Quantitative PET-MRI Imaging Correlated With Transcriptome Analysis for Noninvasive Characterization of Renal Cell Carcinomas
Phase: NA
Conditions: Renal Cell Carcinoma
Sponsor: UNC Lineberger Comprehensive Cancer Center

LI N E B E R G E R  C O M P R E H E N SI V E  C A N C E R  C E N T E R  
C LI NI C A L  O N C O L O G Y R E S E A R C H  P R O G R A M  
U NI V E R SI T Y  O F N O R T H  C A R O LI N A  A T  C H A P E L  HI L L  
P R O T O C OL A M E N D M E N T # 4  
L C C C 1 9 3 0 : Q u a ntit ati ve P E T -M RI I m a gi n g C orrel at e d wit h Tr a nscri pt o me 
A n al ysis f or N o ni n v asi ve C h ar acteriz ati o n of Re n al Cell C arci n o m as  
A M E N D M E N T I N C O R P O R A T E S (c h ec k all t h at a p pl y):  
_ _ _   E dit ori al, a d mi nistr ativ e c h a n g es  
_ _ _ Sci e ntific c h a n g es  
_ _ _ T h er a py c h a n g es  
_x _ _ Eli gi bilit y C h a n g es  
A M E N D M E N T R A TI O N AL E A N D S U M M A R Y:  
T h e c h a n g es i ncl u d e d i n t his a m e n d m e nt r e pr es e nt a b ett er u n d erst a n di n g of t h e p ati e nt 
p o p ul ati o n a n d cli nic al pr actic es of U N C pr ovi d ers. N u m er o us p ati e nts h av e b e e n ev al u at e d si nc e 
t h e b e gi n ni n g of t h e tri al w h o h av e a pri m ar y r e n al m ass s m all er t h a n 7 c m b ut wit h cl e ar evi d e nc e 
of a dv a nc e d dis e as e. A d diti o n ally, as it is st a n d ar d of c ar e f or p ati e nts wit h dist a n t dis e as e t o 
r ec eiv e a cyt or e d uctiv e n e p hr ect o my, i ncl usi o n of p ati e nts fr o m t his s u b-s et of t h e p o p ul ati o n c o ul d 
str e n gt h e n o ur u n d erst a n di n g of t h e h et er o g e n eity of cl e arly m or e a g gr essiv e cc R C C t u m ors.  
List of u p d at es t o t h e pr ot oc ol: 
1.
T h e r a di ol o gic al ev al u ati o n of t u m or siz e w as c h a n g e d fr o m ≥ 7 c m t o ≥ 4  c m as i ncl usi o n
crit eri a i n t h e f oll o wi n g s ecti o ns: 1. 3 a n d 3. 1. 3 .
2.
T h e n u m b er of s a m pl es t o b e c oll ect e d w as c h a n g e d i n s ecti o n 1. 1 t o c orr es p o n d wit h t h e
st u dy d esi g n as d escri b e d i n s ecti o n 7. 1.
3.
T h e excl usi o n crit eri o n 3. 2. 7 “ Evi d e nc e of dist a nt dis e as e o n p hysic al ex a m or i niti al
i m a gi n g” h as b e e n r e m ov e d. It is st a n d ar d pr actic e f or p ati e nts wit h dist a nt cc R C C t o
u n d er g o a cyt or e d uctiv e n e p hr ect o my a n d i ncl usi o n of t h es e p ati e nts c o ul d f urt h er i nfor m
risk-str atific ati o n of p ati e nts wit h cc R C C.
4.
T h e t u m or siz e list e d i n 7. 1 w as c h a n g e d fr o m ≥ 7 c m t o ≥ 4 c m.
5.
T h e excl usi o n crit eri o n 3. 2. 1 w as u p d at e d t o cl arify p ati e nts s uff eri n g fr o m cl a ustr o p h o bi a
s ev er e e n o u g h t o r e q uir e s e d ati o n will b e excl u d e d fr o m t h e st u dy.
T H E A T T A C H E D V E R SI O N D A T E D A u g ust 0 6 , 2 0 2 1 I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C OL  

LI N E B E R G E R  C O M P R E H E N SI V E  C A N C E R  C E N T E R  
C LI NI C A L  O N C O L O G Y R E S E A R C H  P R O G R A M  
U NI V E R SI T Y  O F N O R T H  C A R O LI N A  A T  C H A P E L  HI L L  
 
P R O T O C OL A M E N D M E N T # 3  
 
L C C C 1 9 3 0 : Q u a ntit ati ve P E T -M RI I m a gi n g C orrel at e d wit h Tr a nscri pt o me 
A n al ysis f or N o ni n v asi ve C h ar acteriz ati o n of Re n al Cell C arci n o m as  
 
A M E N D M E N T I N C O R P O R A T E S (c h ec k all t h at a p pl y):  
_ _ _   E dit ori al, a d mi nistr ativ e c h a n g es  
_ _ _ Sci e ntific c h a n g es  
_ _ _ T h er a py c h a n g es  
_ x_ _ Eli gi bilit y C h a n g es  
 
A M E N D M E N T R A TI O N AL E A N D S U M M A R Y:  
 
T h e siz e a n d B MI crit eri a ar e u n n ec ess ary f or t h e s ucc essf ul ex ec uti o n of t h e pr ot oc ol a n d h av e l e d 
t o t h e excl usi o n of m a ny p ot e nti al c a n di d at es w h o ot h er wis e m ay h av e b e e n  g o o d st u dy s u bj ects. 
 
List of u p d at es t o t h e pr ot oc ol: 
1.  R e m ov e d siz e r estricti o ns fr o m s ecti o n 3. 1 I ncl usi o n Crit eri a.  
2.  R e m ov e d B MI li mit fr o m s ecti o n 3. 2 Excl usi o n Crit eri a.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D A pril 2 1, 2 0 2 1  I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C OL  
 
 
 

LI N E B E R G E R  C O M P R E H E N SI V E  C A N C E R  C E N T E R  
C LI NI C A L  O N C O L O G Y R E S E A R C H  P R O G R A M  
U NI V E R SI T Y  O F N O R T H  C A R O LI N A  A T  C H A P E L  HI L L  
 
P R O T O C OL A M E N D M E N T # 2  
 
L C C C 1 9 3 0 : Q u a ntit ati ve P E T -M RI I m a gi n g C orrel at e d wit h Tr a nscri pt o me 
A n al ysis f or N o ni n v asi ve C h ar acteriz ati o n of Re n al Cell C arci n o m as  
 
A M E N D M E N T I N C O R P O R A T E S (c h ec k all t h at a p pl y):  
_ x_   E dit ori al, a d mi nistr ativ e c h a n g es  
_ _ _ Sci e ntific c h a n g es  
_ _ _ T h er a py c h a n g es  
_ x_ _ Eli gi bilit y C h a n g es  
 
A M E N D M E N T R A TI O N AL E A N D S U M M A R Y:  
 
Cl arific ati o n of st u dy pr oc e d ur es driv es t h e c h a n g es of t his a m e n d m e nt. T h e Li n e b er g er 
C o m pr e h e nsiv e C a nc er C e nt er (L C C C) Offic e of Cli nic al a n d Tr a nsl ati o n al R es e arc h ( O C T R) is n o w 
s u p p orti n g p orti o ns of t his w or k. M a ny of t h e c h a n g es i n l a n g u a g e i n t his a m e n d m e nt 
acc o m m o d at e t h e st a n d ar d pr oc e d ur es f or O C T R.  
 
List of u p d at es t o pr ot oc ol:  
1.  O C T R c o m pli a nc e st at e m e nt a d d e d t o s ecti o n 1. 4  
2.  S ec o n d ar y o bj ectiv e m o v e d t o ex pl or at or y s ecti o n  
3.  Eli gi bilit y crit eri a 3. 1. 2 m o difi e d t o i nc or p or at e si g ni n g of b ot h a d ult c o ns e nt a n d HI P A A 
a ut h oriz ati o n  
4.  Eli gi bilit y crit eri a 3. 1. 4 m o difi e d t o i n dic at e s ur g er y is st a n d ar d of c ar e, a n d n ot pl a n n e d p er 
r es e arc h pr ot oc ol 
5.  Eli gi bilit y crit eri a 3. 1. 7 m o difi e d t o i n dic at e n e p hr ect o mi es m ust b e d o n e i n C h a p el Hill, as 
t h er e is c urr e ntly n o m ec h a nis ms t o c oll ect m ulitf oc al tiss u e fr o m ot h er i nstit uti o ns.  
6.  Eli gi bilit y crit eri a 3. 1. 9 r e g ar di n g pr e g n a n c y t ests m o difi e d t o m atc h I R B a p plic ati o n. T his 
m o dific ati o n r e q uir es pr e g n a nc y t esti n g o n t h e d ay of I m a gi n g, r at h er t h a n wit hi n 7 d a ys 
pri or t o i m a gi n g.  
7.  Excl usi o n crit eri a 3. 2. 1 a d d e d t h e n e e d f or l or az e p a m t o t ol er at e M RI.  
8.  Excl usi o n crit eri a 3. 2. 2  e d it e d f or cl arific ati o n t h at g a d oli ni u m c o ntr ast hy p ers e nsiti vity 
s h o ul d b e d oc u m e nt e d 
9.  Excl usi o n crit eri a 3. 2. 8 a n d 3. 2. 1 1 e dit e d t o us e st a n d ar d O C T R l a n g u a g e  
1 0.  St u dy sc h e m a 4. 1 e dit e d f or cl arit y, sc h e m a a n d st u dy pl a n h as n ot c h a n g e d  
1 1.  S ecti o n 4. 2 r e g ar di n g p ati e nt i d e ntific ati o n a n d c o ns e nt u p d at e d t o i ncl u d e st a n d ar d 
l a n g u a g e 
1 2.  S ecti o n 4. 4 e dit e d t o cl arify t h at d osi n g is m e as ur e d a n d r ec or d e d,  b ut c a n n ot b e c o ntr oll e d 
pr ecis el y.  
1 3.  T h e ti m e a n d ev e nts t a bl e i n s ecti o n 5. 0 u p d at e d f or cl arit y, ti m e a n d ev e nts h a v e n ot 
c h a n g e d. 
1 4.  S ecti o n 7. 4 D at a m a n a g e m e nt w as u p d at e d t o d escri b e h o w p ati e nt i nf or m ati o n w o ul d b e 
m ai nt ai n e d  
1 5.  S ecti o ns 8. 2, 8. 3, 8. 4, 8. 5. 2 w er e u p d at e d t o st a n d ar d c o nt ai n l a n g u a g e f or st a n d ar d O C T R 
a n d Li n e b er g er pr oc e d ur es  
 
 
 
 
 
 
T H E A T T A C H E D  V E R SI O N D A T E D M a y 0 7 , 2 0 2 0 I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 

LI N E B E R G E R  C O M P R E H E N SI V E  C A N C E R  C E N T E R  
C LI NI C A L  O N C O L O G Y R E S E A R C H  P R O G R A M  
U NI V E R SI T Y  O F N O R T H  C A R O LI N A  A T  C H A P E L  HI L L  
 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C OL  
 
 
 

LI N E B E R G E R  C O M P R E H E N SI V E  C A N C E R  C E N T E R  
C LI NI C A L  O N C O L O G Y R E S E A R C H  P R O G R A M  
U NI V E R SI T Y  O F N O R T H  C A R O LI N A  A T  C H A P E L  HI L L  
 
L C C C 1 9 3 0 : Q u a ntit ati ve P E T -M RI I m a gi n g C orrel at e d wit h Tr a nscri pt o me 
A n al ysis f or N o ni n v asi ve C h ar acteriz ati o n of Re n al Cell C arci n o m as  
 
Pri nci p al  I n vesti g at or  
Da vi d S. Lal us h , P h D  
De part me nt  of Bi o me dical E n gi neeri n g  
C B # 7 5 7 5, 1 0 0 1 0 Mar y Elle n J o nes B uil di n g  
C ha pel Hill , N C 2 7 5 9 9-7 5 7 5  
 ( 9 1 9) 5 1 3 -7 6 7 1  ( P H O N E) 
( 9 1 9) 5 1 3 -3 8 1 4  ( F A X) 
E mail: dlal us h @e mail. u nc.e d u  
 
 
 
Bi ost atistici a n  
Nai m Ras hi d , P h. D. 
De part me nt of Bi ostatistics  
4 5 0 West Street  
Li ne ber ger, L C C C 2 0 -0 2 0,  C B # 7 2 9 5   
C ha pel Hill, N C  2 7 5 9 9 -7 2 9 5  
P h o ne:  ( 9 1 9) 9 6 6 -8 1 5 0  
E mail: nai m @ u nc.e d u  
 
S p o ns or :  N C T R A C S I nstit ute  
 
F u n di n g  S o urce : N C T R A C S Tra nslati o nal Tea m Scie nce A war d  
 
Versi o n  D ate:  A u g ust 0 6 , 2 0 2 1 

LI N E B E R G E R  C O M P R E H E N SI V E  C A N C E R  C E N T E R  
C LI NI C A L  O N C O L O G Y R E S E A R C H  P R O G R A M  
U NI V E R SI T Y  O F N O R T H  C A R O LI N A  A T  C H A P E L  HI L L  
 
 
 
 
L C C C 1 9 3 0 : Q u a ntit ati ve P E T -M RI I m a gi n g C orrel at e d wit h Tr a nscri pt o me 
A n al ysis f or N o ni n v asi ve C h ar acteriz ati o n of Re n al Cell C arci n o m as  
 
 
Pri nci p al  I n vesti g at or  
Da vi d S. Lal us h, P h D   
De part me nt  of Bi o me dical E n gi neeri n g  
C B # 7 5 7 5, 1 0 0 1 0 Mar y Elle n J o nes B uil di n g  
C ha pel Hill, N C 2 7 5 9 9 -7 5 7 5  
 ( 9 1 9) 5 1 3 -7 6 7 1  ( P H O N E) 
( 9 1 9) 5 1 3 -3 8 1 4  ( F A X) 
E mail: dlal us h @e mail. u nc.e d u  
 
 
Si g n at ure  P a ge  
 
T he  si g nat ure bel o w  c o nstit utes  t he a p pr o val of  t his pr ot oc ol  a n d t he attac h me nts,  a n d 
pr o vi des  t he necessar y  ass ura nces  t hat t his trial will  be  c o n d ucte d acc or di n g t o all 
sti p ulati o ns of  t he pr ot oc ol,  i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y,  a n d 
acc or di n g  t o l ocal le gal a n d re g ulat or y re q uire me nts a n d a p plica ble U. S.  fe deral 
re g ulati o ns a n d I C H g ui deli nes.  
 
Pri nci p al  I n vesti g at or ( PI) N a me:  Da vi d S. Lal us h , P h D 
 
 
PI  Si g n at ure:    
 
 
D ate:  
 
 
 
 
Versi o n  D ate: A u g ust 0 6 , 2 0 2 1 
 

L C C C  1 9 3 0  
PI:  D a vi d L al us h, P h D  
A m e n d m e n t # 4  
A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
i 
 
 
 
 
T A B L E O F  C O N T E N T S  
1. 0  
B A C K G R O U N D A N D  R A TI O N A L E  .................................................................................. 8  
1. 1  
S T U D Y S Y N O P SI S  .................................................................................................................. 8  
1. 2  
B A C K G R O U N D  ...................................................................................................................... 8  
1. 3  
P U R P O S E A N D  R A TI O N A L E  ................................................................................................... 9  
2. 0  
S T U D Y O B J E C TI V E S/ AI M S  A N D  E N D P OI N T S  ........................................................... 1 0  
2. 1  
P RI M A R Y O BJ E C TI V E S  ........................................................................................................ 1 0  
2. 2  
S E C O N D A R Y O BJ E C TI V E S  ........................................... E R R O R ! B O O K M A R K N O T D E FI N E D . 
2. 3  
E X P L O R A T O R Y O BJ E C TI V E S  ............................................................................................... 1 1  
3. 0  
P A TI E N T E LI GI BI LI T Y  .................................................................................................... 1 1  
3. 1  
IN C L U SI O N  C RI T E RI A  .......................................................................................................... 1 1  
3. 2  
E X C L U SI O N  C RI T E RI A ......................................................................................................... 1 1  
4. 0  
S T U D Y P L A N  ....................................................................................................................... 1 2  
4. 1  
S C H E M A  .............................................................................................................................. 1 2  
4. 2  
P A TI E N T ID E N TI FI C A TI O N  A N D C O N S E N T  .......................................................................... 1 2  
5. 0  
TI M E  A N D  E V E N T S  T A B L E  ............................................................................................ 1 5  
6. 0  
E X P E C T E D  RI S K S/ U N A N TI CI P A T E D  P R O B L E M S  ................................................... 1 5  
6. 1  
A S S E S S M E N T O F S A F E T Y  .................................................................................................... 1 5  
6. 2  
E X P E C T E D R I S K S ................................................................................................................ 1 5  
6. 3  
U N A N TI CI P A T E D P R O B L E M S  ............................................................................................... 1 7  
6. 4  
D A T A A N D S A F E T Y M O NI T O RI N G P L A N  ............................................................................. 1 7  
7. 0  
S T A TI S TI C A L  C O N SI D E R A TI O N S  ................................................................................ 1 8  
7. 1  
S T U D Y D E SI G N / ST U D Y E N D P OI N T S  ................................................................................... 1 8  
7. 2  
S A M P L E S I Z E A N D A C C R U A L  .............................................................................................. 1 9  
7. 3  
D A T A A N A L Y SI S P L A N S  ..................................................................................................... 2 0  
7. 4  
D A T A M A N A G E M E N T  ......................................................................................................... 2 0  
8. 0  
S T U D Y M A N A G E M E N T  ................................................................................................... 2 0  
8. 1  
IN S TI T U TI O N A L R E VI E W  B O A R D (I R B) A P P R O V A L A N D C O N S E N T  ................................... 2 0  
8. 2  
R E Q UI R E D D O C U M E N T A TI O N  ............................................................................................. 2 1  
8. 3  
R E GI S T R A TI O N  P R O C E D U R E S  ............................................................................................. 2 1  
8. 4  
D A T A S A F E T Y P L A N  ........................................................................................................... 2 1  
8. 5  
A D H E R E N C E T O  T H E  P R O T O C O L  ......................................................................................... 2 2  
8. 6  
A M E N D M E N T S T O T H E  P R O T O C O L  ..................................................................................... 2 3  
8. 7  
R E C O R D R E T E N TI O N  .......................................................................................................... 2 3  
8. 8  
O B LI G A TI O N S O F  IN V E S TI G A T O R S  ...................................................................................... 2 4  
9. 0  
R E F E R E N C E S  ..................................................................................................................... 2 5  
 

L C C C  1 9 3 0  
PI:  D a vi d L al us h, P h D  
A m e n d m e n t # 4  
A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
8  
 
 
1. 0  
B A C K G R O U N D A N D  R A TI O N A L E  
 
1. 1  
St u d y S y n o psis  
T he o bjecti ve of t his st u d y is t o e val uat e t he utilit y of si m ulta ne o us p ositr o n 
e missi o n t o m o gra p h y ( P E T) a n d 
ma g netic res o na nce i ma gi n g ( M RI) i n 
c haracteri zi n g t he m olec ular s u bt y pes of clear cell re nal cell carci n o mas (cc R C C) 
t o p ote ntiall y i nf or m pr o g n osis a n d treat me nt decisi o ns. Pre vi o us res ults o n a s mall 
n u m ber of s u bjects at U N C de m o nstrate d a rel ati o ns hi p bet wee n P E T -M RI i ma gi n g 
c haracteristics a n d t u m or s u bt y pe c o m p ositi o n as deter mi ne d b y tra nscri pt o me 
a nal ysis of s ur gical c ore sa m ples i n cc R C C. cc R C C has bee n cl assifie d i nt o t w o 
m olec ular s u bt y pes, cc A a n d cc B, o n t he basis of e x pressi o n of a gr o u p of 3 4 ge nes; 
t he t w o s u bt y pes ha ve bee n s h o w n t o ha ve clear differe n ces i n pr o g n osis. T hese 
t u m ors are n ot ori o usl y h eter o ge n e o us; a si n gle t u m or ca n co ntai n b ot h s u bt y pes, 
a n d f ull t u m or m olec ular c haracterizati o n is i nfeasi ble. I ma gi n g, h o we ver, offers a 
s na ps h ot of t he w h ole t u m or. If i ma gi n g c haracteristics pr o ve t o b e pre dicti ve of 
s u bt y pe c o m p ositi o n, earl y pr o g n ostic i nf or mati o n w o ul d be a v aila ble a n d differe nt 
a p pr oac h es t o treat me nt ma y be e na bl e d.  
 
I n t his pr oject, w e will i ma ge 1 7 cc R C C s u bjects o n si m ulta ne o us P E T-M RI a n d 
q ua ntif y t he meta b olicall y -acti ve fracti o n of t h e t u m or fr o m i ma ges. U p t o t e n c ore 
sa m ples will be ta ke n fr o m eac h t u m or p ost -s ur ger y a n d cl assifie d as cc A or cc B 
s u bt y pe usi n g tra nscri pt o me a nal ysis. T he i ma gi n g-base d 
meas ures 
will be 
c orrel ate d wit h t he fracti o n of t u m or c ores classifie d as cc B.  We h y p ot hesize t hat 
t he meta b olicall y-acti ve t u m or v ol u me fracti o n deri ve d fr o m si m ulta ne o us P E T -
M RI i ma gi n g is c orrel ate d wit h t he fracti o n of t u m or c ores cl assifie d as cc B s u bt y pe 
fr o m tra nscri pt o me a nal ysis. 
 
T his st u d y  is desi g ne d  t o pr o vi de  preli mi nar y  i nf or mati o n o n t he relati o ns hi p 
bet wee n i ma gi n g metrics a n d t u m or s u bt y pe c o m p ositi o n i n 1 7 cc R C C s u bjects.  
T he pri mar y  o bjecti ve  is t o e val uate t he ca pa bilities of M RI/ P E T i n pre dicti o n of 
cc B b ur de n .  
 
I nf or mati o n fr o m t his st u d y ma y  be  use d  t o esti mate effect size f or p o wer  
calc ulati o n  a n d sa m ple size c o nsi derati o ns  f or p ossi ble  f ut ure st u dies i n t he use of 
c o m bi ne d P E T -M R t o be use d f or pr o g n ostic i nf or mati o n i n cc R C C cases a n d 
p ote ntiall y t o e na ble ris k -stratificati o n t hat is n ot c urre ntl y p ossi ble. 
 
1. 2  
B ac k gr o u n d  
Si m ulta ne o us P E T/ M R i ma gi n g [ 1]– [ 7] o ffers e x citi n g o p p ort u nities t o vis ualize a n d 
q ua ntif y s oft -tiss ue t u m ors [ 2]. M RI offers s u per b s oft-tiss ue c o ntrast f or a n at o mical 
i nf or mati o n as well as a fle xi ble s uite of ot her tec h ni q ues pr o vi di n g f u ncti o nal a n d 
p h ysi ol o gical i nf or mati o n.  P E T offers se nsiti ve m olec ular i ma gi n g via ra di oacti ve 
tracers a n d is wi del y use d f or assess me nt of t u m or gl uc ose meta b olis m. T o get her, 
t he t w o m o dalities pr o vi de c o m ple me ntar y, s y n er gistic i nf or mati o n. Beca use of 
M RI’s s u p eri or s oft -tiss u e c o ntrast, it is c o nsi dere d a m uc h better a nat o mical g ui de 

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f or P E T q u a ntitati ve a n al yses f or t u m ors i n s oft tiss ue re gi o ns as c o m pare d t o 
sta n dar d-of -care P E T -C T.  Si m ulta ne o us P E T -M R als o pr o vi des i n here ntl y -ali g ne d 
P E T a n d 
M R, efficie nt si m ulta ne o us ac q uisiti o n, a n d t he o p p ort u nit y f or ne w 
a p pr oac h es t o P E T q ua ntitati ve a nal ysis g ui de d b y detaile d M R i ma ges.  
 
N o n metastatic clear cell re nal cell carci n o m as are ge n erall y treat e d 
wit h 
ne p hrect o m y, alt h o u g h researc h h as s u bclassifie d t he m i nt o t w o [8 ] or as ma n y as 
f o ur [9 ] s u bt y pes bas e d o n ge ne e x pressi o n; t he s u bt y pes ha ve b ee n s h o w n t o ha ve 
differi n g pr o g n oses a n d pr o gressi o n [8 ]– [1 1 ]. 
We f oc us pri maril y o n t he t w o 
s u bt y pes cc A a n d cc B [8 ] a n d as k w het h er t hes e t w o e x hi bit disti nct P E T -M RI 
i ma gi n g c haracteristics t hat ca n b e use d t o s u bt y pe t he m n o ni n vasi vel y. A n ei g ht-
s u bject pil ot st u d y c o n d ucte d o n P E T-M RI at U N C de m o nstrate d t hat q ua ntitati ve 
P E T -M RI i ma gi n g, usi n g n o nsta n dar d meas ures i nc or p orati n g t he e ntire t u m or,  was 
str o n gl y c orrel ate d wit h prese nce or a bse n ce of cc B patter ns i n t h e t u m ors [1 2 ]. 
Tra nscri pt o me a nal ysis res ults fr o m t he st u d y j ustifie d t he i m p ort of P E T i n n oti n g 
t hat ma n y of t he u pre g ul ate d ge n es ass ociate d wit h cc B were i n v ol ve d i n gl uc ose 
tra ns p ort a n d meta b olis m, t he me diat ors of 1 8-F D G u pta ke. T h us, t here is a str o n g 
bi ol o gic r ati o nale as t o w h y P E T -M RI c o ul d pre dict cc B b ur de n, b ut t he s mall 
n u m ber of s u bjects i n t hat st u d y li mits c o nfi de nce. Als o, t he fact t hat t hese t u m ors 
are hi g hl y heter o g e ne o us s u g gests t hat i ma gi n g al o ne pr o vi des a n o p p ort u nit y f or 
earl y c h aracteriz ati o n of cc B b ur de n acr oss t he e ntire t u m or w here g e ne e x pressi o n 
pr ofili n g w o ul d be i n vasi ve a n d c ostl y.   Als o, wit h t he e xcelle nt s oft -tiss ue c o ntrast 
of 
M RI, t he s yste m has t he p ote ntial f or greater a nat o mical detail t o g ui de 
i nter pretati o n of F D G acti vit y. UN C has o ne of t he fe w P E T -M R s ca n n ers i n t he 
c o u ntr y, ma ki n g it o ne of fe w ce nters i n t he U S ca pa ble of c o n d u cti n g t his st u d y.  
 
1. 3  
P ur p ose a n d  R ati o n ale  
T his is a  pr os pecti ve  st u d y of  t he use of c o m bi ne d P E T -M R [ 1-7] f or pre dicti o n 
of t u m or s u bt y pe c o m p os iti o n i n cc R C C.  A d diti o nal data a n al ysis usi n g t he pri or 
st u d y fr o m U N C s u g gests a str o n g c orrelati o n bet wee n t he fracti o n of t he t u m or 
e x hi biti n g m o derate t o hi g h F D G u pta ke a n d t he n u m ber of c ores f o u n d t o be cc B 
t y pe.  T hese res ults g ui de t he  h y p ot hesi s of t his st u d y : t he meta b olicall y-acti ve 
t u m or v ol u me fracti o n deri ve d fr o m si m ulta ne o us P E T-M RI i ma gi n g of clear -cell 
re nal cell carci n o mas is c orrel ate d wit h t he fracti o n of t u m or c ores cl assifie d as 
cc B s u bt y pe fr o m tr a nscri pt o me a nal ysis.  If s o, i n t he f ut ure, a p plicati o n of P E T -
M RI ma y offer pr o g n ostic i nf or mati o n a n d o p p ort u nities f or ris k stratificati o n . 
 
We pr o p ose t hat t he res ults of a si n gle P E T-M RI st u d y pri or t o s ur ger y will pre dict 
cc A/cc B c o nte nt of t he t u m or .  Patie nts will ha ve cli nicall y -sus pecte d cc R C C 
base d o n pri or i ma gi n g, wit h t u m or size ≥ 4 c m. S u bjects m ust ha ve a pla n ne d 
ne p hrect o m y s c he d ule t hat will all o w P E T -M RI i ma gi n g wit hi n 4 wee ks pri or t o 
s ur ger y. O nce patie nt i d e ntificati o n occ urs, t he patie nt will be assesse d f or t he 
st u d y via t he i ncl usi o n a n d e xcl usi o n criteria. A m o n g ot her criteria, patie nts m ust 
ha ve n o c o ntrai n dicati o ns a gai nst 1 8 F -F D G P E T n or 
M RI wit h ga d oli ni u m 
c o ntrast. After recr uit me nt b y t he st u d y c o or di nat or a n d i nf or me d c o ns e nt, t he 
patie nt will be a d mitte d t o t he st u d y a n d sc he d ule d f or i ma gi n g.  

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Patie nts i n o ur st u d y will recei ve t heir P E T/ M RI sca n o n t he Bi o gra p h m M R 
c o m bi ne d P E T -M RI s ca n ner at t he Bi o me dical Researc h I ma gi n g Ce nter.  T h e 
P E T -M RI sca ns will be e val uate d retr os pecti vel y a n d will n ot be u se d i n t he 
deter mi nati o n of treat me nt.    
Q ua ntitati ve 
meas ures fr o m P E T a n d 
M RI will be c o m p ute d: 
Q ua ntitati ve 
meas ures fr o m P E T will be c o m p ute d, i ncl u di n g t u m or ma xi m u m S U V, t u m or 
mea n S U V, a n d fracti o n of t u m or v ol u me o ver t hr es h ol d S U V 2. 0 ( F T V O T 2), as  
well as Meta b olic T u m or V ol u me ( M T V) a n d T otal Lesi o n Gl yc ol ysis ( T L G).  
Q ua ntitati ve meas ur es fr o m M RI will be c o m p ute d i ncl u di n g t u m or v ol u me, 
a p pare nt diff usi o n c oeffi cie nt, d y na mic c o ntr ast e n ha nce me nt, a n d t u m or water 
c o nte nt.  All q ua ntitati ve meas u res will be c o m pile d i nt o a c o m plete i ma ge-base d 
c haracteri zati o n of eac h t u m or.     
Patie nts will u n der g o ne p hrect o m y wit hi n 4 wee ks of i ma gi n g. U p t o te n  sa m ples 
will be ta ke n fr o m eac h t u m or, s patiall y distri b ute d, a n d st ore d acc or di n g t he la b 
ma n ual . No n -cc R C C hist ol o gies will be e xcl u de d fr o m f urt her a nal ysis.  R N A will 
be e xtr acte d a n d eac h sa m ple will be classifie d as cc A or cc B usi n g t he 
Clear C o de 3 4 Na n ostri n g classifier as pre vi o usl y descri be d usi n g a 3 4 -ge n e c ust o m 
Na n ostri n g pr o be ( Na n o Stri n g Tec h n ol o gies, Seattle, W A). [1 3 ] Eac h s a m ple will 
t he n be cate g ori ze d as cc B or cc A or e q ui v ocal. T he fracti o n of sa m ples classifie d 
as cc B will be use d i n f urt her a nal ysis.  
 
1. 4  
C o m pli a nce St ate me nt  
T his st u d y will be c o n d ucte d i n f ull acc or da nce t o all a p plica ble U ni versit y of 
N ort h Car oli na ( U N C) Researc h P olicies a n d Pr oce d ures  a n d all a p plica ble 
Fe deral a n d state la ws a n d re g ula ti o ns i ncl u di n g 4 5 C F R 4 6, a n d t he Healt h 
I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) Pri vac y R ule. A n y e pis o de 
of n o n -c o m plia nce will be d oc u me nte d.  
 
T he i n vesti gat ors will p erf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will 
o btai n c o nse nt, a n d will re p ort u ne x pecte d pr o ble ms i n acc or da nce wit h T he U N C 
I R B P olicies a n d Pr oce d ures a n d all fe deral re q uire me nts. C ollecti o n, rec or di n g, 
a n d re p orti n g of data will be acc urate a n d will e ns ure t he pri vac y, healt h, a n d 
welfare of researc h s u bjects d ur i n g a n d after t he st u d y. 
 
 
2. 0  
S T U D Y O B J E C TI V E S/ AI M S  A N D  E N D P OI N T S  
2. 1  
Pri m ar y o bjecti ve s 
2. 1. 1  T o c orrelate q ua ntitati ve metrics fr o m i ma gi n g c haracterizi n g t he t u m or v ol u me 
fracti o n ass ociate d wit h me di u m-t o-hi g h 1 8 -F D G -P E T u pta ke wit h t he fracti o n of 
cc B-p ositi ve c ores base d o n tra nscri pt a nal ysis   
 

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2. 3  
E x pl or at or y O bjecti ve s 
2. 3. 1  
 
  
2. 3. 2  
 
 
 
3. 0  
P A TI E N T  E LI GI BI LI T Y  
3. 1  
I ncl usi o n Criteri a  
S u bject  m ust meet  all of t he i ncl usi o n criteria t o partici pate i n t his st u d y: 
 
3. 1. 1  A ge ≥ 1 8 years of a ge ( n o u p per a ge li mit)  
3. 1. 2  Has v ol u ntaril y pr o vi de d si g ne d i nf or me d c o nse nt t o partici pate a n d HI P A A 
a ut h orizati o n f or release of pers o nal healt h i nf or mati o n . 
3. 1. 3  M ust ha ve cli nical l y-s us pecte d cc R C C base d o n pri or i ma gi n g wit h t u m or size ≥ 4  
c m. 
3. 1. 4  Pl a n ne d t o ha ve sta n dar d of care ne p hrect o m y wit h a sc he d ule t hat ca n 
acc o m m o date a M R -F D G -P E T sca n wit hi n 4 wee ks pri or t o s ur ger y.  
3. 1. 5  M ust be a ble t o u n dersta n d a n d c o m pl y wit h st u d y pr oce d ures f or t he e ntire le n gt h 
of t he st u d y.  
3. 1. 6  M ust recei ve t heir ne p hrect o m y  at U N C C ha pel Hill H os pitals .  
3. 1. 7  If patie nt has a hist or y of pri or mali g na nc y, i ncl u di n g mela n o ma, patie nt m ust be 
ca ncer-free f or t hree or m ore years. N o n-mela n o ma s ki n ca ncers will be i ncl u de d e ve n 
if n ot ca ncer-free f or t hree years.  
3. 1. 8  W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y test 
perf or me d t he da y of a n d pri or t o P E T/ M RI  i ma gi n g. 
3. 1. 9  Willi n g t o u n der g o fi n ger -stic k bl o o d gl uc ose tests. 
 
3. 2  
E xcl usi o n  Criteri a  
A n y  s u bject meeti n g  a n y of t he  f oll o wi n g e xcl usi o n criteria will  be  i neli gi ble f or 
st u d y partici p ati o n:  
 
3. 2. 1  I na bilit y t o t olerate M RI (e. g., i na bilit y t o lie flat f or > 1 h o ur  or  cla ustr o p h o bia 

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re q uiri n g l oraze pa m t o t olerate M RI), 
3. 2. 2  D oc u me nte d h y perse nsiti vit y t o ga d oli ni u m c o ntrast a ge nt  
3. 2. 3  Prese nce of  pace ma ker, i ntracra nial a ne ur ys m cli p, bla d der sti m ulat or, c oc hlear  
i m pla nt or metal near e yes or near pel vis t hat w o ul d create e xcessi ve i ma gi n g  
artifact 
3. 2. 4  Fail ure of t w o bl o o d gl uc ose tests ( bl o o d  gl uc ose le vel greater t ha n 2 0 0 m g/ d L ) o n 
da y of first sc hed ule d sca n visit a n d o n resc he d ule d da y. 
3. 2. 5  Patie nt recei vi n g ne oa dj u va nt t hera p y f or R C C  
3. 2. 6  U n willi n g or u na ble t o c o m plete i nf or me d c o nse nt  
3. 2. 7  I ncarcerate d patie nts or patie nts wit h me dical p o wer of att or ne y  at ti me of 
e nr oll me nt 
 
4. 0  
S T U D Y P L A N  
4. 1  
Sc he m a  
 
 
 
1 If gl uc ose test is n ot passe d ( > 2 0 0 m g/ d L) first ti me, s u bject ca n wait 3 0 mi n utes 
a n d re peat t he test. If fail e d a gai n, t he s u bject ca n resc he d ul e M RI a n d re peat 
gl uc ose a n d pre g na nc y t est. If faile d t wice o n sec o n d tr y, t he s u bject will be 
r esc h e d ul e d f or a n ot h er d ay or excl u d e d fr o m t h e st u dy . 
2S u bject will be gi ve n pre -M RI i nstr ucti o ns. If b ot h creati ni ne is < 1. 8 m g/ D L a n d 
gl uc ose test is < 2 0 0 m g/ d L, t he n s u bject ca n u n d er g o F D G a n d Ga d oli ni u m 
c o ntrasti n g p orti o ns of pr ot oc ol. If o nl y gl uc ose test is passe d, t he n o nl y t he F D G 
i ma gi n g will be d o ne. 
 
4. 2  
P atie nt I de ntific ati o n  a n d C o nse nt  
All patie nts wit h a n a p p oi nt me nt f or a re nal mass at U N C C ha pel Hill H os pital   ma y 

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be a p pr oac he d i n pers o n f or c o nse nt.  I n a pri vate cli nic r o o m, st u d y staff will re vie w 
c o nse nt d oc u me nts wit h p ote ntial partici pa nts a n d a ns wer a n y q uesti o ns. If a patie nt 
desires a d diti o nal ti me or wis hes t o dela y e nr oll me nt i n t he st u d y, he/s he will be 
gi ve n a c o p y of t he c o nse nt d oc u me nt a n d i nf or me d a b o ut h o w t o as k q uesti o ns or 
e nr oll at a later date. E nr oll me nt a n d i nf or me d c o nse nt will be facilitate d b y t he 
st u d y c o or di nat or. If t he s u bject c h o oses t o partici pate i n t he st u d y, he or s he si g ns 
t he c o nse nt a n d is gi ve n a c o p y f or his/ her o w n rec or ds. 
If at a n y p oi nt i n t his pr ocess t he patie nt decli nes, fails t o meet eli gi bilit y criteria, or 
is ot her wise u na ble t o f ulfill t he req uire me nts of t he researc h, he or s he is e xcl u de d 
fr o m f urt her partici pati o n. Patie nts will be pr o vi de d ass ura nce t hat decli ni n g 
partici pati o n will n ot affect t heir cli nical care.  
 
4. 3  
Bl o o d  Dr a w f or Cre ati ni ne  
If s u bjects d o n ot ha ve a  ser u m creati ni ne val ue  wit hi n 3 0 da ys  pri or  t o a 
sc he d ule d P E T -M RI  sca n, t he y will be  re q uire d t o ha ve a bl o o d dra w at U N C  
H os pitals  f or creati ni ne bef ore t heir P E T -M RI  s ca n visit.  T his is t h e n or mal 
pr oce d ure pri or t o ne p hrect o m y , a n d s o t hese bl o o d val ues ca n als o be use d f or 
P E T -M RI sca ns.   . Ser u m creati ni ne m ust be less t ha n 1. 8 m g/ d L  i n or der t o 
pr ocee d wit h t he  D y n a mic C o ntrast E n ha nce me nt M RI part of t he sca n.  If t he 
s u bject d oes n ot meet t hat le vel, t he s u bject will be i ma ge d wit h t he ot her n o n -
c o ntrast se q ue n ces a n d  wit h P E T si nce t he n o n-c o ntrast i ma ges  will still meet 
t he pri mar y o bjecti ve of t he st u d y. 
 
4. 4  
F D G -P E T -M RI  
All patie nts will u n der g o  a M RI  sca n wit h si m ulta ne o us ac q uisiti o n  of [1 8F]  
Fl u de o x y gl uc ose P ositr o n E missi o n  T o m o gra p h y  ( F D G F 1 8 - P E T) . 1 8 F -F D G  is 
a p ositr o n -e mitti n g ra di o p har mace utical use d f or dia g n ostic  p ur p oses.   It is a 
gl uc ose  a nal o g  t hat c o nce ntrates  i n cells rel yi n g u p o n gl uc ose as  a n e ner g y s o urce 
or i n cells w h ose  relia nce o n gl uc ose i ncreases  u n der pat h o p h ysi ol o gical  
c o n diti o ns. Eac h partici pa nt will recei ve a p pr o xi matel y 1 2 m Ci 1 8 F -F D G , t he e xact 
d ose a d mi nistere d t o eac h partici pa nt will be meas ure d a n d rec or de d i n t he st u d y 
rec or ds 
   
S u bjects will ha ve a fi n ger -stic k bl o o d gl uc ose test u p o n re p orti n g t o t he i ma gi n g 
ce nter; bl o o d gl uc ose m ust be bel o w 2 0 0 m g/ d L i n or der t o pr ocee d wit h t he F D G 
i njecti o n. If bl o o d gl uc ose e xcee ds t his le vel, a sec o n d fi n ger-stic k test ma y be 
perf or me d after 3 0 mi n utes, a n d if t he sec o n d test is bel o w t he t hres h ol d, t he F D G 
i njecti o n ma y pr oceed. Faili n g t he sec o n d test will res ult i n t he s u bject bei n g 
resc he d ule d f or a n ot her da y or e xcl u de d fr o m t he st u d y. 
 
I njecti o n of  ga d oli ni u m  c o ntrast  a ge nt (if t h e s er u m creati ni n e test is pass e d: s er u m 
creati ni ne < 1. 8 m g/ d L ) will be  perf or me d  i n t he us ual  ma n ner a n d i ma ges 
si m ulta ne o usl y o btai ne d wit h M RI.   If t he ser u m creati ni ne is a b o ve t he t hres h ol d, 
t he s u bject will n ot recei ve ga d oli ni u m c o ntrast, b ut t he re mai n der of t he sca n ni n g 
pr ot oc ol will pr ocee d.   
 

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Patie nts will ha ve faste d  f or at least 6  h o urs bef ore i ntra ve n o us  i njecti o n of  F D G.   
T o mi ni mize  ra diati o n-a bs or be d  d ose  t o t he bla d der,  patie nts  s h o ul d dri n k at least 
a n 8  o u nce  glass  of  water  pri or  t o dr u g  a d mi nistrati o n.  W he ne ver  p ossi ble,  patie nts 
s h o ul d ta ke t he f oll o wi n g preca uti o ns  f or 1 2 h o urs  after i njecti o n: use d  t oilets 
s h o ul d be fl us he d se veral ti mes after eac h use,  a n d ha n ds  s h o ul d be was he d  
t h or o u g hl y.  If bl o o d, uri ne  or  feces s oil cl ot hi n g, t he cl ot hi n g s h o ul d be was he d  
se paratel y. 
 
Eac h patie nt will be i ma ge d at a si n gle visit. P atie nts will be sc he d ule d f or P E T-
M RI i ma gi n g at Marsic o Hall a n d will recei ve i ma gi n g -da y i nstr ucti o ns fr o m t he 
st u d y c o or di nat or. T he st u d y c o or di nat or will meet t he patie nt at t he i ma gi n g facilit y 
a n d esc o rt t he m t o t he i ma gi n g s uite.  W o me n  of  c hil d beari n g p ote ntial  will u n der g o  
uri ne  pre g n a nc y  test t he da y of a n d pri or t o  t he P E T/ M RI.  
 
Patie nts  will be  pai d  $ 5 0  eac h u p o n c o m pl eti o n of t h e i m a gi n g visit as 
c o m pe nsati o n  f or t heir ti me. 
 
4. 5  
D ur ati o n  of  St u d y  I nter ve nti o n 
T he  st u d y i nter ve nti o n is c o m plete o nce t he patie nt recei ves t heir P E T -M RI  sca n. 
T he  patie nt ma y  b e  wit h dra w n  fr o m t he st u d y pri or  t o t his p oi nt if a n y of t he  
f oll o wi n g a p pl y: 
 
•  I nter-c urre nt  ill ness pre ve nts  c o m pleti o n of  i ma gi n g st u dies 
•  U nacce pta ble  a d verse e ve nt(s) pre ve nts  c o m pleti o n of  i ma gi n g st u dies 
•  Patie nt  deci des  t o wit h dra w fr o m t he st u d y, O R  
•  Ge neral  or s pecific  c ha n ges  i n t he patie nt’s c o n diti o n re n der t he 
patie nt  u nacce pta ble f or c o m pleti o n  of  st u d y i n t he j u d g me nt of  t he 
i n vesti gat or. 
 
After P E T -M RI, patie nts will u n der g o ne p hrect o m y as pla n ne d a n d p er  
sta n dar d of care a n d t u m ors will be sa m ple d as a b o ve (u p t o 1 0 c ores will be 
ta ke n fr o m e ac h t u m or p ost-s ur ger y a n d classifie d as cc A or cc B s u bt y pe 
usi n g tra nscri pt o me a nal ysis). 
 
4. 6  
D ur ati o n  of  F oll o w  U p  
Patie nts  will be  f oll o we d u p via re vie w of  t heir me dical  rec or ds t hr o u g h disease  
rec urre nce or s ur vi val f or u p t o 5  years.  
 
4. 7  
Re m o v al  of  P atie nts  fr o m Pr ot oc ol 
Patie nts  ma y  be  re m o ve d if t he y e x perie nce u na ntici pate d  cla ustr o p h o bia  ca usi n g 
i nt olera nce t o t he M R.  If patie nts  re q uire l oraze pa m i n or der  t o t olerate t he M R, 
t he y will be  wit h dra w n fr o m st u d y partici pati o n.  
 
4. 8  
A bstr acti o n  of  Me dic al  Rec or ds  
Me dical rec or ds  will  be re vie we d a n d data  e xtracte d f or cli nical o utc o mes.  
Pat h ol o gic sta ge , as well as a n y  i nf or mati o n o n rec urre nce a n d s ur vi val.  

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I nf or mati o n c ollecte d  ma y  hel p t o  esta blis h  preli mi nar y  data f or  f ut ure st u dies. 
 
5. 0  
TI M E  A N D  E V E N T S  T A B L E  
 
 
Pre -St u d y  
I m a gi n g S ur ger y  
 
L o n g -
ter m 
f oll o w-
u p 1  
 
Scree ni n g  
X  
 
 
 
I nf or me d C o nse nt 
X  
 
 
 
Pre g n a nc y test 2 
 
X  
 
 
Cre ati ni ne bl o o d dr a w  
X 3 
 
 
 
P E T -M RI  
 
X  
 
 
Gl uc ose Test  
 
X  
 
 
S ur ger y  
 
 
X  
 
C ollecti o n of S ur gic al Tiss ue  
 
 
X  
 
A bstr acti o n of Me dic al Rec or ds  
 
 
 
X  
1L o n g -ter m f oll o w-u p will be restricte d t o a bstracti o n of me dical rec or ds f or a n y data o n rec urre nce a n d/ or 
s ur vi val f or u p t o fi ve years p ost treat me nt.  
2If cli nicall y  a p plica ble  w o me n  of  c hil d beari n g  p ote ntial  will  u n der g o  uri ne  pre g na nc y  test t he da y of a n d 
pri or t o P E T -M RI i ma gi n g  
3Creati ni ne s h o ul d be dra w n wit hi n 3 0 da ys of P E T -M RI i ma gi n g 
 
 
 
6. 0  E X P E C T E D  RI S K S/ U N A N TI CI P A T E D  P R O B L E M S  
6. 1  
Assess me nt of S afet y  
I n ge neral,  a n y patie nt  e nr olle d o n t his pr ot oc ol  a n d w h o u n d er g oes 
a n y p orti o n of t h e P E T -M RI st u d y (i n cl u di n g g a d oli ni u m 
a d mi nistrati o n) will be  e val ua ble f or a d verse e ve nts. 
 
6. 2  
E x pecte d  Ris ks  
 
6. 2. 1  Ris ks of  P E T/ M RI  
E m oti o nal Distress  
E m oti o nal distress is p ossi ble d uri n g M RI.  Tec h n ol o gists will as k s u bjects, bef ore 
i njecti o n, if t he y are cla ustr o p h o bic. Als o, tec h n ol o gists will d o t heir best t o hel p 
c o mf ort a n y s u bject w h o is cla ustr o p h o bic b ut c h o oses t o c o nti n ue. Tec h n ol o gists 
will ha n d s u bjects a s q ueeze ball alar m a n d i nst r uct t he m t o use it i n case of a n y 
disc o mf ort. T he tec h n ol o gist will als o i nf or m t he s u bj ect t hat s he is free t o st o p at 
a n y ti me, f or a n y reas o n.  
 

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Ra diati o n  
Ra diati o n: T he P E T/ M RI s ca ns will e x p ose st u d y partici pa nts t o c o ntr olle d 
a m o u nts of li mite d ra dia ti o n.  T he t otal d ose of ra diati o n fr o m t hese tests is n ot 
a ntici pate d t o ca use a n y a d verse effects of a n y si g nifica nce o ver t hat w hic h t he y 
ma y e x perie n ce o v er t heir sta n dar d of care dia g n ostic i ma gi n g a n d s u bse q ue nt 
t hera pies.   Patie nts e nr olle d i n t his  pil ot st u d y will recei ve a n esti mate d d ose of 
ra diati o n as s pecifi e d b y t he Ra diati o n Safet y C o m mittee.  T he a m o u nt of ris k t o 
t his esti mate d d ose will be e q uate d t o t he a n n u al ra diati o n e x p os ure li mit f or 
ra diati o n w or kers i n t he i nf or me d c o nse nt.  T his ra diati o n e x p os ure i n v ol ves a 
s mall ris k a n d is necessar y t o o btai n t he i nf or mati o n desire d. 
 
T his researc h 
st u d y i n v ol ves 
e x p os ure t o ra diati o n fr o m ra di otracer 
(a p pr o xi matel y 1 2 milli C uries 1 8 F -F D G) use d f or P E T/ M R sca n. T he ra diati o n 
d ose s u bjects will recei ve i n t his st u d y is 1.3  re m. F or c o m p aris o n, a pers o n i n t he 
U nite d States recei v es a ra diati o n e x p os ure of 0. 3 re m per year fr o m nat ural 
bac k gr o u n d s o ur ces. T h e ra diati o n d ose t hat s u bjects will recei v e i n t his st u d y is 
e q ui vale nt t o t he ra di ati o n e x p os ure t hat e ver y o ne recei ves i n 4 . 3 y ears fr o m 
nat ural bac k gr o u n d ra di ati o n f or partici pa nts c o m pleti n g t he P E T sca n. F or 
c o m paris o n, t he p e o ple w h o w or k wit h ra diati o n (ra diati o n w or kers)  are all o we d 
t o recei ve a ra diati o n d ose of 5 re m p er year. T h e a m ou nt of ra diati o n e x p os ure 
recei v e d i n t his st u d y is e q ual t o 2 6  % of  t h e a n n ual ra diati o n e x p os ure li mit f or 
ra diati o n w or kers.  T his ra diati o n e x p os ure i n v ol ves o nl y a s mall ris k a n d is 
necessar y t o o btai n t he researc h i nf or mati o n d esire d. T he ra diati o n e x p os ure 
descri be d here is w h at s u bjects will get fr o m t his researc h st u d y o nl y. It d o es n ot 
i ncl u de a n y e x p os ur e s u bjects ma y ha ve recei ve d or will recei v e fr o m ot her tests 
o utsi de of t his st u d y t hat are a p art of t heir me dical care.  
 
F D G  
I nf or mati o n a b o ut  F D G  F 1 8  was  o btai ne d fr o m t he Prescri bi n g I nf or mati o n  
( A u g ust 
5 
2 0 0 4);  
htt p:// w w w.access data.f da. g o v/scri pts/c der/ dr u gsatf da/  
. 
Acc or di n g  t o t his d oc u me nt , re vie ws of  t he o nc ol o g y  literat ure di d n ot re veal 
re p orte d a d verse reacti o ns w he n  usi n g  1 8 F -F D G  as a dia g n ostic i n c o nj u ncti o n wit h 
P E T.   I n a s u bset ( n = 4 2) of  a safet y data base  of e pile ps y  patie nts  ( n = 3 7 4), 4 patie nts  
ha d tra nsie nt h y p ote nsi o n, 6 ha d  h y p o - or  h y per gl yce mia a n d  3 ha d  tra nsie nt 
i ncreases i n al kali ne p h os p hatase.  
 
Ga d oli ni u m  
A n e xtre mel y rare disease calle d 
Ne p hr o ge ni c S yste mic Fi br osis ( N S F) is 
ass ociate d wit h t he use of ga d oli ni u m c o ntrast a ge nts i n patie nts wit h c hr o nic 
se vere re n al i ns uffici e nc y or re nal d ysf u ncti o n d u e t o he p at o -re n al s y n dr o me or i n 
t he peri-o perati ve li ver tra ns pla ntati o n peri o d.  E x cl usi o n criteria f or t his st u d y are 
i n c o m plia nce wit h t he F o od a n d Dr u g A d mi nistr ati o n’s a d vis or y state me nts.  
 
As part of t h e M Rl pr oce d ure s u bjects ma y recei ve a d y e calle d ga d oli ni u m. 
Ga d oli ni u m ma kes it easi er t o see d etails o n t he M RI pict ures. If s u bj ects ha ve a n y 
pr o ble ms wit h t heir ki d ne ys, t he y ma y be at ris k f or a c o n diti o n calle d Ne p hr o ge nic 

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S yste mic Fi br osis ( N S F) or Ne p hr o ge nic Fi br osi n g Der m o pat h y. N S F has bee n 
re p orte d t o occ ur bet w ee n 2 da ys a n d 1 8 m o nt hs f oll o wi n g i njecti o n of ga d oli ni u m. 
T here is n o k n o w n treat m e nt f or N S F. S o me p e o pl e ha ve e ve n die d  fr o m t his. Si g ns 
a n d s y m pt o ms of N S F ma y i ncl u de: b ur ni n g, s welli n g, har de ni n g or ti g hte ni n g of 
t he s ki n, bl o o d vessels a n d i nter nal or ga ns ( heart, l u n gs, li ver; yell o w s p ots o n t he 
w hite part of t he e yes; j oi nt s welli n g a n d stiff ness; pai n i n t he hi p b o n es or ri bs; 
m uscle wea k n ess.  
 
S u bjects’ st u d y d oct or will c hec k h o w well t h eir ki d ne ys w or k b ef ore t he y are gi ve n 
ga d oli ni u m. De pe n di n g o n h o w well t heir ki d ne ys w or k, t he y m a y n ot b e gi ve n 
ga d oli ni u m at all. N S F has n ot bee n re p orte d i n p e o ple wit h n or mal  ki d ne ys.  
 
S mall a m o u nts of ga d oli ni u m ca n sta y i n t he b o d y i ncl u di n g t he brai n, b o nes, s ki n 
a n d ot her parts of t he b o d y f or a l o n g ti me (se veral m o nt hs t o years)  i n pe o ple wit h 
n or mal ki d ne y f u ncti o n . Pe o ple w h o get ma n y d oses of ga d oli ni u m me dici nes, 
w o m e n w h o are pre g n a nt a n d y o u n g c hil dre n ma y be at i ncrease d ris k fr o m 
ga d oli ni u m sta yi n g i n t he b o d y. S o far, st u dies ha ve n ot f o u n d har mf ul effects of 
ga d oli ni u m i n patie nts wit h n or mal ki d ne ys.  Rarel y, patie nts h a ve re p ort e d pai ns, 
tire d ness, a n d s ki n, muscle or b o ne ail me nts f or a l o n g ti me, b ut t hese s y m pt o ms 
ha ve n ot bee n dir ectl y li n ke d t o ga d oli ni u m.  
 
 
 
 
6. 3  
U n a ntici p ate d Pr o ble ms  
 
6. 3. 1  Defi niti o n  
As defi ne d  b y  U N C’s  I R B, u na ntici pate d  pr o ble ms i n v ol vi n g  ris ks t o st u d y s u bjects 
refers t o a n y i nci de nt, e x perie nce,  or  o utc o me t hat: 
•  
Is u ne x p ecte d (i n ter ms of  nat ure,  se verit y, or fre q ue nc y) gi ve n  (a) t he 
researc h pr oce d ures  t hat are descri be d  i n t he pr ot oc ol -relat e d d oc u me nts,  
s uc h as t he I R B-a p pr o ve d  researc h pr ot oc ol a n d i nf or me d c o nse nt 
d oc u me nt;  a n d ( b) t he c haracteristics  of t he  s u bject p o p ulati o n  bei n g  
st u die d; 
•  
Is relate d or  p ossi bl y  relate d t o a s u bject’s partici pati o n i n t he researc h; 
a n d 
•  
S u g gests  t hat t he researc h places  s u bjects or  ot hers at a greater  ris k of har m  
(i ncl u di n g p h ysical,  ps yc h ol o gical,  ec o n o mic, or s ocial har m)  relate d t o t he 
researc h t ha n was pre vi o usl y  k n o w n or rec o g nize d. 
 
6. 3. 2  Re p orti n g  
A n y  u na ntici pate d  pr o ble m  t hat occ urs  d uri n g  t he c o n d uct  of t his st u d y  a n d t hat 
meets  at le ast t he first t w o criteria liste d i n 6. 3. 1  m ust be  re p orte d t o t he U N C  I R B 
usi n g  t he I R B’s we b -base d  re p orti n g s yste m. 
 
6. 4  
D at a a n d S afet y M o nit ori n g Pl a n  

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T he Pri nci pal I n vesti gat or will pr o vi de c o nti n u o us m o nit ori n g of patie nt safet y i n 
t his trial wit h peri o dic re p orti n g t o t he Data a n d S afet y M o nit ori n g C o m mittee 
( D S M C).  
 
Meeti n gs/telec o nfere n ces will be hel d at a fre q ue n c y de pe n d e nt o n st u d y accr ual, 
a n d i n c o ns ultati o n wit h t he st u d y Bi ostatisticia n.  T hese meeti n gs will i ncl u de t he 
i n vesti gat ors as well as pr ot oc ol n urses, cli nical r esearc h ass ociates, re g ulat or y 
ass ociates, data m a na gers, bi ostatisticia ns, a n d a n y ot her rele va nt pers o n n el t he 
pri nci pal  i n vesti gat ors ma y dee m a p pr o priate.  At t hese meeti n gs, t he res earc h 
tea m will disc uss all iss ues rele va nt t o st u d y pr o gress, i ncl u di n g e nr oll me nt, safet y, 
re g ulat or y, dat a c ollecti o n, etc. 
 
T he tea m will pr o d uce s u m maries or mi n utes of t hese meeti n gs. T h es e s u m maries 
will be a vaila ble f or i ns pecti o n w he n re q ueste d b y a n y of t he re g ulat or y b o dies 
c har ge d wit h t he safet y of h u ma n s u bjects a n d t he i nte grit y of data i ncl u di n g, b ut 
n ot li mite d t o, t he o versi g ht ( Office of H u ma n Researc h Et hics ( O H R E) 
Bi o me dica l I R B, t he O n c ol o g y Pr ot oc ol Re vie w C o m mittee ( P R C) or t he N ort h 
Car oli na Tra C S I nstit ute Data a n d Safet y M o nit ori n g B oar d ( D S M B).   
 
T he U N C L C C C Data a n d Safet y M o nit ori n g C o m mittee ( D S M C) will re vie w t he 
st u d y o n a re g ular ( q uart erl y t o a n n uall y) basis, wit h t he fre q ue n c y of re vie w base d 
o n ris k a n d c o m ple xit y as deter mi ne d b y t he U N C Pr ot oc ol Re vie w C o m mittee.  
T he U N C PI will be res p o nsi ble f or s u b mitti n g t he f oll o wi n g i nf or mati o n f or 
re vie w: 1) safet y a n d accr ual data i ncl u di n g t he n u m ber of patie nts treate d; 2) 
si g nifica nt de vel o p me nts re p orte d i n t he literat ure t hat ma y affect t he safet y of 
partici pa nts or t he et hics of t he st u d y; 3) preli mi nar y res p o nse data; a n d 4) 
s u m maries of tea m meeti n gs t hat ha ve occ urre d si nce t he last r e p ort.  Fi n di n gs of 
t he D S M C re vie w will be disse mi nate d b y me m o t o t he U N C PI, P R C, a n d t he 
U N C I R B a n d D S M B.  
 
7. 0  
S T A TI S TI C A L  C O N SI D E R A TI O N S  
7. 1  
St u d y Desi g n/ St u d y E n d p oi nts  
T he p ur p ose of t he st u d y is t o assess t he utilit y of c o m bi ne d, si m ulta ne o us p ositr o n 
e missi o n t o m o gra p h y ( P E T) a n d ma g netic res o n a nce i ma gi n g ( M RI), c ollecti vel y 
calle d P E T -M R, i n pre dicti n g t he fracti o n of t u m or c ores e x pressi n g t he cc B s u bt y pe.  
T he o ver all desi g n is t o i ma ge patie nts wit h P E T -M R pri or t o s ur ger y a n d e val uate 
q ua ntitati ve metrics fr o m i ma gi n g , a n d t o e val uate t he c orrelati o n of i ma gi n g metrics 
wit h t he res ults of p ost -s ur ger y tra ns cri pt o me a nal ysis.  T he pri mar y e n d p oi nt is t o 
c orrel ate t he M RI-g ui de d P E T metric fracti o nal t u m or v ol u me o ver t hres h ol d S U V 
> 2. 0 ( F T V O T 2) 
wit h t he fracti o n of t u m or c ores classifi e d as cc B fr o m 
tra nscri pt o me a n al ysis.  
 
Patie nts will ha ve s us pecte d  cc R C C base d o n i ma gi n g wit h t u m or size ≥ 4  c m a n d 
f or w h o m s ur gical treat me nt is pla n ne d.  O nce patie nt i de ntificati o n occ urs, t he 
patie nt will be assesse d f or t he st u d y via t h e i ncl usi o n a n d e x cl usi o n criteria 
me nti o ne d a b o ve. T he patie nt will t he n be a p pr oac he d b y a st u d y c o or di nat or  a n d 

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t he st u d y pr ot oc ol e x plai ne d a n d all ris ks o utli ne d. If t he patie nt pr o vi des i nf or me d 
c o nse nt t he p atie nt will b e e nr olle d.  De m o gra p hic data s u c h as patie nt a ge, ge n der, 
c o m or bi dities, a n d pre vi o us treat me nts, et c. will be c ollect e d. T u m or c haracteristics 
will be c ollecte d.   All d ata c ollecte d will be ke pt o n a pass w or d pr otect e d, sec ure d 
ser ver, a n d all p h ysical d oc u me ntati o n will be st ore d i n a l oc ke d ca bi net.   All data 
will be c ollecte d b y t he PI , c o-i n vesti gators  a n d st u d y c o or di nat ors . 
 
Patie nt s will t he n be sc he d ule d f or a pr e-s ur ger y P E T -M R wit hi n f o ur wee ks of 
pla n ne d s ur ger y . 
 
F or all P E T sca ns, patie nts will be i nstr ucte d t o fast, a n d bl o o d gl uc ose le vel will be 
meas ure d pri or t o injecti o n of F D G; if bl o o d gl uc ose e xcee ds 2 0 0 m g/ d L after t w o 
fi n ger-stic k tests, t he patie nt will be resc he d ule d f or a n ot her da y or e xcl u de d fr o m 
t he st u d y .  Patie nts will be i njecte d wit h a p pr o xi m atel y 1 2  m Ci 1 8 F -F D G, a n d t he n 
i ma ge d starti n g 6 0 mi n utes p ost-i njecti o n f or te n mi n utes eac h at o ne or t w o be d 
p ositi o ns f oc use d o n t he pri mar y t u m or site.   M RI se q ue nces t o be r u n will i ncl u de 
c o n ve nti o nal  a nat o mic T 1 - a n d T 2-wei g hte d se q u e nces, hi g h -res ol uti o n T 1 pre- a n d 
p ost -c o ntrast D C E se q ue nces, a n d t he P E T-M R atte n uati o n -c orrecti o n se q u e nce.  
 
T he P E T -M Rs will be e v al uate d retr os pecti vel y b y st u d y pers o n nel as t o t he size of 
t he lesi o n, t he F D G acti vit y as meas ure d b y t u m or-ma xi m u m a n d t u m or -mea n 
sta n dar d u pta ke v al ues ( S U Vs), a d diti o nal P E T metrics ( meta b olic t u m or v ol u me 
( M T V) a n d t otal lesi o n gl yc ol ysis ( T L G)), t he prese nce or a bs e nce of i n vasi o n t o 
a djace nt or ga ns, a n d t he prese n ce or a bse n ce of 
me tastatic or 
m ultif ocal 
disease.   P E T i ma g es will be e v al uate d wit h ali g ne d a nat o mical M RI f or g ui da nce 
as well as deter mi nati o n of t he t u m or m ar gi ns f or c o m p utati o n of t u m or -m ea n S U V ,  
a n d F T V O T 2 . 
 
T he pat h ol o gical s peci me ns will be e val uate d b y a U N C pat h ol o gist.  A gai n, all data 
will be st ore d o n a sec ure d, pass w or d pr otect e d ser ver.  U p t o  te n sa m ples will be 
ta ke n fr o m eac h t u m or, s patiall y distri b ute d, a n d st ore d acc or di n g t o la b ma n ual . 
N o n -cc R C C hist ol o gies will be e xcl u de d fr o m f urt her a nal ysis.  R N A will be 
e xtracte d a n d eac h sa m ple will be classifie d as cc A or cc B usi n g t he Clear C o de 3 4 
Na n ostri n g classifier as pre vi o usl y descri b e d usi n g a 3 4 -g e ne c ust o m Na n ostri n g 
pr o be ( Na n o Stri n g Tec h n ol o gies, Seattle, 
W A). [1 3 ] Eac h sa m ple will t he n be 
cate g oriz e d as cc B or cc A or e q ui v ocal.  If b ot h t u m or t y pes a p pear i n t he sa me 
sa m ple, t he classifier will c h o ose t he cl osest matc h; h o we ver, eac h res ult will be 
re vie we d a n d sa m ples t h at s h o w cl ear ele me nts of b ot h t y pes i n e x pressi o n patter ns 
will be la bele d as e q ui v o cal. T he fracti o n of s a m ples classifie d as clearl y cc B will be 
use d i n f urt her a nal ysis.  
 
T o a d dress t he pri mar y e n d p oi nt, F T V O T 2 will be e val uate d a n d rec or de d f or eac h 
s u bject as will t he fracti o n of sa m ples classifie d as cc B.     
 
 
7. 2  
S a m ple Size a n d Accr u al  

L C C C  1 9 3 0  
PI:  D a vi d L al us h, P h D  
A m e n d m e n t # 4  
A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
2 0  
 
 
T he  st u d y will e nr oll  1 7  eli gi ble patie nts  t hat are bei n g  treate d at U N C H os pitals.   
 
 
7. 3  
D at a A n al ys is Pl a ns 
F or t he pri mar y e n d p oi nt,  eac h s u bject’s F T V O T 2  will be c orrelate d wit h t h e pri mar y 
o utc o me ( fracti o n of c ore classifie d as cc B) a n d c orrelati o n esti mate d usi n g t he n o n -
para metri c S pear ma n c orrelati o n test . 
 
Re gar di n g t he s pecific h y p ot hesis  testi n g of P E T F T V O T 2, wit h N = 1 7, we will 
ha ve a p pr o xi mat el y 5 4 % p o wer t o detect a c orrelati o n of r h o = 0. 5 (a n d 7 4 % p o wer 
t o detect r h o = 0. 6), wit h a T y pe I err or rate of 0. 0 5 a n d utilizi n g t he S pear ma n 
c orrel ati o n test.   T his is c o nsi dere d a c o nser va ti v e esti mate.  Data fr o m t he pri or 
st u d y1  s h o ws a str o n g S pear ma n c orrel ati o n (r h o = . 8 9 6, p = . 0 0 6) bet wee n t he 
fracti o n of c ore sa m ples classifie d as cc B a n d t he P E T t u m or v ol u me fracti o n o ver 
S U V 2. 0 ( F T V O T 2 ). 
 
1 S. A. Br o o ks  et al., “ Alter nate meta b olic pr o gra ms defi ne re gi o nal variati o n of 
rele va nt bi ol o gical feat ures i n re nal cell carci n o ma pr o gressi o n,” Cli nic al C a ncer 
Rese arc h , Ja n 1 9, 2 0 1 6.  ( P MI D: 2 6 7 8 7 7 5 4) 
 
7. 4  
D at a M a n a ge me nt   
I ma ge datasets will be st ore d o n a sec ure ser ver i n t he Bi o me dical Researc h 
I ma gi n g Ce nter wit h patie nt i de ntifiers re m o ve d.  De -i de ntifie d c o pies of t hese ma y 
be st ore d te m p oraril y o n pass w or d -pr otecte d c o m p uters or p orta ble har d dri ves f or 
use i n data a nal ysis.  Q ua ntitati ve data e xtracte d fr o m t he i m a ges a n d res ults of data 
a nal ysis will be mai ntai ne d o n a sec ure ser ver.  All data will be arc hi ve d o n a 
pass w or d -pr otecte d c o m p uter i n t he office of t he PI a n d bac ke d u p wit h a R AI D 
s yste m.  Datasets will be mai ntai ne d f or at least fi ve years fr o m t he cl o se of t he 
st u d y. 
 
 
All s u b ject i nf or mati o n will be c o de d a n d st ore d i n a pass w or d-pr otect e d dat a base, 
s uc h as R E Dca p, a n d accessi ble b y trai n e d st u d y staff o nl y. All s peci me ns will be 
gi ve n a n ot her c o de, a n d will n ot be st ore d wit h s u bject i de ntifiers. T h e  ke y li n ki n g 
s u bject c o des t o i de ntifiers will be pass w or d-pr ot ecte d ke pt i n o n a sec ure -dri ve  
dri ve be hi n d t he sc h o ol of me dici ne fire wall.  
 
 
8. 0  
S T U D Y M A N A G E M E N T  
8. 1  
I nstit uti o n al Re vie w B o ar d (I R B) A p pr o v al a n d C o nse nt  
It is e x pecte d  t hat t he I R B will ha ve t he pr o per  re prese ntati o n a n d f u ncti o n i n 
acc or da nce wit h fe derall y  ma n date d re g ulati o ns. T he  I R B s h o ul d a p pr o ve t he 
c o nse nt  f or m a n d pr ot oc ol.  
 
I n o btai ni n g  a n d d oc u me nti n g  i nf or me d c o nse nt, t he i n vesti gat or s h o ul d c o m pl y 
wit h t he  a p plica ble  re gulat or y  re q uire me nt(s), a n d s h o ul d a d here t o G o o d Cli nical  

L C C C  1 9 3 0  
PI:  D a vi d L al us h, P h D  
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A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
2 1  
 
 
Practice ( G C P) a n d t o et hical pri nci ples  t hat ha ve  t heir ori gi n  i n t he Declarati o n of 
Helsi n ki.  
 
Bef ore  recr uit me nt a n d e nr oll me nt o nt o t his st u d y, t he patie nt  will be gi ve n  a f ull 
e x pla nati o n  of  t he st u d y a n d will be  gi ve n  t he o p p ort u nit y t o re vie w t he c o nse nt 
f or m. Eac h  c o nse nt  f or m m ust i ncl u de  all t he rele va nt ele me nts c urre ntl y  re q uire d 
b y  t he F D A Re g ulati o ns  a n d l ocal or state  re g ulati o ns. O nce t his esse ntial 
i nf or mati o n has bee n  pr o vi de d t o t he patie nt  a n d t he i n vesti gat or is ass ure d t hat t he 
patie nt  u n dersta n ds  t he i m plicati o ns of partici pati n g  i n t he st u d y, t he patie nt  will 
be  as ke d t o gi ve c o nse nt t o partici pate i n t he st u d y b y  si g ni n g a I R B-a p pr o ve d 
c o nse nt f or m. 
 
Pri or  t o a patie nt’s  partici pati o n  i n t he trial, t he writte n  i nf or me d c o nse nt  f or m 
s h o ul d be si g ne d a n d pers o nall y  date d  b y  t he patie nt a n d b y  t h e pers o n w h o  
c o n d ucte d  t he i nf or me d c o nse nt disc ussi o n.  
 
8. 2  
Re q uire d D oc u me nt ati o n  
Bef ore  t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g d oc u me ntati o n  m ust be  
pr o vi de d:   
•  A c o p y  of t he  official  I R B a p pr o val letter f or t he pr ot oc ol  a n d 
i nf or me d c o nse nt 
•  C Vs a n d me dical  lice ns ure f or t he pri nci pal  i n vesti gat or a n d a n y 
ass ociate  i n vesti gat ors w h o will be  i n v ol ve d i n t he st u d y 
•  I n v esti gat or’s si g nat ure d oc u me nti n g u n dersta n di n g of t he pr ot o c ol a n d 
pr o vi di n g c o m mit me nt t hat t his trial will be c o n d ucte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol C olle ge of A merica n Pat h ol o gist ( C A P ) a n d 
Cli nical La b orat or y I m pr o ve me nt 
A me n d me nts ( C LI A) La b orat or y 
certificati o n n u m bers a n d i nstit uti o n la b n or mal val ues.  
 
8. 3  
Re gistr ati o n  Pr oce d ures  
All partici pa nts will be re gistere d a n d e ntere d i nt o t he we b -bas e d cli nical researc h 
platf or m, O nc ore ®.  
 
 
8. 4  D at a m a n a ge me nt a n d M o nit ori n g/ A u diti n g  
Data will be st ore d i n O n c ore ®, t h e L C C C Cli nical Researc h Re gistrati o n Data base, 
w hic h is a sec ure, pass w or d -pr otect e d, we b -base d platf or m a n d accessi ble s olel y t o 
trai ne d st u d y staff. A s ec ure, pass w or d-pr ot ecte d, we b -bas e d R E D Ca p d ata base will 
als o be m ai ntai ne d a n d accessi ble o nl y t o trai ne d st u d y staff.  
 
As a n i n vesti gat or -i nitiate d st u d y, t his trial ma y als o be a u dite d b y t he U N C office of 
Cli nical Researc h e ver y t wel ve m o nt hs.  
 
 
8. 5 D at a S afet y Pl a n  

L C C C  1 9 3 0  
PI:  D a vi d L al us h, P h D  
A m e n d m e n t # 4  
A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
2 2  
 
 
All st u d y s u bjects will recei ve a c o de d i de ntifier  s uc h as “1 9 3 0 -0 0 1 ” w hic h will be 
use d i n all data a nal ysis a n d rec or ds. O nl y t he st u d y c o or di nat or will ha ve t he ke y 
t hat ass ociates t he patie nt’s i de ntifia ble i nf or mati o n wit h t he c o de d i de ntifier, a n d 
t he ke y will be ke pt i n a sec ure l o cati o n. All i ma ge meta data will c o ntai n o nl y t he 
c o de d i de ntifier a n d will be ot her wise a n o n y mize d.  La b data will recei ve o nl y t he 
c o de d i de ntifier.  
 
I ma ge datasets will be st ore d o n a sec ure ser ver i n t he Bi o me dical Researc h 
I ma gi n g Ce nter wit h patie nt i de ntifiers re m o ved. De -i de ntifie d c o pies of t hese ma y 
be st ore d te m p oraril y o n pass w or d -pr otecte d c o m p uters or p orta ble har d dri ves f or 
use i n data a nal ysis.  Q ua ntitati ve data e xtracte d fr o m t he i ma ges , res ults of 
la b orat or y a nal ysis, a n d res ults of data a nal ysis will be mai ntai ne d o n a sec ure 
pass w or d -pr otecte d c o m p uter .  All data will be arc hi ve d o n a pass w or d -pr otecte d 
c o m p uter i n t he office of t he PI a n d bac ke d u p wit h a n a ut o mate d  s yste m.  Datasets 
will be mai ntai ne d f or at least fi ve years fr o m t he cl ose of t he st u d y . 
   
8. 5  
A d here nce t o  t he Pr ot oc ol  
E xce pt  f or a n e mer ge nc y  sit uati o n i n w hic h pr o per  care f or t he pr otecti o n,  safet y, 
a n d well -bei n g  of t he  st u d y patie nt  re q uires alter nati ve treat me nt,  t he st u d y s hall 
be  c o n d ucte d  e xactl y as descri be d  i n t he a p pr o ve d  pr ot oc ol.  
 
8. 5. 1  E mer ge nc y  M o dific ati o ns  
U N C  i n vesti gat ors ma y  i m ple me nt a de viati o n  fr o m, or a c ha n g e of, t he  pr ot oc ol  
t o eli mi nate a n i m me diate hazar d(s)  t o trial s u bjects wit h o ut pri or U N C  I R B 
a p pr o val. 
 
F or  a n y s uc h e mer ge nc y m o dificati o n  i m ple me nte d, a U N C  I R B m o dificati o n  f or m 
m ust be c o m plete d  b y  U N C  Researc h  Pers o n nel  wit hi n fi ve  ( 5) b usi ness  da ys  of  
ma ki n g  t he c ha n ge. 
 
8. 5. 2  Si n gle P atie nt/ S u bject  E xce pti o ns  
Eli gi bilit y 
si n gle 
s u bject 
e xce pti o ns 
are 
n ot 
per mitte d f or 
Li ne ber ger 
C o m pre he nsi ve 
Ca ncer 
Ce nter 
I n vesti gat or 
I nitiate d 
Trials 
u n der 
a n y 
circ u msta nces. Ot her t y pes of si n gle s u bject e xce pti o ns ma y be all o we d if pr o per 
re g ulat or y re vie w 
has 
bee n 
c o m plete d i n 
acc or da nce 
wit h 
Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter’s  Si n gle S u bject E xce pti o ns P olic y.  
 
8. 5. 3  Ot her  Pr ot oc ol De vi ati o ns/ Vi ol ati o ns  
Acc or di n g  t o U N C’s I R B, a pr ot oc ol  de viati o n  is a n y u n pla n ne d varia nce  fr o m a n 
I R B a p pr o ve d  pr ot oc ol  t hat: 
•  Is ge nerall y  n ote d or rec o g nize d after it occ urs  
•  Has  n o s u bsta nti ve effect o n t he ris ks t o researc h partici pa nts  
•  Has  n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n  
or t he val ue of  t he data  c ollecte d 
•  Di d n ot res ult fr o m willf ul or k n o wi n g  misc o n d uct o n t he  part  of  t he 

L C C C  1 9 3 0  
PI:  D a vi d L al us h, P h D  
A m e n d m e n t # 4  
A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
2 3  
 
 
i n vesti gat or(s). 
 
A n u n pla n ne d  pr ot oc ol  varia nce  is c o nsi dere d  a vi olati o n  if t he varia nce meets  
a n y of  t h e f oll o wi n g criteria: 
•  Has  har me d  or  i ncrease d t he ris k of har m  t o o ne or  m ore  researc h 
partici pa nts.  
•  Has  da ma ge d  t he scie ntific i nte grit y of t he  data  c ollecte d  f or t he st u d y. 
•  Res ults  fr o m willf ul or k n o wi n g  misc o n d uct  o n t he  part  of  t he 
i n vesti gat or(s). 
•  De m o nstrates  seri o us or c o nti n ui n g  n o nc o m plia nce  wit h fe deral 
re g ulati o ns, State  la ws, or  U ni versit y  p olicies.  
 
If a de viati o n or  vi olati o n  occ urs  please  f oll o w t he g ui deli nes  bel o w:  
 
Pr ot oc ol  De vi ati o ns: U N C pers o n nel  will rec or d t he de viati o n  i n O n C ore®  ( or 
ot her  a p pr o priate  data base  set u p f or  t he st u d y), a n d re p ort t o a n y s p o ns or or data  
a n d safet y m o nit ori n g  c o m mittee i n acc or da nce wit h t heir  p olicies.  De viati o ns  
s h o ul d be s u m marize d a n d re p orte d t o t he I R B at t he ti me of c o nti n ui n g  re vie w. 
 
Pr ot oc ol  Vi ol ati o ns: Vi olati o ns s h o ul d be  re p orte d b y  U N C  pers o n nel  wit hi n o ne  
( 1) wee k  of t he  i n vesti gat or bec o mi n g  a ware of  t he e ve nt usi n g  t he sa me I R B o nli ne  
mec ha nis m  use d  t o re p ort U na ntici pate d  Pr o ble ms.  
 
U n a ntici p ate d  Pr o ble ms:  
A n y  e ve nts t hat meet  t he criteria f or “ U na ntici pate d  Pr o ble ms”  as defi ne d  b y  
U N C’s  I R B (s ee secti o n 6. 3. 1 ) m ust be  re p orte d b y  t he St u d y C o or di nat or  usi n g  t he 
I R B’s we b -base d re p orti n g  s yste m. 
 
8. 6  
A me n d me nts t o t he  Pr ot oc ol  
S h o ul d a me n d me nts  t o t he pr ot oc ol be re q uire d, t he a me n d me nts  will be  ori gi nate d  
a n d d oc u me nte d b y  t he Pri nci pal  I n vesti gat or at U N C.  It s h o ul d als o be  n ote d t hat 
w he n  a n a me n d me nt t o t he pr ot oc ol  s u bsta ntiall y alters t he st u d y desi g n  or t he  
p ote ntial ris k t o t he  patie nt,  a re vise d c o nse nt  f or m mi g ht  be  re q uire d. 
 
T he  writte n  a me n d me nt,  a n d if re q uire d t he a me n de d c o nse nt  f or m, m ust be se nt 
t o U N C’s I R B f or a p pr o val  pri or t o i m ple me ntati o n. 
 
8. 7  
Rec or d Rete nti o n  
St u d y  d oc u me ntati o n i ncl u des all Case Re p ort  F or ms, data  c orrecti o n  f or ms or  
q ueries,  s o urce d oc u me nts, S p o ns or -I n vesti gat or c orres p o n de nce,  m o nit ori n g  
l o gs/letters, a n d re g ulat or y d oc u me nts (e. g., pr ot oc ol a n d a me n d me nts,  I R B 
c orres p o n de nce  a n d a p pr o val, si g ne d patie nt c o nse nt f or ms). 
 
S o urce d oc u me nts  i ncl u de all rec or di n gs of o bser vati o ns  or n otati o ns  of cli nical 
acti vities a n d all re p orts a n d rec or ds necessar y  f or t he e val uati o n a n d rec o nstr ucti o n 

L C C C  1 9 3 0  
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A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
2 4  
 
 
of  t he cli nical  researc h st u d y. 
 
G o ver n me nt  a ge nc y re g ulati o ns a n d directi ves  re q uire t hat all st u d y 
d oc u me ntati o n  pertai ni n g  t o t he c o n d uct of a cli nical trial m ust be retai ne d b y  t he 
st u d y i n vesti gat or.  I n t he case of  a st u d y wit h a dr u g  see ki n g re g ulat or y a p pr o val 
a n d mar keti n g,  t hese d oc u me nts s hall be retai ne d f or at least t w o years  after t he 
last a p pr o val  of 
mar keti n g  a p plicati o n  i n a n I nter nati o nal C o nfere nce 
o n  
Har m o nizati o n  (I C H) re gi o n.  I n all ot her cases, st u d y d oc u me nts s h o ul d  be  ke pt  
o n file u ntil fi ve years  after t he c o m pleti o n  a n d fi nal st u d y re p ort of t his 
i n vesti gati o nal st u d y. 
 
8. 8  
O bli g ati o ns of  I n vesti g at ors 
T he  Pri nci pal  I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he cli nical  trial at t he 
site i n acc or da nce  wit h Title  2 1 of  t he C o de of Fe deral  Re g ulati o ns  a n d/ or t he 
Declarati o n  of  Helsi n ki.   T he  Pri nci pal  I n vesti gat or is res p o nsi ble f or pers o nall y 
o verseei n g  t he treat me nt of all st u d y patie nts.   T he  Pri nci pal  I n vesti gat or m ust  
ass ure t hat all st u d y site pers o n nel,  i ncl u di n g s u b-i n vesti gat ors a n d ot her st u d y  
staff me m bers,  a d here t o t he st u d y pr ot oc ol  a n d all F D A/ G C P/ N CI  re g ulati o ns 
a n d g ui deli nes  re gar di n g cli nical trials b ot h d uri n g  a n d after st u d y c o m pleti o n. 
 
T he  Pri nci pal  I n vesti gat or at eac h i nstit uti o n or site will be  res p o nsi ble f or 
ass uri n g  t hat all t he re q uire d data  will  be  c ollecte d a n d e ntere d o nt o t he  Case  
Re p ort  F or ms.  Peri o dicall y,  m o nit ori n g  visits will be c o n d ucte d a n d t he Pri nci pal 
I n vesti gat or will  pr o vi de  access  t o his/ her  ori gi nal  rec or ds t o per mit verificati o n 
of pr o per  e ntr y of data. At t he  c o m pleti o n  of  t he st u d y, all case re p ort f or ms will  
be  re vie we d b y  t he Pri nci pal I n vesti gat or a n d will  re q uire his/ her  fi nal si g nat ure 
t o verif y t he acc urac y of  t he data.  

L C C C  1 9 3 0  
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A m e n d m e n t # 4  
A u g u s t 0 6 , 2 0 2 1 
C O N FI D E N TI A L  
U NI V E R SI T Y  O F  N O R T H  C A R O LI N A  
2 5  
 
 
 
9. 0  R E F E R E N C E S  
[ 1] M. S. J u de n h ofer et al., “ Si m ulta ne o us P E T-M RI: a ne w a p pr oac h f or f u ncti o nal a n d 
m or p h ol o gical i ma gi n g,” N at. Me d. , v ol. 1 4, n o. 4, p p. 4 5 9– 4 6 5, A pr. 2 0 0 8.  
[ 2] N. F. Sc h we n zer, H. Sc h mi dt, a n d C. D. Cl a usse n, “ W h ole -b o d y M R/ P E T: 
a p plicati o ns i n a b d o mi nal i ma gi n g,” A b d o m. I m a gi n g , v ol. 3 7, n o. 1, p p. 2 0– 2 8, Fe b. 
2 0 1 2.  
[ 3] G. Dels o et al., “ Perf or m a nce meas ure m e nts of t he Sie me ns m M R i nte grate d w h ole-
b o d y P E T/ M R sca n ner,” J. N ucl. Me d. Off. P u bl. S oc. N uc l. Me d., v ol. 5 2, n o. 1 2, p p. 
1 9 1 4 – 1 9 2 2, Dec. 2 0 1 1.  
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