A Phase II Study of Durvalumab (MEDI 4736) With Radiotherapy for the Adjuvant Treatment of Intermediate Risk Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Larynx, Lip, Oral Cancer, Digestive Organs--Diseases
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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
 
 
P R O T O C O L A M E N D M E N T # 4  
 
 
L C C C 1 7 2 5:  A P hase II St u d y of D ur val u ma b ( M E DI 4 7 3 6) wit h Ra di ot hera p y f or t he 
a dj u va nt treat me nt of I nter me diate Ris k Hea d a n d Nec k S q ua m o us Cell Carci n o ma  
 
A M E N D M E N T 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 d mi nistrati ve c ha n g es  
_ X _ _ Scie ntific c ha n g es (I R B a p pr o val)  
_  _ _   T hera p y c ha n ges (I R B a p pr o val)  
_  _ _   Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
T he p ur p ose of t his a me n d me nt is t o c ha n ge accr ual f or t he st u d y t o 1 8 s u bjects. Statistical 
c o nsi derati o ns i n li g ht of t his c ha n ge ha ve bee n u p date d t o acc o m m o date t he ne w accr ual . 
Dr. S het h’s desi g nati o n was u p date d.  
 
E dit ori al C h a n ges  
1.  W here a p pr o pri ate i n t he hea der, Dr. S het h’s desi g nati o n was c ha n g e d fr o m M D 
t o D O. 
 
Scie ntific  C h a n ges  
1.  Secti o n 1. 1 a n d Sc he ma ha ve bee n u p date d t o acc o m m o date ne w accr ual 
n u m bers.  
2.  Secti o n 5. 1: U p date d Sc h e ma t o acc o m m o date ne w accr ual n u m bers.  
3.  Secti o n 9. 2 has bee n u p d ate d t o i ncl u de ne w statistical descri pti o ns relati ve t o t he 
c ha n ge i n a ccr ual.  
 
 
T H E A T T A C H E D V E R SI O N D A T E D J u ne 1 , 2 0 2 1 I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
 
 
P R O T O C O L A M E N D M E N T # 3  
 
 
L C C C 1 7 2 5:  A P hase II St u d y of D ur val u ma b ( M E DI 4 7 3 6) wit h Ra di ot hera p y f or t he 
a dj u va nt treat me nt of I nter me diate Ris k Hea d a n d Nec k S q ua m o us Cell Carci n o ma  
 
A M E N D M E N T 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 d mi nistrati ve c ha n g es  
_ _ _ _ _ Scie ntific c ha n g es (I R B a p pr o val)  
_ _ _ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ X _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
Pr ot oc ol A me n d me nt 3 was ge nerate d  t o u p date A p pe n di x 1 2. 1, “ D ose M o dificati o n a n d 
T o xicit y Ma na ge me nt G ui deli ne f or D ur val u ma b .” T his u p date  i ncl u ded  t h e i nc or porati o n 
of t he re vise d “ D osi n g M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli n es f or I m m u ne -
Me diate d,  I nf usi o n-Relate d, 
a n d 
N o n -I m m u ne– Me diate d 
Reacti o ns ( M E DI 4 7 3 6 
M o n ot hera p y 
or 
C o m bi nati o n 
T hera p y 
wit h 
Tre meli m u ma b 
or 
Tre meli m u ma b 
M o n ot hera p y) 1 7 Oct o b er 2 0 1 9 Versi o n ( C T C A E v 5. 0) .” T his re vise d versi o n i ncl u de d 
ge neral mec h a nical e diti n g t hr o u g h o ut a n d a d diti o nal or re vise d  ad verse e ve nt s, se verit y 
gra de defi niti o ns , d ose m o dificati o n g ui da nce a n d t o xicit y ma na ge me nt, w here a p pr o piat e . 
S pecific c h a n ges i n t he t o xicities a n d g ui deli nes t hat were i nc or p orate d i nt o t he b o d y of 
t he p r ot oc ol are o utli ne d i n t he bel o w secti o n. A d verse e ve nts were a d de d/ m o difie d i n t he 
Diarr hea/ C olitis, Ras h, a n d E n d ocri n o pat h y secti o ns. Clarificati o n was pr o vi de d f or 
se verit y 
gra des 
i n 
t he 
Peri p heral 
n e ur o m ot or 
s y n dr o mes, 
M y ocar ditis, 
Diarr hea/ C olitis/ Lar ge  
i ntesti ne  
pef orati o n/I nt esti n e 
perf orati o n  
a n d 
M y ositis/ P ol y m y ositis secti o ns. Of n ote,  clarifi cati o n of Gra de i n t h e first He pa titis secti o n 
was a d de d  relati ve t o n or mal or a b n or mal baseli ne le vels; a n d s pecific gra d es, 
ge nerall y, w ere re m o ve d i n t he He patitis Secti o n f or Patie nts wit h H C C (t he s ha de d 
He patitis Secti o n), i nstea d e m p hasizi n g t he le vels i n A S T, A L T or t otal bilir u bi n a n d 
s u bse q ue nt c ha n g es res ulti n g fr o m d ose m o dificati o ns. D ose m o dificati o n la n g ua ge was 
u p date d i n t he G e neral C o nsi derati o n re gar di n g I m m u ne -Me diate d Reacti o ns a n d b ot h 
He patitis secti o ns. T o xicit y ma na ge me nt g ui da nce was u p d ate d i n Di arr h ea/ C olitis Lar ge 
i ntesti ne perf orati o n/I ntesti ne perf orati o n,  t he 
Ras h or 
Der matitis, 
Ne ur ot o xicit y, 
E n d ocri n o pat h y, a n d N e p hritis or re nal d ysf u ncti o n  secti o ns. T his A me n d me nt a ls o 
re d uces re d u n da nt la n g ua ge i n t he pr ot oc ol b y re m o vi n g Secti o ns 7. 2-7. 5 , w hic h reiterates 
t he st u d y ta ble. La n g ua ge perti ne nt t o t h ose secti o ns was rel ocate d, as necessar y, t o t he 
ti me a n d e ve nts ta ble f o ot n otes. T he pre g na n c y sc he d ule has als o be e n a me n de d. 
 
E dit ori al/ A d mi nistr ati ve  
1.  Secti o n 5. 3: Li n ks t o Secti o ns 1 2. 1. 2, 1 2. 2. 3, 1 2. 2. 4 u p date d.  
2.  Secti o n 6. 1. 7: I n cl usi o n of Lar ge I ntesti ne Perf orati o n/I ntesti ne Perf orati o n as a n 
a d verse e ve nt i ncl u di n g T o xicit y Ma na ge me nt m o nit ori n g la n g ua ge. 
3.  Secti o n 6. 1. 7: I ncl usi o n of Der matitis wit h Ras h a d verse e ve nt.  

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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
4.  Secti o n 7. 1: Ti me a n d E ve nts Ta ble:  
a. Pre g na nc y 
R o w: 
A d de d pre g na n c y testi n g at eac h c y cle, re m o ve d 
pare nt hetic al p hrase re gar di n g 7 2 h o ur re q uir e me nt.  
b.  F o ot n ote 1: A d d e d la n g ua ge fr o m te xt t o cl arif y ti mi n g of e ve nts ass ociate d 
wit hi n t his f o ot n ote.  
c. F o ot n ote 2:  
i. A d de d la n g ua g e fr o m te xt descri bi n g me dical hist or y a n d p h ysical 
e xa m details.  
ii. E dite d  B -H C G t o β -H C G  
iii. Clarifie d t hat pre g na nc y tests will perf or me d wit hi n 7 da ys of 
a d mi nistrati o n of t he first d ose of st u d y dr u g f or w o me n of 
c hil d beari n g p ote ntial.  
d.  F o ot n ote 4: Re m o ve d s ecti o n refere nce f or l o n g -ter m f oll o w-u p as t h e 
secti o n d oes n ot e xist a n y m ore. 
e. F o ot n ote 5: 
A d de d la n g ua ge re gar di n g pre -s ur gical i ma gi ni n g a n d 
pat h ol o g y re vie w.  
f. A d de d f o ot n otes 1 1 -1 5 , a d di n g la n g ua g e fr o m Secti o ns 7. 2-7. 5 as 
a p pr o priate  t o c o m pe nsat e f or t he re m o val of Secti o ns 7. 2-7. 5.  
5.  Secti o n 7. 2 t hr o u g h Secti o n 7. 5 ha ve bee n re m o ve d t o re d uce re d u n da n c y  
6.  Secti o n 8. 2 : M m y ocar ditis, e dite d t o M y ocar ditis  
7.  Secti o n 8. 2: A d de d I ntesti nal Perf orati o n a n d t h yr oi ditis as ad verse e ve nt s of 
s pecial i nterest. 
8.  Secti o n 1 2. 1 : D ose M o dificati o n a n d T o xicit y Ma na ge me nt f or D ur val u ma b was 
u p date d t o reflect t he re vise d “D osi n g M o dificati o n a n d T o xicit y Ma na g e me nt 
G ui deli nes f or I m m u ne -Me diate d, I nf usi o n -Relat e d, a n d N o n -I m m u ne– M e diate d 
Reacti o ns ( M E DI 4 7 3 6 M o n ot hera p y or C o m bi nati o n T hera p y wit h Tre meli m u ma b 
or Tre m eli m u ma b M o n ot hera p y) 1 7 Oct o b er 2 0 1 9 Versi o n ( C T C A E v 5. 0).” T his 
u p date pr o vi de d re vise d ad verse ev e nt s a n d s e v erit y defi niti o ns , i ncl u di n g d ose 
m o dificati o ns, a n d t o xicit y ma na ge me nt as a p pr o priate .  
9.  A me n d me nt 1 C o vers h eet: Eli gi bilit y C ha n ges: Ite m 1: T he c ha n ge i na d verta ntl y 
states a c ha n ge t o 2 4 da ys f or a pre g na nc y test, w he n t he c ha n ge was fr o m 2 4 da ys 
t o 3 da ys.  
  
Eli gi bilit y  
1.  Criteri o n 4. 1. 8 was u p dat e d t o pr o vi de a pre g na n c y test wit hi n 7 da ys pri or t o 
a d mi nistrati o n of treat me nt.  
 
T H E A T T A C H E D V E R SI O N D A T E D N ove m ber 5 , 2 0 1 9 I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
 
 
P R O T O C O L A M E N D M E N T # 2  
 
 
L C C C 1 7 2 5:  A P hase II St u d y of D ur val u ma b ( M E DI 4 7 3 6) wit h Ra di ot hera p y f or t he 
a dj u va nt treat me nt of I nter me diate Ris k Hea d a n d Nec k S q ua m o us Cell Carci n o ma  
 
A M E N D M E N T 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 d mi nistrati ve c ha n g es  
_ _ _ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ X _  Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
T h is pr ot oc ol a me n d me nt is t o re vise t he re q uire d a nti bi otic was h o ut f or s u bjects pri or t o 
recei vi n g t heir 1st d os e of d ur val u ma b. A nti bi otics are n o w pr o hi bite d t o be gi ve n less t ha n 
7 da ys pri or t o t he first d ose of d ur val u ma b. If a s u bject recei v es i ntra ve n o us a nti bi otics or 
has a n a nti bi otic treat me nt c o urse of greater t ha n 5 da ys ( oral or I V) t he n t he pre vi o usl y 
re q uire d l o n ger was h o ut peri o d of 1 4 da ys is re q uire d. La n g ua g e s urr o u n di n g ti mi n g a n d 
a m o u nts of ra diati o n t hera p y was als o a me n de d t o i ncrease clarit y a n d u n dersta n di n g.  
A d diti o nall y, t his a me n d me n t is t o u p date t he Pri nci pal I n vesti gat or of t he st u dy fr o m Jare d 
Weiss, M D t o Si d d hart h S het h, D O . 
 
E dit ori al/ A d mi nistr ati ve  
1.  Si d d hart h S het h was u p date d t o t he Pri nci pal I n vesti gat or of t he st u d y.  
2.  T he st u d y sc he ma, Secti o ns 1. 6. 1,  5. 1, 5. 2, 5. 2. 1, 6. 1. 3, 6. 2, 7. 3. 1  a n d t he Ti me a n d 
E ve nts Ta ble f o ot n otes w ere u p d ate d t o clarif y t he ti mi n g a n d fracti o n of ra diati o n 
t hera p y. 
 
Eli gi bilit y  
1.  Criteria 4. 2. 6 u p d ate d t o pr o hi bit a nti bi otics wit hi n less t ha n 7 da ys pri or t o t he first 
d ose of d ur val u ma b. If t he patie nt recei ves eit her I V a nti bi otics or > 5 da y treat me nt 
c o urse ( oral or I V), t he n t he 1std ur val u ma b d ose s h o ul d n ot be gi ve n u ntil 1 4 da ys 
of last a nti bi otic d ose.  
 
T H E A T T A C H E D V E R SI O N D A T E D Oct o ber 2 7 , 2 0 1 9 I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 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 A d mi nistrati ve C ha n ges  
X  Scie ntific C ha n ges  
X  T hera p y C h a n ges  
X  Eli gi bilit y C ha n ges  
 
R ati o n ale f or A me n d me nt :  
D ue t o t he rece nt ne gati v e res ults f or t he use of tre meli m u ma b i n H N S C C , t he pr ot oc ol is 
bei n g re vise d t o treat s u bjects wit h d ur val u ma b a n d ra diati o n al o ne, wit h o ut t he a d diti o n 
of tre meli m u ma b.  T his m ulti -ce nter, si n gle ar m P hase I I tri al will e val uate t he efficac y of 
c o m bi ni n g  ra diati o n t hera p y wit h d ur val u ma b as a dj u va nt t hera p y f or patie nts wit h 
i nter me diate ris k H N S C C. A t otal of 3 3 s u bjects will be accr ue d as de pict e d i n t he st u d y 
sc he ma. T h e treat me nt re gi me n will e val uat e Q 3 wee kl y d ur val u ma b ( 1 5 0 0 m g) wit h 
ra diati o n i n c y cles 1-3, f oll o we d b y si n gle a g e nt d ur val u ma b ( 1 5 0 0 m g) Q 4 wee kl y f or a n 
a d diti o nal t hree c ycl es. T he st u d y’s o bjecti ves, e n d p oi nts a n d data a nal ysis were u p dat e d 
acc or di n g t o t he n e w st u d y sc he ma.  
 
A d mi nistr ati ve c h a n ges  
1.  A d mi nistrati ve e dit orial c ha n ges ma de t hr o u g h o ut t he pr ot oc ol , i ncl u di n g u p dates 
t o T & E Ta ble f or c o nsist e nc y wit h Assess me nts l a n g ua ge. 
2.  U p date d refere nces t o “ U N C C N” t o “ M ultice nter” t hr o u g h o ut t he pr ot oc ol.  
3.  Secti o ns 1. 2 a n d 1. 2. 1 w ere u p dat e d f or clarit y . 
4.  U p date d t he f o ot n otes t o t he ti me a n d e v e nts ta ble t o i ncl u de wi n d o ws f or all st u d y 
visits t hat were pre vi o usl y pr o vi de d else w h ere i n t he pr ot oc ol.  
5.  U p date d T & E Ta ble f o ot n ote # 6 t o i ncl u de a refere nce t o a secti o n i n t he pr ot oc ol 
t hat details a d diti o nal assess me nts t hat 
will be perf or me d t o e n ha nce t he 
i n vesti gati o n a n d dia g n osis of p ote ntial cases of p ne u m o nitis.  
6.  Clarifie d t hat t he de ntal e xa m i n Secti o n 7. 2 nee d o nl y be perf or m e d if it is re q uire d 
per i nstit uti o nal sta n dar d of care  as pre vi o usl y i n dica te d i n t he f o ot n otes of t he T & E 
ta ble. 
7.  Clarifie d t he all o we d wi n d o ws f or Secti o ns 7. 3. 1 , 7. 3. 2  a n d 7. 4.  
8.  U p date d Secti o n s 8. 1. 4 a n d 8. 5. 1 t o clarif y t hat a pre g na nc y wit hi n 9 0 d a ys of t he 
last d ose of d ur val u ma b s h o ul d be re p orte d as a n i m p orta nt me dical e ve nt . 
9.  Re m o ve d refere n ces t o Tre meli m ua b i n Secti o ns 8. 2 , 8. 3 , 8. 5. 2, 8. 5. 2. 1, 8. 5. 2. 2 , 
8. 5. 2. 5  a n d 8. 6 . 
1 0.  U p date d Secti o n 8. 5. 3 t o be c o nsiste nt wit h u p date d pr ot oc ol t e m plate la n g ua ge f or 
F D A re p orti n g.  
1 1.  U p date d Secti o n 8. 6 t o reflect c urre nt U N C j o b titles.  
1 2.  U p date d Secti o n 1 0. 3 t o reflect c urre nt re gistrati o n pr oce d ures.  
1 3.  U p date d Secti o n 1 0. 4 t o reflect c urre nt m o nit ori n g a n d a u diti n g pr oce d ures.  

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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
1 4.  U p date d Secti o n 1 0. 6 t o reflect c urre nt m ultice nter a me n d me nt pr o ce d ures. 
1 5.  Versi o n 1. 1 of t his A me n d me nt i ncl u des t he F A C T Hea d a n d Nec k Q uesti o n naire, 
Versi o n 4, i n Secti o n 1 2. 5.  
 
 
Scie ntific c h a n ges  
1.  Secti o n 1. 1 was u p date d t o s u p p ort t he c ha n ge i n st u d y desi g n.  
2.  Secti o n s 1. 3 , 1. 3 . 2, 1. 5. 1,  1. 7  a n d 7. 6. 1  were  u p date d t o re m o ve refere nces t o 
C T L A 4 c o m bi nati o n t hera p y.  
3.  Secti o ns detaile d C T L A 4 I n hi biti o n, C o m bi nati o n of P D 1/ P D L 1 wit h C T L A 4 
i n hi biti o n a n d C o m bi nati o n D ur val u ma b wit h Tre meli m u ma b were re m o ve d as 
t he y are n o l o n ger a p plica ble t o t he st u d y desi g n. 
4.  Secti o n 1. 5. 1. 1 Rati o nale f or Fi xe d D osi n g of D ur val u ma b , Secti o n 1. 5. 1. 2 
D ur val u ma b D osi n g Sc h e d uli n g a n d Secti o n 1. 6. 1 D ose Rati o nale were u p date d t o 
re m o ve refere nces t o fi x d osi n g of tre meli m u ma b. 
5.  Secti o n 1. 6 Rati o nale f or Cli nical St u d y was u p date d t o pr o vi de a rati o nale f or 
d ur val u ma b m o n ot hera p y i n c o m bi nati o n wit h ra diati o n t hera p y.  
6.  C o -Pri mar y 
O bjecti ves, Sec o n dar y 
O bj ecti ves, E x pl orat or y 
O bjecti ves, 
C o -
Pri mar y E n d p oi nts, Sec o n dar y E n d p oi nts a n d E x pl orat or y E n d p oi nts were u p date d 
t o reflect t he c ha n g e i n st u d y desi g n t o d ur val u ma b m o n ot hera p y in c o m bi nati o n 
wit h ra diati o n t hera p y.  
7.  Re m o ve d secti o n refere n ci n g dr u g -s pecific i nf or m ati o n a b o ut Tre meli m u ma b. 
8.  U p date d Secti o n 9. 0 -9. 3  Statistics t o reflect t he c ha n ges i n st u d y de si g n, pri mar y 
e n d p oi nts, sec o n dar y e n d p oi nts a n d e x pl orat or y e n d p oi nts.  
 
T h er a p y c h a n ges  
1.  T he st u d y w as u p d ate d t o re m o v e c o m bi nati o n t hera p y wit h tr e meli m u ma b 
i ncl u di n g Secti o ns 1. 1, 5. 1, 5. 2 , 5. 2. 1, 5. 3, 5. 4, 5. 5, 5. 6, 5. 7, 5. 9, 6. 0, 6. 1. 3, 7. 1 , 
7. 3. 1 a n d 7. 3. 2.   
2.  T he st u d y w as u p d ate d t o ha ve c o m bi nati o n d ur val u ma b/ra diati o n t he ra p y C ycles 
1 -3 as o p p ose d t o C ycles 2 -4 i ncl u di n g Secti o ns 1. 1, 5. 1, 5. 2 , 5. 2. 1, 6. 1. 3, 6. 2, 7. 1,  
7. 3. 1 a n d 7. 3. 2 . 
3.  T he st u d y was u p date d t o ha ve d ur val u ma b m o n ot hera p y tra nsiti o n t o Q 4 wee kl y 
f or C ycles 4-6 i ncl u di n g Secti o ns 1. 1, 5. 1, 5. 2, 5. 2. 1, 6. 1. 3, 7. 1  a n d 7. 3. 3 . 
4.  T he defi niti o n of d ose li miti n g t o xicit y was re m o ve d fr o m Secti o n 5. 3 as t he st u d y 
will n o l o n ger ha v e a d os e escal ati o n.  
5.  I n V ersi o n 1. 1 of t his A me n d me nt 1, F o ot n ote 9 of t he Ti me a n d E ve nts Ta ble (i n 
re gar d t o bl o o d dra ws) h as bee n m o difie d t o a d d “ …a n d 2 4 m L of bl o o d i n A C D.”  
 
Eli gi bilit y c h a n ges  
1.  Eli gi bilit y criteri o n 4. 1. 8 was u p d ate d t o clarif y t hat t he ser u m pre g na nc y test 
s h o ul d be c o n d ucte d wit hi n 3 da ys pri or t o treat m e nt.  
2.  Eli gi bilit y criteria  4. 1. 9 , 4. 1. 1 0, 4. 2. 7, 4. 2. 8 a n d 4. 2. 1 4 were  u p d ate d t o re m o ve 
refere nces t o c o m bi nati o n t hera p y wit h d ur val u m a b a n d tre meli m u ma b. 
3.  Eli gi bilit y criteri o n 4. 2. 5 was u p date d t o clarif y t hat t he ti mefra me is w hic he ver 
s pecifie d ti mefra me is s h ortest. 

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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
4.  Eli gi bilit y criteri o n 4. 2. 1 3 was u p d ate d t o o nl y pr o hi bit s u bjects fr o m e nr olli n g 
wit h “ u nc o ntr olle d” li ver disease.  
 
 
 
 
 
T he att ac he d versi o n d ate d M ay 2 4 , 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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
L C C C 1 7 2 5 : A P has e I I St u d y of D ur val u ma b  ( M E DI 4 7 3 6) wit h Ra di ot hera p y f or t he 
a dj u va nt treat me nt of I nter me diate Ris k Hea d a n d Nec k S q ua m o us Cell Carci n o ma  
 
Pri nci p al I n vesti g at or  
Si d d hart h S het h , D O   
Di visi o n of He mat ol o g y/ O nc ol o g y  
3 1 1 5 P h ysicia ns Office Bl d g  
1 7 0 Ma n ni n g Dr, C B # 7 3 0 5  
C ha pel Hill, N C 2 7 5 9 9 -7 3 0 5  
9 1 9 -8 4 3 -7 7 0 9  ( P H O N E)     
9 1 9 -9 6 6 -6 7 3 5 ( F A X)  
E mail: Si d d hart h. S het h @ me d. u nc.e d u  
  
Bi ost atistici a n   
Allis o n Deal, M S  
Allis o n
Deal @ me d. u nc. e d u   
P h o ne: 9 1 9 -9 6 6 -1 3 8 7     
Fa x: 9 1 9 -9 6 6 -4 2 4 4  
 
Cli nic al Pr ot oc ol Office  
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
T he U ni versit y of N ort h Car oli na at C ha pel Hill  
4 5 0 West Dri ve, 3 r d Fl o or, C B # 7 2 9 5  
C ha pel Hill, N C 2 7 5 9 9 -7 2 9 5  
 
C P O M ultice nter  Pr oject M a n a ger : 
P h o ne: 9 1 9 -9 6 6 -7 3 5 9  
Fa x: 9 1 9 -9 6 6 -4 3 0 0  
E mail: C P O M ultice nter @ me d. u nc.e d u   
 
S p o ns or : Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter 
 
F u n di n g S o urce : Astra Ze neca  
Versi o n: Pr ot oc ol A me n d me nt # 4  Versi o n 4 . 0 
Versi o n d ate : J u ne 1, 2 0 2 1 

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  
L C C C 1 7 2 5  
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  
 
PI: S het h   
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  
J u ne 1 , 2 0 2 1 
 
L C C C 1 7 2 5: A P has e I I St u d y of D ur val u ma b  ( M E DI 4 7 3 6) wit h Ra di ot hera p y f or t he 
a dj u va nt treat me nt of I nter me diate Ris k Hea d a n d Nec k S q ua m o us Cell Carci n o ma  
 
Pri nci p al I n vesti g at or  
Si d d hart h S het h , D O  
Di visi o n of He mat ol o g y/ O nc ol o g y  
3 1 1 5 P h ysicia ns Office Bl d g  
1 7 0 Ma n ni n g D r, C B # 7 3 0 5  
C ha pel Hill, N C 2 7 5 9 9 -7 3 0 5  
9 1 9 -8 4 3 -7 7 0 9  ( P H O N E)     
9 1 9 -9 6 6 -6 7 3 5 ( F A X)  
E mail: Si d d hart h. S het h @ me d. u nc.e d u   
 
 
 
 
 
Si g n at ure P a ge  
 
T he si g nat ure bel o w c o nstit utes t he a p pr o val of t his pr ot oc ol a n d t he attac h me nts, a n d 
pr o vi des t he n ecessar y ass ura nces t hat t his tri al will be c o n d u cte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d 
acc or di n g t o l ocal le gal a n d re g ulat or y re q uir e me nts a n d a p p lica ble U. S. fe d eral re g ul ati o ns 
a n d I C H g ui deli nes.  
 
Pri nci p al I n vesti g at or ( PI) N a me : _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
PI Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
D ate: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
A me n d me nt: 4  
Versi o n:  4 . 0 
Versi o n d ate : J u ne 1, 2 0 2 1 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
i 
LI S T O F A B B R E VI A TI O N S  
A C D  
Aci d Citrate De xtr ose  
A E  
A d verse e ve nt  
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  
β -H C G  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
B U N  
Bl o o d urea nitr o ge n  
C  
Celsi us  
C B C  
C o m plete bl o o d c o u nt  
C D  
Cl uster of differe ntiati o n  
C L  
C hl ori de  
C LI A  
Cli nical La b orat or y I m pr o ve me nt A me n d me nts  
C O 2  
Bicar b o nate  
C P O  
Cli nical Pr ot oc ol Office  
C T  
C o m p uter t o m o gra p h y  
C T L A -4  
C yt ot o xic T l y m p h oc yte ass ociate d a nti ge n 4  
C T V 6 0  
Cli nical tar get v ol u me 6 0 G y  
D 1  
Da y 1  
D F S  
Disease -free s ur vi val 
d L  
Deciliter  
D L T  
D ose li miti n g t o xicit y  
D N A  
De o x yri b o n ucleic aci d  
D S M C  
Data safet y m o nit ori n g c o m mittee  
E C E  
E xtraca ps ular e xte nsi o n  
e C R F  
Electr o nic case re p ort f or m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E D T A  
Et h yle ne dia mi netetraacetic aci d  
E O R T C  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer  
F  
Fa hre n heit  
F A C T  
F u ncti o nal assess me nt of ca ncer t hera p y  
Fc  
C o nsta nt fra g me nt  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G or g m  
Gra m  
G C P  
G o o d cli nical practice  
G M P  
G o o d Ma n ufact uri n g Practice  
G y  
Gra y  
H Bs -A g  
He p atitis B s urface a nti ge n  
H Bc  
He p atitis B c ore  
H g b  
He m o gl o bi n  
H B V  
He p atitis B  vir us  
H C V  
He p atitis C  vir us  
HI P A A  
Healt h i ns ura nce p orta bilit y act  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H L  
H o d g ki n’s l y m p h o ma  
H N S C C  
Hea d a n d nec k s q ua m o us cell carci n o ma 
H P V  
H u ma n pa pill o ma vir us  
I C 
I m m u ne cells 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I C O S 
I m m u ne c osti m ulat or 
I D S 
In vesti gati o nal dr u g ser vice  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
ii 
I F N 
I nterfer o n 
I G R T 
I ma ge g ui da nce ra diati o n t hera p y 
I g 
I m m u n o gl o b uli n 
I H C 
I m m u n o hist oc he mistr y 
I L D 
I nterstitial l u n g disease 
i m A E 
I m m u ne-me diate d a d verse e ve nt  
I M R T 
I nte nsit y-m o d ulate d ra diati o n t hera p y  
I N D 
I n vesti gati o nal ne w dr u g 
I O 
I m m u n o-o nc ol o g y  
ir A E 
I m m u ne-relate d a d verse e ve nt 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
I ntra ve n o us 
K  
P otassi u m  
K g  
Kil o gra ms  
L C C C  
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
L D H  
Lactate de h y dr o ge nase  
m A B  
M o n ocl o nal a nti b o d y  
M g  
Ma g nesi u m  
M g/ m
2  or m L or m m 3 
Milli gra ms per meter s q uare d or milliliter or c u bic milli meter  
M H C  
Maj or hist oc o m pati bilit y c o m ple x  
M RI  
Ma g netic res o na nce I ma gi n g  
M T D  
Ma xi m u m T olerate d D ose  
N a 
S o di u m  
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 F -B  
N uclear fact or ka p pa li g ht -c hai n e n ha ncer of acti vate d B cells 
N H L  
N o n -H o d g ki n’s l y m p h o ma  
NI H  
Nati o nal I nstit ute of Healt h  
N K  
Nat ural killer  
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 S  
O verall s ur vi val  
P B M C  
Peri p heral bl o o d m o n o n uclear cells  
P C R  
P ol y merase c hai n reacti o n 
P D  
Pr o gressi ve disease  
P D -1/ P D L -1  
Pr o gra m cell deat h rece pt or 1/ Pr 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  
P K  
P har mac o ki netic  
P HI  
Pers o nal healt h i nf or mati o n  
P R C  
Pr ot oc ol re vie w c o m mittee  
Q O L  
Q ualit y of life  
Q W/ Q 2 W/ Q 4 W  
O nce wee kl y/ O nce e ver y 2 wee ks/ O nce e ver y 4 wee ks  
R B C  
Re d bl o o d cell  
R N A  
Ri b o n ucleic aci d  
R T O G  
Ra diati o n O nc ol o g y Gr o u p  
S A E  
Seri o us a d verse e ve nt  
S CI D  
Se vere c o m bi ne d i m m u n o deficie n c y  
S D  
Sta ble disease  
S O C  
Sta n dar d of care  
S O P  
Sta n dar d o perati n g pr oce d ure  
S P O 2  
Sat urati o n of peri p heral o x y ge n  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
iii 
S U S A R  
Seri o us u ne x pecte d a d verse reacti o n  
T 3/ T 4  
T h yr o xi ne 3 or 4  
T C  
T u m or cells  
T C R  
T -cell rece pt or 
TI L  
T u m or i nfiltrati n g l y m p h o c ytes 
T N F/ T N F R  
T u m or necr osis fact or/ Rece pt or  
T P F  
Tiss ue pr oc ure me nt facilit y  
T S H  
T h yr oi d sti m ulati n g h or m o ne  
T U N E L  
Ter mi nal de o x y n ucle oti d yl d U T P tra nferase nic k e n d la beli n g 
( d U T P = de o x y uri di ne tri p h os p hate) 
µl or  µ M  
Micr oliter or micr o m olar  
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  
W T  
Wei g ht  
W O C B P  
W o ma n of c hil d beari n g p ote ntial  
X R T  
Ra diati o n  
Yr or yrs  
Year or years  
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
i v 
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  ........................................................................................... i 
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  .............................................................7  
1. 1  St u d y S y n o psis  ........................................................................................................7  
1. 2  P ost o perati ve Treat me nt i n Hea d a n d Nec k Ca n cer: Cis plati n a n d Ra diati o n as 
Sta n dar d of Care ( S O C)  ....................................................................................................8  
1. 3  I m m u n ot hera p y ........................................................................................................9  
1. 4  P D 1 a n d P D L 1 i n hi biti o n i n metastatic/re c urre nt H N S C C  ...................................1 0  
1. 5  St u d y A ge nt  ...........................................................................................................1 1  
1. 6  Rati o nale f or Cli nical St u d y  ..................................................................................1 2  
1. 7  C orrelati ve St u dies  ................................................................................................1 3  
2. 0  
S T U D Y O B J E C TI V E S  ...................................................................................1 3  
2. 1  Pri mar y O bjecti ve  ..................................................................................................1 3  
2. 2  Sec o n dar y O bj ecti ves  ............................................................................................1 4  
2. 3  E x pl orat or y O bjecti ves  ..........................................................................................1 4  
3. 0  
Criteri a f or E v al u ati o n / St u d y E n d p oi nts  ....................................................1 4  
3. 1  Pri mar y E n d p oi nt  ...................................................................................................1 4  
3. 2  Sec o n dar y E n d p oi nts  .............................................................................................1 4  
3. 3  E x pl orat or y E n d p oi nts  ...........................................................................................1 5  
4. 0  
P A TI E N T E LI GI BI LI T Y  ...............................................................................1 5  
4. 1  I n cl usi o n Criteria ...................................................................................................1 5  
4. 2  E xcl usi o n Criteria  ..................................................................................................1 7  
5. 0  
T R E A T M E N T P L A N  .....................................................................................2 0  
5. 1  Sc he ma  ..................................................................................................................2 0  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
v  
5. 2  Treat me nt D osa g e  ..................................................................................................2 0  
5. 3  T o xiciti es a n d D osi n g Dela ys/ D ose M o dificati o ns  ...............................................2 1  
5. 4  C o nc o mita nt Me dicati o ns/ Treat me nts/ S u p p orti ve Care All o we d  .........................2 2  
5. 5  Pr o hi bite d Me dicati o ns/ Treat me nts  .......................................................................2 3  
5. 6  C o ntrace pti o n Re q uire m e nts  .................................................................................2 3  
5. 7  Ot her M o dalities or Pr oce d ures  .............................................................................2 5  
5. 8  Reas o ns f or Earl y Wit h dra wal fr o m St u d y Treat m e nt  ..........................................2 5  
5. 9  D urati o n of F oll o w U p  ..........................................................................................2 6  
5. 1 0  St u d y Wit h dra wal  ..................................................................................................2 6  
6. 0  
D R U G I N F O R M A TI O N  ................................................................................2 7  
6. 1  D ur val u ma b (I mfi nzi T M ) ........................................................................................2 7  
6. 2  Ra diati o n T hera p y  .................................................................................................3 0  
7. 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 2  
7. 1  Ti me a n d E ve nts Ta ble  ..........................................................................................3 2  
7. 2  C orrelati ve St u dies  ................................................................................................3 5  
7. 3  Ha n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Researc h  ............................3 5  
7. 4  C o m plia nce State me nt  ...........................................................................................3 6  
7. 5  Assess me nt of Safet y  .............................................................................................3 6  
7. 6  Assess me nt of Efficac y  .........................................................................................3 7  
8. 0  
A D V E R S E E V E N T S  .......................................................................................3 7  
8. 1  Defi niti o n s .............................................................................................................3 7  
8. 2  D ur val u ma b A Es of S pe cial I nterest  .....................................................................3 9  
8. 3  D oc u me ntati o n of n o n -seri o us A Es or S A Rs ........................................................4 1  
8. 4  S A Es or Seri o us S A Rs  ..........................................................................................4 2  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
vi  
8. 5  A d verse E v e nt Re p orti n g .......................................................................................4 2  
8. 6  Data a n d Safet y M o nit ori n g Pla n  ..........................................................................4 9  
9. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ...........................................................4 9  
9. 1  St u d y Desi g n/ St u d y E n d p oi nts  ..............................................................................5 0  
9. 2  Sa m ple Size, Accr ual a n d D urati o n of Accr ual  .....................................................5 0  
9. 3  Data A nal ysis Pla ns  ...............................................................................................5 0  
1 0. 0  
S T U D Y M A N A G E M E N T  ..............................................................................5 1  
1 0. 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.....................................5 1  
1 0. 2  Re q uire d D oc u me nt ati o n  .......................................................................................5 1  
1 0. 3  Re gistrati o n Pr oce d ures  .........................................................................................5 2  
1 0. 4  Data Ma na g e me nt a n d M o nit ori n g/ A u diti n g  ........................................................5 2  
1 0. 5  A d here n ce t o t he Pr ot oc ol  .....................................................................................5 3  
1 0. 6  A me n d me nts t o t he Pr ot oc ol  .................................................................................5 5  
1 0. 7  Rec or d Rete nti o n  ...................................................................................................5 5  
1 0. 8  O bli gati o ns of I n v esti gat ors ...................................................................................5 6  
1 1. 0  
R E F E R E N C E S  ................................................................................................5 7  
1 2. 0  
A P P E N DI C E S  .................................................................................................5 9  
1 2. 1  D ose M o dific ati o n & T o xicit y M a n a ge me nt G ui deli nes f or D ur v al u m a b  .....5 9  
1 2. 2  P atie nt H a n d o ut Pr o hi bite d Me dic ati o ns  ..........................................................9 1  
1 2. 3  C oc kcr oft -G a ult F or m ul a  ...................................................................................9 2  
1 2. 4  E C O G Perf or m a nce St at us  ................................................................................9 3  
1 2. 5  F A C T -H N Q u alit y of Life Assess m e nt T o ol  .....................................................9 4  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
8  
3 0 fracti o ns ma y ta ke l o n ger t ha n t he all otte d 6 wee ks  a n d t his is all o we d . Ra diati o n t hera p y m ust 
be sc h e d ule d a n d c o m plete d wit hi n C ycels 1 -3 a n d s h o ul d n ot e xte n d i nt o C ycle 4.  
 
1. 2  
P ost o per ati ve  Tre at me nt i n He a d a n d Nec k C a ncer:  Cis pl ati n a n d R a di ati o n 
as St a n d ar d of C are ( S O C)  
I n t he m o d er n  era,  H N S C C  has  bee n  di vi de d  i nt o virall y  dri ve n  ca ncers  d u e  t o t he 
h u ma n  pa pill o ma  vir us  (H P V ) a n d n o n -H P V  ca ncers, w hic h  are t y picall y me diate d  
b y  s m o ki n g a n d hea v y  alc o h ol us e. L ocall y  a d va n ce d  H N S C C  is treate d wit h  eit her 
c o nc urre nt  c C R T  t hera p y or  s ur ger y f oll o w e d b y  a dj u va nt t hera p y. C o m m o nl y,  
H P V -dri ve n  ca ncers  are treate d wit h  c C R T a n d  t he p r o g n osis is e x cell e nt.  I n 
c o ntrast,  s ur ger y is ge nerall y  reser ve d f or n o n -H P V  dri ve n  ca n cers  or  hi g h -ris k 
H P V -p ositi ve  t u m ors, b ot h  of  w hic h  are ass o ciate d  wit h  i nferi or pr o g n osis.  
U ns ur prisi n gl y,  p ost o perati ve  o utc o mes  i n H N S C C  are p o or.  I n t he pre -a dj u vant  
t hera p y era, l oc al a n d re gi o nal rec urre n ce occ urre d  i n 3 0 %  of  patie nts  a n d dista nt  
rec urre nce i n 2 5 %  [1 ]. A dj u va nt  ra di ot hera p y ( X R T) i m pr o ves o utc o mes,  h o we ver  
less t ha n 5 0 %  patie nts  are disease  free at fi ve y ears.   
 
T w o  p hase  3  st u dies atte m pte d  t o i m pr o ve o utc o mes  f or p ost -o perati ve  H N S C C  
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  
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 eit her 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/ m 2 [2 , 3 ]. A  sec o n d 
st u d y, E O R T C  2 2 9 3 1 , ha d  a si milar ra n d o mizati o n, b ut  differe nt  i n cl 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 d al s prea d, p ositi ve  
resecti o n mar gi ns,  peri n e ural  in v ol ve me nt,  or  v asc 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  [4 ].  
 
A  c o m bi ne d  a n al ysis  of  t hese t w o trials s h o w e d t h at clear be n efit  fr o m t he a d diti o n 
of  cis plati n t o ra diati o n t hera p y was  restricte d t o o nl y  patie nts  wit h  e xtraca ps ular  
e xte nsi o n  ( E C E) or  p ositi ve  s ur gical mar gi ns . T his  be nefit  was  statisticall y 
si g nifica nt i n s u b gr o u p a nal ysis  i n E O R T C  wit h  a str o n g tre n d t o war ds si g nifica nce 
i n R T O G  [5 ]. Si milarl y,  i n l o n g-ter m f oll o w u p  (at 9. 4  years)  of  t he R T O G  st u d y, 
o nl y  patie nts  wit h  E C E  or  p ositi ve  mar gi ns  ha d  a be nefit  i n ter ms of  l oc ore gi o nal 
fail ure a n d dise ase  free s ur vi val ( D F S). Criticall y,  1 0 -ye ar dise ase -free s ur vi val 
( D F S) was  p o or  i n cis plati n  a n d ra diati o n tr eate d patie nts  ( 1 8 %) a n d o nl y  sli g htl y 
i m pr o ve d c o m pare d  t o patie nt s treate d wit h  ra diati o n al o ne ( 1 2 %). Per ha ps  m o st 
i m p orta ntl y, n o  o verall  s ur vi val a d v a nta ge  was  n ote d  w he n  c o m pari n g  cC R T  t o 
X R T  al o ne ( 2 7 % vs  2 0 %,  P = 0 . 0 7) [3 ]. T h us,  t h e treat me nt a d v a nta ge  offere d  b y  
t he a d diti o n  of  cis plati n  is mar gi nal  a n d t here is a l o w t hres h ol d t o e val uate 
e x peri me ntal t hera pe utics wit h  t he h o pe  of  s u peri orit y. 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
9  
Ne vert hel ess , hi g h  ris k patie nts,  wit h  eit her E C E  or  p ositi ve  s ur gical mar gi ns  o n  
t heir s ur gical pat h ol o g y , s h o ul d recei v e cis plati n a n d ra diati o n t hera p y. I n t he 
treat me nt of  patie nts  wit h  i nter me diate ris k fact ors, defi ne d  as h a vi n g  u nfa v ora ble  
pat h ol o gical  fact ors i n t he a bse nce of  E C E  or  p ositi ve  mar gi ns,  t here re mai ns 
wi des prea d  practice  variati o n.  T hese  patie nts  ma y  recei v e eit her n o  a dj u va nt 
t hera p y, X R T  al o ne  or  c C R T, de pe n di n g  o n  i nstit uti o n, patie nt,  a n d pr o vi der  
prefere nce s. I m p orta ntl y, i nter me diate ris k patie nts  w h o  recei ve d ra diati o n t hera p y 
al o ne ha d  a l oc ore gi o nal fail ure ris k of  1 5 -3 5 %  [6 ]. T o  date,  t here are n o  p u blis he d  
st u dies c o m pari n g  ra diati o n t hera p y vers us  c o n c urre nt  s yste mic t hera p y pl us  
ra diati o n i n t his st u d y p o p ulati o n.  As  a res ult, t here is a n o p p ort u nit y  t o e val uate  
e x peri me ntal  t hera pe utics i n t he i nter me diate ris k p o p ulati o n,  w hic h  ma y  i m pr o ve 
o utc o mes.   
1. 2. 1  Cis pl ati n wit h R a di ati o n T her a p y: A Hi g hl y T o xic St a n d ar d of C are  
I n R T O G  9 5 0 1  st u d y, t he rate of  gra de  3 -5  ac ut e t o xicities wit h  ra di ot hera p y al o ne  
was  3 4. 4 %.  T his  rate r ose t o 7 7 %  wit h  t he a d diti o n of  cis plati n t o ra di ot hera p y [7 ]. 
I n cli nical  pra ctice, l o n g-ter m ot o pat h y,  n e p hr o pat h y  a n d n e ur o pat h y  are als o 
c o m m o nl y  see n i n patie nts  treate d wit h  cis plati n  al o ne [8 ]. Fi nall y,  ma n y  H N S C C  
patie nts  are c o nsi d ere d  p o or  ca n di dates  f or cis pl ati n d ue  a d va nce d  a g e, baseli ne  
re nal d ysf u n cti o n,  k n o w n  a u dit or y deficits  i ncl u di n g heari n g  l oss a n d/ or ti n nit us, 
a n d p o or  perf or m a nce  st at us [9 ]. T he  c o m bi nati o n  of  p o o r efficac y  a n d  hi g hl y  t o xic 
si de effects  wit h  cis plati n  o pe ns  t he d o or  f or i n vesti gati n g alter nati ve  tr eat me nt 
strate gies.  
1. 3  
I m m u n ot her a p y 
It is i ncreasi n gl y u n d erst o o d  t hat ca n cers  are rec o g nize d b y  t he i m m u ne s yste m, 
a n d, u n der  s o me cir c u msta nces,  t he i m mu ne  s yste m ma y  c o ntr ol or  e ve n eli mi nate 
t u m ors [1 0 , 1 1 ]. I n hi bit or y pat h wa ys,  als o  k n o w n  as i m m u ne c h ec k p oi nts,  c o ntr ol 
t he d urati o n  a n d  e xte nt of  i m m u ne s yste m acti vit y a n d deli ver  ne g ati ve  si g nals t o 
pre ve nt  i m m u ne reacti o ns b y  t he h ost.  P D -1  is a well -st u die d i n hi bit or y pat h wa y  
t hat lea ds t o d o w n  re g ul ati o n of  T  cell  acti vati o n.  T heref ore,  i m pair e d i m m u ne 
rec o g niti o n occ urs  w he n  a hi g h  p erce nta ge  of  P D -1  T  cells are e x presse d  b y  t he 
t u m or or  f o u n d i n t he t u m or micr oe n vir o n me nt  [1 2 ]. I m m u n o m o d ulat or y a ge nts  
ha ve  bee n  d e vel o pe d  t o tar get t he i n hi bit or y pat h wa ys  wit h  t he g oal  of  re-acti vati n g  
T  cells a n d pr o d uci n g  i m pr o ve d a ntit u m or i m m u ne res p o nse.   
1. 3. 1  P D 1 a n d P D L 1 i n hi biti o n  
P D -L 1  is a me m ber  of  t he B 7  fa mil y of  li ga n ds t hat i n hi bit T -cell acti vit y  t hr o u g h 
bi n di n g  t o t he P D -1  rece pt or a n d t o C D 8 0.  P D -L 1  e x pressi o n  is a n a da pti ve  
res p o nse t hat hel ps  t u m ors e va de detecti o n  a n d eli mi nati o n  b y  t he i m m u ne s yste m. 
E x pressi o n  of  P D -L 1  pr otei n  is i n d uce d b y  i nfla m mat or y si g nals t hat are t y picall y 
ass ociate d wit h  a n a da pti ve i m m u ne res p o nse (e. g. I F Nγ) a n d ca n be  f o u n d o n  b ot h  
t u m or cells ( T C) a n d  t u m or i nfiltrati n g i m m u ne cells (I C). T he  bi n di n g  of  P D -L 1  
t o P D -1  o n  acti vate d  T  cells deli vers  an  i n hi bit or y si g nal t o t he T  cells,  pre ve nti n g  
t he m fr o m killi n g  tar get T C,  a n d pr otecti n g  t he t u m or fr o m i m m u ne eli mi nati o n  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 0  
[1 3 ]. P D -L 1  ma y  als o i n hi bit T  cells t hr o u gh  bi n di n g  t o C D 8 0,  alt h o u g h  t he e x act  
mec ha nis m  is still n ot  el uci date d [1 4 , 1 5 ]. 
 
T he  i n hi bit or y mec h a nis m  descri be d  a b o ve  is c o-o pte d  b y  t u m ors t hat e x press  P D -
L 1  as a  wa y  of  e v a di n g  i m m u ne detecti o n  a n d  eli mi nati o n.  T he  bi n di n g  of  a n a nti-
P D -L 1  a ge nt t o t he P D -L 1  rece pt or i n hi bits t he i nteracti o n of  P D -L 1  wit h  t he P D -
1  a n d C D 8 0  rece pt ors e x presse d o n  i m m u ne cells. T his  acti vit y o verc o mes  P D -L 1 –
me diate d  i n hi biti o n of  a ntit u m or i m m u nit y. W hile  f u ncti o nal bl oc ka d e  of  P D -L 1  
res ults i n T -cell  reacti vati o n, t his mec ha nis m  of  acti o n is differe nt  fr o m direct  
a g o nis m  of  a sti m ulat or y rece pt or s uc h as C D 2 8  [1 6 ]. 
 
I n viv o  st u dies ha v e  s h o w n t hat d ur val u ma b  i n hi bits t u m or gr o wt h  i n x e n o graft  
m o dels  via  a T  cell-de p e n de nt  mec ha nis m  [1 7 ]. P D -L 1  is e x presse d  i n a br oa d  
ra n ge of  ca n cers.  Base d  o n  t hese fi n di n gs, a n a nti-P D -L 1  a nti b o d y  c o ul d be  use d  
t hera pe uticall y t o e n ha n ce a ntit u m or i m m u ne res p o nses i n patie nts  wit h  ca ncer.  
Res ults  of  n o n -cli nical a n d cli nical st u dies of  m o n ocl o nal  a nti b o dies  ( m A bs) 
tar geti n g t he P D -L 1/ P D -1  pat h wa y  ha ve  s h o w n e vi de nce of  cli nical  acti vit y a n d a 
ma na gea bl e  safet y pr ofile,  s u p p orti n g t he h y p ot hesis  t hat a n  a nti-P D -L 1  a nti b o d y  
c o ul d be  use d  t o t hera pe uticall y e n ha nce a ntit u m or i m m u ne res p o nse i n ca ncer  
patie nts  wit h  res p o nses t hat te n d t o be  m ore  pr o n o u nce d  i n patie nts  wit h  t u m ors 
t hat e x press  P D -L 1  [1 8 ]. I n a d diti o n,  hi g h  m u tati o nal b ur de n , f or e xa m ple i n 
bla d der  carci n o ma , ma y  c o ntri b ute t o t he res p o nses see n wit h  i m m u ne t hera p y [1 9 ]. 
1. 3. 2  C o m bi ni n g I m m u n ot her a p y wit h R a di ati o n T her a p y  
Ra diati o n  t hera p y re mai ns a bac k b o n e  i n t he tr eat me nt of  H N S C C  i n defi niti ve,  
palliati ve,  a n d a dj u va nt s etti n g. T he  rati o nale f or p ost o perati ve  ra diati o n is t o tar get 
micr osc o pic  d e p osits  of  ca n cer  cells t hat ma y  re mai n after  res ecti o n [2 0 ]. If 
u ntreate d,  t hese cells ma y  e ve nt uall y  lea d t o a l ocal– re gi o nal rec urre nce. 
I m m u nol o gicall y,  ra di ot h era p y i n d uces a nti ge n  rel ease fr o m t he t u m or a n d da n ger  
si g nals acti vati n g  b ot h  t he h ost ’s i n nate a n d a da pti ve i m m u ne s yste m [2 1 ]. T his  
ma y  lea d t o re v erse t h e t olera n ce t o wea kl y  i m m u n o ge nic t u m or-ass ociate d  
a nti ge ns  a n d elicit  b ot h  l ocal a n d dista nt  a ntica n cer  i m m u ne res p o nse.  
 
Ra diati o n  t hera p y has  bee n  s h o w n t o ha v e  a s y ner gistic effect  wit h  vari o us  
i m m u n o m o d ulati n g a ge nts  [2 2 ]. A d diti o nall y  u pre g ulati o n  of  P D -L 1  e x pressi o n  
lead s t o T  cell  e x ha usti o n,  w hic h  ca us es  resista nce t o treat me nt fr o m ra di ot hera p y 
[2 3 ]. T his  pr o vi des  a rati o nale f or t he c o m bi n ati o n of  P D -L 1  i n hi bit ors wit h  
ra diati o n t hera p y a n d is c urre ntl y  bei n g  e v al uate d  i n m ulti ple  cli nical  trials.    
1. 4  
P D 1 a n d P D L 1 i n hi biti o n i n met ast atic/rec urre nt H N S C C  
I m m u n ot hera p y has  ma d e  s u bsta ntial a d va nces  i n t he care of  i nc ura ble H N S C C,  
wit h  t he recent  F D A  a p pr o val  of  t he i m m u ne c hec k p oi nt  i n hi bit ors pe m br oliz u ma b  
a n d ni v ol u ma b  i n t he sec o n d-li ne setti n g f or p atie nts  wit h  disease  pr o gressi o n  or  
rec urre nce after first li ne plati n u m -base d  c he m ot h era p y.  I n p hase  II st u d y, res p o nse 
rate (R R ) t o p e m br oliz u ma b  i n u nselecte d  a n d m ostl y  hi g hl y  pretreate d  patie nts  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 1  
was  1 6 %  a n d  o verall   s ur vi val (O S ) was  8  m o nt hs,  res ults si g nifica ntl y s u p eri or t o 
t hat e x pecte d  wit h  sta n d ar d t hera p y [2 4 ].  Ni v ol u ma b  was  c o m pare d  i n p hase  III 
st u d y t o sta n dar d of  care  treat me nt wit h  i n vesti gat or’s c h oice of  d o ceta xel,  
met h otre xate  or  cet u xi ma b a n d s h o we d s u peri or s ur vi val [2 5 ]. D ur val u m a b  was  
e val uate d  i n 6 2  patie nts  wit h  rec urre nt or  metast atic  H N S C C  a n d ha d  a n  o verall  
res p o nse rate of  1 2 %  [2 6 ]. Of  n ot e,  i n eac h of  t hese st u dies, t he t o xicit y pr ofile  of  
i m m un ot hera p y  was  n ot a bl y  s u peri or t o t hat s ee n i n maj or  st u dies of  cis plati n. 
Criticall y  f or c o nsi derati o n  of  t hese a ge nts  i n t he a dj u va nt c o nte xt,  s ur vi val 
a d va nta ges  see n i n t hese st u dies a n d i n cli nical  practice  i ncl u de a real pr o p orti o n  of  
l o n g-ter m s ur viv ors.  
1. 5  
St u d y A ge nt  
1. 5. 1  D ur v al u m a b  
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 h e i m m u n o gl o b uli n G 
(I g G) 1 ka p p a s u bclass t hat bl oc ks t he i nteracti o n of P D-L 1 ( b ut n ot pr o gra m me d 
cell deat h li ga n d -2) wit h P D -1 o n T cells a n d C D 8 0 ( B 7. 1) o n i m m u ne cells.  
D ur val u ma b 
has 
bee n e n gi neere d t o re d uce a nti b o d y -de pe n d e nt cell ular 
c yt ot o xicit y a n d c o m ple me nt -de pe n de nt c yt ot o xicit y. I n vitr o st u dies d e m o nstrate 
t hat d ur val u ma b a nta g o nizes t he i n hi bit or y effect of P D-L 1 o n pri mar y h u ma n T 
cells, res ulti n g i n t heir r est ore d pr oliferati o n a n d release of i nterfer o n ga m ma.  
 
As of J ul y 2 0 1 9 , 5 1 2 7  patie nts ha ve bee n e x p ose d t o o ne or m ore d oses of 
d ur val u ma b i n o n g oi n g o pe n -la bel 
Astra Ze n eca-s p o ns ore d or 
Me dI m m u ne -
s p o ns ore d P hase I-III m o n ot hera p y a n d c o m bi nati o n t hera p y st u dies acr oss all 
i n dicati o ns [2 7 ].  
 
I n patie nts 
wit h rec urre nt/ metastatic 
H N S C C  w h o 
recei ve d 
d ur val u ma b 
m o n ot hera p y  fr o m St u d y 1 1 0 8, o verall res p o nse rate ( O R R ) was 7. 3 % acr oss all 
patie nts, 1 6. 7 % i n patie nts wit h P D -L 1 hi g h t u m o rs a n d 2. 7 % i n p atie n ts wit h P D-
L 1 l o w/ ne gati ve t u m o rs. Me dia n O S was 8. 4 m o nt hs a n d O S at 2 4 m o nt hs was 
2 4. 2 %. I n St u d y D 4 1 3 C 0 0 0 1, H N S C C patie nts wit h P D -L 1 % hi g h, O R R was 
1 6. 2 %. T he me dia n d urati o n of treat me nt was 3. 4 5 m o nt hs, w hile t he me dia n O S 
was 7. 1 m o nt hs [2 4 ].  
1. 5. 1. 1  R ati o n ale f or Fi xe d D osi n g of D ur v al u m a b  
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 I st u d y (st u d y 1 1 0 8; N = 2 9 2; d oses = 0. 1 t o 1 0 
m g/ k g o nce e ver y 2 wee ks ( Q 2 W ) or 1 5 m g/ k g o nce e ver y 3 wee ks ( 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 od y wei g ht 
( W T) o n t he P K of d ur val u ma b (c o effi cie 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 st ea d y stat e P K c o nce ntrati o ns ( 5t 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 m ate 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. 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 2  
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 ste a d y state P K c o n ce ntr ati o ns wit h sli g htl y less o verall 
bet wee n -p atie nt varia bilit y wit h fi xe d d osi n g re gi me n.  
 
A fi xe d d osi n g a p pr oac h is preferre d 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 pect ati o n of si milar p har mac o ki netic e x p os ure a n d v aria 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 
W T of 7 5 k g, a fi xe d d os e of 1 5 0 0 m g d ur val u ma b (e q ui vale nt t o 2 0 m g/ k g) will 
be use d  at Q 3 W d uri n g c ycles 1 -3 a n d Q 4 W d uri n g c ycles 4 -6  i n t he c urre nt 
st u d y.  
1. 5. 1. 2  D ur v al u m a b  D osi n g Sc he d ule  
Pre -cli nical a n d cli nic al st u dies ha ve e val uat e d t h e sc h e d uli n g of  d ur val u ma b at 
t w o wee k, t hree wee k, a n d f o ur wee k c ycles. We ha ve d eci de d t o pr ocee d wit h  
d ur val u ma b  Q 3 W  c y cles  w he n us e d i n c o m bi nati o n wit h ra diati o n t hera p y a n d 
t he n Q 4 W  w he n us e d as m o n ot hera p y f oll o wi n g t he c o m pleti o n of ra di ati o n.   
1. 5. 2  R a di ati o n T her a p y + D ur v al u m a b  
I n a si n gle ce nt er s u bset of patie nts wit h s oli d mali g na ncies, a p h ase I/II trial of 
d ur val u ma b i n c o m bi nati o n wit h ra di ot hera p y i n t he palliati ve  setti n g was s h o w n 
t o be safe. T he me dia n d urati o n of e x p os ure t o d ur val u ma b was 5. 2 m o nt hs wit h a 
me dia n deli ver y of 1 1 c y cles (ra n g e, 4 -3 8 c y cles). R T (c o nf or mal 3 D R T, 7 9 % a n d 
i ntracra ni al stere ota ctic R T, 2 1 %) was d eli vere d at 2 8 G y (ra n g e, 6-9 2), i n a me dia n 
n u m ber of fi ve fracti o ns (ra n ge, 1 -1 0) a n d o ver a m e dia n d urati o n of 6 d a ys (ra n ge, 
1 -1 4). Fi ve patie nts ( 5 0 %) re p orte d a n irra diati o n -relate d a d v erse e v e nt gra de 1 or 
2 a n d o n e patie nt h a d t w o gra de 2 A Es. T he m ost fre q ue ntl y re p orte d A E was gra de 
2 m uc ositis. T here were n o gra de t hr ee or hi g h er A Es.  
1. 6  
R ati o n ale  f or Cli nic al St u d y 
T he  rati o nale f or c o m bi ni n g  i m m u n o-o nc ol o g y  (I O) wit h  ra di ot hera p y is 
m ultifact orial.  In  a d diti o n  t o cell deat h  ca use d  b y  hi g h -d ose  ra diati o n, ra di ot hera p y 
has  cr osst al k  wit h  t he i m m u ne s yste m i n t hr ee pri nci ple  wa y s: ( 1) i n d u cti o n of  
i m m u n o ge nic cell deat h  t o recr uit a ntit u m or T  cells t o t he irra diate d site; ( 2) 
u pre g ulati o n  of  maj or  hist oc o m pati bilit y  c o m ple x (M H C ) I e x pressi o n,  w hi c h  w as 
pre vi o usl y  d o w nre g ulate d  f or i m m u ne esca pe;  a n d  ( 3) e x pa nsi o n of  t he di versit y  of  
t he T  cell rece pt or ( T C R) re pert oire t o detect  t u m or a nti ge ns  [2 8 ].  
 
T heref ore,  t he c o m bi nati o n  of  P D -1/ P D -L 1  i n hi bit ors a n d ra di ot hera p y has  t he 
p ote ntial  f or s y n er gistic pr o perties  b y  ( 1) re d u ci n g t he n u m ber  of  M D S Cs  i n t he 
t u m or micr oe n vir o n me nt;  ( 2) i ncreasi n g C D 8 +  t o Tre g  rati o; a n d ( 3) e n ha nci n g  
C D 8 +  i nfiltrati o n, t here b y a u g me nti n g  t he a ntit u m or res p o nse. T here  c urre ntl y  
e xists data  i n m ulti ple  t u m or t y pes s h o wi n g t he p ositi ve  r ole of  c o m bi ni n g  P D -
1/ P D -L 1  i n hi bit ors a n d ra di ot hera p y i n differe nt  t y pes of  t u m ors.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 3  
1. 6. 1  D ose R ati o n ale  
D ur val u ma b  d osi n g  at 1 5 0 0 m g  I V q 3  a n d q 4  wee ks  has  b ee n  pre vi o usl y  st u die d 
a n d has  mi ni mal  t o xicities w he n  c o m bi ne d  wit h  ra diati o n t hera p y. T he  use  of  2  G y  
o ver  3 0  fracti o ns t otali n g a fi nal d ose  of  6 0  G y  is t he sta n dar d ra diati o n d osi n g  
re gi me n i n t he a dj u va nt s etti n g.  
1. 7  
C orrel ati v e St u dies  
T he  t u m or i m m u ne micr oe n vir o n me nt  is a c o m ple x mi xt ure  of  c o m peti n g  cell ular 
p h e n ot y pes. T h us,  a n o pti mal  pre dict or  of  res p o ns e t o i m m u n o m o d ulat or y t hera p y 
will  li kel y i ncl u de feat ures t hat descri be  t u m or ge netics,  t u m or-relate d 
i m m u n os u p pressi o n, a n d a n y e xiste nt  b ut  i ns uffici e nt a nti-t u m or i m m u ne res p o nse. 
C hr o nic  a nti ge n  e x p os ur e i n t he s etti n g of  t u m or gr o wt h  a n d  metastasis  l ea ds t o 
a ner g y a n d d ysf u ncti o n  (e x ha usti o n) of  t h e a d a pti ve i m m u ne res p o nse, i n part  
t hr o u g h i ncrease d e n g a g e me nt  of  t he P D -1  rece pt or wit h  its li ga n d ( P D-L 1).  T he  
net  res ult of  si g nali n g t hr o u g h t his a xis  is a n atte n uati o n  of  t he c yt ot o xic a n d  
c yt o ki ne-pr o d uci n g  ca p acit y  of  t u m or-i nfiltrati n g l y m p h oc ytes, lea di n g t o 
i neffecti ve a ntit u m or  i m m u ne res p o nses. I n p atie nts  wit h  metastatic  mela n o ma,  t he 
fracti o n of  p artiall y  e x ha uste d  c yt ot o xic T  l y m p h oc ytes ( pe C T Ls, t u m or-
i nfiltrati n g C D 8 +  T  cells e x pressi n g  hi g h  le vels of  c yt ot o xic T  l y m p h oc yte–
ass ociate d a nti ge n  4  [ C T L A-4]  a n d P D -1)  str o n gl y c orrelates  wit h  res p o ns e t o a nti–
P D -1  m o n ot hera p y.  We  pla n  t o assess t hese para meters  i n o ur  pr o p ose d  st u d y. 
 
We  h o pe  t o c haract erize t he t u m or i m m u ne micr oe n vir o n me nt  i n m ulti ple  setti n gs 
( 1) i n pre -tr eat me nt, s ur gicall y res ecte d tiss ue, ( 2) d uri n g  v ari o us  ti mes p oi nts  
d uri n g  treat me nt wit h  c o m bi nati o n  I O t h era p y wit h  ra diati o n t hera p y, a n d  ( 3) at  
ti me of  disease  rec urre n ce. C o rrelati ve st u dies will  be  r u n i n b ot h  t u m or a n d bl o o d  
sa m ples.  
 
S pecific  ai ms  i ncl u de: ( 1) e val uati o n  of  t he i m m u n os u p pressi ve bi o mar ker  P D -L 1  
o n  t u m or a n d i m m u ne cells usi n g  i m m u n o hist oc he mistr y a nal ysis  at pre -tr eat me nt 
a n d at disease  rec urre nce. T he  e x pressi o n  of  baseli ne  P D -LI  le vels will  be  assesse d  
f or its pre dicti ve  res p o nse t o rec urre nce; a n d ( 2) meas ure me nt  of  
i nfla m mat or y/i m m u ne si g nat ure i ncl u di n g C D 4,  C D 8,  C D 2 5,  F O X P 3  a n d  
T U N E L/ Cas pase 3  b y  fl o w c yt o metr y t o better  u n dersta n d  the  tr eat me nt-relate d 
c ha n ges  i n t he t u m or micr oe n vir o n me nt.   
2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bjecti ve  
2. 1. 1  T o esti mate me dia n 
3 -year disease free s ur vi val ( D F S) i n patie nts 
wit h 
i nter me diate-ris k H N S C C treate d wit h a dj u va nt d ur val u ma b wit h ra di ot hera p y.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 4  
2. 2  
Sec o n d ar y O bjecti ves  
2. 2. 1  T o c haracteriz e safet y b y e val uati n g Gra de 3 -4  ac ute t o xicities of a dj u va nt 
d ur val u ma b wit h ra di ot h era p y i n i nter me di ate -ris k H N S C C patie nts 
2. 2. 2  T o c haracteriz e t he Gra de 3 -4  c hr o nic t o xicities of a dj u va nt d ur val u ma b wit h 
ra di ot hera p y i n i nter m e diate-ris k H N S C C patie nts. 
2. 2. 3  T o c haracteriz e a n y -gra de c hr o nic t o xicities of a dj u va nt d ur val u ma b 
wit h 
ra di ot hera p y i n i nter m e diate-ris k H N S C C patie nts. 
2. 2. 4  T o esti mate me dia n O S  i n patie nts wit h i nter me diate -ris k H N S C C treate d wit h 
a dj u va nt d ur val u ma b wit h ra di ot hera p y.  
2. 2. 5  T o c orrel ate  P D -L 1 e x pressi o n wit h disease free s ur vi val   
2. 3  
E x pl or at or y O bjecti ves  
2. 3. 1  
  
 
 
 
 
3. 0  
Criteri a f or E v al u ati o n / St u d y E n d p oi nts  
3. 1  
Pri m ar y E n d p oi nt  
3. 1. 1  3 -year D F S will be esti mate d via t h e Ka pla n -M ei er met h o d. D F S is defi ne d as t he 
ti me fr o m D 1 of treat me nt t o ti me of disease rec urre nce or deat h. 
3. 2  
Sec o n d ar y E n d p oi nts  
3. 2. 1  Gra de 3 -5 ac ute t o xicit y will be e val uate d acc or d i n g t o g ui deli nes fr o m N CI 
C T C A E, v 5. 0 
a n d i ncl u de t o xicit y fr o m t he first da y of treat me nt 
wit h 
i m m u n ot hera p y u ntil 3 0 da ys after c o m pleti o n of c o nc urre nt i m m u n ot hera p y a n d 
ra diati o n. T o xicit y  will i ncl u de all t o xicit y attri b ute d t o t he t otal st u d y re gi me n 
(i ncl usi ve of ra di ati o n) n ot j ust t o d ur val u ma b  al o ne. 
3. 2. 2  Gra de c hr o ni c 3 -5 t o xicit y will be e v al uate d acc or di n g t o g ui deli nes fr o m N CI 
C T C A E, v 5. 0 a n d i ncl u de t o xicit y c o nti n ui n g or occ urri n g 3 0 da ys a ft er c o m pleti o n 
of c o nc urre nt i m m u n ot hera p y a n d ra diati o n , a n d will be f oll o we d f or u p t o 6 
m o nt hs.  
3. 2. 3  O S will be esti mate d via t he Ka pla n -M eier met h o d.  O S is defi ne d as t he ti me fr o m 
D 1 of treat me nt t o deat h fr o m a n y ca use.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 5  
3. 2. 4  Meas ure P D -LI e x pressi o n b y i m m u n o hist oc he mistr y. Pre -treat me nt P D-L 1 
e x pressi o n will be c orrelate d wit h disease free s ur vi val f oll o wi n g treat me nt of 
a dj u va nt d ur val u ma b wit h ra di ot hera p y  
3. 3  
E x pl or at or y E n d p oi nts  
3. 3. 1  
 
 
 
 
  
4. 0  
P A TI E N T E LI GI BI LI T Y  
I n or der t o partici p ate i n t his st u d y a s u bject m ust meet all of t he eli gi b ilit y criteria 
o utli ne d bel o w.  
4. 1  
I ncl usi o n Criteri a 
4. 1. 1  Writte n i nf or me d c o nse nt  o btai ne d t o partici p ate i n t he st u d y  a n d HI P A A 
a ut h orizati o n f or releas e of pers o nal healt h i nf or mati o n.  C o nse nt f or t he use of a n y 
resi d ual material fr o m bi o ps y (arc hi val tiss ue) a n d serial bl o o d dra ws will be 
re q uire d f or e nr oll me nt.  
4. 1. 2  A ge ≥ 1 8 years of a g e o n da y of si g ni n g i nf or me d c o nse nt  
4. 1. 3  E C O G Perf or ma nce Stat us of 0 or 1  ( See A p pe n di x 1 2. 4 : E C O G Perf or ma nce 
Stat us)   
4. 1. 4  Hist ol o gicall y c o nfir me d s q ua m o us cell carci n o m a of t he h ea d a n d nec k, i n cl u di n g 
t he f oll o wi n g s u bt y pes: oral ca vit y, or o p h ar y n x, h y p o p har y n x,  lar y n x 
4. 1. 5  M ust ha ve  u n d er g o ne gr oss t otal resecti o n of t he pri mar y t u m or wit h c u rati v e i nte nt 
wit hi n t he past 8 wee ks wit h s ur gical pat h ol o g y de m o nstrati n g ≥ 1 of t he f oll o wi n g 
criteria f or "i nter me diate" ris k of rec urre n ce:  
•  peri ne ural i n vasi o n  
•  l y m p h o vasc ular i n vasi o n 
•  si n gle l y m p h n o de  > 3  c m or at least 2  n o d es wit h o ut e vi de nce of 
e xtraca ps ular e xt e nsi o n  
•  cl ose mar gi ns defi ne d as < 5 m m b ut n ot fra n kl y p ositi ve (i n t he cas e of 
a m bi g u o us, c o ntr o versial, or s u p erse d e d mar gi ns, fi nal cli nical assess me nt 
re gar di n g mar gi n stat us will pre vail) 
•  pat h ol o gicall y c o nf ir me d T 3 or T 4 pri mar y t u m or 
4. 1. 6  N o pri or t hera p y t o pri m ar y t u m or pri or t o s ur gical resecti o n ( n o i n d ucti o n t hera p y 
or rec urre nt disease).  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 7  
s per mici dal a ge nt) starti n g wit h t he first d ose of st u d y t hera p y t hr o u g h 9 0 da ys  after 
d ur val u ma b  m o n ot hera p y is disc o nti n ue d .  
4. 1. 1 1  S u bjects m ust be  willi n g a n d a ble t o c o m pl y wit h st u d y pr oce d ures  base d o n t he 
j u d g me nt of t he i n vesti gat or or pr ot oc ol desi g nee.   
 
4. 2  
E xcl usi o n Criteri a  
S u bjects meeti n g a n y of t he f oll o wi n g e xcl usi o n criteria will n ot be a ble t o 
partici pate i n t his st u d y:  
4. 2. 1  Is c urre ntl y partici pati n g i n or has partici pate d i n a st u d y of a n i n vesti gati o nal a ge nt 
or a n i n vesti gati o nal de vi ce wit hi n 4 wee ks of t he first d ose of treat me nt.  
4. 2. 2  C o nc urre nt e nr ol lme nt i n a n ot her cli nical st u d y, u nless it is a n o bser vati o nal ( n o n -
i nter ve nti o nal) cli nical st u d y or d uri n g t he f oll o w-u p peri o d of a n i nt er ve nti o nal 
st u d y. 
4. 2. 3  Has e vi de nce of met astatic disease at ti me of dia g n osis  
4. 2. 4  Is recei vi n g c o nc urre nt c he m ot hera p y, i n vesti gati o nal dr u g , bi ol o gic, or h or m o nal 
t hera p y f or ca ncer treat m e 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. 
4. 2. 5  Treat me nt wit h a n y i n vesti gati o nal dr u g 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, w hic he ver is s h ort est. 
4. 2. 6  Has n ot recei ve d a n y a nti bi otics < 7 da ys pri or t o 1 st d ose of d ur val u ma b.  If t he 
patie nt recei ves eit her I V a nti bi otics or > 5 d a y treat me nt c o urse  ( oral or I V), t he n 
t he 1st d ur val u ma b d ose s h o ul d n ot be gi ve n u ntil 1 4 da ys of last a nti bi otic d ose.  
D uri n g eli gi bilit y scree ni n g, s u bjects w h o recei ve a n y a nti bi otics wit hi n 3 0 da ys 
pri or t o t he pr o p ose d i nitial i nf usi o n of d ur val u ma b  s h o ul d be fla g ge d a n d re vie we d 
b y t he site’s Pri nci ple I n vesti gat or  t o deter mi ne if t he s u bject is a g o o d ca n di date 
t o recei ve d ur val u ma b. 
4. 2. 7  K n o w n aller g y or h y perse nsiti vit y t o d ur val u ma b  or a n y of t he st u d y dr u g 
e xci pie nts.  
4. 2. 8  Pri or ra n d o mi zati o n or tr eat me nt i n a pre vi o us d ur val u ma b cli nical st u d y re gar dless 
of treat me nt ar m assi g n me nt.  
4. 2. 9   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 bef ore 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 ntr a nasal, i n hale d, t o pical ster oi ds, or l ocal ster oi d i njecti o ns (e. g., i ntra 
artic ular i njecti o n)  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 8  
•  
S yste mic c ortic oster oi ds 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 its e q ui val e nt  
•  
Ster o i ds as pre me dicati o n f or h y perse nsiti vit y reacti o ns (e. g., C T sca n 
pre me dicati o n)  
4. 2. 1 0  Has recei ve d  s yste mic st er oi d t hera p y or a n y ot h er f or m of i m m u n os u p pressi ve 
t hera p y wit hi n 7 da ys pri or t o t he first d ose of trial treat me nt. 
4. 2. 1 1  Acti ve i nfecti o n re q uiri n g s yst e mic t hera p y  i ncl u di n g t u berc ul osis (cli nical 
e val uati o n t hat i ncl u des cli nical hist or y, p h ysical e xa mi nati o n a n d ra di o gra p hic 
fi n di n gs, a n d T B testi n g i n li ne wit h l ocal practice), he p atitis B ( k n o w n p ositi ve 
H B V s urface a nti ge n ( H Bs A g) res ult), he patitis C , or h u ma n i m m u n o deficie nc y 
vir us ( p ositi ve HI V 1/ 2 a nti b o dies).  
•  
Patie nts wit h a past or res ol ve d H B V i nfecti o n ( defi ne d as t he prese n ce of 
he patitis B c ore a nti b o d y [a nti -H Bc] a n d a bse n ce of  H Bs A g) are eli gi ble.  
•  
Patie nts p ositi ve f or he patitis C ( H C V) a nti b o d y are eli gi ble o nl y if 
p ol y merase c h ai n reacti o n is ne gati ve f or H C V R N A .  
4. 2. 1 2  Has a k n o w n c o ntr ai n dicati o n t o ra diati o n t 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 pers e nsiti vi t y t o i o nizi n g ra diati o n s uc h as Ata xia-T ela n giectasia 
a n d Nij me ge n Brea ka ge S y n dr o me  
4. 2. 1 3  Has a hist or y of u nc o ntr olle d li ver disease (i n cl u di n g b ut n ot li mite d t o cirr h osis). 
4. 2. 1 4  S u bjects wit h baseli ne w ei g ht ≤ 4 0 k g ( 8 8  l bs). 
4. 2. 1 5  Fe male p atie nts w h o are p re g na nt or breastfee di n g ( N O T E: breast mil k ca n n ot be 
st ore d f or f ut ure use w hile t he m ot her is bei n g treate d o n st u d y) or male or fe mal e 
patie nts of re pr o d ucti ve p ote ntial w h o are n ot willi n g t o e m pl o y effecti ve birt h 
c o ntr ol fr o m scree ni n g t o 9 0 da ys aft er t h e last d ose of d ur val u ma b m o n ot h era p y .  
4. 2. 1 6  H ist or y of a n ot her pri mar y mali g na nc y e x ce pt f or.  
•  
Mali g na nc y treate d wit h c urati ve i nte nt a n d wit h n o k n o w n acti ve dise ase 
≥5 years bef ore t he first d ose of I P a n d of l o w p ot e ntial ris k f or rec urre nce  
•  
A de q uatel y tr eate d n o n -mela n o ma s ki n ca ncer or le nti g o mali g na wit h o ut 
e vi de nce of disease  
•  
A de q uatel y tre ate d carci n o ma i n sit u wit h o ut e vi de nce of dis ease  
4. 2. 1 7  Hist or y of le pt o me ni n geal carci n o mat osis.  
4. 2. 1 8  Has  a n acti ve a ut oi m m u ne disease  ( or i nfla m mat or y dis or ders) re q uiri n g s yste mic 
treat me nt wit hi n t he past 3 m o nt hs or a d oc u me nte d hist or y of cli nicall y se vere 
a ut oi m m u ne disease, or a s y n dr o me t h at re q uires s yste mic ster oi ds or 
i m m u n os u p pressi ve a ge nts. S u bjects wit h i nfla m mat or y dis or ders  (i ncl u di n g 
i nfla m mat or y b o wel dise ase [e. g., c olitis or Cr o h n's disease], di vertic ulitis [ wit h t he 
e xce pti o n of di vertic ul osis], s yste mic l u p us er yt he mat os us, Sarc oi d osis s y n dr o me, 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
1 9  
or 
We g e ner s y n dr o me [ gra n ul o mat osis 
wit h p ol ya n giitis, 
Gra ves' disease, 
r he u mat oi d art hritis, h y p o ph ysitis, u veitis, etc]).  
T he f oll o wi n g are e xce pti o ns t o t his criteri o n:  
•  
S u bjects wit h vitili g o  or al o pecia  or res ol ve d c hil d h o o d ast h ma/at o p y  
•  
S u bjects w h o  re q uire i nt er mitte nt use of br o nc h o dilat ors or l ocal ster oi d 
i njecti o ns w o ul d n ot be e xcl u de d fr o m t he st u d y.   
•  
S u bjects wit h h y p ot h yr oi dis m (e. g., f oll o wi n g Has hi m ot o s y n dr o me) 
sta ble o n h or m o ne re pl ace me nt or wit h Sj or ge n’s s y n dr o me will n ot be 
e xcl u de d fr o m t he st u d y  
•  
A n y c hr o nic s ki n c o n diti o n t hat d oes n ot re q uire s yste mic t hera p y  
•  
S u bjects  wit h o ut acti ve H N S C C  disease i n t he last 5 years ma y be i ncl u de d 
b ut o nl y after c o ns ultati o n wit h t he st u d y p h ysicia n  
•  
S u bjects wit h celiac dise ase c o ntr olle d b y diet al o ne  
4. 2. 1 9  Has a hist or y of n o n -i nf ecti o us p ne u m o nitis t hat re q uire d ster oi ds or e vi de nce of 
i nterstitial l u n g disease or c urre nt acti ve, n o n-i nfecti o us p ne u m o nitis. 
4. 2. 2 0  Maj or s ur gical pr oce d ure (as defi ne d b y t he I n v esti gat or) wit hi n 2 1  da ys pri or t o 
t he first d ose of i n v esti gati o nal pr o d uct (I P). N ote: L ocal s ur ger y of is olate d lesi o ns 
f or palliati ve i nte nt is acce pta ble.  
4. 2. 2 1  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 p ect oris, car di ac arr h yt h mia, i nterstitial l u n g disease, s eri o us 
c hr o nic gastr oi ntesti nal c o n diti o ns ass ociate d 
wit h diarr hea, 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 uir e me nt, 
s u bsta ntiall y i ncrease ris k of i nc urri n g A Es or c o m pr o mise t he a bilit y of t he patie nt 
t o gi ve writte n i nf or me d c o nse nt . 
4. 2. 2 2  Recei pt of li ve atte n u ate d vacci ne wit hi n 3 0 da ys pri or t o t he first d os e of st u d y 
dr u g. N ote: Patie nts, if e nr olle d, s h o ul d n ot recei ve li ve vacci ne w hilst recei vi n g 
st u d y treat me nt a n d u p t o 3 0 da ys after t h e last d ose of st u d y treat me nt. 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 2  
•  
1 2. 1. 4 I nf usi o n -rel ate d Re acti o ns  
 
Patie nts s h o ul d be t h or o u g hl y e val uate d a n d a p pr o priate eff orts s h o ul d be ma de t o 
r ule o ut n e o plastic, i nf ecti o us, meta b olic, t o xi n, or ot her eti ol o gic ca us es of t he  
i m m u ne-me diate d  a d vers e e ve nt s (i m A Es). 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 i m A E dia g n osis. I n t h e 
a bse nce of a cl ear alter nati ve eti ol o g y, e ve nts s h o ul d be c o nsi dere d p ot e ntiall y 
i m m u ne relate d. 
 
I n a d diti o n, t here are cert ai n circ u msta n ces (e. g., s u bject’s wei g ht falls t o ≤ 3 0 k g/ 
6 6. 6 l bs.) 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 (see 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  pr o vi de d i n A p pe n di x 1 2. 0  as 
n o te d a b o ve).  
 
D ose m o dificati o ns will be ma de acc or di n g t o st u d y pr ot oc ol. Patie nts s h o ul d be 
t h or o u g hl y e val uate d a n d 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 nfecti o us, meta b olic, t o xi n, or ot her eti ol o gic ca us es of t he i m m u ne me diate d  A E s. 
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 i m m u ne me diate d A E dia g n osis. I n t he a bse n ce of a clear 
alter nati ve eti ol o g y, e ve nts s h o ul d be c o nsi dere d p ote ntiall y i m m u ne relate d.  All 
t o xicities will be gra de d acc or di n g t o N CI C T C A E, Versi o n 5. 0 .  
5. 4  
C o nc o mit a nt Me dic ati o ns/ Tre at me nts / S u p p orti ve C are All o we d 
T he Pri nci pal I n vesti gat or m ust be i nf or me d as s o o n as p ossi ble a b o ut a n y 
me dicati o n ta ke n fr o m t h e ti me of scree ni n g u ntil t he e n d of t he cli nica l p h ase of 
t he st u d y (e n d of st u d y treat me nt visit). A n y c o nc o mita nt me dicati o n(s), i ncl u di n g 
her bal pre parati o ns, ta k e n d uri n g t he st u d y will b e rec or de d i n t he eC R F. Refer t o 
A p pe n di x  1 2. 0  f or g ui da nce o n ma na ge me nt of st u d y dr u g-relate d t o xicities. See 
secti o n 5. 2. 1  f or a b o v e d etails . 
 
Best 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, c orrecti o n of 
meta b olic dis or ders, o pti mal s y m pt o m c o ntr ol, a n d pai n ma na g e me nt [i n cl u di n g 
palliati ve ra di ot hera p y t o 
n o n -tar get lesi o ns, etc.]) s h o ul d be pr o vi de d. 
C o nc o mit a nt me dicati o ns or treat me nts (e. g.,  acet a mi n o p he n or di p he n h y dra mi ne) 
dee me d necessar y t o pr o vi de a de q uate pr o p h yl actic or s u p p orti ve care, e xce pt f or 
t h ose me dicati o ns i de ntifie d as “ pr o hi bite d,” i n secti o n 5. 5 , s h o ul d be use d, w he n 
necessar y f or all patie nts.  I n acti vate d vir us vacci nes ( e. g., i nfl ue n za v acci ne) are 
per mitte d.  Dr u gs wit h la xati ve pr o perties a n d her bal or n at ural re me dies f or 
c o nsti pati o n are per mitte d.   
 
 
 
I m m u n os u p pr essi ve 
m e dicati o ns 
(e. g., 
c orti c oster oi ds) are 
all o we d  f or 
ma na ge me nt of t he f oll o wi n g:  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 3  
•  
D ur val u ma b relate d a d verse e v e nts per d os e 
m o dificati o n g ui deli nes 
pr o vi de d i n A p pe n di x 1 2. 0  
•  
Use i n s u bjects wit h c o ntrast aller gies  
•  
Use of i n hale d,  t o pical, a n d i ntra nasal c ortic ost er oi ds is per mitte d 
•  
A te m p orar y p eri o d of ster oi d use  is all o we d if cli nicall y i n dicate d a n d 
c o nsi dere d t o b e esse ntial f or t he ma na ge me nt of n o n -i m m u n ot hera p y 
relate d e ve nts e x p erie n ce d b y t he s u bj ect (e. g., c hr o nic o bstru cti ve 
p ul m o nar y disease, ra diati o n, na usea, etc. ). 
5. 5  
Pr o hi bite d Me dic ati o ns/ Tre at me nts  
T he f oll o wi n g me dicati o ns are pr o hi bite d w hile t h e s u bject is o n st u d y. 
•  
A n y i n vesti gati o nal a ntica ncer t hera p y ot her t ha n t h ose u n der i n vesti gati o n 
i n t his st u d y  
•  
m A bs a g ai nst P D-1 or P D -L 1 ot her t ha n t h ose u n der i n vesti gati o n i n t his 
st u d y 
•  
C he m ot hera p y, i m m u n ot hera p y, or bi ol o gic or h or m o nal t hera p y f or ca n cer 
treat me nt a part fr o m t h os e u n der i n vesti gati o n i n t his st u d y 
•  
I m m u n os u p pr essi 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 ≥1 0 
m g/ da y or pre d nis o ne or e q ui vale nt, 
met h otre xate, azat hi o pri n e, a n d t u m or necr osis fact or -α bl oc kers  
•  
S u niti ni b  
•  
T yr osi ne ki nase i n hi bit ors t hat tar get E G F R ( e. g., erl oti ni b, gefi niti b) 
•  
Li ve atte n uate d vacci nes –  als o wit h h ol d use f or at least 3 0 da ys after 
disc o nti n ui n g st u d y me dicati o ns  
•  
Her bal a n d nat ur al re me dies, w hic h ha v e i m m u ne -m o d ulati n g effects ( e. g., 
gi nse n g, gi n g k o bil o ba, ga n o der ma, astra gal us, etc.)  
 
I n a d diti o n, patie nts s h o ul d n ot d o nate bl o o d w hile partici pati n g i n t his st u d y  a n d  
f or at least 9 0 da ys f oll o wi n g t he last i nf usi o n of d ur val u ma b. 
5. 6  
C o ntr ace pti o n Re q uire me nts  
Fe m ale p atie nt of c hil d be ari n g  p ote nti al  
Fe males 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 p art ner m ust use at least 1 hi g hl y effecti ve met h o d of c o ntrace pti o n ( see Ta ble 
bel o w ) 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 d ur val u ma b m o n ot hera p y  . N o n-
sterilize d male part ners of a fe male patie nt 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 dr u g tr eat me nt a n d t he dr u g was h o ut peri o d is a n acce pta ble 
practice; h o w e ver, p eri o dic 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 birt h c o ntr ol. Fe mal e patie nts s h o ul d als o 
refrai n fr o m br eastfee di n g t hr o u g h o ut t his peri o d. 
 
M ale p ati e nts wit h a fe m ale p art ner of c hil d be ari n g p ote nti al : 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 4  
N o n -sterilize d m ales w h o are se x u all y acti ve wit h a fe male part ner of c hil d beari n g 
p ote ntial m ust use a 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 9 0 da ys 
after recei pt of t he fi nal d ose of d ur v al u ma b m o n ot hera p y. N ot e n ga gi n g i n se x ual 
acti vit y is a n acce pta bl e practice; h o we v er, o ccasi 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 patie nts 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 c hil d beari n g p ote ntial) of male patie nts m ust als o 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 ( Ta ble 1).  
 
Fe m ales of c hil d be ari n g p ote nti al 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 pl ete h ysterect o m y) or p ost -me n o pa usal.  
 
W o me n will be c o nsi dere d p ost -me n o pa usal if t h e y ha ve bee n a me n orr hei c f or 1 2 
m o nt hs 
wit h o ut a n alter nati ve 
me dical  ca use. T he f oll o wi n g a ge -s pecific 
re q uire me nts a p pl y:  
•  
W o me n < 5 0 years of a ge w o ul d be c o nsi dere d p ost -me n o pa usal if t he y ha ve 
bee n a me n orr hei c f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of e x o g e n o us 
h or m o nal treat me nts a n d if t he y ha ve l utei nizi n g h or m o ne  a n d f ollicle-
sti m ulati n g h or m o ne le vels i n t he p ost-m e n o pa us al ra n g e f or t he i nstit uti o n 
or u n der we nt s ur gical sterilizati o n ( bilateral o o p h orect o m y or h ysterect o m y).  
•  
W o me n ≥5 0 years of a ge w o ul d be c o nsi dere d p ost -me n o pa usal if t he y ha ve 
bee n a me n orr hei c f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of all e x o g e n o us 
h or m o nal treat me nts, h a d ra diati o n -i n d uce d me n o pa use wit h last me nses > 1 
year a g o, ha d c h e m ot hera p y -i n d uce d m e n o pa use wit h last me nses > 1 year 
a g o, or u n der we nt s ur gical sterilizati o n ( bilateral o o p h orect o m y, bilateral 
sal pi n gect o m y or h ysterect o m y). 
 
Hi g hl y effecti ve met h o ds of c o ntr ace pti o n , defi ne d as o ne t hat res ults i n a l o w 
fail ure rate (i.e., l ess t ha n 1 % per y ear) w he n us e d c o nsiste ntl y a n d c orrectl y are 
descri be d i n t he Ta ble bel o w.  
 
N ot e: S o me c o ntrace pti o n met h o ds are n ot c o nsi d ere 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, di a 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 ut eri 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 
o f 
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 hasi c 
c o m bi ne d oral c o ntrace pti ve pills).  
 
Hi g hl y effecti ve met h o ds of c o ntr ace pti o n ( < 1 % f ail ure r ate) . See t he 
t a ble bel o w. 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 5  
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 gestr el -rel easi n g 
i ntra uteri ne s yste m (e. g., 
Mire na ®)
a 
 
•  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 nt ®  
•  I ntr a va gi nal: 
Et hi n ylestra di ol/et o n o gestrel -
releasi n g i ntra v a gi nal de vices: 
e. g. N u va Ri n g ®  
•  I njecti o n: Me dr o x y pr o g ester 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 gestr o mi n/et hi n ylestra di ol -
releasi n g tra ns d er mal s yste m: 
e. g. Orth o E vra ®   
•  Mi ni pillc: Pr o gester o ne base d 
oral c o ntrace pti ve pill usi n g 
des o gestrel: Cerazette ® is 
c urre ntl y t he o nl y hi g hl y 
effecti ve pr o gest er o ne b ase d pill  
 
 
 
a 
T his is als o c o nsi dere d a h or m o nal met h o d  
 
5. 7  
Ot her M o d alities or Pr oce d ures  
Ra diati o n t hera p y will be gi ve n per sta n dar d of care.  
5. 8  
Re as o ns f or E arl y Wit h dr a w al fr o m St u d y Tre at me nt  
St u d y t reat me nt s h o ul d 
c o nti n ue t hr o u g h 
c o m pleti o n 
of t he 
a dj u va nt 
i m m u n ot hera p y a n d ra di ati o n t hera p y re gi me n o utli ne d i n Secti o n 5. 2 . S u bjects 
s h o ul d be wit h dra w n fr o m st u d y t hera p y if t he y e x perie nce : 
•  Disease pr o gressi o n  
•  S u bject wei g ht is ≤ 3 0 k g ( 6 6. 6 l bs.) 
•  I nter-c urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt  
•  U nacce pta ble a d verse e v e nt(s)  
•  Pre g na nc y  or i nte nt t o bec o me pre g n a nt  
•  Patie nt deci des t o wit h dra w fr o m st u d y  treat me nt 
•  Ge neral or s pecific c ha n g es i n t he patie nt’s c o n diti o n re n der t he patie nt 
u nacce pta ble f or f urt her treat me nt i n t he j u d g me nt of t he i n vesti gat or.  
•  Patie nt is deter mi ne d t o ha ve met o ne or m ore of t he e xcl usi o n criteria 
f or st u d y partici pati o n at st u d y e ntr y a n d c o nti n ui n g i n vesti gati o nal 
t hera p y mi g ht c o nstit ute a safet y ris k 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 6  
•  Gra de ≥3 i nf usi o n r eacti o n  
•  Patie nt n o nc o m plia nce t hat, i n t he o pi ni o n of t h e i n vesti gat or or 
s p o ns or, warra nts wit h dr a wal; e. g., ref usal t o a d here t o sc h e d ule d visits  
•  I nitiati o n 
of 
alter nati ve 
a ntica n cer t hera p y i ncl u di n g 
a n ot her 
i n vesti gati o nal a ge nt 
•  S u bject is l ost t o f oll o w u p  
5. 9  
D ur ati o n of F oll o w U p  
All p atie nts will be f oll o we d f or u p t o 5  years, or u ntil deat h, w hic he ver o cc urs first 
after re m o val fr o m st u d y treat me nt f or deter mi nati o n of st u d y e n d p oi nts.  Patie nts 
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 f or res ol uti o n 
or sta bilizati o n of t he  a d v erse e v e nt(s). All  p atie nts  (i ncl u di n g t h ose wit h dra w n f or 
A Es)  s h o ul d be f oll o we d after re m o val fr o m st u d y treat me nt as sti p ulate d i n t he 
pr ot oc ol.   
5. 1 0  
St u d y Wit h dr a w al  
Patie nts will be re m o ve d fr o m pr ot oc ol t hera p y a n d t he PI n otifie d w he n a n y of t he 
criteria liste d i n secti o n 5. 8  a p pl y.  T he reas o n f or disc o nti n uati o n of pr ot oc ol 
t hera p y will be d oc u me nt e d o n t he e C R F.   
 
If a patie nt deci des t o wit h draw fr o m t he st u d y (a n d n ot j ust fr o m pr ot oc ol t hera p y) 
an  eff ort s h o ul d be ma de t o c o m plete a n d re p ort st u d y assess me nts as t h or o u g hl y 
as p ossi ble .  At t he ti me of wit h dra wal, t he i n vesti gat or s h o ul d atte m pt t o esta blis h 
as c o m pletel y as p ossi ble t he reas o n  f or t he st u d y wit h dra wal.  
•  
T he patie nt s h o ul d b e as ke d if t he y are willi n g t o all o w f or t he a bstr acti o n 
of rele v a nt i nf or mati o n fr o m t heir me dical rec or d i n or der t o meet t he l o n g 
ter m f oll o w u p (e. g., s ur vi val) o bjecti ves o utli ne d i n t he pr ot oc ol.   
•  
If a patie nt wit h dra ws c o nse nt, t he y s h o ul d b e s pecificall y as k e d if t he y are 
wit h dra wi n g c o nse nt t o:  
o  
all f urt her partici p ati o n i n t he st u d y i ncl u di n g a n y f urt her f oll o w u p 
(e. g., s ur vi val c o ntact tel e p h o ne calls) 
o  
wit h dra wal of c o nse nt t o t he use of t heir st u d y ge nerate d data  
o  
wit h dra wal t o t he use of a n y sa m ples  
•  
A c o m plete fi nal e v al uati o n at t he ti me of t he patie nt’s st u d y wit h dra wal 
s h o ul d be o btai ne d  wit h a n e x pla nati o n of w h y t h e patie nt is wit h dra wi n g 
fr o m t he st u d y.   
•  
If t he p atie nt is no nc o m plia nt a n d d oes n ot ret ur n f or a n e n d of st u d y f oll o w 
u p assess me nt, t his s h o ul d be d oc u me nte d i n t he e C R F.  
•  
If t he reas o n f or re m o val of a patie nt fr o m t he st u d y is a n a d verse e v e nt, t he 
pri nci pal s pecific e ve nt will be rec or de d o n t he e C R F.   
 
E xcessi ve patie nt wit h dra wals fr o m pr ot o c ol t hera p y or fr o m t he st u d y ca n re n der 
t he st u d y u n-i nter preta bl e; t heref ore, u n necessar y wit h dra wal of p atie nts s h o ul d 
be a v oi de d.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 7  
6. 0  
D R U G I N F O R M A TI O N  
T he i n vesti gati o nal dr u g i n t his st u d y is d ur val u ma b (I mfi nzi T M ) a n d will be 
s u p plie d b y Astra Ze neca. 
6. 1  
D ur v al u m a b (I mfi nzi T M )  
6. 1. 1  Descri pti o n  
D ur val u ma b, a h u ma n I g G 1  m A b directe d a gai nst P D -L 1, 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 g G 1 hea v y c hai n t hat re d uces bi n di n g t o 
C 1 q a n d t he Fc  rece pt ors. D ur val u ma b is bei n g de vel o pe d f or t he treat me nt of 
patie nts wit h s oli d t u m ors or he m at ol o gic mali g na nc ies. D ur val u ma b recei ve d 
accelerat e d a p pr o val i n Ma y of 2 0 1 7 as tr eat me nt f or  patie nts wit h  l ocall y a d va nce d 
or metastatic ur ot helial carci n o ma w h o h a ve pr o gresse d d uri n g or wit hi n 1 2 m o nt hs 
of ne oa dj u va nt or a dj u va nt  plati n u m -c o ntai ni n g c he m ot hera p y.  
 
F ul l prescri bi n g i nf or mati o n f or d ur val u ma b is a v aila ble at: 
htt ps:// w w w.az pice ntral. c o m/i mfi nzi/i mfi nzi. p df # pa ge = 1  
6. 1. 2  St or a ge a n d H a n dli n g  
D ur val u ma b will be s u p plie d b y Astra Ze neca as a 5 0 0 m g vial s ol uti o n f or i nf usi o n 
after 
dil uti o n. 
T he s ol uti o n c o ntai ns 
5 0 
m g/ m L 
d ur val u ma b , 
2 6 
m M 
histi di ne/ histi di ne -h y dr 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 ( w/ v) p ol ys or bate 8 0; it h as a p H of 6. 0  a n d de nsit y of 1. 0 5 4 g/ m L . 
T he n o mi nal fill v ol u me is 1 0. 0  m L. I n vesti gati o nal pr o d uct vials are st ore d at 2° C 
t o 8° C ( 3 6° F t o 4 6° F) a n d m ust n ot be fr oze n. 
6. 1. 3  D os a ge a n d A d mi nistr ati o n  
Patie nts  will  recei ve d ur val u ma b ( 1 5 0 0 m g Q 3W)  f or c ycles 1 -3 , f oll o we d b y 
d ur val u ma b 1 5 0 0  m g Q 4 W f or  3  a d diti o nal c y cles (i.e., c ycles 4 -6 ). C o nc o mita nt 
ra di ot hera p y (2  G Y i n 3 0 fracti o ns  f or a t otal of 6 0 G y) will be gi n i n c ycle 1 a n d 
ma y c o nti n ue i nt o c ycle 3 . Ra diati o n t hera p y will ta ke 6 wee ks ( M o n da y -Fri da y) 
or 3 0 da ys a n d occ ur 6 of 9 wee ks t hat defi n e C y cles 1 -3. H o we ver, d ue t o dela ys 
or misse d a p p oi nts, c o m pleti o n of t h ose 3 0 fracti o ns ma y ta ke l o n ger t h a n t he 
all otte d 6 wee ks a n d t his is all o we d. Ra diati o n t hera p y m ust be sc h e d ul e d a n d 
c o m plete d wit hi n C ycles 1 -3 a n d s h o ul d n ot e xte n d i nt o C yc le 4. Please refer t o 
Secti o n 6. 2  f or a d diti o nal details a n d all o wa nces. S u bjects will c o nti n ue o n s t u d y 
t hera p y as d escri b e d u nl ess t here is u n acce pta ble t o xicit y, w it h dra wal of c o nse nt, 
or a n ot her disc o nti n uati o n criteri o n is met  as o utli ne d i n secti o n 5. 8 .   
T he i m m u n ot hera p y re gi me ns will b e i nstit ute d a p pr o xi matel y 3 -5  wee ks after 
s ur ger y.  
•  
Sta n dar d i nf usi o n ti me f or d ur val u ma b  is 6 0 mi n utes ( ± 5 mi n utes). Less t ha n 
5 5 mi n utes is c o nsi dere d a de viati o n.  
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 8  
•  
I n t h e e ve nt t hat t h ere 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 
s h o ul d n ot e xcee d 8 h o urs at r o o m te m perat ur e.  
 
•  
D ur val u ma b d o es 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.  
 
•  
N o i nc o m pati bilities bet wee n d ur val u ma b a n d p ol y vi n ylc hl ori de or p ol y olefi n 
I V ba gs ha v e bee n o bs er ve d. 
6. 1. 4  D ur v al u m a b P re p ar ati o n   
Pre parati o n of d ur val u ma b d oses f or a d mi nistrati o n wit h a n I V ba g  
T otal ti me fr o m nee dl e p u nct ure of t he d ur val u ma b vial t o t he start of 
a d mi nistrati o n s h o ul d n ot e xc ee d:  
•  
2 4 h o urs at 2° C t o 8° C ( 3 6° F t o 4 6° F)  
•  
4  h o urs at r o o m te m perat ure  
 
A d ose of 1 5 0 0  m g (f or p atie nts > 3 0 k g i n wei g ht) will be a d mi nistere d usi n g a n I V 
ba g c o ntai ni n g 0. 9 % ( w/ v) sali ne or 5 % ( w/ v) de xtr ose, wit h a fi nal d ur val u ma b 
c o nce ntr ati o n ra n gi n g fr o m 1 t o 1 5  m g/ m L, a n d deli vere d t hr o u g h a n I V 
a d mi nistrati o n set wit h a 0. 2 - or 0. 2 2 -μ m i n -li ne filter.  
 
A d d 3 0. 0  m L of d ur val u ma b (i.e., 1 5 0 0  m g of d ur val u ma b) t o t he I V ba g. T he I V 
ba g size s h o ul d be selecte d s uc h t hat t he fi nal c o nce ntr ati o n is wit hi n 1 t o 1 5  
m g/ m L. Mi x t he ba g b y ge ntl y i n verti n g t o e ns ure h o m o ge neit y of t he d ose i n t he 
ba g.  
 
T he I V li ne will be fl us he d wit h a v ol u me of I V 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 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 a n d d oc u m e nt if t he li ne was n ot fl us he d.  
6. 1. 5  Dr u g Acc o u nt a bilit y  
T he i n vesti gat or or desi g nee is res p o nsi ble f or kee pi n g acc urat e rec or ds of t he 
cli nical s u p plies recei ve d fr o m t h e c o m p a n y s p o ns or 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 n cl usi o n of t he trial. 
A n acc urat e a n d c urre nt acc o u nti n g of t he dis pe nsi n g a n d ret ur n of i n vesti gati o nal 
st u d y dr u g f or eac h s u bject will be mai ntai ne d o n a n o n g oi n g basis b y a me m ber of 
t he st u d y site staff.  T he a m o u nt of st u d y dr u g dis p e nse d a n d ret ur n e d b y t he s u bject 
will be rec or de d i n t he I n vesti gati o nal Dr u g Acc o u nta bilit y Rec or d.   
6. 1. 6  Ret ur n a n d Rete nti o n of St u d y Dr u g  
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 i n vesti gati o nal pr o d uct 
will be destr o ye d at t he site per i nstit uti o nal p olic y (e. g., U N C I D S dr u g destr ucti o n 
p olic y). It is t he I n v esti 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
2 9  
acc or di n g t o a p plica ble fe deral, stat e, 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 d e d t hat a p pr o priate rec or ds of dis p osal are k e pt.  
 
H a n dli n g a n d Dis p os al : L ocal re q uire m e nts f or dis p osal of hazar d o us dr u gs 
s h o ul d be f oll o we d at e ac h partici pati n g cli nical site. 
 
Please see U N C p olic y o n hazar d o us dr u gs:  
htt p:// ne ws. u nc healt hcare. or g/e m p ne ws/att/ 2 0 1 1/ n o v/a d mi n 0 1 8 8/ .  
6. 1. 7  A d verse E ve nts Ass oci ate d wit h D ur v al u m a b  
T he f oll o wi n g i m m u ne me diate d a d verse e v e nts are ass o ciate d wit h d ur v al u ma b.  
•  
P ne u m o nitis  or i nterstitial l u n g disease : E v al uat e patie nts wit h s us pect e d 
p ne u m o nitis 
wit h ra di o gra p hic i ma gi n g a n d 
ma na ge 
wit h tr eat me nt 
m o dificati o ns a n d c ortic oster oi ds  
•  
He patitis : M o nit or patie nts wit h ab n or mal li ver tests eac h c ycle d uri n g 
treat me nt; 
ma na g e 
i m m u ne-me diate d 
h e patitis 
wit h 
treat me nt 
m o dificati o ns a n d c ortic oster oi ds  
•  
C olitis : M o nit or patie nts 
f or si g ns a n d s y m pt o ms of c olitis or diarr hea 
d uri n g treat me nt; ma na ge 
i m m u ne-me diate d c olitis  wit h treat me nt 
m o dificati o ns , a nti-diarr heal a ge nts,  a n d c ortic oster oi ds  
•  
Lar ge i ntesti ne perf orati o n /i ntesti ne perf orati o n: W he n s y m pt o ms or 
e val uati o n i n dicate a perf orati o n is s us pecte d, c o ns ult a s ur ge o n 
e x perie n ce d i n a b d o mi nal s ur ger y i m me diatel y wit h o ut a n y dela y. 
•  
E n d ocri n o pat hies : 
M o nit or 
patie nts f or t h yr oi d 
dis or ders, 
a dre n al 
i ns ufficie nc y, t y pe 1 dia b etes mellit us a n d h y p o p h ysitis/ h y p o pit uitaris m 
•  
Ras h  or Der matitis (i ncl u di n g Pe m p hi g oi d) : M o nit or patie nts f or i m m u ne -
me diate d ras h a n d vitili g o. 
Ma na ge wit h treat me nt m o dificati o ns a n d 
c ortic oster oi ds  
•  
I m m u ne t hr o m b oc yt o pe nic p ur p ura: M o nit or patie nts f or t hr o m b oc yt o pe nic 
p ur p ura. T his le d t o o ne deat h relate d t o d ur val u ma b. T he patie nt recei ve d 
hi g h -d ose c ortic oster oi ds, h u ma n I g G, a n d rit u xi m a b 
•  
Ne p hritis : M o nit or patie nts f or a b n or mal re nal f u ncti o n pri or t o eac h c ycle 
d uri n g treat me nt; 
m a na ge ne p hritis  wit h treat me nt 
m o dificati o ns a n d 
c ortic oster oi ds  
•  
I nfecti o n: Se vere i nfecti o ns, i ncl u di n g se psis, necr otizi n g fas ciitis, a n d 
os ter o m yelitis, occ urre d i n patie nts recei vi n g d ur val u ma b. M o nit or patie nts 
f or si g ns/s y m pt o ms of i nfecti o n a n d treat wit h a nti-i nfecti ves f or s us pecte d 
or c o nfir me d i nfecti o ns  
•  
I nf usi o n-relat e d reacti o ns: 
M o nit or patie nts f or si g ns a n d s y m pt o ms of 
i nf usi o n-relate d reacti o n. I nterr u pt or sl o w t he rate of i nf usi o n i n patie nts 
wit h mil d or m o derate reacti o ns. Per m a ne ntl y disc o nti n ue d ur val u ma b i n 
patie nts wit h Gra de 3 or 4 reacti o ns  
•  
M y ocar ditis : M o nit or patie nts  f or si g ns/s y m pt o ms of m y ocar ditis. Ma na ge 
m y ocar ditis  wit h treat me nt m o dificati o ns a n d i m m u n os u p pressi ve t hera p y 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
3 0  
i ncl u di n g c ortic oster oi ds a n d i n 
T N F-al p ha i n hi bit ors. Per ma ne ntl y 
disc o nti n ue  d ur val u ma b  i n patie nts wit h Gra de 3 or 4 m y ocar ditis.  
•  
E m br y o -fetal t o xicit y: D ur val u ma b ca n ca us e fetal har m w he n a d mi nistere d 
t o pre g na nt w o m a n.  W O C B P m ust use c o ntrace pti o n d uri n g treat me nt a n d 
f or at least 3 m o nt hs after t he last d ose of d ur val u ma b. 
 
 
Please c o ns ult t h e d ur val u ma b i n vesti gat or ’s br oc h ure a n d p ac k a ge i nsert f or 
a d diti o nal i nf or mati o n.  
6. 2  
R a di ati o n T her a p y  
Patie nts will recei ve ra di ati o n t hera p y c o nc o mita ntl y wit h d ur val u ma b starti n g at 
C ycle 1 . I nstit uti o nal g ui deli nes f or deli ver y of sta n dar d of care ra di ati o n t hera p y 
t o t he hea d a n d n ec k pati e nts will be f oll o we d . 
 
L oc aliz ati o n, Si m ul ati o n, a n d I m m o biliz ati o n  
Patie nts m ust ha ve a n i m m o bilizati o n de vice f or t he h ea 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 patie nts. T he treat me nt pla n ni n g C T sca n ca n b e perf or me d wit h or 
wit h o ut I V c o ntrast. T h e treat me nt pla n ni n g C T s ca n m ust b e perf or m e 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 a 
ma xi m u m of 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 uir e 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  
•  Cli nical tar get v ol u me of 6 0 G y ( 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 p er ati 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 p at h y. 
C T V 6 0 ma y i ncl u de t he br oa der o p erati ve res ecti 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 nti re n o d al re gi o ns i n t he i n v ol ve d 
he mi -nec k ma y b e 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 n cers. 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 gi call 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 less er ris k re gi o ns i n t he o perati ve b e d 
(t hat were i n v ol ve d wit h s ur ger y i n a n y wa y) or re gi o nal n o des  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 v e 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 nte nsit y-m o d ulate d ra diati o n t hera p y ( 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
3 1  
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 ot e: A se parate b o 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 n eral, 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 b e y o n d t he s ki n s urface, t he a p plicati o n of b ol us material o v er 
t his p orti o n of t he P T V ma y be c o nsi d ere 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 P rescri pti o n t o P T Vs:  D os e will b e pres cri be d t o t h e 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 nstrai 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 h e 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 os e  
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 os e  
▪ N o n -tar get Tiss ue 
o  N o m ore t ha n 1 % of t h e tiss ue o utsi de t he P T V s h o ul d recei v e ≥ 
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  
o  C oc hlea:  Mea n d ose < 4 5 G y  
o  Lar y n x:  Mea n d os e < 4 1 G y a n d/ or 6 0 G y t o < 2 0 %  
o  O ptic str uct ures: 0 . 1cc <  5 4 G y  
 
P T V c o vera g e 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 hle a, or lar y n x.  S pari n g of t hes e str u ct 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 u st 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.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
3 2  
7. 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  
7. 1  
Ti m e a n d E ve nts T a ble  
Assess m e nts  
Scree ni n g 2 , 3 
St u d y Tre at m e nt 3  
E n d of 
Tre at m e nt  4 
3 & 6 m o nt hs 
after 
c o m pleti o n of 
st u d y 
t her a p y3  
At 
Ti m e 
Dise ase 
Rec urs 3  
L o n g 
Ter m 
F oll o w -
u p 3, 4 , 1 4 
C 1  
D 1  
C 2  
D 1  
C 3  
D 1  
C 4  
D 1  
C 5  
D 1  
C 6  
D 1  
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
De ntal E xa m 1  
X  
 
 
 
 
 
 
 
 
 
 
P h ysical E xa m a n d Me dical Hist or y 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
E C O G Perf or ma n ce stat us  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
Pre g na n c y Test  1 5  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
C B C wit h Differe ntial  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Ser u m C he mistries a n d L F Ts 1 2  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A m ylase a n d Li pase  
X  
 
 
 
 
 
 
X  
 
 
 
T h yr oi d St u dies 7  
X 7 
 
X 7 
X 7 
X 7 
X 7 
X 7 
X 7 
X 7 
 
 
Uric Aci d  
X  
 X  
 
 
 
 
 
 
 
 
Creati ni ne Cleara n ce 1 3  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
C o nc o mita nt Me dici ne Re vie w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
D u r val u ma b 1 5 0 0 m g I V Q 3 W  
 
X  
X  
X  
 
 
 
 
 
 
 
D ur val u ma b 1 5 0 0 m g I V  Q 4 W  
 
 
 
 
X  
X  
X  
 
 
 
 
Ra diati o n T hera p y ( Dail y, M o n -Fr i da y) 
 
X 1 0  
X 1 0 
X 1 0  
 
 
 
 
 
 
 
T u m or Assess me nt 5  
 X  
 
  
 
 
 
X  
 
 X  
P ne u m o nitis (I L D) Assess me nt 6 , 8 
 
 X  
X  
X  
X  
X  
X  
X  
 
X  
Cl i nical To xicit y Assess me nt 6  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
F A C T -H & N v 4 ( Q O L Assess me nt)  
 
X  
X  
X  
X  
 
 
X  
X  
 
 
Sta n dar d of care i ma gi n g 
( P E T/ C T/ M RI) 
 
 
 
 
X  
 
 
 
 
 
 
Bl o o d dra w t o st u d y i m m u ne s yste m 9  
 
X  
 
 
X  
 
 
X  
X  
X  
X  
Re q uest f or Arc hi val Tiss ue 1 1  
X  
 
 
 
 
 
 
 
 
 
 
S ur gical bi o ps y at rec urre nce  
 
 
 
 
 
 
 
 
 
X  
 
Pr o gressi o n a n d S ur vi val  
 
 
 
 
 
 
 
X  
X  
 
X  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 3  
F o ot n otes t o Ti me a n d E ve nts T a ble  
1.  As re q uir e d per i nstit uti o nal sta n dar d of care.  S h o ul d be o btai ne d 3 wee ks bef ore Da y 
1 if it is re q uire d per i nstit uti o nal sta n dar d of care . 
2.  Hist or y a n d p h ysical e x a m ma y be perf or me d wit hi n 6 wee ks  pri or t o d a y 1 of st u d y 
treat me nt. C o m plete me dical hist or y a n d p h ysical e xa mi nati o n (i ncl u di n g hei g ht, 
wei g ht, a n d vital si g ns)  f or pre-st u d y ass ess me nt; foc use d me dical hist or y a n d p h ysical 
e xa mi nati o n (i ncl u di n g wei g ht)  at s u bse q ue nt assess me nts.  Ot her  e val uati o ns e xce pt 
f or pre g na nc y test a n d b aseli ne i ma gi n g  m ust be perf or me d wit hi n 6 wee ks pri or t o 
Da y 1 of st u d y tr eat me nt. Ser u m β -H C G m ust be p erf or me d wit hi n 7  da ys  pri or t o first 
d ose of st u d y me dicati o n f or w o me n of c hil d -beari n g p ote ntial.  I nitial baseli ne  i ma gi n g 
m ust be wit hi n 4 wee ks of C ycle 1 da y 1 .   
3.  A wi n d o w of +/ - 3 a n d + 7  da ys a p plies t o all st u d y visits u nless ot her wis e s pecifie d.  
T he visits occ urri n g 3 m o nt hs a n d 6 m o nt hs after c o m pleti o n of st u d y t hera p y ha ve a 
wi n d o w of +/ -1 5 da ys. L o n g -ter m f oll o w-u p visits will occ ur per sta n dar d of care 
(S O C ). Als o n ote, c ycles 1 -3 are 3 wee k c ycles a n d c ycles 4 -6 are 4 wee k c ycles.  
4.  T he e n d o f treat me nt visit s h o ul d o nl y occ ur w he n patie nts per ma ne ntl y st o p st u d y 
treat me nt a n d s h o ul d be p erf or me d wit hi n 7  da ys ( +/ -7 da ys) after t he last d ose of st u d y 
me dicati o n. Patie nts w h o ha ve a n o n g oi n g ≥gra de 2 or seri o us  A E ( S A E) at t his visit 
will c o nti n ue t o be f oll o we d u ntil t he e v e nt is res ol ve d or dee me d irre versi ble b y t he 
i n vesti gat or.  
5.  Pre -s ur gical i ma gi n g will be re vie we d. C T or M RI sca n of t he nec k, res ults fr o m 
p h ysical e xa mi nati o n hea d a n d nec k, a n d c hest i ma gi n g ( x -ra y or C T sca n at discreti on 
of p h ysicia n). Pat h ol o g y re p ort f or s ur ger y 
will be re vie we d.  Bas eli ne t u m or 
assess me nt at a mi ni m u m m ust i ncl u de i ma gi n g of nec k a n d c hest ( C T, M RI, a n d/ or 
P E T). O n g oi n g t u m or assess me nt ma y be perf or me d per i nstit uti o nal sta n dar d of care 
a n d ma y i ncl u de i ma gi n g of nec k a n d c h est, nas o p har y n g olar y n g osc o p y, a n d/ or 
p h ysical e xa mi nati o n. T he s t u d y rec o m me n ds i nitial assess me nt at least e ver y 3 m o nt hs 
x 1 year t he n e ver y 6 m o nt hs x 1 year t he n a n n u all y.  
6.  T o xicit y  assesse d per N CI -C T C A E v 5. 0 . C ha n ges i n t he se v erit y of A Es fr o m baseli ne 
s h o ul d be rec or de d i n t he e C R F d uri n g t he trial a n d assesse d f or t heir relati o ns hi p t o 
st u d y t hera p y. If p n e u m o nitis or s us pecte d p ne u m o nitis occ urs, please refer t o Secti o n 
8. 2  f or a d diti o nal assess me nts t hat will be perf or me d t o e n ha nce t he i n vesti gati o n a n d 
dia g n osis of p ote ntial cas es of p ne u m o nitis.  
7.  Free T 3 or free T 4 will o nl y be meas ure d if T S H is a b n or mal or if t here is a cli nical 
s us pici o n of a n A E relate d t o t he e n d ocri ne s yste m. 
8.  P ne u m o nitis (I L D) Ass ess me nt: per secti o n 8. 2, i ncl u di n g p h ysical e xa mi nati o n, O 2, 
a n d a d diti o nal st u dies per discreti o n of st u d y i n vesti gat or  
9.  Bl o o d dra ws f or i m m u ne c orrel ate st u dies will i ncl u de 1 0  m L of w h ole bl o o d i n a si n gle 
sta n dar d ve n o us bl o o d c ollecti o n t u be wit h E D T A a d diti ve , a n d 2 4 m L of bl o o d i n 
c ollecti o n t u bes wit h A C D  a d diti ve. 
1 0.  Ra diati o n t hera p y is a d mi nistere d per sta n dar d ra di ati o n o nc ol o g y re gi me ns, o n a dail y 
basis a n d/ or as sc he d uli n g d uri n g a M o n da y -Fri da y w or ki n g wee k. Ra diati o n t hera p y 
is gi ve n c o nc urre ntl y wit h d ur val u ma b d uri n g C ycles 1-3. D ur val u ma b treat me nt 
C ycles 1 -3 are 3 -wee k l o n g c ycles (t otal of 9 wee ks). Ra diati o n t hera p y will be 
deli vere d at a d ose of 2 G y o ver 3 0 fracti o ns t otali n g a fi nal d ose of 6 0 G y. Ra diati o n 
treat ment will ta ke 6 wee ks ( M o n da y -Fri da y) or 3 0 da ys a n d occ ur f or 6 of 9 wee ks 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 4  
t hat defi ne C ycles 1-3. H o we ver, d ue t o dela ys or misse d a p p oi nt me nts, c o m pleti o n of 
t h ose 3 0 fracti o ns ma y ta ke l o n ger t ha n t he all otte d 6 wee ks a n d t his is all o we d. 
Ra diati o n t her a p y m ust be sc he d ule d a n d c o m plet e d wit hi n C ycles 1 -3 a n d s h o ul d n ot 
e xte n d i nt o C ycle 4. Please refer t o Secti o n 6. 2  f or a d diti o nal details a n d all o wa nces. 
1 1.  O btai n ar c hi v al tiss ue fr o m s ur ger y f or c orrelati v e st u dies if a v aila ble. If i ns ufficie nt 
tiss ue a vaila ble, patie nt c a n still partici pate i n t he cli nical trial. 
1 2.  Ser u m c he mistries i ncl u de 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 os e, calc i u m, ma g nesi u m, al b u mi n. Li ver f u ncti o n tests  ( L F Ts) 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 3.  B ase d o n C oc kr oft G a ult see A p pe n di x  1 2. 3  
1 4.  La b orat or y e val uati o ns are perf or me d per sta n dar d of care. T he o nl y st u d y re q uire d 
e val uati o n is t he bl o o d dr a w f or i m m u ne c orrel ates.  
1 5.  Se r u m pre g na nc y test i n w o me n of c hil d beari n g p ote ntial ( N ote: pre g na nc y test t o be 
perf or me d  wit hi n 7 da ys  of da y 1 of eac h tr eat me nt c ycle) 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 5  
7. 2  
C orrel ati v e 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 g e nerati o n.  We s us pect t hat bi o mar kers of rel e va nce f or 
pre dicti n g treat me nt effi cac 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 s t 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 us e of a n y pre -treat me nt tiss ue re mai ni n g (i.e., arc hi val a n d/or 
fres h tiss ue) f or res earc h p ur p oses. I n a d diti o n, s u bjects will be re q uire d, if c o nse nt 
is pr o vi de d, t o all o w us e of o p erati ve tiss ue at ti me of disease rec urre n ce f or 
researc h p ur p os es (see bel o w).  
7. 2. 1  C ollecti o n of P ost -S ur gi c al Tiss ue f or C orrel ati ve St u dies  
All  s u bjects will  be  as ke d t o pr o vi de  c o nse nt  f or a nal ysis  of  p ost -s ur gical tiss ue. 
A d diti o nall y,  i n t he e ve nt of  dise ase rec urre nce, s u bjects ma y  be  offere d  a n o pti o nal  
sec o n d bi o ps y  t o o btai n  a sa m ple of  t u m or tiss ue. Bl o o d  sa m ples will  be  c ollecte d 
per  a b o ve a n d use d  f or f ut ure u ns pecifie d  researc h if t he patie nt  pr o vi des  c o nse nt.   
 
P ost -s ur gical tiss ue will be e val uate d f or t he i m m u n os u p pressi ve bi o mar ker P D -L 1 
o n t u m or cells usi n g  t he Ve nta na P D-L 1 ( S P 2 6 3) assa y, w hic h is a q ualitati ve I H C 
assa y.  I H C e x pressi o n a nal yses c o nsi der t he mar ker i nte nsit y a n d stai ni n g patter n 
i ncl u di n g distri b uti o n ( perce nta ge of p ositi ve cells) a n d i nte nsit y i n t he f or m of H -
sc ore. I H C a nal ysis a n d s c ori n g will be perf or me d b y a certifie d p at h ol o gist usi n g 
i ma ge a nal ysis s oft ware .   
 
O utc o me fr o m t he a nal ysis will be cal c ulate d acc or di n g t o t he H -s c ore. T he H-sc ore 
ra n ges fr o m 0 t o 3 0 0, a n d it c o nsi ders b ot h i nte nsit y of t he I H C (fr o m 0 t o 3) a n d 
distri b uti o n ( perce nt a ge 
of t he tar g et 
cells 
p ositi ve, fr o m 
0 t o 
1 0 0). 
He mat o x yli n/e osi n a n d P D -L 1 -stai ne d secti o ns will be re vie we d b y a pat h ol o gist 
a n d t he q ua ntit y a n d l ocati o n of P D -L 1 stai ni n g will be q ua ntifie d. T he prese nce 
a n d t y pe of i ntrat u m oral l y m p h oc ytic i nfiltrati o n as deter mi ne d b y  b ut n ot li mite d 
t o C D 4, C D 8, C D 2 5, F O X P 3 will be  q ua ntifie d fr o m tiss ue s peci me ns  per bel o w . 
E x pressi o n of P D -L 1 will be pri oritize d .  
7. 2. 2  P ost -s ur gic al Tiss ue b y Fl o w C yt o metr y  
P ost -s ur gical tiss ue will be e val uate d f or t he e x pressi o n le vel a n d l ocalizati o n of 
mar kers of i nfla m mat or y/i m m u ne si g nat ure t hat ma y i ncl u de b ut n ot be li mite d t o 
C D 4, C D 8, C D 2 5, F O X P 3 a n d T U N E L/ Cas pas e 3 b y fl o w c yt o metr y . 
7. 3  
H a n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Rese a rc h  
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 n cer Ce nter ( L C C C) Tiss ue Pr oc ure m e 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 7 2 5 St u d y 
La b orat or y Ma n u al a n d st ore d i n c o ntai ners wit h c o ntr olle d ac cess. Eac h sa m ple 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 6  
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 b e o n t he s peci me n la bel.  I nf or mati o n a b o ut t he p atie nt’s 
disease will be li n ke d t o t he s peci me ns st or e d i n t he re p osit or y d ata base. T P F -
associate 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 d ata 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. So 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 
patie nt’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 patie nt’s ca ncer de vel o p e 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 res earc h p ur p oses o utli n e d 
wit hi n t he c o nfi nes of t his pr ot oc ol. Sa m ples will be discar de d/ d estr o ye d after 
rele va nt d ata are c ollecte d f or t his st u d y, u nless c o nse nt was o btai ne d fr o m t he 
patie nt t o u se tiss ue f or ot her res earc h p ur p oses (e. g., T P F c o ns e nt f or m was 
si g ne d b y t he p atie nt).  I n t his circ u msta nce, t here is n o ti me li mit o n h o w l o n g 
bi os peci me ns ma y be st ore d.  
o  T he i n vesti gat or m ust a gree 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 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 (e. g., Use of left o ver s peci me ns will re q uire a pr ot oc ol o utli ni n g t he 
researc h pla n f or bi os peci me n use).  
7. 4  
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 n ce wit h  all 
a p plica ble U ni versit y of N ort h Car oli na ( U N C) R esearc h P olicies a n d Pr oce d ures 
a n d all a p plica ble Fe deral a n d state la ws a n d re g ul ati 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 nt a 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 p erf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will 
o btai n c o nse nt a n d asse nt ( u nless a wai v er is gra nte d), 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 P r 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 res earc h s u bjects d uri n g a n d after t he 
st u d y.  
7. 5  
Assess m e nt of S afet y  
A n y patie nt w h o recei ves at least  o ne d ose of st u d y t hera p y o n t his pr ot oc ol will be 
e val ua ble f or t o xicit y.  Eac h patie nt 
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 bl e.  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 5. 0 .   

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 7  
7. 6  
Assess m e nt of Effic ac y  
Disease  free s ur vi val will  be  assesse d  b y  eit her p h ysical  e xa m or  at pre -s pecifie d 
i nter val i ma gi n g as a dic h ot o m o us  varia ble  base d  o n  e vi de nce of  t u m or rec urre nce 
( yes or  n o)  per  cli nicia n’s  assess me nt . O verall  s ur vi val will  be  assesse d  at f oll o w 
u p  visits  as a dic h ot o m o us  varia ble  ( yes or  n o).   
8. 0  
A D V E R S E E V E N T S  
8. 1  
Defi niti o n s  
8. 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 n ce (e. 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 diseas e te m p orall y ass ociate d wit h t he us e of a 
dr u g) i n a patie nt or cli nical i n vesti gati o n 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 us al 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 bl e 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 ociat e d wit h 
t he use of a me di ci nal pr o d uct, w het her or n ot rel ate d t o t he me dici nal pr o d uct.   
 
T he ter m A E is use d t o i ncl u de b ot h seri o us a n d n o n -seri o us A Es. 
 
H os pitalizati o n f or elect i 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 b e 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.  Diseas e 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.  
8. 1. 2  S us pecte d A d verse Re a cti o n  ( S A R) 
A s us pecte d a d vers e 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.   R e 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 m ea ns a n y a d verse e ve nt ca use d b y a dr u g.   
 
Ca usali t 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 rel ati o ns 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 h a 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 h e diseas e u n der 
i n vesti gati o n, a n d a n y ot her u n d erl 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 us e of t he A E: 
•  Si n gle occ urre n ce 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 p atic 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 n ces of a n e v e 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 n ce fr o m o ne or m ulti ple st u dies w o ul d be 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 8  
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 o n a ble 
p ossi bility  t hat t he dr u g ca use d t he e v e nt.   
•  A n a g gre g ate a n al 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 u e 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 ori cal c o ntr ol gr o u p 
8. 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 p ecte 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 m ati o n (e. g., I n vesti gat or’s Br oc h ure 
(I B) f or a n u n a p pr o ve d i n vesti gati o nal pr o d uct or pac ka g e i nsert/s u m mar y of 
pr o d uct c haract eristics f or a n a p pr o ve d pr o d uct).  U ne x pect e 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.   
8. 1. 4  Seri o us A E  or S A R  
A seri o us a d verse e ve nt is a n A E occ urri n g d uri n g a n y st u d y p hase  (i.e., scree ni n g, 
r u n-i n, treat me nt, was h-o ut, f oll o w -u p), at a n y d ose of t he st u d y dr u g : 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 h er 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 hr eate 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 ntial disr u pti o n 
of t he a bilit y t o c o n d uct n or mal life f u ncti o ns;  
•  I m p ort a 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 p erie n ce  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 patie nt or 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.  F or re p orti n g p ur p oses, als o c o nsi der t he occ urre nces of 
p re g na nc y as a n e ve nt w hic h m ust be re p orte d as a n i m p orta nt me dical 
e ve nt.  
 
* 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 
pr i 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. 
 
T he ca usalit y of S A Es (t heir rel ati 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(s) a n d c o m m u nicate d t o Astra Ze neca  
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
3 9  
Pre g na nc y t hat occ urs wi t hi n 9 0 da ys of t he last d ose of d ur val u ma b m ust als o be 
re p orte d as an i m p orta nt  me dical e ve nt . 
8. 2  
D ur v al u m a b A Es of S peci al I nterest  
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 v esti gati o nal Pr o d uct a n d ma y re q uir e 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 v e nts i n or der t o c haract erize a n d u n d ersta n d t h e 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 ne-s u p pressa nts 
a n d/ or h or m o ne re place me nt t hera p y. T hes e 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 i m m u ne -me diate d a d vers e 
e ve nt (i m A E) is d efi ne d as a n A E SI t hat is ass oci ate 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 i m 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 nfecti o us, meta b olic, t o xi n, or ot her 
eti ol o gic ca uses of t he i m A E.  
If t he I n v esti gat or has a n y q uesti o ns i n re gar d t o a n e ve nt bei n g a n i m A E, t he 
I n v esti 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 b serve d wit h d ur v al u m a b i ncl u de: 
•  Diarr hea / C olitis    
•  I ntesti nal p erf orati o n 
•  P ne u m o nitis / I L D  
•  H e patitis / tra nsa mi nas e i ncreases  Ne ur o pat h y / ne ur o m usc ular t o xicit y (e. g. 
G uillai n -Barré, a n d m yast he nia gra vis)  
•  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 a dre nal 
i ns ufficie nc y, dia b etes i nsi pi d us, h y per- a n d h y p ot h yr oi dis m , t h yr oi ditis, a n d 
t y pe I di a 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 ot e ntial 
i m m u ne-me diate d aeti ol o g y i ncl u de, b ut are n ot li mite d t o, pericar ditis, 
sarc oi d osis, u veitis a n d ot her e ve nts i n v ol vi n g t he e yes ki n, hae ma t ol o gical a n d 
r he u mat ol o gical e ve nts, vasc ulitis, n o n-i nfecti o us me ni n gitis a n d n o n-i nfecti o us 
e nce p h alitis  
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 0  
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 v esti gat or’s 
Br oc h ure. 
M ore s pecific 
g ui deli nes f or t heir e val u ati o n a n d treat me nt are d escri be d i n detail i n 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 (see A p pe n di x 1 2. 0 ). 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 g at or i n t he 
e xercis e of his/ her cli nic al 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 A Es 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.  
 
If ne w or 
w orse ni n g p ul m o nar y s y m pt o ms (e. g. d ys p nea) or ra di ol o gical 
a b n or malit y s u g gesti ve of p ne u m o nitis/i nterstitial l u n g disease is o bser ve d, t o xicit y 
ma na ge me nt as des cri b e d i n detail i n 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 (see A p pe n di x 1 2. 0 ) will be a p plie d. T he res ults of t he f ull 
dia g n ostic w or k u p (i n cl u di n g hi g h -res ol uti o n c o m p ute d t o m o gra p h y ( H R C T), 
bl o o d a n d s p ut u m c ult ure, he mat ol o gical para met ers et c .) will be ca pt ure d i n t he 
e C R F. It is str o n gl y rec o m me n de d t o perf or m a f ull dia g n ostic w or k u p, t o e xcl u de 
alter nati ve ca us es s uc h as l y m p ha n gitic carci n o mat osis, i nfecti o n, aller g y, 
car di o ge nic e de ma, or p ul m o nar y he m orr ha g e. I n t he prese nce of c o nfir mat or y 
H R C T  sca ns w here ot her ca uses of res pir at or y s y m pt o ms ha ve bee n e xcl u de d, a 
dia g n osis of p ne u m o nitis (I L D) s h o ul d be c o nsi dere d a n d t he D osi n g M o dificati o n 
a n d T o xicit y Ma na ge m e nt G ui deli nes s h o ul d be f oll o we d.   
 
 
P ne u m o nitis (I L D) i n vesti g ati o n  
T he f oll o wi n g assess m e nts, a n d a d diti o nal assess me nts if re q uir e d, will be 
perf or me d t o e n ha nce t he i n vesti gati o n a n d dia g n osis of p ote ntial cases of 
p ne u m o nitis. T he res ults of t he assess me nt will be c ollecte d.  
•  P h ysical e xa mi nati o n  
− Si g ns a n d s y m pt o ms (c o u g h, s h ort ness of breat h a n d p yre xia, etc.) 
i ncl u di n g a usc ultati o n f or l u n g fiel d will be assess e d. 
•  S p O 2  
− Sat urati o n of peri p heral o x y ge n ( S p O 2)  
•  Ot her ite ms  
− W he n p ne u m o nitis (I L D) is s us pect e d d uri n g st u d y treat me nt  I L D 
mar kers a n d t u m or mar k ers ma y be o btai n e d if felt a p pr o priate b y st u d y 
i n vesti gat ors 
 
A d diti o nal Cli nical c he mistr y:  c-reacti ve pr otei n a n d lactate de h y dr o ge nas e  (C R P, 
L D H ) 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 1  
8. 3  
D oc u me nt ati o n of n o n -seri o us A Es or S A Rs  
F or n o n -s eri o us AE s or S A Rs, d oc u me ntati o n m ust be gi n  fr o m ti me of si g nat ure of 
i nf or me d c o nse nt, t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w-u p 
peri o d ( 9 0 da ys after t he last d ose of d ur val u ma b) .  
 
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 patie nt. 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 v e 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 patie nt 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 patie nt is c o nsi dere d t o h a ve c o nfir me d P D a n d will ha ve 
n o f urt her t u m or ass ess me nts.  
 
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 re s ol uti o n, u ntil t he 
patie nt ret ur ns t o bas eli 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 h at it will re mai n c hr o nic, e v e n if t his e xte n ds be y o n d st u d y 
partici pati o n.  
 
C ollecte d i nf or mati o n s h o ul d be rec or de d i n t he Case Re p ort F or ms ( C R F) f or t hat 
patie nt.  Please i ncl u d e a descri pti o n of t he e v e 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 .  
 
A d verse e ve nts will be rec or de d usi n g a rec o g nize d me dical ter m or di a g n osis t hat 
acc uratel y reflects t he e v e nt  ( C T C A E 5. 0 Me d dra ter ms). A Es will b e ass esse d b y 
t he i n vesti gat or f or s e verit y, relati o ns hi p t o t h e 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 v ari a bles will be c ollecte d f or e ac h A E:  
•  A E ( ver bati m)  
•  T he date w h e n t he A E st arte d a n d st o p pe d  
•  T he ma xi m u m C T C A E gra de re p orte d  
•  C ha n ges i n C T C A E gra d e  
•  W het her t he A E is seri o us or n ot  
•  I n v esti gat or ca us alit y rati n g a gai nst t he I Ps ( yes or n o) 
•  Acti o n ta ke n wit h re g ar d t o I Ps  
•  A d mi nistrati o n of treat me nt f or t he A E  
•  O utc o me  
 
I n a d diti o n, t he f oll o wi n g v ari a bles will be c ollecte d f or S A Es: 
•  Date t he A E met criteria f or S A E  
•  Date t he I n v esti gat or beca me a ware of t he S A E  
•  Seri o us ness criteria f ulfille d  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 2  
•  Date of h os pitalizati o n  
•  Date of disc h ar ge  
•  Pr o ba ble ca us e of deat h  
•  Date of deat h  
•  W het her a n a ut o ps y was perf or me d  
•  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 ot her me dicati o n  
•  Descri pti o n of t he S A E  
 
T he gra di n g scales f o u n d i n t he re vise d N CI C T C A E versi o n 5. 0  will be utilize d 
f or all e ve nts wit h a n assi g ne d C T C A E gra di n g. F or t h ose e ve nts wit h o ut assi g ne d 
C T C A E gra des, t he rec o m me n dati o n i n t he C T C A E criteria t hat c o n verts mil d, 
m o derate, a n d se vere e v e nts i nt o C T C A E gra des s h o ul d be use d. A c o p y of t he 
C T C A E versi o n 5. 0  ca n be d o w nl oa de d fr o m t he Ca ncer T h era p y E v al uati o n 
Pr o gra m we bsite ( htt p://cte p.ca ncer. g o v ). 
 
8. 3. 1  H y’s L a w  
Cases w here a patie nt s h o ws ele vati o ns i n li ver bi oc he mistr y ma y re q uire f urt her 
e val uati o n a n d occ urre n ces of A S T o r A L T ≥3 × U L N t o get her wit h t otal bilir u bi n 
≥2 ×  U L N ma y nee d t o b e re p ort e d as S A Es.  
8. 4  
S A E s or Seri o us S A R s  
8. 4. 1  Ti mi n g  
After i nf or me d c o ns e 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 v e nti o n will be c ollect e 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 n ce 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 m e 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 after treat me nt is disc o nti n ue d.  
8. 4. 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 nc ore ™ f or 
t hat patie nt wit hi n 2 4 h o urs of learni n g of its occ urre n ce .  A d diti o nall y, t he 
M ultice nter  Pr oject Ma n a 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 .  
8. 5  
A d verse E ve nt R e p orti n g  
8. 5. 1  I RB 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 u alif 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 3  
s yste m wit hi n 7 da ys of t he I n vesti gat or b ec o mi n g a ware of t h e 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 o cc urre nce. 
 
M ultice nter  sites:   
•  F or m ultice nter  sites usi n g a l ocal I R B of rec or d, please s u b mit a d verse 
e ve nts per l oc al I R B p olic y.  
 
Pre g na nc y  
Pre g na ncies a n d s us p ecte d pre g na n cies (i ncl u di n g a p ositi ve pre g na n c y test 
re gar dl ess of a g e or dise ase state) of a fe male s u bj ect occ urri n g w hile t he s u bject is 
o n st u d y, or wit hi n 9 0  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 i m p orta nt me dical e ve nts.  T he patie nt is t o be disc o nti n ue d i m me diatel y fr o m 
t he st u d y.  
 
F or m ultice nter  sites, 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 t he M ultice nter  Pr oject Ma na ger i m me diatel y ( wit hi n 2 4 
h o urs)  via email ( prefera ble) t o C P O M ultice nter @ me d. u nc.e d u  or facsi mile t o 9 1 9-
9 6 6 -4 3 0 0.  T he M ultice nter  Pr oject M a na g er will t he n re p ort t he e ve nt t o t he 
F u n di n g S o urce (see re q uire me nts bel o w) .  T he fe male s u bject 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 p erie nce d i n re pr o d ucti ve t o xicit y 
f or f urt her e val u ati o n a n d c o u nseli n g. 
 
T he I n v esti 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 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)  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  M ultice nter  Pr oject 
Ma na ger . If t he o utc o m e of t he pre g na nc y was a b n or mal (e. g., s p o nt a n e o us or 
t hera pe utic a b orti o n), t he I n v esti gat or s h o ul d re port 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 h e seri o us criteria, it m ust be re p orte d 
as a n S A E.   
8. 5. 2  Astr a Ze nec a Re p orti n g Re q uire me nts:  
Astra Ze neca/ Me dI m m u n e ret ai ns 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 
patie nt 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.  
 
All S A Es will be re p orte d,  w het her or n ot c o nsi dere d ca usall y relat e 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 d a ys after t he last d o s e of d ur val u ma b or u ntil t he i nitiati o n of 
alter nati ve a ntica n cer t hera p y. T h e 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 ul at or y A ut h orit y of t he S A E as per 
l ocal re q uir e me nts. 
 
T he i n vesti gat or a n d/ or s p o ns or m ust i nf or m t he F D A, vi a 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 n ce wit h 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 4  
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 Z e neca. A c o p y of t he Me d Watc h/ A d E E Rs re p ort m ust be e maile 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 m ati o n a n d e ns ure t hat t h e F D A 
recei v es 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 t o 
e ns ure t hat t hese re p orts are als o s u b mitte d t o Astra Ze n eca at t he sa me ti m e.  
* A c over p a ge  s h o ul d acc o m pa n y t he Me d W at c h/ A d E E Rs  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 be r 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 n ce n u m ber ( E S R  1 7 -1 2 7 4 1 ) 
* 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 p a ge, t he 
c a us ality of e ve nts i n rel ati o n t o all st u dy medic ati o ns  a n d if t he S A E is r el ate d t o 
dise ase pr o gressi o n , as deter mi ne d b y t he pri n ci pal i n vesti gat or. 
 
* Se n d S A E re p ort a n d acc o m p a nyi n g c over p a ge by w ay of e m ail t o 
Astr a Ze nec a’s desi g n ate d m ail b o x:   
A E Mail b o x Cli nical Trial T C S @astraze neca. c o m  
 
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 to t he F D A still nee d 
t o be re p orte d t o Astra Z e 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 vers e e v e 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 cir c u msta nce less fre q ue ntl y t ha n q uarterl y.   
8. 5. 2. 1  Re p orti n g of de at hs t o Astr a Ze nec a  
All deat hs t hat occ ur d uri n g t he st u d y, or wit hi n t he pr ot oc ol -defi ne d 9 0 -d a y  
p ost -last d ose of d ur val u ma b safet y f oll o w-u p p eri o d m ust be re p orte d t o 
Astra Ze neca as f oll o ws:  
•  Deat h t hat is clearl y t he res ult of disease pr o gressi o n s h o ul d be d oc u me nte d 
b ut s h o ul d n ot be re p orte d as a n S A E.  
•  W here deat h is n ot d ue ( or n ot clearl y d u e) t o pr o gressi o n of t h e diseas e 
u n der st u d y, t he A E ca usi n g t he deat h m ust be re p orte d t o Astra Ze neca as 
a S A E wit hi n 2 4  h o urs . T he re p ort s h o ul d c o ntai n a c om me nt re gar di n g t he 
c o-i n v ol ve me nt of pr o gressi o n of disease, if a p pr o priate, a n d s h o ul d assi g n 
mai n a n d c o ntri b ut or y ca uses of deat h.  
•  Deat hs wit h a n u n k n o w n ca use s h o ul d al w a ys be re p orte d as a S A E.  
8. 5. 2. 2  O ver d ose  
Use of d ur val u ma b i n d oses i n e xcess of t hat s pecifie d i n t he pr ot o c ol is 
c o nsi dere d t o be a n o ver d ose. T here is c urre ntl y n o s pecific tr eat me nt i n t he e ve nt 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 5  
of o ver d ose of d ur val u ma b b  a n d p ossi ble s y m pt o ms of o ver d ose are n ot 
esta blis he d.  
•  A n o ver d ose wi t h ass oci ate d A Es will be rec or de d as t he A E dia g n osis or 
s y m pt o ms i n t he rele va nt A E m o d ules of t he e C R F a n d i n t he O ver d ose 
e C R F m o d ule.  
•  A n o ver d ose wit h o ut ass ociate d s y m pt o ms will o nl y be re p orte d i n t he 
O ver d ose e C R F m o d ule.  
If a n o v er d ose of a n AstraZe n eca I P occ urs i n t h e c o urse of t he st u d y, t he n t he 
I n v esti gat or or ot her site pers o n nel 
will i nf or m a p pr o priate 
Astra Z e neca 
re pres e ntati ves i m me diatel y, or n o l ater t h a n 2 4 h o urs  of w he n he or s he 
bec o mes a w are of it.  
 
T he desi g nate d Astr a Ze neca re pres e 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.  
 
F or o ver d os es ass ociate d wit h a n S A E, t he sta n dar d re p orti n g ti meli nes a p pl y. 
F or ot her o ver d oses, re p orti n g m us t occ ur wit hi n 3 0 da ys. 
8. 5. 2. 3  Pre g n a nc y  
All pre g na ncies a n d o utc o mes of pre g n a nc y s h o ul d be re p ort e d t o Astra Ze neca 
e xce pt f or p re g n a nc y dis c o vere d b ef ore t he st u d y patie nt has recei ve d a n y st u d y 
dr u gs.  
8. 5. 2. 4  M ater n al e x p os ure  
If a p atie nt bec o m es pre g na nt d uri n g t he c o urse of t he st u d y, t he I P s h o ul d be 
disc o nti n ue d i m me diatel 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 I P 
u n der st u d y ma y h a ve i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve 
me dicati o n. 
C o n ge nital a b n or maliti es 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 h e 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 n c 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 nt e d e ve n if t he 
patie nt was disc o nti n ue d fr o m t he st u d y.  
  
If a n y pre g n a nc y o cc urs i n t he c o urse of t he st u d y, t he n t he I n v esti gat or or ot her 
site pers o n nel s h o ul d i nf or m t he a p pr opriate Astra Ze neca re prese ntati ves wit hi n 
1 da y, i.e., i m me diatel y, b ut n o l ater t h a 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 Astr a Ze neca re pres e 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 6  
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 n a ncies.  
 
T he sa me ti meli nes a p pl y w he n o utc o me i nf or m ati o n is a vaila ble.  
8. 5. 2. 5  P ater n al e x p os ure  
Male patie nts 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 aft er t he last d ose of d ur val u ma b.  
 
Pre g na nc y of t he patie nt’s part ner is n ot c o nsi dere d t o be a n A E. H o we v er, t he 
o utc o me of all pre g na n cies (s p o nta ne o us 
miscarria ge, electi ve ter mi n ati o n, 
ect o pic pre g na n c y, n or mal birt h, or c o n ge nital a b n or malit y) occ urri n g fr o m 
9 0  da ys after t he last d ose of d ur val u ma b m o n ot hera p y, 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 rec ei 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 patie nt’s p art 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.  
8. 5. 2. 6  Me dic ati o n err o r  
F or t he p ur p oses of t his cli nical st u d y a me dicati o n err or is a n u ni nte n de d fail ure 
or mista ke i n t he treat m e nt pr ocess f or a n Astra Ze neca st u d y dr u g t hat eit her 
ca uses har m t o t he patie nt or has t he p ote ntial t o ca use har m t o t he patie nt. A 
me dicati o n err or is n ot lac k of efficac y of t he dr u g, b ut rat her a h u ma n or pr ocess 
relate d fail ure w hile t he dr u g is i n c o ntr ol of t he st u d y site staff or patie nt. 
 
Me dicati o n er r or i ncl u des sit uati o ns w here a n err or:  
•  O cc urre d  
•  W as i de ntifie d a n d i nterce pte d bef ore t he patie nt r ecei ve d t h e dr u g  
•  D i d n ot occ ur, b ut circ u msta nces were rec o g nized  t hat c o ul d h a ve le d t o a n 
err or  
•  E xa m ples of e ve nts t o be re p orte d i n cli nical st u dies as me dicati o n err ors: 
•  Dr u g na me c o nf usi o n  
•  Dis pe nsi n g err or e. g. me dicati o n pre p are d i nc orrectl y, e ve n 
if it was n ot act uall y gi ve n t o t he patie nt 
•  Dr u g n ot a d mi nistere d as i n dicate d, f or e xa m ple, wr o n g 
r o ute or wr o n g site of a d mi nistrati o n 
•  Dr u g n ot ta ke n as i n dicate d e. g. ta blet diss ol ve d i n water 
w he n it s h o ul d be ta ke n as a s oli d ta blet  
•  Dr u g n ot st ore d as i nstr ucte d e. g. ke pt i n t he fri d g e w he n it 
s h o ul d be at r o o m te m perat ure  
•  Wr o n g patie nt r ecei ve d t he me dicati o n  
•  Wr o n g dr u g a d mi nistere d t o pati e nt  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 7  
•  E xa m ples of e ve nts t hat d o n ot re q uire re p orti n g as me di cati o n err ors i n 
cli nical st u dies:  
o  Patie nt acci de ntall y 
misse d dr u g d ose(s) e. g. f or g ot t o ta ke 
me dicati o n  
o  Acci de ntal o v er d ose ( will be ca pt ure d as a n o v er d ose)  
o  Patie nt faile d t o ret ur n u n use d me dicati o n or e m pt y pac ka gi n g  
o  Err ors relate d t o b ac k gr o u n d a n d resc ue m e dicati o n, or sta n dar d of 
care me dicati o n i n o p e n la bel st u dies, e v e n if a n A str a Ze neca 
pr o d uct  
•  Me dicati o n err ors are n ot re gar de d as A Es b ut A Es ma y oc c ur as a 
c o nse q ue nce of t he m e dicati o n err or.  
 
If a m e dicati o n err or occ urs i n t he c o urse of t he st u d y, t he n t he I n v esti gat or or 
ot her site pers o n nel i nf or ms t he a p pr o priate Astra Ze neca re pres e ntati ves wit hi n 
1 da y i.e., i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n h e or s he b ec o mes 
a ware of it.  
 
T he desi g nate d Astra Z e n eca re prese ntati ve w or ks wit h t he  I n vesti gat or t o e ns ure 
t hat all rele va nt i nf or m ati o n is c o m plete d wit hi n 1 or 5 cale n dar da ys if t h ere is a n 
S A E ass ociate d wit h t he me dicati o n err or a n d wit hi n 3 0 da ys f or all ot her 
me dicati o n err ors.  
8. 5. 3  F D A E x pe dite d Re p orti n g re q uire me nts  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  ( S A Rs) t hat is b ot h seri o us 
a n d u ne x pecte d t o t he F D A. Please refer t o Secti o n 8. 1. 2  f or t he defi niti o n of a n 
S A R.  
 
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.  
 
Ti mi n g  
F D A m ust be n otifie d of p ote ntial seri o us ris ks wit hi n 1 5 cale n dar da ys after t he 
s p o ns or deter mi nes t he e ve nt re q uir es re p orti n g. F D A 
m ust be n otifie d of 
u ne x pecte d fatal or life -t hreate ni n g s us pecte d a d v erse reacti o ns as s o o n as p ossi ble 
b ut i n n o case l ater t h a n 7 cale n dar da ys after t h e s p o ns or’s i nitial recei pt of t he 
i nf or mati o n. T he s p o ns or m ust be n otifie d of t he S A E b y t he i n vesti gat or wit hi n 2 4 
h o urs of t he e ve nt  a n d t h us t he M ultice nter Pr oject Ma na ger m ust be n otifie d wit hi n  
2 4 h o urs of t he e ve nt.  If t he res ults of a s p o ns or’s i n vesti gati o n s h o w t hat a n a d verse 
e ve nt n ot i nitiall y deter mi ne d t o be re p orta ble is re p orta ble, t he s p o ns or m ust re p ort 
s uc h s us pecte d a d verse reacti o n i n a n I N D safet y re p ort 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 d eter mi nati o n is ma de.  
 
F oll o w -u p  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 8  
T he s p o ns or m ust pr o m ptl y i n vesti gate all safet y i nf or mati o n it recei v es. R ele va nt 
f oll o w-u p i nf or mati o n t o a n I N D safet y re p ort m ust be s u b mitte d as s o o n as t he 
i nf or mati o n is a vaila ble.  
 
N otific ati o n of I nvesti g at ors  
T he s p o ns or m ust n otif y all partici pati n g i n vesti gat ors (i.e., all i n vesti g at ors t o 
w h o m t he s p o ns or is pr o vi di n g dr u g u n der its I N Ds or u n der a n y i n vesti gat or’s 
I N D) i n a n I N D safet y re p ort of p otential seri o us ris ks, fr o m cli nical trials or a n y 
ot her s o urce, as s o o n as p ossi ble, b ut i n n o case l ater t ha n 1 5 cal e n dar d a 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.  
 
Pr ocess  
If t he s p o ns or dee ms t hat a n e v e nt is b ot h a seri o us a d verse reacti o n ( 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 n C ore T M ) 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 p ecte 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 uir e d or a vaila bl e, 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 h ere 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 s u b mitte d o n Me d Watc h b y t he st u d y c o or di nat or.  
 
T he Me d Watc h f or m s h o ul d be e maile d fa x e d t o t he M ultice nter  Pr oject M a na ger at 
C P O M ultice nter 
@ me d. u nc.e d u 
or 
9 1 9 -9 6 6 -4 3 0 0 
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 v e nt a n d ca usalit y.  T he 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 0 A  f or m ca n b e 
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 ur e a n d access f or m 3 5 0 0A , a n d n ot f or m 3 5 0 0).  
 
T he 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 
m ultice nter site of all s eri o us a n d u ne x pecte d S A Rs re p orte d t o t he F D A  as s o o n as 
p ossi ble.   
 
A d diti o n al Re p orti n g Re q uire me nts  
T he f oll o wi n g a d diti o nal ite ms m ust be re p orte d vi a I N D safet y r e p ort:  
•  Fi n di n gs fr o m ot her st u dies. T he s p o ns or m ust re p ort a n y fi n di n gs fr o m 
e pi de mi ol o gical st u dies, p o ole d a nal ysis of m ulti ple st u dies, or cli nical 
st u dies, w het her or n ot c o n d ucte d u n d er a n I N D, a n d w het her or n ot 
c o n d ucte d b y t he s p o ns or, t hat s u g gest a si g nifica nt ris k t o h u ma ns e x p os e d 
t o t he dr u g.  
•  Fi n di n gs fr o m a ni m al or i n vitr o testi n g. T he s p o ns or m ust re p ort a n y 
fi n di n gs fr o m a ni mal or i n vitr o testi n g, w het her or n ot c o n d ucte d b y t he 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
4 9  
s p o ns or, t hat s u g gest a si g nifica nt ris k i n h u ma ns e x p ose d t o t he dr u g, s u c h 
as re p orts of m uta ge nicit y, terat o ge ni cit y, or carci n o ge nicit y, or re p orts of 
si g nifica nt or ga n t o xicit y at or near t he e x p ecte d h u ma n e x p os ure. 
•  I ncre ase d r ate of o cc urre nce of seri o us s us pecte d a dverse re a cti o ns. 
 
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 n ce 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 uir e 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 ulat i o ns/ g ui da nces.  
8. 6  
D at a a n d S afet y M o nit o ri n g Pl a n  
T he Pri nci pal I n vesti gat or s 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).  T he Pri nci pal I n vesti gat ors res p o nsi ble f or t he care of all s u bjects in t his 
st u d y will als o o vers ee t he c o n d u ct of safet y dat a re vi e w meeti n gs o n a re g ular 
basis. Bi -wee kl y safet y re vie w meeti n gs  will be i nstit ute d  u p o n st u d y e nr oll me nt.  
as s o o n as a s u bject(s) e nters t he st u d y, has recei ve d treat me nt wit h d ur val u ma b 
a n d ra diati o n t hera p y  d uri n g C ycles 1 -3 , a n d t he d uri n g t he p ost-tr eat me nt 
e val uati o n peri o d. T h ese meeti n gs will i ncl u de t he i n vesti gat ors  as well as st u d y 
c o or di nat ors , d ata c o or di nat ors , re g ul at or y ass o ciates, cli nical data ma na ge me nt 
ass ociates , 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 me eti 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 ul at or y iss ues, data c ollecti o n, etc. 
A n a ge n d a a n d mi n ute s will be ge n erate d f or eac h meeti n g t o d o c u me nt atte n dees 
a n d s u bject data re vie we d.  
 
Meeti n g  s u m maries will be a vaila ble f or i ns pe cti 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 h ar 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 n cl 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 Res earc 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 n c 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 o ll o wi n g i nf or mati o n f or 
re vie w: 1) safet y a n d accr ual d ata i ncl u di n g t he n u m ber of patie nts tr eate 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 nse dat a; 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 .   
9. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 0  
9. 1  
St u d y Desi g n/ St u d y E n d p oi nts  
Pri mar y e n d p oi nt  is t o esti mate me dia n 3 year disease free s ur vi v al ( D F S) i n 
patie nts wit h i nter me diate -ris k H N S C C treate d wit h a dj u va nt d ur val u m a b wit h 
ra di ot hera p y.   
9. 2  
S a m ple Size, Accr u al  a n d D ur ati o n of Accr u al  
O ur e val ua ble st u d y sa m ple size ( N t otal) is 1 7, a n d we will e nr oll 1 8 t o all o w f or 
p ossi ble n o n -e val ua ble p atie nts .  Base d o n a hist orical c o ntr ol of 1 0 yr D F S is 1 9 %  
( C o o per, R T O G 1 0 1 6), t he 3 year D F S is a p pr o xi mate d t o be 6 0. 8 %.  Base d o n t his 
calc ulati o n, we will nee d a sa m ple size of 1 7 patie nts , t o de tect a 2 3 % differe nce i n 
3 year D F S wit h 8 0 % p o wer (ta bl e bel o w)  a n d o n e-si de d al p ha of 0. 1.  
 
 
 
 
Differe nce fr o m 
Hist orical C o ntr ol   
1 0 %  
2 0 %  
2 3 %  
2 5 %  
  Test si g nific a nce 
le vel,  
0. 0 5 0  
0. 0 5 0  
0. 0 1 0  
0. 0 5 0  
  1 or 2 si de d test ?  
1  
1  
1  
1  
      N ull h y p ot hesis 
pr o p orti o n,  0 
0. 6 0 8  
0. 6 0 8  
0. 6 0 8  
0. 6 0 8  
      Alter n ati ve 
pr o p orti o n,  A  
0. 7 0 8  
0. 8 0 8  
0. 8 3 8  
0. 8 5 8  
  P o wer ( % )  
8 0  
8 0  
8 0  
8 0  
  n  
1 4 1  
3 3  
1 7  
2 0  
 
9. 3  
D at a A n al ysi s Pl a ns 
A n alytic pl a n f or sec o n d ary o bjective : 
T he rat e of g ra de 3-5 ac ute t o xicit y  will be t a b ulate d as descri be d a b o ve t o 
deter mi ne w het her t he criteri o n f or safet y has bee n met. A c o nfi de nce i nter val f or 
t his rate will be calc ulate d base d o n t he met h o ds of K o y o ma T, a n d C he n H. Rates 
of i n di vi d ual t y pes/ gra des of t o xicities will als o be re p ort e d  [3 0 ]. 
 
Me dia n  D F S  will  be  esti mate d usi n g  t he Ka pla n  Meier  met h o d.   
 
A n alytic pl a n f or a d diti o n al sec o n d ary o bjective: 
1. Gra de 3 -5 c hr o ni c t o xicities will be ta b ulate d b y t y pe a n d gra d e.  
 
2 . Me dia n  O S  will  be  esti mate d usi n g  t he Ka pla n  Meier  met h o d .  
 
3 . P D -LI  e x pressi o n  will  be  meas ure d  fr o m bas eli ne  t u m or sa m ple usi n g  I H C. 
E x pressi o n  will  be  c orrelate d  wit h  D F S  usi n g  t he Ka pla n  Meier  met h o d.   A  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 1  
L o g -ra n k test will  c o m pare D F S  bet wee n  t h ose wit h  a n d wit h o ut  P D -L 1  
e x pressi o n.    
 
A n alytic pl a n f or e x pl or at ory O bje ctives:  
1 . H P V stat us will be meas ure d per i nstit uti o nal S O C, t y picall y p 1 6 a n d/ or H P V 
FI S H . T he Ka pl a n 
Mei er met h o d will be use d  a n d a L o g -ra n k test will 
c o m pare D F S bet w ee n H P V p ositi ve/ ne gati ve patie nts.  
 
2 . T u m or i nfiltrati n g le vel ( TI L) ex pressi o n will be meas ure d b y fl o w c yt o metr y 
at baseli ne a n d if p ossi ble at t u m or rec urre n ce.  T h ese le vels will b e c o m pare d 
at t hese ti me p oi n ts usi n g paire d t -tests ( pre vs fi nal p ost assess me nt) or 
l o n git u di nal m o dels t hat acc o u nt f or re p eate d assess me nts w he n a vaila ble.  
T hese m o dels ca n be br oa de ne d t o all o w f or c o m paris o ns t o be ma de acr oss 
t he 4-res p o ns e gr o u ps ( C R/ P R/ S D/ P D) usi n g a nal ysis of c o varia nce m o dels 
wit h baseli ne assess me nts bei n g t he c o vari ate i n t he m o del.   
 
1 0. 0  S T U D Y M A N A G E M E N T  
1 0. 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 pres e ntati o n a n d f u ncti o n i n 
acc or da nce wit h fe der all 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 o c 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 ul at or y re q uir e 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 patie nt 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 rel e 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 patie nt a n d t he i n vesti gat or is ass ur e d t hat t he 
patie nt 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 patie nt 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 o nse nt f or m.  
 
Pri or t o a patie nt’s p arti ci 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 p ers o nall y date d b y t he patie nt 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.  
1 0. 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 b e 
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.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 2  
•  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  
•  Fi na ncial Discl os ur es  
•  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 nic al rese arc h c o ntract  
1 0. 3  
Re gistr ati o n Pr o ce d ures  
Wit hi n 2 4 h o urs of s u bject c o nse nt, all s u bjects are re gistere d i n O n C ore a n d all 
i nf or me d c o nse nt d o c u me ntati o n u pl oa de d i nt o t he O n C ore S u bject C o ns ole b y a 
desi g nee fr o m t he partici pati n g i nstit uti o n . U p o n s u bject re gistrati o n c o m pleti o n , 
t he desi g nee m ust e mail C P O M ultice nter @ me d. u nc.e d u  or call 9 1 9 -9 6 6 -7 3 5 9 ( M -
F 8: 3 0 A M –  5: 0 0 P M E S T) t o alert t he U N C L C C C M ultice nter Offi ce f or i nitial 
re vie w a n d assi g n me nt. 
C o m plete eli gi bilit y pac kets (i nstit uti o nall y-si g ne d 
eli gi bilit y c hec klist a n d f ull s o urce d oc u me ntati o n c o nfir mi n g eli gi bilit y) are  
u pl oa de d b y t he i nstit uti o nal desi g nee i nt o t he O n C ore S u bject C o ns ole a n d t he 
L C C C 
M ultice nter 
Office 
c o nc urre ntl y 
al erte d 
b y 
e mail 
or 
p h o ne 
(C P O M ultice nter @ me d. u nc.e d u ; 9 1 9-9 6 6 -7 3 5 9) t o be gi n re vie w. All  s u bjects m ust 
ha ve fi nal eli gi bilit y verifie d b y t he U N C M ultice nter Pr oject Ma na g er o n be half 
of t he U N C PI pri or t o starti n g treat me nt. Please all o w 2 4 h o urs f or s o urce t o be 
re vie we d a n d n otificati o n of s u bject eli gi bilit y release d. All s u bjects m ust mai ntai n 
eli gi bilit y fr o m t he ti me of t his n otificati o n t hr o u g h t he be gi n ni n g of treat me nt.  
1 0. 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 ollect e d t hr o u g h a we b base d cli nical researc h 
platf or m, O n C ore ® .  Ot h er 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 h eir o w n data o nt o t he we b site via electr o nic cas e re p ort f or ms (e C R Fs).  
M ultice nter  pers o n n el 
will c o or di nate a n d 
m a na ge d ata f or q ualit y c o ntr ol 
ass ura nce a n d i nte grit y.  
 
All data will be c ollecte d a n d e ntere d i nt o O n C ore ® b y t he m ultice nter 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 dat a entere d i nt o 
O n C ore ® . T he 
M ultice nter  Data C o or di nat or ca n be reac he d 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 recei pt. T he L C C C 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 3  
C o m plia nce C o m mittee or t heir d esi g nee will a u dit tr ial 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.  
1 0. 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 h e pr otecti o n, safet y, 
a n d well -bei n g of t h e st u d y patie nt 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 he a p pr o ve d pr ot oc ol.   
1 0. 5. 1  E mer ge nc y M o dific ati o ns  
U N C a n d m ultice nter site  i n vesti gat ors ma y i m ple me nt a de vi ati 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 g e 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:  
F or m ultice nter  site 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 he  U N C Pri nci pal I n vesti gat or f or a gree me nt  
•  T he m ult ice nter  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 ns e is recei ve d, this 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).  
1 0. 5. 2  Si n gle P atie nt/ 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 g er 
C o m pre he nsi ve 
Ca ncer 
Ce nter 
I n vesti gat or I nitiate d 
Tri als 
u n der 
a n y 
circ u msta nces. Ot her t y p es 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 vi e 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.    
1 0. 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 g e 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 p artici pa nts 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 4  
•  Has n o s u bsta nti ve effect o n t he s cie ntific i nte grit y of t he res earc h pla n 
or t he val ue of t h e 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 u ct o n t he p art of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot o c ol v aria nce is c o nsi dere d a vi olati o n  if t he varia n ce m eets a n y 
of t he f oll o wi n g criteri a :  
•  Has har me d or i ncreas e d t he ris k of har m t o o ne or m ore r esearc h 
partici pa nts.  
•  Has da ma ge d t h e 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 
i n 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 vi ati 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 D e vi ati o ns: U N C or m ultice nter site pers o n nel will rec or d t he d e 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.  
 
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p ort e 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 h e 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 Rel yi n g o n T heir 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 uir e d:  
 
Pr ot oc ol De vi ati o ns: I n t he e v e 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 ort e d t o y o ur 
I R B p er i nstit uti o nal p olicies a n d re p orte d t o t h e M ult ice nter Pr oject M a na ger 
wit h i n 5 da ys. U N C -C H will deter mi ne if t he vi olati o n affects t he safet y of t he 
patie nt a n d i nte grit y of t h e data.  O nce y o ur i nstit uti o n’s I R B res p o nse is r ecei ve d, 
please f or war d t o t he M ultice nter  Re g ulat or y Ass o ciate.  
 
U n a ntici p ate d Pr o ble ms:  
U N C  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 5  
A n y e ve nts t hat meet t he criteri a f or “ U na ntici pate d Pr o ble ms” as d efi 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 pers o n nel usi n g t he I R B’s we b -base d 
re p orti n g s yste m.   
 
M ultice nter Sites:  
A n y e ve nts t hat meet t he criteria f or “ U na ntici p ate 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 M ultice nter  Pr oject Ma na g er.   T he 
M ultice nter  Re g ulat or y Ass ociate  will s u b mit re p orta ble e v e nts t o t he U N C I R B 
usi n g t he I R B’s we b -b as e d re p orti n g s yste m.  E xa m ples of s uc h U Ps i ncl u d e 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.  
1 0. 6  
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 h e a me n d me nts will be ori gi nate d 
a n d d oc u me nt e d b y t he Pri nci pal I n v esti gat or at U N C.  It s h o ul d als o b e n ot e d t hat 
w he n a n a m e n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y d esi g n or t he 
p ote ntial ris k t o t he patie nt, a re vise d c o ns e 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 v esti gat ors m ust s u b mit t he a me n d me nt t o t heir i nstit uti o n’s I R B f or a p pr o val.  
F or m ulti -ce nter st u dies, a n y m ultice nter  site m ust s u b mit t heir i nfor me d c o nse nt 
re visi o ns t o t he M ultice nter  Re g ulat or y Ass o ciate  pri or t o s u b missi o n t o t heir I R B.   
1 0. 7  
Rec or d R ete 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 c orres p o n de nce t o I n vesti gat ors , m o nit ori n g l o gs/letters, a n d 
re g ulat or y d o c 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 patie nt c o nse nt f or ms).  
 
S o urce d oc u me nts i ncl u de all rec or di n gs o f 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 res earc h st u d y.  
 
G o ver n me nt a ge n c 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 u ct of a cli nical trial m ust be ret ai ne d b y t he st u d y 
i n vesti gat or.  I n t he cas e of a st u d y wit h a dr u g s ee ki n g re g ul at or y a p pr o val a n d 
mar keti n g, t hese d oc u m e nts s hall be retai n e d f or at least t w o years after t he last 
a p pr o val of mar k eti n g a p plica ti o n i n a n I nter nati o n al 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.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 6  
1 0. 8  
O bli g ati o ns of I n vesti g at ors  
T he Pri nci pal I n v esti 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 n ce wit h Title 2 1 of t h e C o de of Fe d eral 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 h e  treat me nt of all st u d y patie nts.  T he Pri nci pal I n v esti 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 cli nic al 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 v esti 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 v esti gat or will pr o vi de 
access t o his/ her ori gi nal rec or ds t o p er mit verificati o n of pr o per e ntr y of d ata. 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 v esti 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 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 7  
1 1. 0  R E F E R E N C E S  
1.  
Lara m or e, G. E., et al., A dj uv a nt c he m ot her a p y 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 nt er 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.  
2.  
C o o per, J. S., et al., P ost o per at ive 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.  
3.  
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.  
4.  
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 all y 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.  
5.  
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 EO 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. 
8 4 3 -5 0.  
6.  
T u pc h o n g, L., et al., R a n d o mize d st u dy of pre o per ative vers us p ost o per ative 
r a di ati o n t her a py i n a dv a nce d he a d a n d neck c arci n o m a: l o n g -ter m f oll o w-u p of 
R T O G st u dy 7 3 -0 3.  I nt J Ra diat O nc ol Bi ol P h ys, 1 9 9 1. 2 0 ( 1): p. 2 1-8.  
7.  
Tr otti, A., et al., M uc ositis i nci de nce, severity a n d ass oci ate d o utc o mes i n p atie nts 
wit h he a d a n d neck c a n cer receivi n g r a di ot her a p y wit h or wit h o ut c he m ot her a py: 
a syste m atic liter at ure revie w.  Ra di ot her O nc ol,  2 0 0 3. 6 6 ( 3): p. 2 5 3-6 2.  
8.  
Ri velli, T. G., et al., Cis pl ati n b ase d c he m or a di ati o n l ate t oxicities i n he a d a n d neck 
s q u a m o us cell c arci n o m a p atie nts. Disc o v Me d, 2 0 1 5. 2 0 ( 1 0 8): p. 5 7-6 6.  
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 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.  
1 0.  
Disis, M. L., I m m u ne re g ul ati o n of c a ncer. J Cli n O nc ol, 2 0 1 0. 2 8 ( 2 9): p. 4 5 3 1-8.  
1 1.  
D u n n, G. P., L.J. Ol d, a n d R. D. Sc hrei ber, T he t hree Es of c a n cer i m m u n oe diti n g.  
A n n u Re v I m m u n o l, 2 0 0 4. 2 2 : p. 3 2 9-6 0.  
1 2.  
Keir, M. E., et al., P D -1 a n d its li g a n ds i n t oler a nce a n d i m m u nity.  A n n u Re v 
I m m u n ol, 2 0 0 8. 2 6 : p. 6 7 7-7 0 4.  
1 3.  
Z o u, 
W. a n d 
L. 
C he n, 
I n hi bit ory 
B 7-f a mily 
m olec ules i n t he t u m o ur 
micr oe nvir o n me nt.  N at Re v I m m u n ol, 2 0 0 8. 8 ( 6): p. 4 6 7 -7 7.  
1 4.  
B utte, M.J., et al., Pr o gr a m me d de at h -1 li g a n d 1 i nter acts s pecific ally wit h t he B 7 -
1 c osti m ul at ory m olec ule t o i n hi bit T cell res p o nses.  I m m u nit y, 2 0 0 7. 2 7 ( 1): p. 1 1 1-
2 2.  
1 5.  
Paters o n, A. M., et al., T he pr o gr a m me d d e at h -1 li g a n d 1: B 7 -1 p at h w ay restr ai ns 
di a bet o ge nic effect or T cells i n viv o.  J I m m u n ol, 2 0 1 1. 1 8 7 ( 3): p. 1 0 9 7-1 0 5.  
1 6.  
Tal ma d ge, J. E., 
M. D o n k or, a n d E. Sc h olar, I nfl a m m at ory cell i nfiltr ati o n of 
t u m ors: Jekyll or Hy de. Ca ncer Met astasis Re v, 2 0 0 7. 2 6 ( 3-4): p. 3 7 3 -4 0 0.  
1 7.  
Ste wart, 
R., et al., I de ntific ati o n a n d 
C h ar acteriz ati o n of 
M E DI 4 7 3 6, a n 
A nt a g o nistic A nti -P D -L 1 M o n ocl o n al A nti b o dy.  Ca ncer I m m u n ol Res, 2 0 1 5. 3 ( 9): 
p. 1 0 5 2 -6 2.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 8  
1 8.  
Ga n ga d har, T. C. a n d A. K. Sala ma, Cli nic al a p pli c ati o ns of P D -1 -b as e d t h er a py:  a 
f oc us o n pe m br oliz u m a b ( M K-3 4 7 5) i n t he m a n a ge me nt of mel a n o m a a n d ot her 
t u m or ty pes. O nc o T ar gets T her, 2 0 1 5. 8 : p. 9 2 9-3 7.  
1 9.  
Ki m, J., et al., I nv asiv e Bl a d der C a ncer: Ge n o mic I nsi g hts a n d T her a pe utic 
Pr o mise.  Cli n Ca ncer Res, 2 0 1 5. 2 1 ( 2 0): p. 4 5 1 4-2 4.  
2 0.  
Me n de n hall, W. M., et al., P ost o per ative r a di ot her a py 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.  Cli n Me d Res, 2 0 0 6. 4 ( 3): p. 2 0 0-8.  
2 1.  
Par k, B., C. Yee, a n d K. M. Lee, T he effect of r a di ati o n o n t he i m m u ne res p o nse t o 
c a ncers.  I nt J M ol Sci, 2 0 1 4. 1 5 ( 1): p. 9 2 7-4 3.  
2 2.  
Ferrara, 
T. A., J. W. 
H o d ge, a n d J. L. 
G ulle y, 
C o m bi ni n g r a di ati o n a n d 
i m m u n ot her a py f or s y ner gistic a ntit u m or t her a py. C urr O pi n M ol T h er, 2 0 0 9. 
1 1 ( 1): p. 3 7-4 2.  
2 3.  
S pi ott o, M., Y. X. F u, a n d R. R. Weic hsel ba u m, T he i ntersecti o n of  r a di ot her a py 
a n d i m m u n ot her a py: mec h a nis ms a n d cli nic al i m plic ati o ns.  Sci I m m u n ol, 2 0 1 6. 
1 ( 3). 
2 4.  
Ba u ml, J., et al., Pe m br oliz u m a b f or Pl ati n u m - a n d Cet uxi m a b -Refr act ory He a d 
a n d Neck C a ncer: Res ults Fr o m a Si n gle -Ar m, P h ase II St u dy.  J Cli n O nc ol, 2 0 1 7. 
3 5 ( 1 4): p. 1 5 4 2-1 5 4 9.  
2 5.  
Ferris, R. L., et al., Niv ol u m a b f or Rec urre nt 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 1 6. 3 7 5 ( 1 9): p. 1 8 5 6-1 8 6 7.  
2 6.  
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 at h 
li g a n d-1 i m m u ne c heck p oi nt bl ocker d urv al u m a b: Si n gle ce ntre s u bset a n alysis 
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 7.  
Astra Ze neca, D ur v al u m a b ( M E DI 4 7 3 6) I nvesti g at or's Br oc h ure 2 0 1 7.  
2 8.  
F or me nti, 
S. C. 
a n d 
S. 
De maria, 
C o m bi ni n g r a di ot her a py 
a n d 
c a ncer 
i m m u n ot her a py: a p ar a di g m s hift. J Natl Ca ncer I nst, 2 0 1 3. 1 0 5 ( 4): p. 2 5 6-6 5.  
2 9.  
I v a 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.  
3 0.  
K o ya ma, T. a n d H. C he n,  Pr o per i nfere nce fr o m Si m o n's t w o -st a ge desi g ns. Stat 
Me d, 2 0 0 8. 2 7 ( 1 6): p. 3 1 4 5-5 4.  
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
5 9  
1 2. 0  A P P E N DI C E S  
1 2. 1  
D ose M o dific ati o n & T o xicit y M a n a ge me nt G ui deli nes f or D ur v al u m a b  
 
 
T o xicit y gra des per N CI -C T C A E criteria versi o n 5. 0 . 
1 2. 1. 1  I m m u ne-Me di ate d Re a cti o ns - Ge ner al  
See ne xt p a ge  f or det ails.  N ote t hat rec o m me n d e d d ose h ol ds ma y res ult i n lac k 
of pla n ne d s y nc hr o n y bet wee n ra diati o n a n d s yste mic t hera p y. I n t he cas e t hat a 
patie nt re q uires a h ol d of d ose d ue t o t o xicit y, w hic h rec o v ers t o gra de 1 or less a n d 
t he patie nt is eli gi ble t o restart t hera p y, t his will be all o we d. T he l ac k of s y nc hr o n y 
will n ot be c o nsi dere d a de vi ati o n. I m a gi n g ti mi n g will be p ote nti all y del a ye d 
d ue t o s uc h a sit u ati o n a n d t his will als o n ot be a de vi ati o n.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 0  
D osi n g M o dific ati o n a n d T o xicit y M a n a ge m e nt G ui deli nes f or I m m u ne -Me di ate d, I nf usi o n -Rel at e d, a n d  
N o n -I m m u ne– Me di at e d Re acti o ns ( M E DI 4 7 3 6 M o n ot her a p y or C o m bi n ati o n T her a p y wit h Tre m eli m u m a b or 
Tre m eli m u m a b M o n ot her a p y) 1 7 Oct o ber 2 0 1 9 Versi o n ( C T C A E v 5. 0 ) 
Ge ner al C o nsi der ati o ns re g ar di n g I m m u ne -Me di ate d Re acti 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 b ase 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 5. 0. 
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 h e f oll o wi n g c o nditi 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 v ale nt) wit hi n 1 2 wee ks  of t h e start of t he i m m u ne -me diate d 
a d verse e ve nt (i m A E)  
•  
Gra de 3 rec urre nce of a pre vi o usl y e x perie nce d treat me nt -relate d i m 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.  
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 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 h e e ve nt sta bilizes a n d is c o ntr olle d.  
2.  
T h e 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. 
3.  
D oses of pre d nis o ne are at ≤1 0  m g/ d a y or e q ui vale nt.  
Gr a de 3  
De pe n di n g o n t h e 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 d eli nes b el o w. 
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 d eli n es 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 
mec ha nis m c o ul d occ ur i n nearl y all or ga ns, s o me of t h e m n ot n ote d 
s pecificall y i n t h ese g ui d eli nes. 
− 
W h et h er 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 h ese g ui d eli nes or n ot, 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, 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 h e 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 h era p y s h o ul d be c o nsi dere d f or l o w -gra de ( Gra de 
1 or 2, u nless ot h er 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/ d a y P O or I V e q ui v ale 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 ocar ditis, or ot h er 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 h e g ui d eli 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 n ecessar y, d isc ussi n g wit h t h e 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 n crease t h e 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 val e 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 v es 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 h e i m A Es f or s pecific t y pe of 
i m m u n os u p pressi v e) 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 1  
D osi n g M o dific ati o n a n d T o xicit y M a n a ge m e nt G ui deli nes f or I m m u ne -Me di ate d, I nf usi o n -Rel at e d, a n d  
N o n -I m m u ne– Me di at e d Re acti o ns ( M E DI 4 7 3 6 M o n ot her a p y or C o m bi n ati o n T her a p y wit h Tre m eli m u m a b or 
Tre m eli m u m a b M o n ot her a p y) 1 7 Oct o ber 2 0 1 9 Versi o n ( C T C A E v 5. 0 ) 
Ge ner al C o nsi der ati o ns re g ar di n g I m m u ne -Me di ate d Re acti o ns  
D ose M o dific ati o ns  
T o xicit y M a n a ge me nt  
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 as y m pt o matic a m ylase or li pase le vels of > 2 X U L N, 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 ncreatitis, 
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 h er si milar e ve nts e ve n if t h e 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 h er 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 h er si milar e ve nts e ve n if t h e y are n ot c urre ntl y n ote d i n 
t h e g ui d eli 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 h ere 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 d is m, T y pe 1 dia betes mellit us).  
 
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 v es 
s h o ul d pr 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 h er si milar e ve nts e ve n if t h e y are 
n ot c urre ntl y n ote d i n t h e 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 -ter m ster oi d a n d ot her i m m u n os u p pressi v e use, c o nsi der nee d f or 
P n e u m ocystis jir ovecii  p ne u m o nia ( PJ P, f or merl y k n o w n as P n e 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/ Gr a de 4 i nfla m mat or y reacti o ns attri b ute d t o l o cal 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 be nefit -ris k a nal ysis f or t hat patie nt. 
A E A d verse e ve nt; C T C C o m m o n T o xicit y Cr iteria; 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 v e 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 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 2  
1 2. 1. 2  S pecific I m m u ne -Me di ate d Re acti o ns  
A d v erse E ve nts  
Se verit y Gr a de of t he 
E ve nt ( N CI C T C A E 
versi o n  5. 0)  
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  
Ge ner al G ui d a nce  
F o r A n y Gr a de:  
− 
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 n ess of breat h or c o u g h). 
Patie nts s h o ul d be e val u ate d wit h i ma gi n g a n d p ul m o nar y 
f u ncti o n tests, i n cl u di n g ot her dia g n ostic pr oce d ures as 
descri b e d bel o w.  
− 
I nitial w or k-u p ma y i n cl u de cli nical e val u ati 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 T sca n. 
Gr a de 1  
(as y m pt o matic, cli nical 
or dia g n ostic 
o bser vati o ns o nl y; 
i nter ve nti o n n ot 
i n dicate d) 
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 o r Gr a de 1 (r a di o gr a p hic c h a n ges o nl y):  
− 
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.  
− 
C o nsi der P ul m o nar y a n d I nfecti o us Disease c o ns ults.  
Gr a de 2  
(s y m pt o matic; me dical 
i nter ve nti o n i n dicate d; 
li miti n g i nstr u me ntal 
A D L)  
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.  
•  
If t o xicit y i m pr o ves t o Gra de ≤1, 
t h e 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 o r Gr a de 2 ( mil d t o m o der ate ne w s y m pt o ms):  
− 
M o nit or s y m pt o ms dail y a n d c o nsi der h os pitalizati o n.  
− 
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.  
− 
If n o i m pr o ve me nt wit hi n 3 t o 5 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 still n o i m pr o ve me nt wit hi n 3 t o 5 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, pr o m ptl y start 
i m m u n os u p pressi v e 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 e ver y 2 wee ks). Ca uti o n: It is 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 3  
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 d a nce bef ore usi n g i nfli xi ma b.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, or 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns)a 
− 
C o nsi der P ul m o nar y a n d I nfecti o us Dise ase c o ns ults. 
− 
C o nsi der, as necessar y, disc ussi n g wit h st u d y p h ysicia n.  
Gr a de 3 or 4  
( Gra de 3: se vere 
s y m pt o ms; li miti n g 
self-care A D L; o x y ge n 
i n dicate d) 
 
( Gra de 4: life-
t hreate ni n g res pirat or y 
c o m pr o mise; ur ge nt 
i nter ve nti o n i n dicate d 
[e. g., trac he ost o m y or 
i nt u bati o n]) 
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 o r Gr a de 3 or 4 (se vere or ne w s y m pt o ms, ne w/ w orse ni n g h y p o xi a, 
life-t hre ate ni n g): 
− 
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 v ale nt.  
− 
O btai n P ul m o n ar y a n d I nfecti o us Disease c o ns ults; 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 h e patie nt.  
− 
S u p p orti v e care (e. g., o x y ge n).  
− 
If n o i m pr o ve me nt wit hi n 3 t o 5 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 v e 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 e ver y 2 wee ks’ d ose) starte d. 
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.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, 
a n d, i n partic ular, a nti -PJ P treat me nt (refer t o c urre nt N C C N 
g ui deli nes f or treat me nt of ca ncer -relate d i nfecti o ns).a 
Di arr he a/ C olitis  
L ar ge i ntesti ne 
pe rf or ati o n/I ntesti ne 
p erf or ati o n 
A n y Gr a de  
Ge ner al G ui d a nce  
F o r A n y Gr a de:  
− 
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 n crease 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).  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 4  
- 
W h e n s y m pt o ms or e val u ati o n i n dicate a perf orati 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 diatel y wit h o ut a n y dela y.  
− 
Patie nts s h o ul d be t h o r o u g hl y e val u ate 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 n cl u di n g testi n g f or cl ostri di u m 
difficile t o xi n, 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, 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, i ncl u di n g 
perf orati o n.  
− 
Use a nal g esics caref ull y; t h e 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  
( Diarr hea: st o ol 
fre q ue nc y of < 4 o ver 
baseli ne per da y)  
( C olitis: as y m pt o matic; 
cli nical or dia g n ostic 
o bser vati o ns o nl y; 
i nter ve nti o n n ot 
i n dicate d) 
N o d ose m o dificati o ns.  
F o r 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 n cl u di n g h y drati o n, 
electr ol yte re place me nt, die tar 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 d e. Use 
pr o bi otics as per treati n g p h ysicia n’s cli nical j u d g me nt.  
Gr a de 2  
( Diarr hea: st o ol 
fre q ue nc y of 4 t o 6 o ver 
baseli ne per da y;  
li miti n g i nstr u me ntal 
A D L)  
( C olitis: a b d o mi n al 
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 w orse ns, t he n treat as 
Gra de 3 or Gra de 4.  
•  
If t o xicit y i m pr o ves t o Gra de ≤1, 
t h e 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. 
F o r Gr a de 2:  
− 
C o nsi der s y m pt o matic treat me nt, i n cl 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 d e 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 v ale 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 v ale nt, GI c o ns ult 
s h o ul d be o btaine d f or c o nsi derati o n of f urt h er 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 5  
pai n; m uc us or bl o o d i n 
st o ol) 
(Perf orati o n : i n vasi ve 
i nter ve nti o n n ot 
i n dicate d) 
perf orati o n, 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/ d a y starte d.  
− 
If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys des pite 2 t o 4 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 v es 
s uc h as i nfli xi ma b at 5 m g/ k g o nce e ver y 2 wee ks a. 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 d a nce bef ore usi n g i nfli xi ma b. 
− 
C o nsi der, as necessar y, disc ussi n g wit h st u d y p h ysicia n if n o 
res ol uti o n t o Gra de ≤1 i n 3 t o 4 da ys.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
Gr a de 3 or 4  
( Gra de 3 Diarr hea: 
st o ol fre q ue nc y of ≥7 
o ver baseli ne per da y;  
li miti n g self care A D L; 
Gra de 4 Diarr hea: life 
t hreate ni n g 
c o nse q ue nces) 
( Gra de 3 C olitis: se vere 
a b d o mi nal pai n, fe ver;  
ile us; p erit o neal si g ns; 
Gra de 4 C olitis: life -
t hreate ni n g 
c o nse q ue nces, ur ge nt 
i nter ve nti o n i n dicate d) 
( Gra de 3 Perf orati o n:   
i n vasi ve i nter ve nti o n 
i n dicate d;  
Gra de 4 Perf orati o n:  
Gr a de 3  
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 Gra de 3 if t o xicit y d oes n ot 
i m pr o ve t o Gra de ≤1 wit hi n 1 4 da ys; 
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.  
 
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 gime n.  
F o r 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 2 t o 
4  m g/ k g/ da y or e q ui v ale nt.  
− 
M o nit or st o ol fre q ue nc y a n d v ol u me a n d mai ntai n h y drati o n.  
− 
Ur ge nt GI c o ns ult a n d i ma gi n g a n d/ or c ol o n osc o p y as 
a p pr o priate. 
− 
If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys of 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 v ale nt, pr o m ptl y 
start f urt h er i m m u n os u p pressi v es (e. g., i nfli xi ma b at 5 m g/ k g 
o nce e ver y 2 wee ks). C a uti o n : E ns ure GI c o ns ult 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 g e neral 
g ui da nce bef ore usi n g i nfli xi ma b. If perf orati 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 nal s ur ger y 
i m me diatel y wit h o ut a n y dela y . 
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 6  
 
 
life-t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d) 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 7  
He p atitis  
(ele v ate d L F Ts) 
I nfli xi ma b s h o ul d n ot be 
use d f or ma na ge me nt of 
i m m u ne-relate d he patitis. 
A n y  Gr a de  
 
Ge ner al G ui d a nce  
F o r A n y Gr a de  
− 
M o nit or a n d e val u ate li ver f u ncti o n test: A S T, A L T, A L P, a n d 
T B.  
− 
E v al u ate f or alter nati ve eti ol o gies (e. g., viral he patitis, disease 
pr o gressi o n, c o nc o mita nt me dicati o ns).  
Gr a de 1  
(A S T or A L T > U L N 
a n d ≤3. 0 × U L N if 
baseli ne n or mal, 1. 5 -
3. 0 × baseli ne if baseli ne 
a b n or mal; a n d/ or T B 
> U L N a n d ≤1. 5 × U L N 
if baseli ne n or mal, 
> 1. 0 -1. 5 × baseli ne if 
baseli ne a b n or mal)  
•  
N o d ose m o dificati o ns.  
•  
If it w orse ns, t h e n treat as  Gra de 2.  
− 
C o nti n ue L F T m o nit ori n g per pr ot o c ol.  
Gr a de 2   
( A S T or  
A L T > 3. 0 × U L N a n d 
≤5. 0 × U L N if baseli ne 
n or mal, > 3 -5 × baseli ne 
if baseli ne a b n or mal; 
a n d/ or  
T B > 1. 5 × U L N a n d 
≤3. 0 × U L N if baseli ne 
n or mal, > 1. 5 - 
3. 0 × baseli ne if baseli ne 
a b n or mal) 
•  
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.  
•  
If t o xicit y w orse ns, t he n treat as 
Gra de 3.  
•  
If t o xicit y i m pr o ves t o  Gra de ≤1, 
res u me st u d y dr u g/st u d y re gi me n 
after c o m pleti o n of ster oi d ta per.  
F o r Gr a de 2:  
− 
Re g ular a n d fre q ue nt c hec ki n g of L F Ts (e. g., e ver y 1 t o 2 da ys) 
u ntil ele vati o ns of t h ese are i m pr o vi n g or res ol v e d. 
− 
If n o res ol uti o n t o ≤Gra de 1 i n 1 t o 2 da ys, c o nsi der, as 
necessar y, disc ussi n g wit h st u d y p h ysicia n.  
− 
If e ve nt is persiste nt ( > 3 t o 5 da ys) or w orse ns, 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 v ale nt.  
− 
If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys des pite 1 t o 
2  m g/ k g/ da y of pre d nis o ne P O or I V e q ui v ale nt, c o nsi der 
a d diti o nal w or k u p a n d start 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.  
− 
If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys des pite 2 t o 
4  m g/ k g/ da y of 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 v es (i.e., m yc o p he n olate m ofetil).a Disc uss 
wit h st u d y p h ysicia n if m yc o p he n olate m ofetil is n ot a vaila ble. 
I nfli xi m a b s h o ul d N O T be use d. 
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
P L E A S E S E E 
s h a de d are a 
i m me di atel y bel o w 
t his secti o n t o fi n d 
g ui d a nce  f or 
m a n a ge me nt of  
“ He p atitis (ele v ate d 
L F T S) ” i n  H C C 
p atie nts  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 8  
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
Gr a de 3  
 (A S T or  
A L T > 5. 0 × U L N a n d 
≤2 0 × U L N if baseli ne 
n or mal, > 5 -2 0 × 
baseli ne if baseli ne 
a b n or mal; a n d/ or  
T B > 3. 0 × U L N  a n d  
≤1 0. 0 × U L N if baseli ne 
n or mal, > 3. 0 -1 0. 0 × 
baseli ne if baseli ne 
a b n or mal) 
 
 
Gr a de 4  
( A S T or A L T 
> 2 0 × U L N if baseli ne 
n or mal, > 2 0 × baseli ne if 
baseli ne a b n or mal; 
a n d/ or  
T B > 1 0 × U L N if 
baseli ne n or mal, 
> 1 0. 0 × baseli ne if 
baseli ne a b n or mal)   
F or ele vati o ns i n tra nsa mi n ases ≤8 × U L N, 
or ele vati o ns i n T B ≤5 × U L N:  
•  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  
•  Res u me st u d y dr u g/st u d y re gi me n if 
ele vati o ns d o w n gra de t o  Gra de ≤1  
wit hi n 1 4  da ys a n d after c o m pleti o n 
of ster oi d ta per.  
•  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 t he ele vati o ns 
d o n ot d o w n gra de t o Gra de ≤1 wit hi n 
1 4  da ys.  
F or ele vati o ns i n tra ns a mi n ases > 8 × U L N 
or ele vati o ns i n bilir u bi n > 5 × U L N, 
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. 
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 a n y case meeti n g H y’s la w 
criteria ( A S T a n d/ or A L T > 3 × U L N + 
bilir u bi n > 2 × U L N wit h o ut i nitial fi n di n gs 
of c h olestasis [i.e., ele vate d al kali ne P 0 4] 
a n d i n t he a bse nce of a n y alter nati v e 
ca use). b 
F o r 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 at 1 t o 
4  m g/ k g/ da y or e q ui v ale nt.  
− 
If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys des pite 1 t o 
4  m g/ k g / da y met h yl pre d nis ol o ne I V or e q ui v ale nt, pr o m ptl y 
start treat me nt wit h i m m u n os u p pressi v e t h era p y (i.e., 
m yc o p he n olate m ofetil). Disc uss wit h st u d y p h ysicia n if 
m yc o p he n olate is n ot a vaila ble. I nfli xi m a b s h o ul d N O T be 
use d.  
− 
Re q uest He pat ol o g y c o ns ult, a n d perf or m a b d o mi n al w or k u p 
a n d i ma gi n g as a p pr o priate.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
 
 
 
 
 
 
 
 
 
 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
6 9  
 
 
 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 3  
 
Gr a de 1  
(ser u m creati ni n e  
> U L N t o 1. 5 × U L N)  
N o d ose m o dificati o ns.  
F o r Gr a de 1:  
− 
M o nit or ser u m creati ni ne wee kl y a n d a n y acc o m pa n yi n g 
s y m pt o ms. 
•  
If creati ni n e ret ur ns t o baseli ne, res u me its re g ular 
m o nit ori n g per st u d y pr ot oc ol.  
•  
If creati ni n e w orse ns, de pe n di n g o n t he se verit y, treat 
as Gr a de 2, 3, or 4.  
− 
C o nsi der s y m pt o matic treat me nt, i n cl u di n g h y drati o n, 
electr ol yte re place me nt, a n d di uretics.  
− 
If baseli ne ser u m creati ni n e is ele vate d a b o ve n or mal, a n d t here 
is a rise t o > 1 t o 1. 5 × baseli ne, c o nsi der f oll o wi n g 
rec o m me n dati o ns i n t his r o w.  
Gr a de 2  
(ser u m creati ni n e > 1. 5 
t o 3. 0 × baseli ne; > 1. 5 t o 
3. 0 × U L N)  
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 w orse ns, t he n treat as 
Gra de 3 or 4.  
•  
If t o xicit y i m pr o ves t o Gra de ≤1 or 
baseli ne, t h e n res u me st u d y 
dr u g/st u d y re gi me n after c o m pleti o n 
of ster oi d ta per.  
F o r Gr a de 2:  
− 
C o nsi der s y m pt o matic treat me nt, i n cl u di n g h y drati o n, 
electr ol yte re place me nt, a n d di uretics.  
− 
Caref ull y m o nit or ser u m creati ni ne e ver y 2 t o 3 da ys a n d as 
cli nicall y warra nte d.  
− 
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. 
− 
If e ve nt is persiste nt ( > 3 t o 5 da ys) or w orse ns, 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 v ale 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 v ale nt, a d diti o nal 
w or k u p s h o ul d be c o nsi d ere d a n d pr o m pt treat me nt wit h I V 
met h yl pre d nis ol o ne at 2 t o 4  m g/ k g/ da y starte d.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d el i nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
− 
W h e 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 n e 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 o r Gr a de 3 or 4:  
− 
Caref ull y m o nit or ser u m creati ni ne o n dail y basis.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 4  
( Gra de 3: ser u m 
creati ni n e 
> 3. 0 × baseli ne; > 3. 0 t o 
6. 0 × U L N)  
 
( Gra de 4: ser u m 
creati ni n e > 6. 0 × U L N)  
− 
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 v ale 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 v ale nt, 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.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
 
R as h o r Der m atitis 
(i ncl u di n g Pe m p hi g oi d) 
A n y Gr a de  
(refer t o N CI C T C A E 
v  5. 0 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 o r A n y Gr a de:  
− 
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).  
− 
I F T H E R E I S A N Y B U L L O U S F O R M A TI O N, T H E S T U D Y 
P H Y SI CI A N S H O U L D B E C O N T A C T E D A N D S T U D Y 
D R U G DI S C O N TI N U E D I F S U S P E C T S T E V E N S -
J O H N S O N S Y N D R O M E O R T O XI C E PI D E R M A L 
N E C R O L Y SI S.  
Gr a de 1  
N o d ose m o dificati o ns.  
F o r Gr a de 1:  
− 
C o nsi der s y m pt o matic treat me nt, i n cl u di n g oral a nti pr uritics 
(e. g., di p he n h y dra mi n e or h y dr o x yzi n e) a n d t o pical t hera p y 
(e. g., urea crea m).  
Gr a de 2  
F or persiste nt ( > 1 t o 2 wee ks) 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 w orse ns, t he n treat as 
Gra de  3.  
•  
If t o xicit y i m pr o ves t o Gra de ≤1 or 
baseli ne, t h e 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. 
F o r 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 tr eat me nt, i n cl u di n g oral a nti pr uritics 
(e. g., di p he n h y dra mi n e or h y dr o x yzi n e) a n d t o pical t hera p y 
(e. g., urea crea m).  
− 
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 t o 
5  da ys or is w orse ni n g des pite 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, as necessar y, 
disc ussi n g wit h st u d y p h ysicia n 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/ d a y P O or I V 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 5  
e q ui v ale nt. If > 3 0 % b o d y s urface area is i n v ol v e d, c o nsi der 
i nitiati o n of s yste mic ster oi ds pr o m ptl y. 
− 
C o nsi der s ki n bi o ps y if t he e ve nt is p ersiste nt f or > 1 t o 2  wee ks 
or rec urs.  
Gr a de 3 or 4  
F o r 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 te m p oraril y h ol di n g t h e st u d y 
dr u g/st u d y re gi me n d oes n ot pr o vi d e 
i m pr o ve me nt of t he Gra de 3 s ki n ras h t o 
Gra de ≤1 or baseli ne wit hi n 3 0  da ys, t h e n 
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 o r Gr a de 4 ( or life -t hre ate ni n g): 
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 o r Gr a de 3 or 4 ( or life -t hre ate ni n g): 
− 
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 
4  m g/ k g/ da y or e q ui v ale nt.  
− 
C o nsi der h os pitalizati o n.  
− 
M o nit or e xte nt of ras h [ R ule of Ni n es].  
− 
C o nsi der s ki n bi o ps y ( prefera bl y m ore t h a n 1) as cli nicall y 
feasi ble. 
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, a n d 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
− 
C o nsi der, as necessar y, disc ussi n g wit h st u d y p h ysicia n.  
E n d ocri n o p at h y  
(e. g., h y pert h yr oi dis m, 
t h yr oi ditis, 
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; 
e x ocri n e e ve nt of 
a m ylase/li p ase i n crease d 
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 
v 5. 0 f or defi ni n g t he 
C T C gra de/se verit y)  
Ge ner al G ui d a nce  
F o r A n y Gr a de:  
− 
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 n e e ve nts.  
− 
C o nsi der, as necessar y, disc ussi n g wit h st u d y p h ysicia n.  
− 
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 n cl u de hea dac he, fati g ue, be ha vi or 
c ha n ges, c ha n ge d me ntal stat us, verti g o, a b d o mi n al pai n, 
u n us ual b o wel ha bits, p ol y di psia, p ol y uria, h y p ote nsi o n, a n d 
wea k ness.  
− 
Patie nts s h o ul d be t h or o u g hl y e val u ate d t o r ul e 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 
metastas es, or i nfecti o ns).  
− 
De pe n di n g o n t h e s us pecte d e n d ocri n o pat h y, m o nit or a n d 
e val u ate t h yr oi d f u ncti o n tests: T S H, free T 3 a n d free T 4 a n d 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 6  
als o i n cl u de d i n t his 
secti o n) 
 
ot h er rele va nt e n d ocri n e a n d relate d la bs (e. g., bl o o d gl uc ose 
a n d ket o ne le vels, H g A 1c).  
− 
F or as y m pt o matic ele vati o ns i n ser u m a m ylase a n d li pase 
> U L N a n d < 3 × U L N, c ortic oster oi d treat me nt is n ot i n dicate d 
as l o n g as t h ere are n o ot her si g ns or s y m pt o ms of pa ncreatic 
i nfla m mati o n. 
− 
If a patie nt e x perie nces a n A E t h at 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. 
 
Gr a de 1  
N o d ose m o dificati o ns.  
F o r Gr a de 1 (i ncl u di n g t h ose wit h as y m pt o m atic T S H ele v ati o n):  
− 
M o nit or patie nt 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 nsider 
c o ns ultati o n of a n e n d ocri n ol o gist.  
Gr a de 2  
F or Gra de 2 e n d ocri n o pat h y ot her t h a n 
h y p ot h yr oi dis m a n d T y pe 1 dia betes 
mellit us, h ol d st u d y dr u g/st u d y re gi me n 
d ose u ntil patie nt is cli nicall y sta ble.  
•  
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 a n d after c o m pleti o n 
of ster oi d ta per.  
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 
F o r Gr a de 2 (i ncl u d i n g t h ose wit h s y m pt o m atic e n d ocri n o p at h y): 
− 
C o ns ult e n d ocri n ol o gist t o g ui d e e val u ati o n of e n d ocri n e 
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 patie nts wit h a b n or mal e n d ocri n e w or k u p, e xce pt t h ose 
wit h is olate d h y p ot h yr oi dis m or T y pe 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 (e. g., h y dr oc ortis o ne, se x h or m o nes).  
− 
Is olate d h y p ot h yr oi dis m ma y be treate d wit h re place me nt 
t h era 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.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 7  
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 
re gi me n o n t h e f oll o wi n g c o n diti o ns: 
1.  
T h e e ve nt sta bilizes a n d is 
c o ntr olle d. 
2.  
T h e patie nt is cli nicall y sta ble as per 
i n vesti g at 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 ≤1 0  m g/ da y 
or e q ui v ale nt.  
− 
Is olate d T y pe 1 dia betes mellit us ( D M) ma y be treate d wit h 
a p pr o priate dia betic t h era 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. 
− 
O nce patie nts o n ster oi ds are i m pr o vi n g, gra d uall y ta per 
i m m u n os u p pressi v e ster oi ds (as a p pr o priate a n d wit h g ui da nce 
of e n d ocri n ol o gist) o ver ≥2 8 da ys a n d c o nsi der pr o p h ylactic 
a nti bi otics, a ntif u n gals, a n d a nti -PJ P treat me nt (refer t o c urre nt 
N C C N g ui deli nes f or treat me nt of ca ncer -relate d i nfecti o ns).a 
− 
F or patie nts 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.  
Gr a de 3 or 4  
F or Gra de 3 or 4 e n d ocri n o pat h y ot h er 
t h a n h y p ot h yr oi dis m a n d T y pe 1 dia betes 
mellit us, h ol d st u d y dr u g/st u d y re gi me n 
d ose u ntil e n d ocri n o pat h y s y m pt o m(s) are 
c o ntr olle d.  
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 a n d after c o m pleti o n 
of ster oi d ta per.  
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 
re gi me n o n t h e f oll o wi n g c o n diti o ns: 
1.  
T h e e ve nt sta bilizes a n d is 
c o ntr olle d. 
2.  
T h e patie nt is cli nicall y sta ble as per 
i n vesti g at or or treati n g p h ysicia n’s 
cli nical j u d ge me nt.  
F o r Gr a de 3 or 4:  
− 
C o ns ult e n d ocri n ol o gist t o g ui d e e val u ati o n of e n d ocri n e 
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. H os pitalizati o n 
rec o m me n de d. 
− 
F or all patie nts wit h a b n or mal e n d ocri n e w or k u p, e xce pt t h ose 
wit h is olate d h y p ot h yr oi dis m or  T y pe 1 D M, a n d as g ui de d b y 
a n e n d ocri n ol o gist, 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 v ale nt, as well as 
rele va nt h or m o ne re place me nt (e. g., h y dr oc ortis o ne, se x 
h or m o nes).  
− 
F or a dre nal crisis, se vere de h y drati o n, h y p ote nsi o n, or s h oc k, 
i m me diatel y i nitiate I V c ortic oster oi ds wit h mi n eral oc ortic oi d 
acti vit y. 
− 
Is olate d h y p ot h yr oi dis m ma y be treate d wit h re place me nt 
t h era 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 y pe 1 dia betes mellit us ma y be treate d wit h 
a p pr o priate dia betic t h era 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. 
− 
O nce patie nts o n ster oi ds are i m pr o vi n g, gra d uall y ta per 
i m m u n os u p pressi v e ster oi ds (as a p pr o priate a n d wit h g ui da nce 
of e n d ocri n ol o gist) o ver ≥2 8 da ys a n d c o nsi der pr o p h ylactic 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 8  
 
 
3.  
D oses of pre d nis o ne are ≤1 0  m g/ da y 
or e q ui v ale nt.  
a nti bi otics, a ntif u n gals, a n d a nti -PJ P treat me nt (refer t o c urre nt 
N C C N g ui deli nes f or treat me nt of ca ncer -relate d i nfecti o ns).a 
 
Ne ur ot o xicit y  
(t o i ncl u de b ut n ot be 
li mite d t o li m bic 
e nce p halitis a n d 
a ut o n o mic n e ur o pat h y, 
e xcl u di n g M yast he nia 
Gra vis a n d G uillai n -
Barre)  
A n y Gr a de  
( 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 v 5. 0 
f or defi ni n g t he C T C 
gra de/se verit y)  
Ge ner al G ui d a nce  
F o r A n y Gr a de:  
− 
Patie nts s h o ul d be e val u ate 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 nit or patie nt 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 pr iate 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 g y c o ns ult as 
a p pr o priate. 
− 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
7 9  
 
Gr a de 1  
N o d ose m o dificati o ns.  
F o r Gr a de 1:  
− 
See “ A n y Gra de” rec o m m e n dati o ns a b o ve.  
− 
Treat mil d si g ns/s y m pt o ms as Gr a de 1 (e. g.  l oss of dee p 
te n d o n refle xes or parest hesia) 
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/ n e ur o pat hic p ai 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. 
If t o xicit y w orse ns, t he n treat as 
Gra de 3 or 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 i m pr o ves t o Gra de ≤1 a n d 
after c o m pleti o n of ster o i d ta per. 
F o r Gr a de 2:  
− 
C o nsi der, as necessar y, disc ussi n g wit h t h e 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 p re d nis o ne 1 t o 2 m g/ k g/ d a y 
P O or I V e q ui vale nt.  
− 
If n o i m pr o ve me nt wit hi n 3 t o 5 da ys des pite 1 t o 2 m g/ k g/ d a 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 v e t h era p y 
(e. g., I V I G). 
Gr a de 3 or 4  
F o r 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 v e 
t o Gra de ≤1 wit hi n 3 0 da ys. 
 
F o r 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 o r Gr a de 3 or 4:  
− 
C o nsi der, as necessar y, disc ussi n g wit h st u d y p h ysicia n.  
− 
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 v ale nt.  
− 
If n o i m pr o ve me nt wit hi n 3 t o 5 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).  
− 
O nce sta ble, gra d uall y ta per ster oi ds o ver ≥2 8 da ys.  
Peri p her al ne ur o m ot or 
s y n dr o mes 
A n y Gr a de  
Ge ner al G ui d a nce  
F o r A n y Gr a de:  
− 
T h e 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 patie nts ma y 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 0  
(s uc h as G uillai n-Barre 
a n d m yast he nia gra vis)  
u n pre dicta bl y e x perie nce ac ute dec o m pe nsati o ns t h at ca n res ult 
i n s u bsta ntial m or bi dit y or i n t h e w orst case, deat h. S pecial care 
s h o ul d be ta ke 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 n e nt d ys p ha gia, ra pi dl y 
pr o gressi v e 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.  
− 
Patie nts s h o ul d be e val u ate d t o r ule o ut a n y alter nati ve et i 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 h e 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 patie nts wit h u n derl yi n g ca ncer, d ue t o t h e 
m ult i 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 v e n t h e 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 g y 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 mea ns of a 
Ne ur ol o g y c o ns ultati o n.  
− 
It is i m p orta nt t o c o nsi der 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. 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 1  
(G uillai n -Barre [ G B]:  
mil d s y m pt o ms) 
( M yast he nia gra vis 
[ M G]: as y m pt o matic or 
mil d s y m pt o ms; 
cli nical or dia g n ostic 
o bser vati o ns o nl y; 
i nter ve nti o n n ot 
i n dicate d)    
N o d ose m o dificati o ns.  
F o r Gr a de 1:  
− 
C o nsi der, as necessar y, disc ussi n g wit h t h e st u d y p h ys icia n. 
− 
Care s h o ul d be ta ke n t o m o nit or patie nts f or se nti n el s y m pt o ms 
of a p ote ntial dec o m pe nsati o n as descri b e d a b o ve.  
− 
O btai n a Ne ur ol o g y c o ns ult.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 1  
Gr a de 2  
( G B: m o derate 
s y m pt o ms; li miti n g 
i nstr u me ntal A D L) 
( M G: m o derate; 
mi ni mal, l o cal or 
n o ni n vasi ve 
i nter ve nti o n i n dicate d; 
li miti n g a ge-
a p pr o priate 
i nstr u me ntal A D L) 
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 v e t o Gra de ≤1 
wit hi n 3 0 da ys or if t h ere 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 o r Gr a de 2:  
− 
C o nsi der, as necessar y, disc ussi n g wit h t h e st u d y p h ysicia n.  
− 
Care s h o ul d be ta ke n t o m o nit or patie nts f or se nti n el s y m pt o ms 
of a p ote ntial dec o m pe nsati o n as descri b e d a b o ve.  
− 
O btai n a 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).  
 
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 ni a 
gra vis. It is i m p orta nt t o c o nsi der t h at 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  
Patie nts u na b le t o t olerate ster oi ds ma y be ca n di dates 
f or treat me nt wit h plas ma 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 patie nt. 
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 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 h e dia g n osis. 
 
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 h e use of ster oi ds 
as t h e 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  
( Gra de 3 G B: se ver e 
F o r Gr a de 3:  
F o r 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 st u d y p h ysicia n.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 2  
s y m pt o ms; li miti n g self 
care A D L;  
Gra de 4 G B: life-
t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d; 
i nt u bati o n) 
( Gra de 3 M G: se vere or 
me dicall y si g nifica nt 
b ut n ot i m me diatel y 
life-t hreate ni n g; 
h os pitalizati o n or 
pr ol o n gati o n of e xisti n g 
h os pitalizati o n 
i n dicate d; li miti n g self 
care A D L;  
Gra de 4 M G: life -
t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d) 
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 v e 
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 o r 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. 
− 
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 g y 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 n ia 
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  
Patie nts u na ble t o t olerate ster oi ds 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 xicity 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 h e dia g n osis. 
 
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 h e use of ster oi ds 
as t h e 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. 
 
M y oc ar ditis  
A n y Gr a de  
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 o r A n y Gr a de:  
− 
T h e 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, as necessar y, disc ussi n g wit h t h e st u d y p h ysicia n.  
− 
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 p ai n, arr h yt h mia, s h ort n ess 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 u ate 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). A 
Car di 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 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 3  
 
 
assess me nt of w het h er a n d w he n t o c o m plete a car diac bi o ps y, 
i n cl u di n g a n y ot h er dia g n ostic pr oce d ures. 
− 
I nitial w or k-u p s h o ul d i n cl u de cli nical e val u ati o n, B N P, 
car diac e nz y mes, 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 lab 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.  
− 
Patie nts s h o ul d be t h or o u g hl y e val u ate 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 nfe cti o ns) 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 4  
 
 
Gr a de 1  
(as y m pt o matic or mil d 
s y m pt o ms *; cli nical or 
dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot 
i n dicate d) 
* Treat m y ocar ditis wit h 
mil d s y m pt o ms as 
Gra de 2.  
N o d ose m o dificati o ns re q uire d u nless 
cli nical s us pici o n is hi g h, i n w hic h case 
h ol d st u d y dr u g/st u d y re gi me n d ose 
d uri n g dia g n ostic w or k -u p f or ot her 
eti ol o gies. If st u d y dr u g/st u d y re gi me n is 
hel d, res u me after c o m plete res ol uti o n t o 
Gra de 0.  
 
F o r Gr a de 1 ( n o defi niti ve fi n di n gs):  
- 
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, B N P, car diac e nz y mes, E C G, E C H O, 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 as 
cli nicall y i n dicate d. 
- 
C o nsi der usi n g ster oi ds if cli nica l s us pici o n is hi g h. 
 
Gr a de 2, 3 or 4  
( Gra de 2: S y m pt o ms 
wit h m o derate acti vit y 
or e xerti o n)  
 ( Gra de 3: Se vere wit h 
s y m pt o ms at rest or 
wit h mi ni mal acti vit y 
or e xerti o n; i nter -
ve nti o n i n dicate d; ne w 
o nset of s y m pt o ms *)  
( Gra de 4: Life-
t hreate ni n g c o nse-
q ue nces; ur ge nt  
i nter ve nti o n i n dicate d 
(e. g., c o nti n u o us I V 
t h era p y or mec ha nical 
he m o d y na mic s u p p ort))  
 
- If Gra 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  0. If t o xicit y ra pi dl y i m pr o ves t o 
Gra de 0, t h e 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. If t o xicit y d oes n ot 
ra pi dl y i m pr o ve, 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 3-4, 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 o r 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/ d a y or 
e q ui v ale nt after Car di ol o g y c o ns ultati o n has deter mi n e d 
w het h er a n d w he n t o c o m plete dia g n ostic pr oce d ures i n cl u di n g 
a car diac bi o ps y.  
− 
S u p p orti v e care (e. g., o x y ge n).  
− 
If n o i m pr o ve me nt wit hi n 3 t o 5 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, pr o m ptl y start 
i m m u n os u p pressi v e 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 e ver y 2 wee ks). 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 d a nce bef ore usi n g i nfli xi ma b.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, or 
a nti-PJ P treat me nt ( refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 5  
* C o nsi der “ ne w o nset 
of s y m pt o ms” as 
referri n g t o patie nts 
wit h pri or e pis o de of 
m y ocar ditis.  
M y ositis/ P ol y m y ositis 
( “ P ol y/ m y ositis ”) 
A n y Gr a de  
Ge ner al G ui d a nce  
F o r A n y Gr a de:  
− 
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/ p ai n occ urs i n pr o xi mal m uscles 
i n cl u di n g u p per ar ms, t hi g hs, s h o ul d ers, 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 ul t 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 d a 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 d a nce u n der M y ocar ditis. Gi v e n breathi n g 
c o m plicati o ns, refer t o g ui d a nce u n der P ne u m o nitis/I L D.  
Gi v e 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 h e st u d y p h ysicia n.  
− 
I nitial w or k -u p s h o ul d i n cl u de cli nical e val u ati o n, creati ne 
ki n ase, al d olase, L D H, B U N/creati ni n e, e r yt hr oc yte 
se di me ntati o n rate or C-reacti ve pr otei n le vel, uri n e 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 o l 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 d e 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, 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 n cl 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 h e 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. 
Patie nts s h o ul d be t h or o u g hl y e val u ate 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).  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 6  
 
Gr a de 1  
( mil d pai n) 
- N o d ose m o dificati o ns.  
F o r 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 u ati 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 h e st u d y p h ysicia n.  
 
Gr a de 2  
( m o derate p ai n 
ass ociate d wit h 
wea k ness; pai n li miti n g 
i nstr u me ntal acti vities 
of dail y li vi n g [ A D Ls])  
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 v e t o Gra de ≤1 wit hi n 3 0 da ys or 
if t h ere are si g ns of res pirat or y 
i ns ufficie nc y. 
F o r 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 u ati o n.  
− 
C o nsi der, as necessar y, disc ussi n g wit h t h e st u d y p h ysicia n.  
− 
If cli nical c o urse is ra pi dl y pr o gressi v e ( 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 pi dl y pr o gressi v e, start s yste mic 
ster oi ds (e. g., pre d nis o ne 1 t o 2 m g/ k g/ d a y P O or I V 
e q ui v ale nt); if n o i m pr o ve me nt wit hi n 3 t o 5 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 h ere is n o i m pr o ve me nt wit hi n 3 t o 5 da ys, c o nsi der start of 
i m m u n os u p pressi v e 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 e ver y 2 wee ks). 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 d a nce bef ore usi n g i nfli xi ma b.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, or 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 
 
Gr a de 3 or 4  
( Gra de 3: pai n 
ass ociate d wit h se vere 
wea k ness; li miti n g self -
care A D Ls  
 
F o r 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 v e 
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 h e st u d y p h ysicia n.  

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 7  
aA S C O E d ucati o nal B o o k 2 0 1 5 “ Ma na gi n g I m m u ne C hec k p oi nt Bl o c ki n g A nti b o d y Si d e Effects” b y Mic hael P ost o w M D.  
bF D A Li ver G ui d a nce D oc u me nt 2 0 0 9 G ui d a nce f or I n d ustr y: Dr u g I n d uce d Li ver I nj ur y –  Pre mar keti n g Cli nical E val u ati o n.  
A C h E Acet ylc h oli ne esterase; A D L Acti vities of dail y li vi n g; A E A d verse e ve nt;  A L P Al kali ne p h os p hatase test; A L T Ala ni ne a mi n otra nsferase; A S T As partate a mi n otra nsferase; 
B U N Bl o o d urea nitr o ge n; C T C o m p ute d t o m o gra p h y; 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 v e nts; I L D I nterstitial l u n g disease; i m A E i m m u ne -me diate d 
a d verse e ve nt; I G I m m u n o gl o b uli n; I V I ntra ve n o us; GI Gastr oi ntesti nal; L F T Li ver f u ncti o n tests; L L N L o wer li mit of n or mal; M RI  Ma g n etic res o na nce i ma gi n g; N CI  
Nati o nal Ca ncer I nstit ute; N C C N  Nati o nal C o m pre he nsi ve Ca ncer Net w or k; PJ P  P n e u m ocystis jir ovecii  p n e u m o nia (f or merl y k n o w n as P n e u m ocystis c ari nii  p ne u m o nia); 
P O  B y m o ut h; T 3   Trii o d ot h yr o ni n e; T 4 T h yr o xi ne; T B T otal bilir u bi n; T N F T u m or  necr osis fact or; 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. 
 
 
Gra de 4:  life-
t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d) 
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 o r 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.  
− 
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/ d a 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 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 h ere is n o i m pr o ve me nt wit hi n 3 t o 5 da ys, c o nsi der start of 
i m m u n os u p pressi v e 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 e ver y 2 wee ks). 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 d a nce bef ore usi n g i nfli xi ma b.  
− 
C o nsi der w het h er patie nt ma y re q uire I V I G, plas ma p heresis.  
− 
O nce t h e patie nt is i m pr o vi n g, gra d uall y ta per ster oi ds o ver 
≥2 8 da ys a n d c o nsi der pr o p h ylactic a nti bi otics, a ntif u n gals, or 
a nti-PJ P treat me nt (refer t o c urre nt N C C N g ui d eli nes f or 
treat me nt of ca ncer-relate d i nfecti o ns).a 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 8  
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
8 9  
1 2. 1. 3  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 v ersi o n 5. 0)  
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 sta 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 v e t o 
≤Gr a 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 na l 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 h e I n vesti g at or’s cli nical j u d g me nt, a n d 
c o ns ultati o n wit h t h e 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 h a 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 v e nts; N CI Nati o nal Ca ncer I nstit ute.  
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0   
 
J u ne 1 , 2 0 2 1 
 
9 0  
1 2. 1. 4  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  5. 0)  
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 ner al G ui d a nce  
F o r A n y Gr a de:  
− 
Ma na ge per i nstit uti o nal sta n dar d at t h e discreti o n of i n vesti gat or. 
− 
M o nit or patie nts 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 o e 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 o r Gr a de 1:  
T h e 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 o l uti o n of t h e e ve nt. 
 
F o r Gr a de 2:  
T h e 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 o r Gr a de 1 or 2:  
− 
Aceta mi n o p he n a n d/ or a nti hista mi n es 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 o r 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 o r 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 n e, f oll o we d b y I V di p he n h y dra mi n e 
a n d ra niti di ne, a n d I V gl u c 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 v e 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 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
9 1  
1 2. 2  
P atie nt H a n d o ut Pr o hi bite d Me dic ati o ns  
 
T he st u d y me dicati o n (s) y o u are recei vi n g d uri n g t his cli nical trial is 
i m m u n ot hera p y ( d ur val u ma b). It is i m p orta nt f or y o u t o tell y o ur d oct or  if y o u 
st o p ta ki n g a n y re g ular m e dici ne, or if y o u start ta ki n g a ne w me dici ne w hile y o u 
ta ke part i n t his st u d y. W he n y o u tal k a b o ut y o ur me dici ne wit h y o ur st u d y 
d oct or, i ncl u de me dici ne y o u b u y wit h o ut a prescri pti o n at t he dr u g st ore ( o ver -
t he c o u nter re me d y), or a n yt hi n g t hat y o u b u y fr o m t he healt h f o o d st ore or 
gr ocer y st ore ( her bal s u p ple me nt). Ma n y healt h care pres cr i bers ca n write 
prescri pti o ns. Y o u m ust als o tell y o ur ot her pres cri bers ( d oct ors, p h ysicia ns’ 
assista nts or n urse practiti o ners) t hat y o u are ta ki n g part i n a cli nical trial. Bri n g 
t his p a per wit h y o u .  
 
•  W hile recei vi n g d ur v al u m a b a v oi d t he f oll o wi n g:  
o  A n y i n vesti gati o nal a ntica ncer t hera p y ot her t ha n t h ose u n d er 
i n vesti gati o n i n t his st u d y  
o  m A bs a gai nst C T L A -4, P D -1, or P D -L 1 ot h er t ha n t h ose u n der 
i n vesti gati o n i n t his st u d y 
o  C he m ot hera p y, i m m u n ot hera p y, or bi ol o gic or h or m o nal t hera p y f or 
ca ncer treat me nt a part fr o m t h ose u n der i n vesti gati o n i n t his st u d y  
o  I m m u n os u p pr essi 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 os es ≥1 0 
m g/ da y or pre d nis o ne or e q ui vale nt, 
met h otre xate, azat h i o pri n e, a n d t u m or necr osis fact or-α bl oc kers  
o  Dr u gs wit h la xati ve pr o perties a n d h er bal or nat ural re me dies f or 
c o nsti pati o n  
o  S u niti ni b  
o  T yr osi ne ki nase i n hi bit ors t hat tar get E G F R (e g, erl oti ni b, gefi niti b)  
o  Li ve atte n uate d v acci nes –  als o wit h h ol d use f or at least 3 0 da ys after 
disc o nti n ui n g st u d y me dicati o ns  
o  Her bal a n d n at ural re m e dies w hic h ha ve i m m u ne -m o d ulati n g effects 
(e g, gi nse n g, gi n g k o bil o ba, ga n o der m a, astra g al us, etc.) 
•  D o n ot d o nate bl o o d w hile y o u are o n t his st u d y. If y o u per ma ne ntl y st o p 
ta ki ng t he st u d y dr u g ( d ur val u ma b), d o n ot d o nate bl o o d f or at least 9 0 da ys 
after y o u st o p ta ki n g t hes e st u d y dr u gs.  
•  Y o u s h o ul d c hec k wit h y o ur d oct or o r p h ar m acist 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 b al s u p ple me nt.  
o  Y o ur re g ular pres cr i ber s h o ul d c hec k a m e dical refere nce or call 
y o ur st u d y d oct or bef ore pres cri 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 m e is _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ a n d he or s he ca n 
be c o ntact e d at _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _.  
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
9 2  
1 2. 3  
C oc kcr oft -G a ult F or m ul a  
 
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 males:  
 
 
Creati 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)  
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
9 3  
1 2. 4  
E C O G Perf or m a nce St at us  
Gr a d e  
D e s cri pti o n  
0  
N or m al activity. Fully activ e, abl e t o c arry on all pr e dis e as e p erf or m a nc e wit ho ut r estricti on  
1  
Sy m pt o ms b ut a m bul at ory. R estrict ed i n p hysic ally str e nu o us activity, b ut a m b ul at ory an d  
a bl e t o c arry o ut w ork of a li g ht or s e d ent ary n at ur e ( eg, lig ht h o us e w ork, offic e w ork)  
2  
I n b e d < 50 % of th e ti m e. A m bul at ory a n d c a p a bl e of all s elf-c ar e, b ut u n a bl e t o c arry o ut 
a ny w ork activities. U p an d a bo ut m or e t h a n 50 % of w aki n g h o urs.  
3  
I n b e d > 50 % of th e ti m e. C a pa bl e of o nly li mit e d s elf-c ar e, co nfi n e d t o b e d or c hair mor e 
t h a n 5 0 % of w akin g h o urs. 
4  
1 0 0 % b e dri d d e n. C o m pl et ely dis a bl e d. C a n not c arry o n a ny s elf -car e. T ot ally c o nfi n e d t o 
b e d or ch air.  
5  
D e a d.  
S o urc e: Ok e n  M M, Cr e ec h R H, T or m ey D C, H ort o n J, D avis T E, Mc F a d d e n E T et al. T oxicity a n d r es p o ns e crit eri a 
of t h e E ast er n C o o p er ativ e O nc ol o gy Gr o u p. A m J Cli n O nc ol 1 9 8 2; 5 ( 6): 6 4 9 -5 5. 
 
 
 

L C C C 1 7 2 5  
 
C O N FI D E N TI A L  
PI:  Si d S het h, D O  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
A m e n d m e nt # 4 Versi o n 4. 0  
 
J u ne 1 , 2 0 2 1 
 
9 4  
1 2. 5  
F A C T -H N Q u alit y of Life Assess m e nt T o ol  
 
Versi o n 4 is attac he d