Randomized Phase II Study of Sorafenib With or Without Everolimus in Patients With Radioactive Iodine Refractory Hurthle Cell Thyroid Cancer
Phase: PHASE2
Conditions: Refractory Hurthle Cell Thyroid Cancer
Sponsor: Alliance for Clinical Trials in Oncology



 
 
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R A N D O MI Z E D  P H A S E  II S T U D Y  O F  S O R A F E NI B  WI T H
 O R  WI T H O U T
 E V E R O LI M U S  I N 
P A TI E N T S  WI T H
 R A DI O A C TI V E  I O DI N E R E F R A C T O R Y  H Ü R T H L E  C E L L  T H Y R OI D  
C A N C E R  
Pre -Re gistr ati o n Eli gi bilit y Criteri a (see Secti o n 3. 2 ) 
Re q uire d I niti al L a b or at or y V al ues   
Ce ntral pat h ol o g y re vie w s u b missi o n (see § 3. 2. 1 ) 
  
Re gistr ati o n Eli gi bilit y Criteri a ( see § 3. 3) 
 A bs ol ute ne utr o p hil   
Meas ura ble disease as defi ne d i n Secti o n 1 1. 0 . 
c o u nt ( A N C)  ≥ 1 5 0 0/ m m 3 
R AI -refract or y disease (see § 3. 3. 2 ) 
Platelet C o u nt  ≥ 1 0 0, 0 0 0/ m m 3 
Pr o gressi ve disease defi ne d b y R E CI S T criteria <  1 4  
Creati ni ne  ≤ 1. 5 m g/ d L O R  
m o nt hs as i n Secti o n 1 1. 4  
Calc. Creati ni ne   
Metastatic disease or l ocall y a d va nce d u nresecta ble  
Cleara nce (see   
disease  
Allia nce we bsite)  ≥ 3 0 m L/ mi n  
Pri or treat me nt: ra diati o n t her a p y >  2 1  da ys of re gistrati o n; 
T otal Bilir u bi n  ≤ 1. 5 x U L N  
R AI t hera p y >  9 0 da ys of re gistrati o n; C he m ot hera p y or  
S G O T( A S T)  ≤ 2. 5 x U L N  
tar gete d t hera p y >  2 1  da ys of re gistrati o n; a n y n u m ber  
Fasti n g Ser u m   
of pri or li nes of t hera p y; N o pri or use of s orafe ni b  
C h olester ol  ≤ 3 0 0 m g/ d L  
or a n m T O R i n hi bit or (see § 3. 3. 5 ) 
Fasti n g Tri gl yceri de  ≤ 2. 5 x U L N  
N o hist or y of maj or s ur ger y  <  2 8 da ys of re gistrati o n  
  
N o hist or y of i ntracra nial brai n metastasis  
  
N o hist or y of <  6 m o nt hs of re gistrati o n: m y ocar dial i nfarcti o n or u nsta ble a n gi na; Ne w Y or k Heart  
Ass ociati o n gra de III or greater c o n gesti ve heart fail ure; cere br o vasc ular acci de nt; gra de 3 or 4 
peri p heral isc he mia or t hr o m b oe m b olic e ve nt (see § 3. 3. 8 ) 
N o hist or y of li ver disease as i n § 3. 3. 9  
N o hist or y of gastr oi ntesti nal fist ula or gastr oi ntesti nal perf orati o n < 9 0 da ys of re gistrati o n  
N o k n o w n hist or y of pr ol o n ge d Q T s y n dr o me  
N o Gra de  3 or 4 h y perte nsi o n t hat ca n n ot be c o ntr olle d wit h me dica ti o n pri or t o re gistrati o n (see§ 3. 3. 1 2 ) 
C o nc o mita nt me dicati o ns: N o c hr o nic c o nc o mita nt treat me nt wit h str o n g i n hi bit ors of C Y P 3 A 4; N o  
c hr o nic c o nc o mita nt treat me nt wit h str o n g C Y P 3 A 4 i n d ucers; P atie nts re q uiri n g a ntic oa g ulati o n  
m ust be o n sta ble d ose of me dicati o n pri or t o re gistrati o n (se e § 3. 3. 1 3 ) 
N ot pre g na nt a n d n ot n ursi n g (see § 3. 3. 1 4 ) 
A ge ≥ 1 8 years  
E C O G P erf or ma nce Stat us ≤ 2  
Eli gi ble p atie nts m ust ha ve hist o pat h ol o gicall y c o nfir me d H ürt hle cell t h yr oi d ca ncer b y c e ntral re vie w  
Sc he m a , 1 C ycle = 2 8 d a ys * * 
P  
 
 
 
R  
 
A R M 1  
 
 
 
 
R   
 
 
A  
 
S or afe ni b  
P D *  
R E - 
 
E ver oli m us  
E  
 
 
 
N  
 
4 0 0 m g p. o., b.i. d.  
 
R E GI S T E R  
 
1 0 m g p. o., q. d  
R   
C o nfir m ati o n  
 
D  
 
 
 
 
 
 
E  
 
of H ü rt hle Cell  
 
O  
 
 
 
 
 
 
G   
T h yr oi d  
 
M  
 
 
 
 
 
 
I 
 
C a ncer  
 
I 
 
A R M 2  
 
 
 
 
S  
 
 
 
Z  
 
S or afe ni b 4 0 0 m g p. o., b.i. d.  
 
 
 
 
T  
 
 
 
E  
 
a n d  
 
 
 
 
E  
 
 
 
 
 
E ver oli m us 5 m g p. o., q. d.  
 
 
 
 
R   
 
 
 
 
 
 
 
 
 
* P D = Pr o gressi o n of Disease  
* * 2 8- da y c ycle f or 1 2 c ycles ( 1 year). Starti n g wit h c ycle 1 3, t he c ycle le n gt h will be 5 6 da ys. 
Treat me nt is t o c o nti n ue u ntil disease pr o gressi o n or u nacce pta ble a d verse e ve nt. 
Patie nts will be f oll o we d f or fi ve years or u ntil deat h, w hic he ver c o mes first.  
Ple ase refer t o t he f ull pr ot oc ol te xt f or a c o m plete descri pti o n of t he eli gi bilit y criteri a a n d 
tre at me nt pl a n. 
 

 
 
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T a ble of C o nte nts  
Secti o n  
Pa ge  
1. 0  IN T R O D U C TI O N  ...................................................................................................................................... 7 
1. 1  
S orafe ni b ...................................................................................................................................... 8 
1. 2  
E ver oli m us ................................................................................................................................... 8 
1. 3  
C o m bi nati o n of s orafe ni b a n d te msir oli m us/e ver oli m us i n ca ncers ot her t ha n t h yr oi d ca ncer ... 9  
1. 4  
H ürt hle cell t h yr oi d ca ncer ........................................................................................................ 1 0  
1. 5  
Cli nical e x perie nce of s orafe ni b a n d e ver oli m us i n R AI -refract or y t h yr oi d ca ncer .................. 1 0 
2. 0  
O B J E C TI V E S  .................................................................................................................................. 1 1 
2. 1  
Pri mar y o bj ecti ve  ....................................................................................................................... 1 1 
2. 2  
Sec o n dar y o bj ecti ve  ................................................................................................................... 1 1 
3. 0  
P A TI E N T S E L E C TI O N  .................................................................................................................... 1 1 
3. 1  
O n - St u d y G ui deli nes ................................................................................................................. 1 1 
3. 2  
Pre -Re gistrati o n Eli gi bilit y Criteria  ........................................................................................... 1 2 
3. 3  
Re gistrati o n Eli gi bilit y Criteria  ................................................................................................. 1 2 
4. 0  
P A TI E N T R E GI S T R A TI O N  .............................................................................................................. 1 4 
4. 1  
C T E P I n vesti gat or Re gistrati o n Pr oce d ures  .............................................................................. 1 4 
4. 2  
C T S U Re gistrati o n Pr oce d ures  .................................................................................................. 1 5 
4. 3  
Patie nt E nr oll me nt  ..................................................................................................................... 1 7 
4. 4  
A 0 9 1 3 0 2 Pre-re gistrati o n a n d Re gistrati o n Re q uire me nts ........................................................ 1 8  
4. 5  
Re -Re gistrati o n at Cr oss o ver  ..................................................................................................... 1 8 
4. 6  
Stratificati o n Fact ors a n d Treat me nt Assi g n me nts  .................................................................... 1 8 
5. 0  
S T U D Y C A L E N D A R  ........................................................................................................................ 1 9 
6. 0  
D A T A A N D S P E CI M E N S U B MI S SI O N  ............................................................................................. 2 1 
6. 1  
Data Q ualit y P ortal  .................................................................................................................... 2 1 
6. 2  
S peci me n c ollecti o n a n d s u b missi o n  ......................................................................................... 2 2 
7. 0  
T R E A T M E N T P L A N /IN T E R V E N TI O N  ............................................................................................. 2 3 
7. 1  
C Y P 3 A 4 I n hi bit ors  .................................................................................................................... 2 4 
7. 2  
C Y P 3 A 4 I n d ucers  ...................................................................................................................... 2 5 
8. 0  
D O S E A N D T R E A T M E N T M O DI FI C A TI O N S  ................................................................................... 2 5 
8. 1  
A ncillar y t hera p y, c o nc o mita nt me dicati o ns, a n d s u p p orti ve care  ............................................ 2 5 
8. 2  
D ose M o dificati o ns f or S orafe ni b  ............................................................................................. 2 7 
8. 3  
D ose M o dificati o ns f or S orafe ni b + E ver oli m us ....................................................................... 2 9  
8. 4  
D ose M o dificati o ns f or E ver oli m us al o ne (after cr oss o ver)  ...................................................... 3 1 
9. 0  
A D V E R S E E V E N T S  ......................................................................................................................... 3 4 
9. 1  
R o uti ne a d verse e ve nt re p orti n g  ................................................................................................ 3 4 
9. 2  
C T C A E R o uti ne St u d y Re p orti n g Re q uire me nts ...................................................................... 3 4  
9. 3  
E x pe dite d A d verse e ve nt re p orti n g ( C T E P -A E R S ) .................................................................. 3 5 
9. 4  
C A E P Rs  ..................................................................................................................................... 3 7 
1 0. 0  
D R U G IN F O R M A TI O N  .................................................................................................................... 4 8 
1 0. 1  
S orafe ni b ( Ne xa var ®, B A Y 4 3- 9 0 0 6) ....................................................................................... 4 8  
1 0. 2  
E ver oli m us ( R A D 0 0 1, Afi nit or ®) ............................................................................................. 5 1  
1 1. 0  
M E A S U R E M E N T O F E F F E C T  ......................................................................................................... 5 5 
1 1. 1  
Sc he d ule of E val uati o ns:  ........................................................................................................... 5 5 
1 1. 2  
Defi niti o ns of Meas ura ble a n d N o n -Meas ura ble Disease  ......................................................... 5 5 
1 1. 3  
G ui deli nes f or E val uati o n of Meas ura ble Disease  ..................................................................... 5 5 

 
 
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1 1. 4  
Meas ure me nt of Treat me nt/I nter ve nti o n Eff ect ........................................................................ 5 7 
1 1. 5  
Defi niti o ns of a nal ysis varia bles  ................................................................................................ 6 0 
1 2. 0  
E N D O F T R E A T M E N T /IN T E R V E N TI O N  ......................................................................................... 6 0 
1 2. 1  
D urati o n of Treat me nt  ............................................................................................................... 6 0 
1 2. 2  
Ma na gi n g i neli gi ble a n d ca ncele d patie nts a n d maj or pr ot oc ol vi olati o ns ................................ 6 0  
1 2. 3  
E xtra or di nar y Me dical Circ u msta nces  ...................................................................................... 6 0 
1 3. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................................................. 6 1 
1 3. 1  
St u d y O ver vie w  ......................................................................................................................... 6 1 
1 3. 2  
Pri mar y E n d p oi nt ....................................................................................................................... 6 1  
1 3. 3  
Sec o n dar y E n d p oi nts ................................................................................................................. 6 1  
1 3. 4  
T otal Sa m ple Size  ...................................................................................................................... 6 2 
1 3. 5  
E x pecte d Accr ual a n d Accr ual D urati o n  ................................................................................... 6 2 
1 3. 6  
A ntici pate d ti me t o st u d y c o m pleti o n  ........................................................................................ 6 2 
1 3. 7  
A E St o p pi n g R ule ...................................................................................................................... 6 2  
1 3. 8  
Accr ual M o nit ori n g St o p pi n g R ule ........................................................................................... 6 2  
1 3. 9  
Pri mar y E n d p oi nt C o m pleti o n Ti me Esti mati o n ( F or cli nicaltrails. g o v re p orti n g) ................... 6 3  
1 3. 1 0  
 Descri pti ve Fact ors  ............................................................................................................... 6 3 
1 3. 1 1  
I ncl usi o n of W o me n a n d Mi n orities ...................................................................................... 6 4 
1 4. 0  
C O R R E L A TI V E A N D C O M P A NI O N S T U DI E S  ................................................................................. 6 5 
1 5. 0  
G E N E R A L R E G U L A T O R Y C O N SI D E R A TI O N S A N D C R E D E N TI A LI N G  .......................................... 6 5 
1 6. 0  
R E F E R E N C E S  ................................................................................................................................. 6 6 
A P P E N DI X I 
R E GI S T R A TI O N F A TI G U E / UNI S C A L E A S S E S S M E N T S  ..................................................... 6 9 
A P P E N DI X  II 
A L LI A N C E A 0 9 1 3 0 2  O P TI O N A L M E DI C A TI O N C A L E N D A R S  ..................................... 7 0 
 
 

 
 
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1. 0  IN T R O D U C TI O N  
T h yr oi d ca ncers of f ollic ular ori gi n c o nsist of se veral hist ol o gic s u bt y pes wit h di verse ge netic a n d 
bi ol o gic  feat ures  t hat  directl y  i nfl ue nce  cli nical  be ha vi or  a n d  res p o nse  t o  s yste matic  t hera pies.  
Pa pillar y t h yr oi d ca ncer ( P T C), re prese n ti n g 8 0 % of all t h yr oi d ca ncers, f ollic ular t h yr oi d ca ncer, 
a n d H ürt hle cell t h yr oi d ca ncer ma ke u p a gr o u p of mali g na ncies k n o w n as differe ntiate d t h yr oi d 
ca ncer ( D T C).  D T Cs ca n pr o gress t o m ore a g gressi ve f or ms of disease cate g orize d pat h ol o gicall y as 
p o orl y  differe ntiate d  t h yr oi d  ca ncer  ( P D T C)  a n d  a na plastic  t h yr oi d  ca ncer  ( A T C),  a  ra pi dl y 
pr o gressi ve  a n d  fatal  disease  wit h  less  t ha n  o ne  year  s ur vi val  i n  m ost  cases.    Me d ullar y  t h yr oi d 
ca ncers are n ot deri ve d fr o m f ollic ular cells, b ut i nstea d t he paraf o llic ular C-cells.  He nce, me d ullar y 
t h yr oi d ca ncer is c o nsi dere d t o be differe nt t ha n D T C. 
T he  i nci de nce  of  ne w t h yr oi d  ca ncers  is  t he  fastest  gr o wi n g  a m o n g  all  ca ncers f or b ot h  me n  a n d 
w o me n  wit h  a n  esti mate d  4 4, 6 7 0  ne w  cases  a ntici pate d  f or  2 0 1 0 1.    1 0-2 0 %  of  t h yr oi d  patie nts 
de vel o p dista nt metastasis 2 ,3.  S ur gical resecti o n of rec urre nt a n d/ or metastatic t u m ors, a d mi nistrati o n 
of ra di oacti ve i o di ne ( R AI), a n d treat me nt wit h e xter nal bea m irr a diati o n are palliati ve t hera pe utic 
o pti o ns f or a s u bset of patie nts.  O nce t u m ors l ose t he a bilit y t o acc u m ulate R AI a n d are n ot a me na ble 
t o  l oc ore gi o nal  treat me nts,  t hera pe utic  o pti o ns  are  q uite  li mite d  as  tra diti o nal  c he m ot hera pe utic 
a ge nts  are  relati ve l y  i neffecti ve4.    D o x or u bici n is  t he  o nl y  F o o d  a n d  Dr u g  A d mi nistrati o n ( F D A) 
a p pr o ve d  dr u g  f or  t he  treat me nt  of  R AI -refract or y  t h yr oi d  ca ncer  base d  o n  li mite d  cli nical  data 
ge nerate d fr o m t he 1 9 8 0s.   
Treat me nt o pti o ns f or patie nts wit h rec urre nt a n d/ or metastatic t h yr oi d carci n o ma n ot a me na ble t o 
c urati ve  s ur ger y  or  ra di oac ti ve  i o di ne  ( R AI)  are  li mite d;  n o  effecti ve  s yste mic  t hera p y  c urre ntl y 
e xists.    D o x or u bici n  is  t he  o nl y  F D A -a p pr o ve d  a ge nt  f or  t he  treat me nt  of  R AI -refract or y  t h yr oi d 
ca ncer, a n d its efficac y is q uesti o na ble.  
T he disc o ver y of e xciti n g i nsi g hts i nt o t he bi ol o g y of t h yr oi d ca ncer, i ncl u di n g t he e xiste nce of t u m or 
i nitiati n g  ge netic  m utati o ns,  has  greatl y  i nf or me d  t he  c o n d uct  a n d  i nter pretati o n  of  cli nical 
i n vesti gati o ns e val uati n g m olec ularl y tar gete d t hera pies f or t h yr oi d ca ncer. T he mit o ge n acti vate d 
pr ote i n ki nase ( M A P K) si g nali n g pat h wa y is fre q ue ntl y acti vate d i n h u ma n mali g na ncies.   M A P K 
acti vati o n  i n  ca ncer  ca n  res ult  fr o m  alterati o ns  i n  u pstrea m  re g ulat ors  s uc h  as  rece pt or  t yr osi ne 
ki nases ( R T Ks), t he R A S o nc o ge ne, a n d t he R A F seri ne/t hre o ni ne ki nase .  Si g nali n g t hr o u g h t hese 
c o m p o ne nts lea ds t o acti vati o n of t he M A P K ki nase M E K a n d s u bse q ue ntl y t he M A P K E R K.  7 0 % 
of  all  P T C  p ossess  m ut uall y  e xcl usi ve  ge netic  alterati o ns  i n  t he  u pstrea m  acti vat ors  of  M A P K, 
i ncl u di n g t he R T Ks R E T (R E arra n ge d d uri n g T ransfecti o n) a n d  N T R K  ( ne ur otr o p hic t yr osi ne ki nase 
rece pt or) as well as t he si g nali n g m olec ules R A S a n d B R A F 8. H o we ver, t here is n o e vi de nce t hat o ver 
acti vati o n of t he M A P K pat h wa y pla ys a si g nifica nt r ole i n H ürt hle cell t h yr oi d ca ncer.  
T h yr oi d  mali g na ncies  are  hi g hl y  vasc ular  t u m ors.    St u dies  e xa mi ni n g  t he  relati o ns hi p  bet wee n 
micr o vessel de nsit y a n d cli nical o utc o mes ha ve de m o nstrate d t hat h y per vasc ular t u m ors c orres p o n d 
t o w orse disease free s ur vi val relati ve t o less vasc ularize d t u m ors9 ,1 0 .  Vasc ular e n d ot helial gr o wt h 
fact or  ( V E G F)  has  bee n  i de ntifie d  as  a  critical  acti vat or  of  a n gi o ge nesis  i n  t he  t u m or 
micr oe n vir o n me nt via sti m ulati o n of t u m or ass ociate d e n d ot helial cell gr o wt h a n d s ur vi val.  Se veral 
is of or ms  of  V E G F  ha ve  bee n  disc o vere d  ( V E G F-A,  B,  C,  D)  as  well  as  se veral  differe nt  V E G F 
s pecific tra ns me m bra ne rece pt or t yr osi ne ki nases ( Flt-1, K D R/ Fl k -1, Flt -4).  M ulti ple st u dies ha ve 
re p orte d hi g her V E G F e x pressi o n i n pri mar y t h yr oi d ca ncer s peci me ns1 1- 1 5 relati ve t o n or mal t h yr oi d 
tiss ue.  B ot h n or mal a n d mali g na nt t h yr oi d cells ca n secrete V E G F i nt o cell c ult ure me di u m 1 4 ,1 6, a n d 
ser u m V E G F le vels are ele vate d i n patie nts wit h rec urre nt or metastatic well differe ntiate d t h yr oi d 
ca ncers relati ve t o n or mal patie nt c o ntr ols 1 7 ,1 8.  Hi g her V E G F e x pressi o n has bee n c orrelate d t o lar ger 
t u m or  size1 1,  hi g her  t u m ori ge nic  p ote ntial1 5,  metastatic  disease1 9,  a n d  s h orter  rec urre nce  free 
s ur vi val 2 0.  F urt her m ore, o vere x pressi o n of V E G F i n p o orl y t u m ori ge nic cell li nes ca n e n ha nce t u m or 
f or mati o n i n n u de mice via i ncrease d t u m or vasc ularit y, w hile s u p pressi o n of V E G F e x pressi o n via 
a n a ntise nse strate g y decrease d t u m ori ge nic p ote ntial i n a n o nc o ge nicall y a g gressi ve t u m or cell li ne 2 1.  

 
 
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T a ke n t o get her, t hese data s u g gest t hat t he hi g h le vels of V E G F o bser ve d i n patie nts a n d t u m ors ma y 
be a bi ol o gicall y rele va nt c o ntri b ut or t o o nc o ge nic pr o gressi o n i n t h yr oi d ca ncer. 
C o nsiste nt  wit h  data  s u g gesti n g a  relia nce  u p o n  V E G F  acti vati o n f or t he  t u m ori ge nic  p he n ot y pe, 
a nti b o dies 1 7 ,2 2 ,2 3 a n d  s mall m olec ules 2 4 ,2 5 tar geti n g  V E G F  si g nali n g  re d uce  t h yr oi d  t u m or  cell li ne 
gr o wt h i n xe n o graft m o dels.  I n a d diti o n t o bl oc ki n g V E G F i n d uce d e n d ot helial cell mit o ge nesis, t he 
a ntit u m or effects of t hese strate gies ma y als o be relate d t o a direct i m pact u p o n t h yr oi d ca ncer cells, 
w hic h  als o  e x press V E G F rece pt ors  F L T -1  a n d  K D R/ F L K - 12 6 ,2 7.    T hese  data  s u p p ort t he cli nical 
h y p ot hesis t hat V E G F tar gete d a ge nts ma y be effecti ve i n t his disease a n d m ost rece nt cli nical st u dies 
ha ve f oc use d o n t his tar get.  
O ver t he past deca de, t here ha ve bee n m ulti ple p hase II st u dies wit h vari o us tar gete d t hera pies s uc h 
as  s orafe ni b 2 8 ,2 9,  a xiti ni b3 0,  s u niti ni b3 1 ,3 2,  a n d  paz o pa ni b3 3 . All  of  t hese  a ge nts  ha ve  s h o w n  s o me 
acti vit y  i n  t he  treat me nt  of  R AI -refract or y  t h yr oi d  ca ncer.  All  of  t hese  st u d y  ha ve  i ncl u de d  all 
s u bt y pes of D T C, a n d se veral ha ve re p orte d t he res ults f or f ollic ular a n d H ürt hle cell t h yr oi d ca ncers 
as a si n gle gr o u p i nstea d of se parate e ntities. H o we ver, rece nt w or k at Me m orial Sl oa n -Ketteri n g 
Ca ncer Ce nter ( M S K C C) e val uati n g t he ge n o mics of H ürt hle cell t h yr oi d ca ncer has s u g geste d t hat 
it is a c o m pletel y se parate e ntit y3 4.  
W hile t he st u dies of t hese tar gete d t hera pies were all i n “ra di oacti ve i o di ne refract or y” t h yr oi d ca ncer, 
t he y li kel y re prese nt a heter o ge n o us p o p ulati o n. M ost earl y st u dies were i nc o nsiste nt i n eit her t heir 
defi niti o n of w hat ma ke s a t h yr oi d ca ncer refract or y t o ra di oacti ve i o di ne or w hat t y pe of pr o gressi o n, 
if a n y, w o ul d be re q uire d f or st u d y e ntr y. T he earliest st u d y wit h a xiti ni b ha d a res p o nse rate of 3 0 % 
wit h a me dia n pr o gressi o n -free s ur vi val of 1 8. 1 m o nt hs3 0. Paz o pa ni b was re p orte d t o ha ve a res p o nse 
rate of 4 9 % wit h a me dia n pr o gressi o n-free s ur vi val of 1 1. 7 m o nt hs3 3. 
1. 1 
S or af e ni b  
S orafe ni b has bee n t he best st u die d a ge nt i n t his disease. S orafe ni b is a n oral rece pt or ki nase 
i n hi bit or t hat has m ulti ple tar gets i ncl u de R A F, V E G F R 1 -3, a n d platelet -deri ve d gr o wt h fact or 
rece pt or- β3 5. Partial res p o nse rates ha ve bee n re p orte d t o be bet wee n 1 1. 5 %2 9 a n d 2 3 % 2 8. At t his 
p oi nt i n ti me, s orafe ni b is t he rec o m me n d treat me nt f or R AI -refract or y t h yr oi d ca ncer b y t he 
Nati o nal  C o m pre he nsi ve  Ca ncer  Net w or k  g ui deli nes 
  a n d  is  c o m pe n di u m 
a p pr o ve d f or t his i n dicati o n. A p hase III st u d y c o m pari n g s orafe ni b t o place b o (t he D E CI SI O N 
trial) has bee n c o m plete d a n d it has bee n a n n o u nce d t hat it met its pri mar y o bj ecti ve wit h a n 
i m pr o ve me nt  i n  pr o gressi o n-free  s ur vi val  of  5  m o nt hs  c o m pare d  t o  place b o.  I n  a d diti o n,  it 
s h o we d  t hat  s orafe ni b  ha d  a  partial  res p o nse  rate  of  o nl y  1 2. 2 %  wit h  a  disease  c o ntr ol  rate 
(c o m plete/ partial resp o nse or sta ble disease rate f or > 6 m o nt hs) of 5 4. 1 % c o m pare d t o 3 3. 8 % 
f or  place b o.  It  is  n ota ble  t hat  1 8. 8 %  of  patie nts  w h o  recei ve d  s orafe ni b  disc o nti n ue d  d ue  t o 
a d verse  e ve nts 4 0.  I n  a d diti o n,  7 7 %  of  t he  patie nts  o n  t he  s orafe ni b  ar m  re q uire d  a  d ose 
m o dificati o n d ue t o a n a d verse e ve nt, alt h o u g h 3 0. 1 % i n t he place b o ar m re q uire d t he sa me. 
Des pite t he acti vit y see n wit h s orafe ni b i n t h yr oi d ca ncer a n d ot her t y pes of ca ncers, it is n ot 
clear  w hic h  of t he  m olec ular  tar gets are res p o nsi ble  f or  t he  a ntica ncer  effects  i n  eac h  t u m or 
m o del.  F urt her m ore,  b ot h  p hase  II  st u dies  wit h  s orafe ni b  i ncl u de d  s u bjects  wit h  all  t h yr oi d 
ca ncer cell t y pes (i.e., pa pillar y, f ollic ular, H ürt hle, a n d p o orl y differe ntiate d/a na plastic).  
D ue t o t his data, Nati o nal C o m pre he nsi ve  Ca ncer Net w or k ( N C C N) g ui deli nes f or t he treat me nt 
of t h yr oi d ca ncer s pecificall y states t hat s orafe ni b is a n acce pta ble treat me nt f or R AI -refract or y 
t h yr oi d  ca ncer  (c o m pe n di u m  a p pr o ve d)  a n d  is  c urre ntl y  t he  sta n dar d  of  care.  T he  F D A  has 
gra nte d s orafe ni b  pri orit y re vie w f or t he treat me nt of R AI -refract or y t h yr oi d ca ncer. 
1. 2  
E ver oli m us 
E ver oli m us  is  a n  orall y  a vaila ble  i n hi bit or  of  t he  ma m malia n  tar get  of  ra pa m yci n  ( m T O R). 
E ver oli m us is a macr oli de deri vati ve of ra pa m yci n, a nat ural c o m p o u n d pr o d uce d b y b acteria. 

 
 
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E ver oli m us has bee n f or m ulate d f or oral a d mi nistrati o n, a n d is bei n g de vel o pe d as a n a ntica ncer 
a ge nt  a n d  a n  i m m u n os u p pressa nt.  E ver oli m us  selecti vel y  i n hi bits  m T O R,  a n  e v ol uti o naril y -
c o nser ve d i ntracell ular seri ne/t hre o ni ne ki nase i m plicate d i n t he c o ntr ol of pr otei n tra nslati o n 1 ,2.  
E ver oli m us  bi n ds  t he  i ntracell ular  1 2 -kil o dalt o n  i m m u n o p hili n  F K 5 0 6 -bi n di n g  pr otei n 
( F K B P 1 2) wit h hi g h affi nit y; t he res ulti n g F K B P 1 2/e ver oli m us c o m ple x t he n i n hi bits m T O R 
ki nase  acti vit y.  P h os p hati d yli n osit ol  3 -ki nase  ( PI 3 -K)  a n d  A kt  are  well  descri be d  u pstrea m 
re g ulat ors  of  m T O R  acti vit y,  alt h o u g h  ot her  mec ha nis ms  of  m T O R  acti vati o n  ha ve  bee n 
d escri be d. T w o well -c haracterize d p h os p h or ylati o n tar gets of m T O R are eI F 4 E -bi n di n g pr otei n 
( 4 E- B P 1) a n d p 7 0 S 6 ki nase 1 ( S 6 K 1), w hic h re g ulate tra nslati o n of pr otei ns re q uire d f or G 1-S 
p hase pr o gressi o n i n t he cell c ycle. T O R i n hi bit ors s uc h as e ver oli m us us uall y are c yt ostatic 
w he n a d mi nistere d al o ne, alt h o u g h a nti -pr oliferati ve a n d pr o -a p o pt otic effects als o ha ve bee n 
descri be d 1 ,2. 
At  wee kl y  a n d  dail y  sc he d ules  a n d  at  vari o us  d oses  e x pl ore d,  e ver oli m us  is  ge nerall y  well 
t olerate d. T he m ost fre q ue nt a d verse e ve nts (ras h, m uc ositis, fati g ue a n d hea dac he) ass ociate d 
wit h e ver oli m us t hera p y are ma na gea ble. N o n -i nfecti o us p ne u m o nitis has bee n re p orte d wit h 
m T O R i n hi bit ors b ut is c o m m o nl y l o w -gra de a n d re versi ble.  
T he i nitial rati o nale t o e val uati n g e ver oli m us, a n m T O R i n hi bit or, i n t h yr oi d ca ncer is t he belief 
t hat i n t h yr oi d cells, m T O R C 1 acti vit y is re q uire d f or t he pr oliferati ve effects of T S H i n vitr o 
a n d i n vi v o. U n p u blis he d w or k fr o m t he Fa gi n la b at Me m orial Sl oa n -Ketteri n g Ca ncer Ce nter 
s h o ws  t hat  m T O R C 1  is  als o  re q uire d  f or  t he  gr o wt h  pr o m oti n g  effects  of  t he  o nc o pr otei ns 
R E T/ P T C, R A S a n d B R A F i n rat t h yr oi d P C C L 3 cells. Ra pa m yci n is t he pr ot ot y pical m T O R C 1 
i n hi bit or,  as  it  i nterferes  wit h  t he  ass ociati o n  bet wee n  m T O R  a n d  Ra pt or.  Ra pa m yci n  has 
si g nifica nt  gr o wt h  i n hi bit or y  effects  i n  h u ma n  cell  li nes  har b ori n g  e n d o ge n o us  m utati o ns  of 
t hese o nc o pr otei ns. F urt her m ore, C o w de n’s s y n dr o me, w hic h is ca use d b y ger mli ne m utati o ns 
i n P T E N , is ass ociate d wit h a 1 0 % lifeti me ris k of de vel o pi n g t h yr oi d ca ncer. T he wil d-t y pe 
allele  is  ofte n  i nacti vate d  t hr o u g h  e pi ge netic  e ve nts  later  i n  t u m or  pr o gressi o n.  I n  a d diti o n, 
P T E N deficie nc y i n m o use m o dels is ass ociate d wit h f ollic ular t h yr oi d ca ncer a g gressi ve ness 3 6. 
1. 3 
C o m bi n ati o n of s or afe ni b a n d te msir oli m us/e ver oli m us i n c a ncers ot her t h a n t h yr oi d 
c a ncer 
Precli nical  e vi de nce  s u g gests  s y ner g y  w he n  b ot h  t he  M A P K a n d  PI 3 K -m T O R  pat h wa ys  are 
i n hi bite d3.  T he  c o m bi nati o n  of  s orafe ni b wit h  m T O R C 1  i n hi bit ors  i ncreases  cell  deat h  i n 
mela n o mas, w here B R A F  m utati o ns are partic ularl y c o m m o n 4, a n d t he c o m bi nati o n of s orafe ni b 
a n d te msir oli m us was e val uate d i n t he treat me nt of mela n o ma i n a lar ge ra n d o mize d p hase II 
st u d y t hr o u g h t he S o ut h west O nc ol o g y Gr o u p 4 4 a n d e val uate d i n t he treat me nt of ki d ne y ca n cer 
( b y t he Easter n C o o perati ve O nc ol o g y Gr o u p). It is c urre ntl y bei n g e val uate d i n t he treat me nt 
of  gli o blast o ma  m ultif or me  ( N ort h  Ce ntral  Ca ncer  Treat me nt  Gr o u p).  I n  t he  p hase  I  st u d y 
e val uati n g s orafe ni b a n d te msir oli m us (a n ot her m T O R i n hi bit or) 5, a partial res p o nse was see n 
i n  a  s u bject  wit h  pa pillar y  t h yr oi d  ca ncer. T he  c o m bi nati o n  of  s orafe ni b  a n d  e ver oli m us  has 
bee n e val uate d i n a p hase I st u d y f or ki d ne y ca ncer, wit h t he rec o m me n de d d ose of s orafe ni b 
4 0 0 m g t wice a da y wit h e ver oli m us 5 m g dail y 6. I n t he p hase I st u d y, treat me nt-r elate d e ve nts 
t hat occ urre d greater t ha n 2 0 % of t he ti me i ncl u de d diarr hea, ha n d-f o ot s y n dr o me, h y perte nsi o n, 
h y p o p h os p hate mia, h y p ot h yr oi dis m, a n d ras h. P har mac o ki netic data s u g geste d t hat e ver oli m us 
ha d  n o  effects  o n  s orafe ni b  bl o o d  le vels.  T he  m ost  c o m m o n  gra de  3  t o xicit y  was 
h y p o p h os p hate mia  ( 4 5 %)  as  well  as  gra de  3  diarr hea  ( 1 0 %).  At  t he  M T D,  7 5 %  of  p atie nts 
e ve nt uall y  re q uire d  d ose  re d ucti o n  (alt h o u g h  t his  perce nta ge  is  si milar  t o  w hat  is  see n  wit h 
s orafe ni b al o ne i n t he D E CI SI O N st u d y). 

 
 
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1. 4  
H ü rt hle cell t h yr oi d c a ncer  
H ürt hle  cell  t h yr oi d  ca ncers  i n  ge neral  ha ve  n ot  bee n  as  well  st u die d  as  ot her  cel l  t y pes. 
E val uati o n of t he S E E R data base c o nfir ms t hat ca ncer -s pecific s ur vi val is w orse i n t his s u b gr o u p 
c o m pare d  t o  ot her  t h yr oi d  ca ncers 5.  It  acc o u nts  f or  a b o ut  4 %  of  all  t h yr oi d  ca ncers. 
C haracteristicall y,  t he y  are  lar ge  cells  wit h  h y perc hr o matic  n uclei  a n d  a n  a b u n da nt  gra n ular 
c yt o plas m c o ntai ni n g lar ge n u m bers of mit oc h o n dria. 
I n ge neral, H ürt hle cell t h yr oi d ca ncers us uall y prese nt wit h w orse pr o g n ostic feat ures ( ol der 
a ge, lar ger pri mar y t u m ors) t ha n ot her D T C’s 6. C o m pare d t o ot her differe ntiate d t h yr oi d t u m ors, 
H ürt hle cell t h yr oi d ca ncers te n d t o be less res p o nsi ve t o R AI a n d m ore t y picall y ha ve dista nt 
metastases  a n d  a  w orse  s ur vi val
7. H ürt hle  cell  t h yr oi d  ca ncer  ha ve  ofte n  bee n  c o nsi dere d  a 
varia nt of f ollic ular t h yr oi d ca ncer, b ut a n e xte nsi ve a nal ysis of m utati o ns i n D T C at Me m orial 
Sl oa n -Ketteri n g Ca ncer Ce nter ha ve s u g geste d t hat H ürt hle cell t h yr oi d ca ncer is a ver y se parate 
e ntity 4 2. A t otal of 2 7 cases wit h eit her Hü rt hle cell a de n o ma, mi ni mall y i n vasi ve H ürt hle cell 
t h yr oi d  ca ncer  or  wi del y  i n vasi ve  H ürt hle  cell  t h yr oi d  ca ncer  were  e val uate d  f or  s o matic 
m utati o ns. O nc o mi ne a nal ysis of t he ge nes i n t he wi del y i n vasi ve gr o u p s h o w e d t hat B-cate ni n 
is i nti matel y i n v ol ve d i n t he pr ocess as well as t he prese nce of a te msir oli m us-se nsiti ve si g nat ure 
( ge nes relate d t o m T O R i n hi biti o n se nsiti vit y). 
W hile st u dies of D T C ma y i ncl u de H ürt hle cell t h yr oi d ca ncers, t o date t here d oes n ot see m  t o 
be a si n gle st u d y t hat s pecificall y i ncl u des o nl y H ürt hle cell s u bt y pe. N ota bl y, i n t he O hi o State 
p hase II st u d y wit h s orafe ni b f or R AI-refract or y t h yr oi d ca ncer, all of t he res p o nses were i n t he 
pa pillar y  s u b gr o u p  wit h  n o  partial  res p o nses  i n  t he  f ol lic ular/ Hü rt hle  cell  s u b gr o u ps. 
F urt her m ore,  t he  me dia n  pr o gressi o n -free  s ur vi val  i n  t his  latter  gr o u p  was  o nl y  4. 5  m o nt hs 
(c o m pare d t o 1 6 m o nt hs i n t he treat me nt- naï ve pa pillar y t h yr oi d ca ncer s u b gr o u p)2 9. 
1. 5 
Cli nic al e x perie nce of s or af e ni b a n d e ver oli m us i n R AI -refr act or y t h yr oi d c a ncer  
We ha ve rece ntl y c o m plete d a p hase II st u d y e val uati n g t he efficac y of s orafe ni b a n d e ver oli m us 
i n R AI-refract or y t h yr oi d ca ncer. T he p hase II st u d y use d t he rec o m me n de d d ose of s orafeni b 
4 0 0 m g t wice a da y wit h e ver oli m us 5 m g dail y 3 7. I n t he p hase II st u d y of t h yr oi d ca ncer at 
Me m orial Sl oa n -Ketteri n g Ca ncer Ce nter, a t otal of 4 1 patie nts were e nr olle d o nt o t he st u d y of 
w hic h 3 6 are c urre ntl y eli gi ble f or e val uati o n of t he pri mar y e n d p oi nt of res p o nse. Data u p date d 
i n Se pte m ber of 2 0 1 3 ( u n p u blis he d) n o w s h o ws ni ne of t hese patie nts ha d Hü rt hle cell R AI-
refract or y t h yr oi d ca ncer. Of t hese 9 patie nts, 7 ( 7 8 %) ha d eit her a c o nfir me d or u nc o nfir me d 
partial res p o nse a n d 2 ha d sta ble disease ( b ot h patie nts wit h sta ble disease ha ve re mai ne d o n 
st u d y f or greater t ha n 1 year). O nl y 2 of t he 9 patie nts ca me off st u d y i n less t ha n a year ( o ne 
f or pr o gressi o n of disease a n d o ne f or pr ot oc ol-defi ne d t o xicit y). As of Se pte m ber 2 0 1 3 , t he 
me dia n ti me o n st u d y has bee n 5 0 0 da ys (ra n gi n g fr o m 7 6 t o 7 9 1 da ys). B ot h t h e res p o nse rate 
a n d t he ti me o n st u d y are i m pressi vel y hi g her t ha n re p orte d i n t he O hi o State st u d y (i.e., 0 % 
partial  res p o nse  rate;  me dia n  pr o gressi o n  free  s ur vi val  of  4. 5  m o nt hs).  T he  reas o n  f or  t his 
i ncrease i n res p o nse wit h t he a d diti o n of e ver oli m us to s orafe ni b i n t he H ü rt hle Cell s u b gr o u p 
has yet t o be el uci date d, a n d f urt her i n vesti gati o ns are o n g oi n g at Me m orial Sl oa n - Ketteri n g 
Ca ncer Ce nter.  
Base d o n t hese i m pressi ve res ults i n a si n gle ar m p hase II st u d y, al o n g wit h t he lac k of pr o ve n 
efficaci o us  a ge nts  f or  t he  treat me nt  of  Hü rt hle  cell  R AI-refract or y  t h yr oi d  ca ncer,  we  ha ve 
deci de d t o pr ocee d wit h a ra n d o mize d p hase II st u d y i n t his u nc o m m o n ca ncer. 

 
 
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2. 0  
O B J E C TI V E S  
2. 1  
P ri m ar y o bjecti ve  
T o c o m pare t he pr o gressi o n -free s ur vi val ( P F S) bet wee n s orafe ni b a n d e ver oli m us vs. s orafe ni b 
al o ne i n patie nts wit h ra di oacti ve i o di ne refract or y H ürt hle cell t h yr oi d ca ncer  
2. 2 
Sec o n d ar y o bjecti ve  
T o c o m pare t he c o nfir me d res p o nse rate, o verall s ur vi val ( O S), a n d a d verse e ve nt rates bet wee n 
s orafe ni b a n d e ver oli m us vs. s orafe ni b al o ne. 
3. 0  
P A TI E N T S E L E C TI O N  
F or  q uesti o ns re gar di n g  eli gi bilit y  criteria,  see t he  C o ntact  I nf or mati o n  pa ge.  Please  n ote  t hat  t he 
St u d y C hair ca n n ot gra nt wai vers t o eli gi bilit y re q uire me nts.  
3. 1 
O n -St u d y G ui deli nes  
T his cli nical tria l ca n f ulfill its o bjecti ves o nl y if patie nts a p pr o priate f or t his trial are e nr olle d. 
All  rele va nt  me dical  a n d  ot her  c o nsi derati o ns  s h o ul d  be  ta ke n  i nt o  acc o u nt  w he n  deci di n g 
w het her t his pr ot oc ol is a p pr o priate f or a partic ular patie nt. P h ysicia ns s h o ul d  c o nsi der t he ris ks 
a n d  be nefits  of  a n y  t hera p y,  a n d  t heref ore  o nl y  e nr oll  patie nts  f or  w h o m  t his  treat me nt  is 
a p pr o priate.  
Alt h o u g h t he y will n ot be c o nsi dere d f or mal eli gi bilit y (e xcl usi o n) criteria, p h ysicia ns s h o ul d 
rec o g nize t hat t he f oll o wi n g ma y seri o usl y i ncrease t he ris k t o t he patie nt e nteri n g t his pr ot oc ol: 
Liste d bel o w are e xa m ples o nl y, a n d s h o ul d be m o difie d b y t he st u d y c hair as necessar y. 
N O T E t hat t hese g ui deli nes are p hrase d i n t he ne gati ve; i.e., t hese are p ote ntial partici pa nts 
w h o s h o ul d n ot  be e nr olle d t o t he st u d y.  
• 
Ps yc hiatric ill ness w hic h w o ul d pre ve nt t he patie nt fr o m gi vi n g i nf or me d c o nse nt.  
• 
Me dical  c o n diti o n  s uc h  as  u nc o ntr olle d  i nfecti o n  (i ncl u di n g  HI V),  u nc o ntr olle d  dia betes 
mellit us or car diac disease w hic h, i n t he o pi ni o n of t he treati n g p h ysicia n, w o ul d ma ke t his 
pr ot oc ol u nreas o na bl y hazar d o us f or t he patie nt. 
• 
Patie nts  wit h  a  “c urre ntl y  acti ve”  sec o n d  mali g na nc y  ot her  t ha n  n o n -mela n o ma  s ki n 
ca ncers. Patie nts are n ot c o nsi dere d t o ha ve a “c urre ntl y acti ve” mali g na nc y if t he y ha ve 
c o m plete d t hera p y a n d are free of disease f or ≥ 3 year s. 
• 
Patie nts w h o ca n n ot s wall o w oral f or m ulati o ns of t he a ge nt(s).  
• 
M o derate  C Y P  3 A 4  i n hi bit ors,  m o derate  P g P  i n hi bit ors , a n d  dr u gs  t hat  are 
meta b olize d/eli mi nate d  b y  U G T 1 A 1  pat h w a y  are  t o be  use d  wit h  ca uti o n  w hile  o n 
st u d y. 
I n a d diti o n: 
• 
W o me n of c hil d- beari n g p ote ntial ( W O C B P). Defi ne d as all w o me n p h ysi ol o gicall y ca pa ble 
of bec o mi n g pre g na nt, a n d me n of re pr o d ucti ve p ote ntial s h o ul d a gree t o use a n a p pr o priate 
met h o d of birt h c o ntr ol t hr o u g h o ut t heir partici pati o n i n t his st u d y d ue t o t he terat o ge nic  
p ote ntial of t he t hera p y utilize d i n t his trial . Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de 
a c o m bi nati o n of a n y t w o of t he f oll o wi n g (a + b, a +c, or b +c). Ot her a p pr o priate met h o ds of 
birt h c o ntr ol are d or e: 
 
a.  Use of oral, i nj ecte d or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n or; 
b. Place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m (I U S);  

 
 
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c. Barrier met h o ds of c o ntrace pti o n: c o n d o m or occl usi ve ca p ( dia p hra g m or cer vical/ va ult 
ca ps) wit h s per mici dal f oa m/ gel/fil m/crea m/ va gi nal s u p p osit or y;  
d.  T otal a bsti ne nce or; 
e. Male/fe male sterilizati o n.  
3. 2 
P re -Re gistr ati o n Eli gi bilit y Criteri a  
P re -re gistr ati o n pr oce d ures are f o u n d i n Secti o n 4. 1 . 
Use t he s paces pr o vi de d t o c o nfir m a patie nt’s eli gi bilit y b y i n dicati n g Yes or N o as a p pr o priate. 
It is n ot re q uire d t o c o m plete or s u b mit t he f oll o wi n g pa ge(s). 
W he n  calc ulati n g  da ys  of  tests  a n d  meas ure me nts,  t he  da y  a  test  or  meas ure me nt  is  d o ne  is 
c o nsi dere d Da y 0 . T heref ore, if a test were d o ne o n a M o n da y, t he M o n da y f o ur wee ks later 
w o ul d be c o nsi dere d Da y 2 8. 
A fe male of c hil d beari n g p ote ntial is a se x uall y mat ure fe male w h o: 1) has n ot u n der g o ne a 
h ysterect o m y or bilateral o o p h orect o m y; or 2) has n ot bee n nat urall y p ost me n o pa usal f or at least 
1 2  c o nsec uti ve  m o nt hs  (i.e.,  has  ha d  me nses  at  a n y  ti me  i n  t he  prece di n g  1 2  c o nsec uti ve 
m o nt hs). 
_ _ _  
3. 2. 1  
Ce ntr al p at h ol o g y re vie w s u b missi o n  
Patie nts  m ust  ha ve 1 0 re prese ntati ve H & E  stai ne d  t h yr oi d  tiss ue  sli des O R  t u m or  bl oc k 
a vaila ble  f or  s u b missi o n  t o  ce ntral  pat h ol o g y  re vie w.  T his  re vie w  is  ma n dat or y  pri or  t o 
re gistrati o n t o c o nfir m eli gi bilit y. If 1 0 H & E sli des are n ot a vaila ble, 5 H & E sli des will be 
acce pta ble wit h t he c o nse nt of t he PI ( Dr. S her ma n) alt h o u g h a n a d diti o nal  5 sli des ma y still 
nee d  t o  be  re q ueste d  if  t he  ce ntral  pat h ol o gist  re q uires  it  after  re vie wi n g  t he  sli des. See 
Secti o n 4. 4  f or details o n sli de/ bl oc k s u b missi o n.  
3. 3  
Re gistr ati o n Eli gi bilit y Criteri a  
_ _ _  
3. 3. 1 
Me as ur a ble dise ase as defi ne d i n Secti o n 1 1. 0 . 
Patie nts m ust ha ve meas ura ble disease b y R E CI S T criteria, defi ne d as at least o ne lesi o n 
t hat ca n be acc uratel y meas ure d i n at least o ne di me nsi o n (l o n gest dia meter t o be rec or de d) 
as ≥ 2 0 m m wit h c o n ve nti o nal tec h ni q ues or as ≥ 1 0 m m wit h s piral C T sca n; C T m ust be 
perf or me d wit hi n 2 8 da ys of re gistrati o n. 
_ _ _  
3. 3. 2 
R AI -refr act or y dise ase defi ne d as 1 or m ore of t he f oll o wi n g:  
• Patie nts w h o ha ve recei ve d greater t ha n 6 0 0 m Ci of ra di oa cti ve i o di ne i n t heir lifeti me 
O R  
• R AI -a vi d metastatic lesi o n w hic h re mai ne d sta ble i n size or pr o gresse d des pite R AI 
treat me nt wit hi n 9 m o nt hs of R AI treat me nt O R  
• 1 0 % or m ore i ncrease i n ser u m t h yr o gl o b uli n ( o n T S H -s u p pressi o n) wit hi n 9 m o nt hs 
of R AI treat me nt O R   
• I n de x metastatic lesi o n n o n- R AI a vi d o n a dia g n ostic R AI sca n O R  
• Prese nce of F D G a vi d metastatic lesi o ns o n P E T/ C T sca n ( S U V ma x > 5 of a n y si n gle 
lesi o n) 
 
3. 3. 3  P r o gressi ve dise ase  defi ne d b y R E CI S T criteria < 1 4 m o nt hs  (as i n Secti o n 1 1. 4 ).  
  
3. 3. 4 P ati e nts m ust h a ve met ast atic dise ase or l oc all y a d v a nce d u nresect a ble dise ase.  
  
3. 3. 5 P ri o r Tre at me nt  

 
 
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• Patie nts ma y ha ve recei ve d pri or ra diati o n t hera p y t o i n de x lesi o ns ≥ 2 1da ys pri or t o 
re gistrati o n o n t his pr ot oc ol if t here has bee n d oc u me nte d pr o gressi o n b y R E CI S T 
criteria. Pri or ra diati o n t hera p y t o t he n o n -i n de x lesi o ns is all o we d if ≥ 2 1 da ys pri or 
t o re gistrati o n o n t his pr ot oc ol. 
• Pri or R AI t hera p y is all o we d if > 9 0 da ys pri or t o re gistrati o n o n t his pr ot oc ol a n d 
e vi de nce  of  pr o gressi o n  (as  defi ne d  a b o ve)  has  bee n d oc u me nte d  i n  t he i nteri m  (a 
dia g n ostic st u d y usi n g < 1 0 m Ci of R AI is n ot c o nsi dere d R AI t hera p y). 
• Pri or c he m ot hera p y  or tar gete d t hera p y  is all o we d if ≥ 2 1 da ys pri or t o re gistrati o n o n 
t his pr ot oc ol. 
• Patie nt ma y ha ve recei ve d a n y n u m ber of pri or li nes of t hera p y.  
• N o  pri or  use  of  s orafe ni b  or  a n  m T O R  (i ncl u di n g  PI 3 k  or  A K T)  i n hi bit or  f or  t he 
treat me nt of t h yr oi d ca ncer. 
_ _ _ 
3. 3. 6  N o hist or y of m aj or s ur ger y  < 2 8 da ys of re gistrati o n.  
_ _ _ 
3. 3. 7  N o hist or y of i ntr acr a ni al br ai n met ast asis.  
_ _ _ 
3. 3. 8  C ar di o v asc ul ar dise ase : N o hist or y of a n y of t he f oll o wi n g < 6 m o nt hs of re gistr ati o n: 
• M y ocar dial i nfarcti o n or u nsta ble a n gi na  
• Ne w Y or k Heart Ass ociati o n gra de III or greater c o n gesti ve heart fail ure  
• Cere br o vasc ular acci de nt  
•  Gra de 3 or 4 peri p heral isc he mia. 
•  Gra de 3 or 4 t hr o m b oe m b olic e ve nt 
_ _ _ 
3. 3. 9  Li ver dise ase: N o hist or y of t he f oll o wi n g: 
• C hil d P u g h Class B or C li ver disease  
• “ C hr o nic acti ve” he patitis defi ne d as:  
1. 
H Bs A g is p ositi ve > 6 m o nt hs 
2. 
Ser u m H B V D N A 2 0, 0 0 0 I U/ ml ( 1 0 5c o pies/ ml), l o wer val ues 2, 0 0 0 -2 0, 0 0 0 I U/ ml 
( 1 0 4- 1 0 5 c o pies/ ml) are ofte n see n i n H Be A g -ne gati ve c hr o nic he patitis B  
3. 
Persiste nt or i nter mitte nt ele vati o n i n A L T/ A S T le vels  
4. 
Li ver  bi o ps y  s h o wi n g  c hr o nic  he patitis  
wit h  
m o derate  or  se vere 
necr oi n ﬂa m mati o n  
_ _ _ 
3. 3. 1 0  N o  hist or y  of  g astr oi ntesti n al  fist ul a  or  g astr oi ntesti n al  perf or ati o n  <  9 0  da ys  of 
re gistrati o n. 
_ _ _ 
3. 3. 1 1 N o k n o w n hist or y of pr ol o n ge d Q T s y n dr o me . 
_ _ _ 
3. 3. 1 2 N o Gr a de 3 or 4 h y perte nsi o n  (s yst olic B P > 1 6 0 a n d/ or diast olic B P > 1 0 0) t hat ca n n ot be 
c o ntr olle d wit h me dicati o n pri or t o re gistrati o n. 

 
 
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3. 3. 1 3 C o nc o mit a nt Me dic ati o ns:  
• C hr o nic c o nc o mit a nt tre at me nt wit h str o n g i n hi bit ors of C Y P 3 A 4 is n ot all o we d 
o n t his st u d y. Patie nts o n str o n g C Y P 3 A 4 i n hi bit ors m ust disc o nti n ue t he dr u g f or 1 4 
da ys pri or t o re gistrati o n o n t he st u d y. See secti o n 7. 1 f or m ore i nf or mati o n. 
• C hr o nic  c o nc o mit a nt  tre at me nt  wit h  str o n g  C Y P 3 A 4  i n d ucers  is  n ot  all o we d. 
Patie nts m ust disc o nti n ue t he dr u g 1 4 da ys pri or t o t he start of st u d y treat me nt. See 
secti o n 7. 2 f or m ore i nf or mati o n.  
• P atie nts  re q uiri n g  a ntic o a g ul ati o n m ust  be  o n  sta ble  d ose  of  me dicati o n  pri or  t o 
re gistrati o n. 
_ _ _   
3. 3. 1 4 N ot pre g n a nt a n d n ot n ursi n g, beca use t his st u d y i n v ol ves a n i n vesti gati o nal a ge nt w h ose 
ge n ot o xic,  m uta ge nic  a n d  terat o ge nic  effects  o n  t he de vel o pi n g  fet us  a n d  ne w b or n  are 
u n k n o w n. 
T heref ore, f or w o me n of c hil d beari n g p ote ntial o nl y, a ne gati ve  ser u m pre g na nc y test 
d o ne ≤ 7 da ys pri or t o re gistrati o n is re q uire d. 
_ _ _  
3. 3. 1 5 A ge ≥ 1 8 ye ars  
  
_ _ _ 
3. 3. 1 6 E C O G P erf or m a nce St at us ≤ 2. 
 
  
  
3. 3. 1 7 D oc u me nt ati o n of Dise ase:  
Hist ol o gic  D oc u me nt ati o n:  Eli gi ble  p atie nts  m ust  ha ve  hist o pat h ol o gicall y  c o nfir me d 
H ürt hle cell t h yr oi d ca ncer b y ce ntral re vie w.  
_ _ _  
3. 3. 1 8 Re q uire d I niti al L a b or at or y V al ues:  
A bs ol ute Ne utr o p hil C o u nt ( A N C)  
≥ 1, 5 0 0/ m m 3  
Platelet C o u nt  
≥ 1 0 0, 0 0 0/ m m 3 
Creati ni ne  
≤ 1. 5 m g/ d L O R  
Calc. Creati ni ne Cleara nce  
≥ 3 0 m L/ mi n  
T otal Bilir u bi n  
≤ 1. 5 x u p per li mits of n or mal ( U L N)  
S G O T ( A S T)  
≤ 2. 5 x u p per U L N  
Fasti n g Ser u m C h olester ol  
≤ 3 0 0 m g/ d L  
Fasti n g Tri gl yceri de  
≤ 2. 5 x U L N  
 
4. 0  
P A TI E N T R E GI S T R A TI O N  
4. 1 
C T E P I n vesti g at or Re gistr ati o n P r oce d ures  
F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns a n d Nati o nal Ca ncer I nstit ute ( N CI) p olic y 
re q uire  all  i n di vi d uals  c o ntri b uti n g  t o  N CI-s p o ns ore d  trials  t o  re gister  a n d  t o  re ne w  t heir 
registrati o n  a n n uall y.  T o  re gister,  all  i n di vi d uals  m ust  o btai n  a  Ca ncer  T hera p y  E val uati o n 
Pr o gra m  
( C T E P)  
I de ntit y  
a n d  
Access  
Ma na ge me nt  
(I A M)  
acc o u nt  
at 
  I n  a d diti o n,  pers o ns  wit h  a  re gistrati o n  t y pe  of  I n vesti gat or 
(I V R), N o n -P h ysicia n  I n vesti gat or  ( N PI V R),  or  Ass ociate  Pl us  ( A P)  (i.e.,  cli nical  site  staff 
re q uiri n g write access t o O P E N, Ra ve, or acti n g as a pri mar y site c o ntact) m ust c o m plete t heir 
a n n ual re gistrati o n usi n g C T E P’s we b -base d Re gistrati o n a n d Cre de ntial Re p o sit or y ( R C R) at 
    
R C R utilizes fi ve pers o n re gistrati o n t y pes.  
• 
I V R — M D, D O, or i nter nati o nal e q ui vale nt; 

 
 
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acce pte d f or st u dies t hat are n ot re vie we d b y t he CI R B, or if t he st u d y was pre vi o usl y o pe n at 
t he site u n der t he l ocal I R B. I nter nati o nal sites s h o ul d c o nti n ue t o s u b mit Researc h Et hics B oar d 
( R E B) a p pr o val t o t he C T S U Re g ulat or y Office f oll o wi n g c o u ntr y-s pecific re g ulati o ns.  
Sites  partici pati n g  wit h  t he N CI  CI R B  m ust  s u b mit  t he  St u d y  S pecific  W or ks heet  f or  L ocal 
C o nte xt ( S S W) t o t he CI R B usi n g I R B Ma na ger t o i n dicate t heir i nte nt t o o pe n t he st u d y l ocall y. 
T he N CI CI R B’s a p pr o val of t he S S W is a ut o maticall y c o m m u nicate d t o t he C T S U Re g ulat or y 
Office,  b ut  s ites  are  re q uire d  t o  c o ntact  t he  
C T S U  
Re g ulat or y  
Office  at 
 t o esta blis h site prefere nces f or a p pl yi n g N CI CI R B a p pr o vals 
acr oss t heir Si g nat or y Net w or k. Site prefere nces ca n be set at t he net w or k or pr ot oc ol le vel. 
Q uesti o ns a b o u t esta blis hi n g site prefere nces ca n be a d dresse d t o t he C T S U Re g ulat or y Office 
b y e maili n g t he e mail a d dress a b o ve or calli n g 
. 
Sites usi n g t heir l ocal I R B or R E B, m ust s u b mit t heir a p pr o val t o t he C T S U Re g ulat or y Office 
usi n g t he Re g ulat or y S u b missi o n P ortal l ocate d i n t he Re g ulat or y secti o n of t he C T S U we bsite. 
Acce pta ble d oc u me ntati o n of l ocal I R B/ R E B a p pr o val i ncl u des: 
•  
L ocal I R B d oc u me ntati o n; 
• 
I R B-si g ne d C T S U I R B Certificati o n F or m; a n d/ or 
• 
Pr ot oc ol  of  H u ma n  S u bjects  Ass ura nce I de ntificati o n/I R B  Certificati o n/ Declarati o n  of 
E xe m pti o n F or m. 
I n a d diti o n, t he Site-Pr ot oc ol Pri nci pal I n vesti gat or ( PI) (i.e. t he i n vesti gat or o n t he I R B/ R E B 
a p pr o val)  m ust  meet  t he  f oll o wi n g  criteria t o c o m plete  pr ocessi n g  of  t he  I R B/ R E B  a p pr o val 
rec ord: 
•  
H ol ds a n Acti ve C T E P stat us;  
•  
R ostere d at t he site o n t he I R B/ R E B a p pr o val a n d o n at least o ne partici pati n g r oster; 
•  
If usi n g N CI CI R B, r ostere d o n t he N CI CI R B Si g nat or y rec or d; 
•  
I ncl u des t he I R B n u m ber of t he I R B pr o vi di n g a p pr o val i n t he F or m F D A 1 5 7 2 i n t he 
R C R pr ofile; a n d  
•  
H ol ds t he a p pr o priate C T E P re gistrati o n t y pe f or t he pr ot oc ol.  
A d diti o n al Re q uire me nts  
A d diti o nal re q uire me nts t o o btai n a n a p pr o ve d site re gistrati o n stat us i ncl u de:  
•  
A n acti ve Fe deral Wi de Ass ura nce ( F W A) n u m ber;  
•  
A n acti ve r oster affiliati o n wit h t he Lea d Pr ot oc ol Or ga nizati o n ( L P O) or a Partici pati n g 
Or ga nizati o n ( P O); a n d  
•  
C o m plia nce wit h all pr ot oc ol- s pecific re q uire me nts ( P S Rs). 
D o w nl o a di n g Site Re gistr ati o n D oc u me nts:  
D o w nl oa d  t he  site  re gistrati o n  f or ms  fr o m  t he  pr ot oc ol -s pecific  pa ge  l ocate d  o n  t he  C T S U 
me m bers' we bsite. Per missi o n t o vie w a n d d o w nl oa d t his pr ot oc ol a n d its s u p p orti n g d oc u me nts 
is restricte d base d o n pers o n a n d site r oster assi g n me nt. T o partici pate, t he i nstit uti o n a n d its 
ass ociate d i n vesti gat ors a n d staff m ust be ass ociate d wit h t he L P O or a P O o n t he pr ot oc ol.  
•  
L o g o n t o t he C T S U me m bers' we bsite 
 usi n g y o ur C T E P-I A M 
user na me a n d pass w or d;  
•  
Clic k o n Pr ot oc ols i n t he u p per left of y o ur scree n  
•  
E nter t he pr ot oc ol n u m ber i n t he searc h fiel d at t he t o p of t he pr ot oc ol tree, or 

 
 
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•  
Clic k o n t he B y Lea d Or ga nizati o n f ol der t o e x pa n d, t he n select Allia nce , a n d pr ot oc ol 
n u m ber A 0 9 1 3 0 2; 
•  
Clic k o n D oc u me nts, select Site Re gistrati o n, a n d d o w nl o a d a n d c o m plete t he f or ms 
pr o vi de d. ( N ote: F or sites u n der t he CI R B i nitiati ve, I R B data will l oa d a ut o maticall y 
t o t he C T S U as descri be d a b o ve.)  
S u b mitti n g Re g ul at or y D oc u me nts:  
S u b mit  re q uire d  f or ms  a n d  d oc u me nts  t o  t he  C T S U  Re g ulat or y  Office  via  t he  R e g ulat or y 
S u b missi o n P ortal o n t he C T S U we bsite.  
T o  access  t he  Re g ulat or y  S u b missi o n  P ortal  l o g  o n  t o  t he  C T S U  me m bers’  we bsite  
Re g ulat or y  Re g ulat or y S u b missi o n. 
I nstit uti o ns wit h patie nts waiti n g t hat are u na ble t o use t he Re g ulat or y S u b missi o n P ortal s h o ul d 
alert t he C T S U Re g ulat or y Office i m me diatel y at 
 i n or der t o recei ve f urt her 
i nstr ucti o n a n d s u p p ort. 
C hec ki n g Y o ur Site’s Re gistr ati o n St at us:  
Y o u ca n verif y y o ur site's re gistrati o n stat us o n t he me m bers' si de of t he C T S U we bsite.  
•  
L o g o n t o t he C T S U me m b ers' we bsite;  
•  
Clic k o n Re g ulat or y  at t he t o p of y o ur scree n; 
•  
Clic k o n Site Re gistrati o n;  
•  
E nter y o ur 5-c haracter C T E P I nstit uti o n C o de a n d clic k o n G o. 
N ote: T he stat us s h o w n o nl y reflects i nstit uti o nal c o m plia nce wit h site re gistrati o n re q uire me nts 
as  o utli ne d  a b o ve.  It  d oes  n ot  reflect  c o m plia nce  wit h  pr ot oc ol  re q uire me nts  f or  i n di vi d uals 
partici pati n g o n t he pr ot oc ol or t he e nr olli n g i n vesti gat or's stat us wit h t he N CI or t heir affiliate d 
net w or ks. 
4. 3 
P atie nt E nr oll me nt  
T h e O nc ol o g y Patie nt E nr oll me nt Net w or k ( O P E N) is a we b -base d re gistrati o n s yste m a vaila ble 
o n a 2 4/ 7 basis. O P E N is i nte grate d wit h C T S U re g ulat or y a n d r oster data a n d wit h t he Lea d 
Pr ot oc ol Or ga nizati o n ( L P Os) re gistrati o n/ra n d o mizati o n s yste ms or T hera de x  I nteracti ve We b 
Res p o nse S yste m (I W R S) f or retrie val of patie nt re gistrati o n/ra n d o mizati o n assi g n me nt. O P E N 
will p o p ulate t he patie nt e nr oll me nt data i n N CI's cli nical data ma na ge me nt s yste m, Me di data 
Ra ve.  
Re q uire me nts f or O P E N access:   
•  
A vali d C T E P -I A M acc o u nt; 
•  
T o  perf or m  e nr oll me nts  or  re q uest  sl ot  reser vati o ns:    Be  o n  a  L P O  r oster,  E T C T N 
C orres p o n di n g r oster, or P O r oster wit h t he r ole of Re gistrar. Re gistrars m ust h ol d a 
mi ni m u m of a n A P re gistrati o n t y pe; 
•  
If a Dele gati o n of T as ks L o g ( D T L) is re q uire d f or t he st u d y, t he re gistrar(s) m ust h ol d 
t he O P E N Re gistrar tas k o n t he D T L f or t he site; a n d 
•  
Ha ve a n a p pr o ve d site re gistrati o n f or a pr ot oc ol pri or t o patie nt e nr oll me nt.  
T o  assi g n  a n  I n vesti gat or  (I V R)  or  N o n -P h ysicia n  I n vesti gat or  ( N PI V R)  as  t he  tr eati n g, 
cre diti n g, c o nse nti n g, dr u g s hi p me nt (I V R o nl y), or recei vi n g i n vesti gat or f or a patie nt tra nsfer 
i n O P E N, t he I V R or N PI V R m ust list t he I R B n u m ber use d o n t he site's I R B a p pr o val o n t heir 
F or m F D A 1 5 7 2 i n R C R. If a D T L is re q uire d f or t he st u d y, t he I V R or N PI V R m ust be assi g ne d 
t he a p pr o priate O P E N-relate d tas ks o n t he D T L. 

 
 
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5. 0  
S T U D Y C A L E N D A R  
La b orat or y a n d cli nical para meters d uri n g treat me nt are t o be f oll o we d usi n g i n di vi d ual i nstit uti o nal 
g ui deli nes a n d t he best cli nical j u d g me nt of t he res p o nsi ble p h ysicia n. It is e x pecte d t hat patie nts o n 
t his st u d y will be care d f or b y p h ysicia ns e x perie nce d i n t he treat me nt a n d s u p p orti ve care of patie nts 
o n t his trial . 
P re -St u d y Testi n g I nter v als  
•  
T o be c o m plete d ≤ 1 6 D A Y S bef ore re gistrati o n: All la b orat or y st u dies, hist or y a n d p h ysical. 
• 
T o  be  c o m plete d ≤ 2 8  D A Y S  bef ore re gistrati o n:  A n y  X -ra y,  sca n  of  a n y  t y pe  or  ultras o u n d 
w hic h is utilize d f or t u m or meas ure me nt per pr ot oc ol . 
 
 
Pri or t o  
Re gistr ati o n  
D a y 1 a n d 
1 5 of  
C ycles 1 
a n d 2 *  
D a y 1 of e ac h c ycle  
st arti n g wit h C ycle 
3 * * a n d after 
Cr oss o ver  
P ost -
Tre at me nt  
F oll o w -u p * * *  
S ur vi v al a n d 
Dise ase  
St at us 
F oll o w -u p Ψ  
Tests a n d O bser v ati o ns  
 
 
 
 
 
Hist or y a n d P h ysical E xa m  
X  
X  
X  
X  
 
A d verse E ve nt Assess me nt  
X  
X  
E  
X  
 
Bl o o d Press ure  
X  
X  
X  
 
 
W ei g ht  
X  
X  
X  
 
 
P erf or ma nce stat us  
X  
X  
X  
X  
 
E K G (as i n dicate d)  
X  
 
 
 
 
Fati g ue/ U niscale 
Assess me nt  
X  
 
 
 
 
L a b or at or y St u dies  
 
 
 
 
 
Tri gl yceri des, c h olester ol π  
X  
 
X  
X  
 
C B C w/ diff, plts  
X  
X  
X  
X  
 
Ser u m c o m pre he nsi ve ∑ 
X  
X  
X  
X  
 
Ser ol o gic  
He patitis  
B 
S urface  A g  a n d  He patitis  C 
R N A  ( p h ysicia n  discreti o n, 
n ot re q uire d)  
X  
 
 
 
 
 
Ser u m B -H C G  
A  
 
A  
 
 
T h yr o gl o b uli n , Ser u m  
X  
 
B  
 
 
T h yr otr o pi n ( T h yr oi d 
Sti m ulati n g H or m o ne or 
T S H), Ser u m  
X  
 
C  
 
 
St a gi n g  
 
 
 
 
 
C T/ M RI T u m or 
meas ure me nts  
X  
 
D  
 
X  

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
2 0  
U p date # 1 3  
 
* 
All e val uati o ns d uri n g t he first a n d sec o n d c ycle ma y be sc he d ule d f or +/ - 3 da ys of t he sc he d ule d da y.  
* *  P atie nt ma y ha ve all e val uati o ns f or da y +/ - 7 da ys t o starti n g treat me nt. F or t he first 2 c ycles, e val uati o n 
sc he d ule is e ver y 2 wee ks ( +/- 3 da ys) . T he n f or 1 0 c ycles, e val uati o n  sc he d ule is e ver y 4 wee ks ( +/- 7 da ys) . 
After 1 2  c ycles ( 4 8 wee ks ), e val uati o n fre q ue nc y is e ver y 8 wee ks  ( +/- 7 da ys) . 
* * *  P ost treat me nt f oll o w -u p bet wee n 2- 6 wee ks after st u d y treat me nt ter mi nati o n.  
A 
Ser u m beta h u ma n c h ori o nic g o na d otr o pi n pre g na nc y test (i n w o me n of c hil d beari n g p ote ntial) o nl y  < 7 da ys 
bef ore re gistrati o n a n d , after cr oss o ver, < 7 da ys pri or t o starti n g treat me nt wit h e ver oli m us o nl y.  
B 
Ser u m T h yr o gl o b uli n d oes n ot nee d t o be dra w n if cli nicall y n ot i n dicate d (e. g., t he prese nc e of ser u m a nti -
t h yr o gl o b uli n a nti b o dies) after t he baseli ne is d o ne. Ser u m T h yr o gl o b uli n s u g geste d at c ycl e 3 ( +/- 7 da ys) 
a n d t he n e ver y 4 c ycles  ( or 1 6 wee ks +/- 8 wee ks) fr o m t he l ast ti me it was dra w n . 
C 
T h yr otr o pi n ( T h yr oi d Sti m ulati n g H or m o ne or T S H), Ser u m e ver y 2 c ycles  ( or e ver y 8 wee ks, +/ - 2 wee ks).  
D 
E ver y 2 c ycles  ( or e ver y 8 we e ks, +/ - 2 wee ks)  f or t he first 1 2 c ycles. E ver y 2 c ycles ( or e ver y 1 6 wee ks, +/ - 
2 wee ks) t hereafter. T his m ust i ncl u de t he mi ni m u m of t he nec k a n d c hest C T sca n at baseli ne, alt h o u g h a n 
a b d o mi nal a n d pel vic C T sca n are str o n gl y rec o m me n de d at baseli ne. I ntra ve n o us c o ntrast s h o ul d be gi ve n 
u nless t here is i n dicati o n t o o mit; as d oc u me nte d b y t he treati n g p h ysicia n. A M RI of t he  nec k ma y be 
s u bstit ute d f or a C T of t he nec k. D oc u me ntati o n (ra di ol o gic a n d pat h ol o g y  re p ort) of t he di a g n osis sca n m ust 
be s u b mitte d. A P E T/ C T ca n be s u bstit ute d if t he i n de x lesi o ns ca n be meas ure d a p pr o priatel y per R E CI S T 
1. 1.  
E 
A d verse e ve nts s h o ul d be c ollecte d Da y 1 of e ver y c ycle  be gi n ni n g wit h c ycle 3 u ntil year 1 . After 1 2  c ycles 
( 1 year) a d verse e ve nts ca n be c ollecte d e ver y ot her c ycle.  
∑   Al b u mi n, al kali ne p h os p hatase, t otal bilir u bi n, bicar b o nat e, B U N, calci u m, c hl ori de, creati ni ne, gl uc ose,  
p otassi u m, t otal pr otei n, S G O T[ A S T], S G P T[ A L T], s o di u m, bilir u bi n.  
π  All patie nts will ha ve baseli ne li pi d pr ofile. Als o, if it has be e n m ore t ha n 3 m o nt hs si nce t he last li pi d pr ofile, 
it m ust be re peate d at cr oss o ver. It is str o n gl y rec o m me n de d t hese patie nts ha ve a li pi d pr ofile after 2 c ycles, 
t he n e ver y 4 c ycles w hile o n e ver oli m us . 
Ψ 
F or patie nts w h o ha ve c o me off of treat me nt f or pr o gressi o n, n o f urt her sca ns are nee de d. F or patie nts w h o 
ha ve c o me off treat me nt f or a n y ot her reas o n, disease stat us i nf or mati o n (i.e. pr o gressi o n stat us) will be 
c ollecte d e ver y 3 m o nt hs ( +/ - 1 m o nt h) u ntil pr o gressi o n. It ma y be d o ne m ore fre q ue ntl y as per t he 
i n vesti gat or. It n o l o n ger nee ds t o be d o ne if a patie nt be gi ns ot her s yste mic treat me nt f or t he t h yr oi d ca ncer. 
D oc u me ntati o n (ra di ol o gic) m ust be pr o vi de d at pr o gressi o n of disease. I n a d diti o n, s ur vi val a n d disease 
stat us i nf or mati o n is re q uire d a p pr o xi matel y e ver y 6 m o nt hs u ntil 5 years after re gistrati o n.  T his d oes n ot 
re q uire t hat t he s u bj ect be see n a n d/ or e xa mi ne d. F or e xa m ple, f oll o w -u p ma y be d o ne t hr o u g h a tele p h o ne 
call t o t he s u bj ect or his treati n g p h ysicia n .  
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
2 2  
U p date # 1 3  
T he  D Q P  is  accessi ble  b y  site  staff  t hat  are  r ostere d  t o  a  site  a n d  ha ve  access  t o  t he  C T S U 
we bsite. Staff t hat ha ve Ra ve st u d y access ca n access t he Ra ve st u d y data usi n g a direct li n k o n 
t he D Q P. 
T o lear n m ore a b o ut D Q P use a n d access, clic k o n t he Hel p ic o n dis pla ye d o n t he Ra ve H o me, 
D Q P Q ueries, a n d D Q P Deli n q ue nt F or ms m o d ules. 
N ote: S o me Ra ve pr ot oc ols ma y n ot ha ve deli n q ue nt f or m details or re p orts s pecifie d o n t he 
D Q P.  A  pr ot oc ol  m ust  ha ve  t he  Cale n dar  f u ncti o nalit y  i m ple me nte d  i n  Ra ve  b y  t he  Lea d 
Pr ot oc ol Or ga nizati o n ( L P O) f or deli n q ue nt f or m details a n d re p orts t o be a vaila ble o n t he D Q P. 
Site staff s h o ul d c o ntact t he L P O Data Ma na ger f or t heir pr ot oc ol re gar di n g q uesti o ns a b o ut 
Ra ve Cale n dari n g f u ncti o nalit y. 
6. 2 
S peci me n c o llecti o n a n d s u b missi o n 
F or all p atie nts pre -re gistere d t o Alli a nce A 0 9 1 3 0 2 : Real -ti me hist o pat h ol o g y re vie w will be 
c o n d ucte d usi n g t he  t h yr oi d tiss ue fr o m t he dia g n ostic bi o psies. 
 
≤ 3 d a ys 
fr o m pre-
re gistr ati o n 
S u b mit t o:  
M a n d at or y f or all  p atie nts re gistere d t o A 0 9 1 3 0 2:  
1 0 Re prese nt ati ve H & E 
st ai ne d sli des O R  tu m or bl oc k  
X 
Allia nce Bi ore p osit or y at O hi o 
State  
6. 2. 1 S peci me n s u b missi o n usi n g t he Alli a nce Bi os peci me n M a n a ge me nt S yste m  
U S E  O F  T H E  A L LI A N C E  BI O S P E CI M E N  M A N A G E M E N T  S Y S T E M  ( Bi o M S)  I S 
M A N D A T O R Y A N D A L L S P E CI M E N S M U S T B E L O G G E D A N D S HI P P E D VI A T HI S 
S Y S T E M.  
Bi o M S  is  a  we b -base d  s yste m  f or  l o g gi n g  a n d  trac ki n g  all  bi os peci me ns  c ollecte d  o n 
Allia nce  trials.    A ut h orize d  i n di vi d ual s  ma y  access  Bi o M S  at  t he  f oll o wi n g  U R L:  
  usi n g  m ost  sta n dar d  we b  br o wsers 
( Safari, Firef o x, I nter net E x pl orer).  F or i nf or mati o n o n usi n g t he Bi o M S s yste m, please 
refer t o t he ‘ Hel p’ li n ks o n t he Bi o M S we b pa ge t o access t he o n-li ne user ma n ual, F A Qs, 
a n d trai ni n g vi de os.  T o re p ort tec h nical pr o ble ms, s uc h as l o gi n iss ues or a p plicati o n err ors, 
please c o ntact: 
  F or assista nce i n usi n g t he 
a p plicati o n or q uesti o n s or pr o ble ms relate d t o s pecific s peci me n l o g gi n g, please c o ntact: 
 
After l o g gi n g c ollecte d s peci me ns i n Bi o M S, t he s yste m will create a s hi p pi n g ma nifest.  
T his  s hi p pi n g  ma nifest  m ust  be  pri nte d  a n d  place d  i n  t he s hi p me nt  c o ntai ner  wit h  t he 
s peci me ns. 
S hi p me nt of s a m ples  
• 
All  sa m ples  s h o ul d  be  la bele d  wit h  i nstit uti o nal  s ur gical  pat h ol o g y  n u m ber  (t u m or 
sa m ples), st u d y n u m ber, patie nt I D n u m ber patie nt i nitials, sa m ple c ollecti o n date a n d 
ti me  a n d  be  acc o m pa nie d  b y  t he  c o m plete d  s peci me n  s u b missi o n  s hi p pi n g  ma nifest 
w hic h wi ll be ge nerate d b y Bi o M S.  
N ote f or C R A – T he f oll o wi n g P HI m ust be re m ove d or bl acke d o ut f or all s peci me ns 
or re p orts: si g n at ure, n a me, d ate of birt h, ot her i de ntifyi n g i nf or m ati o n, exce pt i niti als 
a n d st u dy i de ntific ati o n n u m ber.  
• 
All sa m ples s h o ul d be s hi p pe d t o t he Allia nce Bi ore p osit or y at O hi o State .  

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
2 4  
U p date # 1 3  
I n patie nts w h o are ra n d o mize d t o s orafe ni b al o ne, we w oul d all o w f or a cr oss o ver t o e ver oli m us 
al o ne ( 1 0 m g orall y dail y) at ti me of pr o gressi o n as a n e x pl orat or y c o h ort. If a patie nt d oes cr oss o ver 
t o e ver oli m us al o ne, e ver oli m us m ust be gi n wit hi n 6 wee ks of t he last d ose of s orafe ni b o n st u d y. If 
resta gi n g ima gi n g has n ot bee n d o ne wit hi n 2 8 da ys bef ore treat me nt wit h e ver oli m us al o ne, it m ust 
be re peate d.  
At t he ti me of cr oss o ver, pre g na nc y test m ust be re peate d. Als o, if it has bee n m ore t ha n 3 m o nt hs 
si nce  t he  last  li pi d  pr ofile,  t he  li pi d  pr ofile  m ust  be re peate d  at  cr oss o ver. Ot her  la b  tests  a n d 
o bser vati o ns will be perf or me d per st u d y cale n dar i n Secti o n 5. 0 .  
Patie nts will re mai n o n treat me nt as l o n g as t here is n o pr o gressi o n of disease, e xcessi ve t o xicit y 
re q uiri n g t he patie nt t o c o me off of trea t me nt, or t he patie nt wit h dra ws fr o m treat me nt. 
Ar m 1:  
A ge nt  
D ose a n d R o ute  
Fre q ue nc y  
C ycle Le n gt h ( Re R x)  
S orafe ni b *  
4 0 0 m g P O  
T wice dail y  
2 8 da ys * * *  
 
Ar m 2:  
A ge nt  
D ose a n d R o ute  
Fre q ue nc y  
C ycle Le n gt h ( Re R x)  
S orafe ni b *  
4 0 0 m g  P O  
T wice dail y  
2 8 da ys * * *  
E ver oli m us * *  
5 m g P O  
O nce dail y  
2 8 da ys * * *  
 
Cr oss o ver f or Ar m 1:  
A ge nt  
D ose a n d R o ute  
Fre q ue nc y  
C ycle Le n gt h ( Re R x)  
E ver oli m us * *  
1 0 m g P O  
O nce dail y  
2 8 da ys * * *  
* S orafe ni b s h o ul d be ta ke n t wice dail y o n a n e m pt y st o mac h o ne h o ur bef ore or t w o h o urs after 
eati n g. T his ta blet s h o ul d be s wall o we d w h ole a n d ca n n ot be cr us he d or c he we d.  
* * E ver oli m us s h o ul d be a d mi nistere d o nce dail y at a p pr o xi matel y t he sa me ti me eac h da y wit h 
or wit h o ut f o o d.  Ta blets s h o ul d be s wall o we d w h ole w it h a glass of water.  T he ta blets m ust 
n ot be c he we d or cr us he d a n d gra pefr uit j uice or  gra pefr uit s h o ul d be a v oi de d.  
* * * After year 1, at t he start of c ycle 1 3, t he c ycle le n gt h will be 5 6 da ys. 
7. 1 
C Y P 3 A 4 I n hi bit ors  
C hr o nic c o nc o mita nt treat me nt wit h str o n g i n hi bit ors of C Y P 3 A 4 is n ot all o we d d uri n g o n t his 
trial. T he f oll o wi n g dr u gs are E X A M P L E S of str o n g i n hi bit ors of C Y P 3 A 4 a n d are n ot all o we d 
d uri n g treat me nt wit h s orafe ni b. 
•  
I n di na vir 
•  
Clarit hr o m yci n  
•  
Ket oc o naz ole 
Beca use lists of t hese a ge nts are c o nsta ntl y c ha n gi n g, please c o ns ult a n d re vie w a n y dr u gs f or 
t heir  p ote ntial  t o  i n hi bit  C Y P 3 A 4.  E xa m ples  of  res o urces  t hat  ma y  be  utilize d  i ncl u de  t he 
pr o d uct i nf or mati o n  f or  t he  i n di vi d ual c o nc o mita nt  dr u g  i n q uesti o n,  me dical refere nce  te xts 
s uc h  as  t he  P hysicia ns’  Des k  Refere nce,  t he  F D A  a n d/ or  I U P UI  we bsites,  or  y o ur  l ocal 
i nstit uti o n’s p har macist. 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
2 5  
U p date # 1 3  
7. 2 
C Y P 3 A 4 I n d ucers  
C hr o nic c o nc o mita nt treat me nt wit h str o n g i n d ucers of C Y P 3 A 4 is n ot all o we d d uri n g o n t his 
trial. T he f oll o wi n g dr u gs are E X A M P L E S of str o n g i n d ucers of C Y P 3 A 4 a n d are n ot all o we d 
d uri n g treat me nt wit h s orafe ni b. 
• 
Rifa m pi n  
• 
Car ba maze pi ne  
Beca use lists of t hese a ge nts are c o nsta ntl y c ha n gi n g, please c o ns ult a n d re vie w a n y dr u gs f or 
t heir  p ote ntial  t o  i n d uce  C Y P 3 A 4.  E xa m ples  of  res o urces t hat  ma y  be  utilize d  i ncl u de  t he 
pr o d uct i nf or mati o n  f or  t he  i n di vi d ual c o nc o mita nt  dr u g  i n q uesti o n,  me dical refere nce  te xts 
s uc h  as  t he  P h ysicia ns’  Des k  Refere nce,  t he  F D A  a n d/ or  I U P UI  we bsites,  or  y o ur  l ocal 
i nstit uti o n’s p har macist. 
8. 0  
D O S E A N D T R E A T M E N T M O DI FI C A TI O N S  
8. 1 
A ncill ar y t her a p y, c o nc o mit a nt me dic ati o ns, a n d s u p p orti ve c are  
8. 1. 1 P atie nts s h o ul d n ot recei ve a n y ot her a ge nt w hic h w o ul d be c o nsi dere d tre at me nt f or 
t he pri m ar y ne o pl as m or i m p act t he pri m ar y e n d p oi nt wit h t he e xce pti o n of t h yr oi d 
h or m o ne re pl ace me nt i n or der t o s u p press t he T S H.  
8. 1. 2 P atie nts  s h o ul d  recei ve  f ull  s u p p orti ve  c are  w hile  o n  t his  st u d y.    T his  i ncl u des  bl o o d 
pr o d uct s u p p ort, a nti bi otic treat me nt, a n d treat me nt of ot her ne wl y dia g n ose d or c o nc urre nt 
me dical c o n diti o ns.  All bl o o d pr o d ucts a n d c o nc o mita nt me dicati o ns s uc h as a nti diarr heals, 
a nal gesics, a n d/ or a ntie metics recei ve d fr o m t he first da y of st u d y treat me nt a d mi nistrati o n 
u ntil 3 0 da ys after t he fi nal d ose will be rec or de d i n t he me dical rec or ds.  
8. 1. 3 Tre at me nt  wit h  h or m o nes or  ot her  c he m ot hera pe utic  a ge nts  ma y  n ot  be  a d mi nistere d 
e xce pt f or ster oi ds gi ve n f or a dre nal fail ure; h or m o nes a d mi nistere d f or n o n -disease -relate d 
c o n diti o ns  (e. g.,  i ns uli n  f or  dia betes);  a n d  i nter mitte nt  use  of  de xa met has o ne  as  a n 
a ntie metic i n s oli d t u m or pr ot oc ols.  
8. 1. 4 A ntie metics  ma y be use d at t he discreti o n of t he atte n di n g p h ysicia n.  
8. 1. 5  Di arr he a:  T his c o ul d be ma na ge d c o nser vati vel y wit h l o pera mi de. T he rec o m me n de d d ose 
of l o pera mi de is 4 m g at first o nset, f oll o we d b y 2 m g e ver y 2 -4 h o urs u ntil diarr hea free 
( ma xi m u m 1 6 m g/ da y). T he f oll o wi n g s u p p orti ve me as ures are als o all o we d:  h y drati o n, 
octre oti de, a n d ot her a nti diarr heals.   
8. 1. 6 P alli ati ve r a di ati o n t her a p y ma y n ot  be a d mi nistere d  d uri n g acti ve treat me nt . Patie nts w h o 
re q uire ra diati o n t hera p y d uri n g acti ve treat me nt will be re m o ve d fr o m pr ot oc ol t hera p y d ue 
t o disease pr o gressi o n. H o we ver, if t he patie nt is ra n d o mize d t o t he s orafe ni b al o ne ar m, 
t he y ma y recei ve palliati ve ra diati o n t hera p y f or a s y m pt o matic lesi o n pri or t o t he cr oss o ver 
f or e ver oli m us if t he f oll o wi n g c o n diti o ns are met: ( 1) t here are R E CI S T 1. 1 lesi o ns prese nt 
o utsi de  of  t he  ra diati o n  fiel d;  ( 2)  E ver oli m us  is  starte d  2  or  m ore  wee ks  after  ra diati o n 
t hera p y is c o m plete d; ( 3) E ver oli m us is starte d wit hi n 6 wee ks of t he last d ose of s orafe ni b. 
8. 1. 7 Alli a nce P olic y C o ncer ni n g t he Use of Gr o wt h F act ors  
Bl o o d pr o d ucts a n d gr o wt h fact ors s h o ul d be utilize d as cli nicall y warra nte d a n d f oll o wi n g 
i nstit uti o nal  p olicies  a n d  rec o m me n dati o ns.    T he  use of  gr o wt h  fact ors  s h o ul d  f oll o w 
p u blis he d  g ui deli nes  of  t he  A merica n  S ociet y  of  Cli nical  O nc ol o g y  2 0 0 6  U p date  of 
Rec o m me n dati o ns f or t he Use of W hite Bl o o d Cell Gr o wt h Fact ors: A n E vi de nce -Base d, 
Cli nical Practice G ui deli ne.  J Cli n O nc ol 2 4( 1 9): 3 1 8 7 - 3 2 0 5, 2 0 0 6. 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
2 6  
U p date # 1 3  
E p oeti n ( E P O) : Use of e p oeti n i n t his pr ot oc ol is per mitte d at t he discreti o n of t he treati n g 
p h ysicia n. 
Fil grasti m ( G -C S F) a n d sar gra m osti m ( G M -C S F)  
1. 
Fil grasti m ( G -C S F)/ pe gfil grasti m a n d sar gra m osti m ( G M -C S F) treat me nt f or patie nts 
is disc o ura ge d. 
2. 
Fil grasti m/ pe gfil grasti m a n d sar gra m osti m ma y be use d : 
a. F or t he treat me nt of fe brile ne utr o pe nia t he use of C S Fs s h o ul d n ot be r o uti nel y 
i nstit ute d as a n a dj u nct t o a p pr o priate a nti bi otic t hera p y. H o we ver, t he use of C S Fs 
ma y  be  i n dicate d  i n patie nts  w h o  ha ve  pr o g n ostic  fact ors  t hat  are  pre dicti ve  of 
cli nical  deteri orati o n  s uc h  as  p ne u m o nia,  h y p ote nsi o n,  m ulti -or ga n  d ysf u ncti o n 
(se psis s y n dr o me) or f u n gal i nfecti o n, as per t he A S C O g ui deli nes.  I n vesti gat ors 
s h o ul d t heref ore use t heir o w n discreti o n i n usi n g t he C S Fs i n t his setti n g.  T he use 
of  C S F  (fil grasti m/ pe gfil grasti m  or  sar gra m osti m)  m ust  be  d oc u me nte d  a n d 
re p orte d. (e. g. o n C R Fs per pr ot oc ol re q uire me nts) 
b. 
If fil grasti m/ pe gfil grasti m or sar gra m osti m are use d, t he y m ust be o btai ne d fro m 
c o m mercial s o urces. 
8. 1. 8 P al mer -pl a nt ar er yt hr o d ysest hesi a ( P P E) s y n dr o me  
P P E  is  a  c o m m o n  si de  effect  of s or afe ni b.  Patie nts  s h o ul d  use  m oist urizers,  a v oi d  heat 
e x p os ure ( direct s u n, sa u nas, etc), treat call uses, a n d s h o ul d re p ort ras h or s y m pt o ms.  I n 
or der  t o  pr oacti vel y  alle viate  P P E,  c o nsi der  usi n g  pr o p h yla xis  bef ore  starti n g  treat me nt. 
E xa m ples of pr o p h yla xis i ncl u de: M oist urizers s uc h as e uceri n, urea crea m.  
8. 1. 9 P ne u m o nitis  
Refer  t o  t he  f oll o wi n g  ta ble  f or  S U G G E S T E D  me dical  ma na ge me nt  of  t he  p ne u m o nitis 
ass ociate d wit h e ver oli m us . T hese are n ot re q uire d a n d i ncl u de d t o pr o vi de site g ui da nce 
f or ma na ge me nt: 
Gra de of 
P ne u m o nitis  
I n vesti gati o ns t o utilize 
Ma n a ge me nt of P n e u m o nitis  
Gra de 1  
C T sca ns wit h l u n g wi n d o ws a n d p ul m o n ar y f u n cti o n testi n g 
i n cl u di n g: s pir o metr y, D L C O, a n d r o o m air O2 sat urati o n at 
rest. Re p eat c h est x-ra y/ C T sca n e ver y 2 C ycl es u ntil ret ur n t o 
b aseli n e.  
N o s p ecific t h era p y is re q uire d  
Gra de 2  
C T sca n wit h l u n g wi n d o ws a n d p ul m o n ar y f u n cti o n testi n g 
i n cl u di n g: s pir o metr y, D LC O, a n d r o o m air O 2 sat urati o n at 
rest. Re p eat eac h s u bse q u e nt C ycl e u ntil ret ur n t o b aseli n e. 
C o nsi d er br o n c h osc o p y *  
S y m pt o matic o nl y. Prescri b e 
c ortic oster oi ds if c o u g h is 
tr o u bles o me. 
Gra de 3  
C T sca n wit h l u n g wi n d o ws a n d p ul m o n ar y f u n cti o n testi n g 
in cl u di n g: s pir o metr y, D L C O, a n d r o o m air O 2 sat urati o n at 
rest.; Re p eat eac h s u bse q u e nt C ycle u ntil ret ur n t o b aseli n e. 
Br o n c h osc o p y is rec o m me n d e d *  
Prescri b e c ortic oster oi ds if 
i nfecti ve ori gi n is r ule d o ut. 
Ta p er as me dicall y i n dicate d.  
Gra de 4  
C T sca n  wit h l u n g wi n d o ws a n d re q uire d p ul m o n ar y f u n cti o n 
testi n g i n cl u d es: s pir o metr y, D L C O, a n d r o o m air O2 sat urati o n 
at rest. Re p eat eac h s u bse q u e nt C ycle u ntil ret ur n t o b aseli n e. 
Br o n c h osc o p y is rec o m me n d e d *.  
Prescri b e c ortic oster oi ds if 
i nfecti ve ori gi n is r ule d o ut. 
Ta p er as me dicall y i n dicate d.  
* A br o nc h osc o p y wit h bi o ps y a n d/ or br o n c h o al ve olar la va ge is rec o m me n d e d.  
8. 1. 1 0 St o m atitis  
T he  f oll o wi n g  are  rec o m me n dati o ns  f or  st o matitis  ma na ge me nt  ass ociate d  wit h 
e ver oli m us , t o pr o vi de sites wit h g ui da nce a n d are n ot re q uire d: 

 
 
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•  
F or  mil d  t o xicit y  ( Gra de  1),  use  c o nser vati ve  meas ures  s uc h  as n o n -alc o h olic 
m o ut h w as h or s alt w ater ( 0. 9 %) m o ut h w as h  se veral ti mes a da y u ntil res ol uti o n. 
•  
F or  m ore  se vere  t o xicit y  ( Gra de  2  or  3),  t he  s u g geste d  treat me nts  are t o pic al 
a n al gesic m o ut h tre at me nts, wit h or wit h o ut t o pic al c ortic oster oi ds 
•  
A ntif u n gal a n d a nti viral a ge nts s h o ul d be a v oi de d d ue t o dr u g i nteracti o n c o ncer ns  
8. 1. 1 1 H y per gl yce mi a  
Patie nts  ta ki n g e ver oli m us  s h o ul d  be  treate d  wit h  a p pr o priate  me dical  t hera py  f or 
h y per gl yce mia.  
8. 1. 1 2 H y perli pi de mi a  
Patie nts  ta ki n g e ver oli m us  s h o ul d  be  treate d  wit h  a p pr o priate  me dical  t hera p y  f or 
h y perli pi de mia a n d a v oi di n g c o nc o mita nt me dicati o ns t hat i nteract wit h st u d y me dicati o n.  
8. 2 
D ose M o dific ati o ns f or S or af e ni b  
•  
If  multi ple  a d verse  e ve nts  are  see n,  a d mi nister  d ose  base d  o n  greatest  re d ucti o n 
re q uire d f or a n y si n gle a d verse e ve nt o bser ve d.  Re d ucti o ns or i ncreases a p pl y t o 
treat me nt gi ve n i n t he prece di n g c ycle a n d are base d o n a d verse e ve nts o bser ve d 
si nce t he pri or dose.  
•  
S orafe ni b will n ot be re- escalate d o nce re d uce d 
•  
If d ose re d ucti o ns be y o n d d ose le vel -2 is re q uire d or s orafe ni b is hel d f or 4 wee ks, 
s orafe ni b will be disc o nti n ue d.  
•  
If m ore t ha n o ne of t hese t o xicities a p pl y, use t he m ost stri n ge nt criteria (i.e., the 
greatest d ose re d ucti o n.)  
•  
If t he patie nt e x perie nces a si g nifica nt a d verse e ve nt re q uiri n g a d ose re d ucti o n at 
t he start of t he ne xt c ycle, t he n t he d ose will re mai n l o were d.   
C T E P -A E R S  re p orti n g ma y be re q uire d f or s o me a d verse e ve nts ( See Secti o n 9. 0 ) 
8. 2. 1 D ose le vels  
D ose re d ucti o n of s orafe ni b will be perf or me d acc or di n g t o t he ta ble bel o w. S orafe ni b will 
be per ma ne ntl y disc o nti n ue d f or patie nts w h o re q uire d ose i nterr u pti o ns of > 2 8 da ys or w h o 
e x perie nce d ose li miti n g t o xicities at d ose le vel -2. Misse d d oses of s orafe ni b will n ot be 
ma de u p.  
D ose 
Le vel  
Dr u g N a me  
D ose  
 0 *  
S orafe ni b  
4 0 0 m g t wice dail y  
-1  
S orafe ni b  
2 0 0 m g t wice dail y  
-2  
S orafe ni b  
2 0 0 m g dail y  
* D ose le vel 0 refers t o t he starti n g d ose.  
• 
If d ose re d ucti o ns be y o n d t he l o west d ose le vel are re q uire d disc o nti n ue all pr ot oc ol 
t hera p y. 
•  
D oses t hat ha ve bee n re d uce d will n ot be re-escalate d. 
8. 2. 2 D ose M o dific ati o ns f or He m at ol o gic T o xicities  

 
 
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Gr a de ≥3  ne utr o pe ni a,  t hr o m b oc yt o pe ni a,  or  ne utr o pe nic  fe ver :  I nterr u pt  s orafe ni b 
u ntil ≤ gra de 2, t he n res u me wit h o ne d ose le vel re d ucti o n of s orafe ni b f or all s u bse q ue nt 
d oses.  
8. 2. 3   D ose M o dific ati o ns f or G astr oi ntesti n al T o xicities  
• Gr a de 2 di arr he a :  I nterr u pt s orafe ni b u ntil diarr hea i m pr o ves t o ≤ gra de 1, t he n res u me 
s orafe ni b at sa me d ose le vel. 
• Gr a de ≥ 3 di arr he a: I nterr u pt s orafe ni b u ntil diarr hea i m pr o ves t o ≤ gra de 2, t he n res u me 
s orafe ni b wit h o ne d ose le vel re d ucti o n. 
• GI P erf or ati o n: Disc o nti n ue s orafe ni b. 
8. 2. 4 D ose M o dific ati o ns f or He p atic D ysf u ncti o n  
• Gr a de 2 bl o o d bilir u bi n i ncre ase d: I nterr u pt s orafe ni b u ntil i m pr o ve d t o gra de 1, t he n 
res u me s orafe ni b at sa me d ose. 
 • Gr a de 3 bl o o d bilir u bi n i ncre ase d: I nterr u pt s orafe ni b u ntil i m pr o ve d t o gra de 1, t he n 
res u me s orafe ni b at 1 d ose le vel re d uce d. 
• Gr a de 4 bl o o d bilir u bi n i ncre ase d : Disc o nti n ue s orafe ni b. 
•  Gr a de  3  tr a ns a mi n ase  i ncre ase d: I nterr u pt  s orafe ni b  u ntil i m pr o ve d  t o  gra de  1,  t he n 
res u me s orafe ni b at 1 d ose le vel re d uce d. 
• Gr a de 4 tr a ns a mi n ase i ncre ase d : Disc o nti n ue s orafe ni b. 
8. 2. 5 D ose M o dific ati o ns f or H y perte nsi o n  
• F or h y perte nsi o n > 1 4 0/ 9 0 a n d ≤1 6 0/ 1 0 0: C o nti n ue s orafe ni b. C o nsi der a d di n g or a dj usti n g a nti-
h y perte nsi ve me dicati o ns (e. g., calci u m c ha n nel bl oc kers as per i nstit uti o n’s g ui deli ne f or H T N 
treat me nt). 
•  F or  persistent  ( > 1 6 0/ 1 0 0)  or  s y m pt o m atic  h y perte nsi o n: I nterr u pt s orafe ni b.  Res u me  w he n 
bl o o d  press ure  i m pr o ves  t o  ≤1 6 0/ 1 0 0.  If s orafe ni b is  i nterr u pte d  f or  >  4  wee ks,  disc o nti n ue 
s orafe ni b t hera p y. 
• Gr a de 4 h y perte nsi o n: Disc o nti n ue all s orafe ni b t hera p y. 
8. 2. 6 D ose M o dific ati o ns f or C ar di ot o xicit y  
• M y oc ar di al isc he mi a : Disc o nti n ue s orafe ni b. 
8. 2. 7 D ose  M o dific ati o ns  f or  S ki n  T o xicit y  ( p al m ar -pl a nt ar  er yt hr o d ysest hesi a  ( P P E) 
s y n dr o me) 
S ki n T o xicit y  
Occ urre nce  
S u g geste d D ose M o dific ati o n  
N u m b ness, d ysest hesia,  parest hesia, 
ti n gli n g, pai nless s welli n g, er yt he ma 
or disc o mf ort of t he ha n ds or feet 
relief w hic h d oes n ot disr u pt t he 
patie nt’s n or mal acti vities  
A n y occ urre nce  
C o nti n ue treat me nt wit h s orafe ni b a n d 
c o nsi der t o pical t hera p y f or s y m pt o matic 
relief 
 
P ai n f ul er yt he ma a n d s welli n g of t he 
ha n ds or feet a n d/ or disc o mf ort 
affecti n g t he patie nt’s n or mal 
acti vities  
1st occ urre nce  
C o nti n ue treat me nt wit h s orafe ni b a n d 
c o nsi der t o pical t hera p y f or s y m pt o matic 
relief. If n o i m pr o ve me nt wit hi n 7 da ys, 
see bel o w 
N o  i m pr o ve me nt 
wit hi n 7 da ys or 
2 n d or 3r d 
occ urre nce  
I nterr u pt s orafe ni b u ntil t o xicit y res ol ves 
t o Gra de 0-1. W he n res u mi n g treat me nt, 
decrease s orafe ni b d ose b y o ne d ose le vel  

 
 
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4t h occ urre nce  
Disc o nti n ue s orafe ni b  
M oist des q ua mati o n, ulcerati o n, 
blisteri n g or se vere pai n t he ha n ds or 
feet, or se vere disc o mf ort t hat ca uses 
t he patie nt t o be u na ble t o w or k or 
perf or m acti vities of dail y li vi n g  
1st or 2 n d 
occ urre nce  
I nterr u pt s orafe ni b u ntil t o xicit y of 
res ol ves t o Gra de 0-1. W he n res u mi n g 
treat me nt, decrease s orafe ni b d ose b y o ne 
d ose le vel  
3r d occ urre nce  
Disc o nti n ue s orafe ni b  
8. 2. 8 D ose M o dific ati o ns f or Ot her N o n -he m at ol o gic T o xicities  
F or  ot her  cli nicall y  si g nifica nt  gra de  3/ 4  n o n -he mat ol o gic  t o xicities  li kel y  relate d  t o 
s orafe ni b, i nterr u pt s orafe ni b. Res u me s orafe ni b at 1 d ose le vel re d uce d w he n t he t o xicit y 
res ol ves t o a cli nicall y acce pta ble le vel ( gra de 1/ 2). 
8. 3 
D ose M o dific ati o ns f or S or af e ni b + E ver oli m us  
• 
If m ulti ple a d verse e ve nts are see n, a d mi nister d ose base d o n greatest re d ucti on re q uire d f or 
a n y si n gle a d verse e ve nt o bser ve d.  Re d ucti o ns or i ncreases a p pl y t o treat me nt gi ve n i n t he 
prece di n g c ycle a n d are base d o n a d verse e ve nts o bser ve d si nce t he pri or d ose.  
•  
S orafe ni b or e ver oli m us will n ot be re-escalate d o nce re d uce d 
• 
If dose re d ucti o ns be y o n d d ose l o west d ose le vel is re q uire d O R s orafe ni b or e ver oli m us is 
hel d f or 4 wee ks, s orafe ni b or e ver oli m us will be disc o nti n ue d. If 1 a ge nt is disc o nti n ue d, 
t he patie nt ma y re mai n o n t he ot her a ge nt. If s orafe ni b is disc o nti n ue d a n d e ver oli m us has 
ne ver bee n d ose re d uce d, t he patie nt ma y ha ve e ver oli m us d ose i ncrease d t o 1 0 m g dail y. 
I n t his sce nari o, d ose le vel c hart f or e ver oli m us i n secti o n 8. 4. 1 s h o ul d be use d. 
• 
If m ore t ha n o ne of t hese t o xicities a p pl y, use t he m ost stri n ge nt criteria (i.e., t he greatest 
d ose re d ucti o n.).   
C T E P -A E R S  re p orti n g ma y be re q uire d f or s o me a d verse e ve nts ( See Secti o n 9. 0 ) 
8. 3. 1 D ose le vels  
D ose re d ucti o n of s orafe ni b a n d e ver oli m us will be perf or me d acc or di n g t o t he ta ble bel o w. 
S orafe ni b  or  e ver oli m us  will  be  per ma ne ntl y  disc o nti n ue d  f or  patie nts  w h o  re q uire  d ose 
i nterr u pti o ns of > 2 8 da ys or w h o e x perie nce d ose li miti n g t o xicities at d ose le vel - 2. Misse d 
d oses of s orafe ni b or e ver oli m us will n ot be ma de u p. T o clarif y, o nl y t he d ose le vel of t he 
offe n di n g a ge nt nee ds t o be d ose re d uce d as per pr ot oc ol if it is clear t hat t he ot her dr u g di d 
n ot ca use t he a d verse e ve nt (e. g., o nl y s orafe ni b nee ds t o be d ose r e d uce d f or ha n d -f o ot 
s y n dr o me). If t here are a n y q uesti o ns, please disc uss wit h pr ot oc ol PI ( Dr. Eric S her ma n).  
D ose Le vel  
Dr u g N a me  
D ose  
 
Dr u g N a me  
 
D ose  
 0 *  
 
S orafe ni b  
4 0 0 m g t wice 
dail y  
E ver oli m us  
5 m g dail y  
-1  
 
S orafe ni b  
2 0 0 m g t wice 
dail y  
E ver oli m us  
2. 5 m g dail y  
-2  
 
S orafe ni b  
2 0 0 m g dail y  
E ver oli m us  
2. 5 m g e ver y ot her 
da y  
* D ose le vel 0 refers t o t he starti n g d ose.  
 
8. 3. 2 D ose M o dific ati o ns f or He m at ol o gic T o xicities  
•  Gr a de  2  t hr o m b oc yt o pe ni a:  I nterr u pt  s orafe ni b  a n d  e ver oli m us  u ntil  gra de  ≤  1,  t he n 
res u me s orafe ni b a n d e ver oli m us at sa me d ose.  

 
 
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• Gr a de ≥3 ne utr o pe ni a, gr a de ≥3 t hr o m b oc yt o pe ni a, or ne utr o pe nic fe ver : I nterr u pt 
s orafe ni b  a n d  e ver oli m us  u ntil  ≤  gra de  2,  t he n  res u me  wit h  o ne  d ose  le vel  re d ucti o n  of 
s orafe ni b a n d e ver oli m us f or all s u bse que nt d oses.  
8. 3. 3 D ose M o dific ati o ns f or G astr oi ntesti n al T o xicities  
• Gr a de 2 di arr he a: I nterr u pt s orafe ni b a n d e ver oli m us u ntil diarr hea i m pr o ves t o gra de ≤ 
1 t he n res u me at sa me d ose.  
• Gr a de ≥ 3 di arr he a: I nterr u pt s orafe ni b a n d e ver oli m us u ntil diarr hea i m pr o ves t o ≤ gra de 
2, t he n res u me s orafe ni b a n d e ver oli m us wit h o ne d ose le vel re d ucti o n of b ot h a ge nts. 
• GI P erf or ati o n: Disc o nti n ue s orafe ni b. 
• Gr a de 3 st o m atitis: I nterr u pt e ver oli m us u ntil ≤ gra de 1 t he n res u me wit h o ne d ose le vel 
re d uce d. 
• Gr a de 4 st o m atitis: Disc o nti n ue e ver oli m us.   
8. 3. 4 D ose M o dific ati o ns f or He p atic D ysf u ncti o n  
• Gr a de 2 bl o o d bilir u bi n i ncre ase d: I nterr u pt s orafe ni b a n d e ver oli m us u ntil i m pr o ve d t o 
gra de 1, t he n res u me s orafe ni b a n d e ver oli m us at sa me d ose.  
• Gr a de 3 bl o o d bilir u bi n i ncre ase d: I nterr u pt s orafe ni b a n d e ver oli m us u ntil i m pr o ve d t o 
gra de 1, t he n res u me s orafe ni b a n d e ver oli m us at 1 d ose le vel re d uce d.  
• Gr a de 4 bl o o d bilir u bi n i ncre ase d: Disc o nti n ue s orafe ni b a n d e ver oli m us. 
• Gr a de 3 tr a ns a mi n ase i ncre ase d: I nterr u pt s orafe ni b a n d e ver oli m us u ntil i m pr o ve d t o 
gra de 1, t he n res u me s orafe ni b a n d e ver oli m us at 1 d ose le vel re d uce d.  
 • Gr a de 4 tr a ns a mi n ase i ncre ase d:  Disc o nti n ue s orafe ni b a n d e ver oli m us.  
8. 3. 5 D ose M o dific ati o ns f or H y perte nsi o n  
•  F or  h y perte nsi o n > 1 4 0/ 9 0  a n d  ≤1 6 0/ 1 0 0:  C o nti n ue  s orafe ni b.  C o nsi der  a d di n g  or 
a dj usti n g a nti -h y perte nsi ve me dicati o ns (e. g., calci u m c ha n nel bl oc kers as per i nstit uti o n’s 
g ui deli ne f or H T N treat me nt)). 
• F or persiste nt ( > 1 6 0/ 1 0 0) or s y m pt o m atic h y perte nsi o n: I nterr u pt s orafe ni b. Res u me 
w he n  bl o o d  press ure  i m pr o ves  t o  ≤1 6 0/ 1 0 0.  If  s orafe ni b  is  i nterr u pte d  f or  >  4  wee ks, 
disc o nti n ue s orafe ni b t hera p y. 
• Gr a de 4 h y perte nsi o n: Disc o nti n ue s orafe ni b 
8. 3. 6 D ose M o dific ati o ns f or C ar di ot o xicit y  
M y oc ar di al isc he mi a : Disc o nti n ue s orafe ni b. 
8. 3. 7 D ose M o dific ati o ns f or S ki n T o xicit y 
• P al m ar-pl a nt ar er yt hr o d ysest hesi a ( P P E) s y n dr o me  
S ki n T o xicit y  
Occ urre nce  
S u g geste d D ose M o dific ati o n  
N u m b ness, d ysest hesia, parest hesia, 
ti n gli n g, pai nless s welli n g, er yt he ma 
or disc o mf ort of t he ha n ds or feet 
relief w hic h d oes n ot disr u pt t he 
patie nt’s n or mal acti vities  
A n y occ urre nce  
C o nti n ue treat me nt wit h s orafe ni b a n d 
c o nsi der t o pical t hera p y f or s y m pt o matic 
relief 
 
P ai nf ul er yt he ma a n d s welli n g of t he 
ha n ds or feet a n d/ or disc o mf ort 
affecti n g t he patie nt’s n or mal 
1st occ urre nce  
C o nti n ue treat me nt wit h s orafe ni b a n d 
c o nsi der t o pical t hera p y f or s y m pt o matic 
relief. If n o i m pr o ve me nt wit hi n 7 da ys, 

 
 
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acti vities  
see bel o w 
N o i m pr o ve me nt 
wit hi n 7 da ys or 
2 n d or 3r d 
occ urre nce  
I nterr u pt s orafe ni b u ntil t o xicit y res ol ves 
t o Gra de 0-1. W he n res u mi n g treat me nt, 
decrease s orafe ni b a n d e ver oli m us d ose 
b y o ne d ose le vel  
 
4t h occ urre nce  
Disc o nti n ue s orafe ni b  
M oist des q ua mati o n, ulcerati o n, 
blisteri n g or se vere pai n t he ha n ds or 
feet, or se vere disc o mf ort t hat ca uses 
t he patie nt t o be u na ble t o w or k or 
perf or m acti vities of dail y li vi n g  
1st or 2 n d 
occ urre nce  
I nterr u pt s orafe ni b u ntil t o xicit y of 
res ol ves t o Gra de 0-1. W he n res u mi n g 
treat me nt, decrease s orafe ni b d ose b y o ne 
d ose le vel  
3r d occ urre nce  
Disc o nti n ue s orafe ni b   
• Gr a de 4 Ac neif or m R as h: I nterr u pt e ver oli m us u ntil gra de ≤ 2, t he n restart at o ne d ose 
le vel decrease d 
• Gr a de 3 M ac ul o p a p ul ar R as h: I nterr u pt s orafe ni b a n d e ver oli m us u ntil gra de ≤ 2, t he n 
restart s orafe ni b a n d e ver oli m us at o ne d ose le vel decrease d  
8. 3. 8 D ose M o dific ati o ns f or P ul m o n ar y T o xicit y  
• Gr a de 2 or 3 p ne u m o nitis: I nterr u pt e ver oli m us u ntil ≤ gra de 1. Res u me e ver oli m us at 
o ne d ose le vel decrease d  
• Gr a de 4 p ne u m o nitis: Disc o nti n ue e ver oli m us  
8. 3. 9 D ose M o dific ati o ns f or Re n al T o xicit y  
• Gr a de 2 i ncre ase d cre ati ni ne: I nterr u pt e ver oli m us u ntil gra de ≤ 1, t he n res u me wit h o ne 
d ose le vel decrease d   
• Gr a de 3 a n d 4 i ncre ase d cre ati ni ne: Disc o nti n ue e ver oli m us 
8. 3. 1 0 D ose M o dific ati o ns f or Met a b olis m  
Gr a de 4 H y per gl yce mi a:  I nterr u pt e ver oli m us u ntil gra de ≤ 2, t he n res u me at sa me d ose 
8. 3. 1 1 D ose M o dific ati o ns f or Ge ner al Dis or ders  
Gr a de  3  E de m a:   I nterr u pt  e ver oli m us  u ntil  ≤  gra de  2,  t he n  res u me  at  o ne  d ose  le vel 
decrease d  
8. 3. 1 2 D ose M o dific ati o ns f or Ot her N o n -he m at ol o gic T o xicities  
F or  ot her  cli nicall y  si g nifica nt  gra de  3/ 4  n o n -he mat ol o gic  t o xicities  li kel y  relate d  t o 
s orafe ni b or e ver oli m us, i nterr u pt s orafe ni b or e ver oli m us. Res u me s orafe ni b or e ver oli m us 
at 1 d ose le vel re d uce d w he n t he t o xicit y res ol ves  t o a cli nicall y acce pta ble le vel ( gra de 1/ 2). 
8. 4 
D ose M o dific ati o ns f or E ver oli m us al o ne ( after cr oss o ver)  
• If m ulti ple a d verse e ve nts are see n, a d mi nister d ose base d o n greatest re d ucti o n re q uire d 
f or a n y si n gle a d verse e ve nt o bser ve d.  Re d ucti o ns or i ncreases a p pl y t o treat me nt gi ve n i n 
t he prece di n g c ycle a n d are base d o n a d verse e ve nts o bser ve d si nce t he pri or d ose. 
• E ver oli m us will n ot be re -escalate d o nce re d uce d 
•  If  d ose  re d ucti o ns  be y o n d  d ose le vel -2  is  re q uire d  or  e ver oli m us  is  hel d f or 4  wee ks, 
e ver oli m us will be disc o nti n ue d.  
• If m ore t ha n o ne of t hese t o xicities a p pl y, use t he m ost stri n ge nt criteria (i.e., t he greatest 
d ose re d ucti o n.).   
C T E P -A E R S  re p orti n g ma y be re q uire d f or s o me a d verse e ve nts ( See Secti o n 9. 0 ) 

 
 
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8. 4. 1 D ose le vels  
D ose re d ucti o n of e ver oli m us will be perf or me d acc or di n g t o t he ta ble bel o w. E ver oli m u s 
will be per ma ne ntl y disc o nti n ue d f or patie nts w h o re q uire d ose i nterr u pti o ns of > 2 8 da ys 
or w h o e x perie nce d ose li miti n g t o xicities at d ose le vel -2. Misse d d oses of e ver oli m us will 
n ot be ma de u p.  
 
D ose Le vel  
 
Dr u g N a me  
 
D ose  
 0 *  
 
E ver oli m us  
1 0 m g dail y  
-1  
 
E ver oli m us  
5 m g dail y  
-2  
 
E ver oli m us  
2. 5 m g dail y  
* D ose le vel 0 refers t o t he starti n g d ose.  
8. 4. 2 D ose M o dific ati o ns f or He m at ol o gic T o xicities  
Gr a de ≥3 ne utr o pe ni a, t hr o m b oc yt o pe ni a, or ne utr o pe nic fe ver : I nterr u pt e ver oli m us 
u ntil ≤ gra de 2, t he n res u me wit h o ne d ose le vel re d ucti o n of e ver oli m us f or all s u bse q ue nt 
d oses.  
8. 4. 3   D ose M o dific ati o ns f or G astr oi ntesti n al T o xicities  
•  Gr a de  ≥  3  di arr he a: I nterr u pt  e ver oli m us  u ntil  diarr hea  i m pr o ves  t o  ≤  gra de  2,  t he n 
res u me e ver oli m us wit h o ne d ose le vel re d ucti o n. 
• Gr a de 3 st o m atitis: I nterr u pt e ver oli m us u ntil ≤ gra de 1 t he n res u me wit h o ne d ose le vel 
re d uce d. 
• Gr a de 4 st o m atitis: Disc o nti n ue e ver oli m us   
8. 4. 4 D ose M o dific ati o ns f or He p atic D ysf u ncti o n  
• Gr a de 2 bl o o d bilir u bi n i ncre ase d: I nterr u pt e ver oli m us u ntil i m pr o ve d t o gra de 1, t he n 
res u me e ver oli m us at sa me d ose. 
• Gr a de 3 bl o o d bilir u bi n i ncre ase d: I nterr u pt e ver oli m us u ntil i m pr o ve d t o gra de 1, t he n 
res u me e ver oli m us at 1 d ose le vel re d uce d. 
• Gr a de 4 bl o o d bilir u bi n i ncre ase d : Disc o nti n ue e ver oli m us. 
• Gr a de 3 tr a ns a mi n ase i ncre ase d: I nterr u pt e ver oli m us u ntil i m pr o ve d t o gra de 1, t he n 
res u me e ver oli m us at 1 d ose le vel re d uce d. 
• Gr a de 4 tr a ns a mi n ase i ncre ase d:  Disc o nti n ue e ver oli m us.  
8. 4. 5 D ose M o dific ati o ns f or S ki n T o xicit y  
• Gr a de 4 Ac neif or m R as h: I nterr u pt e ver oli m us u ntil gra de ≤ 2, t he n restart at o ne d ose 
le vel decrease d 
• Gr a de 3 M ac ul o p a p ul ar R as h: I nterr u pt e ver oli m us u ntil gra de ≤ 2, t he n restart at o ne 
d ose le vel decrease d  
8. 4. 6 D ose M o dific ati o ns f or P ul m o n ar y T o xic it y 
• Gr a de 2 or 3 p ne u m o nitis: I nterr u pt e ver oli m us u ntil ≤ gra de 1. Res u me e ver oli m us at 
o ne d ose le vel decrease d  

 
 
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• Gr a de 4 p ne u m o nitis: Disc o nti n ue e ver oli m us  
8. 4. 7 D ose M o dific ati o ns f or Re n al T o xicit y  
• Gr a de 2 i ncre ase d cre ati ni ne: I nterr u pt e ver oli m us u ntil gra de ≤ 1, t he n res u me wit h o ne 
d ose le vel decrease d   
• Gr a de 3 a n d 4 i ncre ase d cre ati ni ne : Disc o nti n ue e ver oli m us 
8. 4. 8 D ose M o dific ati o ns f or Met a b olis m  
Gr a de 4 H y per gl yce mi a:  I nterr u pt e ver oli m us u ntil gra de ≤ 2, t he n res u me at sa me d ose 
8. 4. 9 D ose M o dific ati o ns f or Ge ner al Dis or ders  
Gr a de  3  E de m a:   I nterr u pt  e ver oli m us  u ntil  ≤  gra de  2,  t he n  res u me  at  o ne  d ose  le vel 
decrease d  
8. 4. 1 0 D ose M o dific ati o ns f or Ot her N o n -he m at ol o gic T o xicities  
F or  ot her  cli nicall y  si g nifica nt  gra de  3/ 4  n o n -he ma t ol o gic  t o xicities  li kel y  relate d  t o 
e ver oli m us,  i nterr u pt  e ver oli m us.  Res u me  e ver oli m us  at  1  d ose  le vel  re d uce d  w he n  t he 
t o xicit y res ol ves t o a cli nicall y acce pta ble le vel ( gra de 1/ 2). 

 
 
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9. 0  
A D V E R S E E V E N T S  
T he pr o m pt re p orti n g of a d verse e ve nts is t he res p o nsi bilit y of eac h i n vesti gat or e n ga ge d i n cli nical 
researc h, as re q uire d b y Fe deral Re g ulati o ns. A d verse e ve nts m ust be descri be d a n d gra de d usi n g t he 
ter mi n ol o g y a n d gra di n g cate g ories defi ne d i n t he 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), Versi o n 4. 0. H o we ver, C T C A E v 5. 0 m ust be use d f or seri o us A E re p orti n g t hr o u g h 
C T E P -A E R S  as  of  A pril  1,  2 0 1 8.  T he  C T C A E  is  a vaila ble  at 
 
 Attri b uti o n t o pr ot oc ol treat me nt f or eac h a d verse e ve nt m ust be deter mi ne d b y 
t he i n vesti gat or a n d re p orte d o n t he re q uire d f or ms, usi n g t he c o des pr o vi de d. 
9. 1 
R o uti ne a d verse e ve nt re p orti n g  
A d verse e ve nt data c ollecti o n a n d re p orti n g, w hic h are re q uire d as part of e v er y cli nical trial are 
d o ne t o e ns ure t he safet y of patie nts e nr olle d i n t he st u dies as well as t h ose w h o will e nr oll i n 
f ut ure st u dies usi n g si milar a ge nts. A d verse e ve nts are re p orte d i n a r o uti ne ma n ner at sc he d ule d 
ti mes acc or di n g t o t he st u d y cale n dar i n Secti o n 5. 0 . F or t his trial, Ra ve is use d f or r o uti ne A E 
re p orti n g. 
S olicite d A d verse E ve nts: T he f oll o wi n g a d verse e ve nts are c o nsi dere d "e x pecte d" a n d t heir 
prese nce/a bse nce  s h o ul d  be  s olicite d,  a n d  se verit y  gra de d,  at  baseli ne  a n d  f or  eac h  c ycle  of 
treat me nt. 
 
C T C A E v 4. 0 Ter m 
C T C A E  v 4. 0  S yste m  Or g a n  Cl ass 
( S O C) 
Ne utr o p hil c o u nt decreas e d 
I n v esti gati o ns 
Platelet c o u nt decr ease d  
I n v esti gati o ns 
He m o gl o bi n decrease d 
I n v esti gati o ns 
H y p er gl yce mia  
Meta b olis m a n d n utriti o n dis or ders 
H y p erte nsi o n  
Vasc ular dis or d ers  
Fati g ue  
Ge neral dis or ders  
Pal mar -pla ntar er yt h ro d ysest hesia 
s y n dr o me 
S ki n a n d s u bc uta ne o us tiss ue dis or ders 
Diarr hea  
Gastr oi ntesti nal dis or ders  
Wei g ht L oss  
I n v esti gati o ns 
9. 2 
C T C A E R o uti ne St u d y Re p orti n g Re q uire me nts  
* C o m bi n ati o ns  of  C T C A E  Gr a de  &  Attri b uti o n  Re q uire d  f or  R o uti ne  A E  D at a 
S u b missi o n o n C ase Re p ort F or ms ( C R Fs)  
Attri b uti o n  
Gr a de 1  
Gr a de 2  
Gr a de 3  
Gr a de 4  
Gr a de 5  
U nrelate d  
 
 
a 
a 
a 
U nli kel y  
 
 
a 
a 
a 
P ossi ble  
 
a 
a, b 
a, b 
a, b 
Pr o ba ble  
 
a 
a, b  
a, b 
a, b 
Defi nite  
 
a 
a, b 
a, b 
a, b 

 
 
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Res ulti n g i n 
H os pitalizati o n ≥ 2 4 hrs 
1 0 Cale n dar Da ys 
2 4- H o ur; 
5 Cale n dar Da ys  
N ot res ulti n g i n 
H os pitalizati o n ≥ 2 4 hrs 
N ot re q uire d 
1 0 Cale n dar 
Da ys  
 
E x pe dite d A E re p orti n g ti meli nes are defi ne d as:  
o  “ 2 4- H o ur; 5 Cale n dar Da ys” - T he A E m ust i nitiall y be re p orte d via C T E P -A E R S  ≤ 2 4 h o urs 
of lear ni n g of t he A E, f oll o we d b y a c o m plete e x pe dite d re p ort ≤ 5 cale n dar da ys of t he 
i nitial 2 4- h o ur re p ort. 
o  “ 1 0 Cale n dar Da ys” - A c o m plete e x pe dite d re p ort o n t he A E m ust be s u b mitte d ≤ 1 0 
cale n dar da ys of lear ni n g of t he A E.  
1 Seri o us a d verse e ve nts t hat occ ur m ore t ha n 3 0 da ys after t he da y of treat me nt re q uire re p orti n g as 
f oll o ws:  
E x pe dite d 2 4 -h o ur n otific ati o n f oll o we d b y c o m plete re p ort ≤ 5 c ale n d ar d a ys f or: 
•  
All Gra de 4, a n d Gra de 5 A Es t hat are at lea st p ossi bl y relate d t o treat me nt 
E x pe dite d 1 0 c ale n d ar d a y re p orts f or:  
•  
Gra de 2 a d verse e ve nts res ulti n g i n h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n a n d 
t hat are at least p ossi bl y relate d t o treat me nt 
•  
Gra de 3 a d verse e ve nts a n d t hat are at least p ossi bl y relate d t o treat me nt  
 
 
A d diti o n al I nstr ucti o ns or E xcl usi o ns:  
• 
All  a d verse  e ve nts  re p orte d  via C T E P -A E R S  (i.e.,  seri o us  a d verse  e ve nts)  s h o ul d  als o  be 
f or war de d t o y o ur l ocal I R B, acc or di n g t o l ocal I R B p olicies. 
• 
Deat h  d ue  t o  pr o gressi ve  disease  s h o ul d  be  re p orte d as  Gra de  5 “ Disease  pr o gressi o n”  i n  t he 
s yste m or ga n class ( S O C) “ Ge neral dis or ders a n d a d mi nistrati o n site c o n diti o ns.” E vi de nce t hat 
t he deat h was a ma nifestati o n of u n derl yi n g disease (e. g., ra di ol o gical c ha n ges s u g gesti n g t u m or 
gr o wt h  or  pr o gressi o n:  cli nical  deteri orati o n  ass ociate d  wit h  a  disease  pr ocess)  s h o ul d  be 
s u b mitte d. 
• 
Treat me n t e x pecte d a d verse e ve nts i ncl u de t h ose liste d i n Secti o n 1 0. 0 , i n t he pac ka ge i nserts f or 
e ver oli m u s a n d s orafe ni b, a n d i n t he C A E P R f or s orafe ni b. N O T E: T he A S A E L c ol u m n of t he 
s orafe ni b C A E P R has bee n re place d wit h t he s pecific pr ot oc ol e xce pti o ns t o e x pe dite d re p orti n g 
( S P E E R) list. T his list n o w i ncl u des ‘e x pecte d’ se verit y gra des i n a d diti o n t o e ve nt ter ms. 
• 
All ne w mali g na ncies m ust be re p orte d t hr o u g h C T E P -A E R S  w het her or n ot t he y are t h o u g ht t o 
be relate d t o eit her pre vi o us or c urre nt treat me nt. All ne w mali g na ncies s h o ul d be re p orte d, i.e. 
s oli d  t u m ors  (i ncl u di n g  n o n-mela n o ma  s ki n  mali g na ncies),  he mat ol o gic  mali g na ncies, 
m yel o d ys plastic s y n dr o me (ac ute m yel o ge n o us le u ke mia, a n d i n sit u t u m ors. I n C T C A E v 5. 0, 
sec o n dar y  mali g na ncies  ma y  be  re p orte d  as  o ne  of  t he  f oll o wi n g  t hree  o pti o ns:  1)  Le u ke mia 
sec o n dar y  t o  o nc ol o g y  c he m ot hera p y,  2)  M yel o d ys plastic  s y n dr o me,  or  3)  Treat me nt -relate d 
sec o n dar y  mali g na nc y. W he ne ver  p ossi ble,  t he 
C T E P -A E R S  re p orts  f or  ne w  mali g na ncies 
s h o uld  i ncl u de  t u m or  pat h ol o g y,  hist or y  or  pri or  t u m ors,  pri or  treat me nt/c urre nt  treat me nt 
i ncl u di n g  d urati o n,  a n y  ass ociate d  ris k  fact ors  or  e vi de nce  re gar di n g  h o w  l o n g  t he  ne w 
mali g na nc y ma y ha ve bee n prese nt, w he n a n d h o w t he ne w mali g na nc y was detecte d, m ol ec ular 
c haracterizati o n or c yt o ge netics of t he ori gi nal t u m or (if a vaila ble) a n d of a n y ne w t u m or, a n d 
ne w mali g na nc y treat me nt a n d o utc o me, if a vaila ble.  

 
 
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G E N E R A L DI S O R D E R S A N D A D MI NI S T R A TI O N SI T E C O N DI TI O N S  - C hills; E de ma face; Facial pai n; 
Fl u li ke s y m pt o ms; L ocalize d e de ma; M ulti -or ga n fail ure; N o n -car diac c hest pai n; P ai n  
H E P A T O BI LI A R Y DI S O R D E R S  - C h olec ystitis; He pati c he m orr ha ge; He pat o biliar y dis or ders - Ot her ( biliar y 
o bstr ucti o n sec o n dar y t o m ulti ple biliar y st o nes)  
I M M U N E S Y S T E M DI S O R DE R S  - Aller gic reacti o n; C yt o ki ne release s y n dr o me; I m m u ne s yste m dis or ders - 
Ot her (s yste mic i nfla m mat or y res p o nse s y n dr o me)  
I N J U R Y, P OI S O NI N G A N D P R O C E D U R A L C O M P LI C A TI O N S - Arterial i nj ur y; Fall; Fract ure; Hi p 
fract ure; Vasc ular access c o m plicati o n; W o u n d de hisce nce 
I N V E S TI G A TI O N S - C P K i ncrease d; Car diac tr o p o ni n I i ncrease d; Car diac tr o p o ni n T i ncrease d; C h olester ol 
hi g h; Ej ecti o n fracti o n decrease d; Fi bri n o ge n decrease d; I n vesti gati o ns - Ot her ( bl o o d urea nitr o ge n hi g h)  
M E T A B O LI S M A N D N U T RI TI O N DI S O R D E R S  - Aci d osis; Al kal osis; De h y drati o n; H y per ma g nese mia; 
H y pertri gl yceri de mia; H y per urice mia; H y p o ma g nese mia; T u m or l ysis s y n dr o me  
M U S C U L O S K E L E T A L A N D C O N N E C TI V E TI S S U E DI S O R D E R S  - Art hritis; C hest wall pai n; Ge neralize d 
m uscle wea k ness; J oi nt ra n ge of m oti o n decrease d; M uscle wea k ness l o wer li m b; M uscle wea k ness u p per li m b; 
M usc ul os keletal a n d c o n necti ve tiss ue dis or der - Ot her (cra m pi n g); M y ositis; Nec k pai n  
N E O P L A S M S B E NI G N, M A LI G N A N T A N D U N S P E CI FI E D (I N C L C Y S T S A N D P O L Y P S)  - Le u ke mia 
sec o n dar y t o o nc ol o gy c he m ot hera p y; M yel o d ys plastic s y n dr o me; T u m or he m orr ha ge; T u m or pai n  
N E R V O U S S Y S T E M DI S O R D E R S  - Ata xia; C o g niti ve dist ur ba nce; De presse d le vel of c o nsci o us ness; 
D ys ge usia; D ys p hasia; E nce p hal o pat h y; E xtra p yra mi dal dis or der; H y dr oce p hal us; Isc he mia cere br o vasc ular; 
Let har g y; Le u k oe nce p hal o pat h y; Me m or y i m pair me nt; M us cle wea k ness left -si de d; M uscle wea k ness ri g ht-si de d; 
Ne ural gia; P eri p heral m ot or ne ur o pat h y; P eri p heral se ns or y ne ur o pat h y; Seiz ure; Str o ke; S y nc o pe; Tre m or; 
Vas o va gal reacti o n  
P S Y C HI A T RI C DI S O R D E R S  - A gitati o n; A n xiet y; C o nf usi o n; De pressi o n; Li bi d o decrease d; P ers o nalit y 
c ha n ge; Ps yc h osis  
R E N A L A N D U RI N A R Y DI S O R D E R S  - C hr o nic ki d ne y disease; He mat uria; Ne p hr otic s y n dr o me; Pr otei n uria; 
Re nal a n d uri nar y dis or ders - Ot her (f ocal se g me ntal gl o m er ul oscler osis); Re nal a n d uri nar y dis or ders - Ot her (ri g ht 
ureter r u pt ure); Re nal calc uli; Re nal he m orr ha ge; Uri nar y fr e q ue nc y; Uri nar y i nc o nti ne nc e; Uri nar y rete nti o n; 
Uri nar y tract o bstr ucti o n; Uri ne disc ol orati o n  
R E P R O D U C TI V E S Y S T E M A N D B R E A S T DI S O R D E R S  - Erectile d ysf u ncti o n; G y nec o mastia; 
He mat osal pi n x; Me n orr ha gia; O varia n he m orr ha ge; Pr ostatic he m orr ha ge; S per matic c or d he m orr ha ge; T estic ular 
he m orr ha ge; Uteri ne he m orr ha ge; Va gi nal fist ula; Va gi nal he m orr ha ge  
R E S PI R A T O R Y, T H O R A CI C A N D M E DI A S TI N A L DI S O R D E R S  - A d ult res pirat or y distress s y n dr o me; 
Aller gic r hi nitis; Br o nc h os pas m; Hicc u ps; H oarse ness; H y p o xia; Lar y n geal m uc ositis; P har y n geal m uc ositis; 
P har y n g olar y n geal pai n; Ple ur al eff usi o n; P ne u m o nitis; P ne u m ot h ora x; P ul m o nar y e de ma; P ul m o nar y fi br osi s; 
Res pirat or y, t h oracic a n d me diasti nal dis or ders - Ot her ( nasal se ptal perf orati o n); Trac heal m uc ositis  
S KI N A N D S U B C U T A N E O U S TI S S U E DI S O R D E R S  - Er yt hr o der ma; H y per hi dr osis; Nail l oss; P ai n of s ki n; 
P ur p ura; Ras h ac neif or m; Scal p pai n; S ki n a n d s u bc uta ne o us tiss ue dis or ders - Ot her ( n o n -life t hreate ni n g s q ua m o us 
cell carci n o ma of s ki n: kerat oca nt h o mas t y pe); S ki n h y per pi g me ntati o n; S ki n h y p o pi g me ntati o n; S ki n ulcerati o n; 
Urticaria  
V A S C U L A R DI S O R D E R S  - Fl us hi n g; He mat o ma; H ot flas hes; H y p ote nsi o n; P hle biti s; Vasc ular dis or ders - Ot her 
(r u pt ure d a ortic a ne ur ys m); V asc ulitis 
 
N ote : S orafe ni b ( B A Y 4 3-9 0 0 6; Ne xa var) i n c o m bi nati o n wit h ot her a ge nts c o ul d ca use a n e xacer bati o n of a n y 
a d verse e ve nt c urre ntl y k n o w n t o be ca use d b y t he ot her a ge nt, or t he c o m bi nati o n ma y res ult i n e ve nts ne ver 
pre vi o usl y ass ociate d wit h eit her a ge nt.  
 
9. 4. 2 C o m pre he nsi ve  A d verse  E ve nts  a n d  P ote nti al  Ris ks  list  ( C A E P R)  f or  E ver oli m us 
( R A D- 0 0 1, N S C 7 3 3 5 0 4) 
T he C o m pre he nsi ve A d verse E ve nts a n d P ote ntial Ris ks list ( C A E P R) pr o vi des a si n gle list 
of re p orte d a n d/ or p ote ntial a d verse e ve nts ( A E) ass ociate d wit h a n a ge nt usi n g a u nif or m 
prese ntati o n of e ve nts b y b o d y s yste m. I n a d diti o n t o t he c o m pre he nsi ve list, a s u bset, t he 
S pecific  Pr ot oc ol  E xce pti o ns  t o  E x pe dite d  Re p orti n g  ( S P E E R),  a p pears  i n  a  se parate 
c ol u m n a n d is i de ntifie d wit h b ol d a n d italicize d te xt. T his s u bset of A Es ( S P E E R) is a list 
of e ve nts t hat are pr ot oc ol s pecific e xce pti o ns t o e x pe dite d re p orti n g t o N CI (e xce pt as n ote d 

 
 
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A d verse e ve nts re p orte d o n e ver oli m us ( R A D -0 0 1) tri als, b ut f or w hic h t here is i ns ufficie nt 
e vi de nce t o s u g gest t h at t here w as a re as o n a ble p ossi bilit y t h at e ver oli m us ( R A D -0 0 1) c a use d t he 
a d verse e ve nt : 
 
B L O O D A N D L Y M P H A TI C S Y S T E M DI S O R D E R S  - T hr o m b otic t hr o m b oc yt o pe nic p ur p ura  
C A R DI A C DI S O R D E R S  - Atrial fi brillati o n; Car diac dis or ders - Ot her ( m y ocar dial a b n or malit y); C hest 
pai n - car diac; Heart fail ure; Left ve ntric ular s yst olic d ysf u ncti o n; M y ocar dial i nfarcti o n; Si n us 
bra d ycar dia; Si n us tac h ycar dia; S u pra ve ntric ular tac h ycar dia  
E N D O C RI N E DI S O R D E R S  - E n d ocri ne dis or ders - Ot her (i ncrease d bl o o d f ollicle sti m ulati n g 
h or m o ne [ F S H] le vels); E n d ocri ne dis or ders - Ot her (i ncrease d bl o o d l utei nizi n g h or m o ne [ L H] le vels); 
H y p ot h yr oi dis m; T est oster o ne deficie nc y  
E Y E DI S O R D E R S  - Bl urre d visi o n; Keratitis  
G A S T R OI N T E S TI N A L DI S O R D E R S  - Ascites; C olitis; Dr y m o ut h; D ys pe psia; D ys p ha gia; 
Flat ule nce; Gast r oes o p ha geal refl u x disease; Gastr oi ntesti nal dis or ders - Ot her ( Die ulaf o y's lesi o n); 
He m orr h oi ds; I ntra- a b d o mi nal he m orr ha ge; Oral pai n; Pa ncreatitis; Peri o d o ntal disease; T o ot hac he  
G E N E R A L DI S O R D E R S A N D A D MI NI S T R A TI O N SI T E C O N DI TI O N S  - C hills; E de ma face ; 
E de ma tr u n k; Fl u li ke s y m pt o ms; N o n- car diac c hest pai n; Pai n 
H E P A T O BI LI A R Y DI S O R D E R S  - He patic fail ure; He pat o biliar y dis or ders - Ot her ( he pat o me gal y)  
I N V E S TI G A TI O N S - Acti vate d partial t hr o m b o plasti n ti me pr ol o n ge d; Bl o o d bicar b o nate decrease d; 
Bl o o d bilir u bi n i ncrease d; Bl o o d lactate de h y dr o ge nase i ncrease d; C P K i ncrease d; G G T i ncrease d; I N R 
i ncrease d; I n vesti gati o ns - Ot her (l o w de nsit y li p o pr otei n raise d); I n vestigati o ns - Ot her 
(t hr o m b oc yt he mia). 
M E T A B O LI S M A N D N U T RI TI O N DI S O R D E R S  - De h y drati o n; Gl uc ose i nt olera nce; 
H y percalce mia; H y per kale mia; H y perli pi de mia; H y p oal b u mi ne mia; H y p ocalce mia; H y p o kale mia; 
H y p o ma g nese mia; H y p o natre mia; Meta b olis m a n d n utriti o n dis or d ers - Ot her ( hi g h a m m o nia)  
M U S C U L O S K E L E T A L A N D C O N N E C TI V E TI S S U E DI S O R D E R S  - B o ne pai n; C hest wall pai n; 
Ge neralize d m uscle wea k ness; M uscle cra m p; M uscle wea k ness l o wer li m b; M yal gia  
N E O P L A S M S B E NI G N, M A LI G N A N T A N D U N S P E CI FI E D (I N C L C Y S T S A N D P O L Y P S)  - 
Ne o plas ms be ni g n, mali g na nt a n d u ns pecifie d (i ncl c ysts a n d p ol y ps) - Ot her ( o varia n c ysts)  
N E R V O U S S Y S T E M DI S O R D E R S  - Dizzi ness; E nce p hal o pat h y; H y dr oce p hal us; Let har g y; 
Parest hesia  
P S Y C HI A T RI C DI S O R D E R S  - A gitati o n; A n xiet y 9; Deliri u m; De pressi o n; I ns o m nia; Irrita bilit y; 
Ma nia  
R E N A L A N D U RI N A R Y DI S O R D E R S  - He mat uria; Pr otei n uria; Uri nar y fre q ue nc y  
R E P R O D U C TI V E S Y S T E M A N D B R E A S T DI S O R D E R S  - D ys me n orr hea; Ge nital e de ma; Irre g ular 
me nstr uati o n; Me n orr ha gia; Va gi nal he m orr ha ge  
R E S PI R A T O R Y, T H O R A CI C A N D M E DI A S TI N A L DI S O R D E R S  - Br o nc h o p ul m o nar y 
he m orr ha ge; P har y n g olar y n geal pai n; Ple ural eff usi o n; Res pirat or y fail ure; Res pirat or y, t h oracic a n d 
me diasti nal dis or ders - Ot her (rales); R hi n orr hea; S ore t hr oat; V oice alterati o n  
S KI N A N D S U B C U T A N E O U S TI S S U E DI S O R D E R S  - Nail l oss; Pal mar - pla ntar er yt hr o d ysest hesia 
s y n dr o me; Ras h ac neif or m; S ki n a n d s u bc uta ne o us tiss ue dis or ders - Ot her ( nail dis or der); S ki n a n d 
s u bc uta ne o us tiss ue dis or ders - Ot her (s ki n lesi o n); S ki n ulcerati o n  
V A S C U L A R DI S O R D E R S  - Fl us hi n g; H y perte nsi o n; L y m p he de ma; P hle bitis; T hr o m b oe m b olic e ve nt; 
Vasc ular dis or ders - Ot her (ac ute b o wel isc he mia); Vasc ular dis or ders - Ot her ( he m orr ha ge)  
 
N ote : E ver oli m us ( R A D- 0 0 1) i n c o m bi nati o n wit h ot her a ge nts c o ul d ca use a n e xacer bati o n of a n y 
a d verse e ve nt c urre ntl y k n o w n t o be ca use d b y t he ot her a ge nt, or t he c o m bi nati o n ma y res ult i n e ve nts 
ne ver pre vi o usl y ass ociate d wit h eit her a ge nt.  

 
 
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9. 4. 2. 1 A d diti o n al  I nstr ucti o ns  or  E xcl usi o n  t o  C T E P -A E R S  E x pe dite d  Re p orti n g 
Re q uire me nts f or P h ase 2 a n d 3 Tri als Utilizi n g a n  A ge nt U n der a C T E P I N D or n o n -
C T E P I N D:  
B L O O D A N D L Y M P H A TI C S Y S T E M DI S O R D E R S  
• 
Gra de   3  ane mia a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot  re q uire  C T E P -
A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
G A S T R OI N T E S TI N A L DI S O R D E R S  
• 
Gra de 3  diarr hea (incl u des diarr hea, e nteritis, e nter oc olitis, c olitis, defecati o n 
ur ge nc y, a n d steat orr hea) a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 3  muc ositis oral  (i ncl u des st o matitis, a p ht ho us st o matitis, gi n gi val 
pai n/s welli n g/ ulcerati o n, gl ossitis, gl oss o d y nia, li p ulcerati o n, m o ut h ulcerati o n, 
t o n g ue ulcerati o n, a n d m uc osal i nfla m mati o n) a n d h os pitalizati o n res ulti n g fr o m 
s uc h d o n ot re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 3  na usea , v o miti n g a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
G E N E R A L DI S O R D E R S A N D A D MI NI S T R A TI O N SI T E C O N DI TI O N S  
• 
Gra de 2 ede ma li m bs a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire C T E P -
A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 2 fati g ue a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire C T E P -A E R S, 
b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 2 fe ver a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire C T E P- A E R S, 
b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
I N F E C TI O N S A N D I N F E S T A TI O N S 
• 
Gra de 3  infecti o n  (i nfecti o n i ncl u des all 7 5 i nfecti o n sites u n der t he 
I N F E C TI O N S A N D I N F E S T A TI O N S S O C) a n d h os pitalizati o n res ulti n g fr o m 
s uc h d o n ot re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
I N V E S TI G A TI O N S 
• 
Gra de 2 ala ni ne a mi n otra nsferase i ncrease d a n d h os pitalizati o n res ulti n g fr o m s uc h 
d o n ot re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 2 al kali ne p h os p hatase i ncrease d a n d h os pitalizati o n res ulti n g fr o m s uc h d o 
n ot re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de  2 as partate  a mi n otra nsferase  i ncrease d a n d  h os pitalizati o n  res ulti n g  fr o m 
s uc h d o n ot re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de  2 ch olester ol  hi g h  a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot  re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 2 c reati ni ne i ncrease d a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 2 ly m p h oc yte c o u nt decrease d a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot 
re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 4 n e utr o p hil c o u nt decrease d a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot 
re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de  4   platelet  c o u nt  decrease d a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot 
re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults.  
• 
Gra de 4  white bl o o d cell decrease d a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot 
re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
M E T A B O LI S M A N D N U T RI TI O N DI S O R D E R S  
• 
Gra de  2 an ore xia a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot  re q uire  C T E P -
A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 

 
 
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• 
Gra de 3  hy per gl yce mia  (H y per gl yce mia ma y res ult i n eit her e xacer bati o n of or 
de vel o p me nt ne w o nset dia betes mellit us ) a n d h os pitalizati o n res ulti n g fr o m s uc h 
d o n ot re q uire C T E P- A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 4  hy pertri gl yceri de mia a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de 2 h y p o p h os p hate mia a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
N E R V O U S S Y S T E M DI S O R D E R S  
• 
Gra de  2 h ea dac he a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot  re q uire  C T E P -
A E R S, b ut s h o ul d be s u b mitte d as part of s t u d y res ults. 
R E S PI R A T O R Y, T H O R A CI C A N D M E DI A S TI N A L DI S O R D E R S  
• 
Gra de 2 c o u g h a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire C T E P -A E R S, 
b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de  2 d ys p nea a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot  re q uire  C T E P -
A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
• 
Gra de  2 epista xis a n d  h os pitalizati o n  res ulti n g  fr o m  s uc h  d o  n ot  re q uire  C T E P -
A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
S KI N A N D S U B C U T A N E O U S TI S S U E DI S O R D E R S  
• 
Gra de 2 ras h mac ul o- pa p ular a n d h os pitalizati o n res ulti n g fr o m s uc h d o n ot re q uire 
C T E P - A E R S, b ut s h o ul d be s u b mitte d as part of st u d y res ults. 
1 0. 0  
D R U G IN F O R M A TI O N  
1 0. 1 
S or af e ni b ( Ne x a v ar ®, B A Y 4 3 - 9 0 0 6) 
Pr oc ure me nt  
S orafe ni b is c o m merciall y a vaila ble.  
F or m ul ati o n  
T he dr u g pr o d uct f or s u p pl y of cli nical st u dies is a n i m me diate release (I R) 2 0 0 m g ta blet.  T he 
ta blets are re d i n c ol or.  
T a blets als o c o ntai n micr ocr ystalli ne cell ul ose, cr oscar mell ose s o di u m, h y dr o x y pr o p yl met h yl 
cell ul ose, ma g nesi u m stearate, s o di u m l a ur yl s ulfate wit h a fil m c oat c o ntai ni n g h y dr o x y pr o p yl 
met h yl cell ul ose, p ol yet h yle ne gl yc ol, tita ni u m di o xi de, a n d re d ir o n o xi de. 
Pre p ar ati o n, St or a ge a n d St a bility 
T he  ta blets  are  pac ka ge d  i n  hi g h -de nsit y  p ol yet h yle ne  b ottles  (cli mate  z o nes  I/II)  or  al u-al u 
blisters (cli mate z o nes III/I V). T he y s h o ul d o nl y be st ore d i n t he pac k pr o vi de d. T he st ora ge 
te m perat ure f or hi g h de nsit y p ol yet h yle ne b ottles s h o ul d n ot e xcee d 2 5º C. 
A d mi nistr ati o n 
A d mi nister o n a n e m pt y st o mac h ( 1 h o ur bef ore or 2 h o urs after eati n g).  W he n gi ve n wit h a 
hi g h  fat  meal,  s orafe ni b  a bs or pti o n  is  re d uce d  a p pr o xi matel y  3 0 %  c o m pare d  wit h  fasti n g 
a d mi nistrati o n.   
Dr u g I nter acti o ns  
C yt oc hr o me P 4 5 0 Effect:  
 
S u bstr ate of C Y P 3 A 4 ( mi n or), U G T 1 A 1  
 
I n hi bits C Y P 2 B 6 ( m o derate), 2 C 8 (str o n g), 2 C 9  ( m o derate), U G T 1 A 1, U G T 1 A 9 
I ncre ase d Effect/ T o xicit y: S orafe ni b ma y i ncrease t he le vels/effects of car b o plati n, d oceta xel, 
d o x or u bici n, fl u or o uracil, a n d iri n oteca n (a n d acti ve meta b olite S N 3 8). S orafe ni b ma y i ncrease 
t he  ser u m  c o nce ntrati o n  of  t he  acti ve meta b olite  of  dacar bazi ne.  S orafe ni b  ma y  e n ha nce t he 

 
 
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a ntic oa g ula nt  effect  of  warfari n.  S orafe ni b  ma y  i ncrease  t he  le vels/effects  of  C Y P 2 B 6 
s u bstrates;  e xa m ple  s u bstrates  i ncl u de  b u pr o pi o n,  pr o met hazi ne,  pr o p of ol,  sele gili ne,  a n d 
sertrali ne.  S orafe ni b  ma y i ncrease  le vels/effects  of  C Y P 2 C 8  s u bstrates;  e xa m ple  s u bstrates 
i ncl u de  a mi o dar o ne,  paclita xel,  pi o glitaz o ne,  re pa gli ni de,  a n d  r osi glitaz o ne.  S orafe ni b  ma y 
i ncrease  le vels/effects  of  C Y P 2 C 9  s u bstrates;  e xa m ple  s u bstrates i ncl u de  b ose nta n,  da ps o ne, 
fl u o xeti ne,  gli me piri de,  gli pizi de,  l osarta n,  m o ntel u kast,  nate gli ni de,  paclita xel,  p he n yt o n, 
warfari n, a n d zafirl u kast. T he le vels/effects of s orafe ni b ma y be i ncrease d b y: be vaciz u ma b; 
C Y P 3 A 4 I n hi bit ors ( Str o n g); de n os u ma b; pi mecr oli m us; tacr oli m us (t o pical); t rast uz u ma b. 
Decre ase d  Effect: S orafe ni b  ma y  decrease t he a bs or pti o n  of  di g o xi n  ta blets.  S orafe ni b  ma y 
decrease t he le vels/effects of fl u or o uracil. S orafe ni b ma y decrease t he ser u m c o nce ntrati o n of 
dacar bazi ne a n d B C G. C Y P 3 A 4 i n d ucers ma y decrease t he le vels/effects of s orafe ni b; e xa m ple 
i n d ucers  i ncl u de  a mi n o gl utet hi mi de,  car ba maze pi ne,  nafcilli n,  ne vira pi ne,  p he n o bar bital, 
p he n yt oi n, a n d rifa m yci ns.  
Please  see  t he  F D A  a p pr o ve d  pac ka ge  i nsert  of  s orafe ni b  f or  a  detaile d  descri pti o n  of  dr u g 
i nteracti o n data a n d rec o m me n dati o ns. 
Et h a n ol/ N utriti o n/ Her b I nter acti o ns:  
F o o d: Bi oa vaila bilit y is decrease d 2 9 % wit h a hi g h -fat meal ( bi oa vaila bilit y is si milar t o fasti n g 
state w he n a d mi nistere d wit h a m o derate-fat meal). 
Her b/ N utrace utical: A v oi d St J o h n’s w ort ( ma y d ecrease t he le vels/effects of s orafe ni b).  
P h ar m ac oki netics 
Bi oa vaila bilit y:  3 8 % t o 4 9 %, re d uce d w he n a d mi nistere d wit h a hi g h- fat meal. 
Pr otei n Bi n di n g:  9 9. 5 %.  S orafe ni b is a p pr o xi matel y e q uall y distri b ute d bet wee n re d bl o o d cells 
a n d plas ma wit h plas ma t o bl o o d rati o of 1. 3 3.  
Meta b olis m:  He patic: via C Y P 3 A 4 ( pri maril y o xi date d t o t he p yri di ne N -o xi de; acti ve, mi n or) 
a n d U G T 1 A 9 ( gl uc ur o ni dati o n) 
Half -life eli mi nati o n: 2 5- 4 8 h o urs 
Ti me t o pea k, plas ma : ~ 3 h o urs 
E xcreti o n : Feces ( 7 7 %, 5 1 % as u nc ha n ge d dr u g); Uri ne ( 1 9 %, as meta b olites)  
A dverse Eve nts  
K n o w n p ote ntial a d verse e ve nts:  C o ns ult t he pac ka ge i nsert f or t he m ost c urre nt a n d c o m plete 
i nf or mati o n. Fre q ue nc y liste d deri ve d fr o m m o n ot hera p y trials. 
C o m m o n k n o w n p ote ntial t o xicities, > 1 0 % :   
Car di o vasc ular: H y perte nsi o n, t hr o m b oe m b olic e ve nt 
Ce ntral ner v o us s yste m: Fati g ue, se ns or y ne ur o pat h y, pai n  
Der mat ol o gic:  Ras h/ des q ua mati o n,  ha n d -f o ot  s y n dr o me,  al o pecia,  pr urit us,  dr y  s ki n, 
er yt he ma  
E n d ocri ne  
&  
meta b olic:  
H y p oal b u mi ne mia,  h y p ocalce mia, 
h y p o p h os p hate mia, 
h y per gl yce mia, li pase i ncrease d, ser u m a m ylase i ncrease d  
Gastr oi ntesti nal:  Diarr hea,  li pase  i ncrease d,  a m ylase  i ncrease d,  a b d o mi nal  pai n,  wei g ht 
l oss, a n ore xia, na usea, v o miti n g, c o nsti pati o n 
He mat ol o gic:  L y m p h o pe nia,  t hr o m b oc yt o pe nia,  I N R  ele vate d,  ne utr o pe nia,  he m orr ha ge, 
le u k o pe nia, pr ol o n ge d A P T T 
He patic:  Li ver  d ysf u ncti o n,  ala ni ne  a mi n otra nsferase  i ncrease d,  al kali ne  p h os p hatase 
i ncrease d, as partate a mi n otra nsferase i ncrease d, bl o o d bilir u bi n i ncrease d 

 
 
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Ne ur o m usc ular & s keletal: M uscle  pai n, wea k ness  
Res pirat or y: D ys p nea, c o u g h  
Less c o m m o n k n o w n p ote ntial t o xicities, 1 % - 1 0 % :  
Car di o vasc ular: Car diac isc he mia/i nfarcti o n, heart fail ure, fl us hi n g  
Ce ntral Ner v o us S yste m: Hea dac he, de pressi o n, fe ver, dizzi ness, i ns o m nia 
Der mat ol o gic: Ac ne,  e xf oliati ve der matitis 
E n d ocri ne & meta b olic: H y per kale mia, h y p o gl yce mia, C h olester ol hi g h, G G T i ncrease d, 
l o w ser u m bicar b o nate, h y per natre mia, h y per urice mia, h y p o kale mia, h y p ocalce mia 
He mat ol o gic: A ne mia, fe brile ne utr o pe nia  
Gastr oi ntesti nal:  A p petite  d ecrease d,  d ys pe psia,  d ys p ha gia,  es o p ha geal  varices  blee di n g, 
gl oss o d y nia,  m uc ositis  oral,  st o matitis,  xer ost o mia,  gastr oi ntesti nal  he m orr ha ge,  a nal 
m uc ositis, rectal m uc ositis, s mall i ntesti nal m uc ositis, ascites  
Ge nit o uri nar y: Erectile d ysf u ncti o n  
He patic : Tra nsa mi nases i ncrease d 
Ne ur o m usc ular  &  s keletal:  J oi nt  pai n,  art hral gia,  m yal gia,  bac k  pai n,  pai n  i n  e xtre mit y, 
m uscle s pas ms  
Re nal: Re nal fail ure, ele vate d creati ni ne, he mat uria, re nal he m orr ha ge, pr otei n uria  
Re pr o d ucti ve s yste m a n d breast dis or ders: He mat osal pi n x, o varia n he m orr ha ge, pr ostatic 
he m orr ha ge,  s per matic  c or d  he m orr ha ge,  testic ular  he m orr ha ge,  uteri ne  he m orr ha ge, 
va gi nal he m orr ha ge 
Res pirat or y:  Br o nc h o p ul m o nar y  he m orr ha ge,  e pista xis,  h oarse ness,  lar y n geal  m uc ositis, 
p har y n geal m uc ositis, trac heal m uc ositis  
Miscella ne o us: Fl u -li ke s y n dr o me, e de ma li m bs, n o n-car diac c hest pai n, i nfecti o n 
Rare k n o w n p ote ntial t o xicities, < 1 % ( Li mite d t o i m p orta nt or life-t hreate ni n g):  
Ac ute  c or o nar y  s y n dr o me,  a na p h yla xis,  left  ve ntric ular  s yst olic  d ysf u ncti o n,  ac ute  re nal 
fail ure, al kali ne  p h os p hatase i ncrease d,  a ortic dissecti o n, arr h yt h mia,  bilir u bi n i ncrease d, 
b o ne  pai n,  car diac  fail ure,  cere bral  he m orr ha ge,  c h ola n gitis,  c h olec ystitis,  de h y drati o n, 
ecze ma,  er yt he ma  m ultif or me,  f ollic ulitis,  gastritis,  gastr o i ntesti nal  perf orati o n, 
gastr oi ntesti nal  refl u x,  g y nec o mastia,  h y perse nsiti vit y  (s ki n  reacti o n,  urticaria), 
h y perte nsi ve  crisis,  h y p o natre mia,  h y per/ h y p ot h yr oi dis m,  j a u n dice,  MI,  m uscle  wasti n g, 
m y ocar dial isc he mia, ne p hr otic s y n dr o me, pa ncreatitis, ple ural eff usi o n, preecla m psia -li ke 
s y n dr o me  (re versi ble  h y perte nsi o n  a n d  pr otei n uria),  res pirat or y  he m orr ha ge,  re versi ble 
p osteri or le u k oe nce p hal o pat h y s y n dr o me ( R P L S), R hi n orr hea I nterstitial L u n g Disease -li ke 
e ve nts (i ncl u des p ne u m o nitis, ra diati o n p ne u m o niti s, ac ute res pirat or y distress, i nterstitial 
p ne u m o nia,  
p ul m o nitis  
a n d  
l u n g  
i nfla m mati o n)  
s ki n  
ca ncer  
(s q ua m o us 
cell/ kerat oaca nt h o mas),  Ste ve ns -J o h ns o n  s y n dr o me,  t hr o m b oe m b olis m,  ti n nit us,  t o xic 
e pi der mal necr ol ysis, tra nsie nt isc he mic attac k, t u m or l ysis s y n dr o me, t u m or pai n 
N ursi n g G ui deli nes 
•  
Dr u g s h o ul d be ta ke n wit h at least 2 5 0 cc of water. S h o ul d be ta ke n wit h o ut f o o d (at 
least 1 h o ur bef ore or 2 h o urs after meals).  D o n ot a d mi nister wit h gra pefr uit j uice. 
•  
Patie nt ma y e x perie nce fl u -li ke s y m pt o ms s uc h as fati g ue, fe ver, aceta mi n o p he n ma y 
be be neficial f or t hese patie nts.  
•  
M o nit or C B C.  I nstr uct patie nts t o re p ort si g ns a n d s y m pt o ms of i nfecti o n a n d e xcessi ve 
br uisi n g or blee di n g t o t he M D. 

 
 
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•  
M o nit or L F T’s. 
•  
Patie nts ma y e x perie nce diarr hea. See secti o n 8. 1. 5 f or ma na ge me nt of diarr hea. 
•  
I nstr uct patie nt t o re p ort se vere a b d o mi nal pai n, as pa ncreatitis is a p ossi bilit y.  
•  
Ma y ca use a n ore xia. E nc o ura ge patie nt t o c o ns u me s mall fre q ue nt meals.  
•  
M o nit or f or si g n/s y m pt o ms of ha n d/f o ot s y n dr o me.  See secti o n 8. 2. 7 f or a p pr o priate 
ma na ge me nt.  
•  
Ma y ca use al o pecia, i nstr uct patie nt of t his p ossi bilit y  
•  
M o nit or f or ras h. T o xic e pi der mal necr ol ysis is a rare b ut seri o us c o n diti o n. I nstr uct 
patie nt t o re p ort a n y ras h t o M D.  
•  
Patie nts o n C o u ma di n s h o ul d be m o nit ore d cl osel y, as d ose ma y nee d t o be a dj uste d 
sec o n dar y t o C Y P 3 A i n hi biti o n. As t here are ma n y p ote ntial dr u g i nteracti o ns, i nstr uct 
patie nt n ot t o start a n y ne w me dicati o n (i ncl u di n g O T C’s or her bal pr o d uc ts) wit h o ut 
c hec ki n g wit h t heir M D first.  
•  
M o nit or bl o o d press ure. I nstr uct patie nts w h o are self -m o nit ori n g t o re p ort a n y i ncrease 
i n t heir bl o o d press ure t o t he st u d y tea m. 
•  
Na usea a n d v o miti n g ma y occ ur. A d mi nister a ntie metics as necessar y  a n d  m o nit or  f or 
t heir effecti ve ness. 
•  
Blee di n g has bee n see n ( GI, res pirat or y, C N S). I nstr uct patie nt t o re p ort a n y blee di n g 
t o  t he  st u d y  tea m  i m me diatel y.  If  blee di n g  is  se vere,  see k  o ut  e mer ge nc y  me dical 
atte nti o n. 
•  
N u mer o us  electr ol yte  i m bala nces  ma y  occ ur 
( h y per natre mia,  h y p ocalce mia, 
h y p o kale mia).  M o nit or  c he mistr y  pa nel  a n d  re p ort  a n y  a b n or malities  t o  t he  treati n g 
p h ysicia n. 
1 0. 2  E ver oli m us ( R A D 0 0 1, Afi nit or ®) 
Pr oc ure me nt:    Dr u g  s u p pl y  is  fr o m  N o vartis;  distri b uti o n  t o  sites  will  be  arra n ge d  bet wee n 
N o var tis a n d t he Allia nce, unless dr u g s h o ul d bec o me c o m merciall y a vaila ble f or t his disease . 
F or m ul ati o n :  T a blets c o ntai ni n g, 5 a n d 1 0 m g of e ver oli m us are blister pac ke d u n der al u mi n u m 
f oil i n u nits of 1 0 ta blets ( 2. 5 m g a vaila ble). E xci pie nts i ncl u de: b ut yl h yr o x yt ol ue ne/ b ut ylate d 
h y dr o x yt ol ue ne  ( B H T),  
ma g nesi u m  stearate,  lact ose,  
h y pr o mell ose/ h y dr o x y pr o p yl 
met h ylcell ul ose, a n d cr os p o vi d o ne.  
Pre p ar ati o n, St or a ge a n d St a bility:   T he st ora ge of e ver oli m us is s u p p orte d b y o n g oi n g sta bilit y 
st u dies. Refer t o la bel f or e x pirati o n date a n d st ora ge c o n diti o ns. 
A d mi nistr ati o n:  E ver oli m us s h o ul d be a d mi nistere d orall y, o nce dail y at t he sa me ti me eac h da y 
eit her c o nsiste ntl y wit h f o o d or c o nsiste ntl y wit h o ut f o o d.  T a blets s h o ul d be s wall o we d w h ole.  
T he ta blets m ust n ot be c he we d or cr us he d a n d gra pefr uit or gra pefr uit j uices s h o ul d be a v oi de d , 
a n d  all  ot her  f o o ds  s h o ul d  be  a v oi de d  t hat  are  k n o w n  t o  i nteract  wit h  C Y P 3 A 4  a n d  P g P 
i n hi bit ors.   
Dr u g I nter acti o ns: A v oi d t he use of str o n g C Y P 3 A 4 or P -gl yc o pr otei n ( P g P)  i n hi bit ors as t hese 
dr u gs  ma y  ca use  i ncrease d  e ver oli m us  c o nce ntrati o ns.    Use  ca uti o n  w he n  e ver oli m us  c o -
a d mi nistere d  wit h  m o derate  C Y P 3 A 4  a n d/ or  P g P  i n hi bit ors.    A v oi d  t he  use  of  c o nc o mita nt 
str o n g C Y P 3 A 4 i n d ucers.   
T he  p har mac o ki netic  i nteracti o n  bet we e n  e ver oli m us  a n d  ot her  c he m ot hera pe utic  a ge nts  is 
bei n g i n vesti gate d, a n d s o me data is a vaila ble.  See t he c urre nt I n vesti gat or’s Br oc h ure f or m ore 

 
 
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c o m pre he nsi ve  i nf or mati o n  as  well  as  rec o m me n dati o ns  f or  use  wit h  c o m p o u n ds  k n o w n  t o 
i nteract wit h e ver oli mus. 
P h ar m ac oki netics : 
A bs or pti o n:  Ra pi d, b ut m o derate 
Pr otei n bi n di n g: 7 4 %  
V d: 1 0 7 t o 3 4 2 L 
Ti me t o pea k, plas ma:  1-2 h o urs  
Meta b olis m:  he patic,  pri nci pall y  via  C Y P 3 A 4.  Meta b olis m  i n v ol ves  de met h ylati o n, 
h y dr o x ylati o n, a n d ri n g de gra dati o n. T here are si x m ai n meta b olites, w hic h ha ve a p pr o xi matel y 
1 0 0- ti mes less acti vit y t ha n t he pare nt e ver oli m us c o m p o u n d.   
Bi oa vaila bilit y:  ~ 3 0 %; s yste m e x p os ure re d uce b y 2 2 % wit h a hi g h -fat meal a n d b y 3 2 % wit h 
a li g ht -fat meal 
Half -life eli mi nati o n: ~3 0 h o urs  
E xcreti o n : Feces ( ~ 8 0 %); uri ne ( ~ 5 % as i nacti ve meta b olite)  
A dverse Eve nts : 
K n o w n p ote nti al a d verse e ve nts:  C o ns ult t he pac ka ge i nsert f or t he m ost c urre nt a n d c o m plete 
i nf or mati o n.  
C o m m o n k n o w n p ote nti al t o xicities, > 1 0 % :   
Car di o vasc ular: Peri p heral e de ma, h y perte nsi o n 
Ce ntral  ner v o us  s yste m:  Fati g ue,  fe ver,  hea dac he,  seiz ure,  pers o nalit y  c ha n ge,  i ns o m nia, 
dizzi ness  
Der mat ol o gic:  Ras h,  cell ulitis,  pr urit us,  c o ntact  der matitis,  e xc oriati o n,  ac ne,  dr y  s ki n,  nail 
dis or der 
E n d ocri ne  &  meta b olic: 
H y perc h olester ole mia,  h y pertri gl yceri de mia,  h y per gl yce mia, 
h y p o p h os p hate mia, h y p o kale mia, bl o o d lactate de h y dr o ge nase i ncrease d 
Gastr oi ntesti nal:  St o matitis,  c o nsti pati o n,  diarr hea,  na usea,  a n ore xia,  v o miti n g,  m uc osal 
i nfla m mati o n, gastr oe nteritis, d ys ge usia 
Ge nit o uri nar y: n o ne 
He mat ol o gic: A ne mia, l y m p h oc yt o pe nia, t hr o m b oc yt o pe nia, ne utr o pe nia ( pa nc yt o pe nia) 
He patic: A S T i ncrease d, A L T i ncrease d, bilir u bi n i ncrease d  
Ne ur o m usc ular & s keletal: Wea k ness, pai n i n e xtre mit y, bac k pai n  
Otic: Otitis me dia  
Re nal: Creati ni ne i ncrease d, he mat uria  
Res pirat or y: U p per res pirat or y i nfecti o n, si n usitis, c o u g h, d ys p nea, nasal c o n gesti o n, r hi nitis, 
p har y n gitis, p ne u m o nitis, e pista xis, p ne u m o nia 
Miscella ne o us: wei g ht decrease d  
Less c o m m o n k n o w n p ote nti al t o xicities, 1 % - 1 0 %:  
Car di o vasc ular:  C hest  pai n,  tac h ycar dia,  a n gi na,  atrial  fi brillati o n,  c hest  disc o mf ort,  e de ma, 
h y perte nsi o n, pal pitati o n, s y nc o pe, c o n gesti ve car di o m y o pat h y, stress car di o pat h y, he m orr ha ge 
( vari o us l ocati o ns) 
Ce ntral  ner v o us  s yste m:  C hills,  a gitati o n,  r estless ness,  a n xiet y,  de pressi o n,  hall uci nati o n, 
he mi paresis, h y perest hesia, malaise, s o m n ole nce  

 
 
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Der mat ol o gic: Pal mar -pla ntar er yt hr o d ysest hesia s y n dr o me, er yt he ma, o n yc h oclasis, pit yriasis 
r osea, s ki n lesi o ns, al o pecia, Hirs utis m, i ncisi o n c o m plicati o ns, h y per hi dr osis, h y pertric h osis 
E n d ocri ne  &  meta b olic:  e xacer bati o n  of  pre -e xisti n g  dia betes  mellit us,  aci d osis,  C us hi n g oi d 
s y n dr o me,  de h y drati o n,  g o ut,  h y percalce mia,  h y per parat h yr oi dis m,  h y per p h os p hate mia, 
h y per urice mia, h y p o gl yce mia, h y p o natre mia, ir o n de ficie nc y, vita mi n B1 2 deficie nc y  
Gastr oi ntesti nal:  Xer ost o mia,  gastritis,  he m orr h oi ds,  d ys pe psia,  d ys p ha gia,  a b d o mi nal 
diste nti o n,  e pi gastric  disc o mf ort,  flat ule nce,  gastr oes o p ha geal  refl u x,  gi n gi val  h y pertr o p h y, 
he mate mesis, ile us, perit o nitis, oral pai n,  a b d o mi nal pai n, gastr oe nteritis viral 
Ge nit o uri nar y: Bla d der s pas m, erectile d ysf u ncti o n, o varia n c ysts, p olla ki uria, p ol y uria, p y uria, 
scr otal e de ma, uri nar y rete nti o n, uri nar y ur ge nc y, uri nar y tract i nfecti o n, me n orr ha gia, va gi nal 
he m orr ha ge, me nstr uati o n dela ye d, a me n orr hea  
He mat ol o gic: He m orr ha ge, le u k oc yt osis, l y m p ha de n o pat h y, t hr o m b oc yt he mia 
He patic: n o ne 
I m m u n ol o gic: H y perse nsiti vit y i ncl u di n g a na p h yla xis 
Ne ur o m usc ular  &  s keletal:  Tre m or,  parest hesia,  ja w  pai n,  art hral gia,  j oi nt  s welli n g,  m uscle 
s pas m, m usc ul os keletal pai n, m yal gia, oste o necr osis, oste o pe nia, oste o p or osis, s p o n d ylitis 
Oc ular: E yeli d e de ma, oc ular h y pere mia, c o nj u ncti vitis, bl urre d visi o n, cataract 
Re nal: Re nal fail ure (i ncl u di n g ac ute re nal fail ure), B U N i ncrease d, h y dr o ne p hr osis, i n terstitial 
ne p hritis, pr otei n uria, re nal arter y t hr o m b osis, re nal i m pair me nt, i ncrease d da yti me uri nati o n  
Res pirat or y: Ple ural eff usi o n, nas o p har y n gitis, br o nc hitis, p har y n g olar y n geal pai n, r hi n orr hea, 
atelectasis, p ul m o nar y e de ma, si n us c o n gesti o n, w heezi n g, p ul m o nar y e m b olis m, he m o pt ysis, 
u p per res pirat or y tract i nfecti o n 
Miscella ne o us: B K vir us i nfecti o n, ca n di diasis, ni g ht s weats  
R are k n o w n p ote nti al t o xicities, < 1 % ( Li mite d t o i m p ort a nt or life- t hre ate ni n g):  
Car di o vasc ular: Fl ui d acc u m ulati o n, ac ute car di o p ul m o nar y e ve nt, car di o ge nic s h oc k, car di o -
res pirat or y  arrest,  m y ocar dial  i nfarcti o n,  e m b olic  str o ke,  dee p  vei n  t hr o m b osis,  c o n gesti ve 
car diac fail ure 
Ce ntral ner v o us s yste m:  A ge usia  
Der mat ol o gic: W o u n d heali n g c o m plicati o n, i m paire d w o u n d heali n g  
E n d ocri ne & meta b olic: Ne w o nset of dia betes mellit us, test oster o ne le vels decrease d  
Gastr oi ntesti nal: Pa ncreatitis, d u o de nal ulcer, es o p ha geal perf orati o n, GI he m orr ha ge, i nter nal 
her nia, i ntesti nal perf orati o n, sali var y gla n d calc ul us  
Ge nit o uri nar y: Az o os per mia, oli g os per mia 
He mat ol o gic:  T hr o m b otic  micr oa n gi o pat h y/t hr o m b otic  t hr o m b oc yt o pe nic  p ur p ura/ he m ol ytic 
ure mic s y n dr o me ( T M A/ T T P/ H U S), ne utr o pe nic se psis, p ure re d cell a plasia  
He patic: He patic c h olestasis, he patitis B reacti vati o n, he patic cirr h osis  
I m m u n ol o gic: D ys p nea, fl us hi n g c hest pai n, a n gi oe de ma 
I nfecti o n: As per gill osis, p ol y o ma vir us i nfecti o n, se psis 
Meta b olis m a n d N utriti o n: n o ne 
Ne ur o m usc ular & s keletal: S y n o vitis, b o ne fiss ure 
Oc ular: Pa pille de ma, reti nal arter y t hr o m b osis, reti nal detac h me nt 
Res pirat or y:  Ac ute  car di o p ul m o nar y  e ve nt,  ac ute  res pirat or y  distress  s y n dr o me,  car di o -
res pirat or y arrest, c hr o nic o bstr ucti ve p ul m o nar y disease, p ul m o nar y h y perte nsi o n 

 
 
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Miscella ne o us: L y m p h o ma, s ki n ca ncer, c o nc o mita nt disease pr o gressi o n, m ulti -or ga n fa il ure. 
I n vesti gat ors or deri n g a n d/ or dis pe nsi n g s u p plie d a ge nts at a n y ti me f or st u d y treat me nt m ust 
be c urre ntl y re gistere d wit h P M B, D C T D, N CI. A re gistere d i n vesti gat or m ust c o -si g n f or ot her 
n o n- re gistere d pers o n nel prescri bi n g t he s u p plie d a ge nts. 
N ur si n g G ui deli nes 
•  
Patie nt ma y e x perie nce hea dac hes.  Treat s y m pt o maticall y wit h a nal gesics, a n d assess 
f or t heir effecti ve ness.  I nstr uct patie nt t o re p ort hea dac hes t hat are n ot relie ve d. 
•  
Fati g ue: W or k wit h patie nt i n e ner g y c o nser vi n g lifest yle.  
•  
A p ht h o us u lcers/ oral m uc ositis: treat s y m pt o maticall y. P ote ntial treat me nts are o ver t he 
c o u nter  salt  a n d  s o da  m o ut h was h,  prescri pti o ns  s uc h  as  visc o us  li d ocai ne  or  ma gic 
m o ut h was h  (c o m bi nati o n  be na dr yl/ maal o x/li d ocai ne).  C o ns ult  wit h  treati n g  pr o vi der 
f or best o pti o n f or y o ur patie nt.   
•  
Me dicati o n s h o ul d be a d mi nistere d at t he sa me ti me eac h da y eit her c o nsiste ntl y wit h 
f o o d or wit h o ut f o o d. T a blets s h o ul d be s wall o we d w h ole; t he y s h o ul d n ot be cr us he d 
or c he we d.  Patie nts s h o ul d be i nstr ucte d t o f oll o w t he re q uire m e nts f or fatt y f o o ds as 
o utli ne d i n t he s pecific pr ot oc ol.  
•  
Patie nts  s h o ul d  be  i nstr ucte d  t o  a v oi d  dri n ki n g  gra pefr uit  or  ot her  citr us  j uice  w hile 
ta ki n g e ver oli m us. 
•  
Ot her dr u gs: E ns ure t hat patie nts are a ware of dr u g -dr u g i nteracti o ns . Assess patie nts’ 
us e of ot her a ge nts, i ncl u di n g O T C ( o ver t he c o u nter) a ge nts a n d her bal s u p ple me nts. 
I nstr uct patie nts n ot t o start a n y me dicati o ns wit h o ut i nf or mi n g treati n g p h ysicia n. 
•  
Na usea: M o nit or f or na usea a n d treat s y m pt o maticall y as re q uire d.  
•  
P ne u m o nitis ca n be se e n i n patie nts ta ki n g e ver oli m us. T here ha ve bee n fatal cases of 
t his re p orte d. I nstr uct patie nts t o re p ort a n y c o u g h, s h ort ness of breat h, fe ver, c hest pai n, 
or a n y ot her relate d s y m pt o ms t o t he healt hcare tea m i m me diatel y. S y m pt o ms s h o ul d 
be assesse d at eac h visit. 
•  
Dia betic patie nts ma y e x perie nce fl uct uati o ns i n t heir bl o o d s u gar. I nstr uct patie nts t o 
m o nit or t heir bl o o d s u gars cl osel y. 
•  
H y perli pi de mia  a n d  h y pertri gl yceri de mia  are  c o m m o n.  M o nit or  li pi d  le vels  cl osel y. 
A d mi nister  li pi d  l o weri n g  a ge nts  as  o r dere d  a n d  m o nit or  f or  t heir  effecti ve ness. 
Pa ncreatitis  ma y  de vel o p  as  a  of  hi g h  li pi d  le vels.  I nstr uct  patie nts  t o  re p ort  ne w  or 
u n us ual a b d o mi nal pai n t o t he st u d y tea m pr o m ptl y. 
•  
I nf or m patie nt of p ossi ble ras h, pr uritis a n d dr y s ki n. I nstr uct patie nt t o re p ort t hese si de 
effects t o t he st u d y tea m.  
•  
M o nit or L F T’s. Re p ort i ncrease L F T’s t o treati n g p h ysicia n.  

 
 
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1 1. 0  
M E A S U R E M E N T O F E F F E C T  
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y usi n g t he ne w i nter nati o nal criteria pr o p ose d 
b y t he re vise d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli nes ( versi o n 1. 1) 3 9.  
C ha n ges i n t he lar gest dia meter ( u ni di me nsi o nal meas ure me nt) of t he t u m or lesi o ns a n d t he s h ort 
a xis meas ure me nts i n t he case of l y m p h n o des are use d i n t he R E CI S T g ui deli ne . 
1 1. 1 
Sc he d ule of E v al u ati o ns:  
F or t he p ur p oses of t his st u d y, patie nts s h o ul d be ree val uate d e ver y 8 wee ks . After 1 2 c ycles ( or 
4 8 wee ks)  of treat me nt, patie nts will be ree val uate d e ver y  1 6 wee ks . 
1 1. 2  Defi niti o ns of Me as ur a ble a n d N o n- Me as ur a ble Dise ase  
1 1. 2. 1 Me as ur a ble Dise ase  
A  n o n -n o dal  lesi o n  is  c o nsi dere d  meas ura ble  if  its  l o n gest  dia meter  ca n  be  acc uratel y 
meas ure d as ≥2. 0 c m wit h c hest x -ra y, or as ≥1. 0 c m wit h C T sca n, C T c o m p o ne nt of a 
P E T/ C T, or M RI.  
A s u perficial n o n - n o dal lesi o n is meas ura ble if its l o n gest dia meter is ≥ 1. 0 c m i n dia meter 
as  assesse d  usi n g  cali pers  (e. g.  s ki n  n o d ules)  or  i ma gi n g.    I n  t he  case  of s ki n  lesi o ns, 
d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he lesi o n, is 
rec o m me n de d. 
A mali g na nt l y m p h n o de is c o nsi dere d meas ura ble if its s h ort a xis is > 1. 5 c m w he n assesse d 
b y C T sca n ( C T sca n slice t hic k ness rec o m me n d e d t o be n o greater t ha n 5 m m).   
T u m or lesi o ns i n a pre vi o usl y irra diate d area are c o nsi dere d meas ura ble disease u n der t he 
f oll o wi n g  c o n diti o ns:  Pr o gressi o n  of  disease  per  R E CI S T  1. 1  si nce  t he  c o m pleti o n  of 
ra diati o n t hera p y. 
1 1. 2. 2 N o n -Me as ur a ble Dise ase  
All  ot her  lesi o ns  ( or  sites  of  disease)  are  c o nsi dere d  n o n -meas ura ble  disease,  i ncl u di n g 
pat h ol o gical n o des (t h ose wit h a s h ort a xis ≥ 1. 0 t o < 1. 5 c m).  B o ne lesi o ns, le pt o me ni n geal 
disease,  ascites,  ple ural/ pericar dial  eff usi o ns,  l y m p ha n gitis  c utis/ p ul m o nis,  i nfla m mat or y 
breast disease, a n d a b d o mi nal masses ( n ot f oll o we d b y C T or M RI), are c o nsi dere d as n o n-
meas ura ble as well.  
N ote:    ‘ C ystic  lesi o ns’  t h o u g ht  t o  re prese nt  c ystic  metastases  ca n  be  c o nsi dere d  as 
meas ura ble lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. H o we ver, 
if n o n-c ystic lesi o ns are prese nt i n t he sa me patie nt, t hese are preferre d f or selecti o n as tar get 
lesi o ns.    I n  a d diti o n,  l y m p h  n o des  t hat  ha ve  a  s h ort  a xis  <  1. 0  c m  are  c o nsi dere d  n o n-
pat h ol o gical (i.e., n or mal) a n d s h o ul d n ot be rec or de d or f oll o we d. 
1 1. 3 
G ui deli nes f or E v al u ati o n of Me as ur a ble Dise ase  
1 1. 3. 1 Me as ure me nt Met h o ds:   
• 
All  meas ure me nts  s h o ul d  be  rec or de d  i n  metric  n otati o n  (i.e.,  deci mal  fracti o ns  of 
ce nti meters) usi n g a r uler or cali pers.  
• 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue m ust be use d t o c haracterize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w -u p. F or patie nts ha vi n g 
o nl y lesi o ns meas uri n g at least 1 c m t o less t ha n 2 c m m ust use C T i ma gi n g f or b ot h 
pre- a n d p ost- treat me nt t u m or assess me nts.   

 
 
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• 
I ma gi n g-base d e val uati o n is preferre d t o e val uati o n b y cli nical e xa mi nati o n w he n b ot h 
met h o ds  ha ve  bee n  use d  at  t he  sa me  e val uati o n  t o  assess  t he  a ntit u m or  effect  of  a 
treat me nt.  
1 1. 3. 2 Acce pt a ble M o d alities f or Me as ur a ble Dise ase: 
• 
C o n ve nti o n al C T a n d M RI:  T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n 
C T sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. If C T sca ns 
ha ve slice t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a m eas ura ble lesi o n s h o ul d 
be t wice t he slice t hic k ness.  
As  wit h  C T,  if  a n  M RI  is  perf or me d,  t he  tec h nical  s pecificati o ns  of  t he  sca n ni n g 
se q ue nces use d s h o ul d be o pti mize d f or t he e val uati o n of t he t y pe a n d site of disease.  
T he lesi o ns s h o ul d be meas ure d o n  t he sa me p ulse se q ue nce.  I deall y, t he sa me t y pe of 
sca n ner s h o ul d be use d a n d t he i ma ge ac q uisiti o n pr ot oc ol s h o ul d be f oll o we d as cl osel y 
as p ossi ble t o pri or sca ns.  B o d y sca ns s h o ul d be perf or me d wit h breat h -h ol d sca n ni n g 
tec h ni q ues, if p ossi ble. 
• 
P E T- C T:  If t he site ca n d oc u me nt t hat t he C T perf or me d as part of a P E T-C T is of 
i de ntical dia g n ostic q ualit y t o a dia g n ostic C T ( wit h I V a n d oral c o ntrast), t he n t he C T 
p orti o n  of  t he  P E T -C T  ca n  be  use d  f or  R E CI S T  meas ure me nts  a n d  ca n  be  use d 
i nterc ha n gea bl y wit h c o n ve nti o nal C T i n acc uratel y me as uri n g ca ncer lesi o ns o ver ti me.   
• 
C hest X -r a y:   Lesi o ns o n c hest x-ra y are acce pta ble as meas ura ble lesi o ns w he n t he y 
are clearl y defi ne d a n d s urr o u n de d b y aerate d l u n g.  H o we ver, C T sca ns are prefera ble.  
• 
P h ysi c al  E x a mi n ati o n:    F or  s u perficial  n o n -n o dal  lesi o ns,  p h ysical  e xa mi nati o n  is 
acce pta ble, b ut i ma gi n g is prefera ble, if b ot h ca n be d o ne. I n t he case of s ki n lesi o ns, 
d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he size of t he lesi o n, 
is rec o m me n de d. 
• 
F D G -P E T:   F D G - P E T sca n ni n g is all o we d t o c o m ple me nt C T sca n ni n g i n assess me nt 
of pr o gressi ve disease [ P D] a n d partic ularl y p ossi ble ' ne w' disease.  A ‘ p ositi ve’ F D G -
P E T sca n ne d lesi o n is defi ne d as o ne w hic h is F D G a vi d wit h a n u p date greater t ha n 
t wice t hat of t he s urr o u n di n g tiss ue o n t he atte n uati o n c orrecte d i ma ge; ot her wise, a n 
F D G -P E T sca n ne d lesi o n is c o nsi dere d ‘ ne gati ve.’  Ne w lesi o ns o n t he basis of F D G -
P E T i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m: 
a. Ne gati ve F D G -P E T at ba seli ne wit h a p ositi ve F D G- P E T at f oll o w- u p is a si g n of 
P D base d o n a ne w lesi o n.  
b. 
N o F D G -P E T at baseli ne a n d a p ositi ve F D G -P E T at f oll o w - u p:   
1)  If t he p ositi ve F D G- P E T at f oll o w -u p c orres p o n ds t o a ne w site of disease 
c o nfir me d b y C T, t his is P D.   
2)  If t he p ositi ve F D G- P E T at f oll o w -u p is n ot c o nfir me d as a ne w site of disease 
o n C T at t he sa me e val uati o n, a d diti o nal f oll o w- u p C T sca ns (i.e., a d diti o nal 
f oll o w-u p sca ns at least 4 wee ks later) are nee de d t o deter mi ne if t here is tr ul y 
pr o gressi o n oc c urri n g at t hat site. I n t his sit uati o n, t he date of P D will be t he 
date of t he i nitial a b n or mal P D G -P E T sca n.   
3)  If t he p ositi ve F D G- P E T at f oll o w -u p c orres p o n ds t o a pre -e xisti n g site of 
disease o n C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic i ma ges, it is 
n ot classifie d as P D.  

 
 
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1 1. 3. 3 Me as ure me nt at F oll o w - u p E v al u ati o n:   
• 
A s u bse q ue nt sca n m ust be o btai ne d wit hi n 9 wee ks, a n d n ot less t ha n 4  wee ks f oll o wi n g 
i nitial d oc u me ntati o n of a n o bj ecti ve stat us of eit her c o m plete res p o nse ( C R) or partial 
res p o nse ( P R).  
• 
I n  t he  case  of  sta ble  disease  ( S D),  f oll o w-u p  meas ure me nts  m ust  ha ve  met  t he  S D 
criteria at least o nce after st u d y e ntr y at a mi ni m u m i nter val of n ot less t ha n 8 wee ks 
(see Secti o n 1 1. 4. 4 ). 
• 
T he c yt ol o g ical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or 
w orse ns d uri n g treat me nt w he n t he meas ura ble t u m or has met criteria f or res p o nse or 
sta ble  disease  is  ma n dat or y  t o  differe ntiate  bet wee n  res p o nse  or  sta ble  disease  (a n 
eff usi o n ma y be a si de effect of t he treat me nt) a n d pr o gressi ve disease if t he eff usi o n is 
si g nifica nt e n o u g h t o be safel y ta p pe d.. 
•  
C yt ol o gic a n d hist ol o gic tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n 
rare cases (e. g., resi d ual lesi o ns i n t u m or t y pes s uc h as ger m cell t u m ors, w here k n o w n 
resi d ual be ni g n t u m ors ca n re mai n.) 
1 1. 4 
Me as ure me nt of Tre at me nt/I nter ve nti o n Effect  
1 1. 4. 1 T ar get Lesi o ns & T ar get L y m p h N o des 
• 
Meas ura ble  lesi o ns  (as  defi ne d  i n 
Secti o n  1 1. 2. 1 )  u p  t o  a ma xi m u m  of  5  lesi o ns, 
re prese ntati ve  of  all  i n v ol ve d  or ga ns,  s h o ul d  be  i de ntifie d  as  “ Tar get  Lesi o ns”  a n d 
rec or de d a n d meas ure d at baseli ne.  T hese lesi o ns ca n be n o n-n o dal or n o dal (as defi ne d 
i n 1 1. 2. 1), w here n o m ore t ha n 2 lesi o ns are fr o m t he sa me or ga n a n d n o m ore t ha n 2 
mali g na nt n o dal lesi o ns are selecte d.  
N ote:  If fe wer t ha n 5 tar get lesi o ns a n d tar get l y m p h n o des are i de ntifie d (as t here ofte n 
will be), t here is n o reas o n t o perf or m a d diti o nal st u dies be y o n d t h ose s pecifie d i n t he 
pr ot oc ol t o disc o ver ne w lesi o ns.   
• 
T ar get lesi o ns a n d tar get l y m p h n o des s h o ul d be selecte d o n t he basis of t heir size, be 
re prese ntati ve of all i n v ol ve d sites of disease, b ut i n a d diti o n s h o ul d be t h ose t hat le n d 
t he msel ves t o re pr o d uci ble re peate d meas ure me nts.  It ma y be t he case t hat, o n occasi o n, 
t he  lar gest  lesi o n  ( or  mali g na nt  l y m p h  n o de)  d oes  n ot  le n d  itself  t o  re pr o d uci ble 
meas ure me nts i n w hic h circ u msta nce t he ne xt lar gest lesi o n ( or mali g na nt l y m p h n o de) 
w h ic h ca n be meas ure d re pr o d uci bl y s h o ul d be selecte d.   
• 
B aseli ne  S u m  of  Di me nsi o ns  ( B S D):    A  s u m  of  t he  l o n gest  dia meter  f or  all  tar get 
lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des will be calc ulate d 
a n d  re p orte d  as  t he  baseli ne  s u m  of  di me nsi o ns  ( B S D).    T he  B S D  will  be  use d  as 
refere nce  t o  f urt her  c haracterize  a n y  o bjecti ve  t u m or  res p o nse  i n  t he  meas ura ble 
di me nsi o n of t he disease.   
• 
P ost -B aseli ne S u m of t he Di me nsi o ns ( P B S D):   A s u m of t he l o n gest dia meter f or all 
tar get  lesi o ns pl us  t he  s u m  of  t he  s h ort  a xis  of  all  t he  tar get  l y m p h  n o des  will  be 
calc ulate d  a n d  re p orte d  as  t he  p ost -baseli ne  s u m  of  di me nsi o ns  ( P B S D).    If  t he 
ra di ol o gist is a ble t o pr o vi de a n act ual meas ure f or t he tar get lesi o n ( or tar get l y m p h 
n o de), t hat s h o ul d be rec or de d, e ve n if it is bel o w 0. 5 c m.  If t he tar get lesi o n ( or tar get 
l y m p h n o de) is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a 
defa ult val ue of 0. 5 c m s h o ul d be assi g ne d.  If it is t he o pi ni o n of t he ra di ol o gist t hat t he 
tar get lesi o n or tar get l y m p h n o de has li kel y disa p peare d, t he meas ure me nt s h o ul d be 
rec or de d as 0 c m. 

 
 
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• 
T he mi ni m u m s u m of t he di me nsi o ns ( M S D) is t he mi ni m u m of t he B S D a n d t he 
P B S D.  
1 1. 4. 2 N o n - T ar get Lesi o ns & N o n- T ar get L y m p h N o des 
N o n -meas ura ble sites of disease ( Secti o n 1 1. 2. 2 ) are classifie d as n o n- tar get lesi o ns or n o n-
tar get l y m p h n o des a n d s h o ul d als o be rec or de d at baseli ne. T hese lesi o ns a n d l y m p h n o des 
s h o ul d be f oll o we d i n acc or d wit h 1 1. 4. 3. 3 . 
1 1. 4. 3 Res p o nse Criteri a  
1 1. 4. 3. 1 All  tar get  lesi o ns  a n d  tar get  l y m p h  n o des  f oll o we d  b y  C T/ M RI/ P E T -C T/ C hest  X -
ra y/ p h ysical  e xa mi nati o n  m ust  be  meas ure d  o n  re-e val uati o n  at  e val uati o n  ti mes 
s pecifie d i n Secti o n 1 1. 1 .  S pecificall y, a c ha n ge i n o bjecti ve stat us t o eit her a P R or 
C R ca n n ot be d o ne wit h o ut re- meas uri n g tar get lesi o ns a n d tar get l y m p h n o des.   
N ote:  N o n -tar get  lesi o ns  a n d  n o n-tar get  l y m p h  n o des  s h o ul d  be  e val uate d  at  eac h 
assess me nt, es peciall y i n t he case o f first res p o nse or c o nfir mati o n of res p o nse.  I n 
selecte d circ u msta nces, certai n n o n-tar get or ga ns ma y be e val uate d less fre q ue ntl y.  
F or e xa m ple, b o ne sca ns ma y nee d t o be re peate d o nl y w he n c o m plete res p o nse is 
i de ntifie d i n tar get disease or w he n pr o gressi o n i n b o ne is s us pecte d. 
1 1. 4. 3. 2  E v al u ati o n of T ar get Lesi o ns 
• 
C o m plete Res p o nse ( C R):  All of t he f oll o wi n g m ust be tr ue:  
a. Disa p peara nce of all tar get lesi o ns.  
b.  Eac h tar get l y m p h n o de m ust ha ve re d ucti o n i n s h ort a xis t o < 1. 0 c m. 
• 
P arti al Res p o nse ( P R): At least a 3 0 % decrease i n P B S D (s u m of t he l o n gest 
dia meter f or all tar get lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get 
l y m p h n o des at c urre nt e val uati o n) ta ki n g as refere nce t he B S D (see Secti o n 
1 1. 4. 1 ). 
• 
P r o gressi o n ( P D):  At least o ne of t he f oll o wi n g m ust be tr ue: 
a.  At least o ne ne w mali g na nt lesi o n, w hic h als o i ncl u des a n y l y m p h n o de t hat 
was n or mal at baseli ne ( < 1. 0 c m s h ort a xis) a n d i ncrease d t o ≥ 1. 0 c m s h ort 
a xis d uri n g f oll o w- u p.  
b. 
At least a 2 0 % i ncrease i n P B S D (s u m of t he l o n gest dia meter f or all tar get 
lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des at c urre nt 
e val uati o n) ta ki n g as refere nce t he M S D ( Secti o n 1 1. 4. 1 ).  I n a d diti o n, t he 
P B S D  m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 0. 5 c m fr o m 
t he M S D.  
c. See Secti o n 1 1. 3. 2  f or details i n re gar ds t o t he re q uire me nts f or P D via 
F D G -P E T i ma gi n g.  
• 
St a ble Dise ase ( S D):  Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R, n or 
s ufficie nt i ncrease t o q ualif y f or P D ta ki n g as refere nce t he M S D. 
1 1. 4. 3. 3  E v al u ati o n of N o n- T ar get Lesi o ns & N o n -t ar get L y m p h N o des 
• 
C o m plete Res p o nse ( C R):  
All of t he f oll o wi n g m ust be tr ue:  
a. Disa p peara nce of all n o n -tar get lesi o ns.  
b.  Eac h n o n-tar get l y m p h n o de m ust ha ve a re d ucti o n i n s h ort a xis t o < 1. 0 c m. 

 
 
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1 1. 5 
Defi niti o ns of a n al ysis v ari a bles  
F or mal defi niti o ns of varia bles use d i n a nal yses ca n b e f o u n d i n t he Statistical C o nsi derati o ns 
secti o n of t he pr ot oc ol. 
1 2. 0  
E N D O F T R E A T M E N T /IN T E R V E N TI O N  
1 2. 1  D ur ati o n of Tre at me nt  
1 2. 1. 1 C R, P R, or S D: Patie nts w h o are i n C R, P R or S D will c o nti n ue o n t hera p y u ntil disease 
pr o gressi o n.   
1 2. 1. 2  Dise ase  P r o gressi o n: Gi ve  a  mi ni m u m  of  6  wee ks  of  t hera p y.  Re m o ve  fr o m  pr ot oc ol 
t hera p y  a n y  patie nt  wit h  disease  pr o gressi o n.  D oc u me nt  details,  i ncl u di n g  t u m or 
meas ure me nts, o n data f or ms.  
After disease pr o gressi o n, patie nts s h o ul d be f oll o we d f or s ur vi val per t he st u d y cale n dar 
(Secti o n 5. 0 ). 
1 2. 1. 3 Disc o nti n u ati o n of st u d y a ge nt: If t he patie nt disc o nti n ues [st u d y a ge nt(s)], patie nts s h o ul d 
be f oll o we d f or s ur vi val per t he st u d y cale n dar ( Secti o n  5. 0). 
1 2. 2  
M a n a gi n g i neli gi ble a n d c a ncele d p atie nts a n d m aj or pr ot oc ol vi ol ati o ns 
Data m ust be s u b mitte d per Secti o n 5. 0  f or patie nts dee me d i neli gi ble or ca ncele d. See als o t he 
F or ms Pac ket f or f ull details of data s u b missi o n re q uire me nts. If a patie nt is dee me d i neli gi ble, 
t he y ma y be re place d. 
1 2. 2. 1 Defi niti o ns  
C a ncelle d P atie nt : A st u d y partici pa nt w h o is re gistere d t o t he trial b ut ne ver recei ves st u d y 
treat me nt. 
I neli gi ble P atie nt: A st u d y partici pa nt w h o is re gistere d t o t he trial b ut d oes n ot meet all of 
t he eli gi bilit y criteria at ti me of re gistrati o n. 
Cli nic al F oll o w -u p : T he f oll o w-u p peri o d w here t he st u d y partic i pa nt is n o l o n ger recei vi n g 
treat me nt, b ut is still f oll o wi n g t he st u d y cale n dar f or tests, e xa ms, a n d c orrelati ve e n d p oi nts 
(e. g., s peci me n c ollecti o n, q ualit y of life, disease assess me nts as re q uire d b y t he st u d y). 
S ur vi v al O nl y F oll o w -u p : T he f oll o w- u p peri o d w here t he st u d y partici pa nt is m o nit ore d 
f or l o n g-ter m e n d p oi nts, is n o l o n ger recei vi n g st u d y treat me nt, a n d is n ot re q uire d t o f oll o w 
t he  st u d y  cale n dar  f or  tests,  e xa ms,  a n d  c orrelati ve  e n d p oi nts  (e. g.,  s peci me n  c ollecti o n, 
q ualit y of life, dise ase assess me nts as re q uire d b y t he st u d y). I n t his f oll o w -u p peri o d, t here 
is a sc he d ule i n w hic h case re p ort f or ms s h o ul d be s u b mitte d, b ut t he p h ysicia n visits are 
base d o n t he sta n dar d of care. 
1 2. 2. 2 F oll o w -u p Re q uire me nts  
Patie nts w h o are dee me d i neli gi ble ma y c o nti n ue pr ot oc ol treat me nt pr o vi de d t he treati n g 
p h ysicia n,  st u d y  c hair,  a n d  E xec uti ve  Officer  a gree  t here  are  n o  safet y  c o ncer ns.  If  t he 
patie nt c o nti n ues pr ot oc ol treat me nt, all sca ns, tests, data s u b missi o n will c o nti n ue as if t he 
patie nt were eli gi ble. N otificati o n of t he l ocal I R B ma y be necessar y per l ocal I R B p olicies.  
1 2. 3  E xtr a or di n ar y Me dic al Circ u mst a nces 
If, at a n y ti me t he c o nstrai nts of t his pr ot oc ol are detri me ntal t o t he patie nt's healt h a n d/ or t he 
patie nt n o l o n ger wis hes t o c o nt i n ue pr ot oc ol t hera p y, pr ot oc ol t hera p y s hall be disc o nti n ue d. I n 
t his e ve nt: 

 
 
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•  
D oc u me nt t he reas o n(s) f or disc o nti n uati o n of t hera p y o n data f or ms. 
•  
F oll o w t he patie nt f or pr ot oc ol e n d p oi nts as re q uire d b y t he St u d y Cale n dar. 
1 3. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 3. 1 
St u d y O ver vie w  
T his ra n d o mize d P hase II trial will c o m pare t he pr o gressi o n -free s ur vi val ( P F S) of s orafe ni b a n d 
e ver oli m us vs. s orafe ni b al o ne i n patie nts wit h ra di oacti ve i o di ne refract or y h ürt hle cell t h yr oi d 
ca ncer.    Pri or  st u dies  h a ve  s h o w n  t hat  t he  me dia n  P F S  is  ge nerall y  ar o u n d  4. 5  m o nt hs  f or 
s orafe ni b al o ne i n t his disease p o p ulati o n 2 9.  It is h o pe d t hat t he c o m bi nati o n of e ver oli m us a n d 
s orafe ni b ca n i ncrease t he me dia n P F S t o at least 9 m o nt hs.  I n a d diti o n t o P F S, t his trial will 
als o  c o m pare  t he  c o nfir me d  res p o nse  rate,  o verall  s ur vi val  ( O S), a n d  a d verse  e ve nt  rates 
bet wee n s orafe ni b a n d e ver oli m us vs. s orafe ni b al o ne.  
1 3. 2 
P ri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt f or t his st u d y will c o m pare P F S bet wee n s orafe ni b a n d e ver oli m us vs. 
s orafe ni b al o ne i n patie nts wit h ra di oacti ve i o di ne refract or y h ürt hle cell t h yr oi d ca ncer.   P F S 
is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he first of eit her disease pr o gressi o n or deat h fr o m 
a n y ca use, w here disease pr o gressi o n will be deter mi ne d base d o n R E CI S T 1. 1 3 9 a n d will be 
d oc u me nte d at eac h e nr olli n g site wit h n o ce ntral re vie w pla n ne d.    
Fi nal A nal ysis : T he pri mar y goal is t o c o m pare s orafe ni b a n d e ver oli m us vs. s orafe ni b al o ne, 
w here t he alter nati ve h y p ot hesis is t hat s orafe ni b a n d e ver oli m us has i m pr o ve d P F S c o m pare d 
t o s orafe ni b al o ne.  We will e nter 1 5 e val ua ble patie nts t o eac h ar m of t he st u d y usi n g a 1: 1 
ra n d o mizati o n sc he me (3 0 e val ua ble patie nts t otal), u nless t he st u d y is st o p pe d earl y at t he ti me 
of t he i nteri m f utilit y a nal ysis (see bel o w). Wit h 1 5 e val ua ble patie nts per ar m, we ha ve 8 0 % 
p o wer  t o  detect  a n  i m pr o ve me nt  i n  t he  me dia n  P F S  fr o m  4. 5  t o  9  m o nt hs ( hazar d  rati o 
( H R) = 0. 5 0), ass u mi n g a 1-si de d si g nifica nce le vel of 0.2 0 a n d a n accr ual rate of 1 patie nt per 
m o nt h.  T he pri mar y a nal ysis will be a c o m paris o n of s orafe ni b a n d e ver oli m us vs. s orafe ni b 
al o ne usi n g a o ne -si de d l o g-ra n k test.  T his a nal ysis will ta ke place after a n a p pr o xi mate 3 6 1 4 
m o nt h accr ual peri o d, a n d after 2 8 t otal e ve nts ha ve occ urre d acr oss b ot h ar ms c o m bi ne d ( w hic h 
s h o ul d ha p pe n after a b o ut 1 2 m o nt hs of f oll o w -u p i n all e val ua ble patie nts). All patie nts w h o 
meet  t he  eli gi bilit y  crit eria,  si g n  t he  c o nse nt  f or m,  a n d  are  ra n d o mize d  will  be  c o nsi dere d 
e val ua ble f or t his e n d p oi nt.  
I nteri m F utilit y A nal ysis:  T he i nteri m f utilit y a nal ysis will ha p pe n after 1 4  e ve nts are o bser ve d 
acr oss b ot h ar ms c o m bi ne d.  T he i nteri m f utilit y b o u n dar y was selecte d usi n g E A S T s oft ware.  
We selecte d a R h o fa mil y " Beta" s pe n di n g f u ncti o n wit h r h o para meter "e q ual" 1. 0 1 5.  T o reject 
t he  alter nati ve  h y p ot hesis  at  t he  i nteri m  a nal ysis  (i.e.  reject  s orafe ni b  a n d  e ver oli m us  as 
pr o misi n g), t he H R will nee d t o be > 1 f or s orafe ni b a n d e ver oli m us vs. s orafe ni b al o ne, w hic h 
c orres p o n ds t o a 1 -si de d p-val ue greater t ha n 0. 5 0. If t he H R is less t ha n or e q ual t o 1 ( 1 -si de d 
p < = 0. 5 0), t he st u d y will c o nti n ue t o f ull accr ual a n d t he fi nal a nal ysis will be c o n d ucte d as 
disc usse d a b o ve.      
1 3. 3 
Sec o n d ar y E n d p oi nts  
T he f oll o wi n g e n d p oi nts will be c o m pare d bet wee n t he 2 ar ms: c o nfir me d res p o nse rate, o verall 
s ur vi val, a n d a d verse e ve nts.   
C o nfir me d Res p o nse Rate:  A patie nt will be classifie d as a c o nfir me d res p o nse per t he R E CI S T 
1. 1 criteria, if t he y ha ve a partial or c o m plete res p o nse f or 2 c o nsec uti ve e val uati o ns at least 4 
wee ks  a part.    T he  pr o p orti o n  of  patie nts  wit h  a  c o nfir me d  res p o nse  wi ll  be  calc ulate d  a n d 
c o m pare d bet wee n t he 2 ar ms usi n g a C hi- s q uare or Fis her’s E xact test.   

 
 
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O verall S ur vi val :  O verall s ur vi val ( O S) is defi ne d as t he ti me fr o m st u d y e ntr y t o deat h fr o m 
a n y ca use.  O S will be esti mate d usi n g t he Ka pla n -Meier met h o d, w he re t he l o g-ra n k test will 
be use d t o c o m pare t he 2 treat me nt ar ms.  
A d verse e ve nts:  T he ma xi m u m gra de f or eac h t y pe of a d verse e ve nt will be s u m marize d usi n g 
C T C A E versi o n 4. 0.  T he fre q ue nc y a n d perce nta ge of gra de 3 + a d verse e ve nts will be c o m pare d 
bet we e n t he 2 treat me nt ar ms.  C o m paris o ns bet wee n ar ms will be ma de b y usi n g eit her t he C hi -
s q uare or Fis her’s E xact test.   
Cr oss o ver patie nts e x pl orat or y a nal ysis:  I n t he cr oss o ver gr o u p t hat recei ves e ver oli m us al o ne, 
we will assess b ot h t he res p o nse rate a n d pr o gressi o n -free s ur vival as a n e x pl orat or y a nal ysis.  
1 3. 4 
T ot al S a m ple Size  
A ma xi m u m of 3 0 e val ua ble patie nts will be accr ue d o nt o t his ra n d o mize d p hase II st u d y u nless 
t he st u d y is cl ose d earl y f or e xcessi ve t o xicit y or lac k of efficac y.  We a ntici pate accr ui n g a n 
a d diti o nal 1 0 % of patie nts t o acc o u nt f or i neli gi bilit y, ca ncellati o n, maj or treat me nt vi olati o n, 
or ot her reas o ns.  T heref ore, ma xi m u m accr ual is 3 4 patie nts ( 1 7 per ar m).  
1 3. 5 
E x pecte d Accr u al a n d Accr u al D ur ati o n  
T he e x pecte d accr ual ra te is a b o ut 1 patie nt per m o nt h f or t he Allia nce gr o u p.  Wit h t his accr ual 
rate, we e x pect t o fi nis h accr ual wit hi n a b o ut 3 6 m o nt hs, ass u mi n g we accr ue 3 4  t otal patie nts.   
1 3. 6 
A ntici p ate d ti me t o st u d y c o m pleti o n  
We a ntici pate t hat t he st u d y will ta ke a p pr o xi matel y 5 years t o c o m plete.  T his all o ws a 1 2-
m o nt h f oll o w -u p f or t he fi nal patie nt e nr olle d, al o n g wit h data e ntr y, data clea n -u p, a n d a nal ysis.   
1 3. 7 
A E St o p pi n g R ule  
T he st o p pi n g r ule s pecifie d bel o w is base d o n t he k n o wle d ge a vaila ble at st u d y de vel o p me nt. 
We n ote t hat t he A d verse E ve nt St o p pi n g R ule ma y be a dj uste d i n t he e ve nt of eit her ( 1) t he 
st u d y re-o pe ni n g t o accr ual after a n y te m p orar y s us pe nsi o n or ( 2) at a n y ti me d uri n g t he c o n d uct 
of  t he  trial  a n d  i n  c o nsi derati o n  of  ne wl y  ac q uire d  i nf or mati o n  re gar di n g  t he  a d verse  e ve nt 
pr ofile  of  t he  treat me nt(s)  u n der  i n vesti gati o n.  T he  st u d y  tea m  ma y  als o  c h o ose  t o  s us pe n d 
accr ual beca use of u ne x pecte d a d verse e ve nt pr ofiles t hat ha ve n ot cr osse d t he s pecifie d  r ule 
bel o w. 
Accr ual will be te m p oraril y s us pe n de d t o t his st u d y if at a n y ti me we o bser ve e ve nts c o nsi dere d 
at  least  p ossi bl y  relate d  t o  st u d y  treat me nt  (i.e.,  a n  a d verse  e ve nt  wit h  attri b ute  s pecifie d  as 
" p ossi ble",  " pr o ba ble",  or  " defi nite")  t hat  satisfy  a n y  of  t he  f oll o wi n g  criteria  f or  eac h  ar m 
se paratel y: 
• 
If at a n y ti me, 3 of t he i nitial 1 0 treate d patie nts or 3 0 % or m ore of all patie nts (i.e. 
w he n accr ual is greater t ha n 1 0 patie nts) ha ve e x perie nce d a gra de 4 a d verse e ve nt.  
• 
If  at  a n y  ti me,  2 patie nts  ha ve  e x perie nce d  a  gra de  5  a d verse  e ve nt  ( n ot  d ue  t o 
pr o gressi ve disease).  
1 3. 8  Accr u al M o nit ori n g St o p pi n g R ule  
Gi ve n t he e x pecte d accr ual rate is ar o u n d 1 patie nt  per m o nt h, it is e x pecte d t h at t he st u d y will 
ta ke ar o u n d 3 6 m o nt hs t o f ull y accr ue.  We pla n t o m o nit or t he accr ual c o nti n uall y a n d if we 
o nl y e n d u p accr ui n g 4 patie nts or less i n t he first year (after st u d y acti vati o n), we will c o nsi der 
st o p pi n g t he trial f or sl o w accr ual.  

 
 
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1 3. 9 
P ri m ar y E n d p oi nt C o m pleti o n Ti me Esti m ati o n  ( F or cli nic altr ails. g o v re p orti n g)  
T he pri mar y e n d p oi nt is a c o m paris o n of P F S bet wee n t he 2 treat me nt ar ms, as disc usse d i n 
detail i n secti o n 1 3. 2.  T he fi nal a nal ysis is e x pecte d t o ta ke place ar o u n d 5 years after t he st u d y 
be gi ns, s o we e x pect t hat t he pri mar y e n d p oi nt c o m pleti o n ti me t o be ar o u n d 5 years after st u d y 
acti vati o n.    
1 3. 1 0   Descri pti ve F act ors  
•  
Metastatic Disease o utsi de t he c hest: Yes vs. N o  
•  
A n y pri or c he m o/ T KI re gi me ns: Yes vs. N o 
o  Pri or V E G F R T KI: Yes or N o  
o  Pri or tar g ete d t hera p y ot her t ha n V E G F R T KI: Yes or N o 
o  Pri or c yt ot o xic c he m ot hera p y (e. g., d o x or u bici n, paclita xel): Yes or N o 
o  Pri or R AI: Yes or N o  
o  Pri or R AI > 6 0 0 m Ci: Yes or N o  
o  Pri or T h yr oi dect o m y: Yes or n o 
•  
A n y lesi o n wit h S U V ma x > 5 (fr o m P E T/ C T sca n i n pri or 6 m o nt hs): Yes vs. N o 

 
 
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1 3. 1 1 I ncl usi o n of W o me n a n d Mi n orities 
T his st u d y will be a vaila ble t o all eli gi ble patie nts, re gar dless of race, ge n der, or et h nic ori gi n.  
T here  is  n o  i nf or mati o n  c urre ntl y  a vaila ble  re gar di n g  differe ntial  effects  of  t his  re gi me n  i n 
s u bsets defi ne d b y race, ge n der, or et h nicit y, a n d t here is n o reas o n t o e x pect s uc h differe nces 
t o e xist.  Base d o n pri or st u dies i n v ol vi n g si milar disease sites, we e x pect a b o ut 2 0 % of patie nts 
will be classifie d as mi n orities b y race a n d a b o ut 7 0 % of pa tie nts t o be w o me n.  E x pecte d sizes 
of racial b y ge n der s u bsets are s h o w n i n t he f oll o wi n g ta ble:  
 
Accr u al T ar gets  
Et h nic C ate g or y  
Se x/ Ge n der  
Fe m ales  
M ales  
T ot al  
His pa nic or Lati n o  
1  
 1  
2  
N ot His pa nic or Lati n o  
 2 3  
 9  
 3 2  
Et h nic C ate g or y: T ot al of all s u bjects  
 2 4  
 1 0  
 3 4  
R aci al C ate g or y  
A merica n I n dia n or Alas ka n Nati ve  
 1  
 1  
 2  
Asia n  
 2  
 1  
 3  
Blac k or Africa n A merica n  
 2  
 1  
 3  
Nati ve Ha waiia n or ot her P acific Isla n der  
 1  
 1  
 2  
W hite  
 1 8  
 6  
 2 4  
R aci al C ate g or y: T ot al of all s u bjects  
 2 4  
 1 0  
 3 4  
 
 
Et h nic 
C ate g ories:  
His p a nic or L ati n o – a pers o n of C u ba n, Me xica n, P uert o Rica n, S o ut h or Ce ntral 
A merica n, or ot her S pa nis h c ult ure or ori gi n, re gar dless of race. T he ter m “ S pa nis h 
ori gi n” ca n als o be use d i n a d diti o n t o “ His pa nic or Lati n o.”  
N ot His p a nic or L ati n o  
R aci al 
C ate g ories: 
A meric a n I n di a n or Al as k a n N ati ve –  a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal 
pe o ples of N ort h, Ce ntral, or S o ut h A merica, a n d w h o mai ntai ns tri bal affiliati o ns or 
c o m m u nit y attac h me nt.  
Asi a n –  a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of t he Far East, 
S o ut heast Asia, or t he I n dia n s u bc o nti ne nt i ncl u di n g, f or e xa m ple, Ca m b o dia, C hi na, 
I n dia, J a pa n, K orea, Mala ysia, Pa kista n, t he P hili p pi ne Isla n ds, T haila n d, a n d 
Viet na m. ( N ote: I n di vi d uals fr o m t he P hili p pi ne Isla n ds ha ve bee n rec or de d as Pacific 
Isla n ders i n pre vi o us data c ollecti o n strate gies.)  
Bl ac k or Af ric a n A meric a n – a pers o n ha vi n g ori gi ns i n a n y of t he blac k racial 
gr o u ps of Africa. Ter ms s uc h as “ Haitia n” or “ Ne gr o” ca n be  use d i n a d diti o n t o 
“ Blac k or Africa n A merica n.”  
N ati ve H a w aii a n or ot her P acific Isl a n der – a pers o n ha vi n g ori gi ns i n a n y of t he 
ori gi nal pe o ples of Ha waii, G ua m, Sa m oa, or ot her Pacific Isla n ds.  
W hite – a pers o n ha vi n g ori gi ns i n a n y of t he ori gi nal pe o ples of E ur o pe, t he Mi d dle 
East, or N ort h Africa.  

 
 
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C O R R E L A TI V E A N D C O M P A NI O N S T U DI E S  
T here are n o c orrelati ve or c o m pa ni o n st u dies a vaila ble f or A 0 9 1 3 0 2. 
1 5. 0  
G E N E R A L R E G U L A T O R Y C O N SI D E R A TI O N S A N D C R E D E N TI A LI N G  
T here are n o cre de ntiali n g re q uire me n ts f or A 0 9 1 3 0 2. 
 

 
 
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R E F E R E N C E S  
1.  Je mal A, Sie gel R, X u J, et al: Ca ncer Statistics, 2 0 1 0. C A Ca ncer J Cli n:caac. 2 0 0 7 3, 2 0 1 0 
2.  D ura nte C, Ha d d y N, Ba u di n E, et al: L o n g- ter m o utc o me of 4 4 4 patie nts wit h dista nt metastases 
fr o m pa pillar y a n d f ollic ular t h yr oi d carci n o ma: be nefits a n d li mits of ra di oi o di ne t hera p y. J Cli n 
E n d ocri n ol Meta b 9 1: 2 8 9 2- 9, 2 0 0 6 
3. 
Fa gi n J A, T uttle R M, Pfister D G: Har vesti n g t he l o w - ha n gi n g fr uit: ki nase i n hi bit ors f or t hera p y 
of a d va nce d me d ullar y a n d n o n me d ullar y t h yr oi d ca ncer. J Cli n E n d ocri n ol Meta b 9 5: 2 6 2 1- 4, 
2 0 1 0 
4. 
Pfister D G, Fa gi n J A: Refract or y t h yr oi d ca ncer: a para di g m s hift i n treat me nt is n ot far off. J 
Cli n O nc ol 2 6: 4 7 0 1- 4, 2 0 0 8 
5.  G offre d o P, R o ma n S A, S osa J A: H ü rt hle cell carci n o ma. Ca ncer 1 1 9: 5 0 4- 5 1 1, 2 0 1 3 
6.  L o pez- Pe na ba d L, C hi u A C, H off A O, et al: Pr o g n ostic fact ors i n patie nts wit h H ürt hle cell 
ne o plas ms of t he t h yr oi d. Ca ncer 9 7: 1 1 8 6- 1 1 9 4, 2 0 0 3 
7. 
S ha ha A R, S ha h J P, L oree T R: Patter ns of n o dal a n d dista nt metastasis base d o n hist ol o gic 
varieties i n d iffere ntiate d carci n o ma of t he t h yr oi d. T he A merica n J o ur nal of S ur ger y 1 7 2: 6 9 2-
6 9 4, 1 9 9 6 
8.  K na uf J A, Fa gi n J A: R ole of M A P K pat h wa y o nc o pr otei ns i n t h yr oi d ca ncer pat h o ge nesis a n d as 
dr u g tar gets. C urr O pi n Cell Bi ol 2 1: 2 9 6- 3 0 3, 2 0 0 9 
9.  D har D K, K u b ota H , K ot o h T, et al: T u m or vasc ularit y pre dicts rec urre nce i n differe ntiate d 
t h yr oi d carci n o ma. A m J S ur g 1 7 6: 4 4 2- 7, 1 9 9 8 
1 0.  Is hi wata T, Ii n o Y, T a kei H, et al: T u m or a n gi o ge nesis as a n i n de pe n de nt pr o g n ostic i n dicat or i n 
h u ma n pa pillar y t h yr oi d carci n o ma. O nc ol Re p 5: 1 3 4 3- 8, 1 9 9 8 
1 1.  B u n o ne G, Vi g neri P, Maria ni L, et al: E x pressi o n of a n gi o ge nesis sti m ulat ors a n d i n hi bit ors i n 
h u ma n t h yr oi d t u m ors a n d c orrelati o n wit h cli nical pat h ol o gical feat ures. A m J Pat h ol 1 5 5: 1 9 6 7-
7 6, 1 9 9 9 
1 2.  Kat o h R, Mi ya gi E, Ka wa oi A, et al: E x pressi o n of vasc ular e n d ot helial gr o wt h fact or ( V E G F) i n 
h u ma n t h yr oi d ne o plas ms. H u m Pat h ol 3 0: 8 9 1- 7, 1 9 9 9 
1 3.  Klei n M, Picar d E, Vi g na u d J M, et al: Vasc ular e n d ot helial gr o wt h fact or ge ne a n d pr otei n: 
str o n g e x pressi o n i n t h yr oi ditis a n d t h yr oi d carci n o ma. J E n d ocri n ol 1 6 1: 4 1- 9, 1 9 9 9 
1 4.  S o h E Y, D u h Q Y, S o b hi S A, et al: Vasc ular e n d ot helial gr o wt h fact or e x pressi o n is hi g her i n 
differe ntiate d t h yr oi d ca ncer t ha n i n n or mal or be ni g n t h yr oi d. J Cli n E n d ocri n ol Meta b 8 2: 3 7 4 1-
7, 1 9 9 7 
1 5. Vi gliet t o G, Ma gli o ne D, Ra m bal di M, et al: U pre g ulati o n of vasc ular e n d ot helial gr o wt h fact or 
( V E G F) a n d d o w nre g ulati o n of place nta gr o wt h fact or ( Pl G F) ass ociate d wit h mali g na nc y i n 
h u ma n t h yr oi d t u m ors a n d cell li nes. O nc o ge ne 1 1: 1 5 6 9- 7 9, 1 9 9 5 
1 6. Vi gliett o G,  R o ma n o A, Ma nz o G, et al: U pre g ulati o n of t he a n gi o ge nic fact ors Pl G F, V E G F a n d 
t heir rece pt ors ( Flt- 1, Fl k- 1/ K D R) b y T S H i n c ult ure d t h yr oc ytes a n d i n t he t h yr oi d gla n d of 
t hi o uracil-fe d rats s u g gest a T S H- de pe n de nt paracri ne mec ha nis m f or g oiter h y per vasc ularizati o n. 
O nc o ge ne 1 5: 2 6 8 7- 9 8, 1 9 9 7 
1 7. Ba uer AJ, Terrell R, D o ni part hi N K, et al: Vasc ular e n d ot helial gr o wt h fact or m o n ocl o nal 
a nti b o d y i n hi bits gr o wt h of a na plastic t h yr oi d ca ncer xe n o grafts i n n u de mice. T h yr oi d 1 2: 9 5 3-
6 1, 2 0 0 2 
1 8.  Y u X M, L o C Y, L a m A K, et al: T he p ote ntial cli nical rele va nce of ser u m vasc ular e n d ot helial 
gr o wt h fact or ( V E G F) a n d V E G F - C i n rec urre nt pa pillar y t h yr oi d carci n o ma. S ur ger y 1 4 4: 9 3 4-
4 0; disc ussi o n 9 4 0- 1, 2 0 0 8 
1 9. Klei n M, Vi g na u d J M, He n ne q ui n V, et al: I ncrease d e x press i o n of t he vasc ular e n d ot helial 
gr o wt h fact or is a pej orati ve pr o g n osis mar ker i n pa pillar y t h yr oi d carci n o ma. J Cli n E n d ocri n ol 
Meta b 8 6: 6 5 6- 8, 2 0 0 1 

 
 
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2 0.  Le n nar d C M, Patel A, Wils o n J, et al: I nte nsit y of vasc ular e n d ot helial gr o wt h fact or e x pressi o n 
is ass ociate d wit h i ncrease d ris k of rec urre nce a n d decrease d disease-free s ur vi val i n pa pillar y 
t h yr oi d ca ncer. S ur ger y 1 2 9: 5 5 2- 8, 2 0 0 1 
2 1.  Belletti B, Ferrar o P, Arra C, et al: M o d ulati o n of i n vi v o gr o wt h of t h yr oi d t u m or- deri ve d cell 
li nes b y se nse a n d a ntise nse vasc ular e n d ot helial gr o wt h fact or ge ne. O nc o ge ne 1 8: 4 8 6 0- 9, 1 9 9 9 
2 2.  Ba uer AJ, Patel A, Terrell R, et al: S yste mic a d mi nistrati o n of vasc ular e n d ot helial gr o wt h fact or 
m o n ocl o nal a nti b o d y re d uces t he gr o wt h of pa pillar y t h yr oi d carci n o ma i n a n u de m o use m o del. 
A n n Cli n La b Sci 3 3: 1 9 2- 9, 2 0 0 3 
2 3. S o h E Y, Ei gel ber ger M S, Ki m KJ, et al: Ne utralizi n g vasc ular e n d ot helial gr o wt h fact or acti vit y 
i n hi bits t h yr oi d ca ncer gr o wt h i n vi v o. S ur ger y 1 2 8: 1 0 5 9- 6 5; disc ussi o n 1 0 6 5-6, 2 0 0 0  
2 4.  H off ma n n S, B urc hert A, W u n derlic h A, et al: Differe ntial effects of cet u xi ma b a n d A E E 7 8 8 o n 
e pi der mal gr o wt h fact or rece pt or ( E G F- R) a n d vasc ular e n d ot helial gr o wt h fact or rece pt or 
( V E G F- R) i n t h yr oi d ca ncer cell li nes. E n d ocri ne 3 1: 1 0 5- 1 3, 2 0 0 7 
2 5.  Sc h oe n ber ger J, Gri m m D, K oss me hl P, et al: Effects of P T K 7 8 7/ Z K 2 2 2 5 8 4, a t yr osi ne ki nase 
i n hi bit or, o n t he gr o wt h of a p o orl y differe ntiate d t h yr oi d carci n o ma: a n a ni mal st u d y. 
E n d ocri n ol o g y 1 4 5: 1 0 3 1- 8, 2 0 0 4 
2 6.  Je breel A, E n gla n d J, Be df or d K, et al: Vasc ular e n d ot helial gr o wt h fac t or ( V E G F), V E G F 
rece pt ors e x pressi o n a n d micr o vasc ular de nsit y i n be ni g n a n d mali g na nt t h yr oi d diseases. I nt J 
E x p Pat h ol 8 8: 2 7 1- 7, 2 0 0 7 
2 7. Vieira J M, Sa nt os S C, Es pa di n ha C, et al: E x pressi o n of vasc ular e n d ot helial gr o wt h fact or 
( V E G F) a n d its rece pt ors i n t h yr oi d carci n o mas of f ollic ular ori gi n: a p ote ntial a ut ocri ne l o o p. 
E ur J E n d ocri n ol 1 5 3: 7 0 1- 9, 2 0 0 5 
2 8.  G u pta- A bra ms o n V, Tr o xel A B, Nell ore A, et al: P hase II trial of s orafe ni b i n a d va nce d t h yr oi d 
ca ncer. J Cli n O nc ol 2 6: 4 7 1 4- 9, 2 0 0 8 
2 9. Kl o os R T,  Ri n gel M D, K n o p p M V, et al: P hase II Trial of S orafe ni b i n Metastatic T h yr oi d 
Ca ncer. J Cli n O nc ol:J C O. 2 0 0 8. 1 8. 2 7 1 7, 2 0 0 9 
3 0.  C o he n E E, R ose n L S, V o kes E E, et al: A xiti ni b is a n acti ve treat me nt f or all hist ol o gic s u bt y pes 
of a d va nce d t h yr oi d ca ncer: res ults fr o m a p hase II st u d y. J Cli n O nc ol 2 6: 4 7 0 8- 1 3, 2 0 0 8 
3 1.  Carr L L, Ma n k off D A, G o ulart B H, et al: P hase II st u d y of dail y s u niti ni b i n F D G- P E T - p ositi ve, 
i o di ne-refract or y differe ntiate d t h yr oi d ca ncer a n d metastatic me d ullar y carci n o ma of t he t h yr oi d 
wit h f u ncti o nal i ma gi n g c orrelati o n. Cli n Ca ncer Res 1 6: 5 2 6 0- 8, 2 0 1 0 
3 2.  C o he n E E, Nee dles B M, C ulle n KJ, et al: P hase 2 st u d y of s u niti ni b i n refract or y t h yr oi d ca ncer. 
J Cli n O nc ol ( Meeti n g A bstracts) 2 6: 6 0 2 5-, 2 0 0 8 
3 3. Bi ble K C, S u ma n VJ, M oli na J R, et al: Efficac y of paz o pa ni b i n pr o gressi ve, ra di oi o di ne-
refract or y, metastatic differe ntiate d t h yr oi d ca ncers: res ults of a p hase 2 c o ns orti u m st u d y. T he 
La ncet O nc ol o g y 1 1: 9 6 2- 9 7 2, 2 0 1 0 
3 4.  Ga nl y I, Ricarte Fil h o J, E n g S, et al: Ge n o mic Dissecti o n of H ü rthle Cell Carci n o ma Re veals a 
U ni q ue Class of T h yr oi d Mali g na nc y. J o ur nal of Cli nical E n d ocri n ol o g y & Meta b olis m, 2 0 1 3 
3 5. Wil hel m S M, A d na ne L, Ne well P, et al: Precli nical o ver vie w of s orafe ni b, a m ulti ki nase 
i n hi bit or t hat tar gets b ot h Raf a n d V E G F a n d PD G F rece pt or t yr osi ne ki nase si g nali n g. M olec ular 
Ca ncer T hera pe utics 7: 3 1 2 9 - 3 1 4 0, 2 0 0 8 
3 6. G ui g o n CJ, Z ha o L, Willi n g ha m M C, et al: P T E N deficie nc y accelerates t u m o ur pr o gressi o n i n a 
m o use m o del of t h yr oi d ca ncer. O nc o ge ne, 2 0 0 8 
3 7.  Harzstar k A L, R ose n ber g J E, Wei n ber g V K, et al: A p hase I st u d y of s orafe ni b a n d R A D 0 0 1 f or 
metastatic clear cell re nal cell carci n o ma. J Cli n O nc ol ( Meeti n g A bstracts) 2 7: 5 1 0 4 -, 2 0 0 9 
3 8.  S.J. P oc oc k, R. Si m o n.  Se q ue ntial treat me nt assi g n me nt wit h bala nci n g f or pr o g n ostic fac t ors i n 
t he c o ntr olle d cli nical trial.  Bi o metrics, 3 1 ( 1 9 7 5), p p. 1 0 3 – 1 1 5. 
3 9. Eise n ha uer E A, T herasse P, B o gaerts J, et al: Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 4 5: 2 2 8- 4 7, 2 0 0 9 
4 0.  Br ose  M S, N utti n g C, J arza b B, Elisei R, Sie na S, Bast h olt L, de la F o uc har diere C, Paci ni F, 
Pasc h ke R, S h o n g Y K, S her ma n SI, S mit J W, C h u n g J W, Sie de nt o p H, M ol nar I, Sc hl u m ber ger 

 
 
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M: S orafe ni b i n l ocall y a d va nce d or metastatic patie nts wit h ra di oacti ve i o di ne -refract or y 
differe ntiate d t h yr oi d ca ncer: T he p hase III D E CI SI O N trial. A S C O Meeti n g A bstracts 3 1: 4, 
2 0 1 3.  
4 1.  S her ma n EJ, H o A L, F ur y M G, Ba xi S S, Ha q ue S, Li ps o n B L, K urz S, Fa gi n J A, Pfister D G: 
P hase II st u d y of e ver oli m us a n d s orafe ni b f or t he trea t me nt of metastatic t h yr oi d ca ncer. A S C O 
Meeti n g A bstracts 3 1: 6 0 2 4, 2 0 1 3.  
4 2.  Ga nl y I, Ricarte Fil h o J, E n g S, G h ossei n R, M orris L G T, Lia n g Y, S occi N, Ka n na n K, M o Q, 
Fa gi n J A, C ha n T A: Ge n o mic Dissecti o n of H ü rt hle Cell Carci n o ma Re veals a U ni q ue Class of 
T h yr oi d Mali g na nc y. J o ur nal of Cli nical E n d ocri n ol o g y & Meta b olis m 9 8: E 9 6 2- E 9 7 2, 2 0 1 3. 
4 3. Bj or nsti M A, H o u g ht o n PJ: T he T O R pat h wa y: a tar get f or ca ncer t hera p y. Nat Re v Ca ncer 
4: 3 3 5- 4 8, 2 0 0 4 
4 4. Petr o ula kis E, Ma ma ne Y, Le Bac q uer O, et al: m T O R si g nali n g: i m plicati o ns f or ca ncer a n d 
a ntica ncer t hera p y. Br J Ca ncer 9 4: 1 9 5 - 9, 2 0 0 6 
4 5.  M ol h oe k K R, Bra uti ga n D L, Sli n gl uff C L, Jr.: S y ner gistic i n hi biti o n of h u ma n mela n o ma 
pr oliferati o n b y c o m bi nati o n treat me nt wit h B- Raf i n hi bit or B A Y 4 3- 9 0 0 6 a n d m T O R i n hi bit or 
Ra pa m yci n. J Tra nsl Me d 3: 3 9, 2 0 0 5 
4 6.  Lasit hi ota kis K G, Si n n ber g T W, Sc hitte k B, et al: C o m bi ne d I n hi biti o n of M A P K a n d m T O R 
Si g nali n g I n hi bits Gr o wt h, I n d uces Cell Deat h, a n d A br o gates I n vasi ve Gr o wt h of Mela n o ma 
Cells. J I n vest Der mat ol 1 2 8: 2 0 1 3- 2 0 2 3, 2 0 0 8 
4 7.  Pat nai k A, Ricart A, C o o per J, et al: A p hase I, p har ma c o ki netic a n d p har mac o d y na mic st u d y of 
s orafe ni b ( S), a m ulti-tar gete d ki nase i n hi bit or i n c o m bi nati o n wit h te msir oli m us ( T), a n m T O R 
i n hi bit or i n patie nts wit h a d va nce d s oli d mali g na ncies. J Cli n O nc ol ( Meeti n g A bstracts) 
2 5: 3 5 1 2-, 2 0 0 7 
4 8.  Harzstar k A L, S mall EJ, Wei n ber g V K, S u n J, R ya n CJ, Li n A M, F o n g L, Br oc ks D R, R ose n ber g 
J E: A p hase 1 st u d y of e ver oli m us a n d s orafe ni b f or metastatic clear cell re nal cell carci n o ma. 
Ca ncer 1 1 7: 4 1 9 4- 4 2 0 0, 2 0 1 1.  
4 9.  Mar g oli n K A, M o o n J, Fla hert y L E, La o C D, A kerle y W L, 3r d, Ot h us M, S os ma n J A, Kir k w o o d 
J M, S o n da k V K: Ra n d o mize d p hase II trial of s orafe ni b wit h te msir oli m us or ti pifar ni b i n 
u ntreate d metastatic mela n o ma ( S 0 4 3 8). Cli n Ca ncer Res 1 8: 1 1 2 9- 3 7, 2 0 1 2. 3 4 8 1 1 6 5 
 
 

 
 
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A P P E N DI X I  
RE GI S T R A TI O N F A TI G U E / UNI S C A L E A S S E S S M E N T S  
 
 
Re gistr ati o n F ati g ue/ U nisc ale Assess me nts  
 
Pri or t o patie nt re gistrati o n, t his f or m is t o be a d mi nistere d b y a n urse/ C R A, c o m plete d b y t he 
patie nt, a n d rec or de d o n t he Re gistrati o n Fati g ue/ U niscale Assess me nts F or m (see F or ms Pac ket).  
 
If nee de d, t his a p pe n di x ca n be a da pte d t o use as a s o urce d oc u me nt.  A b o o klet c o ntai ni n g t his 
assess me nt d oes n ot e xist – please d o n ot or der t his b o o klet. 
 
 
 
 
H o w w o ul d y o u descri be: 
 
y o ur le vel of fati g ue, o n t he a vera ge i n t he past wee k i ncl u di n g t o da y?  
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A P P E N DI X  II  AL LI A N C E A 0 9 1 3 0 2  O P TI O N A L M E DI C A TI O N C A L E N D A R S  
P A TI E N T M E DI C A TI O N DI A R Y – S or afe ni b  2 8- d a y c ycle 
 
T o d a y’s d ate  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
A ge nt:  S or afe ni b  
P atie nt N a me _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( i niti als acce pt a ble) P atie nt St u d y I D  _ _ _ _ _ _ _ _ 
 
I N S T R U C TI O N S T O T H E P A TI E N T: 
1.  C o m plete o ne f or m f or eac h 4 wee k- peri o d w hile y o u ta ke s or afe ni b. 
2. 
S or af e ni b s h o ul d be t a ke n t wice d ail y o n a n e m pt y st o m ac h o ne h o ur bef ore or t w o h o urs 
after e ati n g. T hese t a blets s h o ul d be s w all o we d w h ole a n d c a n n ot be cr us he d or c he we d.  
3.  Rec or d t he date, t he n u m ber of ca ps ules y o u t o o k, a n d w he n y o u t o o k t he m. Rec or d d oses as s o o n 
as y o u ta ke t he m; d o n ot batc h e ntries t o get her at a later ti me.  
4.  If y o u ha ve a n y c o m me nts or n otice a n y si de effects, please rec or d t he m i n t he C o m me nts c ol u m n. 
If y o u ma ke a mista ke w hile y o u write, please cr oss it o ut wit h o ne li ne, p ut y o ur i nitials ne xt t o it, 
a n d t he n write t he c orrecte d i nf or mati o n ne xt t o y o ur i nitials.  E xa m ple: 1 0: 3 0 a m  S B 9: 3 0 a m  
5.  Please ret ur n t his f or m t o y o ur p h ysicia n w he n y o u g o f or y o ur ne xt a p p oi nt me nt. 
 
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P h ysici a n’s Office will c o m plete t his secti o n:  
 
1.  Date patie nt starte d pr ot oc ol treat me nt  
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Date patie nt was re m o ve d fr o m st u d y 
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3.  T otal n u m ber of ca ps ules ta ke n t his m o nt h (eac h size) 
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P h ysicia n/ N urse/ Data Ma na ger’s Si g nat ure 
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P atie nt’s si g n at ure 
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P A TI E N T M E DI C A TI O N DI A R Y – S or afe ni b  5 6- d a y c ycle 
 
T o d a y’s d ate  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
A ge nt:  S or afe ni b  
P atie nt N a me _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( i niti als acce pt a ble) P atie nt St u d y I D  _ _ _ _ _ _ _ _ 
 
I N S T R U C TI O N S T O T H E P A TI E N T: 
1.  C o m plete o ne f or m f or eac h 8 wee k - peri o d w hile y o u ta ke s orafe ni b . 
2. 
S or af e ni b s h o ul d be t a ke n t wice d ail y o n a n e m pt y st o m ac h o ne h o ur bef ore or t w o h o urs 
after e ati n g. T hese t a blets s h o ul d be s w all o we d w h ole a n d c a n n ot be cr us he d or c he we d.  
3.  Rec or d t he date, t he n u m ber of ca ps ules y o u t o o k, a n d w he n y o u t o o k t he m. Rec or d d oses as s o o n 
as y o u ta ke t he m; d o n ot batc h e ntries t o get her at a later ti me.  
4. 
If y o u ha ve a n y c o m me nts or n otice a n y si de effects, please rec or d t he m i n t he C o m me nts c ol u m n. 
If y o u ma ke a mista ke w hile y o u write, please cr oss it o ut wit h one li ne, p ut y o ur i nitials ne xt t o it, 
a n d t he n write t he c orrecte d i nf or mati o n ne xt t o y o ur i nitials.  E xa m ple: 1 0: 3 0 a m  S B 9: 3 0 a m  
5.  Please ret ur n t his f or m t o y o ur p h ysicia n w he n y o u g o f or y o ur ne xt a p p oi nt me nt. 
 
D a y  
 
D ate  
Ti me of d ail y 
d oses( a m/ p m) 
# of c a ps ules t a ke n  
C o m me nts  
1  
 
 
 
 
 
2  
 
 
 
 
 
3  
 
 
 
 
 
4  
 
 
 
 
 
5  
 
 
 
 
 
6  
 
 
 
 
 
7  
 
 
 
 
 
8  
 
 
 
 
 
9  
 
 
 
 
 
1 0  
 
 
 
 
 
1 1  
 
 
 
 
 
1 2  
 
 
 
 
 
1 3  
 
 
 
 
 
1 4  
 
 
 
 
 
1 5  
 
 
 
 
 
1 6  
 
 
 
 
 
1 7  
 
 
 
 
 
1 8  
 
 
 
 
 
1 9  
 
 
 
 
 
2 0  
 
 
 
 
 
2 1  
 
 
 
 
 
2 2  
 
 
 
 
 
2 3  
 
 
 
 
 
2 4  
 
 
 
 
 
2 5  
 
 
 
 
 
2 6  
 
 
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 3  
U p date # 1 3  
 
D a y  
 
D ate  
Ti me of d ail y 
d oses ( a m/ p m)  
# of c a ps ules t a ke n  
C o m me nts  
2 7  
 
 
 
 
 
2 8  
 
 
 
 
 
2 9  
 
 
 
 
 
3 0  
 
 
 
 
 
3 1  
 
 
 
 
 
3 2  
 
 
 
 
 
3 3  
 
 
 
 
 
3 4  
 
 
 
 
 
3 5  
 
 
 
 
 
3 6  
 
 
 
 
 
3 7  
 
 
 
 
 
3 8  
 
 
 
 
 
3 9  
 
 
 
 
 
4 0  
 
 
 
 
 
4 1  
 
 
 
 
 
4 2  
 
 
 
 
 
4 3  
 
 
 
 
 
4 4  
 
 
 
 
 
4 5  
 
 
 
 
 
4 6  
 
 
 
 
 
4 7  
 
 
 
 
 
4 8  
 
 
 
 
 
4 9  
 
 
 
 
 
5 0  
 
 
 
 
 
5 1  
 
 
 
 
 
5 2  
 
 
 
 
 
5 3  
 
 
 
 
 
5 4  
 
 
 
 
 
5 5  
 
 
 
 
 
5 6  
 
 
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 4  
U p date # 1 3  
 
P h ysici a n’s Office will c o m plete t his secti o n:  
 
1.  Date patie nt starte d pr ot oc ol treat me nt  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
2. 
Date patie nt was re m o ve d fr o m  st u d y 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
3.  T otal n u m ber of ca ps ules ta ke n t his m o nt h (eac h size) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
4. 
P h ysicia n/ N urse/ Data Ma na ger’s Si g nat ure 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ = _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
P atie nt’s si g n at ure 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 5  
U p date # 1 3  
 
P A TI E N T M E DI C A TI O N DI A R Y – E ver oli m us 2 8 - d a y c ycle 
 
T o d a y’s d ate  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
A ge nt:  E ver oli m us   
P atie nt N a me _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( i niti als acce pt a ble) P atie nt St u d y I D  _ _ _ _ _ _ _ _ 
 
I N S T R U C TI O N S T O T H E P A TI E N T: 
1.  C o m plete o ne f or m f or eac h 4 wee k- peri o d w hile y o u ta ke e ver oli m us . 
2. 
E ver oli m us s h o ul d be a d mi nistere d o nce d ail y at a p pr o xi m atel y t he s a me ti me e ac h d a y wit h 
or wit h o ut f o o d .  T a blets s h o ul d be s w all o we d w h ole wit h a gl ass of w ater.  T he t a blets m ust 
n ot be c he we d or cr us he d a n d gr a pefr uit j uice or gr a pef r uit s h o ul d be a v oi de d.   
3.  Rec or d t he date, t he n u m ber of ca ps ules y o u t o o k, a n d w he n y o u t o o k t he m. Rec or d d oses as s o o n 
as y o u ta ke t he m; d o n ot batc h e ntries t o get her at a later ti me.  
4. 
If y o u ha ve a n y c o m me nts or n otice a n y si de effects, please rec or d t he m i n t he C o m me nts c ol u m n. 
If y o u ma ke a mista ke w hile y o u write, please cr oss it o ut wit h o ne li ne, p ut y o ur i nitials ne xt t o it, 
a n d t he n write t he c orrecte d i nf or mati o n ne xt t o y o ur i nitials.  E xa m ple: 1 0: 3 0 a m  S B 9: 3 0 a m  
5.  Please ret ur n t his f or m t o y o ur p h ysicia n w he n y o u g o f or y o ur ne xt a p p oi nt me nt. 
 
D a y  
 
D ate  
Ti me of d ail y d ose  # of t a blets t a ke n 
C o m me nts  
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
 
1 0  
 
 
 
 
1 1  
 
 
 
 
1 2  
 
 
 
 
1 3  
 
 
 
 
1 4  
 
 
 
 
1 5  
 
 
 
 
1 6  
 
 
 
 
1 7  
 
 
 
 
1 8  
 
 
 
 
1 9  
 
 
 
 
2 0  
 
 
 
 
2 1  
 
 
 
 
2 2  
 
 
 
 
2 3  
 
 
 
 
2 4  
 
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 6  
U p date # 1 3  
 
D a y  
 
D ate  
Ti me of d ail y d ose  # of t a blets t a ke n 
C o m me nts  
2 5  
 
 
 
 
2 6  
 
 
 
 
2 7  
 
 
 
 
2 8  
 
 
 
 
 
P h ysicia n’s Office will c o m plete t his secti o n:  
 
1.  Date patie nt starte d pr ot oc ol treat me nt  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
2. 
Date patie nt was re m o ve d fr o m st u d y 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
3.  T otal n u m ber of ta blet’s ta ke n t his m o nt h (eac h size) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
4. 
P h ysicia n/ N urse/ Data Ma na ger’s Si g nat ure 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
P atie nt’s si g n at ure 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 7  
U p date # 1 3  
P A TI E N T M E DI C A TI O N DI A R Y – E ver oli m us 5 6 - d a y c ycle 
 
T o d a y’s d ate  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
A ge nt:  E ver oli m us   
P atie nt N a me _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ( i niti als acce pt a ble) P atie nt St u d y I D  _ _ _ _ _ _ _ _ 
 
I N S T R U C TI O N S T O T H E P A TI E N T: 
1.  C o m plete o ne f or m f or eac h 8 wee k - peri o d w hile y o u ta ke e ver oli m us . 
2. 
E ver oli m us s h o ul d be a d mi nistere d o nce d ail y at a p pr o xi m atel y t he s a me ti me e ac h d a y wit h 
or wit h o ut f o o d.  T a blets s h o ul d be s w all o we d w h ole wit h a gl ass of w ater.  T he t a blets m ust 
n ot be c he we d or cr us he d a n d gr a pefr uit j uice or gr a pef r uit s h o ul d be a v oi de d.   
3.  Rec or d t he date, t he n u m ber of ca ps ules y o u t o o k, a n d w he n y o u t o o k t he m. Rec or d d oses as s o o n 
as y o u ta ke t he m; d o n ot batc h e ntries t o get her at a later ti me.  
4. 
If y o u ha ve a n y c o m me nts or n otice a n y si de effects, please rec or d t he m i n t he C o mme nts c ol u m n. 
If y o u ma ke a mista ke w hile y o u write, please cr oss it o ut wit h o ne li ne, p ut y o ur i nitials ne xt t o it, 
a n d t he n write t he c orrecte d i nf or mati o n ne xt t o y o ur i nitials.  E xa m ple: 1 0: 3 0 a m  S B 9: 3 0 a m  
5.  Please ret ur n t his f or m t o y o ur p h ysicia n w he n y o u g o f or y o ur ne xt a p p oi nt me nt. 
 
D a y  
 
D ate  
Ti me of d ail y d ose  # of t a blets t a ke n 
C o m me nts  
1  
 
 
 
 
2  
 
 
 
 
3  
 
 
 
 
4  
 
 
 
 
5  
 
 
 
 
6  
 
 
 
 
7  
 
 
 
 
8  
 
 
 
 
9  
 
 
 
 
1 0  
 
 
 
 
1 1  
 
 
 
 
1 2  
 
 
 
 
1 3  
 
 
 
 
1 4  
 
 
 
 
1 5  
 
 
 
 
1 6  
 
 
 
 
1 7  
 
 
 
 
1 8  
 
 
 
 
1 9  
 
 
 
 
2 0  
 
 
 
 
2 1  
 
 
 
 
2 2  
 
 
 
 
2 3  
 
 
 
 
2 4  
 
 
 
 
2 5  
 
 
 
 
2 6  
 
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 8  
U p date # 1 3  
 
D a y  
 
D ate  
Ti me of d ail y d ose  # of t a blets t a ke n 
C o m me nts  
2 7  
 
 
 
 
2 8  
 
 
 
 
2 9  
 
 
 
 
3 0  
 
 
 
 
3 1  
 
 
 
 
3 2  
 
 
 
 
3 3  
 
 
 
 
3 4  
 
 
 
 
3 5  
 
 
 
 
3 6  
 
 
 
 
3 7  
 
 
 
 
3 8  
 
 
 
 
3 9  
 
 
 
 
4 0  
 
 
 
 
4 1  
 
 
 
 
4 2  
 
 
 
 
4 3  
 
 
 
 
4 4  
 
 
 
 
4 5  
 
 
 
 
4 6  
 
 
 
 
4 7  
 
 
 
 
4 8  
 
 
 
 
4 9  
 
 
 
 
5 0  
 
 
 
 
5 1  
 
 
 
 
5 2  
 
 
 
 
5 3  
 
 
 
 
5 4  
 
 
 
 
5 5  
 
 
 
 
5 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
Allia nce A 0 9 1 3 0 2  
Versi o n Date: 0 9/ 1 1/ 2 0 2 0  
7 9  
U p date # 1 3  
Office will c o m plete t his secti o n:  
 
1.  Date patie nt starte d pr ot oc ol treat me nt  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
2. 
Date patie nt was re m o ve d fr o m st u d y 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
3.  T otal n u m ber of ta blet’s ta ke n t his m o nt h (eac h size) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
4. 
P h ysicia n/ N urse/ Data Ma na ger’s Si g nat ure 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
P atie nt’s si g n at ure 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _