ot or ne ur o pat hies or 
ne ur ot o xicit y, h ol d st u d y 
dr u g/st u d y re gi me n d ose u ntil 
res ol uti o n t o Gra de ≤1. 
F or se ns or y 
ne ur o pat h y/ ne ur o pat hic pai n, 
c o nsi der h ol di n g st u d y 
dr u g/st u d y re gi me n d ose u ntil 
res ol uti o n t o Gra de ≤1. 
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n if Gra de 2 
i m A E d oes n ot res ol ve t o Gra de 
≤ 
 
F or Gr a de 2:  
− 
C o nsi der, as necessar y, disc ussi n g wit h t he  
st u d y p h ysicia n. 
− 
O btai n ne ur ol o g y c o ns ult.  
− 
Se ns or y ne ur o pat h y/ ne ur o pat hic pai n ma y be 
ma na ge d b y a p pr o priate me dicati o ns (e. g., 
ga ba pe nti n or d ul o xeti ne).  
− 
Pr o m ptl y start s yste mic ster oi ds pre d nis o ne 
1 t o 2  m g/ k g/ da y P O or I V e q ui vale nt.  
− 
If n o i m pr o ve me nt wit hi n 2 t o 3 da ys des pite 
1 t o 2  m g/ k g/ da y pre d nis o ne P O or I V 
e q ui vale nt, c o nsi der a d diti o nal w or k u p a n d 
pr o m ptl y treat wit h a d diti o nal 
i m m u n os u p pressi ve t hera p y (e. g., I V I G or 
ot her i m m u n os u p pressa nt de pe n di n g o n t he 
s pecific i m A E). 
Gr a de 3 or 4  
F or Gr a de 3  or 4  
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n.  
F or Gr a de 3 or 4:  
− 
C o nsi der, as necessar y, disc ussi n g wit h 
Cli nical St u d y Lea d . 
− 
O btai n ne ur ol o g y c o ns ult.  
− 
C o nsi der h os pitalizati o n.  
− 
Pr o m ptl y i nitiate e m piric I V 
met h yl pre d nis ol o ne 1 t o 2  m g/ k g/ da y or 
e q ui vale nt. 
− 
If n o i m pr o ve me nt wit hi n 2 t o 3 da ys des pite 
I V c ortic oster oi ds, c o nsi der a d diti o nal 
w or k u p a n d pr o m ptl y treat wit h a d diti o nal 
i m m u n os u p pressa nts (e. g., I V I G or ot her 
i m m u n os u p pressa nt de pe n di n g o n t he 
s pecific i m A E). 
Peri p her al ne ur o m ot or 
s y n dr o mes 
(s uc h as G uillai n- Barre 
a n d m yast he nia gra vis)  
A n y Gr a de  
( Refer t o N CI C T C A E 
a p plica ble versi o n i n 
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E  
gra de/se verit y) 
Ge ner al G ui d a nce  
F or A n y Gr a de:  
− 
T he pr o m pt dia g n osis of i m m u ne -me diate d 
peri p heral ne ur o m ot or s y n dr o mes is 
i m p orta nt, si nce certai n s u bjects ma y 
u n pre dicta bl y e x perie nce ac ute 
dec o m pe nsati o ns t hat ca n res ult i n 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 0 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
 
s u bsta ntial m or bi dit y or i n t he w orst case, 
deat h. S pecial care s h o ul d be ta k e n f or 
certai n se nti nel s y m pt o ms t hat ma y pre dict a 
m ore se vere o utc o me, s uc h as pr o mi ne nt 
d ys p ha gia, ra pi dl y pr o gressi ve wea k ness, 
a n d si g ns of res pirat or y i ns ufficie nc y or 
a ut o n o mic i nsta bilit y.  
− 
T he patie nt  s h o ul d be e val uate d t o r ule o ut 
a n y alter nati ve eti ol o g y (e. g., disease 
pr o gressi o n, i nfecti o ns, meta b olic 
s y n dr o mes or me dicati o ns). It s h o ul d be 
n ote d t hat t he dia g n osis of i m m u ne -me diate d 
peri p heral ne ur o m ot or s y n dr o mes ca n be 
partic ularl y c halle n gi n g i n s u bjects wit h 
u n derl yi n g ca ncer, d ue t o t he m ulti ple 
p ote ntial c o nf o u n di n g effects of ca ncer (a n d 
its treat me nts) t hr o u g h o ut t he ne ura xis. 
Gi ve n t he i m p orta nce of pr o m pt a n d 
acc urate dia g n osis, it is esse ntial t o ha ve a 
l o w t hres h ol d t o o btai n a ne ur ol o gical 
c o ns ult. 
− 
Ne ur o p h ysi ol o gic dia g n ostic testi n g 
(e. g., electr o m y o gra m a n d ner ve c o n d ucti o n 
i n vesti gati o ns, a n d “re petiti ve sti m ulati o n” if 
m yast he nia is s us pecte d) are r o uti nel y 
i n dicate d u p o n s us pici o n of s uc h c o n diti o ns 
a n d ma y be best facilitate d b y m ea ns of a 
ne ur ol o g y c o ns ultati o n.  
− 
It is i m p ort a nt t o c o nsi der t h at t he use of 
ster oi ds as t he pri m ar y tre at me nt of 
G uill ai n -B arre is n ot t y pic all y c o nsi dere d 
effecti ve. P atie nts re q uiri n g tre at me nt 
s h o ul d be st arte d wit h I V I G a n d f oll o we d 
b y pl as m a p heresi s if n ot res p o nsi ve t o I V 
I G. 
 
Gr a de 1  
N o d ose m o dificati o ns.  
F or Gr a de 1:  
− 
C o nsi der, as necessar y, disc ussi n g wit h t he 
st u d y p h ysicia n. 
− 
Care s h o ul d be ta ke n t o m o nit or s u bjects f or 
se nti nel s y m pt o ms of a p ote ntial 
dec o m pe nsati o n as descri be d a b o ve.  
− 
C o ns ult a ne ur ol o gist . 
Gr a de 2  
H ol d st u d y dr u g/st u d y re gi me n 
d ose u ntil res ol uti o n t o Gra de 
≤1.  
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n if it d oes 
n ot res ol ve t o Gra de ≤1 wit hi n 
3 0 da ys or if t here are si g ns of 
res pirat or y i ns ufficie nc y or 
a ut o n o mic i nsta bilit y.  
F or Gr a de 2:  
− 
C o ns ult a ne ur ol o gist.  
− 
C o nsi der disc ussi n g wit h t he Cli nical St u d y 
Lea d, as nee de d.  
− 
Care s h o ul d be ta ke n t o m o nit or s u bjects f or 
se nti nel s y m pt o ms of a p ote ntial 
dec o m pe nsati o n as descri be d a b o ve.  
− 
Se ns or y ne ur o pat h y/ ne ur o pat hic pai n ma y be 
ma na ge d b y a p pr o priate me dicati o ns (e. g., 
ga ba pe nti n or d ul o xeti ne).  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 1 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
M Y A S T H E NI A G R A VI S:  
o  
Ster oi ds ma y be s uccessf ull y use d 
t o treat m yast he nia gra vis. It is 
i m p orta nt t o c o nsi der t hat ster oi d 
t hera p y (es peciall y wit h hi g h 
d oses) ma y res ult i n tra nsie nt 
w orse ni n g of m yast he nia a n d 
s h o ul d t y picall y be a d mi nistere d i n 
a m o nit ore d setti n g u n der 
s u per visi o n of a c o ns ulti n g 
ne ur ol o gist. 
o  
P atie nts u n a ble t o t oler ate 
ster oi ds m a y be c a n di d ates f or 
tre at me nt with pl as m a p heresis 
or I V I G.  S uc h decisi o ns are best 
ma de i n c o ns ultati o n wit h a 
ne ur ol o gist, ta ki n g i nt o acc o u nt 
t he u ni q ue nee ds of eac h s u bject. 
o  
If m yast he nia gra vis-li ke 
ne ur ot o xicit y is prese nt, c o nsi der 
starti n g A C h E i n hi bit or t hera p y i n 
a d diti o n t o st er oi ds. S uc h t hera p y, 
if s uccessf ul, ca n als o ser ve t o 
rei nf orce t he dia g n osis. 
o  
A v oi d me dicati o ns t hat ca n w orse n 
m yast he nia gra vis (e. g. s o me 
a nti bi otics, beta bl oc kers, calci u m 
c ha n nel bl oc kers, m uscle 
rela xa nts). 
G UI L L AI N -B A R R E:  
o  
It is i m p orta nt t o c o nsider here t hat 
t he use of ster oi ds as t he pri mar y 
treat me nt of G uillai n-Barre is n ot 
t y picall y c o nsi dere d effecti ve. 
o  
Patie nts  re q uiri n g treat me nt s h o ul d 
be starte d wit h I V I G a n d f oll o we d 
b y plas ma p heresis if n ot 
res p o nsi ve t o I V I G. 
 
Gr a de 3 or 4  
F or Gr a de 3  or 4  
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n.  
F or Gr a de 3 or 4 (se vere or life -t hre ate ni n g e ve nts): 
− 
C o nsi der, as necessar y, disc ussi n g wit h 
Cli ncal St u d y Lea d, as nee de d . 
− 
Rec o m me n d h os pitalizati o n.  
− 
M o nit or s y m pt o ms a n d o btai n ne ur ol o gical 
c o ns ult. 
M Y A S T H E NI A G R A VI S:  
o  
Ster oi ds ma y be s uccessf ull y use d 
t o treat m yast he nia gra vis. T he y 
s h o ul d t y picall y be a d mi nistere d i n 
a m o nit ore d setti n g u n der 
s u per visi o n of a c o ns ulti n g 
ne ur ol o gist. 
o  
S u bjects  u na ble t o t olerate ster oi ds 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 2 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
ma y be ca n di dates f or treat me nt 
wit h plas ma p heresis or I V I G.  
o  
If m yast he nia gra vis-li ke 
ne ur ot o xicit y prese nt, c o nsi der 
starti n g A C h E i n hi bit or t hera p y i n 
a d diti o n t o ster oi ds. S uc h t hera p y, 
if s uccessf ul, ca n als o ser ve t o 
rei nf orce t he dia g n osis. 
o  
A v oi d me dicati o ns t hat ca n w orse n 
m yast he nia gra vis (e. g. s o me 
a nti bi otics, beta bl oc kers, calci u m 
c ha n nel bl oc kers, m uscle 
rela xa nts).  
G UI L L AI N -B A R R E:  
o  
It is i m p orta nt t o c o nsi der here t hat 
t he use of ster oi ds as t he pri mar y 
treat me nt of G uillai n-Barre is n ot 
t y picall y c o nsi dere d effecti ve.  
o  
S u bjects re q uiri n g treat me nt 
s h o ul d be starte d wit h I V I G a n d 
f oll o we d b y plas ma p heresis if n ot 
res p o nsi ve t o I V I G. 
 
M y oc ar ditis  
A n y Gr a de  
( Refer t o N CI C T C A E 
a p plic a ble versi o n i n  
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E  
gr a de/se verit y)  
Ge ner al G ui d a nce  
Disc o nti n ue dr u g per ma ne ntl y 
if bi o ps y-pr o ve n i m m u ne -
me diate d m y ocar ditis.  
F or A n y Gr a de:  
− 
Patie nts s h o ul d be t h or o u g hl y e val uate d t o  
r ule  o ut  a n y  alter nati ve  eti ol o g y  (e. g., disease 
pr o gressi o n, ot her me dicati o ns, or  
i nfecti o ns) 
− 
T he pr o m pt dia g n osis of i m m u ne -me diate d  
m y ocar ditis is i m p orta nt, partic ularl y i n  patie nts wit h 
baseli ne car di o p ul m o nar y  disease a n d re d uce d car diac 
f u ncti o n. 
− 
C o nsi der disc ussi n g wit h t he Cli nical St u d y  
Lea d, as nee de d.  
− 
M o nit or patie nts f or si g ns a n d s y m pt o ms of  
m y ocar ditis  ( ne w  o nset  or  w orse ni n g  c hest  pai n,  
arr h yt h mia, s h ort ness of breat h,  peri p heral e de ma). As 
s o me  s y m pt o ms  ca n o verla p  wit h  l u n g  t o xicities,  
si m ulta ne o usl y e val uate  f or  a n d  r ule  o ut  p ul m o nar y  
t o xicit y as  well  as ot her  ca uses  (e. g.,  p ul m o nar y  
e m b olis m,
 c o n gesti ve
 heart
 fail ure,   
mali g na nt 
pericar dial eff usi o n). C o ns ult a  car di ol o gist earl y, t o 
pr o m ptl y  assess  w het her  a n d  w he n  t o  c o m plete  a  
car diac bi o ps y, i ncl u di n g a n y ot her dia g n ostic  
pr oce d ures. 
 
 I nitial w or k- u p s h o ul d i ncl u de cli nical  e val uati o n, B -
t y pe  natri uretic  pe pti de  ( B N P),  car diac  e nz y mes,  
electr ocar di o gra m  ( E C G),  ec h ocar di o gra m  ( E C H O),  
m o nit ori n g of  o x y ge nati o n via p ulse o xi metr y (resti n g 
a n d e xerti o n),  a n d  a d diti o nal  la b orat or y  w or k -u p  as 
i n dicate d. S piral C T or car diac M RI ca n  c o m ple me nt 
E C H O  t o  assess  wall  m oti o n  a b n or malities  w he n  
nee de d.  

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 3 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
 
Gr a de 2, 3 or 4  
 
If Gra de 2-4, per ma ne ntl y 
disc o nti n ue st u d y dr u g/st u d y  
re gi me n. 
F or Gr a de 2 - 4: 
− 
M o nit or s y m pt o ms dail y, h os pitalize.  
− 
Pr o m ptl y start I V met h yl pre d nis ol o ne 2 t o 
4 m g/ k g/ da y or e q ui vale nt after Car di ol o g y 
c o ns ultati o n has deter mi ne d w het her a n d w he n t o 
c o m plete dia g n ostic pr oce d ures i ncl u di n g a 
car diac bi o ps y.  
− 
S u p p orti ve care (e. g., o x y ge n).  
− 
If n o i m pr o ve me nt wit hi n 2  t o 3 da ys des pite I V 
m et h yl pre d nis ol o ne at 2 t o 4  m g/ k g/ da y, 
pr o m ptl y start i m m u n os u p pressi ve t hera p y s uc h 
as T N F i n hi bit ors (e. g.,  i nfli xi ma b at 5 m g/ k g I V, 
ma y be re peate d at 2 a n d 6 wee ks after i nitial 
d ose at t he discreti o n of t he treati n g pr o vi der or 
rele va nt practice g ui deli nes. C a uti o n: It is 
i m p ort a nt t o r ule o ut se psis a n d refer t o 
i nfli xi m a b l a bel f or ge ner al g ui d a nce bef ore 
usi n g i nfli xi m a b.  I nfli xi m a b is c o ntr ai n dic ate d 
f or p atie nts w h o h a ve he art f ail ure. 
M y ositis/ P ol y m y ositis 
( “ P ol y/ m y ositis ”) 
A n y Gr a de  
 
 
( Refer t o N CI C T C A E 
a p plica ble versi o n i n 
st u d y pr ot oc ol f or 
defi ni n g t he C T C A E  
gra de/se verit y) 
 
Ge ner al G ui d a nce  
F or A n y Gr a de:  
−     Patie nts s h o ul d be t h or o u g hl y e val uate d t o r ule 
o ut a n y alter nati ve eti ol o g y (e. g., disease pr o gressi o n, 
ot her me dicati o ns, or i nfecti o ns).  
−     M o nit or patie nts f or si g ns a n d s y m pt o ms of 
p ol y/ m y ositis. T y picall y, m uscle wea k ness/ pai n occ urs 
i n pr o xi mal m uscles i ncl u di n g u p per ar ms, t hi g hs, 
s h o ul ders, hi ps, nec k a n d bac k, b ut rarel y affects t he 
e xtre mities i ncl u di n g ha n ds a n d fi n gers; als o diffic ult y 
breat hi n g a n d/ or tr o u ble  s wall o wi n g ca n occ ur a n d 
pr o gress ra pi dl y. I ncrease d ge neral feeli n gs of 
tire d ness a n d fati g ue ma y occ ur, a n d t here ca n be ne w- 
o nset falli n g, diffic ult y getti n g u p fr o m a fall, a n d 
tr o u ble cli m bi n g stairs, sta n di n g u p fr o m a seate d 
p ositi o n, a n d/ or reac hi n g u p.  
−     If p ol y/ m y ositis is s us pecte d, a Ne ur ol o g y 
c o ns ultati o n s h o ul d be o btai ne d earl y, wit h pr o m pt 
g ui da nce o n dia g n ostic pr oce d ures. M y ocar ditis ma y 
c o-occ ur wit h p ol y/ m y ositis; refer t o g ui da nce u n der 
M y ocar ditis. Gi ve n breat hi n g c o m plicati o ns, refer t o 
g ui da nce u n der P ne u m o nitis/I L D. Gi ve n p ossi bilit y of 
a n e xiste nt ( b ut pre vi o usl y u n k n o w n) a ut oi m m u ne 
dis or der, c o nsi der R he u mat ol o g y c o ns ultati o n.  
−     C o nsi der, as necessar y, disc ussi n g wit h t he 
Cli nical St u d y Lea d.  
−     I nitial w or k -u p s h o ul d i ncl u de cli nical e val uati o n, 
creati ne ki nase, al d olase, lactate de h y dr o ge nase 
( L D H), bl o o d urea nitr o ge n ( B U N)/creati ni ne, 
er yt hr oc yte se di me ntati o n rate or C -reacti ve pr otei n 
( C R P) le vel, uri ne m y o gl o bi n, a n d a d diti o nal 
la b orat or y w or k- u p as i n dicate d, i ncl u di n g a n u m ber 
of p ossi ble r he u mat ol o gical/a nti b o d y tests (i.e., 
c o nsi der w het her a r he u mat ol o gist c o ns ultati o n is 
i n dicate d a n d c o ul d g ui de nee d f or r he u mat oi d fact or, 
a nti n uclear a nti b o d y, a nti-s m o ot h m uscle, 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 4 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
a ntis y nt hetase [s uc h as a nti -J o-1], a n d/ or si g nal -
rec o g niti o n particle a nti b o dies). C o nfir mat or y testi n g 
ma y i ncl u de electr o m y o gra p h y, ner ve c o n d ucti o n 
st u dies, M RI of t he m uscles, a n d/ or a m uscle bi o ps y. 
C o nsi der Bari u m s wall o w f or e val uati o n of d ys p ha gia 
or d ys p h o nia.  
 
Gr a de 1  
 
- N o d ose m o dificati o ns.  
F or Gr a de 1:  
− 
M o nit or a n d cl osel y f oll o w u p i n 2 t o 4 da ys 
f or cli nical s y m pt o ms a n d i nitiate e val uati o n 
as cli nicall y i n dicate d.  
− 
C o nsi der Ne ur ol o g y c o ns ult.  
− 
C o nsi der, as necessar y, disc ussi n g wit h t he 
st u d y p h ysicia n. 
 
Gr a de 2  
 
H ol d st u d y dr u g/st u d y re gi me n 
d ose u ntil res ol uti o n t o Gra de 
≤1.  
- Per ma ne ntl y disc o nti n ue 
st u d y dr u g/st u d y re gi me n if 
it d oes n ot res ol ve t o Gra de 
≤1 wit hi n 3 0 da ys or if t here 
are si g ns of res pirat or y 
i ns ufficie nc y. 
F or Gr a de 2:  
− 
M o nit or s y m pt o ms dail y a n d c o nsi der 
h os pitalizati o n. 
− 
O btai n Ne ur ol o g y c o ns ult, a n d i nitiate 
e val uati o n. 
− 
C o nsi der, as necessar y, disc ussi n g wit h t he 
st u d y p h ysicia n. 
− 
If cli nical c o urse is ra pi dl y pr o gressi ve 
( partic ularl y if diffic ult y breat hi n g a n d/ or 
tr o u ble s wall o wi n g), pr o m ptl y start I V 
met h yl pre d nis ol o ne 2 t o 4  m g/ k g/ da y 
s yste mic ster oi ds al o n g wit h recei vi n g i n p ut  
fr o m Ne ur ol o g y c o ns ulta nt  
− 
If cli nical c o urse is n ot  ra pidl y pr o gressi ve, 
start s yste mic ster oi ds (e. g., pre d nis o ne 1 t o 
2 m g/ k g/ da y P O or I V e q ui vale nt); if n o 
i m pr o ve me nt wit hi n 2 t o 3 da ys, c o nti n ue 
a d diti o nal w or k u p a n d start treat me nt wit h 
I V met h yl pre d nis ol o ne 2 t o 4 m g/ k g/ da y 
− 
If after start of I V met h yl pre d nis ol o ne at 2 t o 
4 m g/ k g/ da y t here is n o i m pr o ve me nt wit hi n 
2 t o 3 da ys, c o nsi der start of 
i m m u n os u p pressi ve t hera p y s uc h as T N F 
i n hi bit ors (e. g., i nfli xi ma b at 5 m g/ k g  I V 
ma y be re peate d at  2  a n d 6 wee ks  after 
i nitial d ose at t he discreti o n of t he treati n g 
pr o vi der or rele va nt practice g ui deli nes ). 
C a uti o n: It is i m p ort a nt t o r ule o ut se psis 
a n d refer t o i nfli xi m a b l a bel f or ge ner al 
g ui d a nce bef ore usi n g i nfli xi m a b.  
 
Gr a de 3 or 4  
 
F or Gr a de 3:  
H ol d st u d y dr u g/st u d y re gi me n 
d ose u ntil res ol uti o n t o Gra de 
≤1.  
Per ma ne ntl y disc o nti n ue st u d y 
dr u g/st u d y re gi me n if Gra de 3 
i m A E d oes n ot res ol ve t o Gra de 
≤1 wit hi n 3 0 da ys or if t here are 
si g ns of res pirat or y 
F or Gr a de 3 or 4 (se vere or life -t hre ate ni n g e ve nts): 
− 
M o nit or s y m pt o ms cl osel y; rec o m me n d 
h os pitalizati o n. 
− 
O btai n Ne ur ol o g y c o ns ult, a n d c o m plete f ull 
e val uati o n. 
− 
C o nsi der, as necessar y, disc ussi n g wit h t he 
Cli nical St u d y Lea d . 
− 
Pr o m ptl y start I V met h yl pre d nis ol o ne 2 t o 
4  m g/ k g/ da y s yste mic ster oi ds al o n g wit h 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 5 
 
 
S pecific I m m u ne -Me di ate d Re acti o ns  
A d verse E ve nts  
Se verit y Gr a de of t he 
E ve nt  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
i ns ufficie nc y. 
 
F or Gr a de 4:  
- Per ma ne ntl y disc o nti n ue 
st ud y dr u g/st u d y re gi me n.  
recei vi n g i n p ut fr o m Ne ur ol o g y c o ns ulta nt. 
− 
If after start of I V met h yl pre d nis ol o ne at 2 t o 
4 m g/ k g/ da y t here is n o i m pr o ve me nt wit hi n 
2 t o 3 da ys, c o nsi der start of 
i m m u n os u p pressi ve t hera p y s uc h as T N F 
i n hi bit ors (e. g., i nfli xi ma b at 5 m g/ k g I V, 
ma y be re peate d at 2 a n d 6 wee ks  after 
i nitial d ose at t he discreti o n of t he treati n g 
pr o vi der or rele va nt practice g ui deli nes ). 
C a uti o n: It is i m p ort a nt t o r ule o ut se psis 
a n d refer t o i nfli xi m a b l a bel f or ge ner al 
g ui d a nce bef ore usi n g i nfli xi m a b.  
− 
C o nsi der w het her s u bject ma y re q uire I V I G, 
plas ma p heresis.  
 
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 6 
I nf usi o n- Rel ate d Re acti o ns 
Se verit y Gr a de of 
t he E ve nt ( N CI 
C T C A E 
versi o n 4. 0 3) 
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
A n y Gr a de  
Ge neral G ui da nce  
F or A n y Gr a de:  
− 
Ma na ge per i nstit uti o nal sta n dar d at t he discreti o n of 
i n vesti gat or. 
− 
M o nit or s u bjects f or si g ns a n d s y m pt o ms of i nf usi o n-
relate d reacti o ns (e. g., fe ver a n d/ or s ha ki n g c hills, 
fl us hi n g a n d/ or itc hi n g, alterati o ns i n heart rate a n d 
bl o o d press ure, d ys p nea or c hest disc o mf ort, or s ki n 
ras hes) a n d a na p h yla xis (e. g., ge neralize d  urticaria, 
a n gi oe de ma, w heezi n g, h y p ote nsi o n, or tac h ycar dia).  
Gr a de 1 or 2  
F or Gr a de 1:  
T he i nf usi o n rate of st u d y dr u g/st u d y re gi me n ma y 
be decrease d b y 5 0 % or te m p oraril y i nterr u pte d 
u ntil res ol uti o n of t he e ve nt.  
 
F or Gr a de 2:  
T he i nf usi o n rate of st u d y dr u g/st u d y re gi me n ma y 
be decrease d 5 0 % or te m p oraril y i nterr u pte d u ntil 
res ol uti o n of t he e ve nt. 
S u bse q ue nt i nf usi o ns ma y be gi ve n at 5 0 % of t he 
i nitial i nf usi o n rate. 
F or Gr a de 1 or 2:  
− 
Aceta mi n o p he n a n d/ or a nti hista mi nes ma y be 
a d mi nistere d per i nstit uti o nal sta n dar d at t he discreti o n 
of t he i n vesti gat or.  
− 
C o nsi der pre me dicati o n per i nstit uti o nal sta n dar d pri or 
t o s u bse q ue nt d oses. 
− 
Ster oi ds s h o ul d n ot be use d f or r o uti ne pre me dicati o n 
of Gra de ≤2 i nf usi o n reacti o ns.  
Gr a de 3 or 4  
F or Gr a de 3 or 4:  
Per ma ne ntl y disc o nti n ue st u d y dr u g/st u d y re gi me n.  
F or Gr a de 3 or 4:  
− 
Ma na ge se vere i nf usi o n -relate d reacti o ns per 
i nstit uti o nal sta n dar ds (e. g., I M e pi ne p hri ne, f oll o we d 
b y I V di p he n h y dra mi ne a n d ra niti di ne, a n d I V 
gl uc oc ortic oi d). 
C T C A E C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; I M i ntra m usc ular; I V i ntra ve n o us; N CI Nati o nal Ca ncer I nstit ute.  
 
 
 

L C C C 1 6 2 1  
 
C O N FI D E N TI A L  
PI: J are d Weiss  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Dece m ber 1, 2 0 2 1  
A me n d me nt 4 
9 7 
N o n – I m m u ne-Me di ate d Re acti o ns  
Se verit y Gr a de of t he 
E ve nt ( N CI C T C A E 
versi o n 4. 0 3) 
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
A n y Gr a de  
N ote: D ose m o dificati o ns are n ot re q uire d f or 
A Es n ot dee me d t o be relate d t o st u d y 
treat me nt (i.e., e ve nts d ue t o u n derl yi n g 
disease) or f or la b orat or y a b n or malities n ot 
dee me d t o be cli nicall y si g nifica nt.  
Treat acc or di n gl y, as per i nstit uti o nal st a n dar d. 
Gr a de 1  
N o d ose m o dificati o ns.  
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.  
Gr a de 2  
H ol d st u d y dr u g/st u d y re gi me n u ntil 
res ol uti o n t o ≤Gra de 1 or baseli ne. 
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.  
Gr a de 3  
H ol d st u d y dr u g/st u d y re gi me n u ntil 
res ol uti o n t o ≤Gra de 1 or baseli ne. 
F or A Es t hat d o w n gra de t o ≤Gra de 2 wit hi n 7 
da ys or res ol ve t o ≤Gra de 1 or baseli ne wit hi n 
1 4 da ys, res u me st u d y dr u g/st u d y re gi me n 
a d mi nistrati o n. Ot her wise, disc o nti n ue st u d y 
dr u g/st u d y re gi me n . 
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.  
Gr a de 4  
 
Disc o nti n ue st u d y dr u g/st u d y re gi me n ( N ote: 
F or Gra de 4 la bs, decisi o n t o disc o nti n ue 
s h o ul d be base d o n acc o m pa n yi n g cli nical 
si g ns/s y m pt o ms, t he I n vesti gat or’s cli nical 
j u d g me nt, a n d c o ns ultati o n wit h t he 
S p o ns or.). 
Treat acc or di n gl y, as per i nstit uti o nal sta n dar d.  
N ote: As a p plica ble, f or earl y p hase st u dies, t he f oll o wi n g se nte nce ma y be a d de d: “ A n y e ve nt greater t ha n or e q ual t o Gra de 2, please disc uss wit h 
St u d y P h ysicia n.”  
A E A d verse e ve nt; C T C A E C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; N CI Nati o nal Ca ncer I nstit u te.