Clinical trial NCT03237325
Conditions: Squamous Cell Carcinoma of the Oral Cavity and Oropharynx Oral Mucositis
Keywords: OM Head and Neck Cancer SGX942 Dusquetide Squamous Cell Carcinoma
Sponsor: Soligenix
Start date: 2017-12-04; Completion date: 2021-06-24
Enrollment: 266 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the efficacy of SGX942 compared to placebo in decreasing the duration of severe oral mucositis in patients receiving chemoradiation treatment for the treatment of head and neck cancer

Detailed description:

Arms: arm 1: Patients are randomized 1:1 active/placebo. arm 2: Patients are randomized 1:1 active/placebo.
Interventions: intervention 1: SGX942 intervention 2: Placebo
Intervention descriptions: intervention 1: 1.5 mg/mL SGX942 administered as a 4 minute IV infusion, twice per week starting within 3 days after initiating radiation therapy and continuing through 2 weeks after radiation therapy ends. intervention 2: Placebo is 0.9% sodium chloride (normal saline). The treatment preparation, frequency and duration of therapy are identical to that of the active drug.

Protocol documents:
Prot_002.pdf: 
Pr ot o c ol I D R -O M -0 2 -U S A  
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l
P a g e 1 of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
S G X 9 4 2  ( D U S Q U E TI D E) 
I D R- O M-0 2 -U S A  
A PI V O T A L, D O U B L E -B LI N D, R A N D O MI Z E D, P L A C E B O -C O N T R O L L E D , 
M U L TI N A TI O N A L  S T U D Y O F S G X 9 4 2  ( D U S Q U E TI D E) F O R T H E T R E A T M E N T O F 
O R A L M U C O SI TI S I N P A TI E N T S B EI N G  T R E A T E D WI T H C O N C O MI T A N T 
C H E M O R A DI A TI O N F O R T H E T R E A T M E N T O F S Q U A M O U S C E L L C A R CI N O M A 
O F T H E H E A D A N D N E C K   
S p o ns or:  
S oli ge ni x , Inc. 
2 9 E m m o ns Dri ve 
S uite B- 1 0 
Pri ncet o n, NJ 0 8 5 4 0 
( 6 0 9) 5 3 8- 8 2 0 0
D oc u me nt D at e : 
Ori gi n al  
1 1 J a n uar y 2 0 1 7 
A me n d me nt  1 
2 9 N o ve m ber 2 0 1 7  
A me n d me nt 2  
2 2 J a n uar y 2 0 1 8 
A me n d me nt 3
1 7 Se pte m ber 2 0 1 9 
U S I N D N u m ber:  
 
Me dic al M o nit or  
Ric har d Stra u be, M D 
C O N FI D E N TI A LI T Y S T A T E M E N T  
T he i nf or mati o n i n t his d oc u me nt c o ntai ns tra d e secrets a n d c o m mercial i nf or mati o n t hat are 
pri vile ge d or c o nfi d e ntial a n d ma y n ot be discl ose d u nless s uc h discl os ure is re q uire d b y fe deral 
or state la w or re g ulati o ns . I n a n y e ve nt, p ers o ns t o w h o m t he i nf or mati o n is discl ose d m ust be 
i nf or me d t hat t he i nf or m ati o n is pri vile ge d or c o nfi de ntial a n d ma y n ot be f urt her discl ose d b y 
t he m. T hese restri cti o ns o n discl os ure will a p pl y e q uall y t o all f ut ure i nf or mati o n s u p plie d t o 
y o u, w hic h is i n dicat e d as pri vile ge d or c o nfi d e ntial. 
N C T 0 3 2 3 7 3 2 5




Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
1.  
P R O T O C O L S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
S oli ge ni x, I nc. 
N a me of I n vesti g ati o n al Pr o d uct:  
S G X 9 4 2 ( d us q ueti de),  
 sterile s ol uti o n f or i ntra ve n o us (I V) i nf usi o n 
N a me of Acti ve I n gre die nt:  
D us q ueti de (researc h na me S G X 9 4),
 f ull y s y nt hetic n o vel pe nta pe pti de 
Title of St u d y:  
A  Pi v otal,  D o u ble -Bli n d,  Ra n d o mize d,  Place b o -C o ntr olle d,  M ulti nati o nal  St u d y  of  S G X 9 4 2  
( D us q ueti de)  f or  t he  Treat me nt of  Oral  M uc ositis  i n  Patie nts  Bei n g  Treate d  wit h  C o nc o mita nt  
C he m ora diati o n f or t he Treat me nt of S q ua m o us Cell Carci n o ma of t he Hea d a n d N ec k 
St u d y Ce nter(s): A t otal of 5 0 -6 0 ce nters i n t he U S A a n d E U  
P ri nci p al I n vesti g at or:
 
St u die d Peri o d ( ye ars):  
Esti mate d date first patie nt e nr olle d: N o ve m ber 2 0 1 7 
Esti mate d date last patie nt e nr olle d: Marc h 2 0 2 0 
P h ase of De vel o p me nt:  
P hase 3 
O bjectives:  
P ri m ar y O bjecti ve:  
•  
T o assess t he efficac y of S G X 9 4 2 c o m pare d t o place b o i n decreasi n g t he d urati o n of se vere oral 
m uc ositis ( S O M; defi ne d as W orl d Healt h Or ga nizati o n [ W H O ] Gra de lesi o n ≥3) i n patie nts 
recei vi n g fracti o nate d ra diati o n treat me nts a n d c o nc o mita nt cis plati n c he m ot hera p y, gi ve n as 8 0-
1 0 0 m g/ m 2 e ver y t hir d wee k, f or t he treat me nt of s q ua m o us cell carci n o ma of t he oral ca vit y or 
or o p har y n x.  
Sec o n d ar y O bjecti ves:  
T o assess t he i m pact of S G X 9 4 2 c o m pare d t o place b o o n t he f oll o wi n g  cli nicall y i m p orta nt sec o n dar y 
o bj ecti ves : 
1.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he Area - U n der-t he-C ur ve ( A U C) f or S O M ( W H O 
Gra de ≥3 ) b y ti me pl ot (se verit y - wei g hte d d urati o n) 
2.  T o assess  t he i m pact t hat S G X 9 4 2 has o n the Area - U n der-t he-C ur ve ( A U C) f or ulcerati ve oral 
m uc ositis ( U O M; defi ne d as W H O Gra de ≥2) b y ti me pl ot (se verit y - wei g hte d d urati o n) 
3.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he i nci de nce of S O M 
4.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he q ualit y of life assess me nt usi n g 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 ( E O R T C) Q ualit y of Life Q uesti o n f or 
Hea d a n d Nec k Ca ncer 4 3 q uesti o n ( Q L Q H & N 4 3) i nstr u me nt 
5.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he a m o u nt of  o pi oi ds use d 
 
T o assess t he i m pact of S G X 9 4 2 c o m pare d t o place b o o n t he f oll o wi n g  a d diti o nal sec o n dar y 
o bj ecti ves : 
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n t he c u m ulati ve n u m ber of da ys of R T brea ks 
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n t he d urati o n of S O M; i n all ra n d o mize d patie nts 
recei vi n g fracti o nate d R T a n d c o nc o mita nt cis plati n c he m ot hera p y, gi ve n as 8 0-1 0 0 m g/ m 2 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
e ver y t hir d wee k (I T T p o p ulati o n) 
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n t he d urati o n of U O M 
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n t he c u m ulati ve a m o u nt of pai n re p orte d b y patie nts 
•  
T he d urati o n of S O M usi n g a n alter nati ve defi niti o n calc ulate d as t he n u m ber of da ys fr o m t he 
first oral e xa mi nati o n wit h W H O gra de ≥3 t hr o u g h t he last assess me nt wit h a W H O sc ore ≥3 
(a n d n ot t o t he first assess me nt wit h a W H O gra de < 3) wit h n o f urt her re p orts of a W H O gra de 
≥3 . 
•  
T he d urati o n of S O M i n t he Per- Pr ot oc ol P o p ulati o n defi ne d as patie nts recei vi n g  a c u m ulati ve 
ra diati o n d ose of at least 5 5 G y a n d ha vi n g recei ve d all st u d y dr u g sc he d ule d. 
S af et y O bj ecti ve: 
Safet y o bj ecti ves will i ncl u de t he f oll o wi n g:  
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n t he A d verse E ve nts ( A E) a n d seri o us A d verse E ve nts 
( S A E) 
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n c ha n ges i n safet y la b orat or y val ues  
•  
T o assess t he i m pact t hat S G X 9 4 2 has o n t he Res p o nse E val uati o n Criteria i n S oli d T u m ors 
(R E CI S T ) cate g orizati o n of t he pri mar y t u m or at 1 2 wee ks a n d 1 2 m o nt hs p ost - CR T  
•  
T o assess t he i m pact of S G X 9 4 2 o n t he i nci de nce of re p orte d pres u me d bacterial i nfecti o ns 
bet wee n Baseli ne a n d 6 wee ks after c o m pleti o n of ra diati o n t hera p y ( R T) b y t otal n u m ber a n d 
b y se verit y of i nfecti o n, gra de d usi n g t he Nati o nal Ca ncer I nstit ute’s ( N CI’s) C o m m o n 
T er mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E)  
•  
T o assess t he i m pact of S G X 9 4 2 o n 1 2 m o nt h all- ca use m or talit y 
•  
T o assess t he i m pact of S G X 9 4 2 o n pr o gressi o n free s ur vi val t hr o u g h 1 2 m o nt hs 
Met h o d ol o g y:  
A p pr o xi matel y 2 6 0 patie nts wit h s q ua m o us cell carci n o ma of t he oral ca vit y a n d or o p har y n x sc he d ule d 
t o recei ve a mi ni m u m t otal c u m ulati ve ra diati o n d ose of 5 5 G y fracti o nate d as 2. 0- 2. 2 G y per da y a n d 
c o nc o mita nt cis plati n c he m ot hera p y gi ve n as a d ose of 8 0 -1 0 0 m g/ m 2 (e very t hir d wee k ) will be 
e nr olle d. S u bjects will be ra n d o mize d t o recei ve eit her 1. 5 m g/ k g S G X 9 4 2 or place b o gi ve n as a 4-
mi n ute I V i nf usi o n usi n g a n i nf usi o n or s yri n ge p u m p. Bli n de d st u d y dr u g will be starte d wit hi n 3 da ys 
after starti n g R T  a n d c o nti n ue d t wice a wee k ( 2-4 cale n dar da ys a part) t hr o u g h 2 wee ks after 
c o m pleti o n of t he R T . Efficac y will be assesse d b y oral e xa mi nati o n at eac h treat me nt visit a n d t he n at 
t he 3 t hr o u g h 6 wee ks p ost-R T c o m pleti o n visits. O M will be e val uate d usi n g t he W H O Gra de s ys te m 
a n d perf or me d b y o bser vers trai ne d o n t hese meas ure me nts. S O M is defi ne d as a W H O Gra de of ≥3. 
T he d urati o n of S O M is defi ne d as t he first ti me t he patie nt has a W H O Gra de ≥3 u ntil t he first ti me t he 
patie nt has a W H O Gra de of < 3 wit h n o s u bse q ue nt readi n gs ≥3. Patie nts will be ra n d o mize d ( 1: 1; 1. 5 
m g/ k g S G X 9 4 2: place b o) usi n g a n i nteracti ve we b res p o nse s yste m (I W R S). Ra n d o mizati o n will be 
stratifie d b y site, prese nce of pr o p h ylactic gastr ost o m y fee di n g t u be, a n d t u m or h u ma n pa pill o ma vir us 
( H P V) stat us. 
R o uti ne cli nical c he mistr y a n d he mat ol o g y will be o btai ne d at Scree ni n g/ Baseli ne, t he n at 3, 6, a n d 9 
wee ks w hile recei vi n g st u d y dr u g, a n d t he n at t he 4 a n d 6 wee k p ost- R T c o m pleti o n visit. T he sa me 
t y pe of sca n i nitiall y use d t o sta ge t he t u m or (i.e., c o m p ute d t o m o gra p h y [C T ], ma g netic res o na nce 
i ma gi n g [M RI ] or p ositr o n e missi o n t o m o gra p h y [ P E T ]) will be re peate d at 1 2 wee ks  a n d 1 2 m o nt hs 
after c o m pleti o n of t he ra diati o n t hera p y a n d c o m pare d t o t he i nitial sca n usi n g t he R E CI S T 1. 1 
criteria. 
N u m ber o f P atie nts ( pl a n ne d): 
2 6 0 patie nts ( 1 3 0 S G X 9 4 2 treate d a n d 1 3 0 place b o treate d patie nts) will be e nr olle d.  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
Di a g n osis a n d M ai n Criteri a f or I ncl usi o n:  
I ncl usi o n Criteri a 
Patie nts m ust meet all  of t he f oll o wi n g criteria i n or der t o be eli gi ble f or e nr oll me nt:  
1.  Willi n g a n d a ble t o u n dersta n d a n d si g n a n i nf or me d c o nse nt 
2.  Males or fe males a ge greater t ha n or e q ual t o 1 8 years  
3.  Bi o ps y- pr o ve n s q ua m o us cell carci n o ma of t he oral ca vit y or or o p har y n x wit h o ut dista nt or ga n 
metastases  t hat has bee n e val uate d f or h u ma n pa pill o ma vir us ( H P V) 
4.  Sc he d ule d t o recei ve cis plati n c he m ot hera p y of 8 0- 1 0 0 m g/ m² gi ve n e ver y t hir d wee k 
5.  Sc he d ule d t o recei ve a c o nti n u o us c o urse of c o n ve nti o nal e xter nal bea m irra diati o n de li vere d 
b y i nte nsit y - m o d ulate d ra di ot hera p y (I M R T) as si n gle dail y fracti o ns of 2. 0 t o 2. 2 G y, wit h a 
c u m ulati ve ra diati o n d ose bet wee n 5 5 a n d 7 2 G y at eac h site  
6.  Pla n ne d ra diati o n treat me nt fiel ds m ust i ncl u de at least 2 oral sites (retr o m olar tri g o ne, b uc cal 
m uc osa, fl o or of m o ut h, t o n g ue, or s oft palate), wit h eac h site rec ei vi n g ≥5 5 G y  
7.  All w o me n of c hil d beari n g p ote ntial ( W O C B P) a n d males wit h fe male part ners w h o are 
W O C B P m ust a gree t o t he use of effecti ve c o ntrace pti o n d uri n g t he trial.  
•  
W o me n are c o nsi dere d t o be W O C B P f oll o wi n g me narc he a n d u ntil bec o mi n g p ost-
me n o pa usal u nless per ma ne ntl y sterile ( h ysterect o m y, bilateral sal pi n gect o m y a n d bilateral 
o o p h orect o m y). A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n 
alter nati ve me dical ca use.  
Effecti ve c o ntrace pti o n met h o ds f or W O C B P s h o ul d be starte d pri or t o ra n d o mizati o n a n d 
c o nti n ue d f or a mi ni m u m of 3 5 da ys f oll o wi n g c o m pleti o n of st u d y dr u g a d mi nistrati o n.  
•  
Acce pta ble c o ntrace pti ve met h o ds f or W O C B P are t h ose t hat ac hie ve a fail ure rate of less 
t ha n 1 % per year a n d i ncl u de:  
o  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n:  
 
 Oral  
 
I ntra va gi nal 
 
Tra ns der mal  
o  Pr o gest o ge n - o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n:  
 
Oral  
 
I nj ecta ble 
 
I m pla nta ble 
o  I ntra uteri ne de vice (I U D)  
o  I ntra uteri ne h or m o ne-releasi n g s yste m ( I U S)  
o  Bilateral t u bal occl usi o n  
o  Vasect o mize d  part ner  
o  Se x ual a bsti ne nce defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g 
t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts 
•  
Male s u bjects s h o ul d use c o n d o ms d uri n g treat me nt a n d f or 9 8 da ys f oll o wi n g t he last st u d y 
dr u g a d mi nistrati o n peri o d. 
E xcl usi o n Criteri a  
Patie nts wit h a n y of t he f oll o wi n g criteria are N O T  eli gi ble f or e nr oll me nt: 
1.  C urre nt m uc ositis 




Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 7 of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
Criteri a f or Ev al u ati o n:  
Effic ac y:   
Efficac y will be deter mi ne d i n patie nts w h o ha ve recei ve d e n o u g h ra diati o n e x p os ure t o p ut t he m at 
si g nifica nt ris k of de velo pi n g S O M ( defi ne d as a c u m ulati ve ra diati o n d ose of at least 5 5 G y).  
Pri m ary E n d p oi nt: 
T he pri mar y efficac y o utc o me f or t his st u d y is t he d urati o n of S O M, defi ne d as t he n u m ber of da ys 
fr o m t he first oral e xa mi nati o n wit h a W H O Gra de assess me nt of ≥3 u nt il t he first ti me t he patie nt has 
a W H O Gra de of < 3 wit h n o s u bse q ue nt rea di n gs ≥3 .  
Sec o n d ary e n d p oi nts will be a n alyze d i n hier arc hic al or der: 
1.  T he Area - U n der-t he-C ur ve ( A U C) f or S O M ( W H O Gra de ≥3) b y ti me pl ot (se verit y - wei g hte d 
d urati o n) 
2.  T he Area - U n der-t he-C ur ve ( A U C) f or ulcerati ve oral m uc ositis ( U O M; defi ne d as W H O 
Gra de ≥2) b y ti me pl ot (se verit y - wei g hte d d urati o n) 
3.  T he i nci de nce of S O M  
4.  T he q ualit y of life assess me nt usi n g 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 ( E O R T C) Q ualit y of Life Q uesti o n naire 3 0 q uesti o n m o d ule ( E O R T C Q L Q- C 3 0 
( versi o n 3)) a n d t he E O R T C Hea d a n d Nec k Ca ncer latest 4 3 q uesti o n m o d ule ( Q L Q-H & N 4 3) 
i nstr u me nt 
5.  T he a m o u nt of o pi oi ds use d  
 
T he f oll o wi n g sec o n d ary e n d p oi nts will als o be ex a mi ne d:  
•  
T he c u m ulati ve n u m ber of da ys of ra diati o n treat me nt brea ks 
•  
T he d urati o n of S O M i n all ra n d o mize d patie nts recei vi n g fracti o nate d R T a n d c o nc o mita nt 
cis plati n c he m ot hera p y, gi ve n as 8 0-1 0 0 m g/ m 2 e ver y t hir d wee k (I T T p o p ulati o n) 
•  
T he d urati o n of U O M 
•  
T he c u m ulati ve a m o u nt of pai n re p orte d b y patie nts 
•  
T he d urati o n of S O M usi n g a n alter nati ve defi niti o n calc ulate d as t he n u m ber of da ys fr o m t he 
first oral e xa mi nati o n wit h W H O gra de ≥3 t hr o u g h t he last assess me nt wit h a W H O sc ore ≥3 
(a n d n ot t o t he first assess me nt wit h a W H O gra de < 3) wit h n o f urt her re p orts of a W H O gra de 
≥3.  
•  
T he d urati o n of S O M i n t he Per-Pr ot oc ol P o p ulati o n defi ne d as patie nts recei vi n g a c u m ulati ve 
ra diati o n d ose of at least 5 5 G y a n d all sc he d ule d st u d y dr u g.  
S af et y:  
•  
T he i nci de nce, t y pe, a n d b o d y s yste m cate g orizati o n of A Es 
•  
T he i nci de nce, t y pe, a n d b o d y s yste m cate g orizati o n of S A Es  
•  
T he c ha n ges fr o m B aseli ne f or he mat ol o g y para meters, cli nical c he mistr y para meters, a n d vital 
si g ns 
•  
T u m or stat us at 1 2 wee ks  a n d 1 2 m o nt hs f oll o wi n g c o m pleti o n of R T cate g orize d usi n g t he 
R E CI S T criteria  
•  
T he i nci de nce a n d se verit y of re p orte d i nfecti o ns assesse d b y C T C A E gra di n g  
•  
T he 1 2 m o nt h p ost- R T s ur vi val  




Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 9 of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
2.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
2. 1.  
T a ble of C o nte nts 
1.  
P R O T O C O L S Y N O P SI S  ..................................................................................................... 3 
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ..................... 9 
2. 1.  
T A B L E O F C O N T E N T S  ....................................................................................................... 9 
2. 2.  
L I S T O F T A B L E S  ............................................................................................................. 1 2 
2. 3.  
L I S T O F F I G U R E S ............................................................................................................ 1 2 
2. 4.  
A P P E N DI C E S  ................................................................................................................... 1 3 
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ................................. 1 4 
4.  
I N T R O D U C TI O N............................................................................................................... 1 6 
4. 1. 
S G X 9 4 2  ( DU S Q U E TI D E ) ................................................................................................ 1 6 
4. 2.  
T O XI C O L O G Y  ................................................................................................................. 1 6 
4. 3.  
P R E C LI NI C A L P H A R M A C O L O G Y  ..................................................................................... 1 7 
4. 4.  
P H A S E 1  T RI A L  ............................................................................................................... 1 8 
4. 5.  
P H A S E 2  T RI A L I N H E A D A N D N E C K C A N C E R P A TI E N T S  ................................................ 1 9 
 
 
 
4. 7.  
P A TI E N T P O P U L A TI O N  .................................................................................................... 2 7 
5.  
T RI A L O B J E C TI V E S A N D  P U R P O S E  .......................................................................... 2 8 
5. 1.  
P RI M A R Y O BJ E C TI V E  ..................................................................................................... 2 8 
5. 2.  
S E C O N D A R Y O BJ E C TI V E S  ............................................................................................... 2 8 
5. 3.  
S A F E T Y O BJ E C TI V E S  ...................................................................................................... 2 9 
6.  
I N V E S TI G A TI O N A L P L A N ............................................................................................ 3 0 
6. 1.  
O V E R A L L S T U D Y D E SI G N A N D P L A N : D E S C RI P TI O N  ...................................................... 3 0 
6. 2.  
S P E CI FI C A S S E S S M E N T S  ................................................................................................. 3 2 
6. 2. 1  Or al M uc ositis ( O M) Gr a di n g .................................................................................. 3 2  
6. 2. 2  T u m or St at us ............................................................................................................. 3 2  
6. 2. 3  I nfecti o n .................................................................................................................... 3 3 
6. 2. 4  Hist ory of P ai n a n d O pi oi d Use................................................................................ 3 4  
6. 2. 5  L a b or at ory Assess me nts............................................................................................ 3 4  
6. 2. 5. 1. 
Ser u m Pre g n a nc y T est  ...................................................................................... 3 4 
6. 2. 5. 2. 
He mat ol o g y T ests  ............................................................................................. 3 4 
6. 2. 5. 3. 
Cli nical C he mistr y La b orat or y Tests  ................................................................ 3 4 
6. 2. 6  Ot her Assess me nts  .................................................................................................... 3 5 
6. 2. 6. 1. 
Me dical Hist or y  ................................................................................................ 3 5 
6. 2. 6. 2. 
P h ysical E x a mi nati o n ........................................................................................ 3 5 
6. 2. 6. 3. 
Q ualit y of Lif e Q uesti o n naire  ........................................................................... 3 5 
6. 2. 6. 4. 
Vital Si g ns  ......................................................................................................... 3 5 
6. 2. 6. 5.  Hei g ht a n d B o d y M ass I n de x ( B MI) ................................................................ 3 6  




Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 1 1  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
1 0. 2. 2. 4. Assess me nt of Pai n  ........................................................................................... 5 0 
1 0. 2. 2. 5.  Alter nati ve Meas ure me nt of t he D urati o n of S O M .......................................... 5 0  
1 0. 2. 2. 6.  D urati o n of S O M i n t he Per- Pr ot oc ol P o p ulati o n ............................................. 5 0  
1 1.  A S S E S S M E N T O F S A F E T Y  ............................................................................................. 5 1 
1 1. 1.  O V E R A L L A S S E S S M E N T S  ................................................................................................ 5 1 
1 1. 1. 1  
Assess me nt of A Es  ................................................................................................. 5 1 
1 1. 1. 2  
Assess me nt of S A Es  ............................................................................................... 5 1 
1 1. 1. 3  
Assess me nt of L a b or at ory a n d Vit al Si g ns ........................................................... 5 1  
1 1. 1. 4  
Assess me nt of T u m or Pr o gressi o n at 1 2 weeks a n d 1 2- m o nt hs P ost- R T  ............. 5 2 
1 1. 1. 5  
I nfecti o ns ............................................................................................................... 5 2 
1 1. 1. 6  
Assess me nt of M ort ality T hr o u g h t he 1 2- m o nt h P ost- R T Cli nic Visit  .................. 5 2 
1 1. 1. 7  
Pr o gressi o n -free S urviv al ..................................................................................... 5 2 
1 1. 2.  S A F E T Y P A R A M E T E R S  .................................................................................................... 5 3 
1 1. 2. 1  
A dverse E x perie nce ( A E)  ...................................................................................... 5 3 
1 1. 2. 2  
Seri o us A dverse E x perie nce ( S A E)  ....................................................................... 5 3 
1 1. 3.  R E L A TI O N S HI P T O S T U D Y D R U G  .................................................................................... 5 3 
1 1. 4.  S E V E RI T Y O F A D V E R S E E V E N T  ...................................................................................... 5 4 
1 1. 5.  R E P O R TI N G A D V E R S E E V E N T S  ....................................................................................... 5 4 
1 1. 5. 1  
A dverse E ve nts  ...................................................................................................... 5 4 
1 1. 5. 2  
Seri o us A dverse E ve nts  ......................................................................................... 5 4 
1 1. 6.  D A T A M O NI T O RI N G C O M MI T T E E  ................................................................................... 5 5 
1 2.  S T A TI S TI C S  ....................................................................................................................... 5 7 
1 2. 1.  O V E R VI E W  ..................................................................................................................... 5 7 
 
 
1 2. 3.  F I N A L A N A L Y SI S  ............................................................................................................ 5 8 
1 2. 4.  S A M P L E S I Z E C A L C U L A TI O N  .......................................................................................... 5 8 
1 2. 5.  S E L E C TI O N O F P RI M A R Y A N A L Y SI S P O P U L A TI O N  .......................................................... 5 8 
1 2. 6.  D I R E C T A C C E S S T O S O U R C E D A T A / DO C U M E N T S  ........................................................... 5 8 
1 2. 6. 1  
St u dy M o nit ori n g .................................................................................................. 5 8  
1 2. 6. 2  
Pre -st u dy Ev al u ati o n ............................................................................................ 5 9 
1 2. 6. 3  
Site I niti ati o n Visit  ................................................................................................ 5 9 
1 2. 6. 4  
M o nit ori n g Visits  .................................................................................................. 5 9 
1 2. 6. 5  
Cl ose- o ut Visit  ....................................................................................................... 6 0 
1 2. 7.  A U DI T S A N D IN S P E C TI O N S  ............................................................................................. 6 0 
1 3.  I N S TI T U TI O N A L R E VI E W B O A R D (I R B)/ E T HI C A L C O M MI T T E E ( E C)  ........... 6 1 
1 4.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ................................................ 6 2 
1 5.  E T HI C S  ............................................................................................................................... 6 3 
1 5. 1.  E T HI C A L R E VI E W O F T RI A L  ........................................................................................... 6 3 
1 5. 2.  E T HI C A L C O N D U C T O F T H E S T U D Y  ................................................................................ 6 3 
1 5. 3.  
W RI T T E N IN F O R M E D C O N S E N T  ...................................................................................... 6 3 
1 5. 4.  S U BJ E C T D A T A P R O T E C TI O N  .......................................................................................... 6 3 
1 5. 5.  F I N A N CI A L D I S C L O S U R E ................................................................................................ 6 3 






Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 1 4  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S 
T a ble 2 : A b bre vi ati o ns a n d s peci alist ter ms  
A b bre vi ati o n or s peci alist ter m  
E x pl a n ati o n 
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n der t he c ur ve  
B A L  
Br o nc h oal ve olar la va ge 
B MI  
B o d y mass i n de x  
B U N  
Bl o o d urea nitr o ge n  
C F R  
C o de of fe deral re g ulati o ns 
C ma x  
Ma xi m u m c o nce ntrati o n 
C N S  
Ce ntral ner v o us s yste m  
C O 2 
Car b o n di o xi de 
C P  
C o n diti o nal p o wer  
C R  
C o m plete res p o nse 
C R T  
C he m ora diati o n t hera p y  
C T  
C o m p ute d t o m o gra p h y 
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
C V  
Car di o vasc ular  
D L T  
D ose li miti n g t o xicit y  
D M C  
Data m o nit ori n g  c o m mittee 
E C  
Et hics C o m mittee  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
E M A  
E ur o pea n Me dici nes A ge nc y 
E O R T C  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d cli nical practices 
G L P  
G o o d la b orat or y practices  
H E D  
H u ma n e q ui vale nt d ose  
H C G  
H u ma n c h ori o nic g o na d otr o pi n 
H P V  
H u ma n pa pill o ma vir us 
I B 
I n vesti gat or’s br oc h ure 
I C F 
I nf or me d c o nse nt f or m 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 1 5  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
A b bre vi ati o n or s peci alist ter m  
E x pl a n ati o n 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I D R 
I n nate Defe nse Re g ulat or 
I M R T 
I nte nsit y m o d ulate d ra diati o n t hera p y 
I R B 
I nstit uti o nal Re vie w B oar d 
I T T 
I nte nt t o treat 
I V 
I ntra ve n o us 
I W R S 
I nteracti ve we b res p o nse s yste m 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
mI T T  
M o difie d i nte nt t o treat  
M RI  
Ma g netic res o na nce i ma gi n g  
M T D  
Ma xi m u m t olerate d d ose 
N  
N u m ber  
N CI  
Nati o nal Ca ncer I nstit ute  
N D A  
Ne w dr u g a p plicati o n 
N H P  
N o n - h u ma n pri mate 
N O A E L  
N o o bser ve d a d verse effect le vel 
O M  
Oral m uc ositis  
P E G  
Perc uta ne o us e n d osc o pic gastr o n o m y  
P E T  
P ositr o n e missi o n t o m o gra p h y  
P D  
P har mac o d y na mics  
PI  
Pri nci pal i n vesti gat or  
P K  
P har mac o ki netic  
P P  
Per pr ot oc ol  
P R  
Partial res p o nse  
R B C  
Re d bl o o d cell 
R T  
Ra diati o n t hera p y 
S A E  
Seri o us a d verse e ve nt  
S D  
Sta ble disease  
S O M  
Se vere oral m uc ositis  
T ma x  
Ti me at w hic h t he ma xi m u m bl o o d c o nce ntrati o n was ac hie ve d  
U O M  
Ulcerati ve oral m uc ositis  
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 1 6  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
4.  
I N T R O D U C TI O N 
T his secti o n  c o ntai ns a brief descri pti o n of t he rati o nale a n d a v aila ble i nf or mati o n c o ncer ni n g t he 
c he mistr y, n o n-cli nical p har mac ol o g y a n d t o xic ol o g y, p har mac o ki netics ( P K), 
p har mac o d y n a mics ( P D), a n d pre vi o us cli nical e x perie nce wit h S G X 9 4 2 . Please refer t o t he 
I n v esti gat or's Br oc h ur e (I B) f or a d diti o nal details a n d i nf or mati o n. 
4. 1.  
S G X 9 4 2 ( Dus q ueti de)  
D us q ueti de is a fi ve a mi n o -aci d pe pti de t hat bi n ds t o t he i ntracell ular p 6 2 pr otei n [ 1] res ulti n g i n 
m o d ulati o n of t he i n nat e i m m u ne res p o nse t o b ot h i nfecti o n a n d tiss ue da m a ge b y re d u ci n g 
i n d ucti o n of i nfla m mati o n a n d i ncreasi n g m acr o p ha ge acti vati o n/ recr uit me nt, res ulti n g i n 
i ncreas e d bact erial cleara nce a n d tiss ue heali n g  [ 2- 4]. T he dr u g is f or m ulat e d as a n  a q ue o us, 
sterile s ol uti o n f or i njecti o n c o ntai ni n g 6 0 m g/ m L of d us q ueti de . T he  f or m ulati o n  c o ntai ns  n o 
preser vati ves  a n d  n o e xci pie nts. T he dr u g will be gi ve n at a d ose of 1. 5 m g/ k g. Dr u g will be 
dil ute d i nt o a n i nf use d v ol u me of 2 5 m L a n d a d mi nistere d as a 4- mi n ute i nf usi o n usi n g eit her a n 
i nf usi o n or s yri n ge p u m p.  
4. 2.  
T o xic ol o g y  
N o n - G L P a n d G L P precli nical t o xic ol o g y a n d s afet y p h ar mac ol o g y st u dies were c o n d ucte d i n 
mice a n d n o n- h u ma n pri mates ( N H Ps). Tra nsie nt, hi g h -d ose ac ute t o xicit y was o bser v e d  i n b ot h 
m o use a n d N H P . Res ol uti o n occ urr e d wit hi n mi n utes i n s ur vi vi n g a ni mals wit h n o l o n g-ter m 
se q uelae. 
P il ot t o xic ol o g y st u dies i n dicate d t hat t he ma xi m u m t olerate d d ose ( M T D) of a si n gl e 
a d mi nistrati o n of d us q ueti de, a d mi nistere d as a n I V i njecti o n o ver 3 0 t o 6 0 sec o n ds, is 8 8 m g/ k g 
i n mice. I n N H P, mil d cli nical si g ns (i.e., s h all o w/la b ore d res pirati o n, decrease d acti vit y, 
partiall y cl ose d e yes , a n d m uscle t witc hes) were n ote d i n 1 or b ot h a ni mals after a d mi nistrati o n 
of 9 0 ( 1 a ni mal), 1 8 0 ( b ot h a ni mals), a n d 2 2 0 ( 1 a ni mal) m g/ k g d us q ueti de d uri n g a n d s h ortl y 
after d osi n g. T hes e res ol ve d wit hi n a fe w mi n utes wit h o ut detecta ble resi d ual effects. 
T he safet y of m ulti ple dail y i njecti o ns of d us q ueti de has als o bee n e val u ate d i n G L P st u dies i n 
mice a n d N H Ps. I n mice, d oses of 2 0, 6 0, or 9 0 m g/ k g/ da y w ere gi ve n I V f or 1 4 da ys. Deat hs 
were o bs er ve d at t he hi g h d ose, prece de d mai nl y b y la b ore d res pirati o n a n d rec u m be n c y. 
Let h alit y w as als o o bser v e d i n 1 a ni mal gi v e n 6 0 m g/ k g b ut n o ot her a ni m als e x hi bite d cli nical 
si g ns at t his d ose. N o test article-r elate d m ortalit y or cli nical si g ns w ere o bser ve d at 2 0 m g/ k g. I n 
s ur vi v ors of all gr o u ps, t here w as n o e vi de n ce of t o xicit y i n a n y or ga n or a b n or mal bi oc he mistr y 
or he mat ol o g y. N o A E s were o bs er ve d at 2 0 m g/ k g a d mi nistere d dail y f or 1 4 da ys. 
D us q ueti de at 2 0, 8 0, or 1 6 0 m g/ k g/ da y was gi ve n I V t o c y n o m ol g us m o n ke ys f or 1 4 da ys. 
Tra nsie nt decrease d acti vit y a n d partiall y cl ose d e yes c o nti n ue d t o be o bser ve d d uri n g a n d 
s h ortl y aft er d osi n g at 1 6 0 m g/ k g f or t he first 3 da ys i n m ost a ni mals, t he n s p ora dicall y 
t hr o u g h o ut t he r e mai ni n g d osi n g peri o d. I n all cas es, t hese cli nical si g ns res ol ve d wit hi n a fe w 
mi n utes. N o A E s were o bser ve d o n a n y ot h er meas ure d para meter or micr osc o picall y i n a n y 
tiss ue. T he a d mi nistrati o n of d us q ueti de at d oses of 2 0 a n d 8 0 m g/ k g/ da y di d n ot res ult i n a ny 










Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 2 1  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
T a ble 3: Re p orte d I nfecti o ns  
Tre at me nt Gr o u p  
Pl ace b o  
n = 3 8  
1. 5 m g/ k g 
n = 3 6  
6. 0 m g/ k g 
n = 1 9  
All I nfecti o ns: n 
  ( %) 
  p-v al ue c o m p are d t o pl ace b o 
2 9 
( 7 6 %) 
—  
2 3 
( 6 4 %) 
0. 3 1 1  
8 
( 4 2 %) 
0. 0 1 8  
N o n -f u n g al I nfecti o n: n  
  ( %) 
   p-v al ue c o m p are d t o pl ace b o 
1 7 
( 4 5 %) 
—  
1 0 
( 2 8 %) 
0. 1 5 3  
4 
( 2 1 %) 
0. 1 4 4  
Seri o us I nfecti o n: n  
   ( %) 
   p-v al ue c o m p are d t o pl ace b o 
8 
( 2 1 %) 
—  
7 
( 1 9 %) 
> 0. 9 9 9  
3 
( 1 6 %) 
0. 7 3 5  
 
I n t he mI T T p o p ulati o n, t he n u m ber of p atie nts wit h R E CI S T e val uati o ns cate g orize d as 
c o m plete res p o nses t o t h era p y w as i ncrease d fr o m  1 5/ 3 8 ( 3 9 %) i n t he place b o gr o u p t o 1 7/ 3 6 
( 4 7 %) i n t he 1. 5 m g/ k g S G X 9 4 2 d ose gr o u p, a 2 1 % i ncrease. Disre gar di n g t h ose patie nts wit h 
missi n g or n ot assesse d t u m or stat us, t his i ncrease was 3 4 % i n t he S G X 9 4 2 1. 5 m g/ k g gr o u p. 
T his is c o nsiste nt wit h precli nical st u dies s h o wi n g i m pr o ve d s ur vi val a n d d ecrease d t u m or 
v ol u me size ( 3). O ver t he l o n ger t er m, t he o verall res ol uti o n rate i n t he place b o p o p ulati o n was 
hi g h, ma ki n g f urt h er i m pr o ve me nt diffic ult t o de m o nstrate.  H o we v er, S G X 9 4 2 defi nitel y di d n ot 
decrease t he eff ecti ve ness of C R T t hera p y  (Ta bl e 4 ). Si milarl y, t he o verall 1 -year s ur vi val rate 
was si milar bet wee n gr o u ps a n d m ore fa v ora ble f or t he S G X 9 4 2 treat e d gr o u ps ( Ta ble 5 ).  
T a ble 4: I nci de nce of T u m or C o m plete Res p o nse as a F u ncti o n of Tre at me nt Gr o u p a n d 
Ti me p oi nt  ( S afet y P o p ul ati o n)* 
R E CI S T Res p o nse  
Pl ace b o  
n = 4 1  
1. 5 m g/ k g  
n = 4 2  
3. 0 m g/ k g  
n = 3  
6. 0 m g/ k g  
n = 2 3  
1 -m o nt h f oll o w -u p  
1 5/ 3 2 ( 4 7 %)  
1 7/ 2 7 ( 6 3 %)  
1/ 3 ( 3 3 %)  
4/ 1 6 ( 2 5 %)  
3 -m o nt h f oll o w -u p  
1 7/ 2 7 ( 6 3 %)  
1 8/ 2 7 ( 6 7 %)  
1/ 1 ( 1 0 0 %)  
9/ 1 7 ( 5 3 %)  
6 -m o nt h f oll o w -u p  
1 9/ 2 4 ( 7 9 %)  
1 9/ 2 8 ( 6 8 %)  
1/ 1 ( 1 0 0 %)  
1 0/ 1 4 ( 7 1 %)  
9 -m o nt h f oll o w -u p  
6/ 8 ( 7 5 %)  
1 4/ 1 6 ( 8 8 %)  
2/ 2/ ( 1 0 0 %) 
1/ 3 ( 3 3 %)  
1 2 -m o nt h f oll o w -u p  
2 2/ 2 3 ( 9 6 %)  
1 9/ 2 3 ( 8 3 %)  
1/ 2 ( 5 0 %)  
1 0/ 1 2 ( 8 3 %)  
L O C F * * t hr o u g h 1 2 -m o nt h f oll o w -u p  
2 6/ 3 5 ( 7 4 %)  
2 8/ 3 5 ( 8 0 %)  
1/ 3 ( 3 3 %)  
1 3/ 2 2 ( 5 9 %)  
* P erce nta ge calc ulati o n e xcl u des missi n g/ n ot assesse d e val uati o ns  
* * Last O bser vati o n Carrie d F or war d  
 
T a ble 5: M ort alit y (I T T P o p ul ati o n 1) 
M ort alit y  
Pl ace b o  
n = 4 3  
1. 5 m g/ k g  
n = 4 1  
3. 0 m g/ k g  
n = 3  
6. 0 m g/ k g  
n = 2 4  
T hr o u g h 1 2 -m o nt h f oll o w -u p  
9 ( 2 1 %)  
3 ( 7 %)  
0  
4 ( 1 7 %)  
1 I ncl u des o ne patie nt d yi n g 3 7 3 da ys after recei vi n g t heir last st u d y dr u g d ose 














Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 2 8  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
5.  
T RI A L O B J E C TI V E S A N D  P U R P O S E  
5. 1.  
Pri m ar y O bjecti ve  
T o assess t he efficac y of S G X 9 4 2 c o m pare d t o place b o i n decreasi n g t he d urati o n of S O M  
(defi ne d as W H O Gra d e lesi o n ≥3) i n patie nts recei vi n g fra cti o nate d ra diati o n treat me nts  a n d 
c o nc o mita nt cis plati n c he m ot hera p y, gi ve n as 8 0- 1 0 0 m g/ m2 e ver y t hir d wee k , f or t he treat me nt 
of s q ua m o us cell carci n o ma of t he oral ca vit y or or o p har y n x.  
5. 2.  
Sec o n d ar y O bjecti ves  
T o assess t he i m pact of S G X 9 4 2 c o m pare d t o place b o o n t he f oll o wi n g cli nicall y i m p orta nt 
sec o n dar y o bj ecti ves: 
1.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he Area- U n der-t he- C ur v e ( A U C) f or S O M 
( W H O Gra de ≥3) b y ti me pl ot (se verit y-w ei g hte d d urati o n) 
2.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he Area- U n der-t he- C ur v e ( A U C) f or 
ulcerati ve oral m uc ositis ( U O M; defi ne d as W H O Gra de ≥2) b y ti me pl ot (se verit y -
wei g ht e d d urati o n) 
3.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he i nci de nce of S O M 
4.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he q ualit y of life assess me nt usi n g t he E O R T C 
Q L Q - C 3 0 ( versi o n 3) a n d Q L Q - H & N 4 3 i nstr u me nt 
5.  T o assess t he i m pact t hat S G X 9 4 2 has o n t he a m o u nt of o pi oi ds use d 
 
T o assess t he i m pact of S G X 9 4 2 c o m pare d t o place b o o n t he f oll o wi n g a d diti o nal sec o n dar y 
o bjecti ves : 
•  T o assess t he i m pact t hat S G X 9 4 2 has o n t he c u m ulati ve n u m ber of da ys of R T brea ks 
•  T o assess t he i m pact t hat S G X 9 4 2 has o n t he d urati o n of S O M; i n all ra n d o mize d 
patie nts recei vi n g fracti o nate d R T a n d c o n c o mita nt cis plati n  c he m ot hera p y,  gi ve n as 8 0-
1 0 0 m g/ m 2 (I T T p o p ulati o n) 
•  T o assess t he i m pact t hat S G X 9 4 2 has o n t he d urati o n of U O M 
•  T o assess t he i m pact t hat S G X 9 4 2 has o n t he c u m ulati ve a m o u nt of pai n re p orte d b y 
patie nts  
•  T he d urati o n of S O M usi n g a n alter nati ve d efi niti o n calc ulate d as t he n u m ber of da ys 
fr o m t he first oral e x a mi nati o n wit h W H O gra d e ≥3 t hr o u g h t he last ass ess me nt wit h a 
W H O sc ore ≥3 (a n d n ot t o t he first assess me nt wit h a W H O gra de < 3) wit h n o f urt her 
re p orts of a W H O gra de ≥3 
•  T he d urati o n of S O M i n t he P er- Pr ot oc ol P o p ulati o n defi ne d as p atie nts recei vi n g a 
c u m ulati ve ra diati o n d os e of at least 5 5 G y a n d st u d y dr u g t wi ce per wee k d uri n g a n d f or 
2 wee ks after r a diati o n t hera p y  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 2 9  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
5. 3.  
S afet y O bjecti ve s 
Safet y o bj ecti ves will i ncl u de t he f oll o wi n g:  
•  T o assess t he i m pact t hat S G X 9 4 2 has o n the A d v erse E ve nts ( A E) a n d seri o us A d verse 
E ve nts ( S A E)  
•  T o assess t he i m pact t hat S G X 9 4 2 has o n c ha n ges i n safet y la b orat or y val u es  
•  T o assess t he i m pact t hat S G X 9 4 2 has o n t he Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T ) cate g orizati o n of t he pri mar y t u m or at 1 2 wee ks a n d 1 2 m o nt hs C R T  
•  T o assess t he i m pact of S G X 9 4 2 o n t he i nci de nce of re p orte d pres u me d b acterial 
i nfecti o ns bet wee n Baseli ne a n d 6 wee ks after c o m pleti o n of ra diati o n t hera p y ( R T) b y 
t otal n u m ber a n d b y se verit y of i nfecti o n, gra d e d usi n g t he N ati o nal Ca ncer I nstit ute’s 
( N CI’s) C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) 
•  T o assess t he i m pact of S G X 9 4 2 o n 1 2 m o nt h all- ca use m ortalit y 
•  T o assess t he i m pact of S G X 9 4 2 o n pr o gressi o n free s ur vi val t hr o u g h 1 2 m o nt hs 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 0  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
6.  
I N V E S TI G A TI O N A L P L A N 
6. 1.  
O ver all St u d y Desi g n a n d Pl a n: Descri pti o n  
A p pr o xi matel y 2 6 0 p atie nts will  be e nr olle d i nt o t his P hase 3, place b o -c o ntr olle d, d o u ble- bli n d, 
m ulti nati o nal st u d y t o e v al uate t he efficac y of S G X 9 4 2 c o m pare d t o place b o i n treati n g t he 
d urati o n of S O M  i n patie nts recei vi n g C R T  f or t he treat me nt of hea d a n d n ec k ca n cer. Patie nts 
will be ra n d o mize d i nt o o ne of t w o gr o u ps ( 1. 5 m g/ k g S G X 9 4 2: Place b o) at a 1: 1 rati o. T he y will 
be stratifie d b y site , pres e nce of gastr ost o m y t u b e, a n d H PV stat us . Patie nts will recei ve t heir 
i nitial bli n de d I V st u d y dr u g ( 1. 5 m g/ k g S G X 9 4 2 or place b o) wit hi n 3 da ys of starti n g ra diati o n.  
T he pri mar y efficac y o ut c o me f or t his st u d y is t he d urati o n of S O M, defi ne d as t he n u m ber of 
da ys fr o m t he first or al e x a mi nati o n wit h a W H O Gra de assess me nt of 3 or 4 t hr o u g h t he first 
da y t h at a W H O Gr a de of < 3 is rec or de d wit h n o s u bse q ue nt assess me nts ≥3 . O M  will be 
e val uate d usi n g t he W H O  sc ori n g f or O M .  
Patie nts will be scree ne d t o assess t heir eli gi bilit y pri or t o ra n d o mizati o n. After ra n d o mizati o n, 
s u bjects will be gi n treat me nt wit h st u d y dr u g wit hi n 3 da ys of i nitiati n g R T .  
Patie nts will recei ve st u d y dr u g w hile u n der g oi n g C R T  a n d c o nti n ue t o recei ve st u d y dr u g f or 2 
wee ks  after t he c o m pleti o n of t heir R T . St u d y visit days will be e v er y t hir d da y ( ± 1 da y) . O n 
st u d y visit da ys, p atie nts will recei ve t he 4- mi n ute  i nf usi o n of st u d y dr u g. St u d y dr u g will n ot be 
gi ve n o n t he s a me da y as c he m ot hera p y . St u d y dr u g ca n be gi ve n at a n y ti me d uri n g t he visit 
da y, b ut m ust occ ur o n t h e sa me cale n dar da y t hat is t he st u d y visit da y. T h e st u d y visit cale n d ar 
e xte n ds t o 2 wee ks  p ost-c o m pleti o n of R T .  
Efficac y will be f urt her assesse d at t he 3  t hr o u g h 6 wee k s p ost-R T c o m pleti o n visits. F oll o w - u p 
visits will be c o n d ucte d at 1 2 wee ks a n d 1 2 m o nt hs after t he last ra diati o n d ose t o c o nti n ue t o 
e val uate safet y a n d s ec o n dar y e n d p oi nts. 
Bel o w is a ta bl e o utli ni n g t he st u d y sc h e d ule of pr oce d ures a n d ass ess me nts. T he st u d y w ee k 
desi g nati o ns ass u me a 7- wee k  C R T sc he d ule. T h ese ti mes ma y re q uire a dj ust me nt (as descri be d 
bel o w) if t he treat me nt c o urse is s h orter or if treat me nt brea ks pr ol o n g t he C R T f or m ore t ha n 7 
wee ks.  
 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 1  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
T a ble 7 : Sc he d ule of E ve nts b y Wee k 
St u d y w ee k  
Scree n  
B ase 2 
1 w 3 
2 w  
3 w  
4 w  
5 w  
6 w  
7 w  
8 w  
9 w  
1 0 w  
1 1 w  
1 2 w  
1 3 w  
1 5 - 5 5 w  
1 9 w  
5 9 w  
P ost -R T 1 
 
 
 
 
 
 
 
 
 
1 w  
2 w  
3 w  
4 w  
5 w 4 
6 w  
2 m -1 1 m 5 
1 2 w  
1 2 m  
M e dic al Hist or y  
X 
X 
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X 
2 X 
X 
X 
X 
X 
X  
X  
X 
I nf or me d 
C o nse nt  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
R a n d o miz ati o n  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hist or y of P ai n 
a n d O pi oi d Use  
 
X 
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X 
2 X 
X 
X 
X 
X 
 
X  
X 
Assess me nt of 
I nfecti o ns 
 
X 
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X 
2 X 
X 
X 
X 
X 
 
 
 
R a di ati o n 6 
 
 
5 X  
5 X  
5 X  
5 X  
5 X  
5 X  
5 X  
 
 
 
 
 
 
 
 
 
Cis pl ati n 6 
 
 
X  
 
 
X  
 
 
X  
 
 
 
 
 
 
 
 
 
A d mi nister 
Dr u g  
 
 
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
 
 
 
 
 
 
 
W H O O M
7 
 
X 
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
X 
X 
X 
X 
 
 
 
P E G T u be U se 
 
X 
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
X 
X 
X 
X 
 
 
 
V S 8 
X  
X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
X  
X  
X  
X  
 
 
 
P h ysic al E x a m  
X  
X  
 
 
 
 
 
 
 
 
X 1 3 
 
 
 
X  
 
 
 
S afet y L a bs 9 
X  
X 1 2 
 
 
X  
 
 
X  
 
 
X 1 3 
 
X  
 
X  
 
 
 
A Es  
 
X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
2 X  
X  
X  
X  
X  
 
 
 
T u m or Sc a n 1 0 
X 1 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X 
Ser u m 
Pre g n a nc y  
X 
X 1 2 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
H P V St at us  
X 1 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q u alit y of Life  
 
X 
 
 
 
X 
 
 
 
 
X 1 3 
 
 
 
 
 
 
 
 
1 P ost -R T =  ti me fr o m t h e last ra diati o n t h era p y treat me nt 
2 Baseli ne i nf or mati o n n ee ds t o be o btai n e d pri or t o ( 0 t o 9 6 h o urs b ef ore) t h e first d ose of 
st u d y dr u g 
3 w = wee ks  
4 O nl y t o be d o ne if W H O sc ore is ≥2 at Wee k 4 P ost -R T visit  
5 m = m o nt hs; patie nt c o ntact (cli nic visit, tele p h o n e, or e mail) re q uire d m o nt hl y t hr o u g h 
t he 1 2-m o nt h cli nic visit  
6 Ti mi n g of ra diati o n a n d c h e m ot h era p y at discreti o n of pri mar y care p h ysicia ns  
7 W H O O M = oral m u c ositis gra di n g wit h W H O Oral M u c ositis Gra di n g s yste m  
8 Vital si g ns t o  i ncl u d e te m p erat ure, wei g ht, p ulse, res pirati o ns, a n d seate d bl o o d press ure; 
Hei g ht will be o btai n e d at Baseli ne o nl y  
9 Safet y la bs = he mat ol o g y a n d cli nical c h e mistr y p a n els  
1 0 Sca n = o btai n i nitial sta gi n g C T/ P E T/ M RI sca ns (scree ni n g sca n m ust be wit hi n  6 wee ks 
pri or t o Baseli n e)  
1 1 Nee d t o c o nfir m t h at t h e i nitial dia g n ostic sca ns were C T, P E T, or M RI a n d t he t u m or 
was teste d f or H P V stat us  
1 2 Re p eat test re q uire d if Baseli ne sa m ple > 7  da ys fr o m Scree ni n g  
1 3 T o b e d o n e o nl y o n t h e sec o n d visit i n wee k 2  p ost - R T  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 2  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
It is ass u me d t hat p atie nts will recei ve 7 w ee ks of R T . I n practice, s o me patie nts will ha ve a 
s h orter c o urs e (l o wer pla n ne d ra diati o n d ose) or st o p treat me nt earl y. Si milarl y, p atie nts wit h R T 
brea ks w h o c o m plete 7 w ee ks of R T ma y re q uire treat me nt f or m ore t ha n 7 wee ks. All p ost- R T  
visits will be sc he d ule d fr o m t he last  R T  s o t hat if t he R T  is c o m plete d after 6 wee ks, st u d y dr u g 
will be c o nti n ue d f or t he 2 wee ks f oll o wi n g ( Wee ks 7 a n d 8) a n d t he 1 2 w ee ks  p ost-ra di ati o n 
sca n will be  o btai ne d i n Wee k 18 . Si milarl y, if t here are treat me nt brea ks s uc h t hat R T  c o m pletes 
i n st u d y Wee k 8, t he st u d y dr u g will c o nti n ue f or 2 wee ks ( Wee ks 9 a n d 1 0) a n d t he 1 2 w ee ks 
p ost- ra diati o n sca n will b e o btai ne d at Wee k 2 0. 
6. 2.  
S pecific Assess me nts  
6. 2. 1  
Or al M uc ositis ( O M) Gr a di n g  
O M will be e val uate d b y pers o n nel trai ne d i n t he use of t he W H O Oral M uc ositis Gra di n g 
s yste m w hic h  i ncl u d es b ot h p h ysical a n d f u ncti o n al i nf or mati o n. T his gra di n g s yste m is wi del y 
utilize d i n O M cli nical researc h tri als i ncl u di n g t h e P hase 2 trial a n d is s h o w n i n  Ta ble 8 . 
T a ble 8 : W H O Or al M uc ositis Gr a di n g S yste m 
Sc or e 
Fi n di n gs  
0 
N o fi n di n gs O R  
Pai n or er yt he ma ( n ot b ot h)  
1 
Pai n a n d er yt he ma A N D  
N o ulcer  
2 
Ulcer a n d/ or pse u d o me m bra ne, A N D  
A ble t o eat s oli d f o o d A N D 
A ble t o dri n k  
3 
Ulcer a n d/ or pse u d o me m bra ne, A N D  
N ot a ble t o eat s oli d f o o d A N D 
A ble t o dri n k  
4 
Ulcer a n d/ or pse u d o me m bra ne, A N D  
N ot a ble t o eat s oli d f o o d A N D 
N ot a ble t o dri n k  
O nl y me dical pers o n n el at t he site w h o ha ve u n d er g o n e trai ni n g a n d certifi cati o n i n usi n g t he 
W H O Gra di n g s yst e m will perf or m t he O M ass ess me nts.  
6. 2. 2  
T u m or St at us  
T he t u m or res p o nse t o tr eat me nt will be use d as a safet y e n d p oi nt. Res ults at 1 2 wee ks  a n d 1 2 
m o nt hs p ost- R T will be c o m par e d t o t he Scree ni n g res ults usi n g t he R E CI S T 1. 1 s yste m. T he 
e val uati o n criteri a f or t he tar get lesi o n (t he pri mar y hea d a n d n ec k carci n o ma) are s h o w n i n 
Ta ble 9 ; t he criteria f or n o n-tar get lesi o ns are s h o w n i n Ta ble 1 0 ; a n d t he criteria f or o v erall 
cate g orizati o n of t he t u m or stat us are s h o w n i n T a ble 1 1 . I n a d diti o n, details pertai ni n g t o 
rec urre nce of disease, a d diti o nal t hera p y, or s ur ger y re q uire d  after t he acti ve treat me nt p has e of 
t he trial is c o m plete d will be c ollecte d a n d rec or de d i n t he e C R F t hr o u g h o ut all f oll o w u p visits 
u ntil 1 2 m o nt hs f oll o wi n g t he last R T treat me nt.  
  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 3  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
T a ble 9: R E CI S T E v al u ati o n of t he T ar get Lesi o n 
T ar get Lesi o n Res p o nse  
Me as ure me nt  
C o m plet e Res p o nse ( C R) 
All tar get lesi o ns g o ne  
Partial Res p o nse ( P R)  
> 3 0 % decrease fr o m baseli ne  
Pr o gressi ve Disease  
> 2 0 % i ncrease fr o m s mallest s u m of l o n gest dia meter rec or de d 
si nce treat me nt starte d ( best res p o nse) 
Sta ble Disease ( S D)  
Neit her Pr o gressi ve D isease n or Partial Res p o nse 
 
T a ble 1 0: R E CI S T E v al u ati o n of t he N o n- t ar get Lesi o n 
T ar get Lesi o n Res p o nse  
Me as ure me nt  
C o m plete Res p o nse ( C R)  
All n o n- tar get lesi o ns g o ne 
T u m or mar kers g o ne 
Sta ble Disease ( S D)  
Persiste nce of ≥1 n o n -tar get lesi o n 
T u m or mar ker le vel ele vate d  
Pr o gressi ve Disease  
E nlar ge me nt of n o n -tar get lesi o ns 
 
T a ble 1 1 : O ver all R E CI S T Res p o nse 
T ar get Lesi o ns  
N o n -t ar get Lesi o ns 
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
C R  
N o  
C o m plete Res p o nse  
C R  
S D  
N o  
Partial Res p o nse  
P R  
N o n - Pr o gressi ve 
D isease 
N o  
Partial Res p o nse  
S D  
N o n - Pr o gressi ve 
D isease 
N o  
Sta ble Disease  
P r o gressi ve D isease 
A n y  
Yes or N o  
Pr o gressi ve Disease  
A n y  
P r o gressi ve D isease 
Yes or N o  
Pr o gressi ve Disease  
A n y  
A n y  
Yes  
Pr o gressi ve Disease  
 
6. 2. 3  
I nf ecti o n 
I nfecti o ns will be r e p orte d at eac h cli nic visit t hr o u g h t o t he 6-wee k  p ost-R T visit . A n y i de ntifie d 
i nfecti o n will be cate g orize d as pres u me d  f u n gal, pres u me d viral, or pres u me d bacteri al . T he 
se verit y of eac h r e p orte d infecti o n will be gra d e d 1 t o 5 usi n g t he C T C A E.  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 4  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
6. 2. 4  
Hist or y of P ai n a n d O pi oi d  Use  
E x ce pt f or t he Scree ni n g visit, a t e ver y st u d y visit, t he st u d y staff will re vie w wit h t he patie nt 
t heir c urr e nt pai n le vel as well as t he ca us e of t heir pai n. Eff orts will be ma d e t o differe ntiate  
pai n d ue t o O M  vers us ot her ca us es of pai n. T h e st u d y staff will als o re vie w wit h t he patie nt 
t heir c urr e nt prescri pti o ns f or pai n me dicati o n ( o pi oi ds) wit h s pecial care ta ke n t o re vie w t he as 
nee de d  me di cati o ns t he p atie nts ha ve bee n  gi ve n as well as t he fre q ue nc y  wit h w hic h t he y are 
ta ki n g t he m. D etails f or all of t he a b o ve will be rec or de d i n t he e C R F.  
I n a d diti o n, site staff will re vie w t he st u d y-s pecifi c oral h y gie ne re q uire me nts wit h t he patie nt o n 
a wee kl y b asis.  
6. 2. 5  
L a b or at or y Ass ess me nts  
6. 2. 5. 1.  
Ser u m Pre g n a nc y Test  
Bl o o d sa m ples will be o btai ne d at t he Scree ni n g, Baseli ne  (if Baseli ne > 7 d a ys  fr o m Scree ni n g), 
a n d 6 wee k s p ost-R T  visits f or a ser u m pre g na n c y test  ( h u ma n c h ori o nic g o na d otr o pi n [ HC G])  
f or all w o me n w h o are of c hil d beari n g p ote ntial.  
6. 2. 5. 2.  
He m at ol o g y Tests 
T he he mat ol o g y pa nel will be perf or me d at t he Ce ntral La b orat or y o n sa m ples c ollecte d at  
Scree ni n g,  Baseli ne ( if Scree ni n g tests w ere o bt ai ne d > 7 d a ys  fr o m Bas eli ne), Wee k 3 , Wee k  6, 
a n d at t he 2- w ee k p ost-R T, t he 4- wee k  p ost-R T visit  a n d t he 6-wee k p ost- R T visit s. T he pa nel 
will c o nsist of t he f oll o wi n g tests:  
•  Re d bl o o d cell c o u nt ( R B C) 
•  He mat ocrit  
•  He m o gl o bi n 
•  R B C i n dices  
•  Platelet c o u nt  
•  W hite bl o o d cell c o u nt ( W B C) 
•  W B C differe ntial c o u nt 
6. 2. 5. 3.  
Cli nic al C he mistr y L a b or at or y Tests 
T he cli nical c h e mistr y p a nel will be perf or m e d at t he Ce ntral La b orat or y o n sa m ples c ollecte d at 
Scree ni n g, Baseli ne ( if Scree ni n g tests w ere o bt ai ne d > 7 d a ys  fr o m Bas eli ne), Wee k 3 , Wee k 6, 
a n d at t he 2 - w ee k p ost-R T, t he 4- wee k  p ost-R T a n d t he 6-wee k p ost- R T visit s. T he pa nel will 
c o nsist of t he f oll o wi n g t ests: 
•  Ser u m s o di u m 
•  Ser u m p otassi u m 
•  Ser u m c hl ori de 
•  Ser u m bicar b o nat e ( C O 2) 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 5  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  Ala ni ne a mi n otra nsf eras e  ( A L T) 
•  As partate a mi n otra nsferase ( A S T)  
•  T otal bilir u bi n  
•  Al kali ne p h os p hatase 
•  T otal pr otei n  
•  Ser u m creati ni ne  
•  Bl o o d urea nitr o ge n ( B U N) 
6. 2. 6  
Ot her Assess me nts  
6. 2. 6. 1.  
Me dic al Hist or y  
De m o gra p hic i nf or mati o n will be c ollecte d at Scree ni n g a n d i ncl u de t h e f oll o wi n g i nf or mati o n 
t hat will be rec or d e d i n t he Electr o nic Cas e Re p or t F or m (e C R F ): 
•  Birt h date  
•  Se x  
•  Race  
•  Et h nic gr o u p 
•  S m o ki n g hist or y 
•  Alc o h ol c o ns u m pti o n  
At eac h st u d y visit, i nteri m  me dical hist or y will be o btai ne d a n d rec or d e d.  
6. 2. 6. 2.  
P h ysic al E x a mi n ati o n 
A c o m plete p h ysical e x a mi nati o n will be perf or m e d a n d all a b n or m alities n ote d i n t he e C R F at 
Scree ni n g , Baseli ne , the 2- wee k  p ost-R T visit , a n d t he 6- wee k  p ost-R T visit . 
6. 2. 6. 3.  
Q u alit y of Lif e Q uesti o n n aire  
A Q ualit y of Life Q u esti o n naire will be c o m plete d b y eac h p atie nt at Baseli ne, 4 wee ks a n d at 
t he e n d of st u d y dr u g treat me nt ( 2 wee ks p ost-R T) a n d re vi e we d a n d e ntere d b y t h e site 
pers o n nel i nt o t he e C R F. T he E O R T C Q L Q - C 3 0 ( versi o n 3) a n d t he E O R T C Q L Q - H & N 4 3 
i nstr u me nt will be use d f or t hese assess me nts. 
6. 2. 6. 4.  
Vit al Si g ns  
Vital si g ns will be c ollect e d at eac h st u d y visit u p t o a n d i ncl u di n g t he 6-wee k  p ost-R T visit . 
Vital si g ns will i ncl u de t he f oll o wi n g meas ure m e nts: 
•  Heart r ate  
•  Res pirat or y rate  
•  Te m perat ur e  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 6  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  Bl o o d press ur e (seate d ) 
•  Wei g h t 
6. 2. 6. 5.  
Hei g ht  a n d B o d y M ass I n de x ( B MI)  
Hei g ht will be c ollecte d at B as eli ne o nl y a n d B o d y Mass I n d e x ( B MI) a ut o maticall y calc ulate d . 
6. 3.  
Visit Sc he d ule  
6. 3. 1  
Scree ni n g  
T he S cree ni n g visit m ust be d o ne wit hi n 4 wee ks pri or t o t he Bas eli ne visit. Pri or t o starti n g t he 
st u d y me dicati o n, t he res ults of all tests m ust be re vie we d t o ass ure t hat t he patie nt meets all 
e ntr y criteri a. Pr oce d ures t o be d o ne at t his visit are: 
•  O btai n I nf or me d C o nse nt F or m (I C F) si g nat ure 
•  Ass ure t hat t he i nitial t u m or i ma gi n g is  c o m pati ble wit h R E CI S T Criteria  ( C T, M RI, or 
P E T sca ns)  
•  Ass ure t hat t he t u m or was e val uate d f or H P V stat us  
•  Assess me nt of e ntr y criteria  
•  C o m plete Me dical Hist or y  
•  C o m plete P h ysi cal E x a mi nati o n  
•  Vital Si g ns  
•  Ser u m H C G pre g na n c y t est ( w o me n o nl y) 
•  He mat ol o g y Pa n el   
•  Cli nical C he mistr y Pa n el  
6. 3. 2  
B aseli ne  D a y  
Baseli ne assess me nt will be c o m plete d pri or t o ra diati o n, c he m ot hera p y,  a n d st u d y dr u g 
a d mi nistrati o n  b ut wit hi n 9 6 h o urs of t he i nitial st u d y dr u g treat me nt. Patie nt will be see n  o n t he 
first da y of st u d y dr u g treat me nt. T he e ntr y criteria will be re vie we d a n d a n i nteri m me dical 
hist or y ta ke n t o ass ure t h at t he patie nt meets all e ntr y criteria. If t he patie nt still q ualifies, t he y 
will u n der g o t he f oll o wi n g pr o ce d ur es: 
•  I nteri m Me dical Hist or y 
•  Ra n d o mizati o n 
•  Vital si g ns  
•  A d verse e ve nts ( be gi n c ollecti n g after ra n d o mizati o n) 
•  P h ysical E x a m   
•  He mat ol o g y Pa n el  (if m ore t ha n 7 d a ys  fr o m Scree ni n g sa m ple) 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 7  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  Cli nical C he mistr y Pa n el  (if m ore t ha n 7 d a ys  fr o m Scree ni n g sa m ple) 
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore)  
•  Q ualit y of Lif e  assess me nt  
•  Ser u m Pre g n a nc y  (if m or e t ha n 7 d a ys  fr o m Scree ni n g sa m ple)  
•  Hist or y of p ai n a n d o pi oi d me dicati o n use 
•  Assess me nt of I nf ecti o ns 
6. 3. 3  
St u d y  Dr u g A d mi nistr ati o n Visits D uri n g R T  
St u d y visit da ys occ ur t wice wee kl y (e ver y 3 da ys +/- 1 da y) t hr o u g h t he c o m pleti o n of R T. T he 
first st u d y visit m ust occ ur wit hi n 3 da ys of i nitiati n g R T. T he st u d y visit sc he d ule s h o ul d be 
a d here d t o a n d is i n de pe n de nt of C R T a d mi nistrati o n.  At st u d y dr u g a d mi nistrati o n visits, t he 
f oll o wi n g will be perf or me d: 
•  I nteri m Me dical Hist or y  
•  Vital si g ns  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d details of p erc uta ne o us e n d osc o pic gastr ost o m y ( P E G ) t u be us e (if a p plica ble) 
•  St u d y Dr u g a d mi nistrati o n  
•  Hist or y of p ai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
•  Q ualit y of Lif e assess me nt  ( Wee k 4 o nl y) 
•  I n a d diti o n t o t he a b o ve, r o uti ne safet y la b oratories will be o btai ne d d uri n g Wee ks 3 a n d 
6 f or:  
o  Bl o o d c ollecti o n f or h e m at ol o g y a n d cli nical c he mistr y pa nel 
6. 3. 4  
St u d y Dr u g A d mi nistr ati o n Wee k 1 After R T  
St u d y visit da ys occ ur t wice wee kl y (e ver y 3 da ys ± 1 da y) f or t he first wee k f oll o wi n g 
c o m pleti o n of R T. At t hese st u d y dr u g a d mi nistrati o n visits, t he f oll o wi n g will be p erf or me d: 
•  I nteri m Me dical Hist or y  
•  Vital si g ns  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d details of gastr ost o m y t u be use (if a p plica ble ) 
•  St u d y Dr u g a d mi nistrati o n  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 8  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  Hist or y of p ai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
6. 3. 5  
St u d y Dr u g A d mi nistr ati o n Wee k 2 After R T  
St u d y visit da ys occ ur t wice wee kl y (e ver y 3 da ys +/- 1 da y) f or t he sec o n d wee k f oll o wi n g 
c o m pleti o n of R T. At t hese st u d y dr u g a d mi nistrati o n visits, t he f oll o wi n g will be p erf or me d: 
•  I nteri m Me dical Hist or y  
•  Vital si g ns  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d details of gastr ost o m y t u be use (if a p plica ble)  
•  St u d y Dr u g a d mi nistrati o n  
•  Hist or y of p ai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
•  I n a d diti o n, t he fi nal da y of st u d y dr u g a d mi nistrati o n (last visit Wee k 2 p ost-R T) t he 
f oll o wi n g a d diti o nal assess me nts will be perf or me d: 
•  Bl o o d c ollecti o n f or h e m at ol o g y a n d cli nical c he mistr y pa nels 
•  P h ysical e x a mi nati o n  
•  Q ualit y of Lif e assess me nt  
6. 3. 6  
Wee k 3 P ost -R T Visit   
Patie nts will be see n o nce i n t he t hir d wee k f oll o wi n g c o m pleti o n of R T f or t he f oll o wi n g: 
•  I nteri m Me dical Hist or y  
•  Vital si g ns  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d  details of g astr ost o m y t u be use (if a p plica ble)  
•  Hist or y of p ai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
6. 3. 7  
Wee k 4 P ost -R T Visit  
P atie nts will be see n o nce i n t he f o urt h wee k f oll o wi n g c o m pleti o n of R T f or t he f oll o wi n g: 
•  I nteri m Me dical Hist or y  
•  V ital si g ns  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 3 9  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d details of g astr ost o m y t u be use (if a p plica ble)  
•  Hist or y of Pai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
•  Bl o o d c ollecti o n f or h e m at ol o g y a n d cli nical c he mistr y pa nels 
6. 3. 8  
Wee k 5 P ost- R T Visit  ( o nl y t o be d o ne if W H O sc ore is ≥2 at Wee k 4 P ost -R T)  
Patie nts will be see n o nce i n t he fift h wee k f oll o wi n g c o m pleti o n of R T if t he patie nt ha d a n O M 
gr a de i n W ee k 4 p ost- R T t hat was ≥2  f or t he f oll o wi n g: 
•  I nteri m Me dical Hist or y  
•  Vital si g ns  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d details of g astr ost o m y t u be use (if a p plica ble)  
•  Hist or y of Pai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
6. 3. 9  
Wee k 6 P ost- R T V isit 
Patie nts will be see n o nce i n t he si xt h wee k f oll o wi n g c o m pleti o n of R T f or t he f oll o wi n g: 
•  I nteri m Me dical Hist or y  
•  Vital si g ns  
•  A d verse e ve nts  
•  Cli nical e val uati o n of m uc ositis ( W H O Sc ore) 
•  Rec or d details of gastr ost o m y t u be use (if a p plica ble) 
•  Bl o o d c ollecti o n f or h e m at ol o g y a n d cli nical c he mistr y pa nels 
•  Hist or y of p ai n a n d o pi oi d use 
•  Assess me nt of I nf ecti o ns 
•  P h ysical e x a mi nati o n  
•  Ser u m H C G pre g na n c y t est ( w o me n o nl y) 
6. 3. 1 0  
M o nt hl y  ( 2- t o 1 1-M o nt h P ost -R T ) F oll o w-u p C o nt acts  
All patie nts will be c o ntacte d at least o nce per m o nt h  ( ± 2 wee ks) t hr o u g h 1 1 m o nt hs (e x ce pt f or 
t he 1 2 wee k/ 3 m o nt h f oll o w- u p visit) f oll o wi n g c o m pleti o n of t heir last R T treat me nt t hr o u g h 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 0  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
eit her cli nic visits or tele p h o ne c o ntacts. F or e ac h c o ntact , t he f oll o wi n g i nf or mati o n t hat will be 
e ntere d i nt o t he e C R F:  
•  Vital stat us  
•  E vi de nce of rec urre n ce of t he pri mar y t u m or 
•  I nitiati o n of a d diti o nal a nti-ca ncer t hera p y 
6. 3. 1 1  
1 2 w ee ks ( 3 -M o nt h ) P ost -R T F oll o w -u p Visit  
Patie nts will ha ve a cli nic visit at 1 2 wee ks ( ± 3 w ee ks)  a n d t h e f oll o wi n g will be perf or me d: 
•  I nteri m Me dical Hist or y  
•  Hist or y of p ai n a n d o pi oi d use 
•  Re peat of t h e sa m e sca ns use d at t he i nitial t u m or sta gi n g t o be use d i n a R E CI S T 1. 1 
c o m paris o n 
•  Rec or d of t u m or stat us i n cl u di n g e vi d e nce of t u m or rec urre n ce a n d a d diti o n al a nti-ca n cer 
t hera pies 
6. 3. 1 2  
1 2 M o nt h  P ost -R T F oll o w -u p Visit  
Patie nts ha ve t heir last st u d y visit at 1 2 m o nt hs ( ± 2 8 da ys) p ost -R T a n d t he f oll o wi n g will be 
perf or me d : 
•  I nteri m Me dical Hist or y  
•  Hist or y of p ai n a n d o pi oi d use 
•  E val uati o n of t u m or stat us 
•  Re peat of t he sa m e sca ns use d a t t he i nitial t u m or sta gi n g t o be use d i n a R E CI S T 1. 1 
c o m paris o n  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 1  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
7.  
S E L E C TI O N A N D WI T H D R A W A L O F S U B J E C T S  
7. 1.  
S u bject I ncl usi o n Criteri a  
Patie nts e nr olle d i nt o t his trial m ust meet all  of t he f oll o wi n g criteria:  
1.  Willi n g a n d a ble t o u n dersta n d a n d si g n a n i nf or m e d c o nse nt 
2.  Males or fe m ales a ge grea ter t ha n or e q ual t o 1 8 years 
3.  Bi o ps y- pr o ve n s q u a m o us cell carci n o ma of t he oral ca vit y or or o p har y n x wit h o ut dista nt 
or ga n metastases  t h at has bee n e v al uate d f or h u ma n pa pill o ma vir us ( H P V) 
4.  Sc he d ule d t o recei ve cis plati n c he m ot hera p y of 8 0 - 1 0 0 m g/ m² gi ve n e v er y t hir d wee k  
5.  Sc he d ule d t o recei ve a c o nti n u o us c o urse of c o n v e nti o nal e xter nal bea m irra diati o n 
deli vere d b y I M R T as si n gle d ail y fracti o ns of 2. 0 t o 2. 2 G y, wit h a c u m ulati ve ra diati o n 
d ose bet wee n 5 5 a n d 7 2 G y at eac h site 
6.  Pla n ne d ra diati o n treat me nt fiel ds m ust i ncl u de at least 2 oral sites (retr o m olar tri g o n e, 
b uccal m uc osa, fl o or of m o ut h, t o n g ue, or s oft palate), wit h eac h site recei vi n g ≥5 5 G y  
7.  All w o me n of c hil d beari n g p ote ntial ( W O C B P) a n d males wit h fe male p art ners w h o are 
W O C B P m ust a gree t o t he use of effecti ve c o ntrace pti o n d uri n g t he tri al 
 
•  W o me n are c o nsi der e d t o be W O C B P f oll o wi n g me narc h e a n d u ntil bec o mi n g p ost-
me n o pa usal u nless per m a ne ntl y sterile ( h ysterect o m y, bilateral sal pi n gect o m y a n d 
bilateral o o p h orect o m y). A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 
m o nt hs wit h o ut a n alter nati ve me dical ca use.  
 
Effecti ve c o ntrace pti o n met h o ds f or W O C B P s h o ul d be starte d pri or t o ra n d o mizati o n 
a n d c o nti n ue d f or a mi ni m u m of 3 5 da ys f oll o wi n g c o m pleti o n of st u d y dr u g 
a d mi nistrati o n.  
 
•  Ac ce pt a ble c o ntr ace pti ve met h o ds f or W O C B P are t h ose t hat ac hie v e a fail ure rat e of 
less t ha n 1 % per year a n d i ncl u de:  
o  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n: 
  Oral  
 I ntr a va gi nal 
 Tra ns der m al  
o  Pr o gest o ge n - o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n:  
 Oral  
 I njecta ble 
 I m pla nta bl e 
o  I ntr a uteri ne d e vice (I U D)  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 2  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
o  I ntr a uteri ne h or m o ne-rel easi n g s yst e m ( I U S)  
o  Bilater al t u bal occl usi o n  
o  Vasect o mize d  part ner 
o  Se x ual a bsti ne nce de fi ne d as refrai ni n g fr o m het er ose x ual i nterc o urse 
d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts 
•  M ale s u bject s s h o ul d use c o n d o ms d uri n g treat me nt a n d f or 9 8 da ys f oll o wi n g t he 
last st u d y dr u g a d mi nistrati o n peri o d. 
7. 2.  
S u bject E xcl usi o n  Criteri a  
Patie nts wit h a n y of t he f oll o wi n g criteria are N O T  eli gi ble f or e nr oll me nt:  
1.  C urre nt m uc ositis  
2.  C urre nt  cli nicall y si g nifi ca nt acti ve i nfecti o n  t hat i n t he o pi ni o n of t he I n v esti gat or w o ul d 
ma ke t he m a n u nfit partici pa nt i n t he trial  
3.  Pla n ne d t o re cei v e Er bit u x ™ ( Cet u xi ma b) or si milar tar gete d t hera p y bet wee n baseli ne 
a n d 6 wee ks p ost- ra diati o n t hera p y 
4.  C urre nt use of pr o hi bite d t hera pies liste d i n Secti o n 8. 2  
5.  Pri or ra diati o n t o t he hea d a n d nec k 
6.  C he m ot hera p y treat me nt wit hi n t he pre vi o us 1 2 m o nt hs 
7.  T u m ors of t he li ps, si n uses, sali var y gla n ds, nas o p har y n x, h y p o p har y n x, or lar y n x  
8.  E vi de nce of si g nifica nt r e nal, he patic, h e mat ol o gi c, or i m m u n ol o gic disease deter mi ne d 
b y a n y o n e of t he f oll o wi n g: ( t he b el o w are e x a m ples of e vi de nce of si g nifi ca nt disease, 
n ot re q uire d tests) 
a. Esti mate d creati ni ne cleara nce < 3 0 m L/ mi n  
b.  A L T or A S T le vel gr eater t ha n 1 0 -f ol d t he u p per li mit of n or mal or t otal bilir u bi n 
gr eater t ha n 3 -f ol d t he u p per li mit of n or mal 
c. Ma nifestati o ns of e n d- sta ge li ver disease, s u c h as ascites or he p atic 
e nce p h al o pat h y 
d.  T hr o m b oc yt o p e nia (less t ha n 6 0, 0 0 0 cells/ m m 3) 
e. C D 4 +  T cell c o u nt bel o w 2 0 0 cells per µ L ( verificati o n o nl y re q uire d if t here is a 
cli nical dia g n osis of HI V i nfecti o n)  
9.  E vi de nce of i m me diate life -t hreate ni n g diseas e or a life e x pecta nc y of less t ha n 3 m o nt hs 
1 0.  W o me n w h o are pr e g na nt or breast- fee di n g 
1 1.  Partici pati o n i n a n y st u d y i n v ol vi n g a d mi nistrati o n of a n i n vesti gati o nal a ge nt wit h i n 3 0 
da ys of ra n d o mizati o n i nt o t his st u d y 
1 2.  A n y c o n diti o n t hat, i n t he o pi ni o n of t he I n vesti gat or, w o ul d c o m pr o mise t he safet y of t h e 
s u bject or q ualit y of t he data 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 3  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
7. 3.  
P atie nt  Wit h dr a w al Criteri a  
Patie nts ha ve t he ri g ht t o wit h dra w fr o m t his trial at a n y ti m e (as descri be d i n t he i nf or me d 
c o nse nt d oc u me nt) wit h o ut prej u dice t o f urt her care. A n i n vesti gat or ma y wit h dra w a patie nt 
fr o m t he st u d y at a n y ti me f or a n y of t he f oll o wi n g reas o ns:  
•  T he patie nt wit h dra ws his/ her c o nse nt or ref us es f oll o w- u p e val uati o ns.  
•  T he patie nt is l ost t o f oll o w - u p a n d will n ot atte n d f urt her st u d y visits. 
•  T he i n vesti gat or deter mi nes t hat f urt her p artici pati o n w o ul d be detri me ntal t o t he 
patie nt’s healt h or w ell -b ei n g.  
•  T he patie nt fails t o c o m pl y wit h t he st u d y re q uire me nts t o  ca use har m t o s elf or seri o usl y 
i nterfer e wit h t he vali dit y of t he st u d y res ults. 
•  T he fe mal e patie nt bec o mes pre g na nt d uri n g t he treat me nt peri o d. I n t his case, treat me nt 
s h o ul d be halte d a n d t he patie nt f oll o we d u ntil t he e n d of t he pre g na nc y. If a c hil d is 
b or n, t he i nfa nt s h o ul d be f oll o we d t hr o u g h at least 6 m o nt hs of a ge. 
•  At t he discreti o n of t he site i n vesti gat or if h e/s he feels t hat it is i n t he best me dical 
i nterest of t he patie nt. 
•  T he patie nt misses m ore t ha n 5 c o nsec uti ve s c he d ule d R T sessi o ns. 
•  P atie nts wit h dra w n fr o m t he st u d y will ha ve as ma n y of t he trial assess me nts c o m plete d 
as t he patie nt per mits i ncl u di n g bl o o d tests  a n d sca ns b ut n ot i ncl u di n g O M sc ori n g. All 
ot her t hera pi es i ncl u di n g ra diati o n t hera p y, t h e t y p e a n d fre q ue n c y of c h e m ot hera p y, a n d 
oral treat me nts will re mai n at t he discreti o n of t he cli nical tea m.  Patie nts will be ce ns ore d 
i n t he efficac y a n al ys es at t he ti me of wit h dra wal. 
•  Patie nts wit h dra w n fr o m t he trial will n ot be re place d b ut e nr oll me nt will c o nti n ue u ntil a 
mi ni m u m of 2 6 0 patie nts ha ve bee n e nr olle d. 
7. 4.  
Ter mi n ati o n of t he St u d y  
T he st u d y ma y b e ter mi n ate d earl y f or a n y of t he f oll o wi n g reas o ns: 
•  A healt h a ut h orit y or D M C  re q uests ter mi nati o n of t he st u d y. 
•  It has b ee n d eter mi ne d t h at t he ris k le vel ass oci ate d wit h t he e x peri me ntal dr u g is 
si g nifica nt a n d warra nts t er mi nati o n of t he st u d y.  
•  S oli ge ni x , f or reas o ns ot her t ha n safet y, ma y ter mi nate t he st u d y at a n y ti me b y writte n 
n otice of i nte n de d ter mi nati o n pr o vi de d at least t hirt y ( 3 0) da ys pri or t o ter mi nati o n. 
•  T he i n vesti gat or or I R B/ E C, f or reas o ns ot h er t ha n safet y, ma y ter mi nat e p artici pati o n of 
t his site i n t he st u d y b y writte n n otice of i nte n de d t er mi nati o n pr o vi de d at least t hirt y (3 0) 
da ys pri or t o ter mi nati o n.  
•  A n y ot her cla us e descri be d i n t he i n di vi d ual site St u d y A gree me nt (e. g., if G C Ps or ot her 
re g ulat or y pr o ce d ur es ar e n ot f oll o we d; if e nr oll me nt rate is n ot s ufficie nt t o meet st u d y 
g oa ls). 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 4  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
8.  
T R E A T M E N T O F S U B J E C T S 
8. 1.  
Descri pti o n of  St u d y Dr u g  
A p pr o priate d os es of st u d y dr u g will be a d mi nistere d t o s u bjects wit hi n 3 da ys of t he first da y of 
R T  a n d t he n t wice w ee kl y ( e ver y t hir d d a y ±  1 da y) t hereafter u ntil 2 wee ks after c o m pleti o n of 
R T .  
Patie nts will be see n 3, 4, 5 a n d 6 wee ks  a n d t he n at 1 2 wee ks a n d 1 2 m o nt hs after t he last d ose 
of R T , b ut will n ot be treate d wit h st u d y dr u g at t h ose ti mes. 
8. 2.  
C o nc o mit a nt Me dic ati o ns  
S u bjects will be treate d o n a n o ut patie nt basis. If p atie nts re q uire h os pitalizati o n f or n o n- st u d y 
relate d c o m plicati o ns of t hera p y, all p ossi ble st u d y pr oce d ures will be perf or me d. R T  a n d 
assess me nt of t u m or b ur de n i n all s u bjects will be c o n d ucte d as cli nicall y a p pr o priate, f oll o wi n g 
st u d y-s pecifie d pr ot oc ols. All s u bjects will recei ve c o nc o mita nt cis plati n c h e m ot hera p y ( 8 0- 1 0 0 
m g/ m 2) f or treat me nt of ca ncer of t he oral ca vit y a n d or o p har y n x.  
C o nc o mita nt dr u gs ta ke n b y t he p atie nt d uri n g t h e treat me nt p hase a n d t hr o u g h t he 6- wee k  p ost-
R T  visit s h o ul d be rec or d e d i n t he e C R F. I n ge n eral, t he ge neri c na me of t he dr u g s h o ul d be 
use d. Dr u g na mes, es peci all y c o m bi nati o n pre parati o ns, s h o ul d n ot i ncl u de t he d ose of eac h 
c o m p o ne nt dr u g i n t he na me b ut s h o ul d be n ote d i n t he d ose- Na m e: “ D oc usate/ Se n na” D os e 
“ 5 0/ 8. 6” rat her t ha n N a me: “ D oc usat e 5 0 m g - Se n na 8. 6 m g”. C o m p o ne nts of a n y m o ut h was h 
prescri be d s h o ul d b e liste d- i nstea d of “ M a gic M o ut h was h” rec or de d “ M o ut h was h- 
Maal o x/ Li d o cai ne”.  
T he f oll o wi n g m e dicati o ns/t hera pies s h o ul d N O T  be use d i n e nr olle d p atie nts  (fr o m baseli ne 
t hr o u g h 6 w ee ks p ost-R T) : 
•  A mif osti ne ( Et h y ol ® )  
•  Be nz y d a mi ne h y dr o c hl ori de  
•  Cet u xi ma b ( Er bit u x ® ) 
•  Ce vi meli ne h y dr o c hl ori d e ( E v o x ac ® )  
•  Gl uta mi ne as a pr o p h ylactic a ge nt f or m uc ositis  
•  De vices f or m uc ositis i ncl u di n g Gel Clair, M u Gar d, E pisil a n d Ca p h os ol 
•  G M - C S F (e. g., Le u ki ne® ) 
•  I L- 1 1 ( N e u me ga® )  
•  ‘ Ma gic m o ut h was h’, ‘ Miracle m o ut h was h’ or ot h er m o ut h was h s ol uti o ns c o ntai ni n g a n y 
of t he f oll o wi n g:  
•  C hl or he xi di ne  
•  H y dr o ge n per o xi de  
•  Di p he n h y dra mi ne  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 5  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  Tetrac ycli ne  
•  Palifer mi n ( Ke pi va n ce ® ) or ot her kerati n oc yte or fi br o blast gr o wt h fact or 
•  Pil ocar pi ne h y dr oc hl ori d e ( Sala ge n ® )  
•  P o vi d o ne-i o di ne ri nses  
•  Ster oi d ri nses  
•  S ucralfate i n s us pe nsi o n f or m ( use of s u cralfate ta blets is n ot pr oscri be d)  
•  Ot her  bi ol o gic  res p o ns e  m o difiers  – e x ce pt  he mat o p oietic  gr o wt h  fact ors  f or  t h e  
ma na ge me nt of a ne mia or m yel os u p press i o n 
•  L o w le v el laser t h era p y   
•  Ot her i n vesti gati o nal a ge nts f or m uc ositis  
8. 3.  
Tre at me nt C o m pli a nce  
Patie nts will be treate d wit h a n I V i nf usi o n wit nesse d b y site p ers o n nel d uri n g t heir d ail y 
ra diati o n treat me nt cli nic a p p oi nt me nts a n d, t heref ore, c o m plia nce wit h st u d y cli nic visits is 
e x pecte d t o be hi g h w hile t he c he m or a diati o n treat me nts are c o nti n ui n g.  
E ver y eff ort will be ma d e b y t h e patie nt a n d t he st u d y staff t o e ns ure t hat  patie nts ca n c o m plete 
t he assi g n e d tas ks of t he trial o n sc he d ule a n d as p er pr ot oc ol pri or t o b ei n g c o nse nte d. E ver y 
eff ort s h o ul d be ma d e, w he n me dicall y res p o nsi bl e, t o a v oi d treat me nt brea ks or dela ys. 
8. 4.  
R a n d o miz ati o n a n d Bli n di n g  
Patie nts  will be ra n d o mize d 1: 1 t o S G X 9 4 2: place b o usi n g a ra n d o mizati o n c o de ge n erate d b y a n 
i n de pe n de nt statisticia n. Ra n d o mizati o n will be perf or me d usi n g a n I nteracti ve We b Res p o nse 
S yste m (I W R S) i n a d o u ble- bli n d fas hi o n. Eac h vial of S G X 9 4 2  a n d t he i d e nticall y a p peari n g 
place b o vials will be s u p plie d a n d la bele d wit h a u ni q ue bli n de d i de ntif yi n g c o d e. T he I W R S 
will assi g n vial(s) of t h e a p pr o priate st u d y material t o be use d f or eac h pati e nt a n d eac h i nf usi o n 
usi n g t his bli n de d c o de.  
Patie nts will be stratifie d at ra n d o mizati o n b y H P V stat us , prese nce of a gastr ost o m y t u be at 
ra n d o mizati o n, a n d st u d y site. 
Gi ve n t he e xtre mel y s h ort half life of S G X 9 4 2 ( mi n utes), it is a ntici pate d t hat k n o wle d ge of 
w het her t he p atie nt recei ve d place b o or S G X 9 4 2 will rarel y be n e e de d. If, h o we ver, t he PI a n d/ or 
t he pri mar y care cli nical tea m belie ve t hat t his i nf or mati o n is necessar y t o o pti mall y treat a n 
e nr olle d patie nt, t he cli ni cal data ma n a ge me nt tea m ( D S G) s h o ul d be c o ntacte d ( 2 4 h o ur/ 7 da y 
a vaila bilit y) usi n g t he c o ntact di recti o ns a v aila ble i n t he e C R F p ortal. T he st u d y dr u g assi g n me nt 
f or t hat patie nt will be deter mi ne d a n d c o nfir mati o n of t he st u d y dr u g recei ve d will be 
i m me diatel y se nt. 
 






Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 8  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 0.  
A S S E S S M E N T O F E F FI C A C Y  
1 0. 1.  
Pri m ar y Effic ac y E n d p oi nt  
Cli nical e val uati o n of  m uc ositis will be perf or me d a n d gra de d b y trai ne d st u d y e v al uat ors i n 
acc or d a nce wit h W H O Oral M uc ositis Gra di n g s yste m, as detaile d i n Ta ble 8  at eac h st u d y dr u g 
a d mi nistrati o n visit a n d o nce a w ee k t hr o u g h 6 wee ks p ost- R T.  
T he d urati o n of S O M is t he pri mar y e n d p oi nt f or t his cli nical trial.  
S O M is defi ne d a W H O sc ore of ≥3 ( 3 or 4). Res ol uti o n of S O M is defi ne d as t he first 
assess me nt wit h a W H O sc ore < 3 wit h n o f urt her re p orts of a W H O gra de of ≥3. T he d urati o n of 
S O M is defi ne d as t he n u m ber of da ys fr o m t he first W H O sc ore ≥3 t o t he first da y wit h W H O 
sc ore ≤3 wit h n o f urt her occ urr e nce of W H O sc ore ≥3. If t he patie nt h as n ot met t he 
re q uire me nts f or res ol uti o n of S O M b y t he 6- wee k p ost- R T visit, he/s he will be c o nsi dere d 
ce ns ore d at t hat visit ( or p oi nt of disc o nti n uati o n of t he st u d y, if t he p atie nt disc o nti n ues pri or t o 
t hat ti me p oi nt). T o facilitate cal c ulati o n of a l o g -ra n k test wit h o ut ce ns ori n g patie nts wit h 
desira ble o utc o mes ( n o S O M), patie nts w h o d o n ot e x perie nce S O M  will be treate d as ha vi n g a 
d urati o n of S O M  of 0. 0 1 da ys . T h e pri mar y e n d p oi nt a nal ysis will be c o n d u cte d i n t he mI T T 
p o p ulati o n. 
1 0. 2.  
Sec o n d ar y Effic ac y  E n d p oi nts  
1 0. 2. 1  
Pri m ar y Sec o n d ar y A n al yses 
T he pri mar y sec o n d ar y e n d p oi nts are liste d bel o w i n hierarc hical or der a n d will be c o m pare d i n 
t he mI T T p o p ul ati o n. 
1 0. 2. 1. 1.  Se verit y -w ei g hte d D ur ati o n of S O M ( Are a -U n der t he  S O M -Ti me  C ur v e)  
T he se verit y - wei g hte d d urati o n of S O M will be calc ulate d b y t he A U C of t he S O M vers us ti me 
c ur ve. T his will be calc ul ate d b y t he f or m ula f or b aseli ne (t a) t o ti me t he last re p orte d W H O 
sc ore r ec or d e d (t b): 
 
( 
)
( 
)( 
)
∑
−
=
+
+
−
+
=
−
1
1
1
2
b
a
i
i
i
i
i
a
b
t
t
y
y
t
t
A U C
 
w here t i re pr ese nts t he date of t he i t h W H O assess me nt, a n d y
i re prese nts t h e val ue of t he it h W H O 
assess me nt f or W H O ass ess me nts f or w hic h t he s c ore is ≥3.  
1 0. 2. 1. 2.  Se verit y -w ei g hte d D ur ati o n of U O M ( Are a -U n der t he S O M -Ti me C ur ve)  
T he  se verit y- wei g hte d d urati o n of UO M will b e calc ulate d b y t he A U C of t he U O M vers us ti me 
c ur ve. T his will be calc ul ate d b y t he f or m ula f or b aseli ne (t a) t o ti me t he last re p orte d W H O 
sc ore r ec or d e d (t b): 
 
( 
)
( 
)( 
)
∑
−
=
+
+
−
+
=
−
1
1
1
2
b
a
i
i
i
i
i
a
b
t
t
y
y
t
t
A U C
 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 4 9  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
w here t i re pr ese nts t he date of t he it h W H O assess me nt, a n d y
i re prese nts t h e val ue of t he it h W H O 
assess me nt f or W H O ass es s me nts f or w hic h t he s c ore is ≥2. 
1 0. 2. 1. 3.  I nci de nce of S O M 
T he i nci de nce of S O M will be calc ulate d as t h e perce nt of p atie nts wit hi n eac h treat me nt gr o u p 
w h o ha ve at least o ne W H O sc ore ≥3.  
1 0. 2. 1. 4.  Q u alit y of Lif e  
A Q ualit y of Life Q u esti o n naire ( Q o L) will be c o m plete d b y eac h p atie nt at Baseli ne, 4 w ee ks 
a n d at t he e n d of st u d y dr u g treat me nt ( 2 w ee ks p ost- R T) a n d re vie we d a n d e ntere d b y t he site 
pers o n nel i nt o t he e C R F. T he E O R T C Q L Q - C 3 0 ( versi o n 3) a n d t he E O R T C Q L Q- H & N 4 3 
i nstr u ment will be use d f or t hese assess me nts.  T h e c ha n ge fr o m Baseli ne i n t he Q o L at t he e n d of 
t he st u d y will be c o m par e d bet wee n treat me nt gr o u ps.  
1 0. 2. 1. 5.  A m o u nt of O pi oi d Me dic ati o n Use d  
At eac h st u d y visit, st u d y pers o n nel will rec or d t he a m o u nt of o pi oi d me dicati o n t hat t he patie nt 
re p orts ha vi n g ta ke n o v er t he pre vi o us 2 4 h o urs. E ac h t y pe of me di cati o n a n d w het her it was 
use d beca us e of O M p ai n or ot her t y pes of p ai n will be n ote d i n t he e C R F. Eac h o pi oi d d ose will 
be c o n vert e d t o a n “ oral m or p hi ne d ose e q ui vale nt d ose” a n d t he t otal a m o u nt of o pi oi d use d f or 
eac h p atie nt s u m me d o ver eac h visit fr o m b aseli ne t o 6 wee ks p ost-c o m pleti o n of t he ra diati o n 
t hera p y. Patie nts wit h missi n g visits will ha ve t heir o pi oi d usa ge esti mate f or t he missi n g data b y 
usi n g a n a ver a ge of t heir o pi oi d use f or t he a vaila ble visits usi n g f or m ula detaile d i n t he S A P. 
T he mea n a n d m e dia n a m o u nt of t otal o pi oi ds use d i n eac h of t he treat me nt gr o u ps will be 
c o m pare d.  
1 0. 2. 2  
Ot her Sec o n d ar y A n al yses  
I n a d diti o n t o t he pri mar y sec o n dar y a nal yses p erf or me d i n hierarc hical or der, se veral a d diti o nal 
sec o n dar y a nal yses will be perf or me d.   
1 0. 2. 2. 1.  C u m ul ati ve N u m ber of Tre at me nt B re a ks  
F or t he a nal ysis p ur p oses f or t his st u d y, treat me nt brea ks will be defi ne d as missi n g 3 or m ore 
sc he d ule d c o nsec uti ve R T treat me nt sessi o ns. T he c u m ulati ve d urati o n of treat me nt brea ks f or 
eac h p atie nt will be calc ulate d b y s u m mi n g t he act ual n u m ber of treat me nt brea k da ys ( ≥3 da ys  
per  brea k) t hr o u g h t he fi nal R T treat me nt a n d c o m pari n g t hes e bet w ee n treat me nt gr o u ps. 
1 0. 2. 2. 2.  D ur ati o n of S O M i n t he I T T P o p ul ati o n 
Usi n g t he a b o ve defi niti o ns, t he d urati o n of S O M will be c o m pare d b et wee n treat me nt gr o u ps i n 
all patie nts ra n d o mize d (I T T p o p ul ati o n). 
1 0. 2. 2. 3.  D ur ati o n of Ulcer ati ve Or al M uc ositis ( U O M)  
U O M is defi ne d as a W H O sc ore ≥2.  Res ol uti o n of U O M is defi ne d as t he first assess me nt wit h 
a W H O sc ore < 2 wit h n o f urt her r e p orts of a W H O gra de of ≥2. T he d urati o n of U O M is defi ne d 
as t he n u m ber of d a ys fr o m t he first W H O sc ore ≥2 t o t he first da y wit h W H O sc ore < 2  wit h n o 
f urt her occ urr e nce of W H O sc ore ≥2. If t he p atie nt has n ot met t he re q uire me nts f or res ol uti o n of 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 0  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
U O M b y t h e 6 - wee k p ost- R T visit, he/s he will be c o nsi dere d ce ns ore d at t h at visit ( or p oi nt of 
disc o nti n uati o n of t he st u d y, if t he p atie nt disc o nti n ues pri or t o t hat ti m e p oi nt). F or statistical 
reas o ns, patie nts w h o d o n ot e x perie nce S O M  will be treate d as ha vi n g a d urati o n of U O M of 
0. 0 1. T he a nal ysis will be d o ne i n t he mI T T p o p ulati o n. 
1 0. 2. 2. 4.  Assess me nt of P ai n  
At eac h st u d y visit, t he patie nt’s assess me nt of t heir pai n o ver t he pre vi o us 2 4 h o urs will be 
rec or d e d b y st u d y pers o n nel usi n g a s cale of 1- 1 0. Patie nts wit h missi n g visits will ha ve t heir 
pai n esti mate d f or t he missi n g data b y a vera gi n g t heir pai n sc ores re p orte d usi n g t he f or m ula 
detaile d i n t he S A P.  
1 0. 2. 2. 5.  Alter n ati ve Me a s ure me nt of t he D ur ati o n of S O M 
T he d urati o n of S O M defi ne d as t he n u m ber of d a ys fr o m t he first oral e x a mi nati o n wit h W H O 
gr a de ≥3 t hr o u g h t he last assess me nt wit h a W H O sc ore ≥3 (a n d n ot t o t he firs t assess me nt wit h 
a W H O gra de < 3) wit h n o f urt her r e p ort s of a W H O gra de ≥3. 
1 0. 2. 2. 6.  D ur ati o n of S O M i n t he Per -Pr ot oc ol P o p ul ati o n  
T he d urati o n of S O M i n t he Per- Pr ot oc ol P o p ulati o n defi ne d as p atie nts recei vi n g a c u m ulati ve 
ra diati o n d ose of at least 5 5 G y a n d ha v i n g recei v e d all sc he d ule d st u d y dr u g d oses.  
 
 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 1  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 1.  
A S S E S S M E N T O F S A F E T Y  
1 1. 1.  
O ver all Assess me nts  
Safet y i n t his trial will be assesse d  b y t he f oll o wi n g c o m p aris o ns bet wee n treat me nt gr o u ps: 
•  Assess me nt of t he i nci de nce, t y pe, a n d b o d y s yste m cate g orizati o n of A Es 
•  Assess me nt of t he i nci de nce, t y pe, a n d b o d y s yste m cate g orizati o n of S A Es  
•  Assess me nt of t he c h a n ges fr o m baseli ne f or he m at ol o g y para meters, cli nical c he mistr y 
para meters, a n d vital si g ns 
•  Assess me nt of t u m or pr o gr essi o n at 1 2 wee ks  a n d 1 2 m o nt hs f oll o wi n g c o m pleti o n of R T  
classifie d usi n g t h e R E CI S T t u m o r stat us s yste m 
•  T he i nci de nce a n d se v erit y of i nfecti o ns gra d e d usi n g C T C A E  criteria  
•  Assess me nt of m ortalit y t hr o u g h t he 1 2- m o nt h p ost- R T cli nic visit  
1 1. 1. 1  
Assess me nt of A Es  
Site pers o n nel will q uesti o n a n d rec or d i n t he e C R F all re p orte d A Es, as d efi ne d i n Sec ti o n 
1 1. 2. 1  t hat are r e p orte d b et wee n r a n d o mizati o n t hr o u g h t he 6 w ee k p ost- R T visit. T he PI will 
assess  of t he se v erit y of t he A E usi n g t h e C T C A E criteria ( A p pe n di x 1). T he A Es will be c o de d 
as t o preferre d t er mi n ol o g y, a n d b o d y s yste m usi n g t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) usi n g a c o m p uter a ut o- c o der a n d all assi g n me nts re vi e we d b y  a bli n de d 
me dical re vie wer. T h e n u m ber of e v e nts a n d t he n u m ber of patie nts wit h eac h e ve nt defi ne d b y 
t he pref err e d ter m a n d b y b o d y s yste m cate g or y will be prese nte d. A d diti o n al ta bles will 
c o m pare t he re p ort e d A Es b y pr eferre d ter m a n d b o d y s yste m clas sificati o n classifie d b y 
C T C A E se verit y gra de ( 1 - 5) a n d se p arat el y b y PI assess me nt of rel ati o ns hi p t o st u d y dr u g. 
1 1. 1. 2  
Assess me nt of S A Es  
Site pers o n nel will q uesti o n a n d rec or d i n t he e C R F all re p orte d S A Es, as d efi ne d i n Secti o n 
1 1. 2. 2  t hat are r e p orte d b et wee n r a n d o mizati o n t hr o u g h t he 6 w ee k  p ost-R T visit.  T he S A Es will 
be c o de d as t o pref err e d ter mi n ol o g y, a n d b o d y s yste m usi n g t he Me dical Dicti o nar y f or 
Re g ulat or y  Acti vities ( Me d D R A) usi n g a c o m p uter a ut o- c o d er a n d all assi g n me nts re vie we d b y 
a bli n de d me dical r e vie w er. S u m mar y ta bles i ncl u di n g t he n u m ber of e v e nts a n d t he n u m ber of 
patie nts wit h eac h e v e nt defi ne d b y t he preferre d t er m a n d b y b o d y s yste m cate g or y will be 
prese nte d. A d diti o nall y, t he re p ort e d S A Es b y preferre d t er m a n d b o d y s yst e m classificati o n 
classifie d b y C T C A E se v erit y gra de ( 1 -5) a n d se p aratel y b y PI ass ess me nt of relati o ns hi p t o 
st u d y dr u g. A n arr ati ve s u m mar y of t he patie nt’s S A E will be i ncl u de d i n t he fi nal Cli nical St u d y 
Re p ort. 
1 1. 1. 3  
Assess me nt of L a b or at or y a n d Vit al Si g ns 
Eac h o f t he l a b orat or y t ests o utli ne d i n Secti o n 6. 2. 5  a n d eac h of t he vital si g ns o utli ne d i n 
Secti o n 6. 2. 6. 4  will be s u m marize d f or eac h  c ollecti o n peri o d b y treat me nt gr o u p as: 
•  Gr o u p mea n 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 2  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  Gr o u p sta n dar d d e viati o n 
•  Gr o u p me dia n 
•  Gr o u p ra n ge 
A d diti o nall y, eac h e v al uati o n will be s u m marize d as a c ha n ge fr o m b aseli n e f or eac h p atie nt b y 
treat me nt gr o u p as: 
•  Gr o u p mea n 
•  Gr o u p sta n dar d d e viati o n 
•  Gr o u p me dia n 
•  Gr o u p ra n ge 
Usi n g t he Ce ntr al La b or at or y’s n or mal ra n ges a n d sta n dar d ta ble of n or mal vital si g ns, eac h 
assess me nt will be classifie d as “ n or m al”, “l o w ”, or “ hi g h ” a n d s hift ta bles f or eac h para meter 
s h o w n of eac h assess me nt b y treat me nt gr o u p will be dis pla ye d.  
1 1. 1. 4  
Assess me nt of T u m or Pr o gressi o n  at 1 2 w ee ks  a n d 1 2- m o nt hs P ost- R T  
Sca ns at 1 2 wee ks a n d 1 2 - m o nt hs p ost-R T will be c o m pare d t o t he i nitial i ma ges  usi n g t he 
R E CI S T 1. 1 s yst e m as o utli ne d i n Ta ble 9 , Ta ble 1 0 , a n d Ta ble 1 1 . T h e perce nt of t he p atie nts 
cate g orize d as h a vi n g a “c o m plete t u m or res p o nse” at 1 2 wee ks a n d 1 2 m o nt hs p ost- R T will be 
c o m pare d b et wee n t h e tr eat me nt gr o u ps. A d diti o nall y, t he p erce nt of t he patie nts cate g oriz e d as 
ha vi n g a “c o m plet e t u m or res p o nse” or “ p artial t u m or res p o nse” at 1 2 wee ks  a n d 1 2 m o nt hs 
p ost- R T will be c o m pare d bet wee n t he treat me nt gr o u ps. 
1 1. 1. 5  
Inf ecti o ns  
Patie nts will be assesse d at eac h cli nical visit t hr o u g h t he 6 - wee k p ost-R T visit as t o t he pre se nce 
of pr o ba ble cli nical i nfecti o ns. All cli nical dia g n oses of i nfecti o ns will be classifie d as pres u me d 
f u n gal, pres u me d vir al, or pres u me d bacteri al. T he se verit y of eac h i nfecti o n will be gra de d 
usi n g t he C T C A E ( A p p e n di x 1). T he i nci de nce of all re p orte d i nfecti o ns, t he n u m ber of p atie nts 
wit h re p orte d i nfecti o ns, t he n u m ber of pres u me d f u n gal, t he n u m ber of pres u me d viral a n d t he 
n u m ber of pres u m e d bact erial i nfecti o ns will be c o m pare d bet w ee n treat me nt gr o u ps. T h e 
i nci de nce of eac h t y p e of i nfecti o n (f u n gal, viral, a n d bacterial) b y se verit y gra de ( 1 -5) will be 
dis pla ye d.  
1 1. 1. 6  
Assess me nt of M ort alit y T hr o u g h t he 1 2 -m o nt h P ost- R T Cli nic Visit  
All deat hs t hr o u g h t h e 1 2- m o nt h f oll o w- u p visit will be c ollecte d. T he n u m ber of deat hs i n eac h 
gr o u p will be c o m par e d usi n g a sta n d ar d c hi-s q u are d a nal ysis. T he n u m b er of deat hs o ver ti me 
will be c o m pare d usi n g a Ka pla n -Mei er s ur vi val c ur ve a n d t he s ur vi val c ur ves c o m pare d usi n g a 
l o g-r a n k test. 
1 1. 1. 7  
Pr o g ressi o n -f ree S ur vi v al 
T he d urati o n of pr o gressi o n free s ur vi val will be calc ulate d fr o m t he date of ra n d o mizati o n t o t he 
earliest date of t he f oll o wi n g:  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 3  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
•  T he patie nt die d  
•  T he patie nt ha d a n i ma gi n g r e p ort of t u m or pr o gressi o n ( R E CI S T 1. 1 e val u ati o n of less 
t ha n “ C o m plete Res p o nse”) 
•  T he patie nt c o m plete d t h eir 1 2 m o nt h f oll o w- u p assess me nt.  
Patie nts l ost -t o-f oll o w-u p will be ce ns ore d at t he ti me of t heir last assess me nt.  
1 1. 2.  
S afet y P ar a meters  
1 1. 2. 1  
A d verse E x perie nce ( A E ) 
A n y n o xi o us or u ni nte n de d e ve nt t hat occ urs i n ass ociati o n wit h t he use of a n i n vesti gati o nal 
a ge nt i n h u ma ns , w het her c o nsi dere d rel ate d t o t he i nvesti g ati o n al a ge nt or n ot. T his defi niti o n 
e nc o m passes s y m pt o ms or si g ns r e p orte d b y t he s u bject or detecte d b y t he i n vesti gat or or ot h er 
c o m pete nt o bser v er, as w ell as me dicall y i m p orta nt de viati o ns fr o m n or malit y i n t he res ults of 
a ncillar y i n vesti gati o ns. If prese nt at ti me of first d ose of st u d y dr u g, s uc h A Es m ust be rec or d e d 
as part of t he me di cal hist or y.  
Treat me nt -E mer ge nt A d verse E x perie nce : A n A E t hat is ne w i n o nset or a ggra vate d i n se v erit y 
or fre q u e nc y f oll o wi n g e ntr y i nt o t he st u d y. I n a d diti o n, a n y pat h ol o gical fi n di n g o n p h ysical 
e x a mi nati o n or dia g n ostic pr oce d ure t hat is ne w i n occ urre nce or e x acer bate d i n c o m paris o n wit h 
t he s u bject's stat us at st u d y e ntr y is c o nsidere d a treat me nt -e mer ge nt A E if it re q uires a n y 
me dical or s ur gical i nter ve nti o n w hats oe ver (i ncl u di n g, b ut n ot li mite d t o, a d diti o nal dia g n ostic 
pr oce d ur es or alterati o n of prescri be d t hera p y). 
All A Es, w het her j u d ge d t o be relate d or n ot t o t he st u d y dr u g, s h o ul d be rec or de d i n b ot h t he 
me dical rec or d a n d t he e C R F. T he start a n d res ol uti o n dates, t he j u d g me nt of t he se verit y of t h e 
A E, t he j u d g me nt of t he r elati o ns hi p of t he A E t o t he st u d y dr u g, t h e acti o n ta ke n f or s u bse q u e nt 
d ose of st u d y dr u g, a n d t he o utc o me s h o ul d be n ote d . 
1 1. 2. 2  
Seri o us A d verse E x peri e nce ( S A E)  
A n y A E occ urri n g at a n y d ose t hat res ults i n a n y of t he f oll o wi n g o ut c o mes: 
•  Deat h  
•  A life -t hreate ni n g A E 
•  Pr ol o n gati o n of e xisti n g h os pitalizati o n or s u bse q ue nt nee d f or h os pitalizati o n 
•  A persiste nt or si g nifica nt disa bilit y/i nca p acit y  
•  A c o n ge nital a n o mal y/ birt h defect  
•  A me dical or s ur gical i nte r ve nti o n t o pre v e nt o ne of t he a b o ve 
1 1. 3.  
Rel ati o ns hi p t o St u d y Dr u g  
T he relati o ns hi p of a n A E t o t he assi g ne d st u d y dr u g  is ass esse d usi n g t he f oll o wi n g defi niti o ns: 
N ot Rel at e d : T he dr u g e x perie nce is clearl y relat e d t o ot her fact ors s uc h as t he 
patie nt’s/s u bject’s cli nical state, t hera pe utic i nter v e nti o ns , or c o nc o mita nt dr u gs.  


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 4  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
P ossi bl y Rel ate d: T h e dr u g e x perie nce f oll o ws a reas o na bl e se q ue n ce fr o m t he  ti me of dr u g 
a d mi nistrati o n a n d/ or f oll o ws a k n o w n res p o ns e patter n t o t he st u d y dr u g, b ut c o ul d ha ve bee n 
pr o d uce d b y ot her fact ors s uc h as t he patie nt’s/s u bject’s cli nical state, t hera pe utic i nter ve nti o ns, 
or c o nc o mita nt dr u gs. 
Rel ate d: T he dr u g e x perie nce f oll o ws a reas o n a bl e te m p oral se q u e nce fr o m t he ti me of dr u g 
a d mi nistrati o n , f oll o ws a k n o w n res p o nse p atter n t o t he st u d y dr u g, a n d ca n n ot be reas o n a bl y 
e x plai ne d b y ot her fact ors s uc h as t he patie nt’s/s u bject’s cli nical state, t hera pe utic i nter ve nti o ns, 
or c o nc o mita nt dr u gs.  
1 1. 4.  
Se verit y of A d verse E ve nt  
A cli nical deter mi nati o n of t he i nte nsit y of a n A E  s h o ul d be d o ne f or all re p orte d A Es. T he 
se verit y assess me nt s h o ul d use t he C T C A E gra di n g s yste m t hat assess es t he se verit y of eac h A E 
fr o m gra des 1 - 5. T he gra di n g s yste m ca n b e f o u n d i n A p pe n di x 1. 
1 1. 5.  
Re p orti n g A d verse E ve nts  
1 1. 5. 1  
A d verse E ve nts  
All A Es t hat occ ur after a n y p atie nt/s u bject has b ee n e nr olle d, b ef ore treat me nt, d uri n g 
treat me nt, or wit hi n 6 wee ks ( ± 4 da ys) f oll o wi n g t he cessati o n of R T treat me nt , w het her or n ot 
t he y are relate d t o t he st u d y, m ust be r ec or d ed i n t he e C R F. All A Es s h o ul d be n ote d i n t he e C R F 
wit hi n 3 da ys of b ei n g rec o g nize d. A n y a d vers e e ve nt t hat is eit her a S A E or p ote ntial S A E 
s h o ul d be ha n dle d wit hi n t he ti mefra mes gi ve n i n secti o n 1 1. 5. 2 , bel o w. Eac h treat me nt -
e mer ge nt A E s h o ul d be r e p orte d s p o nta ne o usl y or i n res p o nse t o ge neral, n o n- directe d 
disc ussi o n wit h t he atte n di n g n urse or p h ysicia n (e. g., h as t here bee n a n y c ha n ge i n s u bject stat us 
si nce t he last assess me nt peri o d?). F or eac h treat m e nt -e mer ge nt A E, t he i n v esti gat or s h o ul d 
o btai n all t he i nf or mati o n re q uire d t o c o m plet e t he A E pa ge of t h e cas e re p ort f or m, i n 
acc ord a nce wit h t he g ui deli nes t hat acc o m p a n y it.  
All treat me nt -e mer ge nt A Es, re gar dless of seri o us ness, se verit y, or pres u me d relati o ns hi p t o 
st u d y t her a p y, m ust be rec or de d usi n g me dical ter mi n ol o g y c o nsiste nt wit h t he s o urce d o c u me nt 
a n d o n t he A E pa ge. W he ne ver p ossi ble, dia g n os es s h o ul d be gi v e n w he n si g ns a n d s y m pt o ms 
are d ue t o a c o m m o n eti ol o g y. I n v esti gat ors m ust rec or d t heir o pi ni o n c o n cer ni n g t he 
relati o ns hi p of t he A E t o st u d y t her a p y o n t he A E pa ge. 
All treat me nt -e mer ge nt A Es m ust be f oll o we d u ntil res ol uti o n or u ntil t he 6- m o nt h f oll o w u p 
visit . All meas ures re q uir e d f or A E ma na ge me nt a n d t he ulti mate o utc o me of t he A E m ust be 
rec or d e d i n t he s o urce d o c u me nt a n d re p orte d o n t he A E pa ge. T he res ol uti o n date f or all 
rec or d e d A Es s h o ul d be e ntere d wit hi n 3 da ys of deter mi nati o n t hat t he A E has res ol ve d.  
1 1. 5. 2  
Seri o us A d verse E ve nts  
All S A Es t hat occ ur aft er a n y p atie nt/s u bject has b ee n e nr olle d, b ef ore treat me nt, d uri n g 
treat me nt, or wit hi n six wee ks ( ± 4 d a ys) f oll o wi n g t he last R T , w het h er or n ot t he y are relate d t o 
t he st u d y, m ust be rec or d e d o n f or ms pr o vi de d i n t he eC R F.  
W he n t he i n vesti gat or, or trai ne d desi g nee, bec o m es a ware t hat a s eri o us or p ote ntiall y seri o us 
A E (as defi ne d a b o v e) has occ urr e d, t he site m o nit or or Me dical M o nit or m ust be n otifie d 




Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 6  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
T he D M C ma y re q u est a n y safet y data i n cl u di n g, b ut n ot li mit e d t o, S A Es, A Es, a n d la b orat or y 
val ues. T he D M C ma y als o re q uest a n y efficac y d ata i ncl u di n g, b ut n ot li mite d t o t he pri mar y 
a n d sec o n dar y o utc o mes t o e val uate be n efit t o ris k.  
T he D M C will re vie w u n bli n de d data at t he i nteri m a nal ys es a n d ma k e rec o m me n d ati o ns t o halt 
t he trial f or o ver w hel mi n g efficac y, or s afet y c o n cer ns, or f or f utilit y; c o nti n ue t he trial as 
writte n; or resize t he trial base d o n t h e place b o d urati o n of S O M. 






Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 5 9  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
I n acc or da n ce wit h t he G ui deli nes f or t he M o nit ori n g of Cli nical I n vesti gati o ns prese nte d i n t he 
I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) G ui da nce o n G C Ps ( E 6), S oli ge ni x will select, 
eit her directl y or t hr o u g h s u bc o ntract, q ualifie d i n di vi d uals t o m o nit or t he pr o gress of t he st u d y 
a n d a d her e nce t o pr ot oc ol b y t he i n di vi d ual cli nical sites. 
1 2. 6. 2  
Pre -st u d y E v al u ati o n 
T his i nitial e nc o u nter wit h t he site will esta blis h t hat t he site has all of t he n ecessar y ele me nts t o 
s uccessf ull y partici pate i n t he pr o p ose d pr ot oc ol i ncl u di n g a d e q uate trai ne d staff, a de q u ate free 
ti me of t he staff, a d e q uat e facilities f or s afe a n d pr o per trial c o n d u ct, e vi de n ce f or p ot e ntial 
e nr oll me nt of s uita ble patie nts, a de q uate researc h p har mac y s u p p ort, t he prese nce of a n I R B / E C 
meeti n g t he l o cal a n d F D A re q uire m e nts, a n d a c o m mit me nt f or trai ni n g of all i n v ol ve d staff o n 
t he pr ot oc ol. 
1 2. 6. 3  
Site I niti ati o n Visit  
T he Me dical M o nit or ( or trai ne d des i g nee) will i nitiate t he st u d y after o n- site trai ni n g of t he 
partici pati n g st aff at t he i nstit uti o n. T o pics c o vere d will i ncl u de trai ni n g o n:  
•  T he i n vesti gati o nal stat us of t he st u d y dr u g a n d t he re q u ire me nts f or its acc o u nta bilit y 
•  Bac k gr o u n d o n t he st u d y dr u g 
•  Details of t he pr ot oc ol i n cl u di n g patie nt sel ecti o n, st u d y dr u g a d mi nistrati o n, pr oce d ures 
t o be perf or m e d, a n d visit sc he d ules 
•  Critical nat ure of o btai ni n g i nf or m e d c o nse nt i n acc or da n ce wit h t he D eclarati o n of 
Helsi n ki a n d I C H G ui da nce o n G C Ps ( E 6) bef ore e nr olli n g eac h s u bject i n t he st u d y 
•  T he o bli gati o n t o e ns ur e I R B re vi e w a n d a p pr o val f or t he st u d y, i ncl u di n g t he pr ot oc ol, 
a me n d me nts,  I C F a n d a n y a d v ertise me nts, is o btai ne d pri or t o its i nitiati o n at his/ her 
cli nical site, t o e ns ure c o nti n ui n g re vie w of t he st u d y b y t he I R B, a n d t o k ee p S oli ge ni x 
i nf or me d of s uc h a p pr o v al a n d s u bse q ue nt acti o ns c o ncer ni n g t he st u d y 
1 2. 6. 4  
M o nit ori n g Visits  
S oli ge ni x or t heir trai ne d desi g nee will perf or m o n -site m o nit ori n g visits as fre q ue ntl y as it 
dee ms necessar y. At t hes e visits, t he site m o nit or will c o m pare t he dat a e nt ere d i nt o t he e C R F 
wit h t he s o urce d oc u m e nts a n d c hec k f or pr ot oc ol c o m plia nce i ncl u di n g a rec or d of i nf or me d 
c o nse nt, e nr oll me nt criteria, all s u bject assess me nts, all a d verse e x perie n ces , a n d all c o nc o mita nt 
me dicati o ns. I n a d diti o n, st u d y dr u g a n d s u p p orti n g rec or ds will be re vie w e d. A d diti o nall y, t he y 
ass ure t hat all seri o us, lif e -t hreate ni n g or fatal a d v erse e x perie n ces are bei n g re p orte d 
i m me diatel y [ a n d i n n o case later t h a n t we nt y-f o ur ( 2 4) h o urs after t h e e ve nt] t o t he Me dical 
M o nit or or desi g n ee at S oli ge ni x. 
Fi n di n gs fr o m t hese r e vie ws will be disc usse d wit h t he i n vesti gat or a n d staff. C o m plete d pa ges 
of t he e C R F will be e v al uate d at eac h visit. T he d ates of t he m o nit ori n g visits will be rec or de d i n 
a si g n-i n l o g t hat will be ke pt at t he site. T he st u d y c o or di nat or a n d i n v esti gat or are e x pecte d t o 
be a vaila ble f or q uesti o ns, t he s o urce d o c u me ntati o n rea dil y a vaila bl e, a n d a s uita ble 
e n vir o n me nt pr o vi de d f or re vie w of st u d y- rel ate d d oc u me nts. 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 0  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 2. 6. 5  
Cl ose- o ut Visit  
T he cli nical res ear c h m o nit or(s) will perf or m a n e n d of trial visit t o e ns ure t hat:  
•  All dr u g r ec o n ciliati o n f or ms are acc urate a n d c o m plete.  
•  All u n use d st u d y dr u g is ret ur ne d t o t he a p pr o priat e l ocati o n. 
•  All data iss ues are res ol v e d a n d e C R F are c o m plete d a n d verifie d.  
•  T he I R B h as bee n n otifie d t hat t he st u d y has b ee n c o m plete d. 
•  T he i n vesti gat or at eac h site is a ware t h at t he st u d y has bee n c o m plet e d a n d n o f urt her 
s u bjects are e nr olle d. 
1 2. 7.  
A u dits a n d I ns pecti o ns  
Healt h A ut h orities (e. g., F D A, t he E M A, or c o u ntr y Healt h A ut h orities), i n t he pers o n of a 
trai ne d a n d pr o p erl y a ut h orize d e m pl o yee, ma y re q uest access t o all st u d y rec or ds, i ncl u di n g 
s o urce d oc u m e nts, f or i ns pecti o n a n d c o p yi n g. T h e i n vesti gat or will i m me diatel y n otif y 
S oli ge ni x of a n y u pc o mi n g i ns pecti o ns.  
Peri o dic a u diti n g i ns pecti o ns ma y als o be c o n d uct e d b y a re prese nt ati ve of t he Q ualit y 
Ass ura nce De p art me nt of S oli ge ni x or its trai ne d desi g nee(s). 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 1  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 3.  
I N S TI T U TI O N A L R E VI E W B O A R D (I R B)/ E T HI C A L 
C O M MI T T E E ( E C)  
All partici pati n g ce nters m ust ha ve i n place eit her a n I R B or t h e E C t hat meets all of t he criteria 
o utli ne d i n Secti o n 3 of t he I C H “ G ui da n ce f or I n d ustr y ; E 6 G o o d Cli nical Practice:  
C o ns oli date d G ui da nce”. C o pies of t he I R B/ E C me m bers hi p list a n d pr oce d ures s h o ul d be 
pr o vi de d t o t he S oli ge ni x . 
It is t he r es p o nsi bilit y of t he site’s Pri nci pal I n vesti gat or ( PI) t o o btai n I R B/ E C writte n a p pr o val 
of t he pr ot oc ol, t he I nf or me d C o nse nt F or m, patie nt c o m pe nsati o ns details, a n d a n y 
a d vertise me nts t o be use d i n c o n d uct of t he trial. N o patie n t ca n b e e nr olle d i nt o t he trial pri or t o 
o btai ni n g t hese d o c u me nts. It is als o t he site’s PI res p o nsi bilit y t o : 
Ass ure  t hat n o de viati o ns fr o m, or c ha n ges of, t he pr ot oc ol s h o ul d be i nitiate d wit h o ut pri or 
writte n I R B/ E C a p pr o v al/fa v ora ble o pi ni o n of a n a p pr o priate a me n d me nt, e x ce pt w he n 
necessar y t o eli mi nate i m me diate hazar ds t o t he s u bjects or w he n t he c ha n ge(s) i n v ol ves o nl y 
l o gistical or a d mi nistrati ve as pects of t h e trial (e. g., c h a n ge of m o nit or(s), tele p h o ne n u mber(s))  
Pr o m ptl y re p ort t o t he I R B/ E C:  
o  All d e viati o ns fr o m, or c ha n ges t o, t he pr ot oc ol t o eli mi nate i m me diate hazar ds t o 
t he trial s u bjects 
o  A n y c ha n ges i n creasi n g t he ris k t o s u bjects a n d/ or affecti n g si g nifica ntl y t h e 
c o n d uct of t he trial 
o  All A Es  t hat are b ot h seri o us a n d u ne x pecte d  w het her see n at t hat i nstit uti o n or 
re p orte d fr o m S oli ge ni x  
o  A n y n e w i nf or mati o n t hat ma y affect a d versel y t h e safet y of t h e s u bjects or  t he 
c o n d uct of t he trial. 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 2  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 4.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
It is t he r es p o nsibilit y of t he PI or his/ her desi g nee t o ass ure t hat all i nf or mati o n i n t he e C R F is 
acc ur ate a n d c o m plete. T he e C R F will perf or m i m me diate i nter nal c o nsiste nc y c hec ks t o 
mi ni mize p ote ntial f or err o ne o us data (e. g., date of birt h after d ate of ra n d o mizati o n). S oli ge ni x 
will use m o nit ors t o re vie w e ntere d d ata i n t he e C R F a n d ma ke p eri o dic site visits t o c o m pare 
e C R F data wit h s o urce d oc u me nts. Peri o dic i nteri m a u dits fr o m S oli ge ni x’s Q ualit y D e part me nt 
or t heir desi g nee will be c o n d ucte d t o ass ure t hat all I C H g ui deli nes are b ei n g f oll o we d a n d 
i de ntif y a n y s yste mic pr o ble ms wit h t he data or pr oce d ures.  Fi nal a u dits will be c o n d ucte d at 
re pres e ntati ve sites. 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 3  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 5.  
E T HI C S 
1 5. 1.  
Et hic al Re vie w of Tri al  
T he fi nal st u d y pr ot oc ol, i ncl u di n g t he fi nal v ersi o n of t he S u bject I nf or m ati o n a n d C o nse nt 
F or ms, m ust be a p pr o v e d i n writi n g b y I R B / E C bef ore e nr ol l me nt of a n y s u bject i nt o t he st u d y. 
T he PI or t heir desi g nee is res p o nsi ble f or i nf or mi n g t he I R B / E C of a n y S A Es  a n d a me n d me nt(s) 
t o t he pr ot oc ol as per re g ulat or y re q uire m e nts. 
1 5. 2.  
Et hic al C o n d uct of t he St u d y  
T he st u d y will be p erf or me d i n acc or d a nce wit h t he et hical pri nci ples i n t h e Decl arati o n of 
Helsi n ki, G C P s a n d a p plica ble r e g ulat or y re q uire me nts.  
1 5. 3.  
Writte n I nf or me d C o nse nt  
T he I n vesti gat or will e ns ure t hat t he s u bject or a l e gall y a ut h orize d re prese ntati ve of t he s u bject 
are gi ve n f ull a n d a de q u ate oral a n d writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p ossi ble ris ks 
a n d be nefit s of t he st u d y. S u bjects m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he 
st u d y at a n y ti me. T h e s u bject s h o ul d be gi v e n t he o p p ort u nit y t o as k q uesti o ns a n d all o we d ti me 
t o c o nsi der t he i nf or mati o n pr o vi de d. T he s u bject’s si g ne d a n d d ate d i nf or m e d c o nse nt m ust be 
o bt ai ne d bef ore c o n d ucti n g a ny st u dy s pecific pr oce d ure . T he c o nse nt f or m t hat is use d m ust 
meet t he re q uir e me nts as o utli ne d i n t he I C H G ui d a nce o n G C Ps ( E 6) a n d m ust be a p pr o ve d b y 
b ot h t he re vie wi n g I R B / E C a n d b y S oli ge ni x. 
1 5. 4.  
S u bject D at a P r otecti o n 
T he S u bject I nf or m ati o n a n d C o nse nt F or m will e x plai n t hat st u d y data will be st ore d i n a 
c o m p uter data b ase, mai ntai ni n g c o nfi d e ntialit y . S u bjects i n t his data base will be i de ntifie d b y 
i nitials or e nr oll me nt c o de/s u bject n u m ber o nl y. A n a ut h orize d re pres e ntati ve of a re g ulat or y 
a ut h orit y ma y re q uire dir ect access t o parts of t h e trial site rec or ds rele va nt t o t he st u d y, 
i ncl u di n g s u bjects’ me di cal hist or y f or dat a verifi cati o n p ur p oses. 
1 5. 5.  
Fi n a nci al Discl os ure  
T he F D A has iss ue d r e g ulati o ns ( 2 1 C F R Part 5 4) t hat re q uire S p o ns ors (i n t his case S oli ge ni x) 
t o s u b mit c o m plete a n d acc urat e certificati o n or discl os ure state me nts t o certif y t he a bse nce of 
certai n fi n a ncial i nter ests of cli nical i n vesti gat ors a n d/ or discl ose t h ose fi na ncial i nterests, as 
re q uire d, w h e n cli nical st u dies are s u b mitte d t o t he F D A i n s u p p ort of mar keti n g a p pr o val of a 
ne w dr u g a p plicati o n ( N D A). T hes e re g ulati o ns are i nte n de d t o e ns ure t hat fi na ncial i nterests a n d 
arra n ge me nts of cli nical i n vesti gat ors, t hat c o ul d affect relia bilit y of d ata s u b mitte d t o t he F D A 
i n s u p p ort of mar keti n g a p pr o val, ar e i de ntifie d a n d discl ose d b y t he S p o ns or. 
Re gar dless of t he l ocati o n of t he cli nical site, all cli nical i n vesti gat ors partici pati n g i n t his 
cli nical trial s hall be as ke d t o discl ose pr o prietar y (e. g., pate nt, lice nsi n g a gree me nt) a n d 
fi na ncial ( e. g., st oc k o pti o ns, r o yalty) i nterests as t he y p ertai n t o S oli ge ni x, pri or t o partici pati n g 
i n t he st u d y. I n a d diti o n, cli nical i n vesti gat ors will be re q uire d t o c o ns ult wit h S oli ge ni x bef ore 
ac q uiri n g a n y fi n a ncial i nterest i n t he c o m pa n y a n d m ust discl ose a n y c h a n ge i n t heir pr o p rietar y 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 4  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
or fi na ncial i nter ests if it occ urs d uri n g t he c o urse of t he st u d y a n d f or o n e year f oll o wi n g st u d y 
c o m pleti o n. Cli nical i n vesti gat or is defi n e d u n der Title 2 1 C F R Part 5 4 as a n i n vesti gat or or s u b-
i n vesti gat or liste d o n t he F D A F or m 1 5 7 2 t hat is directl y i n v ol ve d i n t he treat me nt or e val uati o n 
of researc h s u bjects. T he re q uire me nt f or pr o pri etar y a n d fi na n cial discl os ure als o i ncl u des a n y 
o w ners hi p b y t he s p o use or a n y de pe n d e nt c hil d of t he i n vesti gat or. 
If t he F D A deter mi nes t hat t he fi na ncial i nterests of a n y cli nical i n vesti gat or raise seri o us 
q uesti o ns a b o ut t he i nte grit y of t he d ata, t he F D A will ta ke a n y acti o n it dee ms necessar y t o 
e ns ure t he r elia bilit y of t he data, i ncl u di n g: 
I nitiati n g a ge n c y a u dits of t he data deri ve d fr o m t he cli nical in vesti gat or i n q uesti o n; 
Re q uesti n g t hat t he S p o ns or s u b mit f urt her a nal ys es of data, e. g., t o e val uat e t he effect of t h e 
cli nical i n vesti gat or’s dat a o n o verall st u d y o utc o me;  
Re q uesti n g t hat t he a p plica nt c o n d uct a d diti o nal i n de pe n de nt st u dies t o c o nfir m t he res ults of t he 
q uesti o ne d st u d y; a n d/ or 
Ref usi n g t o treat t he c o v ere d cli nical st u d y as pr o vi di n g data t hat ca n be t h e basis f or a n a ge n c y 
acti o n. 
If t he S p o ns or d oes n ot i ncl u de certificati o n or discl os ure, or b ot h, if re q uire d, or d oes n ot certif y 
t hat it was n ot p ossi ble t o o btai n t he i nf or mati o n, t he F D A m a y ref use t o fil e t he N D A . 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 5  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 6.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 6. 1.  
I ns pecti o n of Rec or ds 
As n ote d i n Secti o n 1 3. 6, it is t he res p o nsi bilit y of t he PI a n d t he partici p ati n g i nstit uti o n t o 
ass ure t hat a p pr o priate tri al -relat e d m o nit ori n g, a u dits, I R B/ E C re vi e w, a n d re g ulat or y 
i ns pecti o n(s) ca n b e carri e d o ut b y ass uri n g direct access t o s o urce d ata/ d oc u me nts. T hese 
i ns pecti o ns ma y b e c o n d ucte d b y S olige ni x  or its desi g nee or re prese ntati v es of t he F D A, E M A, 
or l ocal Healt h A ge ncies.  
1 6. 2.  
Rete nti o n of Rec or ds  
It is t he j oi nt res p o nsi bilit y of b ot h t he site PI a n d t he i nstit uti o n t o ta ke meas ures t o pre v e nt 
acci de nt al or pre mat ure d estr ucti o n of all st u d y d o c u me nts i ncl u di n g t he s o urce d oc u m e nts. 
Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 years after t he l ast a p pr o val of a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o p e n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n; at least 2 years ha v e ela pse d si nce t he f or mal disc o nti n uati o n of 
cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct; or 7 years si nce t h e cl ose -o ut of t he cli nical 
trial. S oli ge ni x  will i nf or m t he i n vesti gat or /i nstit uti o n as t o w he n t hese d oc u me nts n o l o n ger 
nee d t o be r etai ne d . 
If t he res p o nsi ble i n vesti gat or retires, rel ocates, or f or ot her reas o n wit h dra ws fr o m t he 
res p o nsi bilit y of kee pi n g t he st u d y r ec or ds, c ust o d y m ust be tra nsferre d t o a pers o n w h o will 
acce pt t he res p o nsi bilit y. S oli ge ni x m ust be n otifie d i n writi n g a n d a ppr o ve of t he na me a n d 
a d dress of t he n e w c ust o dia n. 
1 6. 3.  
P u blic ati o n C o m mittee  
T he S p o ns or, S oli ge ni x, is c o m mitte d t o t he pr o m pt p u blicati o n of t he res ults of t his trial 
re gar dl ess of t he o utc o m e. A P u blicati o n C o m mittee will be a p p oi nte d t o re vie w a n d pre pare a 
ma n uscri pt f or s u b missi o n t o a n a p pr o priat e peer-re vie we d sci e ntific j o ur nal. Me m bers hi p t o t he 
c o m mittee will be offer e d, at a mi ni m u m,  t o t he st u d y’s PI , t he 6 sites e nr olli n g t he hi g hest 
n u m ber of e v al ua ble pati e nts i nt o t he trial, t he st u d y statisti cia n, a n d re prese ntati ves of S oli ge ni x . 
Ot her me m bers ma y b e a p p oi nte d at t he i nitial P u blicati o n C o m mittee meeti n g.  
 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
 Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 6  of 6 7  
A m e n d m e nt 1: 2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7  S e pt e m b er 2 0 1 9  
1 7.  
I N V E S TI G A T O R A G R E E M EN T  
 
I h a ve r ea d t he f ore g oi n g pr ot oc ol a n d a gree t hat it c o ntai ns all necessar y d etails f or carr yi n g o ut 
t his st u d y. I will c o n d uct t he st u d y as o utli ne d herei n, i n acc or da n ce wit h l o cal a n d fe deral 
re g ulati o ns, G o o d Cli nical Practices a n d will 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 c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his st u d y. I will disc uss t his material wit h t he m t o e ns ure t he y 
are f ull y i nf or m e d re gar di n g t he st u d y dr u gs a n d t he c o n d uct of t he st u d y. 
I will use o nl y t he i nf or me d c o nse nt f or m a p pr o ve d b y t he I nstit uti o nal Re vie w B oar d/ Et hics 
C o m mittee a n d S oli ge ni x a n d will f ulfill all res p o nsi bilities f or s u b mitti n g perti ne nt i nf or mati o n 
t o t he I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee res p o nsi ble f or t his st u d y. 
I f urt her a gree t hat t he H ealt h A ut h orities, S oli ge ni x, or t heir desi g nee(s) s hall ha ve access t o a n y 
s o urce d oc u m e nt fr o m w hic h case re p ort f or m i nf or mati o n ma y h a ve bee n ge n erat e d. 
I a gree t hat I a n d all i n vesti gat ors liste d o n t he F D A F or m 1 5 7 2 s hall i nf or m S oli ge ni x of a n y 
e q uit y i nter est i n t he c o m pa n y pri or t o a n d d uri n g partici pati o n i n t his trial. I f urt her a gree t hat I 
a n d all liste d i n vesti gat ors will c o ns ult wit h S oli ge ni x bef ore ac q uiri n g a n y fi na ncial i nterest i n 
t he c o m pa n y d uri n g t he st u d y a n d f or o ne year aft er t he st u d y’s c o m pleti o n. 
 
 
 
 
 
 
I n v esti gat or's Si g nat ure 
Date  
 
 
 
 
Na me of I n v esti gat or ( T y pe d or Pri nte d) 
 
 
 
 
 
 


Pr ot o c ol I D R -O M -0 2 -U S A  
 
 
Ori gi n al: 1 1 J a n u ar y 2 0 1 7  
C o nfi de nti a l 
P a g e 6 7  of 6 7  
A m e n d m e nt 1:  2 9 N o v e m b er 2 0 1 7   
A m e n d m e nt 2: 2 2 J a n u ar y 2 0 1 8  
A m e n d m e nt 3: 1 7 S e pt e m b er 2 0 1 9  
1 8.  
R E F E R E N C E S  
1.  
Y u, H. B., et al., Se q uest os o me- 1/ p 6 2 is t he key i ntr acell ul ar t ar get of i n n ate defe nse 
re g ul at or pe pti de. J Bi ol C he m, 2 0 0 9. 2 8 4 ( 5 2): p. 3 6 0 0 7- 1 1. 
2.  
N ort h, J. R., et al., A n ovel a p pr o ac h f or e mer gi n g a n d a nti bi otic resist a nt i nfecti o ns: 
I n n ate Defe ns e Re g ul at ors as a n a g n ostic t her a py. J Bi otec h n ol o g y, 2 0 1 6. 2 2 6 : p. 2 4-
3 4. 
3.  
K u dri m oti, M. K., et al., R a n d o mize d, Pl ace b o- C o ntr olle d P h ase 2 a Cli nic al a n d 
Precli nic al D at a De m o nstr ati n g a Si g nific a nt a n d C o nsiste nt Re d ucti o n i n D ur ati o n of 
Or al M uc ositis wit h a N ovel I n n ate D efe nse R e g ul at or.  J Bi otec h n ol o g y, 2 0 1 6. 2 3 9 : p. 
1 1 5- 1 2 5. 
4.  
Sc ott, M. G., et al., A n a nti- i nfective pe pti de t h at selectively m o d ul ates t he i n n ate 
i m m u ne res po nse.  N at Bi otec h n ol, 2 0 0 7. 2 5 ( 4): p. 4 6 5- 7 2. 
5.  
D o ni ni, O., et al., Re d uce d I nfecti o n a n d M uc ositis i n C he m ot her a py- Tre ate d A ni m als 
F oll o wi n g I n n ate Defe nse M o d ul ati o n Usi n g a N ovel Dr u g C a n di d ate.  Bl o o d, 2 0 1 0. 
1 1 6 ( A S H A n n ual Meeti n g A bstracts): p. 3 7 8 1. 
6.  
W H O, W. H. O., W H O H a n d b o ok f or re p orti n g res ults of c a ncer tre at me nt.  1 9 7 9, 
Ge ne va.  
7.  
S o nis, S. T., Ne w t h o u g hts o n t he i niti ati o n of m uc ositis.  Oral Dis, 2 0 1 0. 1 6 ( 7): p. 5 9 7-
6 0 0. 
8.  
Me hta, C. R. a n d S.J. P oc oc k, A d a ptive i ncre as e i n s a m ple size w he n i nte ri m res ults are 
pr o misi n g: a pr actic al g ui de wit h ex a m ples.  Stat Me d, 2 0 1 1. 3 0 ( 2 8): p. 3 2 6 7- 8 4. 
 

SAP_003.pdf: 
SGX942 (DUSQUETIDE)
IDR-OM-02-USA
A PIVOTAL, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED,
MULTINATIONAL STUDY OF SGX942 (DUSQUETIDE) FOR THE TREATMENT OF
ORAL MUCOSITIS IN PATIENTS BEING TREATED WITH CONCOMITANT
CHEMORADIATION FOR THE TREATMENT OF SQUAMOUS CELL CARCINOMA
OF THE HEAD AND NECK
STATISTICAL ANALYSIS PLAN
Version:  
3.0
Release Date:
24 November 2020
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by federal 
or state law or regulations. In any event, persons to whom the information is disclosed must be 
informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you 
which is indicated as privileged or confidential.
NCT03237325


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Signature Significance
The following significance is lent to the signatures on the Approvals page of this document.
Signature
Significance
Author
By signing, the author is attesting that the content of the document is 
complete and accurate.
Reviewer
By signing, the reviewer is attesting that the document’s approach and 
contents are compliant with the study protocol, all appropriate, regulatory 
requirements, and other significant guidelines. This individual(s) has 
reviewed the document for accuracy and completeness.


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Table of Contents
LIST OF ABBREVIATIONS..........................................................................................................................6
INTRODUCTION.......................................................................................................................................7
1
STUDY OBJECTIVES.........................................................................................................................7
1.1
PRIMARY OBJECTIVE.........................................................................................................................7
1.2
SECONDARY OBJECTIVES...................................................................................................................7
1.2.1
Clinically Important Secondary Objectives.............................................................................7
1.2.2
Additional Secondary Objectives.............................................................................................7
1.3
SAFETY OBJECTIVES..........................................................................................................................7
2
STUDY DESIGN ...............................................................................................................................8
2.1
PRIMARY EFFICACY ENDPOINT........................................................................................................12
2.2
SECONDARY EFFICACY ENDPOINTS.................................................................................................12
2.2.1
Hierarchical Sequential Secondary Endpoints .......................................................................12
2.2.2
Other Secondary Endpoints ...................................................................................................12
2.3
SAFETY ENDPOINTS.........................................................................................................................12
2.4
STUDY ENDPOINT DEFINITION.........................................................................................................13
2.4.1
Oral Mucositis (OM) Grading...............................................................................................13
2.4.2
Tumor Status .........................................................................................................................13
3
STATISTICAL CONSIDERATIONS ....................................................................................................14
3.1
SAMPLE SIZE CALCULATION ...........................................................................................................14
3.2
ANALYSIS POPULATIONS.................................................................................................................15
3.2.1
Safety Population ..................................................................................................................15
3.2.2
Intent-to-treat (ITT) Population ............................................................................................15
3.2.3
Modified Intent-to-treat (mITT) Population ..........................................................................15
3.2.4
Per Protocol (PP) Population...............................................................................................15
3.3
METHODOLOGY AND CONVENTIONS ...............................................................................................15
3.4
ADDITIONAL DATA HANDLING RULES AND PRESENTATION SPECIFICATIONS .................................16
4
SUBJECT DISPOSITION..................................................................................................................16
5
PROTOCOL DEVIATIONS...............................................................................................................17
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ..........................................................17
7
MEDICAL HISTORY........................................................................................................................17
8
PRIOR AND CONCOMITANT MEDICATIONS ..................................................................................17
9
EFFICACY ANALYSES .....................................................................................................................18
9.1
ANALYSIS OF PRIMARY ENDPOINT ..................................................................................................18
9.2
SENSITIVITY ANALYSIS OF PRIMARY ENDPOINT..............................................................................18
9.3
ANALYSES OF SECONDARY ENDPOINTS...........................................................................................19
9.3.1
Hierarchical Secondary Endpoints .......................................................................................19


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9.3.2
Other Secondary Endpoints...................................................................................................19
9.4
ENDPOINT CALCULATIONS...............................................................................................................20
9.4.1
Severity-weighted Duration of OM (Area-Under the OM-Time Curve)................................20
9.4.2
Duration of SOM in the ITT Population................................................................................20
9.4.3
Duration of UOM..................................................................................................................20
9.4.4
Incidence of SOM..................................................................................................................20
9.4.5
Quality of Life........................................................................................................................20
9.4.6
Cumulative Treatment Break Duration .................................................................................21
9.4.7
Incidence of UOM .................................................................................................................21
9.4.8
Assessment of Pain................................................................................................................21
9.4.9
Amount of Opioid Medication Used ......................................................................................21
10
SAFETY ANALYSES ........................................................................................................................21
10.1
ADVERSE EVENTS.......................................................................................................................21
10.2
CLINICAL LABORATORY PARAMETERS.......................................................................................22
10.3
VITAL SIGNS...............................................................................................................................22
10.4
ASSESSMENT OF TUMOR PROGRESSION.......................................................................................23
10.5
INFECTIONS.................................................................................................................................23
10.6
ASSESSMENT OF MORTALITY ......................................................................................................23
10.7
PROGRESSION-FREE SURVIVAL...................................................................................................24
APPENDIX 1:  DATA HANDLING CONVENTIONS .....................................................................................24
1.
IMPUTATION RULES FOR START DATES...........................................................................................24
2.
IMPUTATION RULES FOR END DATES...............................................................................................24
3.
DERIVATION RULES OF NUMERIC VALUES OF CLINICAL LABORATORY PARAMETERS....................25
4.
MISSING DATA FOR SOM DURATION CALCULATIONS......................................................................25
5.
ANALYSIS ADJUSTMENTS DUE TO IMPACT OF COVID-19 PANDEMIC .................................................25


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LIST OF ABBREVIATIONS
AE 
Adverse Event 
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area-Under-the-Curve
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CP
Conditional Power
CRT 
Chemoradiation Therapy
CTCAE
Common Terminology Criteria for Adverse Events
eCRF
Electronic Case Report Form
EORTC
European Organization for Research and Treatment of Cancer 
HCG
Human Chorionic Gonadotropin
HNC
Head and Neck Cancer
HPV
Human Papillomavirus
ITT
Intent-to-Treat
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
mITT
Modified Intent-to-Treat
n
Number 
NCI
National Cancer Institute
OM 
Oral Mucositis
PD
Protocol Deviation
PI
Principal Investigator
QLQ-H&N43
Quality of Life Question for Head and Neck Cancer 43 
RECIST
Response Evaluation Criteria in Solid Tumors
PP
Per Protocol
PT
Preferred Term
RBC
Red Blood Cell
RT
Radiation Therapy
SAE 
Serious Adverse Event 
SAP
Statistical Analysis Plan
SI
Systeme Internationale
SOC
System Organ Class
SOM
Severe Oral Mucositis
TEAE
Treatment-Emergent Adverse Event
UOM 
Ulcerative Oral Mucositis
WBC
White Blood Cell
WHO
World Health Organization
WHO Drug
World Health Organization Drug Dictionary


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INTRODUCTION
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the statistical 
analyses of efficacy and safety as outlined and/or specified in the study protocol.  Specifications of tables, 
figures, and data listings are contained in a separate document (table shells). 
1
STUDY OBJECTIVES
1.1
PRIMARY OBJECTIVE

To assess the efficacy of SGX942 (dusquetide) compared to placebo in decreasing the duration of 
severe oral mucositis (SOM; defined as World Health Organization [WHO] Grade lesion ≥3) 
through 6-week post-RT in patients receiving fractionated radiation treatments and concomitant 
cisplatin chemotherapy, given as 80-100 mg/m2 every third week, for the treatment of squamous 
cell carcinoma of the oral cavity or oropharynx.
1.2
SECONDARY OBJECTIVES
1.2.1
Clinically Important Secondary Objectives 
1.
To assess the impact that SGX942 has on the Area-Under-the-Curve (AUC) for SOM (WHO 
Grade ≥3) by time plot (severity-weighted duration)
2.
To assess the impact that SGX942 has on the Area-Under-the-Curve (AUC) for ulcerative oral 
mucositis (UOM; defined as WHO Grade ≥2) by time plot (severity-weighted duration)
3.
To assess the impact that SGX942 has on the incidence of SOM
4.
To assess the impact that SGX942 has on the quality of life assessment using the European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 (version 3) and QLQ-
H&N43 instrument
5.
To assess the impact that SGX942 has on the amount of opioids used
1.2.2
Additional Secondary Objectives 

To assess the impact that SGX942 has on the cumulative number of days of RT breaks

To assess the impact that SGX942 has on the duration of SOM; in all randomized patients 
receiving fractionated RT and concomitant cisplatin chemotherapy, given as 80-100 mg/m2 

To assess the impact that SGX942 has on the duration of UOM

To assess the impact that SGX942 has on the cumulative amount of pain reported by patients
1.3
SAFETY OBJECTIVES

To assess the impact that SGX942 has on the Adverse Events (AE) and Serious Adverse Events 
(SAE)

To assess the impact that SGX942 has on changes in safety laboratory values

To assess the impact that SGX942 has on the Response Evaluation Criteria in Solid Tumors 
(RECIST) categorization of the primary tumor at 12 weeks and 12 months post chemoradiation 
therapy (CRT)

To assess the impact of SGX942 on the incidence of reported presumed bacterial infections 
between Baseline and 6 weeks after completion of radiation therapy (RT) by total number and by 
severity of infection, graded using the National Cancer Institute’s (NCI’s) Common Terminology 
Criteria for Adverse Events (CTCAE)


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
To assess the impact of SGX942 on 12 month all-cause mortality

To assess the impact of SGX942 on progression free survival through 12 months
2
STUDY DESIGN
Approximately 260 patients will be enrolled into this Phase 3, placebo-controlled, double-blind, 
multinational study to evaluate the efficacy of SGX942 compared to placebo in treating the duration of 
SOM in patients receiving chemoradiation therapy (CRT) for the treatment of head and neck cancer 
(HNC). The study sample size takes into account the recommendation of the study Data Monitoring 
Committee (DMC) to increase the study sample size to 260 subjects.  Up to an additional 10% may be 
enrolled to offset the impact of study dropouts (i.e., those subjects that do not receive 55 Gy radiation) 
and missing data which are each expected to potentially increase during the COVID-19 pandemic.
Patients will be randomized into one of two groups (1.5 mg/kg SGX942:Placebo) at a 1:1 ratio. They will 
be stratified by site, presence of gastrostomy tube, and human papilloma virus (HPV) status. Patients will 
receive their initial blinded intravenous (IV) study drug (1.5 mg/kg SGX942 or placebo) within 3 days 
following the initiation of RT.
The primary efficacy outcome for this study is the duration of SOM, defined as the number of days from 
the first oral examination with a WHO Grade assessment of 3 or 4 through the first day that a WHO 
Grade of <3 is recorded with no subsequent assessments ≥3 through the 6-week post-RT visit. Oral 
mucositis (OM) will be evaluated using the WHO score for OM.
Patients will be screened to assess their eligibility prior to randomization. After randomization, subjects 
will begin treatment with study drug within 3 days following the initiation of RT.
Patients will receive study drug while undergoing CRT and continue to receive study drug for 2 weeks 
after the completion of their RT. Dosing will be twice weekly.  Study visit days will be every third day 
(+/-1 day). On study visit days, patients will receive the 4-minute infusion of study drug. Study drug will 
not be given on the same day as chemotherapy. Study drug can be given at any time during the visit day, 
but must occur on the same calendar day that is the study visit day. The twice weekly study drug 
treatment visit calendar extends to 2 weeks post-completion of RT.
Efficacy will be further assessed at the 3 through 6 weeks post-RT completion visits. Follow-up visits will 
be conducted at 6 and 12 months after the last radiation dose to continue to evaluate safety and secondary 
endpoints.
Figure 1 summarizes the overall study design and Table 1 outlines the study schedule of procedures and 
assessments. The study week designations assume a 7-week CRT schedule. These times may require 
adjustment (as described below) if the treatment course is shorter or if treatment breaks prolong the CRT 
for more than 7 weeks.


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Figure 1: Study Schema


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Table 1: Schedule of Events by Week
Study week
Screen
Base2
1w3
2w
3w
4w
5w
6w
7 w
8w
9w
10w
11w
12w
13w
15- 55 w
19w
59w
Post-RT1
1w
2w
3w
4w
5w4
6w
2m-11 m5
12w
12m
Medical History
X
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
X
X
X
Informed 
Consent
X
Randomization
X
History of Pain 
and Opioid Use 
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
X
X
Assessment of 
Infections
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
Radiation6
5X
5X
5X
5X
5X
5X
5X
Cisplatin6
X
X
X
Administer 
Drug
2X
2X
2X
2X
2X
2X
2X
2X
2X
WHO OM7
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
PEG Tube Use
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
VS8
X
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
Physical Exam
X
X
X13
X
Safety Labs9
X
X12
X
X
X13
X
X
AEs
X
2X
2X
2X
2X
2X
2X
2X
2X
2X
X
X
X
X
Tumor Scan10
X11
X
X
Serum 
Pregnancy 
X
X12
X
HPV Status
X11
Quality of Life
X
X
X13
1 Post-RT = time from the last radiation therapy treatment
2 Baseline information needs to be obtained prior to (0 to 96 hours before) the first dose of study drug
3 w = weeks
4 Only to be done if WHO score is ≥2 at Week 4 Post-RT visit
5 m = months; patient contact (clinic visit, telephone, or email) required monthly through the 12-month clinic visit
6 Timing of radiation and chemotherapy at discretion of primary care physicians
7 WHO OM = oral mucositis grading with WHO Oral Mucositis Grading system
8 Vital signs to include temperature, weight, pulse, respirations, and seated blood pressure; Height will be obtained at Baseline only
9 Safety labs = hematology and clinical chemistry panels


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10 Scan = obtain initial staging CT/PET/MRI scans (screening scan must be within 6 weeks prior to Baseline)
11 Need to confirm that the initial diagnostic scans were CT, PET, or MRI and the tumor was tested for HPV status
12 Repeat test required if Baseline sample >7 days from Screening
13 To be done only on the second visit in week 2 post-RT 


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2.1
PRIMARY EFFICACY ENDPOINT
The primary efficacy outcome for this study is the duration of SOM through the 6-week post-RT visit, 
defined as the number of days from the first oral examination with a WHO Grade assessment of ≥3 until 
the first time the patient has a WHO Grade of <3 is recorded with no subsequent readings ≥3. (mITT 
population).  
2.2
SECONDARY EFFICACY ENDPOINTS
2.2.1
Hierarchical Sequential Secondary Endpoints
Multiple endpoints in this trial are expected to be clinically important. To maintain the nominal p-value, 
the following five secondary endpoints will be tested in a fixed sequence, hierarchical test procedure. In 
this procedure, a sequential comparison of the groups for each endpoint will be calculated with 
unadjusted p-values. If the test is statistically significant, the null-hypothesis that the groups are the 
same will be rejected and testing of the next endpoint will be done. Once an analysis has a p-value 
above the threshold, no further endpoints will be formally tested.  All 5 analyses will be conducted in 
the mITT population.
1.
Comparison of the AUC for SOM (WHO Grade ≥3) by time plot (severity-weighted duration)
2.
Comparison of the AUC for UOM (defined as WHO Grade ≥2) by time plot (severity-weighted 
duration)
3.
Comparison of the incidence of SOM
4.
Comparison of the quality of life assessment using the EORTC QLQ-C30 and QLQ-H&N43 
instrument
5.
Comparison of the total amount of opioids used
2.2.2
Other Secondary Endpoints

Comparison of the cumulative number of days of RT breaks (mITT population)

Comparison of the duration of SOM; in all randomized patients receiving fractionated RT and 
concomitant cisplatin chemotherapy, given as 80-100 mg/m2 (ITT population)

Comparison of the duration of UOM (mITT population)

Comparison of the cumulative amount of pain reported by patients (mITT population)
2.3
SAFETY ENDPOINTS

Comparison of the incidence, type, and body system categorization of AEs

Comparison of the incidence, type, and body system categorization of SAEs

Comparison of the changes from Baseline for hematology parameters, clinical chemistry 
parameters, and vital signs

Comparison of tumor status at 12 weeks and 12 months following completion of RT categorized 
using the RECIST [1.1] criteria

Comparison of the incidence and severity of reported infections assessed by CTCAE grading

Comparison of all-cause mortality through 12 months follow-up

Comparison of progression-free survival through 12 months follow-up


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2.4
STUDY ENDPOINT DEFINITION
2.4.1
Oral Mucositis (OM) Grading
OM will be evaluated by personnel trained in the use of the WHO Oral Mucositis Grading system 
which includes both physical and functional information. This grading system is widely utilized in OM 
clinical research trials including the SGX942 Phase 2 trial and is shown in Table 2.
Table 2: WHO Oral Mucositis Grading System
Only medical personnel at the site who have undergone training and certification in using the
WHO Grading system will perform the OM assessments.
2.4.2
Tumor Status 
The tumor response to treatment will be used as a safety endpoint. Results at 12 weeks and 12 months 
post-RT will be compared to the Screening results using the RECIST 1.1 system. The evaluation 
criteria for the target lesion (the primary head and neck carcinoma) are shown in Table 3; the criteria for 
non-target lesions are shown in Table 4; and the criteria for overall categorization of the tumor status 
are shown in Table 5. In addition, details pertaining to recurrence of disease, additional therapy, or 
surgery required after the active treatment phase of the trial is completed will be collected and recorded 
in the electronic case report form (eCRF) throughout all follow up visits until 12 months (±28 days) 
following the last RT treatment.


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Table 3: RECIST Evaluation of the Target Lesion 
Table 4: RECIST Evaluation of the Non-target Lesion
Table 5: Overall RECIST Response
3
STATISTICAL CONSIDERATIONS
3.1
SAMPLE SIZE CALCULATION
Sample size assessments are based on testing the hypothesis of superiority with a two-sample log rank 
test using the median duration of SOM, an equal allocation ratio, a 90% power (1-β), and an α level of 
0.05. In the Phase 2 clinical trial, the median duration of SOM was 30 days in the placebo group and 10 
days in the 1.5 mg/kg SGX942 treatment group. Because of the variability of reported results for SOM in 
the patient population, a conservative assumption was made that the median duration of SOM among 
patients receiving a minimum of 55 Gy of cumulative radiation will be 13 days in the placebo group and 8 




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Unless otherwise stated, all statistical tests will be two-sided hypothesis tests performed at the 5% level of 
significance for main effects, and all confidence intervals will be two-sided 95% confidence intervals. All 
analyses will be performed using SAS® Version 9.3 or higher. 
3.4
ADDITIONAL DATA HANDLING RULES AND PRESENTATION 
SPECIFICATIONS
The following general guidelines will apply to all statistical analyses and data presentations:

Baseline is defined as the last available value obtained prior to the first dose of study drug, radiation 
and chemotherapy but within 96 hours of the initial drug treatment unless otherwise specified in this 
SAP.
Systeme Internationale (SI) units will be used for laboratory value presentations.  
Age is calculated as of date that the informed consent form was signed.
- age = the integer part of ((date of informed consent – birth date+1)/365.25)
Body weight, height and temperatures will be converted using the following formula:
- kg = lb/2.2
- cm = 2.54 x in
- °C = (5/9) x (°F – 32)
All percentages will be rounded to one decimal place and lined up by the decimal place. The 
percentage will be suppressed when the count is zero.
Any p-values will be rounded to three decimal places and will be presented as ‘<0.001’ if they are 
less than 0.001 after rounding.
For continuous variables that are recorded as “<X” or “>X”, the value of “X” will be used in the 
calculation of summary statistics. The original values will be used for the listings.
Decimal places will be presented as follows: 
- n: integer
- minimum and maximum: same precision as in the database
- mean and median: one more decimal place than minimum and maximum
- standard deviation: two more decimal places than minimum and maximum
4
SUBJECT DISPOSITION
The following subject data will be summarized: 

Number of subjects screened

Number of subjects randomized but not treated

Number and percentage of subjects in each analysis population 

Number and percentage of subjects who completed or prematurely discontinued. Subjects who 
prematurely discontinued the study will be summarized by primary reason for discontinuation.


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5
PROTOCOL DEVIATIONS
All instances of protocol non-compliance (protocol deviations [PDs]) will be tracked during study 
monitoring. Major PDs will be summarized by treatment group and category. Major PDs are those which 
may have an impact on the safety or protection of the subject, or impact the overall quality of the data. 
They may include, but are not limited to:

Failure to obtain informed consent

Failure to report an SAE

Subject did not meet inclusion/exclusion criteria

Drug dispensing/dosing errors
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Demographic parameters and important baseline characteristics will be summarized by treatment group 
for the Safety, PP, ITT and mITT populations. Baseline characteristics include but may not be limited to 
age, age group, sex, country, ethnicity, race, weight, height, body mass index (BMI), HPV status, and 
presence of a gastrostomy tube at randomization.
Descriptive statistics of baseline values for other parameters such as vital signs, laboratory values, and 
efficacy parameters will be summarized with the post-baseline values in the corresponding safety and 
efficacy tables.
7
MEDICAL HISTORY
Medical history will be coded using Medical Dictionary for Regulatory Affairs (MedDRA) version 20.0.  
Coded medical history terms will be summarized by system organ class (SOC) and preferred term (PT) 
for the Safety and mITT populations. At each level of summarization, subjects will only be counted once 
if multiple history items were recorded.
8
PRIOR AND CONCOMITANT MEDICATIONS
The World Health Organization Drug Dictionary (WHO Drug) version B3 2018 March 1st  will be used to 
classify prior and concomitant medications by therapeutic class and generic name. Prior medication is 
defined as any medication taken prior to the first dose date of the study medication.  Concomitant 
medication is defined as any medication taken between the day of first dose of the study medication or 
start of CRT (whichever is earliest) and 6 weeks after completion of RT. Medications taken before the 
first dose date and continued on or after the first dose date are categorized as both prior and concomitant 
medications.
Prior and concomitant medications will be summarized by the Anatomical Therapeutic Chemical (ATC) 
classification level 3 and generic name for the Safety and mITT populations. At each level of 
summarization, subjects will only be counted once if multiple drugs in that category are used. 
Please see Appendix 1 for data handling conventions for any missing medication dates.


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9
EFFICACY ANALYSES        
Efficacy will be conducted in the mITT population unless otherwise specified. Sensitivity analyses will 
include the same assessments in the ITT and PP populations.        
9.1
ANALYSIS OF PRIMARY ENDPOINT
As detailed in Table 2, the clinical evaluation of mucositis will be performed and graded by trained study 
evaluators in accordance with the WHO Oral Mucositis Grading system at each study drug administration 
visit and for Week 3 through Week 6 post-RT. 
SOM is defined as OM with WHO Grade ≥3. The duration of SOM is defined as the number of days from 
the first WHO score ≥3 to the first day with a WHO score <3 with no further occurrence of a WHO score 
≥3.  A log-rank test will be used to compare the duration of SOM of the two treatment groups. 
Resolution of SOM is defined as the first assessment with a WHO score <3 with no further reports of a 
WHO grade of ≥3. If the patient has not met the requirements for resolution of SOM by the 6-week post-
RT visit, he/she will be considered censored at that visit (or the point of discontinuation from the study, if 
the patient discontinues prior to that time point). For statistical reasons, patients who do not experience 
SOM will be treated as having a duration of 0.01 days. 
Possible scenarios for onset of SOM are displayed below in Figure 2, along with the derivation of 
duration of SOM.
Figure 2: Duration of SOM (Primary Analysis)
9.2
SENSITIVITY ANALYSIS OF PRIMARY ENDPOINT
The same statistical method as for primary analysis will be used for sensitivity analysis, however, 
duration of SOM will be calculated from the first time the patient has a SOM to the last time the patient 
has a SOM. For statistical reasons, patients who do not experience SOM will be treated as having a 
duration of 0.01 days.


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Possible scenarios for onset of SOM are displayed below in Figure 3, along with the duration of SOM.
Figure 3: Duration of SOM (Sensitivity Analysis)
9.3
ANALYSES OF SECONDARY ENDPOINTS
9.3.1
Hierarchical Secondary Endpoints
Multiple endpoints in this trial are expected to be clinically important. To control type 1 error, the 
following five secondary endpoints will be tested in a fixed sequence, hierarchical test procedure. In 
this procedure, a sequential comparison of the groups for each endpoint will be calculated with 
unadjusted p-values. If the test is statistically significant, the null-hypothesis that the groups are the 
same will be rejected and testing of the next endpoint will be done. Once an analysis has a p-value 
above the threshold, no further endpoints will be formally tested. All 5 analyses will be conducted in 
the mITT population. The hierarchical orders of these endpoints are:
1.
Comparison of the AUC for SOM (WHO Grade ≥3) by time plot (severity-weighted duration)
2.
Comparison of the AUC for UOM (defined as WHO Grade ≥2) by time plot (severity-weighted 
duration)
3.
Comparison of the incidence of SOM
4.
Comparison of the quality of life assessment using the EORTC QLQ-C30 and QLQ-H&N43  
instrument
5.
Comparison of the total amount of opioids used
9.3.2
Other Secondary Endpoints

Comparison of the cumulative number of days of RT breaks (mITT population)

Comparison of the duration of SOM; in all randomized patients receiving fractionated RT and 
concomitant cisplatin chemotherapy, given as 80-100 mg/m2 (ITT population)

Comparison of the duration of UOM (mITT population)

Comparison of the cumulative amount of pain reported by patients (mITT population)


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9.4
ENDPOINT CALCULATIONS
The procedures for calculating these endpoints are given below.
9.4.1
Severity-weighted Duration of OM (Area-Under the OM-Time Curve)
The severity-weighted duration of OM (either SOM or UOM) will be calculated by the AUC of the OM 
versus time curve. This will be calculated by the formula from baseline (ta) to the time of the last 
reported WHO score recorded (tb):
where ti represents the date of the ith WHO assessment, and yi represents the value of the ith WHO 
assessment for WHO assessments for which the score is ≥3 (for SOM) or ≥2 (for UOM). The WHO 
score for the (i+1)th assessment does not need to be ≥ 3 (for SOM) or ≥2 (for UOM) but will be 
assigned a value of 0 if it is <3 (for SOM) or <2 (for UOM). If a patient experiences SOM or UOM at 
the 6-week post-RT visit (the last time point at which OM is measured), the AUC of that visit will be 
counted as 0. The AUC of SOM or UOM will be compared between treatment groups using a one-way 
ANOVA test.
9.4.2
Duration of SOM in the ITT Population
Using the same definition and statistical method as for primary endpoint, the duration of SOM will be 
compared between treatment groups in the ITT population.
9.4.3
Duration of UOM 
UOM is defined as a WHO score ≥2. The duration of UOM is defined as the number of days from the 
first WHO score ≥2 to the first day with WHO score <2 with no further occurrence of WHO score ≥2.  
A log-rank test will be used to compare the duration of UOM between the two treatment groups. 
Resolution of UOM is defined as the first assessment with a WHO score <2 with no further reports of a 
WHO grade of ≥2. If the patient has not met the requirements for resolution of UOM by the 6-week 
post-RT visit, he/she will be considered censored at that visit (or the point of discontinuation from the 
study, if the patient discontinues prior to that time point). For statistical reasons, patients who do not 
experience UOM will be treated as having a duration of 0.01 days.  
9.4.4
Incidence of SOM
The incidence of SOM will be calculated as the percent of patients within each treatment group who 
have at least one WHO score ≥3. The incidence of patients with SOM will be compared between 
treatment groups using the chi-square test.
9.4.5
Quality of Life
A Quality of Life Questionnaire will be completed by each patient at Baseline, 4 weeks and end of 
study drug treatment (2 weeks post-RT). The EORTC QLQ-C30 (version 3) and the EORTC QLQ-
H&N43 instrument will be used for these assessments. 12 multiple-item scales (fear of progression, 
body image, dry mouth and sticky saliva, pain in the mouth, sexuality, problems with senses, problems 
with shoulder, skin problems, social eating, speech, swallowing, and problems with teeth) and 7 single-


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item scales (coughing, lymphoedema, neurological problems, trismus, social contact, weight loss, and 
problems with wound healing) will be computed and summarized by visit, including change from 
baseline. 
9.4.6
Cumulative Treatment Break Duration
The cumulative duration of treatment breaks for each patient will be calculated by summing the actual 
number of treatment break days (≥3 days break) through the final RT treatment and will be compared 
between treatment groups using a one-way ANOVA test.
9.4.7
Incidence of UOM
The incidence of UOM will be calculated as the percent of patients within each treatment group who 
have at least one WHO score ≥2. The incidence of patients with UOM will be compared between 
treatment groups using the chi-square test.
9.4.8
Assessment of Pain
At each study visit, the patient’s assessment of their pain over the previous 24 hours will be recorded by 
study personnel using a scale of 1-10. Descriptive statistics of pain assessments will be summarized by 
visit, including change from baseline. The Wilcoxon rank sum test will be used to compare the pain 
scale between treatment groups at each visit.
9.4.9
Amount of Opioid Medication Used
At each study visit, study personnel will record the amount of opioid medication that the patient reports 
having taken over the previous 24 hours. Type and usage of medication will also be collected. 
Descriptive statistics of the amount of opioid medication used, normalized to a calculated oral morphine 
equivalent, will be summarized by visit. Total opioid used will be summarized though the 
treatment period (baseline through 6 weeks post-radiation treatment) and compared between 
treatment groups. Values will be compared between treatment groups using a one-way ANOVA test. 
Mean ± standard deviation will be plotted for each visit.  
10 SAFETY ANALYSES
The safety analysis will be performed using the Safety Population.  Safety parameters include adverse 
events (AEs), laboratory parameters, vital signs, infections, assessment of tumor progression, and 
assessment of mortality and assessment of progression-free survival.
10.1
ADVERSE EVENTS 
Adverse events will be coded using MedDRA version 20.0. An overall summary of AEs will present the 
frequency and percentage of patients with AEs, treatment-emergent AEs (TEAEs), TEAEs leading to 
discontinuation of study, TEAEs leading to death, and SAEs. A TEAE is defined as an AE that is new in 
onset or aggravated in severity or frequency following the first study drug administration and reported 
between randomization through the 6 week post-RT visit or 4 weeks post last study drug infusion, 
whichever is longer. An SAE is defined as an AE that results in any of the following outcomes:
• Death
• A life-threatening AE


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• Prolongation of existing hospitalization or subsequent need for hospitalization
• A persistent or significant disability/incapacity
• A congenital anomaly/birth defect
• A medical or surgical intervention to prevent one of the above
The number and percentage of patients reporting TEAEs in each treatment group will be tabulated by    
(1) SOC and PT, (2) by SOC, PT, and severity, and (3) by SOC, PT, and relationship to study drug. If 
more than one event occurs with the same preferred term for the same patient, the patient will be counted 
only once for that preferred term using the most severe and most related occurrence for the summarization 
by severity and by relationship to the study drug, respectively. AEs with missing severity and relationship 
to the study drug will be treated as “severe” and “related” respectively. In addition, the number and 
percentage of patients reporting SAEs in each treatment group will be tabulated by SOC and PT. AEs that 
started before the first study drug administration will be included in listings but not in summaries.
If there are any missing dates for AEs, please see Appendix 1 for data handling conventions.
10.2
CLINICAL LABORATORY PARAMETERS
Descriptive statistics for laboratory values (in SI units) and changes from baseline at each assessment 
time point will be presented by treatment group for the following laboratory parameters:

Serum pregnancy test: human chorionic gonadotropin (HCG)

Hematology: red blood cell count (RBC), hematocrit, hemoglobin, RBC indices, platelet count, 
white blood cell count (WBC), and WBC differential count

Chemistry: serum sodium, serum potassium, serum chloride, serum bicarbonate (CO2), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, 
total protein, serum creatinine, and blood urea nitrogen (BUN)
Laboratory values will be classified as “normal”, “low”, or “high” based on the central laboratory’s 
normal ranges. Shift tables for each parameter will be tabulated by treatment group.
10.3
VITAL SIGNS
Descriptive statistics for vital sign values and their changes from baseline at each visit will be presented 
by treatment group for the following vital sign parameters:

Heart rate

Respiratory rate

Temperature

Blood pressure (seated)

Weight
Vital sign values will be classified as “normal”, “low”, or “high” based on standard criteria listed in 
Table 6 below. Shift tables for each parameter will be tabulated by treatment group.


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Table 6: Standard Criteria for Vital Signs
Vital Sign 
Parameter
Criteria
Observed Value
High
 100
Heart Rate
(beats per minute)
Low
 60
High
 20
Respiratory Rate
(breaths per minute)
Low
 12
High
≥ 140
Systolic Blood
Pressure (mm Hg)
Low
 85
High
≥ 90
Diastolic Blood
Pressure (mm Hg)
Low
 50
10.4
ASSESSMENT OF TUMOR PROGRESSION 
Scans at 12 weeks and 12-months post-RT will be compared to the initial images using the RECIST 1.1 
system as outlined in Tables 3, 4, and 5 and compared for overall classification as well as the target and 
non-target lesion evaluations. The number and percentage of patients in each overall response category 
will be summarized by treatment group.
10.5
INFECTIONS
Patients will be assessed at each clinical visit through the 6-week post-RT visit as to the presence of 
probable clinical infections. All clinical diagnoses of infections will be classified as presumed fungal, 
presumed viral, or presumed bacterial. The severity of each infection will be graded using the CTCAE 
(see protocol appendix 1). 
The number and percentage of patients with any reported infections, presumed fungal infections, 
presumed viral infections and presumed bacterial infections will be summarized by treatment group. The 
incidence of patients with all reported infections and each type of infection (fungal, viral, bacterial) by 
severity grade (1-5) will be displayed.
10.6
ASSESSMENT OF MORTALITY
All deaths through the 12-month follow-up visit will be collected. The number of deaths in each treatment 
group will be compared using a standard chi-square analysis. Time to death and the cumulative 
probability of death will be summarized using Kaplan-Meier estimates. In addition, a log-rank test will be 
used to compare the survival distributions between treatment groups. Kaplan-Meier survival curves will 
be plotted for both treatment groups. 


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10.7
PROGRESSION-FREE SURVIVAL
The date that a patient’s cancer progress, defined by a diagnosed with a new cancer, recurrent cancer or 
initiates more chemotherapy, will be collected on a monthly basis. Progression-free survival will be 
calculated from the time of enrollment to the earliest of date of cancer progression, death, or 12 months. If 
a subject drops out, withdraws or is terminates participation study early for some other reason, the subject 
will be censored at the last know status. Kaplan-Meier progression free survival curves with be 
constructed for the treatment groups and the curves compared using a log-rank test. 
APPENDIX 1:  DATA HANDLING CONVENTIONS
1.
IMPUTATION RULES FOR START DATES
The following imputation rules apply to incomplete start dates of adverse events and medications.
Whole date is missing
The date of first study drug administration will be assigned to the missing fields.
Missing day and month

If the year is same as the year of the first study drug administration, then the day and month of the 
first study drug administration will be assigned to the missing fields.

If the year is prior to the year of the first study drug administration, then December 31 will be 
assigned to the missing fields.

If the year is after the year of the first study drug administration, then January 1 will be assigned to 
the missing fields.
Missing month only
Treat day as missing and replace both month and day according to the above procedure.
Missing day only 

If the month and year are same as the year and month of the first study drug administration, then the 
date of the first study drug administration will be assigned to the missing day.

If the month and year are before the year and month of the first study drug administration, then the 
last day of the month will be assigned to the missing day.

If the month and year are after the year and month of the first study drug administration, then the 
first day of the month will be assigned to the missing day.
If the stop date is complete and the imputed start date as above is after the end date, the end date will be 
imputed for the start date. 
2.
IMPUTATION RULES FOR END DATES
The following imputation rules apply to incomplete end dates of medications.
Whole date is missing
The date of last study drug administration will be assigned to the missing fields.
Missing day and month

If the year of the incomplete end date is the same as the year of the last study drug administration, 
then the day and month of the last study drug administration will be assigned to the missing fields. 


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
If the year of the incomplete end date is prior to the year of the last study drug administration, then 
December 31 will be assigned to the missing fields. 

If the year of the incomplete end date is after the year of the last study drug administration, then 
January 1 will be assigned to the missing fields.
Missing month only
Treat day as missing and replace both month and day according to the above procedure.
Missing day only 

If the month and year of the incomplete end date are the same as the month and year of the last 
study drug administration, then the day of the last study drug administration will be assigned to the 
missing day. 

If the month and year are before the year and month of the last study drug administration, then the 
last day of the month will be assigned to the missing day.

If the month and year are after the year and month of the last study drug administration, then the 
first day of the month will be assigned to the missing day.
3.
DERIVATION RULES OF NUMERIC VALUES OF CLINICAL LABORATORY 
PARAMETERS
If a character string (“>x”, “<x” or “=x”) is reported for a parameter of the numerical type, the numeric 
part of the value (“x”) will be derived and used in the statistical analyses.  However, the actual values as 
reported in the database will be presented in data listings.
4.
MISSING DATA FOR SOM DURATION CALCULATIONS
As noted above (Section 9.1), the primary analyses will examine the duration of SOM and censor the 
patient’s data when missing. For clarity, censored visits will carry forward the last WHO score recorded 
for the subject through to discontinuation. For sensitivity analyses, the data will be analyzed assuming 
that the SOM remains at the last recorded WHO grade for the entire trial (irrespective of early study 
termination) and, again, assuming that the SOM was 0 throughout the trial period. 
5.
ANALYSIS ADJUSTMENTS DUE TO IMPACT OF COVID-19 PANDEMIC
Reference is made to the FDA Guidance for Industry, “Statistical Considerations for Clinical Trials 
During the COVID-19 Public Health Emergency,” June 2020.  While many of the patients were 
in the treatment portion of their participation, the COVID-19 pandemic interrupted normal clinical 
operations with an impact on patient retention, the number and degree of protocol deviations, the ability 
to obtain protocol specified measurements, the ability to ship clinical specimens, and decreased the 
availability of clinical research personnel to perform protocol related activities. The ultimate impact of 
this unprecedented disruption in the clinical trial and the resulting number of dropouts, missing data, and 
partial data remains unclear at this time, Currently, the protocol specifies a last-value forward method of 
handling missing data and all patients in the mITT population are included in the analyses even if the final 
4-6 weeks of experimental therapy is not delivered. To address the impact of the pandemic on this study, 
we will:

Drop patients at specific sites in which the COVID-19 activities created extensive problems with 
documentation, data collection and/or patient enrollment and compliance;  

Terminate the trial early; and


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
Conduct sensitivity analyses on primary, secondary and safety analyses to understand the 
potential impact of the pandemic (with an assigned “start date” to the pandemic of January 1, 
2020 based on the onset of disease potentially impacting participating European sites).