Clinical trial NCT03077243
Conditions: Carcinoma, Squamous Cell Head and Neck Neoplasms Oropharyngeal Neoplasms
Keywords: Human Papillomavirus Oropharynx Oropharyngeal Squamous Cell Carcinoma Squamous Cell Carcinoma Radiation Therapy Chemotherapy p16
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2016-12-01; Completion date: 2022-12-14
Enrollment: 195 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study is to evaluate whether genomic based risk-stratification can be used in deciding whether to de-intensify in patients with Human Papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC) with \> 10 pack years smoking history. Hypothesis: Patients with HPV-associated OPSCC, \> 10 pack years smoking history, and non-mutated p53 will have similar 2 year progression-free survival (PFS) as patients with \< 10 pack years smoking history.

Detailed description:
The proposed study is a follow-up study to LCCC 1120 and 1413. The investigators have shown that de-intensification is efficacious in these two phase II studies. A major question is whether the investigators can de-intensify in patients with HPV-associated oropharyngeal cancer who have smoking histories. The investigators' hypothesis is that genomic profiling of patients' tumors (specifically for p53 mutations) will help in triaging patients to de-intensification versus standard of care. Patients with HPV-associated OPSCC will be enrolled regardless of smoking history and p53 mutational status will be assessed in patients with a smoking history. The investigators will use the same de-intensification chemoradiotherapy regimen already evaluated in LCCC 1120 and 1413 in patients with HPV-associated OPSCC who have a minimal smoking history and in patients with a smoking history but with wild-type p53. Patients with a smoking history who have mutated p53 will not receive de-intensified chemoradiotherapy, but instead will receive standard doses. The hypothesis is that by using genomics in the patients with a significant smoking history, the investigators will better select those who can be safely de-intensified. Circulating free HPV DNA (cf-HPV-DNA) will also be prospectively assessed from blood samples.

Arms: arm 1: Subjects with Oropharyngeal Squamous Cell Carcinoma receiving radiotherapy and/or chemotherapy.
Interventions: intervention 1: Intensity Modulated Radiotherapy (IMRT) intervention 2: Cisplatin (or alternative) intervention 3: Assessment for surgical evaluation
Intervention descriptions: intervention 1: 60- 70 Gy at 2 Gy/fx intervention 2: The acceptable weekly chemotherapy regimens are Cisplatin 30 to 40 mg/m2 (first choice), Cetuximab 250mg/m2 (second choice), Carboplatin AUC 1.5 and paclitaxel 45 mg/m2 (third choice), Carboplatin AUC 3 (fourth choice). Chemotherapy will be given intravenously weekly during IMRT, 6 -7 total doses. intervention 3: Decision for surgical evaluation will be based on the results of the PET/CT and clinical exam 10-16 weeks after CRT. Patients with a positive PET/CT scan will undergo surgical evaluation at the discretion of the surgeon. Patients with a negative PET/CT scan will be observed.

Protocol documents:
Prot_SAP_000.pdf: 
LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
R E S E A R C H P R O T O C O L  
S T U D Y N U M B E R( S):  
L C C C 1 6 1 2  
 
P R O T O C O L( S) TI T L E:  
P 5 3 m utati o nal stat us a n d circ ulati n g free H P V 
D N A f or t he m a na ge m e nt of H P V -ass ociate d 
Or o p har y n geal S q ua m o us Cell Ca ncers   
S P O N S O R:  
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
 
A M E N D M E N T N U M B E R:  
 
A me n d me nt 1 5  
V E R SI O N D A T E:  
1 8 A u g ust 2 0 2 3  
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
Pr ot oc ol A me n d me nt # 1 5  
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f or t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers  
A M E N D M E N T I N C O R P O R A T E S:  
_ X _  E dit orial, a d mi nistrati ve c ha n g es  
_ X _  Scie ntific c ha n g es  
_ _  T hera p y c ha n ges  
_ _   Eli gi bilit y C ha n ges  
R ati o n ale f or a me n d me nt:  T he p ur p ose of t his a me n d me nt is t o re m o ve patie nt 
re p orte d assess me nts a n d u p date d pr ot oc ol re p orti n g re q uire me nts.  
E dit ori al, a d mi nistr ati ve c h a n ges:  
T hr o u g h o ut  
_ _ _  
Gra m matical a n d m ec ha nical e dits ma de t hr o u g h o ut  
T hr o u g h o ut  
Pr ot oc ol PI u p d ate d t o Dr. We n d ell Yar br o u g h, a d diti o nal 
c o-i n vesti gat ors a n d st u d y pers o n nel re m o v e d fr o m 
pr ot oc ol.  
Scie ntific c h a n ges:  
Secti o n  
2. 2. 3  
a n d 
3. 2. 3  _ _ _  
Sec o n dar y o bjecti ve a n d e n d p oi nt c o m pari n g hea d a n d n ec k q u alit y of 
life bef ore, d uri n g a n d after C R T re m o ve d.  
Secti o n 
2. 2. 4  
a n d 
3. 2. 4  
Sec o n dar y o bje cti ve a n d e n d p oi nt c o m pari n g s p eec h a n d s wall o wi n g 
f u ncti o n bef ore a n d after C R T re m o ve d.  
Secti o n 5. 1 1  All patie nt assess me nts re m o ve d, i ncl u di n g Q ualit y of Life a n d Patie nt 
Re p orte d O utc o mes as well as S peec h a n d S wall o w e val uati o ns.  
Secti o n 5. 1 2  La n g ua ge d relate d t o Q O Ls, P R Os a n d t he E A T -1 0 assess me nt relati ve 
t o st u d y d urati o n re m o ve d.  
Secti o n 6. 2  
La n g ua ge relati ve t o re p orti n g u p date d t o a d d j usticati o n lac k of trial 
relate d a d vers e e v e nt re p orti n g. La n g ua ge f or affiliate sites a n d U N C 
re m o ve d 
Secti o n 7. 2  
Refere n ces t o Q O Ls, P R Os, a n d s peec h a n d s wall o w f u ncti o n re m o ve d 
fr o m statistical a nal ysis secti o n.  
A p pe n di x  
Q O L, P R O a n d S peec h a n d S wall o w assess me nts re m o ve d.  
A p pe n di x  
Secti o n 1 0. 2 a d de d, Ti me a n d E ve nts ta ble u p d ate d t o ca pt ure c ha n g es t o 
pr ot oc ol st u d y desi g n.  
T H E A T T A C H E D V E R SI O N D A T E D A u g ust 1 8, 2 0 2 3  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  
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 1 4  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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):  
_ _ _ E dit orial, a d mi nistrati ve c ha n ges  
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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
Scie ntific c h a n ges  
 
•  Tar get a ccr ual i ncrease d t o 2 5 0 ( Secti o ns 5. 1 a n d 7. 1)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 6/ 1 7 / 2 0 2 0 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 1 3  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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):  
_ _ _  E dit orial, a d mi nistrati ve c ha n ges  
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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
Scie ntific c h a n ges  
 
•  As of t he date of t his pr ot oc ol, n o bl o o d s peci me ns will be o btai ne d be y o n d Wee k 
4 of  treat me nt.  ( Secti o n 5. 5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 5/ 0 8/ 2 0 2 0 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 1 2  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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 ges  
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)  
X     Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  A d d
 as a C o-I n v esti gat or (c o ver pa ges) 
 
Scie ntific c h a n ges  
 
•  Tar get a ccr ual i ncrease d t o 2 0 0 ( Secti o ns 5. 1 a n d 7. 1)  
•  Bl o o d c ollecti o n ti me p oi nts re vise d ( Secti o n 5. 5, Ti me a n d E ve nts ta ble 
[ A p pe n di x]) 
 
Eli gi bility c h a n ges  
 
•  C urre nt acti ve s m o kers e xcl u de d ( Secti o ns 4. 2, Eli gi bilit y C hec klist [ A p pe n di x])  
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 1/ 0 7/ 2 0 2 0 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
P R O T O C O L A M E N D M E N T # 1 1  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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 ges  
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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  A d d 
, M D as a C o-I n v esti gat or (c o ver pa ges) 
 
Scie ntific c h a n ges  
 
•  Tar get a ccr ual i ncrease d t o 1 8 0 ( Secti o ns 5. 1 a n d 7. 1)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 1 0/ 0 9/ 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 1 0  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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):  
_ _ _    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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
Scie ntific c h a n ges  
 
•  N u m ber of bl o o d t u bes t o be c ollecte d at eac h ti me p oi nt f or U N C -C H pati e nts 
i ncreas e d t o t w o ( Secti o n 5. 5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 7/ 0 1 / 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 9  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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 ges  
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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  Clarificati o n re gar di n g p ote ntial a d diti o nal p ost -treat me nt bl o o d dra ws ( Secti o n 
5. 5)  
 
Scie ntific c h a n ges  
 
•  Tar get a ccr ual i ncrease d t o 1 6 0 ( Secti o ns 5. 1 a n d 7. 1) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 5 /2 9 / 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
P R O T O C O L A M E N D M E N T # 8  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f or t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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 ges  
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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  C o -i n vesti gat or list u p date d ( C o ver pa g es) 
 
 
Scie ntific c h a n ges  
 
•  Details o n cf H P V -D N A a nal yses m o difie d as f oll o ws ( Secti o n s 5. 1 a n d 5. 5 , Ti me 
a n d E ve nts ta ble ): 
o  Bl o o d dra ws re d uce d t o 2 ti me p oi nts d uri n g treat me nt ( vs. 6)  
o  T w o t u bes t o be dra w n fr o m U N C -C H patie nts at baseli ne ( vs. 1)  
o  A d diti o nal t u bes ma y be dra w n p ost -treat me nt at PI’s discreti o n  
•  Fle xi bilit y i n ti mi n g all o we d f or p ost -tr eat me nt c hest xra ys a n d t h yr oi d la bs 
( Ti me a n d E ve nts ta ble) 
•  A E re p orti n g r e q uire me nts li mite d t o wit hi n 3 0 da ys  f oll o wi n g cessati o n of 
treat me nt ( Secti o n 6. 2) 
•  Patie nt assess me nts m o difie d as f oll o ws ( Secti o ns 5. 1 1. 1 a n d 5. 1 2, Ti me a n d 
E ve nts ta ble):  
o  T hr o u g h year 5 p ost -treat me nt o nl y 
o  Disc o nti n ue d u p o n ca ncer rec urre n ce  
•  T otal tar get accr ual i ncrease d fr o m 1 2 0 t o 1 4 0 ( Secti o ns 5. 1 a n d 7. 1)  
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 2/ 0 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 7  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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):  
_ _ _    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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
Scie ntific c h a n ges  
 
•  M o difie d t o i n dicate t hat, i n a d diti o n t o patie nts wit h > 1 0 pac k years s m o ki n g 
hist or y, t h ose wit h a n e xte nsi ve s m o keless t o bacc o hist or y ma y als o recei ve 
ge netic testi n g of t heir t u m or ( base d o n t he PI’s assess me nt) t o deter mi ne recei pt 
of de -i nte nsife d tr eat me nt (secti o ns 1. 8, 5. 1, a n d 5. 4). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 6/ 0 1/ 2 0 1 8 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # 6  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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):  
_ _ _    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)  
X       T hera p y c ha n g es (I R B a p pr o val)  
_ _ _    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
T her a py c h a n ges  
 
•  Treat me nt pla n re vise d s uc h t hat f or patie nts wit h T 0 -2 N 0 -1 diseas e, > 1 0 pac k 
years s m o ki n g hist or y, c he m ot hera p y will be at t h e discreti o n of t he treati n g 
p h ysicia n (secti o n 5. 7).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 5 / 02 / 2 0 1 8 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # 5  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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) 
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  A d diti o n of Bl u m ber g ( U N C) (c o ver pa ges)  
•  E dit S O P refere n ce n u m ber (secti o n 6. 2)  
 
Scie ntific c h a n ges  
 
•  FI S H a n al ysis of C C N D 1  b y t he U N C C yt o ge ntics La b orat or y h as bee n 
eli mi nate d (secti o n s 1. 8 , 5. 1,  5. 4 )   
•  Re vise n u m ber of sli des nee de d f or ge n etic testi n g (secti o n 5. 4)  
•  E x pa n de d wi n d o w of p ost -treat me nt M o difie d Bari u m S wall o w (secti o n 5. 1 1. 2, 
Ti me a n d E ve nts ta ble)  
•  Clarificati o n of ti me p oi nt f or first p ost -treat me nt t h yr oi d f u ncti o n testi n g ( Ti me 
a n d E ve nts ta ble)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 3/ 0 8/ 2 0 1 8 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # 4  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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)  
X       T hera p y c ha n g es (I R B a p pr o val)  
_ _ _    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  C o -i n vesti gat or c ha n ges:  a d diti o n of  
 ( U F P TI), re m o v al of  
 
( U N C),  
 ( U N C), N. 
 ( U N C), 
 ( U N C),  
( U N C), 
 
( Re x) (c o v er pa g es) 
•  Ne w site: U ni versit y of Fl ori da Pr ot o n T hera p y I nstit ute (c o ver pa g es, secti o ns 
1. 1 a n d 8. 4)  
•  Re visi o n/clarificati o n of p ost -treat me nt bl o o d dra ws a n d s hi p pi n g ti mefra me 
(secti o n 5. 5) 
•  All o w f or discreti o n of  ti mi n g of p ost-treat me nt lar y n g osc o p y ( A p p e n di x - Ti me 
a n d E ve nts ta ble ) 
•  Clarificati o n of sta gi n g g ui deli nes  f or eli gi bilit y ( AJ C C 7t h e diti o n) (secti o n 4. 1. 2)  
 
Scie ntific c h a n ges  
 
•  I n crease i n tar get accr ual t o 1 2 0 (secti o n 7. 1) 
 
 
T her a py c h a n ges  
 
•  A d diti o n of pr ot o n ra di ot hera p y as all o wa ble R T (secti o n 5. 6)  
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 7 /0 7 / 2 0 1 7 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # 3  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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)  
_ _ _    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  A d diti o n of t hree U F L c o -i n vesti gat ors:  Sil ver, G o pala n, a n d Da n g; s pelli n g 
c orrecti o n f or Dz ie giele ws ki (c o ver pa ges) 
•  M o dificati o n t o re gistrati o n  pr oce d ures t o clarif y t he re q uire m e nts t hat patie nts 
be re gistere d wit h U N C pri or t o e nr oll me nt o n t he st u d y a n d t hat t he U N C st u d y 
c o or di nat or c o nfir m eli gi bilit y criteria pri or t o treat me nt start (secti o n 8. 3)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 1/ 2 5/ 2 0 1 7 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # 2  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
 
•  Clarificati o n t hat H P V a n d/ or  p 1 6 testi n g t o be perf or me d, a n d t his testi n g ma y be 
perf or me d at o utsi de i nstit uti o ns ( secti o n 5. 3, Ti me a n d E ve nts Ta bl e) 
•  Clarificati o n t hat sites ma y se n d t u m or bl oc k f or ge netic assess me nt (s ecti o n 5. 4)  
•  D etails a d de d re gar di n g bl o o d sa m ples f or cf H P V -D A N, i ncl u di n g s hi p pi n g 
a d dress (s ecti o n 5. 5)  
•  
 a n d 
 m o ve d fr o m C o -I n vesti gat ors t o C o-Pri nci pal 
I n v esti gat ors (c o v er pa g es) 
•  Delete 
 as C o-I n v esti gat or, a n d a d d 
 a n d  
 
 (c o v er pa g es) 
•  Clarificati o n of A E re p orti n g (secti o n 6. 2)  
•  Clarificati o n of ti mi n g f or pre -t x M B S (secti o ns 3. 2. 4, 5. 1 1. 2, Ti me a n d E v e nts 
Ta ble)  
•  Clarificati o n of ti mi n g f or first p ost -C R T c hest x -ra y ( Ti me a n d E v e nts Ta ble) 
 
Scie ntific c h a n ges  
 
•  Re visi o n t o data a nal ysis pla n t o all o w f or a d diti o n al a nal yses of st u d y dat a 
(secti on 7. 2 ) 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 1 1 / 22 / 2 0 1 6 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # 1  
 
 
L C C C 1 6 1 2: P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers    
 
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 ges  
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)  
X    Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit ori al, a d mi nistr ative c h a n ges  
•  Clarificati o n of a u dit pr ocess ( sectio n 9. 4), o bli gati o ns of i n vesti gat ors (secti o n 
9. 8), a n d rec or d rete nti o n (secti o n 9. 7)  
•  Secti o n 6. 2 e dite d t o i ncl u de e xtra c he m ot hera p y d ose f or t h o se s u bjects wit h a 
p 5 3 m utati o n  
•  Clarificati o n of bl o o d c ollecti o n a n d s hi p pi n g pr ocess b y ot her partici p ati n g sites 
(secti o n 6. 0) 
•  T u m or pa nel s peci me n re q uire me nts re m o ve d fr o m A p pe n di x a n d perti ne nt 
i nf or mati o n a d de d t o secti o n 5. 4 
•  Sc he ma i n Secti o n 5. 1 rela bele d as Fi g ure 2  
Scie ntific c h a n ges  
•  Clarificati o n of ti me p oi nts f or Q O L a n d S wall o wi n g assess me nts (secti o ns 3. 2. 3, 
3. 2. 4, 6. 6. 1, 6. 6. 2 ) 
•  C orrecti o n of d ose c o nstrai nts (secti o n 6. 1. 4)  
•  Re visi o ns t o Ti me a n d E ve nts Ta ble ( a p p e n di x)  
Eli gi bility c h a n ges  
•  Re visi o ns t o eli gi bilit y criteria m o dif yi n g ti me fra me of select i ncl usi o n critieria 
( pri or t o treat me nt r at her t ha n pri or t o re gistrati o n) a n d a d di n g e xcl usi o n critieria 
(s yste mic l u p us, ps oriatic art hritis) (secti o n 4. 0 a n d ap pe n di x)  
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D 0 9/ 2 1/ 2 0 1 6 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  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
L C C C 1 6 1 2  
P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f or t he m a n a ge me nt of 
H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers  
C O N FI D E N TI A LI T Y A N D I N V E S TI G A T O R S T A T E M E N T  
T he i nf or mati o n c o ntai ne d i n t his pr ot oc ol are c o nfi de ntial a n d pr o prietar y i nf or mati o n of 
Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter,  a n d e x ce pt as ma y be re q uire d b y fe deral, state , 
or l ocal la ws or re g ulati o n, ma y n ot b e discl ose d t o ot hers wit h o ut pri or writte n per missi o n 
of Li ne ber ger C o m pre h e nsi ve Ca ncer Ce nt er . 
I ha v e rea d t he pr ot oc ol, i ncl u di n g all a p pe n dices, a n d I a gree t hat it c o ntai ns all of t he 
necessar y i nf or mati o n f or me a n d m y staff t o c o n d u ct t his st u d y as descri be d. I will c o n d uct 
t his st u d y as o utli ne d herei n, i n acc or da nce wit h t he re g ulati o ns stated i n t he Fe d eral C o de 
of Re g ulati o ns f or G o o d Cli nical Practices a n d I nt er nati o nal C o nfere nce o n Har m o nizati o n 
g ui deli nes a n d will ma ke a reas o n a ble eff ort t o c o m plete t he st u d y wit hi n t he ti me 
desi g nate d.  
I will pr o vi de all st u d y pers o n nel u n der m y s u p er visi o n c o pies of t he pr ot oc ol a n d a n y 
a me n d me nts, a n d access t o all i nf or mati o n pr o vi de d b y Li ne ber ger C o m pre he nsi ve Ca ncer 
Ce nter  or s pecifie d d esi g nees. I will disc uss t he material wit h t he m t o e ns ure t hat t he y are 
f ull y i nf or me d a b o ut t he st u d y. 
 
Pri nci pal I n v esti gat or Na me ( pri nte d)  
Si g nat ure  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Date  
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
L C C C 1 6 1 2 : P 5 3 m ut ati o n al st at us a n d circ ul ati n g free H P V D N A f o r t he 
m a n a ge me nt of H P V -ass oci ate d Or o p h ar y n ge al S q u a m o us Cell C a ncers  
 
Pri nci p al I n vesti g at or  
We n dell Yar br o u g h , M D  
Pr ofess or  
De part me nt of Ot olar y n g ol o g y  
1 0 1 Ma n ni n g Dri ve, Ca m p us B o x 7 0 7 0  
C ha pel Hill, N C  2 7 5 9 9 -7 0 7 0  
( 9 1 9) 8 4 3-7 0 9 1 ( p h o ne)  
E mail: dell @ me d. u nc.e d u  
 
 
Bi ost atistici a n  
Xia n mi n g Ta n, P h D  
Assista nt Pr ofess or  
De part me nt of Bi ostatistics  
 
 
S p o ns or :  Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter 
 
 
 
 
Versi o n D ate:  8/ 1 8/ 2 0 2 3  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
i 
T A B L E O F C O N T E N T S  
C o nt e nt s  
S U M M A R Y O F C H A N G E S  ............................................................................................. i 
C O N FI D E N TI A LI T Y A N D I N V E S TI G A T O R S T A T E M E N T  .............................. x vii  
L C C C 1 6 1 2: P 5 3 m utati o nal stat us a n d circ ulati n g free H P V D N A f or t he ma na ge me nt 
of H P V -ass ociat e d Or o p har y n geal S q ua m o us Cell Ca ncers  ......................................... x viii  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  ..................................................................6  
1. 1  
St u d y S y n o psis  ......................................................................................................6  
1. 2  
Sta n dar d of care C R T f or O P S C C .........................................................................6  
1. 3  
H P V relate d O P S C C  .............................................................................................6  
1. 4  
Pr os pecti ve Cli nical Data o n H P V p ositi ve H N S C C  ............................................7  
1. 5  
U N C De -i nte nsific ati o n c he m ora di ot hera p y re gi me n ...........................................8  
1. 6  
Ge n o mic c haract erizati o n of H P V -ass ociat e d a n d T o bacc o -ass ociat e d 
Or o p har y n geal c a ncer  .......................................................................................................9  
1. 7  
Circ ulati n g free H P V D N A (cf H P V -D N A)  ........................................................1 0  
1. 8  
Rati o nale ..............................................................................................................1 0  
2. 0  
S T U D Y O B J E C TI V E S  .........................................................................................1 1  
2. 1  
Pri mar y O bjecti ve:  ..............................................................................................1 1  
2. 2  
Sec o n dar y O bj ecti ves  ..........................................................................................1 1  
3. 0  
E N D P OI N T S  .........................................................................................................1 2  
3. 1  
Pri mar y E n d p oi nt  ................................................................................................1 2  
3. 2  
Sec o n dar y E n d p oi nts  ...........................................................................................1 2  
4. 0  
P A TI E N T E LI GI BI LI T Y  ....................................................................................1 2  
4. 1  
I n cl usi o n Criteria .................................................................................................1 2  
4. 1. 1  
≥ 1 8 years of a ge ( n o u p p er a ge li mit)  ............................................................... 1 2  
4. 1. 2  
T 0 -3, N 0 t o N 2c, M 0 s q u a m o us cell carci n o ma of t he or o p har y n x ( AJ C C 7 t h 
e diti o n) 1 2  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
ii 
4. 1. 3  
Bi o ps y pr o ve n s q ua m o us cell carci n o ma t hat is H P V a n d/ or p 1 6 p ositi ve  ....... 1 2  
4. 1. 4  
Ra di ol o gic c o nfir mati o n of t he a bse n ce of he mat o ge n o us metastasis wit hi n 1 2 
wee ks pri or t o treat me nt; at a mi ni m u m, c hest x -ra y is re q uire d. C T i ma gi n g of t he c hest 
or P E T/ C T is acce pta ble.  .................................................................................................. 1 2  
4. 1. 5  
E C O G Perf or ma n ce Stat us 0 -1  .......................................................................... 1 2  
4. 1. 6  
C B C/ differe ntial o btai ne d wit hi n 8 wee ks pri or t o treat me nt, wit h a de q u ate b o ne 
marr o w f u ncti o n defi ne d as f oll o ws:  ................................................................................ 1 2  
4. 1. 7  
A de q uate re nal a n d h e patic f u ncti o n wit hi n 4 wee ks pri or t o treat me nt, defi n e d 
as f oll o ws:  ......................................................................................................................... 1 2  
4. 1. 8  
Ne gati ve pre g na nc y t est wit hi n 2 wee ks pri or t o treat me nt f or w o m e n of 
c hil d beari n g p ote ntial ........................................................................................................ 1 3  
4. 1. 9  
W o me n of c hil d beari n g p ote ntial a n d male partici pa nts w h o are s e x uall y acti ve 
m ust practice a d e q uate c o ntrace pti o n d uri n g treat me nt a n d f or 6 wee ks f oll o wi n g 
treat me nt. .......................................................................................................................... 1 3  
4. 1. 1 0  
Patie nts m ust be dee me d a ble t o c o m pl y wit h t he treat me nt pla n a n d f oll o w -u p 
sc he d ule............................................................................................................................. 1 3  
4. 1. 1 1  
Patie nts m ust pr o vi de st u d y s pecific i nf or m e d c o nse nt pri or t o st u d y e ntr y  ..... 1 3  
4. 2  
E xcl usi o n Criteria  ................................................................................................1 4  
4. 2. 1  
Pri or hist or y of ra diati o n t hera p y t o t he hea d a n d n ec k  ..................................... 1 4  
4. 2. 2  
Pri or hist or y of hea d a n d nec k ca ncer.  ............................................................... 1 4  
4. 2. 3  
U nresecta ble diseas e (e. g. i m m o bile n o de o n p h ysical e xa m, n o d al disease t hat 
ra di o gra p h gic all y i n v ol ves t he car oti d arteries, n er ves) ................................................... 1 4  
4. 2. 4  
C urre ntl y ta ki n g Disease M o dif yi n g R he u mat oi d Dr u gs ( D M R Ds)  ................. 1 4  
4. 2. 5  
Se vere, acti ve c o -m or bi dit y, defi ne d as f oll o ws:  ............................................... 1 4  
4. 2. 6  
K n o w n HI V p ositi ve.  ......................................................................................... 1 4  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
iii 
 .... C urre nt acti ve s m o ker, defi ne d as acti ve ci garette s m o ki n g wit hi n t he 6 m o nt hs pri or t o 
e nr oll me nt.  ........................................................................................................................ 1 4  
4. 2. 7 ................................................................................................................................... 1 4  
5. 0  
S T U D Y P L A N  .......................................................................................................1 5  
5. 1  
Sc he ma  ................................................................................................................1 5  
5. 2  
Pretreat me nt E val u ati o ns:  All patie nts will ha ve sta n dar d of care e val u ati o n a n d 
sta gi n g pr oce d ures. .........................................................................................................1 5  
5. 2. 1  
C o m plete hist or y a n d p h ysical e xa m i ncl u di n g wei g ht a n d perf or ma n ce stat us.
 
1 5  
5. 2. 2  
C o m pleti o n of pa ne n d osc o p y wit h directe d bi o psi es a n d bilateral t o nsillect o mies 
if t he pri mar y is u n k n o w n is str o n gl y rec o m me n d e d, b ut n ot re q uire d. ........................... 1 5  
5. 2. 3  
C o m pleti o n of t he f oll o wi n g ra di ol o gical st u dies:  ............................................. 1 5  
5. 2. 4  
C o m plete de ntal e val uati o n is rec o m me n de d. .................................................... 1 6  
5. 2. 5  
C o m pleti o n of t he f oll o wi n g la b orat or y st u dies: C B C, ser u m c he mistries, li ver 
f u ncti o n tests, a n d pre g n a nc y test if fe m ale. ..................................................................... 1 6  
5. 3  
H P V a n d/ or p 1 6 testi n g  .......................................................................................1 6  
5. 4  
Ge netic Assess me nt .............................................................................................1 6  
5. 5  
Circ ulati n g free H P V -D N A (cf H P V -D N A)  ........................................................1 7  
5. 6  
Ra diati o n T hera p y  ...............................................................................................1 7  
5. 6. 1  
C T si m ulati o n  ..................................................................................................... 1 7  
5. 6. 2  
Tar get a n d Or ga n at Ris k V ol u mes:  ................................................................... 1 8  
5. 6. 3  
I M R T/ Pr ot o n Treat me nt Pla n ni n g ..................................................................... 1 9  
5. 6. 4  
D ose C o nstrai nts:  ............................................................................................... 1 9  
5. 6. 5  
Treat me nt V erificati o n  ....................................................................................... 2 0  
5. 6. 6  
Ra diati o n Treat me nt Brea ks  ............................................................................... 2 0  
5. 7  
C he m ot hera p y  .....................................................................................................2 0  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
i v 
5. 7. 1  
D ose M o dificati o ns f or c he m ot hera p y  ............................................................... 2 1  
5. 7. 2  
C ha n gi n g C he m ot hera p y Re gi me ns  ................................................................... 2 1  
5. 8  
P ost -C he m ora di ot hera p y Assess me nt of Cli nical Res p o nse  ...............................2 1  
5. 9  
S ur ger y after C R T  ...............................................................................................2 1  
5. 1 0  
Ot her T hera p y  .....................................................................................................2 1  
5. 1 0. 1  
Per mitte d S u p p orti ve T hera p y  ........................................................................... 2 1  
5. 1 0. 2  
N o n -per mitte d S u p p orti ve T hera p y  ................................................................... 2 2  
5. 1 0. 3  
Ot her S u p p orti ve Care Cli nical St u dies  ............................................................. 2 2  
5. 1 1  
D urati o n of St u d y  ................................................................................................2 2  
5. 1 2  
D urati o n of F oll o w U p  ........................................................................................2 2  
6. 0  
A D V E R S E E V E N T S  ............................................................................................2 3  
6. 1  
Defi niti o n  ............................................................................................................2 3  
6. 2  
Re p orti n g  .............................................................................................................2 3  
6. 3  
Treat me nt of A d v erse E v e nt  ...............................................................................2 3  
7. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................2 4  
7. 1  
St u d y Desi g n/ St u d y E n d p oi nts  ...........................................................................2 4  
7. 2  
Data A nal ysis Pla n  ..............................................................................................2 7  
7. 3  
Safet y Meeti n gs  ...................................................................................................2 7  
8. 0  
S T U D Y M A N A G E M E N T  ....................................................................................2 7  
8. 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 ..................................2 7  
8. 2  
Re q uire d D oc u me nt ati o n .....................................................................................2 8  
8. 3  
Re gistrati o n Pr oce d ures .......................................................................................2 8  
8. 4  
Data Ma na g e me nt a n d M o nit ori n g/ A u diti n g  ......................................................2 8  
8. 5  
A d here n ce t o t he Pr ot oc ol  ...................................................................................2 9  
8. 5. 1  
E mer ge nc y M o difi cati o ns  .................................................................................. 2 9  
8. 5. 2  
Si n gle Patie nt/ S u bject E xce pti o ns  ...................................................................... 2 9  
8. 5. 3  
Ot her Pr ot oc ol De viati o ns/ Vi olati o ns  ................................................................ 3 0  
8. 6  
A me n d me nts t o t he Pr ot oc ol  ...............................................................................3 1  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
v  
8. 7  
Rec or d Rete nti o n  .................................................................................................3 1  
8. 8  
O bli gati o ns of I n v esti gat ors  ................................................................................3 1  
9. 0  
R E F E R E N C E S  ......................................................................................................3 3  
1 0. 0  A P P E N DI X  ............................................................................................................3 6  
1 0. 1  
Eli gi bilit y C hec klist .............................................................................................3 7  
1 0. 2  
Ti me a n d E ve nts Ta ble  ..........................................................................................1  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
6  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
St u d y S y n o psis  
T he pr o p ose d st u d y is a f oll o w -u p st u d y t o L C C C 1 1 2 0 a n d 1 4 1 3.  We h a ve o bser ve d a n 
e xcelle nt pat h ol o gical c o m plete res p o nse rate ( L C C C 1 1 2 0) a n d pr o gressi o n free s ur vi val 
( P F S) ( L C C C 1 41 3 ) i n patie nts wit h H P V p ositi ve a n d/ or p 1 6 p ositi ve l o w-ris k 
or o p har y n geal s q ua m o us cell carci n o ma ( O P S C C) w h o recei ve d de-i nte nsifie d 
c he m ora di ot hera p y ( C R T).  We h a ve s h o w n t hat de -i nte nsificati o n is efficaci o us i n t hese 
t w o p hase II st u dies.  We are lea ders i n t he ge n o mic classificati o n of h ea d a n d nec k 
ca ncer, a n d i n vesti gat ors at L C C C 
) ha ve s h o w n t hat H P V-
ass ociate d or o p h ar y n geal ca ncer ha s a u ni q ue ge n etic pr ofile.  A maj or q u esti o n is 
w het her w e ca n d e -i nte nsif y i n patie nts wit h H P V-ass ociate d or o p h ar y n geal ca ncer w h o  
ha ve  s m o ki n g hist ories. T he ai m of t he c urre nt st u d y is t o b uil d u p o n o ur t w o p hase II 
st u dies a n d t he ge n o mic pr ofili n g st u dies.  O ur h y p ot hesis is t hat ge n o mic pr ofili n g of 
patie nt s’ t u m ors (s pecificall y f or p 5 3 m utati o ns) will hel p i n tria gi n g patie nts t o de -
i nte nsificatio n vers us sta n dar d of care. We will e nr oll patie nts wit h H P V -ass ociate d 
O P S C C re gar dless of s m o ki n g hist or y a n d will assess p 5 3 m utati o nal s tat us i n patie nts 
wit h a s m o ki n g hist or y.  We will use t he sa me de -i nte nsificati o n c he m ora di ot hera p y 
re gi me n we h a ve alrea d y e val uate d i n L C C C 1 1 2 0 a n d 1 4 1 3 i n patie nts wit h H P V -
ass ociate d O P S C C w h o ha ve a mi ni mal s m o ki n g hist or y a n d i n patie nts wit h a s m o ki n g 
hist or y b ut wit h wil d -t y pe p 5 3.  If patie nts wit h a s m o ki n g hist or y ha ve m utate d p 5 3  t he y 
will n ot recei ve de -i nte nsifie d c he m or a di ot hera p y, b ut i nstea d will recei ve sta n dar d 
d oses.  O ur pri mar y o bj ecti ve will be 2 year P F S.  I n L C C C 1 4 1 3  t he pri m ar y n ull 
h y p ot hesis was 2 year P F S of 8 7 %.  We h y p ot hesi ze, t hat b y usi n g ge n o mics i n t he 
patie nts wit h a si g nica nt s m o ki n g hist or y we will better select t h ose w h o we ca n safel y 
de -inte nsif y  a n d t hat t he 2 year P F S will i m pr o ve t o 9 3 %. We will als o pr os p ecti vely 
assess circ ulati n g free H P V D N A  (cf-H P V -D N A)  fr o m bl o o d sa m ples.  T his st u d y will 
be m ulti -i nstit uti o nal, wit h patie nts als o e nr olli n g at t he U ni versit y of Fl ori da, 
Gai nes ville, Fl ori da ; t he U ni versit y of Fl ori da Pr ot o n T hera p y I nsit ute, Jac ks o n ville, F L ; 
a n d Re x Ca ncer Ce nter of Ralei g h, R alei g h, N ort h Car oli na . 
1. 2  
St a n d ar d of c are C R T f or O P S C C  
T he sta n dar d treat me nt r e gi me n f or H P V -ass ociat e d or o p har y n geal or u n k n o w n pri mar y 
s q ua m o us cell carci n o ma of t he hea d a n d nec k is 7 0 G y, 2 G y per da y, 3 5 fracti o ns, o ver 
7 wee ks wit h 2 t o 3 d oses of cis plati n 1 0 0 m g/ m 2.  M ost i nstit uti o ns perf or m  a P E T/ C T at 
1 0 t o 1 6  wee ks  aft er C R T  t o assess res p o nse.  De pe n di n g o n t he cli nical res p o nse, 
patie nts ma y ha ve t o ha v e a bi o ps y of t he pri mar y site a n d/ or a nec k dissecti o n after 
treat me nt. T y picall y pati e nts wit h a ne gati ve P E T/ C T sca n are o bs er ve d (i.e. n o s ur ge r y).  
Sta n dar d C R T is ass ociate d wit h si g nifica nt ac ute t o xicity wit h m ost patie nts 
e x perie n ci n g gra d e 3 a n d 4 ac ute t o xicit y d uri n g tr eat me nt.  F urt h er m ore, a p pr o xi matel y 
2 0 % of patie nts wi ll ha ve Gra de 3 -4 l o n g -ter m m or bi dit y relate d t o t heir defi niti ve C R T. 
1. 3  
H P V rel ate d O P S C C  
T he i nci de nce of O P S C C is i ncreasi n g a n d is t h o u g ht t o be sec o n dar y t o H P V i nfecti o n 
of t he or o p har y n geal m u c osa 1 -8.   E vi de nce is acc u m ulati n g t hat s u g gests t hat H P V-


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
7  
p ositi ve H N S C C ma y be a disti nct cli nical a n d bi ol o gical e ntit y.  T he affect e d i n di vi d uals 
are m or e li kel y t o be w hite me n, y o u n ger t ha n 6 0 years of a ge, u n marrie d, a n d ha ve a 
mi ni mal hist or y of alc o h ol or t o bacc o use 3 ,9 -3 0.  H P V-p ositi ve H N S C C ha s a hi g her 
res p o nse rate t o ne oa dj u v a nt c he m ot hera p y a n d i n ge neral h as a better pr o g n osis t o 
t hera p y as c o m pare d t o H P V-ne gati ve H N S C C 1 0 ,1 3 ,1 8 ,1 9 ,2 2.  Bi ol o gicall y, t he H P V 
o nc o pr otei ns E 6 a n d E 7 i nacti vate t he t u m or s u p press or pr otei ns p 5 3 a n d p R b, 
res pecti vel y. I n acti vati o n of p R B b y E 7 lea ds t o u pre g ulati o n of t he p 1 6 t u m or s u p press or 
pr otei n.  T h us, o vere x pressi o n of p 1 6 ma y be re g ar de d as a bi o ma r ker f or H P V-p ositi ve 
H N S C C 1 8 ,2 9.  F urt her m ore, H P V-p ositi ve H N S C C is m ore li kel y t o be ass ociate d wit h a 
wil d -t y pe p 5 3, u nli ke t o bacc o -i n d u ce d H N S C C1 1.  Beca use of t h e o bser ve d i m pr o ve d 
pr o g n osis a n d disti nct m olec ular pr ofile, s o me ha ve s u g geste d t hat H P V -p ositi ve t u m ors 
ma y be m ore se nsiti ve t o C R T.  T he sta n dar d C R T re gi me n f or m ost H N S C C is 7 0 G y 
wit h 3 c ycles of c o n c urre nt cis plati n at 1 0 0 m g/ m 2 3 1. L ess i nte nsi ve c he m ot hera p y a n d/ or 
ra diati o n ma y be j ust as effecti ve i n H P V-relat e d or o p har y n geal H N S C C a n d re d uce t h e 
se verit y of ac ute t o xicit y a n d l o n g-ter m m or bi dit y ass ociate d wit h C R T.  
1. 4  
Pr os pecti ve Cli nic al D at a o n H P V p ositi ve H N S C C  
N u mer o us retr os p ecti ve st u dies ha ve s h o w n t hat p atie nts wit h H P V -p ositi ve H N S C C 
ha ve a si g nifica ntl y better pr o g n osis t ha n patie nts wit h H P V -ne gati ve H N S C C 5 ,2 5 ,2 9.  
T hese preli mi nar y data h a ve bee n verifi e d i n a nal yses of pr os pecti ve cli nical trials 1 0 ,1 3 ,1 8.  
Fa k hr y et al. e val u ate d t h e H P V stat us of 9 6 patie nts wit h lar y n geal or or o p har y n geal 
S C C fr o m a n Easter n  C o o perati ve O nc ol o g y Gr o u p ( E C O G) p has e II trial.  Patie nts wit h 
H P V p ositi ve t u m ors ha d hi g her res p o nse rates aft er i n d ucti o n c he m ot hera p y ( 8 2 % vs. 
5 5 %, p = 0. 0 1) a n d C R T  ( 8 4 % vs. 5 7 %, p = 0. 0 0 7) as c o m pare d t o t h ose wit h H P V-
ne gati ve t u m ors.  T he 2 y ear o verall s ur vi val w as als o i m pr o ve d  - 9 5 % ( H P V p ositi ve) 
vs. 6 2 % ( H P V ne gati ve). Lasse n et al. a n al yze d t h e Da nis h Hea d a n d Nec k Ca ncer Gr o u p 
( D A H A N C A) 5 trial a n d o bser ve d a n i m pr o ve d l ocal-re gi o nal c o ntr ol, disease s pecifi c 
s ur vi val, a n d o verall s ur vi val i n patie nts w h ose t u m ors were p 1 6 p ositi ve (a s urr o gate 
mar ker f or H P V) v ers us t h ose w h o were p 1 6 ne g ati ve 1 8.   
 
T he R T O G 0 1 2 9 pr os pecti ve ra n d o mize d trial als o vali date d H P V p ositi vit y as bei n g a 
str o n g, i n de pe n de nt pr o g n ostic fact or f or o verall a n d pr o gressi o n free s ur vi val 1 0.   R T O G 
0 1 2 9 c o m pare d accelerate d fracti o nati o n ra di ot hera p y wit h sta n dar d fracti o nati o n, b ot h 
wit h c o nc urre nt cis plati n ( 2 c ycles i n t he f or mer a n d 3 c ycles i n t he latter).  T here was n o 
statistical differe n ce i n o verall or pr o gressi o n free s ur vi val bet wee n t h e t w o ar ms.  P ost -
h oc a nal ysis of H P V stat us a n d o utc o mes i n t he O P S C C s u bset s h o we d a si g nifica nt 
i m pr o ve me nt i n O S ( 8 2. 4 %, vs. 5 7. 1 % at 3 year; P < 0. 0 0 1) a n d P F S i n t he H P V p ositi ve 
t u m ors. After acc o u nti n g f or ot her pr o g n ostic fact ors, H P V p ositi vit y c o nferre d a 5 8 % 
re d ucti o n i n t he ris k of d eat h ( hazar d rati o, 0. 4 2; 9 5 % CI, 0. 2 7 t o 0. 6 6).   L oc ore gi o nal 
c o ntr ol was i m pr o ve d i n t he H P V -p ositi ve t u m ors; h o we ver, dista nt metast atic c o ntr ol 
a n d t he rate of sec o n d m ali g na ncies were si milar f or b ot h H P V -p ositi ve a n d ne gati ve 
O P S C C s u b gr o u ps. T hr o u g h rec ursi ve p orti o ni n g a nal ysis t his O P S C C c o h ort was 
stratifie d i nt o l o w, i nter me diate, a n d hi g h ris k gr o u ps f or deat h ( 3 y ear O S of 9 3 %, 
7 0. 8 %, a n d 4 6. 2 % res pecti vel y).  T he fact ors use d f or stratificati o n, i n  or der of 
i m p orta nce, were:  H P V stat us, pac k-years of t o bacc o s m o ki n g, t u m or sta ge, a n d n o dal 
sta ge.  T o be cate g oriz e d as ha vi n g l o w ris k of deat h, a patie nt m ust ha ve a H P V -p ositi ve 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
8  
t u m or a n d eit her ha v e ≤ 1 0 pac k years of t o bacc o s m o ki n g a n d a n y N sta ge or >1 0  pac k 
years of t o ba cc o s m o ki n g a n d N 0 -N 2a n o dal sta g e.   
 
O ’S ull iva n et al. c o n d uct e d a lar g e retr os p ecti ve st u d y of 8 9 9 O P S C Cs patie nts treate d at 
t he Pri ncess Mar garet H os pital i n T or o nt o, Ca na da
3 2.  H P V stat us was ascertai ne d i n 5 0 5 
( 5 6 %):  3 8 2 H P V p ositi ve a n d 1 2 3 H P V ne g ati ve.  All patie nts were tr eate d wit h 
ra diati o n al o ne or C R T fr o m 2 0 0 1 t o 2 0 0 9, wit h a me dia n f oll o w-u p of 3. 9 years.  
Rec ursi ve p orti o ni n g a nal ysis se gre gate d H P V -p ositi ve patie nts i nt o l o w ( T 1 -3 N 0 -N 2c) 
a n d hi g h ( T 4 or N 3) dista nt metastasis ris k:  9 3 % vs. 7 6 % res pecti vel y.  F urt her m ore , 
s m o ki n g > 1 0 pac k years re d uce d o v erall s ur vi val b ut di d n ot i m pact rec urre nce free 
s ur vi val (l ocal, r e gi o nal, a n d dista nt rec urre n ces) i n H P V-p ositi ve patie nts.  T his s u g gests 
t hat ot her ass ociate d t o b acc o -relate d dise ase ma y be t he reas o n f or d ecreas e d s ur vi val i n 
H P V -p ositi ve s m o kers vs. H P V -p ositi ve n o n -s m o kers.  Als o, t he rec urre nce free s ur vi val 
was e xcelle nt ( > 9 0 %) i n l o w-ris k H P V-p ositi ve patie nts  wit h T 1 -2, N 0 -1 disease treate d 
wit h R T al o ne vs. C R T .  T h us t he a d diti o n of c he m ot hera p y t o ra diati o n i n t his ver y 
fa v ora bl e l o w-sta ge s u bs et ma y n ot be necessar y.  
 
A n u na ns were d q uesti o n is w het her we ca n s afel y de -i nte nsif y i n patie nts wit h H P V-
ass ociate d O P S C C w h o ha ve si g nifica nt s m o ki n g hist ories ( > 1 0 pac k y ears).  T he 
pr o p ose d st u d y will hel p t o a ns wer t his q uesti o n.    
1. 5  
U N C De -i nte nsific ati o n c he m or a di ot her a p y re gi m e n  
We ha v e c o m plete d t w o p hase II st u dies e val uati n g t he efficac y of a de -i nte nsifie d 
c he m ora di ot hera p y r e gi me n i n fa v ora bl e ris k or o p har y n geal s q u a m o us cell carci n o ma.  
I n L C C C 1 1 2 0 we tr eate d 4 5 patie nts wit h de-i nten sifie d c he m ora di ot hera p y.   Eli gi ble 
patie nts ha d H P V -p ositi ve a n d/ or p 1 6 -p ositi ve O P S C C, T 0 –  T 3, N 0 –  N 2c, M 0, a n d <  
1 0 pac k years of s m o ki n g. Patie nts recei ve d 6 0 G y of I nte nsit y M o d ulate d Ra di ot hera p y 
(I M R T) wit h c o nc urre nt wee kl y i ntra ve n o us cis plati n ( 3 0 m g/ m2).  Dia g n ostic i ma gi n g 
( C T a n d/ or M RI) was  o bt ai ne d 4 t o 8 wee ks after c o m pleti o n of C R T t o assess res p o nse.  
All patie nts ha d  s ur gical resecti o n of a n y cli nicall y a p pare nt resi d ual pri mar y t u m or or 
bi o ps y of t he pri mar y site if t here was  n o e vi de nce of resi d ual t u m or a n d u n der we nt  a 
nec k dissecti o n t o e nc o m pass at least t h ose n o dal l e vel(s) t hat w ere p ositi ve pre -
treat me nt, wit hi n 4 t o 1 4 wee ks after C R T.  T he pri mar y e n d p oi nt of L C C C 1 1 2 0 was  t he 
rate of p C R . 4 5  patie nts e nr olle d a n d 4 3  were e v al ua ble f or t he pri mar y e n d p oi nt.  T he 
o bser ve d p C R rate was 8 6 % ( 3 7 /4 3 ), w hic h is e x celle nt a n d wit hi n t he e x p ecte d res ult f or 
a p ositi ve o utc o me .  We f urt her o bser ve d l o w er fee di n g t u be use ( wit h n o p er me na nt 
fee di n g t u bes) a n d fa v ora ble patie nt re p orte d o utc o mes relate d t o dr y m o ut h a n d 
d ys p ha gia (t he t w o m ost c o m m o n c hr o nic t o xicities) as c o m pare d t o sta n dar d d ose 
c he m ora di ot her ap y 3 3. 
 
I n o ur sec o n d p h ase II st u d y, we e val u ate d t he sa me de-i nte nsifie d re gi me n wit h t he 
f oll o wi n g m o dificati o ns:   
1)  We di d n ot re q uir e s ur gical e val u ati o n after de -i nte nsifie d C R T.  I nste a d, we 
pef or me d 1 2 wee k p ost -treat me nt P E T/ C T a n d pef or me d p ost C R T nec k 
dissecti o n o nl y i n cases w here t he ~ 1 2 wee k P E T -C T wa s p ositi v e f or resi d ual 
a de n o pat h y.  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
9  
 
2)   We o mitte d c he m ot h era p y i n t he m ost fa v ora ble s u b gr o u ps  ( p 1 6/ H P V 
p ositi ve, T 0 -2, N 0 -1, ≤ 1 0 pac k years) bas e d o n e xisiti n g data of treati n g t hese 
patie nts wit h R T al o ne 3 2 ,3 4.  
3)  We all o w e d e nr oll me nt of patie nts wit h m o derate b ut re m ote s m o ki n g 
hist ories ( s m o ki n g hist or y of ≤ 3 0 pac k-y ears wit h ≥5 years of a bsti ne nce fr o m 
s m o ki n g).  T his was base d  o n data fr o m P ri ncess Mar garet H os pital  w hic h 
s u g gest t hat m o derate  t o bacc o use di d n ot affect ca ncer c o ntr ol rat es i n H P V-
p ositi ve patie nts 3 2.  
 
4)   We all o w e d  wee kl y c he m ot hera p y re gi me ns ot her t ha n cis plati n.  Cis plati n 
3 0 m g/ m 2 was t he preferre d re gi me n, b ut if per me dical o nc ol o gist e val uati o n, 
cis plati n was dee me d u nt olera ble (e. g. pre -e xisti n g heari n g l oss, ele vat e d 
creati ni ne, n e ur o pat h y) ot her wee kl y re gi me ns were all o we d (cet u xi ma b a n d 
car b ota x ol ).   
 
5)  T he pri mar y o bj ecti ve was c ha n g e d t o 2 year P F S.  
 
7 2 / 8 0 patie nts ha ve e nr olle d.  We e x p ect L C CC  1 4 1 3  t o c o m plete accr ual b y t he ti me t he 
c urre nt st u d y is o pe ne d.  T hree p atie nts ha ve ha d ca ncer rec urre nce ( me dia n f oll o w u p  6. 9  
m o nt hs,  ra n ge 1. 3  –  1 8. 7 m o nt hs ):  t w o patie nts ha d  dista nt rec urre nces (l u n g a n d b o ne) 
a n d o ne ha d a l ocal r ec urre nce i n t he b ase of t o n g ue.   
 
T o get her, L C C C 1 1 2 0 a n d 1 4 1 3  ( n = 1 1 5 patie nts, t otal) ha ve s h o w n t hat d e -i nte nsifie d 
c he m ora di ot hera p y is efficaci o us  a n d has a fa v ora ble t o xicit y pr ofile as c o m pare d t o 
sta n dar d d ose c he m ora di ot hera p y. 
  
1. 6  
Ge n o mic c h ar acteriz ati o n of H P V -ass oci ate d a n d T o b acc o -ass oci ate d 
Or o p h ar y n ge al c a ncer  
H P V - ass ociate d O P S C C has a differe nt ge n o mic pr ofile as c o m pare d t o H P V -ne gati ve, 
t o bacc o ass o ciate d O P S C C3 5.  Se mi nal w or k d o ne b y Dr.  
s usi n g t he t u m or ca ncer 
ge n o me atlas has s h o w n t hat H P V -ne gati ve t o bacc o ass ociate d O P S C C c haracteristicall y 
has p 5 3 m utati o ns a n d C C N D 1 a m plificati o ns.  T hese ge netic alterati o ns are rarel y (if 
e ver) s ee n i n H P V -ass oci ate d O P S C C, es peciall y t h ose wit h mi ni mal s m o ki n g hist ories.  
Dr 
 et al . h a ve f urt her c h aracterize d t he t u m or ge n o mic pr ofiles i n patie nts wit h 
H P V - ass ociate d O P S C C wit h si g nifica nt s m o ki n g hist ories ( > 1 0 pac k y ears) .  T he y 
o bser ve d t hat n ot all H P V -ass ociate d O P S C C are t he sa me o n t he ge n etic le vel, 
es peciall y i n t h ose wit h  > 1 0 pac k y ear s m o ki n g hist or y 
 et al.  use d ne xt -
ge n erati o n se q u e nci n g t o a nal yze g e netic m utati o ns i n 6 6 H P V -p ositi ve or o p har y n geal 
ca ncer patie nts, w h o w ere als o cate g orize d i nt o gr o u ps base d o n s m o ki n g hist or y. T he y 
f o u n d t hat disease-free a n d o verall s ur vi val were better i n t he less t ha n 1 0-pac k year 
gr o u p, a n d t here were differe n ces i n m utati o ns bet wee n t he t w o gr o u ps bas e d o n s m o ki n g 
hist or y.  M utati o ns i n ge nes s uc h as T P 5 3, C D K N 2 A, K R A S a n d N O T C H 1 al m ost 
e xcl usi vel y o bser ve d  i n t he >  1 0 pac k -year gr o u p w hile H L A -A m utati o ns were al m ost 
e xcl usi vel y i n t he li g hter s m o ki n g gr o u p. T hese data pr o vi de a m olec ul ar criteria base d 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 0  
o n ge n o mic m utati o ns t o hel p better stratif y ris k/ pr o g n osis a n d p ote ntiall y t o g ui de 
treat me nt selecti o n, na m el y w het her d e-i nte nsificati o n s h o ul d be use d. 
 
T he pr o p ose d st u d y ai ms t o b uil d u p o n t he w or k of 
 et al. a n d 
 et al. b y 
e val uati n g w het her ge n o mic pr ofili n g ca n be use d t o better select patie nts f or de -
i nte nsificati o n.  B y better selecti n g  patie nts ( usi n g ge n o mic pr ofili n g, see bel o w) f or de -
i nte nsificati o n, we h y p ot hesize t hat we ca n f urt her i m pr o ve t he 2 year P F S t o 9 3 % f or 
patie nts wit h H P V - ass ociate d O P S C C re gar dless of s m o ki n g hist or y.  
1. 7  
Circ ul ati n g free H P V D N A (cf H P V-D N A)  
Circ ulati n g cell free plas ma D N A (cf D N A) ca n b e a se nsiti ve bi o mar ker of t u m or b ur de n 
t hat is accessi ble b y si m ple p hle b ot o m y.  Circ ulati n g free H P V D N A is det ecta ble ( vi a 
p ol y merase c h ai n reacti o n) i n patie nts wit h H P V -ass ociate d O P S C C a n d a hi g hl y s pecif ic 
circ ulati n g bi o mar ker f or H P V p ositi ve H N S C C.  Li mite d data o n a s mall n u m ber of 
patie nts ha ve s h o w n t hat cf H P V -D N A le vels be c o me lar gel y u n detecta ble p ost -C R T i n 
m ost patie nts, a n d t hat cf H P V -D N A le v els i ncrease at t he ti me of rec urre nce, t h us 
s u g gestin g t hat cf H P V -D N A ma y be pr o g n ostic 3 5 -3 7. U N C-L C C C has t he u ni q ue a bilit y 
t o e val uate cf H P V-D N A usi n g di gital dr o plet P C R ( d d P C R) tec h n ol o g y.  Dr. Ga ora v 
G u pta’s la b has d e vel o pe d a d d P C R assa y f or H P V s u bt y pe 1 6 t hat is e x q uisitel y 
se nsiti ve a n d s pecific i n l a b orat or y tests, a n d has s uccessf ully detecte d cf H P V -D N A i n 2 
o ut of 2 patie nts t hat ha v e bee n a nal yze d t o date ( Fi g ure 1).  I n t his st u d y we will 
pr os pecti vel y c olle ct bl o o d sa m ples pre -tr eat me nt, d uri n g, a n d after treat me nt t o e val uate 
t he ki netics of cf H P V-D N A i n all patie nts. We are partic ularl y i ntereste d i n t he ki netics 
d uri n g treat me nt as it ma y be use d t o g ui de f urt her st u dies: e. g. t o hel p g ui de w he n t o 
st o p ra diati o n or, if le vels d o n ot bec o me u n detecta ble d uri n g s o me p oi nt of treat me nt, 
o ne ma y c ha n g e c h e m ot hera p y or c o nti n ue wit h a dj u va nt c he m ot hera p y.    
 
1. 8  
R ati o n ale  
T he pr o p ose d st u d y will b uil d u p o n o n o ur se mi nal pri or p hase II a n d ge n o mic 
c haracteri zati o n st u dies b y le vera gi n g u ni q ue cli nical/tra nslati o nal stre n gt hs at U N C -
L C C C:  ca ncer ge n o mics a n d cf H P V -D N A. O ur o ver -arc hi n g h y p ot hesis is t hat t he 
 
Fi g ure 1 A) Li nearit y o ver a br oa d ra n g e of H P V -1 6 D N A usi n g a d d P C R 
assa y desi g ne d t o t he E 7 ge ne.  B) Baseli ne le vels of cf H P V -D N A i n 2 
patie nts wit h H P V + H N S C C, a n d t u m or sta ge i n dicate d.  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 1  
ge n o mic c haract erizati o n of O P S C C t u m or s peci me ns fr o m patie nts wit h > 1 0 pac k year 
s m o ki n g hist or y ca n b e use d t o hel p d eci de w het her de-i nte nsificati o n w o ul d be 
effic aci o us.   
 
Beca use of t h e p ositi ve res ults of o ur first t w o de -i nte nsificati o n st u dies ( L C C C 1 1 2 0, 
L C C C 1 4 1 3)  a n d t he e mer gi n g ge n o mic ris k stratisficati o n data fr o m 
s et al . a n d 
et al., we are pr o p osi n g c o n d ucti n g a si milar st u d y wit h t he maj or m o dificati o n  
of : 
 
1.   T u m or Ge netics :   T u m or ge netics will be assesse d i n all patie nts wit h > 1 0 pac k year 
s m o ki n g hist or y, a n d select patie nts wit h e xte nsi ve s m o keless t o bacc o hist or y, base d o n 
t he PI’s assess me nt.  T he U N C M olec ular Ge netics La b orat or y will perf or m a m utati o n 
pa nel i nterr o gati n g select e d re gi o ns of 2 6 g e nes ( p 5 3 m utati o n is t he m ost c o m m o n t o 
t his patie nt p o p ulati o n ) usi n g ne xt-ge nerati o n se q ue nci n g.  P 5 3  m utati o nal stat us will be 
use d t o assess eli gi bilit y of patie nts wit h > 1 0 pac k years s m o ki n g hist or y.  
 
2.  Circ ulati n g free H P V D N A :   I n t his st u d y we will pr os pecti vel y c ollect bl o o d sa m ples 
pre -treat me nt, d uri n g, a n d after treat me nt t o e val u ate t he ki netics of cf H P V-D N A i n all 
patie nts.  
 
3.  Pri mar y e n d p oi nt :  O ur h y p ot hesis is t hat b y usi n g ge n o mic pr ofili n g i n t he patie nts 
wit h H P V -ass ociate d O P S C C a n d > 1 0 pac k year s m o ki n g hist or y t hat we will be better 
a ble t o select t h ose p atie nt s wit h H P V -ass ociate d O P S C C w h o w o ul d safel y be nefit fr o m 
de -i nte nsificati o n.  T he pri mar y e n d p oi nt is P F S, h o we ver b y usi n g ge n o mics t o select 
t he m ost fa v ora ble p atie nts wit h a > 1 0 pac k year s m o ki n g hist or y, we esti mate t he  P F S 
t o be 9 3 % (f or t h e e ntire p o p ulati o n, re gar dless of s m o ki n g), i nstea d of t he 8 7 % as has 
bee n re p orte d i n pre vi o us st u dies 1 0 a n d o ur pri or st u dies .   
 
2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
P ri m ar y O bjecti ve :   
T o e val uate w h et her g e n o mic base d ris k -stratificati o n ca n be use d i n deci di n g w het her t o 
de -i nte nsif y i n patie nts wit h H P V-ass ociate d O P S C C wit h > 1 0 pac k years s m o ki n g 
hist or y.   H y p ot hesis:  Patie nts wit h H P V -ass ociate d O P S C C, > 1 0 pac k years s m o ki n g 
his t or y, a n d n o n-m utate d p 5 3 will ha ve si milar 2 year P F S as p atie nts wit h < 1 0 pac k 
years s m o ki n g hist or y.  
2. 2  
Sec o n d ar y O bjecti ve s 
T o pr os pecti vel y assess if t he c ha n g es i n plas ma circ ulati n g free H P V D N A d uri n g a n d 
after treat me nt are ass oci ate d wit h cli nical o utc o m es i n patie nts wit h H P V -ass ociate d 
O P S C C.  H y p ot hesis:  C ha n ges i n le vels of plas m a circ ulati n g free H P V D N A d uri n g a n d 
after treat me nt will c orrelate wit h ca ncer c o ntr ol rates . 
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 2  
T o assess t he 2 year cli ni cal o utc o mes of l ocal c o ntr ol ( L C), re gi o nal c o ntr ol ( R C), l ocal -
re gi o nal c o ntr ol ( L R C), dista nt metastasis free s ur vi val ( D M F S), a n d o v erall s ur vi val 
( O S). 
3. 0  
E N D P OI N T S  
3. 1  
Pri m ar y E n d p oi nt  
Patie nts wit h H P V -p ositi ve a n d/ or p 1 6 -p ositi ve O P S C C will recei ve de -i nte nsifie d C R T.  
T he 2 year P F S will be e val uate d.  O ur n ull h y p ot hesis ( H 0) is t hat t he P F S rate is 9 3 % 
a n d o ur alter nate h y p ot hesis ( H 1) is t hat t he P F S rate is 8 6 %.  
3. 2  
Sec o n d ar y E n d p oi nt s 
Circ ul ati n g free H P V -D N A:   Ki netic of cf H P V -D N A c o p y n u m bers d uri n g a n d after 
treat me nt. 
Cli nic al O utc o mes:   Ka pla n Mei er esti mates of L C , R C , L R C , D M F S , a n d O S  will be 
calc ulate d. 
4. 0  
P A TI E N T E LI GI BI LI T Y  
4. 1  
I ncl usi o n Criteri a 
4. 1. 1  ≥ 1 8 years of a ge ( n o u p p er a ge li mit)  
4. 1. 2  T 0 -3 , N 0 t o N2 c, M 0 s q u a m o us cell carci n o ma of t he or o p har y n x ( AJ C C 7t h 
e diti o n)  
4. 1. 3  Bi o ps y pr o ve n  s q ua m o us cell carci n o ma t hat is H P V a n d/ or p 1 6 p ositi ve  
4. 1. 4  Ra di ol o gic c o nfir mati o n of t he a bse n ce of he mat o ge n o us metastasis wit hi n 1 2 
wee ks pri or t o tr eat me nt; at a mi ni m u m, c hest x -ra y is re q uire d. C T i ma gi n g of 
t he c hest or  P E T/ C T is acce pta bl e.  
4. 1. 5  E C O G Perf or ma n ce Stat us 0 -1  
4. 1. 6  C B C/ differe ntial o btai ne d wit hi n 8  wee ks pri or t o treat me nt, wit h a de q u ate 
b o ne marr o w f u ncti o n defi ne d as f oll o ws : 
4. 1. 6. 1  Platelets ≥ 1 0 0, 0 0 0 cells/ m m 3  
4. 1. 6. 2  He m o gl o bi n ≥ 8. 0 g/ dl ( N ote: T he use of tra nsf usi o n o r ot her i nter ve nti o n t o 
ac hie ve H g b ≥ 8. 0 g/ dl is acce pta ble.)  
4. 1. 7  A de q uate re nal a n d h e patic f u ncti o n wit hi n 4 wee ks pri or t o treat me nt, defi n e d as 
f oll o ws: 
4. 1. 7. 1  Ser u m creati ni ne < 2. 0 m g/ dl  
4. 1. 7. 2  T otal bilir u bi n < 2 x t he i nstit uti o nal U L N  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 3  
4. 1. 7. 3  A S T or A L T < 3 x t he i nstit uti o nal U L N.  
 
 
N ote t hat p h ysicia n attest ati o n of patie nt ha vi n g n o k n o w n hist or y of li ver disease ca n 
ta ke t he place of bilir u bi n a n d A S T/ A L T la bs. 
4. 1. 8  
Ne gati ve pre g na nc y t est wit hi n 2 wee ks pri or t o tr eat me nt f or w o m e n of c hil d beari n g 
p ote ntial  
4. 1. 9  
W o me n of c hil d beari n g p ote ntial a n d male partici pa nts w h o are s e x uall y acti ve m ust 
practice a de q u ate c o ntr ace pti o n d uri n g treat me nt a n d f or 6 wee ks f oll o wi n g treat me nt.  
4. 1. 1 0  Patie nts m ust be dee me d a ble t o c o m pl y wit h t he treat me nt pla n a n d f oll o w -u p sc he d ule.  
4. 1. 1 1  Patie nts m ust pr o vi de st u d y s pecific i nf or m e d c o nse nt pri or t o st u d y e ntr y  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 4  
4. 2  
E xcl usi o n Criteri a  
4. 2. 1  Pri or hist or y of ra diati o n t hera p y t o t he hea d a n d n ec k  
4. 2. 2  Pri or hist or y of hea d a n d nec k ca ncer.  
4. 2. 3  U nresecta ble diseas e  (e. g. i m m o bile n o de o n p h ysical e xa m, n o d al disease t hat 
ra di o gra p h gic all y i n v ol ves t he car oti d arteries, n er ves) 
4. 2. 4  C urre ntl y ta ki n g Disease M o dif yi n g R he u mat oi d Dr u gs ( D M R Ds)  
4. 2. 5  Se vere, acti ve c o -m or bi dit y, defi ne d as f oll o ws:  
4. 2. 5. 1  U nsta ble a n gi na a n d/ or c o n gesti ve heart fail ure re q uiri n g 
h os pitalizati o n wit hi n t he last 6 m o nt hs  
4. 2. 5. 2  Tra ns m ural m y ocar dial i nfarcti o n wit hi n t he last 6 m o nt hs  
4. 2. 5. 3  Ac ute bacterial or f u n gal i nfecti o n re q uiri n g i ntra v e n o us a nti bi otics at 
t he ti me of re gistrati o n 
4. 2. 5. 4  C hr o nic O bstr ucti ve P ul m o nar y Diseas e e xacer bati o n or ot her 
res pirat or y ill ness re q uiri n g h os pitalizati o n or precl u di n g st u d y 
t hera p y at t he ti me of re gistrati o n 
4. 2. 5. 5  He patic i ns uffici e nc y res ulti n g i n cli nical ja u n dice a n d/ or c oa g ulati o n 
defects; N ote, h o we ver, c oa g ulati o n  para met ers are n ot re q uire d f or 
e ntr y i nt o t his pr ot oc ol.  
4. 2. 5. 6  Pre -e xisti n g ≥ gra de 2 n e ur o pat h y  
4. 2. 5. 7  Pri or or ga n tra ns pla nt  
4. 2. 5. 8  S yste mic l u p us  
4. 2. 5. 9  Ps oriatic art hritis . 
4. 2. 6  
K n o w n HI V p ositi ve .   
HI V p ositi ve patie nts are k n o w n t o ha ve w ors e cli nical o utc o mes es peciall y f or 
l ocal, re gi o nal, a n d dista nt ca ncer c o ntr ol.  T his p o orer pr o g n osis is t h o u g ht t o 
be sec o n dar y t o a c o m pr o mise d i m m u ne s yste m.  T h us, de -escalati o n of 
ra diati o n a n d c h e m ot hera p y is n ot j ustifia ble. 
4. 2. 7  
C urre nt acti ve s m o ker, defi ne d as acti ve ci garette s m o ki n g wit hi n t he 6 m o nt hs 
pri or t o e nr oll me nt.  
 
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 5  
5. 0  
S T U D Y P L A N  
5. 1  
Sc he m a   
  
 
 
Fi g ure 2 :  Sc he m a 
 
Fi g ure 2 : T he pri mar y o bjecti ve of t his st u d y is t o assess t he 2 year P F S of H P V -ass ociate d 
O P S C C after ge netic ris k base d de -i nte nsifi e d C R T.  All patie nts wit h ≤ 1 0 pac k years s m o ki n g 
hist or y will recei ve de -i nte nsifie d C R T.  Patie nts wit h > 1 0 pac k years s m o ki n g hist or y , a n d 
select patie nts wit h e xte nsi ve s m o keless t o bacc o hist or y ( base d o n t he PI’s assess me nt),  will 
ha ve ge n etic assess me nt of t heir t u m ors ( pre -treat me nt arc hi val tiss ue or bi o psies), a n d if p 5 3 is 
m utate d, t he y will recei v e a n a d diti o n al 1 0 G y f or a t otal ra diati o n d ose of 7 0 G y ( w hic h is t he 
hist orical, sta n dar d)  a n d o ne a d diti o nal wee kl y c h e m ot hera p y d ose .  T h os e wit h > 1 0 pac k year 
s m o ki n g hist or y a n d wit h o ut t he p 5 3 m utati o n will recei v e t he de-i nte nsifie d re gi me n.  
Circ ulati n g free H P V D N A will be assesse d pre -treat me nt, d uri n g treat me nt, a n d p ost-treat me nt 
at m o nt hs 3, 6, 1 2, 1 8, a n d 2 4  ( See Secti o n 5. 5 f or details o n bl o o d c ollecti o n ti me p oi nts).  
5. 2  
Pretre at me nt E v al u ati o ns :  All patie nts will ha ve sta n dar d of care e v al uati o n a n d 
sta gi n g pr oce d ures.   
5. 2. 1  C o m plete hist or y a n d p h ysical e xa m i ncl u di n g wei g ht a n d perf or ma n ce stat us.  
5. 2. 2  C o m pleti o n of pa ne n d osc o p y wit h directe d bi o psi es a n d bilateral t o nsillect o mies if t he 
pri mar y is u n k n o w n  is str o n gl y rec o m me n de d, b ut n ot re q uire d.   
5. 2. 3  C o m pleti o n of t he f oll o wi n g ra di ol o gical st u dies:   
at least c o ntraste d n ec k C T a n d c hest x -ra y.  C hest C T, P E T/ C T a n d/ or M RI are o pti o nal 
st u dies. C T of t he nec k s h o ul d ha ve I V c o ntrast u nless c o ntrai n dicate d (all er g y or a d v erse 
reacti o n or re nal iss ues).  P E T/ C T is satisfact or y a n d ca n be d o n e i nstea d of or i n a d diti o n 
t o c o ntraste d nec k C T a n d c hest x-ray.   Pretreat me nt ultras o u n d e val uati o n wit h p ossi ble 
F N A is per missi ble t o sta ge t he nec k pri or t o treat me nt.  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 6  
5. 2. 4  C o m plete de n tal e val uati o n is rec o m me n de d.  
5. 2. 5  C o m pleti o n of t he f oll o wi n g la b orat or y st u dies: C B C, ser u m c he mistries, li ver f u ncti o n 
tests, a n d pre g na n c y test if fe male.  
5. 3  
H P V a n d / or p 1 6 testi n g  
H P V a n d / or p 1 6 testi n g will be perf or me d vi a fl u oresce n ce i n-sit u h y bri di zati o n a n d 
i m m u n o hist oc he mistr y, res pecti vel y.  Met h o ds a n d tec h ni q ues f or t hes e tests ha ve bee n  
esta blis he d b y t he U N C H , U F , a n d R e x Ca ncer Ce nter of Ralei g h  De part me nt s of 
Pat h ol o g y a n d t hese bi o mar kers are alrea d y r o uti nel y e xa mi ne d f or all hea d a n d nec k 
t u m or s peci me ns o btai ne d at t hese i nstit uti o ns. T his testi n g ma y be perf or m e d  o n F N A 
tiss ue o btai ne d fr o m a nec k n o de.  Res ults of H P V a n d/ or P 1 6 testi n g perf or me d at 
i nstit uti o ns o utsi de of t he st u d y site are acce pta bl e. 
5. 4  
Ge netic Assess me nt    
All patie nts wit h > 1 0 pac k years s m o ki n g hist or y , a n d select patie nts wit h e xte nsi ve 
s m o keless t o bacc o hist or y ( base d o n t he PI’s assess me nt), will ha ve t heir t u m or assesse d 
( pre-tr eat me nt arc hi val tiss ue/ bi o ps y) f or p 5 3 m utati o nal stat us.  T he U N C M olec ular 
Ge netics La b orat or y will perf or m a m utati o n pa n el i nterr o gati n g selecte d re gi o ns of 2 6 
ge nes usi n g ne xt -ge n erati o n se q ue nci n g ( Tr u Si g ht T u m or Pa nel ®, A p pe n di x).  Ge nes 
assesse d are liste d i n t he a p pe n di x. T he t ur n ar o u n d ti me f or t hese tests is a p pr o xi matel y 
t w o wee ks.  O nl y p 5 3 m utati o nal stat us will be use d t o ris k stratif y. T he ot her 2 5 
a nal yze d g e nes ( Tr u Si g ht T u m or Pa nel ®) will n ot be use d t o deci de o n w het her a patie nt 
wit h > 1 0 pac k years will recei v e de -i nte nsifie d C R T. We will arc hi ve t h at data a n d 
a nal yze it retr os pecti vel y.  Ot her partici p ati n g ce nters will o ver ni g ht s hi p tiss ue sa m ples  
t o U N C f or ge netic assess me nt as f oll o ws:  Te n ( 1 0)  u nstai ne d secti o ns fr o m f or mali n -
fi xe d, paraffi n-e m be d de d tiss ue o n plai n, u nc oate d glass sli des ( 4 micr o ns  t hic k); a n 
H & E stai ne d sli de t o all o w pat h ol o gist d oc u me ntati o n t hat s ufficie nt t u m or is prese nt (if 
tiss ue e x hi bits less t ha n 2 0 % t u m or, s peci me ns are e nric he d f or t u m or b y m a n ual macr o-
dissecti o n t o all o w better assa y se nsiti vit y); a n d a c o p y of t he s ur gical pat h ol o g y re p ort t o 
assist i n bl oc k selecti o n, t o d oc u me nt a nat o mic site, a n d t o c o nfir m hist o pat h ol o gic 
dia g n osis of carci n o ma.   Alter nati vel y, sites ma y s e n d arc hi v al tiss ue i n a f or mali n fi xe d 
paraffi n e m be d de d bl o c k ( F F P E) i n place of t he sli des.  
 
We will be assessi n g a n arr o w er n u m ber of ge n etic alterati o ns i n t his pr o p osal, as 
c o m pare d t o t he p u blis he d/ prese nte d w or ks of Dr.
.  T his decisi o n was 
ma de o ut of necessit y t o e ns ure t he feasi bilit y (i.e. , t w o wee k t ur n ar o u n d ti me) of 
i nc or p orati n g ge n o mic i nf or mati o n t o pr os pecti vel y g ui de treat me nt. T h us we are li mite d 
t o e val uati n g a sele ct n u m ber of ge n etic alterati o ns, a n d are f oc usi n g t he desi g n of o ur 
st u d y o n p 5 3 m utati o nal stat us.  Ot her m utati o nal e ve nts ma y be usef ul i n ris k 
stratificati o n, h o we ver we h y p ot hesize t hat t he ce ntral r ole of p 5 3 i n r e g ulati n g t he cell 
c ycle a n d miti gati n g ra di ati o n a n d c he m ot hera p y se nsiti vit y ma ke it t he i deal bi o mar ker 
t o use i n o ur pr o p osal.    


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 7  
5. 5  
Circ ul ati n g free H P V -D N A (cf H P V -D N A)  
Pre vi o us versi o ns of t his pr ot oc ol ha ve det aile d vari o us re q uire me nts re gar di n g bl o o d 
s peci me n c ollecti o n ti me p oi nts as t he trial has e v ol ve d.  T hese ha v e i ncl u de d bl o o d 
c ollecti o n at pretr eat me nt, wee kl y d uri n g treat me nt, a n d u p t o 5 p ost -treat me nt ti me 
p oi nts.  As of Ma y 8, 2 0 2 0, bl o o d s peci me ns will o nl y be c ollecte d at pre -treat me nt a n d 
Wee k 4 of treat me nt.   O n e t u be  will be dra w n at eac h ti me p oi nt.  Circ ulati n g plas ma 
D N A will be e xtr acte d a n d cf H P V-D N A will be q ua ntifie d usi n g o ur d d P C R assa y usi n g 
t he Bi ora d Q X-2 0 0 ( 
 G u pta’s la b).  A d diti o nal e x pl orat or y a nal yses o n plas ma 
cf D N A s a m ples ma y be perf or me d i n st u d y c o -i n vesti gat or la b orat ori es.  A d diti o nal 
sa m ples ma y be o btai ne d at t he PI’s discreti o n.  If necessar y, eac h a d diti o nal dra w will be 
o ne Strec k t u be.   U N C will pr o vi de Strec k B C T t u bes t o o t her partici pati n g ce nters f or 
bl o o d c ollecti o n.   After s a m ple is dra w n, t u be s h o ul d be i n verte d 1 0 ti mes t o mi x t he 
preser vati ve.   Sites  will o ver ni g ht s hi p bl o o d sa m ples  wit hi n o ne b usi ness da y  t o U N C i n 
Fe d E x b o x es wit h o ut ice  f or assess me nt (f or sa m ples c ollecte d o n Fri da y, s hi p pi n g o n 
M o n da y is fi ne) . If necessar y f or batc h s hi p me nt, sites ma y wait t o s hi p bl o o d sa m ples, 
b ut m ust s hi p wit hi n o ne wee k ( 5 b usi ness d a ys) of t he date t he earliest sa m ple was 
dra w n.  
 
S peci me ns will be retai n e d i n defi nitel y u nless a s pecific partici pa nt c h o os es t o wit h dra w 
fr o m t he st u d y.  S h o ul d a patie nt wit h dra w fr o m t his st u d y, a n y s peci me ns t hat ha ve bee n 
c ollecte d, a n d t hat c o ntai n i nf or mati o n t hat ca n be use d t o i de ntif y t he part i ci pa nt will be 
destr o ye d.   A n y s peci me ns t hat ha ve bee n stri p p e d of i de ntif yi n g i nf or mati o n ca n n ot be 
li n ke d bac k t o t he partici pa nt, a n d t heref ore will n ot be destr o ye d. 
 
Tiss ue a n d bl o o d sa m ples s h o ul d be se nt o ver ni g ht ( or b y U N C c o urier) t o 
 
at t he f oll o wi n g a d dress:  De part me nt of Ra di ati o n O nc ol o g y; U N C Ca ncer H os pital; 1 0 1 
Ma n ni n g Dri ve, C B # 7 5 1 2; C ha pel Hill, N C 2 7 5 9 9 -7 5 1 2.  Please n otif y  
n b y 
p h o ne 
 or e mail (
w he n s a m ples are s hi p pe d.  
5. 6  
R a di ati o n T her a p y   
All patie nts will recei ve I nte nsit y M o d ulate d Ra di ot hera p y Treat me nts (I M R T) or pr ot o n 
ra di ot hera p y.  All patie nts will be i nitiall y pla n ne d t o 6 0 G y at 2 G y/f x, 3 0 f x, o nce a d a y.  
T he t ur n ar o u n d ti me f or ge netic testi n g of pre -treat ment  tiss ue (arc hi v al or bi o ps y) is 
a p pr o xi matel y t w o wee ks. It is e x p ecte d t hat d uri n g t he first c o u ple of wee ks f o t he i nitial 
6 0 G y pla n t hat t he ge netic a nal ysis will be c o m plete d f or t he p atie nts wit h > 1 0 pac k 
years.  S h o ul d o ne of t hese patie nts ha ve a p 5 3 m utati o n a n a d diti o nal 2 n d ra diati o n pla n 
(“ b o ost pla n”) of 1 0 G y at 2 G y/f x will be d o ne.  T h us t he t otal d ose for pati e nts wit h 
H P V -ass ociate d O P S C C, > 1 0 pac k y ears, a n d p 5 3 m utate d will be 7 0 G y , t he sta n dar d 
d ose  (tw o ra di at o n pla ns, se q ue ntial b o ost).   
5. 6. 1  C T si m ul ati o n  
C T si m ulati o n will be o btai ne d wit h I V c o ntr ast f or treat me nt pla n ni n g p ur p oses f or all 
patie nts.  F or patie nt s recei vi n g pr ot o n t hera p y, a n o n-c o ntrast C T si m ulati o n will als o be 
perf or me d.  T he hea d a n d nec k area will be i m m o bilize d wit h a n a q ua plast mas k.  
Patie nts will be p ositi o ne d i n t he nec k e xte n de d p ositi o n.  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 8  
5. 6. 2  T ar get a n d Or g a n at Ris k V ol u mes:   
5. 6. 2. 1  Gr oss T u m or V ol u me ( G T V) :  is defi ne d as all k n o w n gr oss disease d eter mi ne d 
o n t he C T si m ulati o n sca n .  
5. 6. 2. 2  Hi g h Ris k Cli nical Tar get V ol u mes ( C T V -H R) :  is defi ne d as t he G T V pl us a  
n o n -u nif or ml y e x pa n de d 5 t o 1 0 m m t o acc o u nt f or hi g h ris k areas of 
micr osc o pic s prea d .  F or sit uati o ns w here t he pri m ar y t u m or was re m o ve d wit h 
t he bi o ps y (e. g. t o nsillect o m y) a n d t he pri mar y t u m or ca n n ot be see n o n 
ra di o gra p hic i ma gi n g t he bi o ps y site will be i ncl u de d i n t he C T V-H R.  F or 
patie nts wit h a n u n k n o w n pri mar y ( T 0) t he i psilat eral or o p h ar y n x ( base of 
t o n g ue, t o nsil, s oft palate) will be i ncl u de d i n t he C T V-H R v ol u me.  
5. 6. 2. 3  Sta n dar d Ris k Cli nical Tar get V ol u me ( C T V -S R) :  is defi ne d as t he el ecti v e 
n o dal re gi o ns.  T he c o ns e ns us g ui deli nes  f or t he n o de ne gati ve a n d n o de 
p ositi ve nec ks p u blis he d b y Gre g oire et al. will be use d as a g ui de t o defi ne t he 
C T V -S R 3 6 ,3 7. F or t he sit uati o n of t he u n k n o w n pri mar y (i.e. T 0), t h e 
nas o p har y n x will be i ncl u de d i n t he C T V -S R.  T he f oll o wi n g g ui deli nes will be 
use d i n deli neati n g t he C T V -S R . 
5. 6. 2. 3. 1   N o de p ositive he mi -neck (i psil ater al or c o ntr al ater al t o t he pri m ary site) 3 6:  
T he f oll o wi n g electi ve n o dal re gi o ns s h o ul d be i ncl u de d i n t he C T V -S R:  
Le vels I b -V a n d retr o p har y n geal. T he cra ni al e xte nt t o t he base of s k ull of 
Le vel II a n d retr o p h ar y n geal n o des s h o ul d be el ecti vel y irra diate d.  
5. 6. 2. 3. 2   I psil ater al n o de ne g ative he mi-neck 3 7:  T he f oll o wi n g electi ve n o dal re gi o ns 
s h o ul d be i ncl u de d i n t he C T V-S R:  Le vels II – I V a n d retr o p h ary n geal  area.   
T he cra nial e xte nt t o t he base of s k ull of Le v el II a n d retr o p h ar y n geal n o des 
s h o ul d be electi vel y irra diate d.   
5. 6. 2. 3. 3  C o ntr al ater al n o de ne g ative he mi -n eck 3 7:  T he c o ntralateral par oti d ma y be 
s pare d b y o mitti n g irra di ati o n of t he cra nial p orti o n of Le vel II a n d 
retr o p har y n geal r e gi o n, d efi ne d as t he Le vel II, retr o p har y n geal re gi o n a b o ve 
t he tra ns vers e pr ocess of t he C 1 verte brae a n d/ or w here t he p ost eri or bell y of 
t he di gastric m uscle cr osses o ver t he j u g ular v ei n.  C o ntralateral nec k 
irra diati o n ma y be c o m pletel y o mitte d f or well lat eralize d t o nsil ca n cers, 
defi ne d as h a vi n g n o i n vasi o n of t he base of t o n g ue, a n d mi ni mal i n vasi o n of 
t he s oft palate (i.e. > 1 c m fr o m t he u v ula)3 8. 
5. 6. 2. 3. 4  U nk n o w n Pri m ary:   T he a b o ve electi ve n o dal irra diati o n g ui deli nes will be 
use d.  F urt her m ore t he nas o p har y n x will be i ncl u de d i n t he C T V -S R.  
5. 6. 2. 4  Pla n ni n g Tar get V ol u mes ( P T V) :  T o acc o u nt f or dail y set u p err ors, t he C T V -
H R will be e x pa n de d u nif or ml y b y 3 m m t o create a Hi g h Ris k Pla n ni n g Tar get 
V ol u me ( P T V -H R).  T he C T V -S R will be e x pa n d e d u nif or ml y  b y 3 m m t o 
creat e a Sta n dar d Ris k Pla n ni n g Tar get V ol u me ( P T V -S R).  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
1 9  
5. 6. 2. 5  Or ga ns at Ris k ( O A R) :  T he f oll o wi n g n or mal tiss ues will be se g me nte d o n C T 
si m ulati o n sca n:  s pi nal c or d, brai nste m, par oti ds, c oc hleae, a n d lar y n x.    
5. 6. 2. 6  Pla n ni n g Ris k V ol u mes ( P R V) :  O A R(s) will be u nif or ml y e x pa n de d 3 m m t o 
creat e i n di vi d ual Pla n ni n g Ris k V ol u mes ( P R V).   
D ose S pecific ati o n :  D ose pai nti n g I M R T , passi v e-scattered pr ot o n t hera p y,  or i nte nsit y 
m o d ulate d pr ot o n ra di ot h era p y (I M P T) will be use d a n d a ll d oses will be s pecifie d t o t he 
P T V.  T he P T V -H R a n d P T V -S R will be treate d t o t he f oll o wi n g res pecti v e t otal d oses:  
6 0 G y a n d 5 0  G y.  T he d ose per fracti o n t o t he P T V-H R a n d P T V -S R will be 2 G y per 
da y  a n d 1.6 7  G y per da y res pecti vel y  f or I M R T a n d I M P T.  Beca use t he passi ve scattere d 
pr ot o n tec h ni q ue is n ot c o n d u ci ve t o a d ose-p ai nti n g strate g y, b ot h t he P T V -H R a n d 
P T V -S R will recei ve  2 G y per da y usi n g a s e q ue ntial b o ost.  T he t otal n u m be r of 
fracti o ns will be 30 . All fiel ds will be treate d o nce a da y M o n da y t hr o u g h Fri da y.  All 
patie nts will be i nitiall y pla n ne d t o 6 0 G y at 2 G y/f x, 3 0 f x, o nce a da y.  T he t ur n ar o u n d 
ti me f or ge netic testi n g of pre-tr eat me nt tiss ue (arc hi val or bi o ps y) is a p pr o xi matel y t w o 
wee ks. It is e x p ecte d t hat d uri n g t he first c o u ple of wee ks o f t he i nitial 6 0 G y pla n t hat 
t he ge netic a n al ysis will be c o m plete d f or t he pati e nts wit h > 1 0 pac k years.  S h o ul d o ne 
of t hese patie nts ha v e a p 5 3 m utati o n a n a d diti o nal 2 n d ra diati o n pla n (“ b o ost pla n”) of 1 0 
G y at 2 G y/f x will be ma de f or t he P T V -H R.  T h us t he t otal d ose f or patie nts wit h H P V -
ass ociate d O P S C C, > 1 0 pac k years, a n d p 5 3 m utati o n will be 7 0 G y (t w o ra diat o n pla ns, 
se q ue ntial b o ost).   
5. 6. 3  I M R T/ Pr ot o n Tre at me nt Pl a n ni n g  
 P T V’s a n d P R V will be i ncl u de d i n t he ra di ot hera p y o pti mizati o n. D ose o bjecti ves will 
be c h ose n f or t he ra di ot hera p y o pti mizati o n base d o n pre vi o us i nstit uti o nal e x perie n ce.  
D ose pai nti n g  will be use d t o create o ne ra di ot hera p y pla n  f or I M R T a n d I M P T. T he 
P T V -S R c o nt o urs will e nc o m pass t he P T V -H R c o nt o urs.  T he d ose t o t he P T V -S R pla n 
will be 5 0 G y at 1. 6 7  G y per dail y fracti o n  i n 3 0 fracti o ns. T he P T V -H R will be treate d t o 
6 0 G y at 2 G y per dail y fracti o n i n 3 0 fracti o ns .  F or passi ve-scattere d pr ot o n pla ns, a 
se q ue ntial b o ost tec h ni q u e will be all o we d, a n d t h e d ose t o t he P T V-S R will be 5 0 G y st 
2 G y per dail y fracti o n, a n d t he P T V -H R will recei ve a n a d diti o nal 1 0 G y (c u m ulati ve 
d ose: 6 0 G y) at 2 G y per dail y fracti o n.  F or t h ose patie nts re q uiri n g a b o ost pla n, t he 
P T V -H R will recei ve a n a d diti o nal 1 0 G y at 2 G y per dail y fracti o n i n 1 0 fracti o ns .  
I M R T/ Pr ot o n ra di ot hera p y t o treat t he e ntire n ec k is preferre d, h o we ver a matc he d l o w 
a nteri or nec k fiel d p h ot o n tec h ni q ue ma y be us e d o nl y if it d oes n ot res ult i n si g nifica nt 
d ose heter o g e neit y f or t h e P T V -H R .  Pr ot o n t hera p y  will be s pecifie d i n G y( R B E)  
( p h ot o n e q ui vale nts) t o a cc o u nt f or t he i n h ere nt r a di o bi ol o gical differe n ces bet wee n 
pr ot o n a n d p h ot o n t hera pies; t h us, t he treat me nts s h o ul d be c o nsi d ere d bi ol o gicall y 
e q ui vale nt.  
 
5. 6. 4  D ose C o nstr ai nts :   
T hese a p pl y t o b ot h patie nts w h o recei v e a t otal d ose of 6 0  G y or 7 0 G y.  
▪ P T V -H R a n d P T V -S R   
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 % of t he P T V s h o ul d recei ve ≥ 1 1 0 % of t he pres cri be d d os e  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 0  
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 pres cri be d d os e  
▪ N o n -tar get Tiss ue 
o  N o m ore t ha n 1 % of t he tiss ue o utsi de t he P T V s h o ul d recei ve ≥ 1 1 0 % of t he 
prescri be d d os e  
▪ 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 %  
 
P T V c over a ge s h o ul d n ot be c o m pr o mise d t o m eet t he d ose c o nstr ai nts  of t he p ar oti d, 
c oc hle a, or l ary nx.  S p ari n g of t hese str uct ures is left at t he discreti o n  of t he tre ati n g 
r a di ati o n o nc ol o gists .  T he d ose c o nstr ai nts  f or t he s pi n al c or d a n d br ai nste m m ust be 
s atisfie d.  T his m ay be d o ne at t he c ost of alteri n g t he P T V.   
5. 6. 5  Tre at me nt Verifi c ati o n  
Wee kl y ort h o g o nal fil ms or c o ne bea m C T’s s h o ul d be perf or m e d t o verif y patie nt set u p  
(at least). 
5. 6. 6  R a di ati o n Tre at me nt Bre a ks  
I d eall y, treat me nt brea ks, if necessar y, s h o ul d n ot e xcee d 5 treat me nt d a ys at a ti me a n d 
1 0 treat me nt da ys t otal. Treat me nt br ea ks s h o ul d be all o we d o nl y f or res ol uti o n of se vere 
ac ute t o xicit y a n d/ or f or i nterc urre nt ill ness a n d n ot f or s ocial or l o gisti cal r eas o ns.  
5. 7  
C he m ot her a p y  
I n o ur i nitial st u d y, L C C C 1 1 2 0, all patie nts were starte d o n a re gi me n of cis plati n 
3 0 m g/ m 2 gi ve n i ntra ve n o usl y o ver 6 0 mi n utes wee kl y d uri n g I M R T; 6 t otal d oses f or a 
t otal of 1 8 0 m g/ m2.   H o we ver, if cis plati n was n ot t olerate d, it was per missi ble t o s witc h 
t o alter nati ve, acce pt a ble wee kl y c he m ot hera p y re gi me ns s uc h as cet u xi ma b, car b o plati n, 
or car b o pl ati n/ta x ol.   F or t he pr o p ose d st u d y, cis plati n is t he preferre d ma n date d first 
c h oice c h e m ot hera p y, h o we ver alter nati ve wee kl y re gi me ns are per missi ble.   T y pical 
reas o ns f or a patie nt n ot bei n g a ble t o recei ve cis plati n i ncl u de re nal i ns uffi cie nc y a n d 
hist or y of heari n g l oss.  J ustificati o n f or n ot usi n g cis plati n m ust be d oc u me nte d.  
A nal ysis of a pr os pecti ve nati o nal re gistr y, L o n git u di nal O nc ol o g y Re gistr y of Hea d a n d 
Nec k Carci n o ma ( L O R H A N), s h o we d t hat t he t hree m ost c o m m o nl y prescri be d 
c o nc urre nt ( wit h ra di ati o n) re gi me ns (i n or d er) are si n gle a ge nt cis plati n ( 5 1 %), si n gle-
a ge nt cet u xi ma b ( 2 1 %), a n d car b o pl ati n pl us paclita xel ( 7 %).  Si n gle a ge nt car b o plati n 
was i nfre q u e ntl y use d ( 3 %)  
 et al. Ca ncer 2 0 1 1; 1 1 7: 1 6 7 9 – 8 6.). T he acce pta ble 
wee kl y c h e m ot hera p y re gi me ns t hat ma y be use d o n t his st u d y are t he f oll o wi n g:  
•  Cis plati n 3 0  t o 4 0 m g/ m 2 ( preferre d, first c h oice) 
•  Cet u xi ma b 2 5 0 m g/ m 2  ( preferre d, sec o n d c h oice) 
•  Car b o plati n A U C 1. 5 a n d paclita xel 4 5 m g/ m 2 ( preferre d, t hir d c h oi ce) 
•  Car b o plati n A U C 3  ( preferre d, f o urt h c h oice) 
C he m ot hera p y  will be gi ve n i ntra ve n o usl y wee kl y d uri n g  ra di ot hera p y. 6 t otal d oses will 
be gi ve n. It is preferre d t hat t he d oses be a d mi nistere d o n da ys 1, 8, 1 5, 2 2, 2 9, a n d 3 6; 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 1  
h o we ver, t his is n ot ma n dat or y.   Patie nts wit h t he p 5 3 m utati o n will recei ve  o ne 
a d diti o nal wee kl y c h e m ot hera p y d ose.   C he m ot her a py will n ot be give n t o p atie nts wit h 
T 0 -2 N 0 -1 dise ase , ≤ 1 0 p ac k ye ars s m o ki n g hist ory .  F or p atie nts wit h T 0-2 N 0 -1 
dise ase, > 1 0 p ac k ye ars s m o ki n g hist ory, w het her or n ot t he p atie nt receives 
c he m ot her a py will be at t he discreti o n of t he tre ati n g p hysici a n.  
5. 7. 1  D ose M o dific ati o ns f or c he m ot her a p y  
Beca use of t h e l o w wee kl y d osa ge of c h e m ot hera p y , we a ntici pate fe w d os e 
m o dificati o ns sec o n dar y t o ac ute t o xicities.  D ose m o dificati o ns are all o we d 
a n d will be directe d b y t h e treati n g me dical o nc ol o gist  acc or di n g t o his/ her 
discreti o n  o n a n i n di vi d ual patie nt basis .   
5. 7. 2  C h a n gi n g C he m ot her a p y Re gi m e ns  
 I n t he e ve nt t hat cis plati n is hel d f or 1 wee k a n d t he patie nt is still dee me d 
u na ble t o recei ve f urt her wee kl y cis plati n ( beca us e of cis plati n -relate d 
t o xicit y), patie nt will be s witc he d t o a n ot her pr ot o c ol -acce pta ble wee kl y 
c he m ot hera p y re gi me n (cet u xi ma b, car b o plati n/ta x ol, or car b o plati n).  
 
Ot her c ha n g es ma y be d o ne o n a case -b y -cas e basis de pe n di n g o n t he sta n d ar d of practice 
of t he treat i n g me dical o nc ol o gist.    
5. 8  
P ost -C he m or a di ot her a p y Assess m e nt of Cli nic al Res p o nse  
P E T/ C T will be perf or me d 1 0 t o 1 6 wee ks ( o pti m all y at wee k 1 2) after C R T t o assess 
res p o nse.  All patie nts will be e val uate d via cli nical e xa m a n d fi ber o ptic lar y n g osc o p y b y 
t he ra diati o n o nc ol o gist a n d hea d a n d n ec k s ur ge o n ( o pti o nal) ar o u n d t he s a me ti me as 
t he P E T/ C T sca n.  N ote t hat t he fi ber o ptic lar y n g osc o p y nee d o nl y be d o ne o nce, at eit her 
6 or 1 2 wee ks p ost -C R T, wit h a d diti o nal lar y n g osc o p y pr oce d ures p erf or m e d at t he 
discreti o n of t he p h ysicia n.  Decisi o ns f or s ur gical e val uati o n will be base d o n t he res ults 
of t he P E T/ C T  a n d cli nical e xa m at t hat ti me .  Ot h er o pti o nal i ma gi n g st u dies ma y be 
perf or me d  (e. g. C T sca n 4 t o 6 wee ks aft er c o m pl eti o n of C R T ).    
5. 9  
S ur ger y after C R T  
Patie nts wit h a p ositi ve P E T/ C T sca n will u n der g o s ur gical e val u ati o n at t he discreti o n  of 
t he s ur ge o n.  T his ma y i n cl u de bi o psies a n d/ or o nc ol o gical resecti o ns of t he pri mar y 
t u m or a n d l y m p h n o de metastases. T he t y p e of s ur gical pr oce d ure will be left t o t he 
discreti o n  of t he s ur ge o n h o we ver t he g oal will be t o re m o ve a n y s us pecte d resi d ual 
t u m or wit h a ne gati ve resecti o n mar gi n w hile mai n tai ni n g or ga n preser vati o n.  Patie nts 
wit h a ne gati ve P E T/ C T sca n will be o bser ve d.    
5. 1 0  
Ot her T her a p y  
5. 1 0. 1  Per mitte d S u p p orti ve T her a p y  
All s u p p orti ve t hera p y f or o pti mal me dical care will be gi ve n d uri n g t he st u d y peri o d at 
t he discreti o n of t he atte n di n g p h ysicia n(s) wit hi n t he para met ers of t he pr ot oc ol  
5. 1 0. 1. 1  A ntie metics  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 2  
Pr o p h ylactic a ntie metics a n d s u p p orti ve t hera p y f or na usea a n d v o miti n g are per mitte d 
a n d hi g hl y rec o m me n de d i n patie nts partici pati n g i n t his st u d y. T hese i nter ve nti o ns 
s h o ul d be ma de acc or di n g t o i nstit uti o nal g ui deli nes.  
5. 1 0. 1. 2  N utriti o n al S u p ple me nt ati o n  
Cl ose m o nit ori n g of patie nts’ v ol u me stat us a n d b o d y wei g ht is str o n gl y rec o m me n de d.   
N utriti o nal s u p ple me ntati o n t hr o u g h a nas o gastric or gastr ost o m y fee di n g t u be s h o ul d be  
co nsi dere d i n patie nts w h o are u na bl e t o mai ntai n h y drati o n or e x perie nce m ore t ha n 1 0 % 
l oss of b o d y wei g ht d ue t o m uc ositis.  
5. 1 0. 2  N o n -per mitte d S u p p orti ve T her a p y  
5. 1 0. 2. 1  He m at o p oietic Gr o wt h F act ors  
He mat o p oietic gr o wt h fact ors are n ot p er mitte d d uri n g ra diati o n t hera p y. Gr o wt h fact ors 
are o nl y per mitte d if a d mi nistere d after ra diati o n t hera p y has b ee n c o m plete d. 
Er yt hr o p oiesis sti m ulati n g a ge nts are n ot per mitte d.  
5. 1 0. 3  Ot her S u p p orti ve C are Cli nic al St u dies  
Patie nts will be all o we d t o partici pate i n ot her s u p p orti ve care cli nical st u di es t hat d o n ot 
i nterfere wit h t he treat me nt pla n of t he c urre nt st u d y. 
5. 1 1  
D ur ati o n of St u d y  
T he pri mar y e n d p oi nt of t his st u d y is t o e val uate t he 2 year P F S rate after de-i nte nsifie d 
C R T i n H P V -p ositi ve a n d/ or p 1 6 p ositi ve O P S C C.  Patie nt partici pati o n c o ncl u des after 
2 years of f oll o w -u p aft er c o m pleti o n of C R T.  H o we ver, patie nts will c o nti n ue l o n g -ter m 
r o uti ne f oll o w-u p as is o ur i nstit uti o nal p olic y .   
5. 1 2  
D ur ati o n of F oll o w U p  
After c o m pleti o n of tr eat me nt patie nts will be f oll o we d acc or di n g t o o ur i nstit uti o nal 
sta n dar d practice:  cli nical e val uati o ns e ver y 2 t o 3 m o nt hs f or 2 years,  e ver y 6 m o nt hs 
f or 3 a d diti o nal years, t he n yearl y t hereafter.  As part of r o uti ne s ur v eilla nce patie nts will 
recei v e c hest i ma gi n g e v er y 6 m o nt hs f or 2 years t he n yearl y t hereafter a n d t h yr oi d 
f u ncti o n st u dies will be c hec ke d e ver y 6 m o nt hs f or 2 years the n  yearl y t hereaft er.   
 
O ur r o uti ne sta n dar d practice f or all of o ur hea d a n d nec k ca ncer patie nts is t o e nc o ura g e 
p ost -treat me nt de ntal f oll o w-u p a n d care.  T his st u d y d oes n ot i ncreas e t he nee d f or p ost -
treat me nt de ntal c are or i ncreas e t he ris k of d e ntal c o m plicati o n.  I n fact it ma y decrease 
t he ris k/i nci de nce of p ost-treat me nt de ntal c o m plicati o ns beca us e t he ra diati o n d ose is 
bei n g re d uce d t o 6 0 G y.  T h us we will c o nti n ue t o practice o ur r o uti ne p ost -treat me nt 
de ntal care rec o m me n dati o ns.    
 
See t he Ti me a n d E v e nts Ta ble i n t he A p pe n di x f or a s u m mar y of t he p atie nt 
assess me nts/ pr oce d ures a n d ti me peri o ds.  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 3  
6. 0  
A D V E R S E E V E N T S  
6. 1  
Defi niti o n  
A n a d vers e e x perie nce is a n y u nt o war d me dical o cc urre nce 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 m ace 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 d verse e x p erie nce or 
e ve nt ( A E) ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
me dici nal (i n vesti gati o nal) pr o d uct, w het her or n ot relate d t o t he me dici nal 
(i n vesti gati o nal) pro d uct.   
 
H os pitalizati o n f or ele cti ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he res ult of 
a n A E (e. g., s ur gical i nserti o n of ce ntral li ne) nee d n ot be c o nsi dere d A Es a n d s h o ul d n ot 
be rec or de d as a n A E.  Disease pr o gressi o n s h o ul d n ot be rec or de d as a n A E, u nless it is 
attri b uta ble b y t he i n vesti gat or t o t he st u d y t hera p y.  
 
I n t his st u d y, t o xicit y will be assesse d acc or di n g t o t he N CI C o m m o n Ter mi n ol o g y 
Criteria f or A d v erse E v e nts ( C T C A E), versi o n 4. 0, a vaila ble at: 
htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m . 
 
6. 2  
Re p orti n g  
Patie nts will be recei vi n g ra diati o n, c he m ot hera p y, a n d s ur gical treat me nts wit hi n  t he 
acce pte d sta n dar d of care.  We e x p ect patie nts t o e x perie nce t he k n o w n t o xi cities t hat are 
ass ociate d wit h t hese sta n dar d treat me nts , b ut o nl y at a l o wer rate a n d se verit y t han  
patie nts treate d wit h acce pte d ra diati o n a n d c h e m ot hera p y d osi n g . Si nce treat me nts 
m o dalities are t he sa me (ra diati o n a n d c h e m ot hera p y) , b ut d ose s of ra di ati o n a n d 
c he m ot hera p y  are re d u ce d t hr o u g h t his dei nte nsificati o n pr ot oc ol, n o a d verse e ve nts will 
be attri b uta ble t o  t he trial treat me nt. I n t he R T O G 0 1 2 9 st u d y, base d o n t he sa me 
dei nte nsificati o n treat me nt, t he o verall rate of gra de 3 or 4 ac ut e t o xic e ve nts was 
a p pr o xi matel y 8 0 % a n d t he late gra d e 3 or 4 t o xic e ve nts was a p pr o xi matel y 2 5 % of 
t hose  see n i n c o ntr ol pati e nts treate d wit h acce pt e d ra diati o n a n d c h e m ot hera p y d ose s.  
Beca use p atie nts o n t his trial recei ve  de -i nte nsifie d c he m ot hera p y a n d ra diati o n b y 
re d uci n g t he t otal d ose of ra diati o n to  6 0 G y a n d a d mi nisteri n g n o c he m ot hera p y or 
Cis plati n 3 0 m g/ m 2 wee kl y  t he ac ute a n d lat e t o xicities ca n o nl y be decreas e d i n trial 
patie nts c o m pare d t o  hist orical  n or ms .  
 
T his de -escalati o n  trial decreases ra diati o n a n d c h e m ot hera p y d oses c o m pare d t o 
acce pte d d osi n g f or hea d a n d nec k ca ncer ; t heref ore, ad verse e v e nts  will n ot be re p ort e d  
si nce t here is n o c h a nce t hat a d verse e ve nts are tri al relate d. 
6. 3  
Tre at me nt of A d vers e E ve nt  
Patie nts w h o de vel o p a n y a d verse e ve nt w hile o n st u d y will recei ve sta n dar d of care 
treat me nt.  Ra diati o n, cis plati n, a n d s ur ger y are alrea d y sta n d ar d of care treat me nts f or 
t hese patie nts.  Sta n dar d of care treat me nt f or k n o w n p ote ntial a d verse e ve nts fr o m t hese 
treat me nts are esta blis he d. 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 4  
7. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
7. 1  
St u d y Desi g n/ St u d y E n d p oi nts  
T he mai n o bjecti ve of t his P hase -II trial is t o esti mate t he t w o-year pr o gressi o n -free 
s ur vi val pr o ba bilit y ( P F S P) i n t his gr o u p of patie nts treate d wit h de-escal ate d 
ra di ot hera p y.  T h e pla n n e d t otal sa m ple size is 8 0 patie nts. ( T his n u m ber was i ncrease d t o 
1 2 0 as of J ul y 7, 2 0 1 7 , 1 4 0 as of Fe br uar y 7, 2 0 1 9 , 1 6 0 as of Ma y 2 9, 2 0 1 9 , 1 8 0 as of 
Oct o ber 9, 2 0 1 9 , 2 0 0 as of Ja n uar y 7, 2 0 2 0, a n d 2 5 0 as of J u ne 1 7, 2 0 2 0.  Please see 
details bel o w.)  T he recr uit me nt p hase is e x pecte d t o last 4 8  m o nt hs Dr o p o ut is e x p ecte d 
t o be a b o ut 1 0 %, base d o n a pre vi o us trial ( L C C C 1 1 2 0), he nce we e x pect a t otal of 2 2 5 
patie nts t o c o m plete t he st u d y.  
 
T he statistical ai m is p hrase d as a h y p ot h esis test wit h t he n ull h y p ot hesis bei n g t hat t he 
t w o-year P F S P is 0. 9 3  a n d t he alter nati ve h y p ot hesis bei n g t hat t he t w o -year P F S P is 0. 8 6 
( or less). A o n e sa m ple bi n o mial test will be use d t o assess t his h y p ot hesis. If t he n ull 
h y p ot hesis is rejecte d t he c o ncl usi o n will be t hat t he de -es calat e d treat me nt is i nferi or t o 
t he sta n dar d treat me nt. If t he n ull h y p ot hesis is n ot rejecte d t he c o ncl usi o n will be t hat t he 
de -escalate d tr eat me nt is at least as g o o d as t he st a n dar d R T.  
 
We gi ve p o wer calc ulati o ns f or t w o sa m ple sizes. F or a s a m ple size of n = 7 3 ( patie nts 
w h o c o m plete t he st u d y), t he n ull h y p ot hesis will be rejecte d if 1 1 or m ore patie nts fail. 
Fail ure is defi ne d as n ot reac hi n g t he t w o -y ear ti me p oi nt pr o gressi o n -free. Defi ni n g 
P( Reject H 0)  t o be t he pr o ba bilit y of rejecti n g t he n ull h y p ot hesis, t he perf or ma nce of the 
test is s u m marize d i n t he f oll o wi n g ta ble. 
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0 ) 
0. 9 3  
0. 0 3  
0. 8 6  
0. 5 8  
0. 8 0  
0. 9 4  
0. 7 5  
0. 9 9  
 
F or a s a m ple size of n = 8 0  patie nts, t he n ull h y p ot hesis will be rejecte d if 1 2 or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g  ta ble. 
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0 ) 
0. 9 3  
0. 0 2  
0. 8 6  
0. 5 7  
0. 8 0  
0. 9 4  
0. 7 5  
0. 9 9  
 
F or n = 7 3  t o 78 , t he critic al p oi nt is 1 1 fail ures. F or n =7 9  a n d 8 0, t he critical p oi nt is 1 2 
fail ures. Wit h t hese critic al p oi nts, t y pe-I err or ra n ges fr o m 0.0 2 3 t o 0.0 4 5 de pe n di n g o n 
sa m ple size. 
 
S a m ple size a n d p o wer re -c al c ul ati o n:  O n J ul y 7, 2 0 1 7, t he PI, n otici n g t he hi g her t ha n 
e x pecte d p atie nt accr ual rate, deci de d t o i ncrease sa m ple size t o 1 2 0. T his s h o ul d res ult i n 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 5  
a b o ut 1 0 8 patie nts t o c o m plete t he st u d y, after acc o u nti n g f or dr o p-o ut wit h a n e x pecte d 
dr o p -o ut rate of 1 0 %.  
 
F or a s a m ple size of n = 1 0 8 patie nts, t he n ull h y p ot hesis will be rejecte d if 1 3 or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g  ta ble.  
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0 ) 
0. 9 3  
0. 0 4  
0. 8 6  
0. 7 6  
0. 8 0  
0. 9 9  
0. 7 5  
1. 0 0  
 
F or n = 1 0 0 t o 1 0 1, t he critical p oi nt is 1 2 fail ures. F or n = 1 0 2 t o 1 0 8, t he critical p oi nt is 
1 3 fail ures. Wit h t hese critical p oi nts, t y pe -I err or ra n ges fr o m 0. 0 2 6 t o 0. 0 5 0 de pe n di n g 
o n sa m ple size.  
 
S a m ple size a n d p o wer re -c al c ul ati o n:  O n Fe br uar y 7, 2 0 1 9, t he PI, n otici n g t he hi g her 
t ha n e x pect e d patie nt accr ual rate, deci de d t o i ncrease sa m ple size t o 1 4 0. T his s h o ul d 
res ult i n a b o ut 1 2 6 patie nts t o c o m plete t he st u d y, after acc o u nti n g f or dr o p-o ut wit h a n 
e x pecte d dr o p -o ut rat e of 1 0 %.  
 
F or a s a m ple size of n = 1 2 6 patie nts, t he n ull h y p ot hesis will be rejecte d if 1 3 or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g ta ble.  
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0)  
0. 9 3  
0. 0 3  
0. 8 6  
0. 7 9  
0. 8 0  
0. 9 9  
0. 7 5  
1. 0 0  
 
F or n = 1 2 0 t o 1 2 3, t he critical p oi nt is 1 4 fail ures. F or n = 1 2 4 t o 1 2 8, t he critical p oi nt is 
1 5 fail ures. Wit h t hese critical p oi nts, t y pe -I err or ra n ges fr o m 0. 0 3 0 t o 0. 0 5 0 de pe n di n g 
o n sa m ple size.  
 
S a m ple size a n d p o wer re -c al c ul ati o n:  O n Ma y 2 9, 2 0 1 9, t he PI, waiti n g f or t he 
o pe n i n g of L C C C 1 9 1 2 a n d n otici n g t he c o m pleti o n of accr ui n g pla n ne d 1 4 0 patie nts, 
deci de d t o i ncrease s a m ple size t o 1 6 0. T his s h o ul d res ult i n a b o ut 1 4 4 patie nts t o 
c o m plete t he st u d y , after acc o u nti n g f or dr o p-o ut wit h a n e x pect e d dr o p -o ut rate of 1 0 %.  
 
F or a s a m ple size of n = 1 4 4 patie nts, t he n ull h y p ot hesis will be rejecte d if 1 6 or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g ta ble.  
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0)  
0. 9 3  
0. 0 4 5  
0. 8 6  
0. 8 7 0  
0. 8 0  
0. 9 9  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 6  
0. 7 5  
1. 0 0  
 
F or n = 1 4 0 t o 1 4 3, t he critical p oi nt is als o 1 6 fail ures. Wit h t hese critical p oi nts, t y pe -I 
err or ra n ges fr o m 0. 0 3 6 t o 0. 0 4 3 de pe n di n g o n sa m ple size.  
 
S a m ple size a n d p o wer re -c al c ul ati o n:  O n Oct o ber  9, 2 0 1 9, t he PI, waiti n g f or t he 
o pe n i n g of L C C C 1 9 1 2 a n d n otici n g t he c o m pleti o n of accr ui n g pla n ne d 1 6 0 patie nts, 
deci de d t o i ncrease s a m ple size t o 1 8 0. T his s h o ul d res ult i n a b o ut 1 6 2  patie nts t o 
c o m plete t he st u d y , after acc o u nti n g f or dr o p-o ut wit h a n e x pect e d dr o p -o ut rate of 1 0 %.  
 
F or a s a m ple size of n = 1 6 2  patie nts, t he n ull h y p ot hesis will be rejecte d if 1 8  or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g ta ble.  
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0)  
0. 9 3  
0. 0 0 3  
0. 8 6  
0. 4 5  
0. 8 0  
0. 9 6  
0. 7 5  
1. 0 0  
 
F or n = 1 5 9  t o 16 1 , t he critical p oi nt is als o 1 8  fail ures. Wit h t hese critical p oi nts, t y pe-I 
err or ra n ges fr o m 0. 0 3 0  t o 0. 03 5  de pe n di n g o n sa m ple size.  
 
S a m ple size a n d p o wer re -c al c ul ati o n:  O n Ja n uar y 7, 2 0 2 0, t he PI, waiti n g f or t he 
o pe n i n g of L C C C 1 9 1 2 a n d n otici n g t he c o m pleti o n of accr ui n g pla n ne d 1 8 0 patie nts, 
deci de d t o i ncrease s a m ple size t o 2 0 0 . T his s h o ul d res ult i n a b o ut 18 0  patie nts t o 
c o m plete t he st u d y , after acc o u nti n g f or dr o p-o ut wit h a n e x pect e d dr o p -o ut rate of 1 0 %.  
 
F or a s a m ple size of n = 1 8 0  patie nts, t he n ull h y p ot hesis will be rejecte d if 1 9  or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g ta ble.  
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0)  
0. 9 3  
0. 0 4 8  
0. 8 6  
0. 9 3  
0. 8 0  
0. 9 9  
0. 7 5  
1. 0 0  
 
F or n = 1 7 7  t o 17 9 , t he critical p oi nt is als o 1 9  fail ures. Wit h t hese critical p oi nts, t y pe-I 
err or ra n ges fr o m 0. 0 4 2  t o 0. 04 8  de pe n di n g o n sa m ple size.  
 
S a m ple size a n d p o wer re -c al c ul ati o n:  O n J u ne 1 7, 2 0 2 0, t he PI, waiti n g f or t he 
o pe ni n g of L C C C 1 9 1 2 a n d n otici n g t he c o m pleti o n of accr ui n g pla n ne d 2 0 0 patie nts, 
deci de d t o i ncrease s a m ple size t o 2 5 0. T his s h o ul d res ult i n a b o ut 2 2 5 patie nts t o 
c o m plete t he st u d y , after acc o u nti n g f or dr o p-o ut wit h a n e x pect e d dr o p -o ut rate of 1 0 %.  
 
F or a s a m ple size of n = 2 2 5 patie nts, t he n ull h y p ot hesis will be rejecte d if 2 3 or m ore 
patie nts fail. T he perf or m a nce of t h e test is s u m marize d i n t he f oll o wi n g ta ble.  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 7  
 
Tr ue 2 -ye ar P F S P  
P( Reject H 0)  
0. 9 3  
0. 0 4 5  
0. 8 6  
0. 9 6  
0. 8 0  
0. 9 9  
0. 7 5  
1. 0 0  
 
F or n = 2 2 0 t o 2 2 4, t he critical p oi nt is als o 2 3 fail ures. Wit h t hese critical p oi nts, t y pe -I 
err or ra n ges fr o m 0. 0 3 6 t o 0. 0 4 5 de pe n di n g o n sa m ple size.  
 
7. 2  
D at a A n al ysis Pl a n  
T he mai n h y p ot hesis test will be perf or me d as descri be d a b o v e. S u b gr o u p a nal yses t o 
c o m pare P F S bet wee n patie nts wit h ≤ 1 0 pac k years vs patie nts wit h > 1 0 p ac k years ( b ut 
wit h n o p 5 3 m utati o n ) s m o ki n g hist or y will be c o n d ucte d usi n g l o g -ra n k test. A d diti o nall y, 
a Ka pla n-M eier c ur ve will be esti mate d f or P F S, l ocal c o ntr ol, re gi o nal c o ntr ol, l ocal-
re gi o nal c o ntr ol, dista nt metastasis free s ur vi val a n d o verall s ur vi val . C irc ulati n g free H P V 
D N A bef ore , d uri n g, a n d after C R T will be c o m pare d, usi n g t he paire d t -test or Mc Ne mar’s 
test as a p pr o priate. As a n e x pl orat or y a n al ysi s, j oi nt m o deli n g of l o n git u di nal cf H P V-D N A 
a n d ti me-t o-pr o gressi o n will be c o n d ucte d t o e x a mi ne t he ass ociati o n bet wee n ti me-
var yi n g cf H P V -D N A a n d disease pr o gressi o n . We will als o perf or m e x pl orat or y a nal yses 
of t he ot her ge netic alterati o ns t hat are assesse d b y t he Tr u Si g ht T u m or Pa nel ® a n d 
fl oresce nt i n-sit u h y bri di zati o n st u dies.   
 
I n a d diti o n t o t he a b o ve, ot her e x pl orat or y a nal yses utilizi n g st u d y-relate d data ma y be 
perf or me d.  T hese a nal ys es will be c o nsiste nt wit h t he o verarc hi n g ai ms of t he st u d y.  
7. 3  
S afet y Meeti n gs  
T he pri nci pal i n vesti gat or will pr o vi de c o nti n u o us m o nit ori n g of patie nt safet y i n t his 
st u d y wit h peri o dic re p orti n g t o t he Data 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 or will s u b mit s u m maries, t o get her wit h f or matte d re p orts, t o t he 
D S M C  f or re vie w.  T h e re p orts will be re vie we d at t he ti me of t he a p p oi nte d meeti n g 
sc he d ule esta blis he d b y t his c o m mittee.  F oll o wi n g re vie w, t he D S M C  will re p ort its 
rec o m me n dati o ns, t o get h er wit h t he pri nci pal i n vesti gat or re p ort, t o t he O nc ol o g y P R C.  
T hese re p orts will be re vi e we d b y t he P R C at t he ti me of t he st u d y’s a n n ual I R B re n e wal.  
W he n warra nt e d, t he P R C a n d/ or D S M C  will ha ve t he prer o gati ve t o re q u est a d d iti o nal 
i nf or mati o n. 
8. 0  
S T U D Y M A N A G E M E N T  
8. 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 p ecte d t hat t he I R B will ha ve t he pr o per re prese ntati o n a n d f u n cti o n i n acc or da nce 
wit h fe derall y ma n date d re g ulati o ns.  T he I R B s h o ul d a p pr o ve t he c o ns e nt f or m a n d 
pr ot oc ol.  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 8  
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 ulat or y re q uire me nt(s), a n d s h o ul d a d here t o G o o d Cli nical Practice ( G C P) 
a n d t o et hical pri nci ples t hat ha ve t heir ori gi n i n t he Decl arati o n of Helsi n ki.  
 
 
 
Bef ore recr uit me nt a n d e nr oll me nt i 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 ns e nt f or m m ust i ncl u de all t he rel e va nt el e 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 ure 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 onse 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 partici pati o n i n t he trial, t he writte n i nf or me d c o nse nt f or m s h o ul d be 
si g ne d a n d pers o n all 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.  
8. 2  
Re q uire d D oc u me nt ati o n  
Bef ore t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g d oc u me ntati o n m ust be 
pr o vi de d t o t he Cli nical Pr ot oc ol Office ( C P O) at t he U ni versit y of N ort h Car oli na.  
 
•  A c o p y of t he official I R B a p pr o val letter f or t he pr ot oc ol a n d i nf or me d 
c o nse nt  
•  I R B me m bers hi p list 
•  C Vs a n d me dical lice ns ure f or t he pri nci pal i n vesti gat or a n d a n y ass o ciate 
i n vesti gat ors w h o will be i n v ol ve d i n t he st u d y 
•  A c o p y of t he I R B -a p pr o ve d c o nse nt f or m  
•  E xec ute d cli nic al researc h c o ntract  
8. 3  
Re gistr ati o n Pr o ce d ures  
All patie nts m ust be re gistere d wit h t he S t u d y C o or di nat or at t he De part me nt of 
Ra diati o n O nc ol o g y at t he U ni versit y of N ort h Car oli na  bef ore e nr oll me nt i n t he st u d y.   
Si g ne d c o nse nt f or ms s h o ul d be se nt t o t he U N C C o or di nat or f or t his p ur p ose.  
A d diti o nal patie nt i nf or mati o n ma y be re q u este d fr o m t he U N C C o or di nat or t o c o m plete 
re gistrati o n.  Eli gi bilit y criteria m ust be c o nfir m e d wit h t he U N C St u d y C o or di nat or 
bef ore t h e start of tr eat m e nt . 
8. 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 U ni versit y of N ort h Car oli na will ser ve as t he c o or di nati n g ce nter f or t his trial.  All 
data will be c ollecte d, e ntere d, a n d mai ntai n e d i n sec ure d s er vers i n t he De p artme nts  of 
Ra diati o n O nc ol o g y at t he U ni versit y of N ort h Car oli na , t he U ni versit y of Fl ori da, t he 
U ni versit y of Fl ori da Pr ot o n T hera p y I nstit ute, a n d Re x Ca ncer Ce nt er of Ralei g h  b y t he 
S t u d y C o or di nat or s. De -i de ntifie d, pass w or d pr otecte d data fr o m patie nts e nr olle d at t he 
U ni versit y of Fl ori da , t h e U ni versit y of Fl ori da Pr ot o n T hera p y I nstit ute, a n d Re x Ca ncer 
Ce nter of Ralei g h  will be electr o nicall y s u b mitte d t o t he De part me nt of Ra diati o n 
O nc ol o g y at t he U ni versit y of N ort h Car oli na via a sec ure d c o m p uter ser ver.  T he data 
will be p o ole d at U N C w here pers o n nel t here will c o or di nate a n d m a na ge d ata f or q ualit y 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
2 9  
c o ntr ol ass ura n ce a n d i nt e grit y.  Data a n al ysis will ta ke place at U N C as well.  As a n 
i n vesti gat or i nitiate d st u d y, t his trial will be a u dite d b y U N C’s Office of Cli nical Trials 
( O C T) Cl nical Trials Q u alit y Ass ura nce ( C T Q A) Pr o gra m a n n uall y.   
8. 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 he st u d y p atie 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 x actl y as des cri be d i n t he a p pr o ve d pr ot oc ol.   
8. 5. 1  E mer ge nc y M o dific ati o ns  
U N C a n d Affiliate i n vesti gat ors ma y i m ple me nt a de viati o n fr o m, or a c ha n ge of, t he 
pr ot oc ol t o eli mi nate a n i m me diate hazar d(s) t o tri al 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 u c h e mer ge nc y m o dificati o n i m ple me nte d, a U N C I R B m o dificati o n f or m m ust 
be c o m plete d b y U N C R esearc 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 Affiliate i n vesti gat ors rel yi n g o n t heir o w n i nstit uti o n’s I R B, as s o o n as p ossi ble after 
t he m o dificati o n has bee n ma de, t he i m ple me nte d de viati o n or c ha n g e a n d t he reas o ns f or 
it s h o ul d be s u b mitte d t o: 
 
o  T o U N C Pri nci pal I n vesti gat or f or a gree m e nt  
o  T he Affiliate i nstit uti o n’s I R B f or re vie w a n d a p pr o val.  ( O nce I R B’s 
res p o nse is recei ve d, this s h o ul d be f or war de d t o t he U N C St u d y 
C o or di nat or ). 
   
8. 5. 2  Si n gle P atie nt/ S u bject E xce pti o ns  
F or I nstit uti o ns Rel yi n g o n U N C’s I R B:  
A n y re q uest t o e nr oll a si n gle s u bject w h o d oes n ot meet all t he eli gi bilit y criteria of t his 
st u d y re q uires t he a p pr o val of t he U N C Pri nci pal I n vesti gat or a n d t he U N C I R B.  
 
F or I nstit uti o ns Rel yi n g o n T heir O w n I R B:  
A n y re q uest t o e nr oll a si n gle s u bject w h o d oes n ot meet all t he eli gi bilit y criteria of t his 
st u d y re q uires t he a p pr o val of t he U N C Pri nci pal I n vesti gat or a n d t he partici pati n g 
i nstit uti o n’s I R B, per its p olic y.  Please for war d t he I R B res p o nse t o t he U N C St u d y 
C o or di nat or b y facsi mile or via e mail wit hi n 1 0 b usi ness da ys after t h e ori gi nal 
s u b missi o n.   
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 0  
8. 5. 3  Ot her Pr ot oc ol De vi ati o ns/ Vi ol ati o ns  
All ot her pla n ne d de viati o ns fr o m t he pr ot oc ol m ust ha ve pri or a p pr o val b y t he Pri nci pal 
I n v esti gat or a n d t he U N C I R B.  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 n ce 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  
•  Has n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n or t he 
val ue of t he dat a c ollect e d  
•  Di d n ot res ult fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot oc ol v aria nce is c o nsi dere d a vi olati o n  if t he varia nce: 
•  Has har me d or i ncrease d t he ris k of har m t o o ne or m ore researc h partici pa nts.  
•  Has da ma ge d t 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 v esti 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 ul ati 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 wit h o ut pri or a p pr o val fr o m t he Pri nci pal I n vesti gat or, 
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 pers o n nel will re p ort t o a n y s p o ns or or data a n d safet y 
m o nit ori n g c o m mittee i n acc or da nce wit h t heir p olicies.  De viati o ns s h o ul d be 
s u m marize d a n d re p orte d t o t he I R B at t he ti me of c o nti n ui n g re vie w.  
 
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 v esti 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 uire d: 
 
Pr ot oc ol D e vi ati o ns: Affiliate  pers o n nel will re p ort t o a n y s p o ns or or data a n d safet y 
m o nit ori n g c o m mittee i n acc or da nce wit h t heir p olicies.  De viati o ns s h o ul d be 
s u m marize d a n d re p orte d t o t he I R B at t he ti me of c o nti n ui n g re vie w.  
 
Pr ot oc ol Vi ol ati o ns: A n y pr ot oc ol vi olati o n t hat occ urs m ust be re p orte d t o y o ur I R B 
per  i nstit uti o nal p olicies a n d re p ort e d t o t he UN C  St u d y  C o or di nat or  wit hi 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 h e patie nt a n d i nte grit y of 
t he data.  O nce y o ur i nstit uti o n’s I R B res p o nse is recei ve d, pl ease f or war d t o t he U N C 
St u d y C o or di nat or.  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 1  
8. 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 nte 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 be n ote d t hat w he n a n 
a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y desi g n or t he p ote ntial ris k t o t he 
patie nt, a re vise d c o nse nt f or m mi g ht be re q uire d.   
 
F or I nstit uti o ns Rel yi n g o n U N C’s I R B : 
T he writte n a me n d m e nt, a n d if re q uir e 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 U N C I R B a p pr o ve d a me n d me nt t o t heir i nstit uti o n’s I R B 
f or a p pr o val.  F or m ulti-ce nter st u dies, a n y affiliat e site m ust s u b mit t heir i nf or me d 
c o nse nt re visi o ns t o t he U N C St u d y C o or di nat or pri or t o s u b missi o n t o t heir I R B.   
 
8. 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 data bases , s o urce d oc u me nts, S p o ns or-I n vesti gat or 
c orres p o n d e nce, m o nit ori n g l o gs/letters, a n d re g ul at or y d oc u me nts (e. g., pr ot oc ol a n d 
a me n d me nts, I R B c orres p o n de nce a n d a p pr o val, si g ne d patie nt c o nse nt f or ms).  
 
S o urce d oc u me nts i ncl u d e all rec or di n gs of o bser vati o ns or n otati o ns of cli nical acti vities 
a n d all re p orts a n d rec or ds necessar y f or t he e val u ati o n a n d rec o nstr ucti o n of t he cli nical 
researc h st u d y. 
 
G o ver n me nt a g e nc y re g ulati o ns a n d directi ves re q uire t hat all st u d y d oc u me ntati o n 
pertai ni n g t o t he c o n d uct of a cli nical trial m ust be retai ne d b y t he st u d y i n v esti gat or.  I n 
t he case of a st u d y wit h a dr u g see ki n g r e g ulat or y a p pr o val a n d mar keti n g, t hese 
d oc u me nts s hall be retai n e d f or at least t w o years after t he last a p pr o val of mar keti n g 
a p plicati o n i n a n I nter n ati o nal C o nfere nce o n Har m o nizati o n (I C H) re gi o n.  I n all ot her 
cases, st u d y d oc u me nts s h o ul d be ke pt o n file u ntil t hree years aft er t he c o m pl eti 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. 
 
8. 8  
O bli g ati o ns of I n vesti g at ors  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he cli nical trial at t he site i n 
acc or da nce wit h Title 2 1 of t he C o de of Fe deral Re g ulati o ns a n d/ or t he Declarati o n of 
Helsi n ki.  T he Pri nci pal I n vesti gat or is res p o nsi ble f or pers o nall y o versee i n g t he 
treat me nt of all st u d y patie nts.  T he Pri nci pal I n vesti gat or m ust ass ure t hat all st u d y site 
pers o n nel, i ncl u di n g s u b -i n vesti gat ors a n d ot her st u d y staff me m bers, a d here t o t he st u d y 
pr ot oc ol a n d all F D A/ G C P/ N CI re g ul ati o ns a n d g ui deli nes re gar di n g  cli nical trials b ot h 
d uri n g a n d after st u d y c o m pleti o n.  
 
T he Pri nci pal I n vesti gat or at eac h i nstit uti o n or site will be res p o nsi ble f or ass uri n g t hat 
all t he re q uire d d ata will be c ollecte d a n d s u b mitte d as re q ueste d b y U N C. Ori gi nal 


L C C C 1 6 1 2  
 
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PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 2  
rec or ds will be ma de a v aila ble t o t he Pri nci pal I n v esti gat or u p o n re q uest t o per mit 
verificati o n of pr o per e ntr y of data.  
 
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 3  
9. 0  
R E F E R E N C E S  
 
1.  
Ca nt o M, De vesa S. Oral ca vit y a n d p har y n x ca n cer i nci de nce rates i n t he U nite d States, 
1 9 7 5 -1 9 9 8. Or al O nc ol. 2 0 0 2; 3 8: 6 1 0 -6 1 7.  
2.  
C hat ur ve di A, E n gels E, A n ders o n W, al. e. I n ci de nce tr e n ds f or h u ma n pa pill o ma vir us -
relate d a n d -u nrel ate d oral s q ua m o us cell carci n o mas i n t he U nite d States. J Cli n O nc ol. 
2 0 0 8; 2 6: 6 1 2 -6 1 9.  
3.  
D' S o uza G, krei mer A, Visci di R, al. e. Case -c o ntr ol st u d y of h u ma n pa pill o ma vir us a n d 
or o p har y n geal ca n cer. N E n gl J Me d. 2 0 0 7; 3 5 6: 1 9 4 4 -1 9 5 6.  
4.  
Frisc h M, Hjal gri m H, J ae ger A, al. e. C ha n gi n g p atter ns of t o nsillar s q ua m o us cell 
carci n o ma i n t he U nite d States. C a ncer C a uses C o ntr ol. 2 0 0 0; 1 1: 4 8 9 -4 9 5.  
5.  
Gillis o n M, K oc h W, Ca p o ne R, al. e. E vi de nce f or a ca us al ass ociati o n bet wee n h u ma n 
pa pill o ma vir us a n d a s u bset of hea d a n d nec k ca n cers. J N atl C a ncer I nst. 2 0 0 0; 9 2: 7 0 9 -
7 2 0.  
6.  
Sc ha ntz S, Y u G. Hea d a n d nec k ca ncer i nci de nce tre n ds i n y o u n g A merica ns, 1 9 7 3 -
1 9 9 7, wit h a s pecial a n al ysis f or t o n g ue ca n cer. Arc h Ot ol ary n g ol He a d N eck S ur g. 
2 0 0 2; 1 2 8: 2 6 8 -2 7 4.  
7.  
S hi b os ki C, Sc h mi dt B, J or da n R. T o n g ue a n d t o nsil carci n o ma:  i ncreasi n g tre n ds i n t he 
U. S. p o p ulati o n a ges 2 0 -4 4 years. C a ncer. 2 0 0 5; 1 0 3: 1 8 4 3 -1 8 4 9.  
8.  
S hi b os ki C, S hi b os ki S, S Sil ver ma n J. Tre n ds i n oral ca n cer rates i n t he U nite d States, 
1 9 7 3 -1 9 9 6. C o m m u nity De nt or al E pi de mi ol. 2 0 0 0; 2 8( 2 4 9 -5 6).  
9.  
Al bers A, Vis us C, Ts u kis hir o T, al. e. Alterati o ns i n t he T -cell rece pt or v ari a ble beta 
ge ne -restricte d pr ofile of C D 8 + T l y m p h oc ytes i n t he peri p heral circ ulati o n of patie nts 
wit h s q ua m o us cell carci n o ma of t he hea d a n d nec k. Cli n C a ncer Res. 2 0 0 6; 1 2: 2 3 9 4 -
2 4 0 3.  
1 0.  
A n g K, Harris J, W heel er R, al. e. H u ma n paill o ma vir us a n d s ur vi val of p atie nts wit h 
or o p har y n geal ca n cer. N E n gl J Me d. 2 0 1 0; 3 6 3: 2 4 -3 5.  
1 1.  
Braa k h uis B, S nij ders P, Ke u ne W, al. e. Ge netic patter ns i n hea d a n d nec k ca ncers t hat 
c o ntai n or lac k tr a nscri pti o nall y acti ve h u ma n pa pill o ma vir us. J N atl C a ncer I nst. 
2 0 0 4; 9 6: 9 9 8 -1 0 0 6.  
1 2.  
De Weese T, Wals h J, Dille ha y L, al. e. H u m a n pa pill o ma vir us E 7 a n d E 7 o nc o pr otei ns 
alter cell c y cle pr o gressi o n b ut n ot ra di ose nsiti vit y of carci n o ma cells treat e d wit h l o w -
d ose -rate ra diti o n. I nt J R a di at O nc ol Bi ol P hys. 1 9 9 7; 3 7: 1 4 5 -1 5 4.  
1 3.  
Fa k hr y C, Westra W, Li S, al. e. I m pr o ve d s ur vi v al of patie nts wit h h u ma n 
pa pill o ma vir us -p ositi ve hea d a n d n ec k s q ua m o us cell carci n o ma i n a pr os p ecti ve cli nical 
trial. J N atl C a ncer I nst. 2 0 0 8; 1 0 0: 2 6 1 -2 6 9.  
1 4.  
G u pta A, Lee J, Wil ke W, al. e. Ra diati o n res p o ns e i n t w o H P V -i nfect e d hea d-a n d-n ec k 
ca ncer cell li nes i n c o m paris o n t o a n o n -H P V -i nf ecte d cell li ne a n d relati o ns hi p t o 
si g nali n g t hr o u g h A K T. I nt J R a di at O nc ol Bi ol P hys. 2 0 0 9; 7 4: 9 2 8 -9 3 3.  
1 5.  
H off ma n n T, S o n k ol y E, Ha user U, al. e. Alterati o ns i n t he p 5 3 pat h wa y a n d t heir 
ass ociati o n wit h ra di o - a n d c he m ose nsiti vit y i n hea d a n d n ec k s q ua m o us cell carci n o ma. 
Or al O nc ol. 2 0 0 8; 4 4: 1 1 0 0 -1 1 0 9.  
1 6.  
Kl uss ma n n J, M o ore n J, Le h ne n M, al. e. Ge netic si g nat ures of H P V -relate d a n d 
u nrelate d or o p h ar y n geal carci n o ma a n d t heir pr o g n ostic i m plicati o ns. Cli n C a ncer Res. 
2 0 0 9; 1 5: 1 7 7 9 -1 7 8 6.  


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C O N FI D E N TI A L  
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Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 4  
1 7.  
K u mar B, C or dell K, Lee J, al. e. E G F R, p 1 6, H P V Titer, Bcl -x L a n d p 5 3, se x, a n d 
s m o ki n g as i n dicat ors of res p o nse t o t hera p y a n d s ur vi val i n or o p har y n geal ca ncer. J Cli n 
O nc ol. 2 0 0 8; 2 6: 3 1 2 8 -3 1 3 7.  
1 8.  
Lasse n P, Eri kse n J, Ha milt o n -D ut oit S, al. e. Effect of H P V -ass oci ate d p 1 6I N K 4 A 
e x pressi o n o n res p o ns e t o ra di ot hera p y a n d s ur vi val i n s q ua m o us cell carci n o ma of t he 
hea d a n d n ec k. J cli n O n c ol. 2 0 0 9; 2 7: 1 9 9 2 -1 9 9 8.  
1 9.  
Licitra L, Perr o n e F, B ossi P, al. e. Hi g h -ris k h u ma n pa pill o ma vir us affects pr o g n osis i n 
patie nts wit h s ur gicall y treate d or o p h ar y n geal s q ua m o us cell carci n o ma. J Cli n O nc ol. 
2 0 0 6; 2 4( 5 6 3 0 -6).  
2 0.  
L o ha va nic h b utr P, H o uc k J, Fa n W, al. e. Ge n o me wi de ge n e e x pressi o n pr ofiles of H P V -
p ositi ve a n d H P V -ne gati ve or o p har y n geal ca ncer:  p ote ntial i m plicati o ns f or treat me nt 
c h oices. Arc h Ot ol ary n g ol He a d Neck S ur g. 2 0 0 9; 1 3 5: 1 8 0 -1 8 8.  
2 1.  
Marti nez I, Wa n g J, H o bs o n K, al. e. I de ntificati o n of differe ntiall y e x presse d ge nes i n 
H P V -p ositi ve a n d H P V -ne gati ve or o p har y n geal s q ua m o us cell carci n o mas. E ur J 
C a ncer. 2 0 0 7; 4 3: 4 1 5 -4 3 2.  
2 2.  
M or k J, Lie A, Glattre E, al. e. H u ma n pa pill o ma vir us i nfecti o n as a ris k fact or f or 
s q ua m o us-cell carci n o ma of t he hea d a n d nec k. N E n gl J Me d. 2 0 0 1; 3 4 4: 1 1 2 5 -1 1 3 1.  
2 3.  
Pa dilla L, Le u n g B, Cars o n L. E vi de nce of a n ass ociati o n bet wee n h u m a n pa pill o ma vir us 
a n d i m paire d c h e m ot hera p y -i n d uce d a p o pt osis i n cer vical ca n cer cells. Gy nec ol O nc ol. 
2 0 0 2; 8 5: 5 9 -6 6.  
2 4.  
Sa xe na A, Yas har C, Ta yl or D, al. e. Cell ular res p o nse t o c he m ot hera p y a n d ra diati o n i n 
cer vical ca n cer. A m J O bstet Gy nec ol. 2 0 0 5; 1 9 2: 1 3 9 9 -1 4 0 3.  
2 5.  
Sc h wartz S, Y ue h B, Mc D o u gall J, al. e. H u ma n paill o ma vir us i nfecti o n a n d s ur vi val i n 
oral s q ua m o us cell ca ncer:  a p o p ulati o n -base d st u d y. Ot ol ary n g ol He a d Neck S ur g. 
2 0 0 1; 1 2 5: 1 -9.  
2 6.  
S meets S, Braa k h uis B, A b bas S, al. e. Ge n o m e -wi de D N A c o p y n u m b er alterati o ns i n 
hea d a n d n ec k s q ua m o us cell carci n o mas wit h or wit h o ut o nc o ge ne -e x pressi n g h u ma n 
pa pill o ma vir us. O nc o ge n e. 2 0 0 6; 2 5: 2 5 5 8 -2 5 6 4.  
2 7.  
S pa n os W, N o wic ki P, Lee D, al. e. I m m u ne res p o nse d uri n g t hera p y wit h cis plati n or 
ra diati o n f or h u ma n p a pill o ma vir us-relate d h ea d a n d nec k ca ncer. Arc h Ot ol ary n g ol 
He a d Neck S ur g. 2 0 0 9; 1 3 5( 1 1 3 7 -4 6).  
2 8.  
Tse n g C, Tri m ble C, Ze n g Q, al. e. L o w -d os e ra di ati o n e n ha nces t hera p e utic H P V D N A 
vacci nati o n i n t u m or -beari n g h osts. C a ncer I m m u n ol I m m u n ot her. 2 0 0 9; 5 8: 7 3 7 -7 4 8.  
2 9.  
Wei n ber g er P, Y u Z, Hafft y B, al. e. M olec ular classificati o n i de ntifies a s u bset of h u ma n 
pa pill o ma vir us -ass ociate d or o p har y n geal ca n cers wit h fa v ora ble pr o g n osis. J Cli n O nc ol. 
2 0 0 6; 2 4: 7 3 6 -7 4 7.  
3 0.  
Westra W, Ta u be J, P oet a M, al. e. I n v erse relati o ns hi p bet wee n h u ma n pa pill o ma vir us -
1 6 i nfecti o n a n d disr u pti ve p 5 3 ge ne m utati o ns i n s q ua m o us cell carci n o ma of t he hea d 
a n d nec k. Cli n C a ncer R es. 2 0 0 8; 1 4: 3 6 6 -3 6 9.  
3 1.  
Net w or k N C C. N C C N Cli nic al Pr actice G ui deli nes i n O nc ol o gy.  2 0 1 1.  
3 2.  
O' S ulli va n B, H ua n g S H, Si u L L, et al. Dei nte nsificati o n ca n di date s u b gr o u ps i n h u ma n 
pa pill o ma vir us -relate d or o p har y n geal ca ncer acc or di n g t o mi ni mal ris k of dista nt 
metastasis. J o ur n al of cli nic al o nc ol o gy : offici al j o ur n al of t he A meric a n S ociety of 
Cli nic al O nc ol o gy. Fe b 1 0 2 0 1 3; 3 1( 5): 5 4 3 -5 5 0.  
3 3.  
C hera B S, A m d ur RJ, Te p per J, et al. P hase 2 Trial of De -i nte nsifie d C he m ora diati o n 
T hera p y f or Fa v ora ble -Ris k H u ma n Pa pill o ma vir us -Ass ociate d Or o p har y n geal 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
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Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
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S q ua m o us Cell Carci n o ma. I nter n ati o n al j o ur n al of r a di ati o n o nc ol o gy, bi ol o gy, p hysics. 
Dec 1 2 0 1 5; 9 3( 5): 9 7 6 -9 8 5.  
3 4.  
Gar de n A S, As per J A, M orris o n W H, et al. Is c o n c urre nt c he m ora di ati o n t he treat me nt of 
c h oice f or all patie nts wit h Sta ge III or I V hea d a n d nec k carci n o ma? C a ncer. Mar 1 5 
2 0 0 4; 1 0 0( 6): 1 1 7 1 -1 1 7 8.  
3 5.  
Ca ncer Ge n o me Atlas N. C o m pre he nsi ve ge n o mic c haracteri zati o n of hea d a n d nec k 
s q ua m o us cell carci n o mas. N at ure. Ja n 2 9 2 0 1 5; 5 1 7( 7 5 3 6): 5 7 6-5 8 2.  
3 6.  
Gre g oire V, Eis br uc h A, Ha m oir M, Le ve n d a g P. Pr o p osal f or t he deli neati o n of t he 
n o dal C T V i n t he n o de -p ositi ve a n d t he p ost -o perati ve nec k. R a di ot her a p y a n d o nc ol o gy 
: j o ur n al of t he E ur o pe a n S ociety f or T her a pe utic R a di ol o gy a n d O nc ol o gy. A pr 
2 0 0 6; 7 9( 1): 1 5 -2 0.  
3 7.  
Gre g oire V, Le ve n da g P, A n g K K, et al. C T -b ase d deli neati o n of l y m p h n o de le vels a n d 
relate d C T Vs i n t he n o de-ne gati ve nec k: D A H A N C A, E O R T C, G O R T E C, N CI C, R T O G 
c o nse ns us g ui deli nes. R a di ot her a py a n d o nc ol o gy : j o ur n al of t he E ur o pe a n S ociety f or 
T her a pe utic R a di ol o gy a n d O nc ol o gy. Dec 2 0 0 3; 6 9( 3): 2 2 7 -2 3 6.  
3 8.  
O' S ulli va n B, War de P, Grice B, et al. T h e be nefits a n d pitfalls of i psilateral ra di ot hera p y 
i n carci n o ma of t he t o nsillar re gi o n. I nter n ati o n al j o ur n al of r a di ati o n o nc ol o gy, bi ol o gy, 
p hysics. Oct 1 2 0 0 1; 5 1( 2): 3 3 2 -3 4 3.  
3 9.  
Aar o ns o n N K, A h me dzai S, Ber g ma n B, et al. T he E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer Q L Q -C 3 0: a q ualit y -of -life i nstr u me nt f or use i n i nter nati o nal 
cli nical trials i n o nc ol o g y. J o ur n al of t he N ati o n al C a ncer I nstit ute. Mar 3 
1 9 9 3; 8 5( 5): 3 6 5 -3 7 6.  
4 0.  
Bj or dal K, Ha m merli d E, A hl ner -El m q vist M, et al. Q ualit y of life i n hea d a n d nec k 
ca ncer patie nts: vali dati o n of t he E ur o pea n Or g a nizati o n f or Researc h a n d Treat me nt of 
Ca ncer Q u alit y of Life Q uesti o n naire -H & N 3 5. J o ur n al of cli nic al o nc ol o gy : offici al 
j o ur n al of t he A meric a n S ociety of Cli nic al O nc ol o gy. Mar 1 9 9 9; 1 7( 3): 1 0 0 8 -1 0 1 9.  
4 1.  
R ose n be k J C, R o b bi ns J A, R oec ker E B, C o yle J L, W o o d J L. A pe netrati o n -as pirati o n 
scale. Dys p h a gi a. S pri n g 1 9 9 6; 1 1( 2): 9 3 -9 8.  
4 2.  
Belafs k y P C, M o ua de b D A, Rees CJ, et al. Vali dit y a n d relia bilit y of t he Eati n g 
Assess me nt T o ol ( E A T -1 0). T he A n n als of ot ol o gy, r hi n ol o gy, a n d l ary n g ol o gy. Dec 
2 0 0 8; 1 1 7( 1 2): 9 1 9 -9 2 4.  
4 3.  
C hera B S, Var gas C, M orris C G, et al. D osi metric st u d y of pel vic pr ot o n ra di ot hera p y f or 
hi g h -ris k pr ostate ca n cer. I nter n ati o n al j o ur n al of r a di ati o n o nc ol o gy, bi ol o gy, p hysics. 
N o v 1 5 2 0 0 9; 7 5( 4): 9 9 4 -1 0 0 2.  
4 4.  
Pi g n o n J, Maitre Al, Maillar d E, al. e. Meta -a nal ysis of c he m ot hera p y i n h ea d a n d n ec k 
ca ncer ( M A C H -N C):  a n u p date o n 9 3 ra n d o mise d trials a n d 1 7, 3 4 6 patie nts. R a di ot her 
O nc ol. 2 0 0 9; 9 2( 4 -1 4).  
 
 
 
 


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U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 6  
1 0. 0  A P P E N DI X   


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 7  
1 0. 1  
Eli gi bilit y C hec klist  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 8  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
3 9  
 


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
 
1 0. 2  
Ti m e a n d E ve nts T a ble  
 
 
 
 
 
 
 
 
 
 
 
 
F o ot n otes:  
1.  E xact ti mi n g of f oll o w -u p visits is fle xi ble base d o n p h ysica n’s sta n dar d of care  
2.  Str o n gl y rec o m me n de d, b ut n ot re q uire d  
3.  First p ost -C R T c hest x -ra y t o be d o ne 6 m o nt hs aft er p ost -C R T P E T/ C T; Fle xi bilit y i n ti mi n g is all o we d base d o n s c he d uli n g 
of patie nt’s a p p oi nt me nts  
St u d y Assess me nts  
Pri or t o C R T  
Wee kl y D uri n g C R T  
Wee ks 3 a n d 6 of 
C R T  
6 -1 6 Wee ks After 
C R T  
1 0 -1 6  Wee ks After 
C R T  
3, 6, 1 2 , 1 8 a n d 2 4 
M o nt h s After C R T  
E ver y 2 -3 M o nt hs 
f or 2 yrs after C R T, 
e ver y 6 m o nt hs f or 
3 yrs t he n yearl y 1  
E ver y 6 m o nt hs f or 
2 yrs after C R T, t he n 
yearl y  
Cli nical E val uati o n  
×  
×  
 
 
×  
 
×  
 
Pa ne n d osc o p y (if pri mar y u n k n o w n) 2  
×  
 
 
 
 
 
 
 
C o ntraste d nec k C T ( or P E T/ C T)  
×  
 
 
 
 
 
 
 
C hest X -Ra y  
×  
 
 
 
 
 
 
× 3  
De ntal E val uati o n 2  
×  
 
 
 
 
 
 
 
La bs: C B, ser u m c h e mistries, li ver f u ncti o n tests, 
pre g na nc y ( F)  
×  
 
 
 
 
 
 
 
H P V a n d/ or p 1 6 testi n g  
×  
 
 
 
 
 
 
 
Ge n etic assess me nt (if > 1 0 pac k year s m o ki n g 
hist or y)  
×  
 
 
 
 
 
 
 
Circ ulati n g free H P V -D N A ( bl o o d sa m ple) 
×  
× 4, 8  
 
 
 
× 5, 8  
 
 
N CI -C T C A E ( p h ysicia n)  
×  
 
×  
 
×  
 
 
×  
Fi ber o ptic Lar y n g osc o p y  
×  
 
 
×  
 
 
× 6  
 
P E T/ C T  
 
 
 
 
×  
 
 
 
T h yr oi d F u ncti o n  
 
 
 
 
 
 
 
× 7  


L C C C 1 6 1 2  
 
C O N FI D E N TI A L  
PI:   We n dell Y a r br o u g h , M D 
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Versi o n/ D ate :  1 8 A u g ust 2 0 2 3  
 
 
 
4.  Wee k 4 a n d 6 o nl y  
5.  A d diti o nal p ost -treat me nt sa m ples at PI’s discreti o n  
6.  At pr o vi der’s discreti o n  
7.  First o ne ma y be d o n e at sa me ti me as first p ost -C R T c hest x -ra y; fl e xi bilit y i n ti mi n g is all o we d base d o n sc he d uli n g of 
patie nt’s a p p oi nt me nts  
8.  See Secti o n 5. 5  f or det ails o n ti me p oi nts base d o n e nr oll me nt date.