Pilot Study of Ponatinib in Biliary Cancer Patients With FGFR2 Fusions
Phase: PHASE2
Conditions: Malignant Hepatobiliary Neoplasm
Sponsor: Mayo Clinic



 
3  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
I n de x 
Sc he ma  
  1. 0  
Bac k gr o u n d  
  2. 0 
G oals  
  3. 0 
Patie nt Eli gi bilit y  
  4. 0 
T est Sc he d ule  
  5. 0  
Stratificati o n  Fact or s  
  6. 0  
Re gistrati o n/ Ra n d o mizati o n Pr oce d ures 
  7. 0 
Pr ot oc ol Treat me nt  
  8. 0 
D osa ge M o dificati o n Base d o n A d verse E ve nts  
  9. 0 
A ncillar y Treat me nt/ S u p p orti ve Care  
1 0. 0  
A d verse E ve nt ( A E) Re p orti n g a n d M o nit ori n g  
1 1. 0 
Treat me nt E val uati o n Usi n g R E CI S T G ui d eli ne 
1 2. 0 
Descri pti ve Fact ors  
1 3. 0 
Treat me nt/ F oll o w - u p Decisi o n at E val uati o n of Patie nt  
1 4. 0  
B o d y Fl ui d Bi os peci me ns 
1 5. 0 
Dr u g I nf or mati o n  
1 6. 0  
Statistical C o nsi derati o ns a n d Met h o d ol o g y 
1 7. 0 
Pat h ol o g y C o nsi derati o ns/ Tiss ue Bi os peci me ns  
1 8. 0 
Rec or ds a n d  Data C ollecti o n Pr oce d ures  
1 9. 0  
B u d get 
2 0. 0 
Refere nces  
C o nse nt F or m  
 
A p pe n di x I –  E C O G Perf or ma nce Stat us  
A p pe n di x II – Patie nt  Me dicati o n Diar y  
A p pe n di x III – Patie nt I nf or mati o n S heet 
A p pe n di x I V –  E O R T C Q L Q - C 3 0 
A p pe n di x V – E O R T C Q L Q -BI L 2 1  
A p pe n di x VI – S ki n de x- 1 6  
A p pe n di x VII – B o wel F u ncti o n Q uesti o n naire  
A p pe n di x VIII – U niscale  
A p pe n di x I X – Was It W ort h It  
A p pe n di x X – C hil d -P u g h Classificati o n  
A p pe n di x XI: M E DI C A TI O N G UI D E Icl usi g
® 
(e ye-C L U E -si g) ( p o nati ni b) T a blets  
A p pe n di x XII:  Pr o hi bite d Dr u g s Affecti n g t he Q T I nter val 
 
 

 
4  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
Sc he m a  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If a patie nt is dee me d i neli gi ble or a ca ncel, please refer t o Secti o n 1 3. 0 f or f oll o w- u p i nf or mati o n. 
 
* C ycle = 2 8 da ys  
 
 
Ge neric na me:    P o nati ni b  
Bra n d na me(s): Icl usi g ™ 
Ma y o  A b bre viati o n:   P O N A TI NI B   
  
A vaila bilit y:   pr o vi de d b y A RI A D P har mace uticals  
    
P o nati ni b 4 5 m g P O o nce dail y  
Da y 1 - 2 8  
Re gistr ati o n  
E ve nt M o nit ori n g  
per Secti o n 1 8. 0 
Disease pr o gressi o n  
U nacce pta ble a d verse e ve nts  
Patie nt ref usal  

 
5  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
1. 0 
B ac k gr o u n d   
 
1. 1  
Bili ar y C a ncers  
Biliar y ca ncers c o m prise mali g na nt t u m ors of t he i ntra he patic a n d e xtra he patic bile d ucts, 
gall bla d der a n d a m p ulla. K n o w n ris k fact ors f or c h ola n gi ocarci n o ma are t he li ver fl u kes 
O. viverri ni  a n d C. si ne nsis  i n hi g h pre vale nce e n de mic re gi o ns i n s o ut heast Asia,1- 3 as 
well as pri mar y scler osi n g c h ol a n gitis, 4- 7 Car oli’s disease, 8 he patitis B a n d he patitis C, 9- 1 4 
o besit y, 1 3 he pat olit hiasis 1 5 , 1 6 a n d t h or otrast c o ntrast e x p os ure. 1 7 , 1 8 I ncrease d i nci de nce of 
gall bla d der ca ncer  has bee n ass ociate d wit h gallst o nes, o besit y, a ge, fe male ge n der, a n d 
S.  ty p hi,  S.  p ar aty p hi,  H.  pyl ori  a n d  H.  bilis  i nfecti o ns.1 9 Re gi o ns  of  hi g her  i nci de nce 
i ncl ude C hile 2 0  a n d N ort her n I n dia/ Pa kista n.1 9  
 
S ur gical  a p pr oac hes  s uc h  as  resecti o n  a n d  tra ns pla ntati o n  re prese nt  t he  o nl y  c urati ve 
treat me nt a p pr oac hes.2 1 U nf ort u natel y, m ost patie nts prese nt wit h s ur gicall y u nresecta ble 
or  metastatic  disease  at  dia g n osis.  S yste mic  t hera p y  wit h  ge mcita bi ne  a n d  cis plati n  has 
bee n esta blis he d as t he sta n dar d of care f or patie nts wit h a d va nce d disease. 2 2 H o we ver, 
m ost  patie nts  e ve nt uall y  e x perie nce  pr o gressi o n  of  t heir  disease  a n d  t here  is  i m mi ne nt  
nee d f or n o vel t hera pe utic a p pr oac hes. 
 
1. 2  
F G F R P at h w a y i n C a ncer  
Me m bers  of  t he  F G F R  fa mil y  ( F G F R 1 -4)  ha ve  bee n  ass ociate d  wit h  m utati o ns, 
a m plificati o ns  a n d  tra nsl ocati o n  e ve nts  wit h  o nc o ge nic  p ote ntial. 2 3 F G F R  f usi o ns  wit h 
o nc o ge n ic  acti vit y  ha ve  bee n  pre vi o usl y  i de ntifie d  i n  bla d der  ca ncer  ( F G F R 3),2 4  
l y m p h o ma  ( F G F R 1  a n d  F G F R 3),2 5 , 2 6 ac ute  m yel oi d  le u ke mia  ( F G F R 1), 2 7   m ulti ple 
m yel o ma, 2 8  m yel o pr oliferati ve ne o plas ms 2 9  a n d m ost rece ntl y gli o blast o ma m ultif or me 
( F G F R 1  a n d  F G F R 3).3 0   F usi o ns  i n v ol vi n g  F G F R  fa mil y  me m bers  ma y  be  b ot h 
t hera pe uticall y  rele va nt  a n d  acti o na ble.  T he  F G F R  t yr osi ne  ki nase  i n hi bit ors  ( T KI) 
d o viti ni b 3 1  a n d N V P- B GJ 3 9 83 2  are c urre ntl y i n cli nical de vel o p me nt a n d t he F G F R T KI 
p o nati ni b 3 3    was  rece ntl y  a p pr o ve d  b y  t he  F D A  f or  use  i n  T 3 1 5I  m uta nt  c hr o nic 
m yel o ge n o us le u ke mia. F G F 7 ( kerati n oc yte gr o wt h fact or) has bee n pre vi o usl y li n ke d t o 
p o or  pr o g n osis  i n  patie nts  wi t h  biliar y  tract  ca ncer  a n d  a  s mall  m olec ule  F G F R  ki nase 
i n hi bit or,  Ki 2 3 0 5 7,  has  de m o nstrate d  efficac y  i n  precli nical  m o dels.3 4 F G F R 2,  F G F R 3 
a n d  F G F R 4  ha ve  bee n  f o u n d  t o  be  o vere x presse d  i n  biliar y  ca ncers,  partic ularl y  t h ose 
har b ori n g I D H 1 a n d 2 m utati o ns. 3 5  
 
We  ha ve  i de ntifie d  rec urre nt  f usi o ns  of  F G F R 2  i n  patie nts  wit h  a d va nce d  i ntra he patic 
c h ola n gi ocarci n o ma  i n  t he  setti n g  of  o n g oi n g  w h ole  ge n o me  se q ue nci n g  st u dies. 
C o nc o mita nt acti vati o n of t he F G F R casca de ( p h os p h or -F G F R 2, i ncrease d e x pressi o n of 
ot her  F G F R  me m bers:  F G F R 3  a n d  F G F R 4) has  bee n  el uci date d i n t hese  i nsta nces.  We 
f o u n d f usi o ns of F G F R 2 wit h M G E A 5, BI C C 1 or T A C C 3 i n o ur st u d y. T he F G F R ge nes 
e nc o de m ulti ple str uct ural varia nts t hr o u g h alter nati ve s plici n g. N ota bl y, t he F G F R 2 -III b 
is of or m  was  prese nt  i n  all  of  t hese  f usi o ns  a n d  has  bee n  s h o w n  t o  ha ve  selecti vit y f or 
e pit helial  cells  as  o p p ose d  t o  t he  F G F R 2 -IIIc  is of or m,  w hic h  is  f o u n d  selecti vel y  i n 
mese nc h y mal  cells. 3 6 Gi ve n  t hat  biliar y  ca ncers  are  of  e pit helial  ori gi n  a n d  t hat  ca ncer 
ass ociate d  fi br o blasts  ha ve  bee n  i m plicate d  i n  t he  setti n g  of  a  paracri ne  l o o p  wit h 
c h ola n gi ocarci n o ma  t u m or  cells, 3 7 , 3 8 f urt her  c haracterizati o n  of  F G F R 2-III b  s pecific 
li ga n ds, F G F 7 a n d F G F 1 0, w hic h ha ve n o bi n di n g t o F G F R 2-IIIc, w o ul d be warra nte d. 
Para d o xicall y,  F G F R 2 -III b  has  bee n  descri be d  as  a  t u m or  s u p press or  i n  pre-cli nical 
s yste ms  of  bla d der  ca ncer  a n d  pr ostate  ca ncer.3 9 , 4 0 As  s uc h,  F G F R  si g nali n g  is  clearl y 
c o nte xt de pe n de nt a n d will e x hi bit varia bili t y i n dis parate t u m or t y pes. 
 

 
6  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
A d diti o nal  st u dies  t o  c haracterize  t he  pre vale nce  of  t he  rece ntl y  i de ntifie d  F G F R 2 
a berrati o ns i n a lar ger c o h ort of biliar y ca ncers are u n der wa y. I n vitr o f u ncti o nal st u dies 
c haracterizi n g t he f usi o ns are als o u n der wa y.  
 
We  p r o p ose  t o  st u d y  p o nati ni b  pr os pecti vel y  i n  t he  c o nte xt  of  a  pil ot  st u d y  i n  patie nts 
wit h  F G F R 2  f usi o ns  t hat  are  i de ntifie d  t hr o u g h  o ur  real  ti me  w h ole  ge n o me  a nal ysis 
eff orts. 
 
1. 2  
P o n ati ni b  
 
1. 2 1    
Che mical  
A P 2 4 5 3 4 ( U nite d States A d o pte d Na me [ U S A N]: p o nati ni b) is a n o vel, orall y-
a vaila ble t yr osi ne  ki nase i n hi bit or ( T KI). A pri mar y tar get is B C R - A B L, a n 
a b n or mal t yr osi ne ki nase t hat is t he hall mar k of c hr o nic m yel oi d le u ke mia 
( C M L). B C R- A B L is e x presse d fr o m a f usi o n ge ne f or me d b y t he rearra n ge me nt 
of t he brea k p oi nt cl uster re gi o n ( B C R) o n c hr o m os o me 2 2 wit h t he c-a bl pr ot o-
o nc o ge ne ( A B L) o n c hr o m os o me 9 ( B C R- A B L). P o nati ni b is a ne w c he mical 
e ntit y pre pare d b y c he mical s y nt hesis. T he p o nati ni b acti ve p har mace utical 
i n gre die nt ( A PI) is t he m o n o-h y dr oc hl ori de salt ( A P 2 4 5 3 4 h y dr oc hl ori de, or 
A P 2 4 5 3 4 H Cl). P o nati ni b f or i n vesti gati o nal use is s u p plie d as w hite o pa q ue 
ca ps ules c o ntai ni n g n o mi nall y 2 m g, 5 m g or 1 5 m g of p o nati ni b or as 1 5 m g or 
4 5 m g r o u n d, w hite, fil m- c oate d ta blets. 
 
1. 2 2   
N o ncli nical 
A precli nical de vel o p me nt pr o gra m has bee n c o m plete d t o s u p p ort cli nical trials 
o n p o nati ni b. I n vitr o assa ys de m o nstrate d t hat p o nati ni b p ote ntl y i n hi bits t he 
ki nase e nz y matic acti vit y of t he  T 3 1 5I A B L ki nase d o mai n, as well as t hat of t he 
nati ve ( u n m utate d) e nz y me. I n l e u ke mia cell  li nes e x pressi n g t hese B C R-A B L 
varia nts, p o nati ni b p ote ntl y i n hi bite d B C R- A B L si g nali n g,  lea di n g t o i n hi biti o n 
of cell ular pr oliferati o n a n d i n d ucti o n of a p o pt osis. P o nati ni b als o p ote ntl y 
i n hi bits t he pr oliferati o n of cell li nes e x pressi n g other maj or cli nicall y o bser ve d  
i mati ni b-resista nt m uta nts of B C R- A B L. I n vi v o a ntit u m or acti vit y has bee n 
s h o w n i n t u m or-beari n g m o use m o dels.  
 
P o nati ni b is als o a p ote nt i n hi bit or of certai n ot her t yr osi ne ki nases i m plicate d i n 
t he i nitiati o n a n d pr o gressi o n of le u ke mias a n d ot her t u m or t y pes. I n partic ular, it 
i n hi bits F L T 3, w hic h is fre q ue ntl y m utati o nall y acti vate d i n ac ute m yel oi d 
le u ke mia ( A M L), a n d i n hi bits all me m bers of t he F G F R fa mil y, w hic h are 
i m plicate d i n a variet y of m yel o pr oliferati ve dis or ders a n d s oli d t u m or 
i n dicati o ns. P o nati ni b als o i n hi bits se veral ot her ki nases, i ncl u di n g KI T, R E T, 
S R C,  V E G F R, P D G F R, a n d TI E 2.  T a ke n t o get her, t he ki nase i n hi biti o n pr ofile 
of p o nati ni b s u g gests t he p ote ntial f or cli nical  acti vit y i n ot her he mat ol o gic a n d  
n o n he mat ol o gic mali g na ncies i n a d diti o n t o C M L. 
 
Precli nical safet y assess me nt st u dies were perf or me d o n p o nati ni b i ncl u di n g 6 -
m o nt h oral t o xic ol o g y st u dies i n rats a n d c y n o m ol g us m o n ke ys. T he rat was 
s h o w n t o be t he m ost se nsiti ve s pecies t o t he t o xic ol ogic effects of p o nati ni b. I n 
t he 6- m o nt h oral t o xic ol o g y st u d y i n rats, t he n o o bser ve d a d verse effect le vel 
( N O A E L) was 0. 2 5 m g/ k g/ da y. Hi g her d ose le vels of 0. 7 5 a n d 2 m g/ k g/ da y 
ca use d m ortalit y of s o me a ni mals. Hist ol o gic e xa mi nati o n re veale d decrease d  

 
7  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
n u m bers of c h o n dr oc ytes al o n g t he p h ysis i n t he fe m ur at t he 0. 7 5 a n d 2 
m g/ k g/ da y d ose le vels,a n d l y m p h oi d de pleti o n was o bser ve d i n t he t h y m us at t he 
2 m g/ k g/ da y d ose le vel. T he a d mi nistrati o n of p o nati ni b t o c y n o m ol g us m o n ke ys 
f or 6 m o nt hs at oral d ose le vels of 0. 2 5, 0. 7 5 a n d 2 m g/ k g/ da y was well t olerate d 
wit h n o p o nati ni b -relate d micr osc o pic fi n di n gs bei n g o bser ve d at a n y d ose le vel.  
T o xicit y st u dies i n pre g na nt rats de m o nstrate d fetal malf or mati o ns a n d e m br y o-
fetal t o xicit y at d ose le vels of 1 a n d 3 m g/ k g/ da y, res pecti vel y, a n d hi g her. I n a 
p h ot ot o xicit y st u d y i n pi g me nte d rats, si g ns of mi ni mal oc ular p h ot ot o xicit y were 
o bser ve d at 5 a n d 1 0 m g/ k g. 
 
1. 2 3 
Cli nical  
Icl usi g recei ve d accelerate d a p pr o val i n t he U nite d States ( U S) ( Dece m ber 2 0 1 2) 
a n d a p pr o val i n t he E ur o pea n U ni o n ( E U) (J ul y 2 0 1 3) f or patie nts wit h refract or y 
C M L or P hila del p hia c hr o m os o me -p ositi ve ( P h +) le u ke mias. As of 0 6 J a n uar y 
2 0 1 4, 7 5 3 patie nts ha ve recei ve d p o nati ni b t hera p y t hr o u g h cli nical st u dies, a n d 
1 3 1 2 t hr o u g h gl o bal e x pa n de d a ccess pr o gra ms.  
 
F oll o wi n g a p pr o val of p o nati ni b i n t he U S a n d t he E U, m ore t ha n 9 0 0 patie nts 
ha ve bee n treate  wit h p o nati ni b c o m merciall y.  Si nce t he pre vi o us u p date t o t his 
I n vesti gat or Br oc h ure ( Versi o n 5, 2 5 Fe br uar y 2 0 1 3), re g ulat or y acti o ns were 
ta ke n b y A RI A D P har mace uticals ( A RI A D) a n d/ or t he c o m pete nt a ut h orities 
f oll o wi n g i ncrease d c u m ulati ve ris k of vasc ular occl usi ve e ve nts o bser ve d i n 
patie nts  usi n g p o nati ni b. Fr o m a de vel o p me nt pers pecti ve, o n 0 8 Oct o ber 2 0 1 3, 
t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) place d a partial cli nical h ol d o n all 
ne w patie nt e nr oll me nts i n cli nical  st u dies wit h p o nati ni b, a n d a p hase 3 st u d y 
( E PI C: A P 2 4 5 3 4- 1 2- 3 0 1) was ter mi nate d o n 1 7 Oct o ber 2 0 1 3. Fr o m a 
p ost mar keti n g a ut h orizati o n pers pecti ve, pri or a p pr o val s u p ple me nt/t y pe II 
variati o n were e val uate d b y t he F D A a n d t he E ur o pea n Me dici nes A ge nc y  
( E M A), res pecti vel y, t o re vise p o nati ni b pr o d uct i nf or mati o n t o i ncl u de u p date d 
data a n d  war ni n g/ preca uti o ns o n arterial t hr o m b oe m b olic e ve nts, ve n o us 
t hr o m b oe m b olic e ve nts, car diac fail ure/left ve ntric ular d ysf u ncti o n ( L V D), a n d 
car di o vasc ular deat hs. T he t y pe II variati o n  recei ve d a p ositi ve o pi ni o n fr o m 
E ur o pe’s C o m mittee f or H u ma n Me dici nal Pr o d ucts ( C H M P) o n 2 1 N o ve m ber 
2 0 1 3. S u bse q ue nt t o c o m pleti o n of t he T y pe II variati o n pr oce d ure, a referral 
pr oce d ure u n der article 2 0 of re g ulati o n ( E C) N o. 7 2 6/ 2 0 0 4 was tri g gere d. I n t he 
U S, w hile  e val uati o n of ne w safet y data was o n g oi n g, t he F D A re q ueste d 
A RI A D o n 3 1 Oct o ber 2 0 1 3 t o te m p oraril y s us pe n d c o m mercial distri b uti o n a n d 
mar k eti n g of Icl usi g i n t he U S. O n 2 0 Dece m ber 2 0 1 3, t he F D A a gree d wit h t he 
re vise d U S Prescri bi n g I nf or mati o n, a n d c o m mercializati o n of Icl usi g was 
res u me d i n t he U S i n Ja n uar y 2 0 1 4. A d diti o nal i nf or mati o n ca n be f o u n d wit hi n 
t h I n vesti gat or’s br oc h ure.  
 
 
1. 3  
Circ ul ati n g t u m or D N A b ase d bi o m ar kers  
Cell -free t u m or-s pecific D N A i n circ ulati n g plas ma (ct D N A) has bee n rece ntl y s h o w n t o 
be a p ote ntial bi o mar ker f or s oli d ca ncers. S pecific m utati o ns ca n be trac ke d i n ct D N A 
a n d reflect disease b ur de n i n breast, o varia n, c ol orectal a n d ot her n o n- he mat ol o gical 
ca ncers.  E xte nsi ve a nal ysis of selecte d plas ma sa m ples ca n pr o vi de i nsi g hts i nt o 
ac q uire d resista nce t o m olec ularl y tar gete d treat me nts a n d s u b -cl o nal ge n o mic e v ol uti o n 
of ca ncers.  
 

 
8  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
T here is a dire nee d f or a cc urate circ ulati n g bi o mar kers f or c h ola n gi ocarci n o mas. 
A nal ysis of ct D N A wit hi n t his st u d y pr o vi des a n o p p ort u nit y t o de vel o p a pers o nalize d 
bi o mar ker f or m o nit ori n g of t u m or b ur de n. A d diti o nal c orrelati ve a nal ysis ma y all o w 
i de ntificati o n of mec ha nis ms t hat ca use pri mar y or ac q uire d resista nce t o treat me nt 
p o nati ni b i n c h ola n gi ocarci n o ma. T his ma y e na ble m olec ular stratificati o n of 
c h ola n gi ocarci n o ma f or p o nati ni b or ot her m olec ularl y tar gete d a ge nts usi n g circ ulati n g 
t u m or D N A a nal ysis. 
 
2. 0  
G o als    
 
2. 1 
Pri mar y  
 
2. 1 1 
T o assess t he cli nical be nefit rate   (c o nfir me d c o m plete or partial res p o nse or 
sta ble disease f or 4 or m ore c ycles) of p o nati ni b i n F G F R a berra nt a d va nce d 
biliar y ca ncers  
 
2. 2  
Sec o n dar y 
 
2. 2 1  
T o esti mate pr o gressi o n free s ur vi val , o verall s ur vi val, a n d C A 1 9- 9 res p o nse rate 
of t hese patie nts  
 
2. 2 2  
T o esti mate t he a d verse e ve nt  pr ofile of p o nati ni b  
 
2. 3 
Tra nslati o nal/ C orrelati ve  Researc h  
 
2. 3 1    
Esta blis h preli mi nar y c orrelati o ns bet wee n F G F R 2 f usi o ns a n d e vi de nce of a n y 
cli nical be nefit 
 
2. 3 2   
Asse ss preli mi nar y e val uati o n of F G F R 2 pat h wa y pert ur bati o n wit h p o nati ni b 
 
2. 3 3   
T o descri be patie nt-re p orte d healt h -relate d q ualit y of life a n d s y m pt o ms  
 
 
3. 0 
P atie nt Eli gi bilit y     
 
3. 1  
I ncl usi o n Criteria   
 
3. 1 1  
A ge ≥1 8 years  
 
  
    
3. 1 2 
Hist ol o gical/c yt ol o gi cal c o nfir mati o n of biliar y ca ncer . 
 
 
3. 1 3   
C o nfir mati o n of  a d va nce d biliar y ca ncer t hat is refract or y or i nt olera nt t o 
ge m cita bi ne or fl u or o p yri mi di ne base d t hera p y  wit h F G F R 2 f usi o n [ usi n g 
Ne xt - Ge n se q ue nci n g assa ys (s uc h as F o u n dati o n O ne ®) or fl u orescent i n sit u 
h y bri dizati o n ( FI S H) brea k -a part assa ys ] or F G F R pat h wa y 
m utati o n/a m plificati o n [ usi n g Ne xt -Ge n se q u e nci n g ass a ys (s uc h as 
F o u n dati o n O ne ®)].  Assa ys m ust be perf or me d i n a C LI A certifie d la b orat or y 
a n d d o ne as a C LI A vali date d test or R U O i n a C LI A l a b orat or y.   
 
3. 1 4  
Meas ura ble disease as defi ne d i n Secti o n 1 1. 0.    
 
3. 1 5 
E C O G Perf or ma nce Stat us ( P S) 0, 1 or 2  ( A p pe n di x I). 
 

 
9  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
3. 1 6  
T he f oll o wi n g la b orat or y val ues o btai ne d ≤ 1 4 da ys pri or t o re gistrati o n.  
•  
A bs ol ute ne utr o p hil c o u nt ( A N C ) ≥ 1 5 0 0/ m m3 
•  
Platelet c o u nt ≥ 1 0 0, 0 0 0/ m m3 
•  
He m o gl o bi n ≥ 9. 0 g/ d L 
•  
T otal  bilir u bi n ≤ 1. 5 x u p per li mit of n or mal ( U L N), u nless d ue t o Gil bert’s 
s y n dr o me  
•  
As partate tra nsa mi nase  ( A S T) a n d Ala ni ne A mi n otra nsferase ( A L T)   < 3  x 
U L N 
•  
Creati ni ne ≤ 1. 5 x u p per li mit of n or mal ( UL N)  
•  
Ser u m li pase a n d a m ylase ≤ 2. 5 x u p per li mit of n or mal ( U L N). N ote: If 
s u bj ect has t u m or i n v ol ve me nt i n t he li ver ≤ 3 x U L N.  
 
3. 1 7 
Ne gati ve  pre g na nc y test d o ne ≤ 7 da ys pri or t o re gistrati o n, f or w o me n of 
c hil d beari n g p ote ntial o nl y.  
 
  
3. 1 8   
Rec o vere d fr o m pri or ra di ot hera p y a n d/or s yste mic t hera p y relate d t o xicities t o  
  
Gra de ≤ 1 
 
3. 1 9a  Pr o vi de i nf or me d writte n c o nse nt. 
 
3. 1 9 b 
Life e x pecta nc y ≥ 3 m o nt hs 
 
3. 1 9c  Willi n g t o ret ur n t o e nr olli n g i nstit uti o n f or f oll o w - u p ( d uri n g t he Acti ve 
M o nit ori n g P hase of t he st u d y).  
 
N ote:  D uri n g t he Active M o nit ori n g  P h ase of a st u dy (i.e., active tre at me nt a n d 
o bserv ati o n), p artici p a nts m ust be willi n g t o ret ur n t o t he c o nse nti n g i nstit uti o n 
f or f oll o w- u p. 
 
3. 1 9 d  Fe male a n d male patie nts w h o are fertile  a gree t o use a n effecti ve f or m of 
c o ntrace pti o n wit h t heir se x ual part ners fr o m r e gistrati o n t hr o u g h 4 m o nt hs after 
t he e n d of treat me nt. 
 
3. 1 9e 
A bilit y t o c o m plete q uesti o n naire(s) b y t he msel ves or wit h assista nce.  
 
 
 
3. 2  
E xcl usi o n Criteria   
 
3. 2 1  
A n y of t he f oll o wi 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 :  
•  
Pre g na nt w o me n 
•  
N ursi n g w o me n 
•  
Me n or w o me n of c hil d beari n g p ote ntial w h o are u n willi n g t o e m pl o y 
a de q uate c o ntrace pti o n 
 
3. 2 2 
C o -m or bi d s yste mic ill nesses or o t her se vere c o nc urre nt disease w hic h, i n t he 
j u d g me nt of t he i n vesti gat or, w o ul d ma ke t he patie nt i na p pr o priate f or e ntr y i nt o 

 
1 0  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
t his st u d y or i nterfere si g nifica ntl y wit h t he pr o per assess me nt of safet y a n d 
t o xicit y of t he prescri be d re gi me ns. 
 
3. 2 3  
I m m u n oc o m pr o mise d patie nts a n d patie nts k n o w n t o be HI V p ositi ve a n d 
c urre ntl y recei vi n g a n tiretr o viral t hera p y.  N O T E:  Patie nts wit h a k n o w n hist or y 
of HI V i nfecti o n are n ot eli gi ble f or t his trial. 
 
  
3. 2 4  
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve 
i nfecti o n, s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, car diac 
arr h yt h mia, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce 
wit h st u d y re q uire me nts. 
 
3. 2 5 
Recei vi n g a n y ot her i n vesti gati o nal a ge nt w hic h w o ul d be c o nsi dere d as a 
treat me nt f or t he pri mar y ne o plas m. 
 
3. 2 6  
Pri or s yste mic c he m ot hera p y, ra diati o n t hera p y or maj or s ur ger y ≤ 3 0 da ys pri or  
t o re gistrati o n. 
 
3. 2 7  
C o nc urre nt use of a n y ot her a p pr o ve d or i n vesti gati o nal a ntica ncer a ge nts,  
  
i ncl u di n g h or m o nal a ge nts 
 
3. 2 8  
Pri or nitr os o urea or mit o m yci n C < = 6 wee ks pri or t o re gistrati o n.   
 
3. 2 9a  Patie nts wit h gastr oi ntesti nal c o m ori bi d ities t hat w o ul d affect i nta ke or 
a bs or pti o n of p o nati ni b 
 
3. 2 9 b  U ntreate d or pr o gressi ve brai n metastases  
 
3. 2 9c   Pri or treat me nt wit h or aller gic reacti o ns attri b ute d t o c o m p o u n ds of si milar 
c he mical or bi ol o gic c o m p ositi o n t o p o nati ni b  
 
3. 2 9 d 
Cli nicall y u nc o ntr olle d h y perte nsi o n ( diast olic bl o o d press ure > 9 0 m m H g; 
s yst olic > 1 4 0 m m H g).  N O T E: Patie nts wit h h y perte nsi o n s h o ul d be u n der g oi n g 
treat me nt at st u d y e ntr y f or bl o o d press ure c o ntr ol. 
 
3. 2 9e 
Pre vi o us or c o nc urre nt mali g na nc y e xce pt a de q uatel y treate d basal or s q ua m o us 
cell s ki n ca ncer, i n sit u carci n o ma of t he cer vi x, or ot her s oli d t u m or treate d 
c urati vel y a n d wit h o ut e vi de nce of rec urre nce f or at least 5 years  
 
3. 2 9f 
Hist or y of si g nifica nt blee di n g dis or der u nrelate d t o ca ncer  
 
3. 2 9 g 
Hist or y of  ac ute pa ncreatitis wit hi n 1 year pri or t o  re gistrati o n, c hr o nic 
pa ncreatitis, alc o h ol a b use or u nc o ntr olle d h y pertri gl yceri de mia (tri gl yceri des 
> 4 5 0 m g/ d L) 
 
3. 2 9 h  Cli nicall y si g nifica nt, u nc o ntr olle d, or acti ve car di o vasc ular disease, s pecificall y 
i ncl u di n g, b ut n ot restricte d t o: 
•  
A n y  hist or y of m y ocar dial i nfarcti o n, str o ke, or re vasc ularizati o n  
•  
U nsta ble a n gi na or tra nsie nt isc he mic attac k wit hi n 6 m o nt hs pri or t o 
re gistrati o n  

 
1 1  
M C 1 3 4 5 
M C C C A d de n d u m 1 
 
•  
C o n gesti ve heart fail ure wit hi n 6 m o nt hs pri or t o re gistrati o n, or left 
ve ntr ic ular ejecti o n fracti o n ( L V E F) less t ha n l o wer li mit of n or mal per 
l ocal i nstit uti o nal sta n dar ds wit hi n 6 m o nt hs pri or t o re gistrati o n 
•  
Hist or y of cli nicall y si g nifica nt (as deter mi ne d b y t he treati n g p h ysicia n) 
atrial arr h yt h mia 
•  
A n y hist or y of ve ntric ular  arr h yt h mia 
•  
Acti ve ve n o us t hr o m b oe m b olis m i ncl u di n g dee p ve n o us t hr o m b osis or 
p ul m o nar y e m b olis m t hat is n ot a me na ble t o treat me nt wit h 
a ntic oa g ula nts.  
•  
Patie nts wit h c o n ge nital pr ol o n ge d Q T s y n dr o mes a n d a b n or mal 
baseli ne pr ol o n ge d Q Tc ( > 4 5 0 ms i n me n a n d > 4 7 0 ms i n w o me n).  
•  
P atie nts wit h an ejecti o n fracti o n ≤ 5 0 % as assesse d b y a b aseli ne 
ec h ocar di o gra m.  
 
3. 2 9i   T a ki n g me dicati o ns t hat are k n o w n t o be ass ociate d wit h T orsa des de P oi ntes 
(see A p pe n di x XII ) 
3. 2 9j   T a ki n g a n y me dicati o ns or her bal s u p ple me nts t hat are k n o w n t o be str o n g 
i n hi bit ors of C Y P 3 A 4 ≤1 4 da ys pri or t o re gistrati o n. (see S ecti o n 9. 9 b) 

1 2                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
4. 0  
Test Sc he d ule  
C ycle = 2 8 da ys  
 
Acti ve M o nit ori n g P hase  
 
 
T ests a n d 
pr oce d ures 
≤1 4 da ys  
pri or t o 
re gistrati o n 
 
C ycle 1 
Da y 1  ( ± 
2 
da ys) pri or 
t o 
treat me nt 
 
 
C ycle 1 
Da ys 8, 
1 5, 2 2 
pri or t o  
treat me nt 
C ycle 2 
a n d 
be y o n d 
Da y 1 ( ± 
2 da ys) 
pri or t o 
treat me nt 
 
Q 8 
wee ks 
fr o m 
C ycle 
1 Da y 
1 ( ± 5 
da ys)  
E ver y 
3 
C ycles  
starti n g 
at e n d 
of 
C ycle 
3 ( ± 5 
da ys)  
E n d of 
treat me nt 
Hist or y a n d 
e xa m, wt, 
E C O G  
X 
 
 
X  
 
 
X 
Hei g ht , C hil d 
P u g h sc ore  
X 
 
 
 
 
 
 
Vital s3 
X  
X  
X  
X  
 
 
X  
He mat ol o g y 
gr o u p 
 
W B C, A N C, 
H g b, P L T  
X 
 
X 
 
X 
 
X 
 
 
X 
C he mistr y 
gr o u p 
  S o di u m, 
p otassi u m, 
c hl ori de, 
bicar b o nate, 
t otal pr otei n, 
al b u mi n, 
calci u m, 
gl uc ose, 
B U N, t otal 
bilir u bi n, 
creati ni ne, 
al kali ne 
p h os p hatase, 
S G O T 
( A S T), S G P T 
( A L T) 
X 
X 
 
X 
 
 
X 
A m ylase R  
X  
X  
X  
X  
 
 
 
Li pase R  
X  
X  
X  
X  
 
 
 
C A 1 9 -9  
 
X  
 
X 5 
 
 
 
E K G R  
X  
 
 
 
 
X  
 
Ec h ocar di o gra m  
X  
 
 
X 1 0 
 
 
 
T u m or 
meas ure me nt 
a n d I ma gi n g 
( C T or M RI 
as cli nicall y 
X 1 
 
 
 
 
X 2 
 
 

1 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
i n dicate d) 
Pre g na nc y test  
X 4  
 
 
 
 
 
 
P atie nt 
q uesti o n naire 
b o o klet  
X 9 
 
 
X 9 
 
 
 
A d ve rse e ve nt 
assess me nt 
X 
 
X 
X 
 
 
 
Researc h 
Arc hi val Tiss ue 
( o pti o nal) 
X 8 
 
 
 
 
 
 
Researc h Tiss ue 
Bi o ps y 
( o pti o nal) 
 
 
 
X 7, R 
 
 
X 6 
Researc h bl o o d 
sa m ples 
( O pti o nal) 
X 
 
 
X 
 
 
X 
1. 
I ma gi n g st u dies s uc h as C T sca ns, a n d M RIs ca n be perf or me d ≤2 8 da ys pri or t o re gistrati o n.  
Use sa me i ma gi n g t hr o u g h o ut t he st u d y.  Assess me nt b y p h ysical e xa m s h o ul d be d o ne ≤1 4 
da ys pri or t o re gistrati o n. 
2. 
T u m or assess me nt m ust be perf or me d at least e ver y 8 wee ks. T u m or assess me nt s h o ul d be 
perf or me d at a n y ti me d uri n g t he treat me nt c ycle t hat disease pr o gressi o n is cli nicall y 
s us pecte d s o t hat patie nt ca n g o off treat me nt a n d recei ve ot her t hera p y.  
3.   I ncl u des wei g ht, bl o o d press ure, p ulse a n d te m perat ure 
4.   W o me n of c hil d beari n g p ote ntial o nl y.  M ust be d o ne ≤7 da ys pri or t o re gistrati o n. 
5.   O nl y t o be c ollecte d if > U L N o n C ycle 1 Da y 1 
6.   If patie nt has e x perie nce d disease pr o gressi o n a n d at s uc h ti me a sta n dar d of care bi o ps y is   
      or dere d b y t he treati n g p h ysicia n, waste s peci me n will be c ollecte d, fres h fr oze n a n d st ore d 
f or f ut ure c orrelati ve st u dies. Perf or m o nl y if arc hi val s peci me n was a vaila ble.  
7.   Perf or m  o nl y if arc hi val s peci me n was  a vaila ble. 
8.  Arc hi val F F P E a n d/ or fres h fr oze n tiss ue c ollecte d i n setti n g of sta n dar d of care pr oce d ures.    
9.  Patie nt q uesti o n naire b o o klet m ust be use d; c o pies are n ot acce pta ble f or t his s u b missi o n.  
B o o klet s h o ul d be c o m plete d b y patie nt pri or t o    
     re vie w of treat me nt res p o nse a n d disc ussi o ns of patie nt’s ge neral healt h si nce last treatme nt 
e val uati o n. 
1 0 Ec h ocar di o gra ms t o be c o m plete d at baseli ne a n d t he n e ver y 2 c ycles f or t he d urati o n of st u d y 
treat me nt. 
R  Researc h f u n de d (see Secti o n 1 9. 0). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
5. 0 
Str atific ati o n  F act ors: N o ne.  
6. 0  
Re gistr ati o n/ R a n d o miz ati o n Pr oce d ures  
6. 1  
T o re gister a patie nt, access t he Ma y o Cli nic Ca ncer Ce nter ( M C C C) we b pa ge 
a n d e nter t he re gistrati o n/ra n d o mizati o n a p plicati o n.  T he 
re gistrati o n/ra n d o mizati o n a p plicati o n is a vaila ble 2 4 h o urs a da y, 7 da ys a wee k.  
Bac k u p a n d/ or s yste m s u p p ort c o nt act i nf or mati o n is a vaila ble o n t he We b site.  
If u na ble t o access t he We b site, call t he M C C C Re gistrati o n Office at (
 bet wee n t he h o urs of 8 a. m. a n d 4: 3 0 p. m. Ce ntral Ti me ( M o n da y t hr o u g h 
Fri da y).  
 
T he i nstr ucti o ns f or t he re gistrati o n/ra n do mizati o n a p plicati o n are a vaila ble o n 
t he M C C C we b pa ge 
 a n d detail t he 
pr ocess f or c o m pleti n g a n d c o nfir mi n g patie nt re gistrati o n.  Pri or t o i nitiati o n of 
pr ot o col tr eat me nt, t his pr ocess m ust be c o m plete d i n its e ntiret y a n d a M C C C 
s u bj ect I D n u m ber m ust be a vaila ble as n ote d i n t he i nstr ucti o ns.  It is t he 
res p o nsi bilit y of t he i n di vi d ual re gisteri n g t he patie nt t o c o nfir m t he pr ocess has 
bee n s uccessf ull y c o m plete d pri or t o release of t he st u d y a ge nt.  Patie nt 
re gistrati o n via t he re gistrati o n/ra n d o mizati o n a p plicati o n ca n be c o nfir me d i n 
a n y of t he f oll o wi n g wa ys: 
•  
C o ntact t he M C C C Re gistrati o n Office 
.  If the patie nt was 
f ull y re gistere d, t he M C C C Re gistrati o n Office staff ca n access t he 
i nf or mati o n fr o m t he ce ntralize d data base a n d c o nfir m t he re gistrati o n. 
•  
Refer t o “I nstr ucti o ns f or Re m ote Re gistrati o n” i n secti o n 
“ Fi n di n g/ Dis pla yi n g I nf or mati o n a b o ut A Re gistere d S u bj ect.” 
 
6. 2  
D oc u me ntati o n of I R B a p pr o val m ust be o n file i n t he Re gistrati o n Office bef ore 
a n i n vesti gat or ma y re gister a n y patie nts.  
 
I n a d diti o n t o s u b mitti n g i nitial I R B a p pr o val d oc u me nts, o n g oi n g I R B a p pr o val 
d oc u me ntati o n m ust be o n file ( n o less t ha n a n n uall y) at t he Re gistrati o n Office 
(fa x: 
).  If t he necessar y d oc u me ntati o n is n ot s u b mitte d i n a d va nce 
of atte m pti n g patie nt re gistrati o n, t he re gistrati o n will n ot be acce pte d a n d t he 
patie nt ma y n ot be e nr olle d i n t he pr ot oc ol u ntil t he sit uati o n is res ol ve d. 
 
W he n t he  st u d y has bee n per ma ne ntl y cl ose d t o patie nt e nr oll me nt, s u b missi o n of 
a n n ual I R B a p pr o vals t o t he Re gistrati o n Office is n o l o n ger necessar y.  
 
6. 3 
Pri or t o acce pti n g t he re gistrati o n, re gistrati o n a p plicati o n will verif y t he 
f oll o wi n g: 
•  
I R B a p pr o val at t he re gisteri n g i nstit uti o n 
•  
Patie nt eli gi bilit y  
•  
E xiste nce of a si g ne d c o nse nt f or m 
•  
E xiste nce of a si g ne d a ut h orizati o n f or use a n d discl os ure of pr otecte d healt h 
i nf or mati o n 
 
6. 4  
A n o pti o nal c orrelati ve researc h c o m p o ne nt is part of t his st u d y, t here will be a n 
o pti o n t o select if t he patie nt is t o be re gistere d o nt o t his c o m p o ne nt (see Secti o n s 
1 4. 0 a n d 1 7. 0). 

1 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
•  
P atie nt has/ has n ot gi ve n per missi o n t o ha ve a tiss ue bi o ps y at c ycle 2, da y 1.  
•  
P atie nt has/ has n ot gi ve n per missi o n t o all o w a n y e xcess tiss ue c oll ecte d w hile o n 
t his st u d y t o be use d f or researc h st u dies 
•  
P atie nt has/ has n ot gi ve n per missi o n f or bl o o d c ollecti o n at scree ni n g, Pri or t o eac h 
c ycle, a n d at e n d of st u d y t o be use d f or researc h st u dies.  
  
  
 
  
6. 5 
At t he ti me of re gistrati o n, t he f oll o wi n g w ill be rec or de d: 
•  
Patie nt has/ has n ot gi ve n per missi o n f or his/ her tiss ue a n d bl o o d sa m ple(s) t o 
be st ore d a n d use d i n f ut ure researc h of biliar y ca ncer at Ma y o Cli nic  
•  
Patie nt has/ has n ot gi ve n per missi o n f or his/ her tiss ue a n d bl o o d sa m ple(s) t o 
be st ore d a n d use d i n f ut ure researc h at Ma y o Cli nic t o lear n a b o ut, pre ve nt, 
or treat a n y ot her healt h pr o ble ms 
•  
Patie nt has/ has n ot gi ve n per missi o n f or Ma y o Cli nic t o gi ve his/ her tiss ue 
a n d bl o o d  sa mp le(s) t o researc hers at ot her i nstit uti o ns 
 
6. 6  
Treat me nt ca n n ot be gi n pri or t o re gistrati o n a n d m ust be gi n ≤ 7 da ys after 
re gistrati o n. 
 
6. 7 
Pretreat me nt tests/ pr oce d ures (see Secti o n 4. 0) m ust be c o m plete d wit hi n t he 
g ui deli nes s pecifie d o n t he test sc he d ule.  
 
6. 8 
All re q uire d baseli ne s y m pt o ms (see Secti o n 1 0. 6 ) m ust be d oc u me nte d a n d 
gra de d. 
 
6. 9a 
Treat me nt o n t his pr ot oc ol m ust c o m me nce at a Ma y o Cli nic i nstit uti o n u n der t he 
s u per visi o n of a me dical o nc ol o gist. 
 
6. 9 b  
St u d y dr u g is a vaila ble o n site.  
 
6. 9c 
Patie nt q uesti o n naire b o o klet is a vaila ble o n site; c o pies are n ot acce pta ble f or 
t his s u b missi o n.  
 
7. 0  
P r ot oc ol Tre at me nt 
 
  
7. 1 
Treat me nt Sc he d ule  
 
A ge nt  
D ose Le vel  
R o ute  
D a y  
P o nati ni b  
4 5 m g o nce dail y  
P O  
Da ys 1 -2 8  
 
7. 2  
F or t his pr ot oc ol, t he patie nt m ust ret ur n t o t he c o nse nti n g i nstit uti o n f or 
e val uati o n at least e ver y 2 8 da ys  ( +/- 2 da ys) d uri n g treat me nt ( Acti ve 
M o nit ori n g P hase). 
 
7. 3   
Patie nts s h o ul d recei v e l o w-d ose as piri n (e. g. 8 1 m g/ da y), as pr o p h yla xis a gai nst 
arterial t hr o m b otic e ve nts, if n ot c o ntrai n dicate d . 
 
7. 4  
Patie nts s h o ul d recei ve treat me nt w it h a stati n, as pr o p h yla xis a gai nst arterial 
t hr o m b otic e ve nts, if n ot c o ntrai n dicate d. At or vastati o n, 1 0- 2 0 m g per da y, is 
s u g geste d. 

1 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
8. 0  
D os a ge M o dific ati o n B ase d o n A d verse E ve nts  
 
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. 
 
A L E R T : 
A D R re p orti n g m ay be re q uire d f or s o me a dverse eve nts (See Secti o n 1 0) 
 
8. 1  
D ose Le vels ( Base d o n A d verse E ve nts i n T a bles 8. 2)  
D ose 
Le vel  
P o n ati ni b  
 0 *  
 
4 5 m g P O o nce dail y  
-1  
 
3 0 m g P O o nce dail y  
-2  
 
1 5 m g P O o nce dail y  
* D ose le vel 0 refers t o t he starti n g d ose.  
 
 
8. 2 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
B A S E D O N I N T E R V A L A D V E R S E E V E N T  
I n vesti gati o ns 
Ne utr o p hil c o u nt 
decrease d ≥ Gra de 3  
P o nati ni b  
O mit  p o nati ni b  
Res u me at 4 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 4 5 m g: 
O mit  p o nati ni b 
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  

1 7                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
Platelet  c o u nt 
decrease d ≥ Gra de 3  
O mit  p o nati ni b  
Res u me at 4 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 4 5 m g: 
O mit  p o nati ni b 
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urr e nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
Ser u m a m ylase 
i ncrease d ≥ Gra de 3 
wit h n o ra di o gra p hic 
fi n di n gs 
P o nati ni b  
O mit  p o nati ni b  
Res u me at 4 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 4 5 m g: 
O mit  p o nati ni b 
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Re c urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
Ser u m a m ylase 
i ncrease d ≥ Gra de 3 
wit h ra di o gra p hic 
fi n di n gs or Gra de 4 
P o nati ni b  
O mit  p o nati ni b  
Re peat i ma gi n g acc or di n g t o cli nica l care 
After res ol uti o n b y i ma gi n g, res u me at 3 0 
m g after rec o ver y t o ≤gra de 1  
 
Rec urre nce at 3 0 m g: 
Re peat a b o ve  
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  

1 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
 
Ala ni ne 
a mi n otra nsferase 
i ncrease d ( A L T) a n d/ or 
As pa rtate 
a mi n otra nsferase 
i ncrease d ( A S T) ≥ 
Gra de 3  
P o nati ni b  
O mit  p o nati ni b  
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
 
Ala ni ne 
a min otra nsferase 
i ncrease d ( A L T) O R  
As partate 
a mi n otra nsferase 
i ncrease d ( A S T) ≥ 
Gra de 3 A N D Bl o o d 
bilir u bi n i ncrease d  ≥ 2 
x U L N A N D  Al kali ne 
p h os p hatase >  2 x U L N  
P o nati ni b  
Disc o nti n ue p o nati ni b  
Gastr oi ntesti nal 
Dis or ders  
Pa ncreatitis ≥ Gra de 2  
P o nati ni b  
O m it p o nati ni b  
Perf or m ultras o u n d or a b d o mi nal C T sca n 
wit h c o ntrast 
If i ma gi n g is p ositi ve, c o nti n ue t o o mit 
p o nati ni b a n d re peat acc or di n g t o cli nical 
care 
If i ma gi n g is ne gati ve, or after res ol uti o n 
b y i ma gi n g, res u me at 4 5 m g after 
rec o ver y t o ≤ gra de 1 
 
Rec urre nce at 4 5 m g: 
Re peat a b o ve, e xce pt res u me at 3 0 m g 
after rec o ver y t o ≤ gra de 1 
 
Rec urre nce at 3 0 m g: 
Re peat a b o ve, e xce pt res u me at 1 5 m g 
after rec o ver y t o ≤ gra de 1 
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  

1 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
Pa ncreatitis ≥ Gra de 3  
P o nati ni b  
O mi t p o nati ni b  
Perf or m ultras o u n d or a b d o mi nal C T sca n 
wit h c o ntrast 
If i ma gi n g is p ositi ve, c o nti n ue t o o mit 
p o nati ni b a n d re peat acc or di n g t o cli nical 
care 
If i ma gi n g is ne gati ve, or after res ol uti o n 
b y i ma gi n g, res u me at 3 0 m g after 
rec o ver y t o ≤ gra de 1 
 
Rec urre nce at 3 0 m g: 
Re peat a b o ve, e xce pt res u me at 1 5 m g 
after rec o ver y t o ≤ gra de 1 
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
Pa ncreatitis ≥ Gra de 4  
P o nati ni b  
Disc o nti n ue p o nati ni b  
Ner v o us S yste m 
Dis or ders  
Str o ke  a n y Gra de 
P o nati ni b  
Disc o nti n ue p o na ti ni b 
 
Peri p heral se ns or y 
ne ur o pat h y ≥ Gra de 2  
P o nati ni b  
Please see secti o n 8. 4 3  bel o w f or 
g ui da nce  
Car diac Dis or ders  
Left ve ntric ular s yst olic 
d ysf u ncti o n ≥ Gra de 3 
P o nati ni b  
O mit  p o nati ni b  
Res u me at 4 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 4 5 m g :  
O mit  p o nati ni b 
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
Left ve ntric ular s yst olic 
d ysf u ncti o n ≥ Gra de 4 
Disc o nti n ue p o na ti ni b 
 
 
 
M y ocar dial I nfarcti o n 
a n y Gra de 
 
Disc o nti n ue p o nati ni b  
 
 

2 0                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
S ki n a n d 
s u bc uta ne o us tiss ue 
dis or ders 
Ras h mac ul o -pa p ular ≥ 
Gra de 2 des pite o pti mal 
s y m pt o matic t hera p y 
P o nati ni b  
O mit  p o nati ni b  
Res u me at 4 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at  4 5 m g: 
O mit  p o nati ni b 
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
Ras h mac ul o -pa p ular ≥ 
Gra de 3 des pite o pti mal 
s y m pt o matic t hera p y 
O mit  p o nati ni b  
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g: 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g: 
Disc o nti n ue p o nati ni b  
Vasc ular Dis or ders  
 
 
 
 
T hr o m b oe m b olic e ve nt 
≥ Gra de 1  
Disc o nti n u e p o nati ni b 

2 1                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
 
H y perte nsi o n Gra de 2 
or 3 
A nti h y perte nsi ve me dicati o n s h o ul d be 
i nitiate d or o pti mize d t o ac hie ve tar get 
bl o o d press ure bef ore i nterr u pti o n or d ose 
re d ucti o n of t he st u d y treat me nt at t he 
discreti o n of t he i n vesti gat or.  If 
h y perte nsi o n is p ersiste nt des pite 
a de q uate a nti - H T N t hera p y i ncl u di n g 
titrati o n of a nti- H T N me dicati o n or 
i ntr o d ucti o n of a d diti o nal a nti-H T N 
me dicati o ns, d ose i nterr u pti o n a n d 
re d ucti o n is rec o m me n de d acc or di n g t o 
t he bel o w g ui deli nes: 
H ol d p o nati ni b 
Res u me at 3 0 m g afte r rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g 
Disc o nti n ue p o nati ni b  
 
H y perte nsi o n ≥ Gra de 4  P o nati ni b  
O mit  p o nati ni b  
Res u me at 3 0 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 3 0 m g 
O mit  p o nati ni b 
Res u me at 1 5 m g after rec o ver y t o ≤ 
gra de 1  
 
Rec urre nce at 1 5 m g 
Disc o nti n ue p o nati ni b  
I nj ur y, p ois o ni n g a n d 
pr oce d ural 
c o m plicati o ns 
W o u n d c o m plicati o n ≥ 
Gra de 2 
P o nati ni b  
See secti o n 8. 4 7 f or g ui da nce  
Ge neral dis or ders a n d 
a d mi nistrati ve site 
c o n diti o ns 
E de ma li m bs ≥ Gra de 2  
P o nati ni b  
See secti o n 8. 4 5 f or g ui da nce  
E ye Dis or ders  
E ye Dis or ders –  Ot her  
P o nati ni b  
See secti o n 8. 4 4 f or g ui da nce  

2 2                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
  Use t he N CI C o m m o n Ter mi n ol o gy Cri teri a f or A dverse Eve nts ( C T C A E) versi o n 4. 0 * u nless 
ot her wise s pecifie d   
C T C A E  
S yste m/ Or g a n/ Cl ass 
( S O C) 
 
A D V E R S E E V E N T  
 
A G E N T  
 
A C TI O N * *  
Ot her N o n -
He mat ol o gic e ve nts  
≥ Gra de 3  
 
 
 
 
 
P o nati ni b  
O mit dr u g a n d f oll o w patie nt at least  
wee kl y u ntil a d verse e ve nt has res ol ve d t o 
gra de ≤ 2, restart a ge nt  at ne xt l o wer d ose 
le vel.  See secti o ns 8. 4 1 t hr o u g h 8. 4 7 f or 
g ui da nce o n ot her n o n- he mat ol o gic 
e ve nts 
* 
L ocate d at htt p:/cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns.ctc. ht m  
* *   Use t he f oll o wi n g t o descri be acti o ns i n t he Acti o n c ol u m n: 
 O mit = Treat me nt  is n ot gi ve n f or t he da y/ da ys t hat are o mitte d  a n d will n ot be 
ma de u p, b ut treat me nt ma y res u me o nce t he a d verse e ve nt has res ol ve d as 
ma n date d i n T a ble 8. 2.  F or e xa m ple, if treat me nt is o mitte d o n Da y 8, b ut t he 
a d verse e ve nt has res ol ve d b y Da y 1 5, treat me nt ma y res u me o n Da y 1 5.  
 H ol d/ Dela y = Treat me nt ca n be ma de u p as part of t his c ycle  
 Disc o nti n ue = Treat me nt is t otall y st o p pe d  
 
N O T E:   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 f or t hat e ntire s u bse q ue nt c ycle.  
If t hat c ycle is c o m plete d wit h n o f urt her a d verse e ve nts > Gra de 2, t he n t he d ose ma y be 
i ncrease d, at t he i n vesti gat or’s discreti o n, o ne le vel at a ti me, i n t he f oll o wi n g c ycles.  
 
N O T E:   A d verse e ve nts re q uiri n g a d ose -re d ucti o n ste p f or a n y or all dr u gs be y o n d t he t w o 
d ose- re d ucti o n ste ps (le vels – 1 a n d – 2) will be at t he discreti o n of t he treati n g p h ysicia n, if 
t he decisi o n is ma de f or t he patie nt t o be ke pt o n st u d y.  T hese d ose re d ucti o ns m ust be 
clearl y rec or de d i n re p orte d cli nical data.  
 
8. 3   
A ne w c o urse of treat me nt ma y be gi n o n t he sc he d ule d Da y 1 of a ne w c ycle 
if:  
•   
T he A N C is ≥ 1 5 0 0/ μ L;  
•   
T he platelet c o u nt is ≥ 7 5, 0 0 0/ μ L;  
•  
A n y ot her P o nati ni b relate d a d verse e ve nt t hat ma y ha ve occ urre d has 
res ol ve d t o ≤ Gra de 1 or baseli ne se verit y.  
 
If t hese c o n diti o ns are n ot met o n sc he d ule d Da y 1 of a ne w c ycle, t he s u bject 
will be e val ua te d at least wee kl y a n d t he ne w c ycle of treat me nt will n ot be 
i nitiate d u ntil t he a d verse e ve nt has res ol ve d as descri be d a b o ve.  
 
W he n t hera p y is res u me d it will be c o nsi dere d da y o ne of t his ne w c ycle. If 
P o nati ni b  was halte d d uri n g t h e pre vi o us c ycle a n d was restarte d wit h a o ne -
le vel d ose re d ucti o n wit h o ut re q uiri n g a n i nterr u pti o n f or t he re mai n der of t he 
c ycle, t he n t hat re d uce d d ose le vel will be i nitiate d o n Da y 1 of t he ne w c ycle. 
If p o n ati ni b w as o mitte d f or t he re m ai n der of t he pre vi o us c ycle or if t he 
ne w c ycle is del a ye d d ue t o a d verse e ve nt ne wl y e nc o u ntere d o n t he 
sc he d ule d D a y 1, t he n t he sc he d ule d c ycle will be starte d wit h a o ne-le vel 
d ose re d ucti o n. If t he st u d y dr u g ca n n ot be restarte d wit hi n 2 8 da ys of t he 

2 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
sc he d ule d Day 1 of a gi ve n c ycle, t he p atie nt will be re m o ve d fr o m st u d y 
treat me nt a n d will pr ocee d t o e ve nt m o nit ori n g.  
 
8. 4   
A d diti o nal a d verse e ve nt g ui da n ce: 
8. 4 1  
He pat ot o xicit y:  Icl usi g ca n ca use h e pat ot o xicit y, i ncl u di n g li ver 
fail ure a n d d eat h. F ul mi na nt he patic fail ure lea di n g t o deat h occ urre d i n 
a n Icl usi g-treate d patie nt wit hi n o ne wee k of starti n g Icl usi g. T w o 
a d diti o nal fatal cas es of ac ute li ver fail ure als o occ urre d. T he fatal 
cases occ urr e d i n patie nts wit h blast p hase C M L ( B P -C M L) or 
P hila del p hia c hr o m os o me p ositi ve ac ute l y m p h o blastic le u ke mia ( P h + 
A L L). Se ver e he p at ot o xicit y occ urre d i n all diseas e c o h orts. Icl usi g 
treat me nt ma y res ult i n el e vati o n i n A L T, A S T, or b ot h. M o nit or li ver 
f u ncti o n tests at baseli ne, t he n at least m o nt hl y or as cli nicall y 
i n dicate d. I nterr u pt, re d u ce, or disc o nti n ue Icl usi g as cli nicall y 
i n dicate d.  
8. 4 2  
Pa ncreatitis:  Cli nical pa ncreatitis occ urre d i n 6 % ( 2 8/ 4 4 9) of 
patie nts ( 5 %, gra d e 3) treate d wit h Icl usi g. Pa ncreatitis res ulte d i n 
disc o nti n uati o n or treat me nt i nterr u pti o n i n 6 % of patie nts ( 2 5/ 4 4 9). 
T he i nci de nce of treat me nt- e mer ge nt li pase ele vati o n was 4 1 %. C hec k 
ser u m li pase e ver y 2 wee ks f or t he first 2 m o nt hs a n d t he n m o nt hl y 
t hereafter or as cli nicall y i n dicate d. C o nsi der a d diti o nal ser u m li pase 
m o nit ori n g i n patie nts wit h a hist or y of p a ncreatitis or alc o h ol a b use. 
D ose i nterr u pti o n or re d u cti o n ma y b e re q uire d. I n cases w h ere li pas e 
ele vati o ns ar e acc o m pa ni e d b y a b d o mi nal s y m pt o ms, i nterr u pt 
treat me nt wit h Icl usi g a n d e val uate p atie nts f or pa ncreatitis. D o n ot 
c o nsi der rest arti n g Icl usi g u ntil patie nts ha ve c o m plete res ol uti o n of 
s y m pt o ms a n d li pase le v els are less t ha n 1. 5 x U L N. 
8. 4 3   Ne ur o pat h y: Peri p heral a n d cra nial ne ur o pat h y ha ve occ urre d i n 
Icl usi g-treat e d patie nts. O verall, 1 3 % ( 5 9/ 4 4 9) of Icl usi g-treat e d 
patie nts e x perie nce d a peri p heral ne ur o pat h y e v e nt of a n y gra d e ( 2 %, 
gr a de 3/ 4). I n cli nical trials, t he m ost c o m m o n peri p heral ne ur o pat hies 
re p orte d w ere p eri p heral ne ur o pat h y ( 4 %, 1 8/ 4 4 9), parest hesia ( 4 %, 
1 7/ 4 4 9), h y p o est hesia ( 2 %, 1 1/ 4 4 9), a n d h y perest hesia ( 1 %, 5/ 4 4 9). 
Cra nial ne ur o pat h y d e vel o pe d i n 1 % ( 6/ 4 4 9) of Icl usi g- treate d patie nts 
( < 1 %, gr a de 3/ 4). Of t he patie nts w h o de vel o pe d n e ur o pat h y, 3 1 % 
( 2 0/ 6 5) de vel o pe d n e ur o pat h y d uri n g t he first m o nt h of treat me nt. 
M o nit or patie nts f or s y m pt o ms of ne ur o pat h y, s uc h as h y p o est hesia, 
h y perest hesia, p arest hesi a, disc o mf ort, a b ur ni n g s e nsati o n, ne ur o pat hic 
pai n, or wea k ness. C o nsi der i nterr u pti n g Icl usi g a n d e val uate if 
ne ur o pat h y is s us pecte d.  
8. 4 4  
Oc ular T o xicit y:  Seri o us oc ular t o xicities lea di n g t o bli n d ness 
or bl urre d visi o n ha ve o cc urre d i n Icl usi g- treate d patie nts. Reti nal 
t o xicities i ncl u di n g mac ular e de ma, reti nal vei n occl usi o n, a n d reti nal 
he m orr ha ge occ urre d i n 3 % of Icl usi g-treate d p atie nts. C o nj u ncti val or 

2 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
c or neal irritati o n, dr y e ye, or e ye pai n o cc urre d i n 1 3 % of patie nts. 
Vis ual bl urri n g o cc urre d i n 6 % of t he patie nts. Ot her oc ular t o xicities 
i ncl u de cataracts, gla u c o ma, iritis, iri d oc yclitis, a n d ulcerati ve k eratitis. 
C o n d uct c o m pre he nsi ve e ye e x a ms at baseli ne a n d peri o dicall y d uri n g 
treat me nt. 
8. 4 5   Fl ui d Rete nti o n: Seri o us fl ui d rete nti o n e ve nts occ urre d i n 3 % 
( 1 3/ 4 4 9) of patie nts treate d wit h Icl usi g. O ne i nsta nce of brai n e d e ma 
was fatal. I n t otal, fl ui d rete nti o n occ urre d i n 2 3 % of t he patie nts. T he 
m ost c o m m o n fl ui d rete nti o n e ve nts were p eri p heral e de ma ( 1 6 %), 
ple ural eff usi o n ( 7 %), a n d pericar dial eff usi o n ( 3 %). M o nit or patie nts 
f or fl ui d rete nti o n a n d m a na ge p atie nts as cli nicall y i n dicate d. I nterr u pt, 
re d uce, or disc o nti n ue Icl usi g as cli nicall y i n dicat e d. 
8. 4 6  
Car diac Arr h yt h mias:  S y m pt o matic bra d yarr h yt h mias t hat le d 
t o a re q uire m e nt f or pace ma ker i m pla ntati o n occ urre d i n 1 % ( 3/ 4 4 9) of 
Icl usi g-treat e d patie nts. A d vise patie nts t o re p ort si g ns a n d s y m pt o ms 
s u g gesti ve of sl o w heart rate (fai nti n g, dizzi ness, or c hest pai n). 
S u pra ve ntric ular t ac h yarr h yt h mias occ urre d i n 5 % ( 2 5/ 4 4 9) of Icl usi g-
treate d patie nts. Atri al fi brillati o n was t he m ost c o m m o n 
s u pra ve ntric ular tac h yarr h yt h mia a n d o cc urre d i n 2 0 patie nts. F or 1 3 
patie nts, t he e ve nt le d t o h os pitalizati o n. A d vise patie nts t o  re p ort si g ns 
a n d s y m pt o ms of r a pi d heart rate ( pal pitati o ns, dizzi ness). I nterr u pt 
Icl usi g a n d e val u ate. 
8. 4 7   C o m pr o mise d W o u n d Heali n g a n d Gastr oi ntesti n al Perf orati o n: 
Si nce Icl usi g m a y c o m pr o mise w o u n d heali n g, i nt err u pt Icl usi g f or at 
least 1 wee k pri or t o maj or s ur ger y. Seri o us gastr oi ntesti nal perf orati o n 
(fist ula) occ urre d i n o n e patie nt 3 8 da ys p ost-c h ol ec ystect o m y.  
 
9. 0  
A ncill ar y Tre at me nt/ S u p p orti ve C are  
 
9. 1  
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.  
 
9. 2 
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 
( 4 2) U p date of Rec o m me n dati o ns f or t he Use of He mat o p oietic C ol o n y-
Sti m ulati n g Fact ors: E vi de nce -Base d, Cli nical Practice G ui deli nes.  J Cli n O nc ol 
J ul y 1, 2 0 0 6, v ol. 2 4 n o. 1 9 3 1 8 7- 3 2 0 5.  
 
9. 3  
Patie nts s h o ul d recei ve f ull s u p p orti ve care 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 dmi 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. 
 
9. 4 
V asc ul ar Occl usi o n  

2 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
Arterial a n d ve n o us t hr o m b osis a n d occl usi o ns, i ncl u di n g fatal m y ocar dial 
i nfarcti o n, str o ke, ste n osis of lar ge arterial vessels of t he brai n, se vere peri p heral 
vasc ular disease, a n d t he nee d f or ur ge nt re vasc ularizati o n pr oce d ures ha ve 
occ urre d i n at least 2 7 % of Icl usi g -treate d patie nts fr o m t he p hase 1 a n d p hase 2 
trials. Icl usi g ca n ca use fatal a n d life-t hreate ni n g vasc ular occl usi o n wit hi n 2 
wee ks of starti n g treat me nt. Icl usi g ca n als o ca use rec urre nt or m ulti -site vasc ular 
occl usi o n.  
 
T he me dia n ti me t o o nset of t he first vasc ular occl usi o n e ve nt was 5 m o nt hs. 
Icl usi g ca n ca use fatal a n d life t hreate ni n g vasc ular occl usi o n i n patie nts treate d 
at d ose le vels as l o w as 1 5 m g per da y.  
 
Patie nts wit h a n d wit h o ut car di o vasc ular ris k fact ors, i ncl u di n g patie nts a ge 5 0 
years or y o u n ger, e x perie nce d t hese e ve nts. Vasc ular occl usi o n a d verse e ve nts 
were m ore fre q ue nt wit h i ncreasi n g a ge a n d i n patie nt s wit h pri or hist or y of 
isc he mia, h y perte nsi o n, dia betes, or h y perli pi de mia (see Ta ble 4). 
 
Cli nicia ns s h o ul d c o nsi der w het her t he be nefits of Icl usi g treat me nt are e x pecte d 
t o e xcee d t he ris ks of t hera p y. I n patie nts s us pecte d of de vel o pi n g arterial 
t hr o m b otic e ve nts, i nterr u pt or st o p Icl usi g. A be nefit-ris k c o nsi derati o n s h o ul d 
g ui de a decisi o n t o restart Icl usi g t hera p y.  C o nsi der d ose m o dificati o n or 
disc o nti n uati o n of Icl usi g i n patie nts w h o de vel o p seri o us ve n o us 
t hr o m b oe m b olis m a n d M o nit or f or e vi de nce of t hr o m b oe m b olis m a n d 
v asc ul ar occl usi o n. I nterr u pt or st o p Icl usi g i m me di atel y f or v asc ul ar 
occl usi o n.   
 
9. 5  
H y perte nsi o n  
Treat me nt -e mer ge nt h y perte nsi o n occ urre d i n 6 7 % of patie nts ( 3 0 0/ 4 4 9). Ei g ht  
( 2 %) treate d wit h Icl usi g i n cli nical trials e x perie nce d treat me nt-e mer ge nt 
s y m pt o matic h y perte nsi o n as a seri o us a d verse reacti o n, i ncl u di n g h y perte nsi ve 
crisis. Patie nts ma y re q uire ur ge nt cli nical i nter ve nti o n f or h y perte nsi o n 
ass ociate d wit h c o nf usi o n, hea dac he, c hest pai n, or s h ort ness of breat h [see 
A dverse Re acti o ns ( 6)] . I n patie nts wit h baseli ne s yst olic B P < 1 4 0 m m H g a n d 
baseli ne diast olic B P < 9 0 m m H g, 7 8 % ( 2 2 0/ 2 8 2) e x perie nce d treat me nt- e mer ge nt 
h y perte nsi o n; 4 9 % ( 1 3 9/ 2 8 2) de vel o pe d Sta ge 1 h y perte nsi o n ( defi ne d as s yst olic 
B P ≥1 4 0 m m H g or diast olic B P ≥9 0 m m H g) w hile 2 9 % de vel o pe d Sta ge 2 
h y perte nsi o n ( defi ne d as s yst olic B P ≥1 6 0 m m H g or diast olic B P ≥1 0 0 m m H g). 
I n 1 3 1 patie nts wit h Sta ge 1 h y perte nsi o n at baseli ne, 6 1 % ( 8 0/ 1 3 1) de vel o pe d 
Sta ge 2 h y perte nsi o n. M o nit or a n d ma na ge bl o o d press ure el e vati o ns d uri n g 
Icl usi g use a n d treat h y perte nsi o n t o n or malize bl o o d press ure. I nterr u pt, d ose 
re d uce, or st o p Icl usi g if h y perte nsi o n is n ot me dicall y c o ntr olle d. 
 
9. 6  
He art F ail ure  
Fatal a n d seri o us heart fail ure or left ve ntric ular d ysf u ncti o n occ urre d i n 5 % of 
Icl usi g-treate d patie nts ( N = 2 2). Ei g ht perce nt of patie nts ( N = 3 5) e x perie nce d 
a n y gra de of heart fail ure or left ve ntric ular d ysf u ncti o n. M o nit or patie nts f or 
si g ns or s y m pt o ms c o nsiste nt wit h heart fail ure a n d treat as cli nicall y i n dicate d, 
i ncl u di n g i nterr u pti o n of Icl usi g. C o nsi der disc o nti n uati o n of Icl usi g i n patie nts 
w h o de vel o p seri o us heart fail ure  
 

2 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
9. 7  
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). 
 
I n t he e ve nt of Gra de 3 or 4 diarr hea, t he f oll o wi n g s u p p orti ve meas ures are 
all o we d:  h y drati o n, octre oti de, a n d a nti diarr heals.   
 
If diarr hea is se vere (re q uiri n g i ntra ve n o us re h y drati o n) a n d/ or ass ociate d wit h 
fe ver or se vere ne utr o pe nia ( gra de 3 or 4), br oa d-s pectr u m a nti bi otics m ust be 
prescri be d.  Patie nts wit h se vere diarr hea or a n y diarr hea ass ociate d wit h se vere 
na usea or v o miti n g s h o ul d be h os pit alize d f or i ntra ve n o us h y drati o n a n d 
c orrecti o n of electr ol yte i m bala nces.  
 
9. 8  
T L S:  Cli nicall y si g nifica nt T u m or L ysis S y n dr o me ( T L S) has bee n re p orte d at 
t he i nitiati o n of treat me nt wit h T KIs i n C M L patie nts.  T he patie nts at ris k of 
T L S are t h ose wit h hi g h t u m or/le u ke mic b ur de n pri or t o treat me nt.  T hese 
patie nts s h o ul d be m o nit ore d cl osel y, es peciall y at t he i nitiati o n of treat me nt.  
A p pr o priate T L S preca uti o ns a n d pr o p h ylactic treat me nt (s uc h as a g gressi ve 
h y drati o n wit h fl ui ds a n d t he i nitiati o n of all o p uri n ol 6 0 0 m g/ da y or ot her 
a p pr opriate treat me nts) s h o ul d be i nitiate d pri or t o t he start of t hera p y f or t h ose at 
ris k f or T L S.  Ras b uricase a n d ot her a p pr o priate treat me nts f or h y per urice mia or 
T L S are per mitte d.  
 
9. 9a  
P r ol o n ge d Q Tc F : If a pr ol o n gati o n of Q T c F is o bser ve d, it is i m p orta nt t o 
perf or m ser u m electr ol yte a nal ysis (i ncl u di n g p otassi u m, calci u m, a n d 
ma g nesi u m) a n d c orrect a n y si g nifica nt a b n or malities wit h s u p ple me nts if bel o w 
n or mal li mits.  It is als o necessar y t o re vie w all c o nc o mita nt me dicati o ns t he 
patie nt is o n a n d dis c o nti n ue me dicati o ns t hat are k n o w n or s us pecte d t o ca use 
Q T pr ol o n gati o n. 
If n o c o ntri b uti n g reas o n is i de ntifie d a n d t he reas o n f or Q Tc F pr ol o n gati o n is 
belie ve d t o be d ue t o st u d y me dicati o n, d ose i nterr u pti o n a n d re d ucti o n 
g ui deli nes f or ge neral n o n- he mat ol o gic t o xicities i n 8. 2 f or p o nati ni b s h o ul d be 
f oll o we d.  A d diti o nall y, wee kl y E C G m o nit ori n g is rec o m me n de d f or 4 wee ks 
u p o n res u m pti o n of st u d y dr u g, t he n m o nt hl y f or 6 m o nt hs, a n d t he n e ver y 3 
m o nt hs f or t he re mai n der of t he st u d y, or m ore fre q ue nt l y as cli nicall y i n dicate d. 
 
9. 9 b  
Base d o n i n vitr o st u dies, p o nati ni b is a s u bstrate of C Y P 3 A 4/ 5 a n d t o a lesser 
e xte nt C Y P 2 C 8 a n d C Y P 2 D 6. P o nati ni b als o i n hi bits t he P- gl yc o pr otei n ( P - g p), 
A T P - bi n di n g cassette G 2 ( A B C G 2) [als o k n o w n as B C R P], a n d bile salt e x p ort 
p u m p ( B S E P) tra ns p orter s yste ms i n vitr o. 
 
Dr u gs T hat Are Str o n g I n hi bit ors of C Y P 3 A E nz y mes 
I n a dr u g i nteracti o n st u d y i n healt h y v ol u nteers, c o-a d mi nistrati o n of Icl usi g 
wit h ket oc o naz ole i ncrease d plas ma p o nati ni b A U C 0-i nf a n d C ma x b y 7 8 % a n d 
4 7 %, res pecti vel y. W he n a d mi nisteri n g Icl usi g wit h str o n g C Y P 3 A i n hi bit ors 
(e. g., b oce pre vir, clarit hr o m yci n, c o ni va pta n, gra pefr uit j uice, i n di na vir, 
itrac o naz ole, ket oc o naz ole, l o pi na vir/rit o na vir, nefaz o d o ne, nelfi na vir, 
p osac o naz ole, rit o na vir, sa q ui na vir, tela pre vir, telit hr o m yci n, v oric o naz ole), t he 
rec o m me n de d starti n g d ose s h o ul d be re d uce d at t he discreti o n of t he treati n g 
p h ysicia n. Patie nts ta ki n g c o nc o mita nt str o n g i n hi bit ors ma y be at i ncrease d ris k 
f or a d verse reacti o ns. 

2 7                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
Dr u gs T hat Are Str o n g I n d ucers of C Y P 3 A E nz y mes 
C oa d mi nistrati o n of Icl usi g wit h str o n g C Y P 3 A i n d ucers was n ot e val uate d i n 
vitr o or i n a cli nical trial; h o we ver, a re d ucti o n i n p o nati ni b e x p os ure is li kel y. 
C oa d mi nistrati o n of str o n g C Y P 3 A i n d ucers (e. g., car ba maze pi ne, p he n yt oi n, 
rifa m pi n, a n d St. J o h n’s W ort) wit h Icl usi g s h o ul d be a v oi de d u nless t he be nefit 
o ut wei g hs t he p ossi ble ris k of p o nati ni b u n dere x p os ure. M o nit or patie nts f or 
si g ns of re d uce d efficac y. 
 
Dr u gs T hat Ele vate Gastric p H  
C oa d mi nistrati o n of Icl usi g wit h dr u gs t hat ele vate t he gastric p H was n ot 
e val uate d i n a cli nical trial. Base d o n t he c he mical pr o perties of p o nati ni b, 
ele vate d gastric p H ma y re d uce bi oa vaila bilit y a n d e x p os ure. C oa d mi nistrati o n of 
Icl usi g wit h dr u gs t hat ele vate t he gastric p H (e. g., pr ot o n p u m p i n hi bit ors, H 2 
bl oc kers, or a ntaci ds) s h o ul d be a v oi de d u nless t he be nefit o ut wei g hs t he p ossi ble 
ris k of p o nati ni b u n dere x p os ure. M o nit or patie nts f or si g ns of re d uce d efficac y. 
 
Dr u gs T hat Are S u bstrates of t he P - g p or A B C G 2 Tra ns p orter S yste ms 
I n vitr o st u dies de m o nstrate t hat Icl usi g i n hi bits t he P- g p a n d A B C G 2 [als o 
k n o w n as B C R P] tra ns p orter s yste ms. T he effect of c oa d mi nistrati o n of Icl usi g 
wit h se nsiti ve s u bstrates of t he P - g p (e. g., alis kire n, a m brise nta n, c olc hici ne, 
da bi gatra n ete xilat e, di g o xi n, e ver oli m us, fe x ofe na di ne, i mati ni b, la pati ni b, 
mara vir oc, nil oti ni b, p osac o naz ole, ra n olazi ne, sa xa gli pti n, sir oli m us, sita gli pti n, 
t ol va pta n, t o p oteca n) a n d A B C G 2 [als o k n o w n as B C R P] (e. g., met h otre xate, 
mit o xa ntr o ne, i mati ni b, iri n oteca n, la pati ni b, r os u vastati n, s ulfasalazi ne, 
t o p oteca n) tra ns p orter s yste ms o n e x p os ure of t hese s u bstrates has n ot bee n 
e val uate d i n cli nical st u dies.  
 
1 0. 0 
A d verse E ve nt ( A E) Re p orti n g  a n d M o nit ori n g  
 
1 0. 1 
A d verse E ve nt C h ar acteristics  
 
C T C A E ter m ( A E descri pti o n) a n d gr a de:  T he descri pti o ns a n d gra di n g 
scales f o u n d i n t he re vise d N CI 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 will be utilize d f or A E re p orti n g.  All a p pr o priate 
treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E versi o n 4. 0.  A c o p y 
of t he C T C A E versi o n 4. 0 ca n be d o w nl oa de d fr o m t he C T E P we b site:  
(htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic a p plicati o ns/ctc. ht m )    
 
1 0. 1 1 
A d verse e ve nt m o nit ori n g a n d re p orti n g is a r o uti ne part of e ver y cli nical 
trial.  First, i de ntif y a n d gra de t he se verit y of t he e ve nt usi n g t he C T C A E 
versi o n 4. 0 .  Ne xt, deter mi ne w het her t he e ve nt is e x pecte d or 
u ne x pecte d (see Secti o n 1 0. 2 ) a n d if t he a d verse e ve nt is relate d t o t he 
me dical treat me nt or pr oce d ure (see Secti o n 1 0. 5 ).  Wit h t his 
i nf or mati o n, deter mi ne w het her t he e ve nt m ust be re p orte d as a n 
e x pe dite d re p ort (see Secti o n 1 0.). E x pe dite d re p orts are t o be c o m plete d 
wit hi n t he ti mefra mes a n d via t he mec ha nis ms s pecifie d i n Secti o ns 1 0. 4. 
All A Es re p orte d via e x pe dite d mec ha nis ms m ust als o be re p o rte d via t he 
r o uti ne data re p orti n g mec h a nis ms defi ne d b y t he pr ot oc ol (see Secti o ns 
1 0. 6 a n d 1 8. 0). 
 

2 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 0. 1 2  
Eac h C T C A E ter m i n t he c urre nt versi o n is a u ni q ue re prese ntati o n of a 
s pecific e ve nt use d f or me dical d oc u me ntati o n a n d scie ntific a nal ysis a n d is a 
si n gle Me d D R A L o west Le vel Ter m ( L L T).  Gra de is a n esse ntial ele me nt of 
t he G ui deli nes a n d, i n ge neral, relates t o se verit y f or t he p ur p oses of 
re g ulat or y re p orti n g t o N CI. 
 
N O T E:  A se vere A E, as d efi ne d b y t he a b o ve gra di n g scale, is N O T  
t he sa me as seri o us A E w hi c h is defi n e d i n t he ta ble i n Secti o n 1 0. 4. 
 
 
1 0. 1 3  Me dical c o n diti o ns/ diseases prese nt bef ore starti n g st u d y treat me nt are 
o nl y c o nsi dere d a d verse e ve nts if t he y w orse n after starti n g st u d y 
treat me nt (a n y pr oce d ures s pecifie d i n t he pr ot oc ol). A d verse e ve nts 
occ urri n g bef ore starti n g st u d y treat me nt b ut after si g ni n g t he i nf or me d 
c o nse nt f or m are rec or de d. A b n or mal la b orat or y val ues or test res ults 
c o nstit ute a d verse e ve nts o nl y if t he y i n d uce cli nical si g ns or s y m pt o ms 
or re q uire t hera p y, a n d are  rec or de d. 
 
 
1 0. 1 4  A n y seri o us a d verse e ve nt occ urri n g after t he patie nt has pr o vi de d 
i nf or me d c o nse nt, has starte d ta ki n g t he st u d y me dicati o n, a n d u ntil 4 
wee ks after t he patie nt has st o p pe d st u d y partici pati o n m ust be re p orte d. 
T his i ncl u des t he p eri o d i n w hic h t he st u d y pr ot oc ol i nterferes wit h t he 
sta n dar d me dical treat me nt gi ve n t o a patie nt (e. g. treat me nt wit h dra wal 
d uri n g was h o ut peri o d, c ha n ge i n treat me nt t o a fi xe d d ose of 
c o nc o mita nt me dicati o n). T he peri o d after disc o nti n ui n g st u d y dr u g ma y 
be e xte n de d if t here is a str o n g s us pici o n t hat t he dr u g has n ot yet bee n 
eli mi nate d. 
 
1 0. 2  
E x pecte d vs. U ne x pecte d E ve nts  
 
•  
T he deter mi nati o n of w het her a n A E is e x pecte d is base d o n a ge nt-
s pecific i nf or mati o n pr o vi de d i n Secti o n 1 5. 0 of t he pr ot oc ol a n d t he 
st u d y s pecific c o nse nt f or m. 
 
•  
U ne x pecte d A Es are t h ose n ot liste d i n t he a ge nt -s pecific 
i nf or mati o n pr o vi de d i n Secti o n 1 5. 0 of t he pr ot oc ol a n d t he st u d y 
s pecific c o nse nt f or m. 
 
N O T E : “ U ne x pecte d a d verse e x perie nces” mea ns a n y a d verse e x perie nce t hat is 
neit her i de ntifie d i n nat ure, se verit y, or fre q ue nc y of ris k i n t he i nf or mati o n 
pr o vi de d f or I R B re vie w n or me nti o ne d i n t he c o nse nt f or m.  
 
1 0. 3 
Assess me nt of Attri b uti o n  
 
W he n assessi n g w het her a n a d verse e ve nt is relate d t o a me dical treat me nt o r 
pr oce d ure, t he f oll o wi n g attri b uti o n cate g ories are utilize d: 
Defi nite - T he a d verse e ve nt is cle arly rel ate d t o t he a ge nt(s). 
Pr o ba ble - T he a d verse e ve nt is likely rel ate d t o t he a ge nt(s). 
P ossi ble - T he a d verse e ve nt m ay be rel ate d t o t he a ge nt(s). 
U n li kel y - T he a d verse e ve nt is d o u btf ully rel ate d t o t he a ge nt(s). 
U nrelate d - T he a d verse e ve nt is cle arly N O T rel ate d t o t he a ge nt(s). 
 

2 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
E ve nts deter mi ne d t o be p ossi bl y, pr o b a bl y or defi nitel y attri b ute d 
t o a me dic al tre at me nt s u g gest t here is e vi de nce t o i n dic ate a c a us al 
rel ati o ns hi p bet wee n t he dr u g a n d t he a d verse e ve nt .  
 
1 0. 3 1   A Es E x perie n ce d U tilizi n g I n vesti g ati o n al A ge nts a n d C o m merci al 
A g e nt(s) o n t he S A M E  Ar m 
 
N O T E:   W he n a c o m mercial a ge nt(s) is (are) use d o n t he 
sa me treat me nt ar m as t he i n vesti gati o nal a ge nt/i nter ve nti o n 
(als o, i n vesti gati o nal dr u g, bi ol o gic, cell ular pr o d uct, or ot her 
i n vesti gati o nal t hera p y u n der a n I N D), t he e ntire c o m bi nati o n 
(ar m) is t he n c o nsi dere d a n i n vesti gati o nal i nter ve nti o n f or 
re p orti n g. 
 
R o uti ne Re p orti n g  
 
•  R o uti ne A E re p orti n g f or P hase 1 a n d P hase 2 cli nical st u dies 
usi n g a n i n vesti gati o nal a ge nt /i nter ve nti o n i n c o mbi nati o n wit h a 
c o m mercial a ge nt is state d i n t he pr ot oc ol.  See Secti o n 1 0. 6.  
 
•  R o uti ne A E re p orti n g f or P hase 3 cli nical st u dies usi n g a n 
i n vesti gati o nal a ge nt/i nter ve nti o n a n d a c o m mercial a ge nt i n 
c o m bi nati o n m ust be re p orte d as defi ne d b y t he ge neral 
g ui deli nes pr o vi de d b y s p o ns ors, Gr o u ps, Ca ncer Ce nters, or 
Pri nci pal I n vesti gat ors.  See Secti o n 1 0. 6. 
 
E x pe dite d Re p orti n g  
 
•  A n A E t hat occ urs o n a c o m bi nati o n st u d y m ust be assesse d i n 
acc or da nce wit h t he g ui deli nes f or i n vesti gati o nal a ge nts/i nter ve nti o ns 
i n Secti o n 1 0. 4, a n d  w here i n dicate d, a n e x pe dite d re p ort m ust be 
s u b mitte d. 
 
• A n A E t hat occ urs pri or t o a d mi nistrati o n of t he i n vesti gati o nal 
a ge nt/i nter ve nti o n m ust be assesse d as s pecifie d i n t he pr ot oc ol. I n 
ge neral, o nl y Gra de 4 a n d 5 A Es t hat are u ne x pecte d wit h at least 
p ossi ble attri b uti o n t o t he c o m mercial a ge nt re q uire a n e x pe dite d 
re p ort.  Refer t o Secti o n 1 0. 4 f or s pecific A E re p orti n g 
req uire me nts or e xce pti o ns.  
 
•  C o m mercial a ge nt e x pe dite d re p orts m ust be s u b mitte d t o t he F D A via 
Me d Watc h . 
 
•  A n i n vesti gati o nal a ge nt/i nter ve nti o n mi g ht e xacer bate t he e x pecte d 
A Es ass ociate d wit h a c o m mercial a ge nt.  T heref ore, if a n e x pecte d 
A E (f or t he c o m mercial a ge nt) occ urs wit h a hi g her de gree of se verit y, 
e x pe dite d re p orti n g is re q uire d.  T he cli nical i n vesti gat or m ust 
deter mi ne se verit y.  
 
 

3 1                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
a p pr o priate re g ulat or y a ut h orities i n acc or da nce wit h A p plica ble La w, wit hi n 2 4 h o urs 
after re p orti n g i ncl u di n g t he s u b missi o n d oc u me nts. 
Pr o vi de c o pies, al o n g wit h t he U PI R T S O c o ver s heet, b y fa x 
 t o t he 
M C C C Re g ulat or y Affairs U nit ( R A U) Ris k I nf or mati o n S pecialist w h o will 
deter mi ne a n d c o m plete I R B re p orti n g. T he R A U will s u b mit t o t he M C C C S A E 
C o or di nat or a n d t he M C C C I N D C o or di nat or t o deter mi ne if F D A s u b missi o n is 
nee de d.  
 
 
E V E N T T Y P E  
R E P O R TI N G P R O C E D U R E  
Ot her Gra de 4 or 5 E ve nts 
a n d/ or A n y H os pitalizati o ns 
D uri n g Treat me nt N ot 
Ot her wise Warra nti n g a n 
E x pe dite d Re p ort  
C o m plete a N otificati o n F or m: Gra de 4 or 5 N o n- A E R 
Re p orta ble E ve nts/ H os pitalizati o n F or m electr o nicall y via 
t he M C C C  Re m ote Data E ntr y S yste m  or pa per f or m  wit hi n 
5 w or ki n g da ys of t he date t he cli nical researc h ass ociate 
( C R A) is a ware of t he e ve nt(s) necessitati n g t he f or m. 
If a n e x pe dite d writte n re p ort has bee n s u b mitte d, t his f or m 
d oes n ot nee d t o be s u b mitte d. 
 
  
 
1 0. 4 1  A d verse E ve nts of S peci al I nterest ( A E SIs)  
 
Vasc ular occl usi ve e ve nts ha ve bee n i de ntifie d as A E SIs f or p o nati ni b.  
T hese i ncl u de arterial a n d ve n o us t hr o m b otic a n d occl usi ve a d verse 
e ve nts t hat meet t he criteria f or S A Es ( see secti o n 1 0. 1) a n d t h ose 
a d verse e ve nts t hat d o n ot meet t he S A E criteria.  A E SIs re q uire o n g oi n g 
m o nit ori n g b y i n vesti gat ors a n d ra pi d i de ntificati o n a n d c o m m u nicati o n 
b y t he i n vesti gat or t o t he st u d y s p o ns or.  All A E SIs, w het her S A Es or 
n ot, m ust be re p orte d wit hi n 2 b usi ness da ys of t he st u d y s p o ns or 
a ware ness t o A RI A D .   
 
A RI A D  has deter mi ne d t hat t he e ve nts liste d bel o w ( w het her c o nsi dere d 
seri o us or n o n-seri o us b y i n vesti gat ors) s h o ul d be c o nsi dere d A E SIs: 

3 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
S yste m Or ga n Class 
( S O C) 
 
A d verse e ve nt/ S y m pt o ms  
 
C T C A E Gra de at w hic h t he e ve nt 
w ill n ot be e x pe dite dl y re p orte d 
Ge neral dis or ders a n d 
a d mi nistrati o ns site 
c o n diti o ns 
 
Fati g ue  
Gra de 3  
 
Gastr oi ntesti nal 
Dis or ders  
 
 
Na usea  
Gra de 3  
 
V o miti n g  
Diarr hea  
I n vesti gati o ns 
N e utr o p hil c o u nt decrease d  
Gra de 3  a n d Gra de 4 
 
W hite bl o o d cell c o u nt decrease d  
Platelet c o u nt decrease d  
Bl o o d a n d l y m p hatic 
s yste m dis or ders 
A ne mia  
Gra de 3 a n d Gra de 4 
 
S pecific pr ot oc ol e xce pti o ns t o e x pe dite d re p orti n g s h o ul d be re p orte d 
e x pe diti o usl y b y i n vesti gat ors O N L Y  if t he y e xcee d t he e x pecte d gra de of t he 
e ve nt  a n d/ or re q uire h os pitalizati o n 
 
1 0. 5  
Ot her Re q uire d Re p orti n g  
 
1 0. 5 1  Persiste nt or Si g nifica nt Disa bilities/I nca paci ties 
 
A n y A E t hat res ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial 
disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns (f or merl y referre d t o 
as disa bilities), c o n ge nital a b n or mities or birt h defects, must be re p orte d 
i m me diatel y if t he y occ ur at a n y ti me f oll o wi n g treat me nt wit h a n a ge nt u n der 
a n I N D/I D E si nce t he y are c o nsi dere d t o be a seri o us A E a n d must be re p orte d 
t o t he s p o ns or as s pecifie d i n 2 1 C F R 3 1 2. 6 4( b). 
 
1 0. 5 2   Deat h  
A n y deat h occ urri n g wit hi n 3 0 d a ys of t he last d ose, re gar dles s 
of attri b uti o n t o a n a ge nt/i nter ve nti o n u n der a n I N D/I D E 
r e q uir es e x p e dit e d r e p orti n g wit hi n 2 4-h o urs.  
 
A n y deat h occ urri n g greater t ha n 3 0 da ys wit h a n attri b uti o n of 
p ossi ble, pr o ba ble, or defi nite t o a n a ge nt/i nter ve nti o n u n der a n 
I N D/I D E r e q uir es e x pe dit e d r e p orti n g wit hi n 2 4 -h o urs.  
 
Re p o rt a bl e c at e g o ri es of De at h   
 
•  
De at h attri b ut a bl e t o a C T C A E t er m.  
 
•  
De at h Ne o n at al:  A dis or d er c h ar a ct eri ze d b y 
c ess ati o n of lif e d uri n g t h e first 2 8 d a ys of lif e.  
 
•  
De at h N O S:  A c ess ati o n of lif e t h at c a n n ot b e 
attri b ut e d t o a C T C A E t er m ass o ci at e d wit h Gr a d e 5.  

3 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
•  
S u d d e n d e at h N O S:  A s u d d e n ( d efi n e d as i nst a nt or 
wit hi n o n e h o ur of t h e o ns et of s y m pt o ms) or a n 
u n o bs er ve d c ess ati o n of lif e t h at c a n n ot b e attri b ut e d 
t o a C T C A E t er m ass o ci at e d wit h Gr a d e 5. 
 
•  
De at h d u e t o pr o gr essi ve dis e as e s h o ul d b e r e p ort e d 
as Gr a d e 5 “ Ne o pl as ms b e ni g n, m ali g n a nt a n d 
u ns p e cifi e d (i n cl c ysts a n d p ol y ps) – Ot h e r 
( P r o g r essi v e Dis e as e) ” u n d er t h e s yst e m or ga n cl ass 
( S O C) of t h e s a me n a me.  E vi d e n c e t h at t h e d e at h 
was a ma nif est ati o n of u n d erl yi n g dis e as e ( e. g., 
r a di ol o gi c al c h a n ges s u g g esti n g t u m or gr o wt h or 
pr o gr essi o n: cli ni c al d et eri or ati o n ass o ci at e d wit h a 
dis e as e pr o c ess) s h o ul d b e s u b mitt e d.  
 
1 0. 5 3  Sec o n dar y Mali g na nc y 
 
4  
A sec o n d ary m ali g n a ncy is a ca ncer ca use d b y treat me nt f or a 
pre vi o us ma li g na nc y (e. g., treat me nt wit h i n vesti gati o nal 
a ge nt/i nter ve nti o n, ra diati o n or c he m ot hera p y).  A 
sec o n dar y mali g na nc y is n ot c o nsi dere d a metastasis of t he 
i nitial ne o plas m. 
 
5  
All  sec o n dar y mali g na ncies t hat occ ur f oll o wi n g treat me nt 
wit h a n a ge nt u n der a n I N D/I D E be re p orte d . T hree o pti o ns 
are a vaila ble t o descri be t he e ve nt: 
 
o  Le u ke mia sec o n dar y t o o nc ol o g y c he m ot hera p y (e. g., 
Ac ute  
M yel oc yt ic Le u ke mia [ A M L]) 
 
o  M yel o d ys plastic s y n dr o me ( M D S)  
 
o  Treat me nt -relate d sec o n dar y mali g na nc y 
 
•  
A n y mali g na nc y p ossi bl y r elate d t o ca ncer treat me nt 
(i ncl u di n g A M L/ M D S) s h o ul d als o be re p orte d via t he 
r o uti ne re p orti n g mec ha nis ms o utli ne d i n eac h pr ot oc ol. 
 
1 0. 5 4  Sec o n d Mali g na nc y  
 
6  
A sec o n d mali g na nc y is o ne u nrelate d t o t he treat me nt of a 
pri or mali g na nc y (a n d is N O T a metastasis fr o m t he i nitial 
mali g na nc y).  Sec o n d mali g na ncies re q uire O N L Y r o uti ne 
re p orti n g. 
 
1 0. 5 5  Pre g na nc y  
 

3 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
T o  e ns ure  patie nt  safet y,  eac h  pre g na nc y  occ urri n g  w hile  t he  patie nt  is 
o n  st u d y  treat me nt  m ust  be  re p orte d  t o A RI A D  wit hi n  2 4  h o urs  of 
lear ni n g  of  its  occ urre nce.  T he  pre g na nc y  s h o ul d  be  f oll o we d  u p  t o 
deter mi ne  o utc o me,  i ncl u di n g  s p o nta ne o us  or  v ol u ntar y  ter mi nati o n, 
details  of  t he  birt h,  a n d  t he  prese nce  or  a bse nce  of  a n y  birt h  defects, 
c o n ge nital a b n or malities, or mater nal a n d/ or ne w b or n c o m plicati o ns.  
Pre g na nc y s h o ul d be rec or de d o n a Cli nical St u d y Pre g na nc y F or m a n d 
re p orte d  b y  t he  i n vesti gat or  t o  t he  o nc ol o g y A RI A D  Dr u g  Safet y  a n d 
E pi de mi ol o g y  ( D S & E)  de part me nt.  Pre g na nc y  f oll o w -u p  s h o ul d  be 
rec or de d  o n  t he  sa me  f or m  a n d  s h o ul d  i ncl u de  a n  assess me nt  of  t he 
p ossi ble  relati o ns hi p  t o  t he A RI A D  st u d y  treat me nt  of  a n y  pre g na nc y 
o utc o me.  A n y  S A E  e x perie nce d  d uri n g  pre g na nc y  m ust  be  re p orte d  o n 
t he S A E Re p ort F or m. 
 
1 0. 6  
Re q uire d R o uti ne Re p orti n g  
A d verse e ve nts t o be gra de d at eac h e val uati o n a n d pretreat me nt 
s y m pt o ms/c o n diti o ns t o be e val uate d at baseli ne per t he C T C A E v 4. 0 gra di n g 
u nless ot her wise state d i n t he ta ble bel o w: 
 
 
S yste m Or ga n Class 
( S O C) 
 
A d verse e ve nt/ S y m pt o ms  
 
Baseli ne  
Eac h  
e val uati o n 
Ge neral dis or ders a n d 
a d mi nistrati o ns site 
c o n diti o ns 
Fati g ue  
X  
X  
Fe ver ( P yre xia)  
X  
X  
E de ma li m bs  
X  
X  
Gastr oi ntesti nal 
Dis or ders  
Na usea  
X  
X  
V o miti n g  
X  
X  
# of st o ols  
X  
 
Diarr hea  
 
X  
C o nsti pati o n  
 
X  
A b d o mi nal pai n  
X  
X  
Ras h mac ul o -pa p ular  
X  
X  
I n vesti gati o ns 
Ne utr o p hil c o u nt decrease d  
X 
X 
Platelet c o u nt decrease d  
X  
X  
C o u g h  
X  
X  
P ne u m o nitis  
X  
X  
 
  
1 0. 6 1 S u b mit via a p pr o priate M C C C Case Re p ort F or ms (i.e., pa per or electr o nic, as 
a p plica ble) t he f oll o wi n g A Es e x perie nce d b y a patie nt a n d n ot s pecifie d i n 
Secti o n 1 0. 6: 
1 0. 6 1 1 Gra de 2 A Es dee me d p ossi bly, pr o b a bly, or defi nitely  relate d t o 
t he st u d y treat me nt or pr oce d ure. 
 
1 0. 6 1 2  Gra de 3 a n d 4 A Es re gar dless of attri b uti o n t o t he st u d y 
treat me nt or pr oce d ure. 
 
1 0. 6 1 3  Gra de 5 A Es ( Deat hs) 
 
1 0. 6 1 3 1   
A n y deat h wit hi n 3 0 da ys of t he patie nt’s last st u d y 

3 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
treatme nt or pr oce d ure re gar dless of attri b uti o n t o 
t he st u d y treat me nt or pr oce d ure. 
 
1 0. 6 1 3 2  
A n y deat h m ore t ha n 3 0 da ys after t he patie nt’s last 
st u d y treat me nt or pr oce d ure t hat is felt t o be at least 
p ossi bl y treat me nt relate d m ust als o be s u b mitte d as 
a Gra de 5 A E, wit h a C T C A E t y pe a n d attri b uti o n 
assi g ne d. 
 
1 0. 6 2    Refer t o t he i nstr ucti o ns i n t he F or ms Pac ket ( or electr o nic data e ntr y 
scree ns, as a p plica ble) re gar di n g t he s u b missi o n of late occ urri n g A Es 
f oll o wi n g c o m pleti o n of t he Acti ve M o nit ori n g Phase (i.e., c o m plia nce 
wit h T est Sc he d ule i n Secti o n 4. 0). 
 
1 1. 0 
Tre at me nt E v al u ati o n Usi n g R E CI S T G ui deli ne  
 
N O T E:  T his st u d y uses pr ot oc ol R E CI S T v 1. 1 te m plate date d 2/ 1 6/ 2 0 1 1 .  See t he 
f o ot n ote f or t he ta ble re gar di n g meas urea ble disease i n Secti o n 1 1.4 4, as it pertai ns t o 
data c ollecti o n a n d a nal ysis.  
 
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) . C ha n g es 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 val uati 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 
reeval uate d e ver y 8  wee ks.  I n a d diti o n t o a baseli ne sca n, c o nfir mat or y sca ns 
s h o ul d als o be o btai ne d 8 wee ks f oll o wi n g i nitial d oc u me ntati o n of o bj ecti ve 
res p o nse. 
 
1 1. 2 
Defi niti o ns of Meas ura ble a n d N o n -Meas ura ble Disease  
 
1 1. 2 1   Meas ura ble Disease  
 
1 1. 2 1 1   A n o n- n o dal lesi o n is c o nsi d ere 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.  
 
1 1. 2 1 2   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. 
 
1 1. 2 1 3  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 de d t o be n o greater t ha n 5 m m).   
 
N O T E:   

3 7                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
T u m or lesi o ns i n a pre vi o usl y irra diate d area are n ot c o nsi dere d 
meas ura ble disease .  
 
1 1. 2 2 
N o n -Meas ura ble Disease  
 
1 1. 2 2 1  All ot her lesi o ns ( or sites of disease) are c o nsi dere d n o n-
meas ura ble diseas e, 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 n t 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 val uati o n of M eas ura ble Disease 
 
1 1. 3 1  Meas 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 dentifie 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.   
•  
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 pta ble M o dalities f or Meas ura ble Disease:       
 
•  
C o n ve nti o nal C T a n d M RI:  T his g ui deli ne has defi ne d meas ura b ilit 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 meas 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 h e 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 

3 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
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 meas uri n g ca ncer lesi o ns o ver ti me.   
 
•  
C hest X- ra 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 ysical E xa mi nati 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 h er 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 baseli 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:   
 
i.  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.   
 
ii.  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 
n e 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 occ 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.   
 
iii  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.  
 
c. F D G -P E T ma y be use d  t o u p gra de a res p o nse t o a C R i n a ma n ner 
si milar t o a bi o ps y i n cases w here a resi d ual ra di o gra p hic 
a b n or malit y is t h o u g ht t o re prese nt fi br osis or scarri n g.  T he use 

3 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
of F D G -P E T i n t his circ u msta nce has bee n descri be d i n t he 
pr ot oc ol a n d s u p p orte d b y dis ease-s pecific me dical literat ure f or 
t he i n dicati o n.  H o we ver, it m ust be ac k n o wle d ge d t hat b ot h 
a p pr oac hes ma y lea d t o false p ositi ve C R d ue t o li mitati o ns of 
F D G - P E T a n d bi o ps y res ol uti o n/se nsiti vit y. 
 
1 1. 3 3 
Meas ure me nt at F oll o w -u p E val uati o n:   
 
•  
A s u bse q ue nt sca n m ust be o btai ne d 8 wee ks f oll o wi n g i nitial 
d oc u me ntati o n of a n o bjecti 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  8 wee ks (see Secti o n 1 1. 4 4). 
 
•  
T he c yt ol o gical 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 diseas e 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. 
 
•  
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  
Meas ure me nt of 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 le si 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 

4 0                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
mali g na nt l y m p h n o de) w hic h ca n be meas ure d re pr o d uci bl y s h o ul d 
be selecte d.   
 
•  
Baseli 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 bj ecti 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 -Baseli 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.  
 
•  
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 Criteria 
 
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 of 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 n ee 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 val uati o n of T ar get Lesi o ns  

4 1                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
•  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. 
 
•  Partial 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 a s refere nce t he 
B S D ( see Secti o n 1 1. 4 1).  
 
•  Pr 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. 
  
•  Sta ble Disease ( 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.  

4 2                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
1 1. 4 3 3  E val uati o n of N o n- T ar get Lesi o ns & N o n -tar 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 ode 
m ust ha ve a re d ucti o n i n s h ort 
a xis t o < 1. 0 c m. 
 
•  N o n -C R/ N o n -P D:   
Persiste nce of o ne or m ore n o n-
tar get lesi o ns or n o n-tar get l y m p h 
n o des.  
 
 
•  Pr 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 incl 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.  U ne q ui v ocal pr o gressi o n of 
e xisti n g n o n-tar get lesi o ns a n d 
n o n-tar get l y m p h n o des.  
( N O T E:  U ne q ui v ocal 
pr o gressi o n s h o ul d n ot 
n or mall y tr u m p tar get lesi o n 
a n d tar get l y m p h n o de stat us.  
It m ust be re prese ntati ve of 
o verall disease stat us c ha n ge.)  
   
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.  
 
1 1. 4 4 O verall O bjecti ve Stat u s 
 
  
T he o verall o bjecti ve stat us f or a n e val uati o n is deter mi ne d b y c o m bi ni n g 
t he patie nt’s stat us o n tar get lesi o ns, tar get l y m p h n o des, n o n-tar get 
lesi o ns, n o n-tar get l y m p h n o des, a n d ne w disease as defi ne d i n t he 
f oll o wi n g ta bles:  
 
 
F or Patie nts wit h M eas ura ble Disease  

4 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
1 2. 4  
Pri mar y ris k fact ors:  
1 2. 4. 1  Pri mar y scler osi n g c h ola n gitis:  Yes vs N o vs U n k n o w n  
1 2. 4. 2  Cirr h osis:  Yes vs N o vs U n k n o w n 
1 2. 4. 3  He patitis C:  Yes vs N o vs U n k n o w n  
1 2. 4. 4  He pa titis B:  Yes vs N o vs U n k n o w n 
1 2. 4. 5  Dia betes mellit us:  Yes vs N o vs U n k n o w n  
1 2. 4. 6  C h ole d oc hal c yst:  Yes vs N o vs U n k n o w n 
1 2. 4. 7  N o n -Alc o h olic Fatt y Li ver Disease:  Yes vs N o vs U n k n o w n  
1 2. 4. 8  S m o ki n g:  Yes vs N o vs U n k n o w n  
1 2. 4. 9  Cr o h n’s disease:  Yes vs N o vs U n k n o w n  
1 2. 4. 1 0  Ulcerati ve c oliti s:  Yes vs N o vs U n k n o w n 
1 2. 4. 1 1  Li ver fl u ke i nfestati o n:  Yes vs N o vs U n k n o w n 
1 2. 4. 1 2  Car oli’s disease:  Yes vs N o vs U n k n o w n  
1 2. 4. 1 3  T h or otrast e x p os ure:  Yes vs N o vs U n k n o w n 
 
1 2. 5  
Defi niti ve s ur gical pr oce d ure perf or me d:  Si m ple se g me ntal resecti o n vs 
M ulti ple se g me ntal resecti o n s vs L o bect o m y vs E xte n de d l o bect o m y vs W hi p ple 
o perati o n vs Bile d uct resecti o n a n d a nast o m osis or he patic ojej u n ost o m y vs 
Ot her (s pecif y)  
 
1 2. 6  
C hil d - P u g h Classificati o n (see A p pe n di x X) :  Gra de A ( 5- 6 p oi nts) vs Gra de B 
( 7- 9 p oi nts) vs Gra de C ( 1 0- 1 5 p oi nts) 
 
1 2. 7  
I S H A K Fi br osis Sc ore:  0 n o fi br osis vs 1, 2 p ortal fi br osis vs 3, 4 fi br o us se pta vs 
5 n o d ular f or mati o n a n d i nc o m plete cirr h osis vs 6 esta blis he d cirr h osis 
 
1 2. 8  
E vi de nce of P S C i n a djace nt tiss ue:  D uct o pe nia vs D uctal or d uct ular 
pr oliferati o n vs C o nce ntric fi br osis of i ntra he patic d uct vs N o ne 
 
 
1 3. 0 
Tre at me nt/ F oll o w – u p Decisi o n at E v al u ati o n of P atie nt   
 
1 3. 1  
Patie nts w h o are C R, P R, or S D will c o nti n ue treat me nt per pr ot oc ol. 
 
1 3. 2  
Patie nts w h o de vel o p P D w hile recei vi n g t hera p y will g o t o t he e ve nt m o nit ori n g 
p hase.  
 
1 3. 3  
Patie nts w h o g o off pr ot oc ol treat me nt f or reas o ns ot her t ha n P D will g o t o t he 
e ve nt  m o nit ori n g p hase per Secti o n 1 8. 0. 
 
1 3. 4  
A patie nt is dee me d i neli gi ble if after re gistrati o n, it is deter mi ne d t hat at t he ti me 
of re gistrati o n, t he patie nt di d n ot satisf y eac h a n d e ver y eli gi bilit y criteria f or 
st u d y e ntr y.  T he patie nt ma y c o nti n ue treat me nt off-pr ot oc ol at t he discreti o n of 
t he p h ysicia n as l o n g as t here are n o safet y c o ncer ns, a n d t he patie nt was 
pr o perl y re gistere d. T he patie nt w ill g o directl y t o t he e ve nt m o nit ori n g p hase of 
t he st u d y ( or off st u d y, if a p plica ble).  
•  
If t he patie nt recei ve d treat me nt, all data u p u ntil t he p oi nt of c o nfir mati o n of 
i neli gi bilit y m ust be s u b mitte d.  E ve nt mo nit ori n g will be re q uire d per 
Secti o n 1 8. 0 of t he pr ot oc ol.  

4 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
•  
If t he patie nt ne ver recei ve d treat me nt, o n-st u d y material a n d t he E n d of 
Acti ve Treat me nt/ Ca ncel N otificati o n F or m m ust be s u b mitte d. N o f urt her 
data s u b missi o n is necessar y .  
 
1 3. 5 
A patie nt is dee me d a m aj or vi ol ati o n , if pr ot oc ol req uire me nts re gar di n g 
treat me nt i n c ycle 1 of t he i nitial t hera p y are se verel y vi olate d t hat e val ua bilit y 
f or pri mar y e n d p oi nt is q uesti o na ble.  All data u p u ntil t he p oi nt of c o nfir mati o n 
of a maj or vi olati o n m ust be s u b mitte d.  T he patie nt will g o directl y t o t he e ve nt-
m o nit ori n g p hase of t he st u d y.  T he patie nt ma y c o nti n ue treat me nt off- pr ot oc ol 
at t he discreti o n of t he p h ysicia n as l o n g as t here are n o safet y c o ncer ns, a n d t he 
patie nt was pr o perl y re gistere d.  E ve nt m o nit ori n g will be re q uire d per S ecti o n 
1 8. 0 of t he pr ot oc ol.  
 
1 3. 7 
A patie nt is dee me d a c a ncel  if he/s he is re m o ve d fr o m t he st u d y f or a n y reas o n 
bef ore a n y st u d y treat me nt is gi ve n.  O n- st u d y material a n d t he E n d of Acti ve 
Treat me nt/ Ca ncel N otificati o n F or m m ust be s u b mitte d.  N o f urt her data 
s u b missi o n is necessar y. 
 

4 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 4. 0  
B o d y Fl ui d Bi os peci me ns  
 
1 4. 1  
B o d y Fl ui d Bi os peci me ns  
 
1 4. 1 1  Circ ulati n g t u m or D N A a nal ysis  
Plas ma sa m ples will be c ollecte d pre -treat me nt, at t he be gi n ni n g of eac h c ycle of treat me nt a n d at t he e n d of acti ve 
m o nit ori n g. T hese sa m ples will be use d t o q ua ntif y t u m or -s pecific s o matic m utati o ns, pre-i de ntifie d i n t u m or bi o ps y 
a nal ysis t o assess w het her ct D N A ca n trac k disease b ur de n as see n o n i ma gi n g i n c h ola n gi ocarci n o ma. A s u bset of t hese 
sa m ples will be a nal yse d usi n g m ore e xte nsi ve ge n o mic met h o ds s uc h as w h ole e x o me se q ue nci n g t o assess t he p ote ntial 
of usi n g ct D N A f or m olec ular stratificati o n a n d m o nit ori n g of ac q uire d resista nce.  
 
1 4. 1 2     B o d y fl ui d bi os peci me n s u b missi o n 
St u d y  
O pti o n al or 
M a n d at or y  
B o d y fl ui d  
T u be  
V ol u me  < 1 4 d a ys 
pri o r t o 
re gistr ati o n 
C ycle 
2 a n d 
be y o n d 
D a y 1  
E n d of 
tre at me nt 
P r ocess 
at site  
Te m per at ure 
c o n diti o ns 
f or st or a ge 
ct D N A 
a nal ysis 
plas ma 
sa m ples 1 
O pti o n al 
Bl o o d  
E D T A  
1 0 m L  
( 2) 
X  
X  
X  
Y  
Fracti o nate d 
t o plas ma, 
1 m L ali q u ots 
st ore d at -8 0  
1. If t u m or bi o psies or a d diti o nal treat me nts are bei n g a d mi nistere d t he sa me da y, bl o o d sa m ples f or circ ulati n g D N A a nal ysis  s h o ul d be 
c ollecte d bef ore a n y t u m or ma ni p ulati o n or treat me nt 
2. Peri p heral Bl o o d M o n o n uclear Cells ( P B M Cs) s h o ul d be is olate d fr o m t he sa me bl o o d sa m ple  as plas ma at pre -re gistrati o n scree ni n g 
visit  a n d c ycle 2 da y 1 b y is olati n g t he b uff y c oat. 
 
 
 
 
 

4 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 5. 1 2 
F or m ul ati o n : P o nati ni b is a ne w c he mical e ntit y pre pare d b y c he mical 
s y nt hesis.  T he p o nati ni b acti ve p har mace utical i n gre die nt ( A PI) is t he 
m o n o- h y dr oc hl ori de salt ( A P 2 4 5 3 4 h y dr oc hl ori de, or A P 2 4 5 3 4 H Cl). 
 
P o nati ni b f or i n v esti gati o nal use is s u p plie d as 1 5 m g a n d 4 5 m g r o u n d, 
w hite, fil m -c oate d ta blets.  T he ta blet f or m ulati o n i ncl u des i nacti ve 
i n gre die nts lact ose m o n o h y drate, micr ocr ystalli ne cell ul ose, s o di u m 
starc h gl yc olate, c oll oi dal silic o n di o xi de, ma g nesi u m stearate, 
p ol yet h yle ne gl yc ol, talc, p ol y vi n yl alc o h ol, a n d tita ni u m di o xi de. 
 
1 5. 1 3 
P re p ar ati o n a n d st or a ge : P o nati ni b dr u g pr o d uct is rec o m me n de d f or 
st ora ge at c o ntr olle d r o o m te m perat ure ( 2 0° C t o 2 5° C [ 6 8° F t o 7 7° F]). 
 
1 5. 1 4  A d mi nistr ati o n:   P o nati ni b ta blets s h o ul d be ta ke n o nce dail y, at  
a p pr o xi matel y t he sa me ti me eac h da y.  
 
I n a st u d y t o assess t he effect of b ot h a hi g h-fat a n d a l o w-fat meal o n t he 
bi oa vaila bilit y a n d p har mac o ki netics of p o nati ni b, neit her t y pe of diet 
i m pacte d t he P K p o nati ni b.  P o nati ni b ma y be a d mi nistere d wit h o ut 
re gar d t o f o o d i nta ke.   
 
 
1 5. 1 5  P h ar m ac o ki netic i nf or m ati o n : 
a)  A bs or pti o n – Ma xi m u m p o nati ni b bl o o d le vels ge nerall y 
occ urre d 4 t o 6 h o urs f oll o wi n g a d mi nistrati o n of p o nati ni b a n d 
t he me dia n tma x  i n t he 1 5 t hr o u g h 6 0 m g c o h orts was 4 h o urs.  T he 
mea n stea d y -state C ma x a n d A U C a p peare d t o i ncrease i n a 
ma n ner a p pr o xi matel y pr o p orti o nal wit h i ncreasi n g d ose, 
partic ularl y i n t he 1 5 - t o 6 0- m g d ose ra n ge.  I n t he 1 5 m g c o h ort, 
t he ge o metric mea n C ma x o n Da y 2 9 was 4 8. 5 n M (c oefficie nt of 
variati o n [ % C V] 4 9. 3).  N ota bl y, dail y d oses of 1 5 m g ac hie ve d 
stea d y state C ma x  plas ma c o nce ntrati o ns t hat s ur passe d 4 0 n M, a 
c o nce ntrati o n t hat is s ufficie nt t o i n hi bit via bilit y of cells 
e x pressi n g all B C R-A B L m uta nts teste d ( b y > 5 0 %), i ncl u di n g 
T 3 1 5I, a n d t o s u p press t he e mer ge nce of a n y m uta nt cl o nes i n a 
precli nical m uta ge nesis assa y.   
b)  Distri b uti o n – I n vitr o, p o nati ni b was f o u n d t o be 9 9. 9 % b o u n d 
t o plas ma pr otei ns.   
 
c)  Meta b olis m –  C Y P 3 A 4 a n d t o a lesser e xte nt C Y P 2 C 8, 
C Y P 2 D 6 a n d C Y P 3 A 5 are i n v ol ve d i n t he p hase I meta b olis m of 
p o nati ni b i n vitr o.  P o nati ni b is als o meta b olize d b y esterases 
a n d/ or a mi dases.   
  
d)  E xcreti o n – He patic eli mi nati o n is t he maj or e xcret or y r o ute 
f or p o nati ni b i n h u ma ns.  F oll o wi n g a si n gle oral d ose of 1 4 C-
la bele d p o nati ni b, a p pr o xi matel y 8 7 % of t he ra di oacti ve d ose is 
rec o vere d i n t he feces a n d a p pr o xi matel y 5 % in t he uri ne.   T he 
stea d y-state ter mi nal eli mi nati o n half -life after oral a d mi nistrati o n 
of p o nati ni b i n patie nts was bet wee n 2 0 a n d 2 9 h o urs f or d oses 
≥1 5 m g. 
  
  
 
1 5. 1 6 
P ote nti al Dr u g I nter acti o ns :  Base d o n i n vitr o st u dies, D DIs d ue t o 
eit her C Y P i n hi biti o n or i n d ucti o n b y p o nati ni b are hi g hl y u nli kel y i n 

4 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
cli nical trials usi n g t he rec o m me n de d dail y d ose of 4 5  m g, a n d i n 
i n vesti gati o nal trials i ncl u di n g d oses as hi g h as 6 0 m g.  I n vitr o st u dies 
als o de m o nstrate t hat h u ma n C Y P 3 A 4 is i n v ol ve d i n t he meta b olis m of 
p o nati ni b.  I n vie w of t his, a dr u g i nteracti o n st u d y was perf or me d wit h a 
str o n g C Y P 3 A 4 i n hi bit or i n healt h y s u bjects.  Ket oc o naz ole c o-
a d mi nistrati o n i ncrease d p o nati ni b C ma x  a n d A U C b y 4 7 % a n d 7 8 %, 
res pecti vel y.  Als o c o nsi deri n g t he r ole of C Y P 3 A 4 i n t he meta b olis m of 
p o nati ni b, a dr u g i nteracti o n st u d y is u n der wa y wit h t he str o n g C Y P 3 A 4 
i n d ucer rifa m pi n.  Res ults are n ot yet a vaila ble.  Si nce C Y P 3 A 4 
c o ntri b utes t o t he meta b olis m of p o nati ni b, str o n g i n d ucers or i n hi bit ors 
of C Y P 3 A 4 s h o ul d be use d wit h ca uti o n or a v oi de d alt o get her. 
 
Base d o n t he c h e mical pr o perties of p o nati ni b, ele vate d gastric p H ma y 
re d uce bi oa vaila bilit y a n d e x p os ure.  C oa d mi nistrati o n of p o nati ni b wit h 
la ns o praz ole, a dr u g t hat ele vates t he gastric p H, is c urre ntl y u n der 
i n vesti gati o n i n a cli nical trial; h o we ver, res ults are not yet a vaila ble.  
C oa d mi nistrati o n of p o nati ni b wit h dr u gs t hat ele vate t he gastric p H (e g, 
pr ot o n p u m p i n hi bit ors, H 2 bl oc kers, or a ntaci ds) s h o ul d be a v oi de d 
u nless t he be nefit o ut wei g hs t he p ossi ble ris k of p o nati ni b 
u n dere x p os ure.   
 
I n vitr o st u dies de m o nstrate t hat p o nati ni b i n hi bits t he P - g p a n d A B C G 2 
[als o k n o w n as B C R P] tra ns p orter s yste ms.  T he effect of 
c oa d mi nistrati o n of p o nati ni b wit h se nsiti ve s u bstrates of t he P- g p a n d 
A B C G 2 [als o k n o w n as B C R P] tra ns p orter s yste ms o n e x p os ure of t hese 
s u bstrates has n ot bee n e val uate d i n cli nical st u dies. 
 
Dr u gs t hat are e xte nsi vel y b o u n d t o plas ma pr otei ns mi g ht 
dis place p o nati ni b fr o m bi n di n g sites i n plas ma a n d p o nati ni b 
mi g ht dis place ot her dr u gs b o u n d t o plas ma pr otei ns.  Ca uti o n 
s h o ul d be o bser ve d w he n a d mi nisteri n g c o nc o mita nt me dicati o ns, 
s uc h as warfari n, pr o pra n ol ol, p he n yt oi n, a n d diaze pa m, w hic h are 
e xte nsi vel y b o u n d t o plas ma pr otei n. 
 
1 5. 1 7  K n o w n p ote nti al t o xicities:  
Si de effects fre q ue ntl y re p orte d ( m ore th a n 1 0 % o f p ati e nts) inc lu de : 
A n  up p er res pirat or y i nfecti o n li ke t he co m m o n c ol d, L o w bl o o d c o u n ts 
i nclu d i n g w hite bl o o d cells (w hic h  ma y i ncrease t he ris k of i nfectio n ), 
platele ts (w h ic h ma y i ncrease t he ris k of blee d i n g) or  re d bl oo d cells 
(w hic h  ca n cau se y o u t o feel tire d), Decrease d a ppet ite, Tro u b le get tin g 
a deq u ate am o u nt or q u alit y of slee p, Hea dache, Di zzi ness, Hi g h bl o o d 
pres s ure, S h ort ness of breat h, C o u g h, Pai n i n t he bell y, D iarr hea, 
V o mi tin g, C o n sti pati o n, Na usea, In crease  lipase le v el (a n e nz y me 
m eas ure d i n t he bl o o d t hat reflects f u nctio n of t he pa n creas, Ele va tio n s i n 
lip ase ma y i n dicate i nfla m matio n of t he pa n creas), In crease  li ver 
enz y m es ( A S T a n d A L T) w hic h  ca n i ndic ate da ma ge t o cells i n t he li ver, 
S ki n  Ras h (r e d de ne d s ki n or re d ras h wit h  or wit h o ut r aise d bu m ps), D r y 
S ki n, Pa i n t hat ma y occ ur i n t he j oi nts, m uscles, b o ne, bac k or li m bs, 
M u scle cra m ps a n d pa i n, Fati gue, We a k nes, Ab n or m al b u ild u p of flu i d 
w hic h  ma y ca use s wellin g i n t he ha n ds, feet, a n kles, feet, face or all o v er 
y o u r b o d y, Fe ver, P ai n 

5 0                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
Si de eff ects less f re q ue ntl y re p orte d ( 1 – 1 0% o f patie nts)  
P n e um o n ia (a n i nfla mm ati o n of t he l un g, ge neral l y ca use d b y 
i nfectio n, t h at ma y be acc o m pa nie d b y c o u g h , p hle gm , fe ver, 
s har p c hest  pai n, s ha ki n g c hills, s weatin g, d ifficu lt y b reat hin g 
a n d re q u ires i m me diate me dical atte ntio n), I n flam m atio n o r 
i nfecti o n of o ne or m o re hair fo llicles. A ha ir fo llicle is a n 
o p e ni ng i n t he ski n t hat e ncl oses a stran d of hai r fro m w hic h  t he 
hai r gr ows , Feb rile ne utr o pe nia (a c on d itio n m ar ke d b y fe ver a n d 
l o wer-t ha n- n or mal n u m be r of ne u tro p h ils i n t he bl o o d w hic h  
c o ul d i ncrease t he ris k of in fectio n), De h y dra tio n, L o w le v els of 
i m p ortant ele ctrol y te le vels i n y o ur  bl o o d i ncl u di n g a bn or m all y 
l o w lev els of so di u m ( w h ic h ca n cau se fati gu e, na usea, 
hea d ac he), l o w le vels of p o tassiu m ( w h ic h ca n caus e irre gu lar 
heart bea ts),  l o w le vels of calciu m ( w h ic h ca n cau se m uscle 
s pas ms, t witc hes or cram ps o r nu m b n ess/tin gli n g i n y o u r fin gers, 
t oes a n d aro u n d y o ur m o ut h ), a n d  l o w le vels of p h o s ph or u s 
(w hic h  ca n cau se b o ne pain, c o nf u sio n, m u scle wea k ness), Hi g h 
bl o o d s ug ar le vels, Hi g h c o nce ntr atio n o f uric aci d i n t he bl o o d 
w hic h  c o ul d res ult i n i nfla m matio n of a j oi nt 
(" go ut" ), pr o ble ms w it h uri natio n o r ki dne y st o n e, fe ver, c hills, fati gue, 
I ncrease d trigl y ceri de le vel s ( bl o o d fat), Weig h t decrease d, C o nf usio n al 
state ( deliriu m ), is a state t hat y o u mig h t u n clear  i n y o ur mi n d a b o ut 
s o met hi ng, Cere br o vas c ular accide nt, c o m m o n l y k n ow n as  a str o ke, is a n 
e pis o de i n w hic h  s o me of t he b rai n tissue is da ma ge d b y a disru p tio n o f 
b l oo d fl o w t o t he brai n a n d ma y cau se s u d de n, wea k ness or nu m b n ess o n 
o ne side of t he b o d y, dif fic ult y s peaki n g a n d re q u ires i m me diate m e dical 
atte ntio n , Cere bral i nfarctio n, a n area of brai n tiss ue da ma ge d b y a 
d isru p ti o n of  bl o o d t o t he brai n, Lac k of e ner g y, or lac k of i nterest i n 
d oi n g t hi ngs, Mi g rai ne hea dach e, Cran ial o r p erip h eral neur o p at h y,  
c o n diti o ns i n w hic h nerv es t hat  c o me fro m t he b rai n (cran ial n erves) 
w hic h  s up p l y t he face a n d e yes a n d ner ves t hat c o me fr o m t he s pi nal cor d 
( perip h eral n erves) ha ve bee n d a ma ge d w hic h  ma y cau se vis ual 
d ist ur ba nces,  n u m b ness, ti n glin g, pri c klin g se nsat i o n,  a n d eit her 
decr ease d or incr ease d se nsiti vit y of t he s ki n t o t o uc h or pai n or the ear t o 
s o u nd, Tra n sie nt isc he mic attacks, c o m m o n l y k n ow n as  a TI A  or mi ni 
str o ke, a TI A is a n  e piso de i n w hic h s o me o f t he bra i n tiss ue is da ma ge d 
b y a d isru p tio n o f bl oo d fl o w t o t he bra i n t hat ma y cau se s ud d e n 
we a kn ess or n u m b ness o n o ne side of t he b o d y, dif ficu lt y s pea ki n g a n d 
req u ires im m e diate me dical atte nti o n, E ye pr o ble ms ca n occ ur incl u di n g 
dr y e ye, bl u rred v isi o n, e ye irritati o n or pai n, re dn ess of t he eye a n d less 
fre qu e ntl y, cataracts, glauc o m a (a c o n ditio n of i ncrease d press ure i n t he 
e ye w hic h ca n lea d t o l oss of visi o n), a n d i nfla mma tio n or a n ulc er of t he 
c or nea w hic h is t he clear, d o me- s ha pe d tiss ue o n t he fr o nt of y o ur e ye 
t hat c o vers the p u p il a n d t he iris, M y ocard ial i nfarctio n, c o m m o nl y 
k n o w n as heart attac k, a m y ocard ial i nfarct i o n is a n e pis o de i n w hic h 
s ome o f t he heart's  bl o o d s up p l y is sev erel y cut o ff o r restricte d, ca usin g 
t he heart m uscle t o s uffer a n d die fr o m lac k of o x y ge n, Pain , disc o mf ort 
o r press ure i n t he c hest cau se d b y i ns ufficie nt bl o o d s up p l y t o t he heart  
m us cle, P ericar d ial effusi o n ( a n a bn or m al b u ild u p o f flu i d i nside t he sac 
t hat c o vers t he h eart  w hic h  ma y cau se c hest pain, dif ficult y b reat hin g a n d 

5 1                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
fev er), Irre gu lar heart  r h yt h ms i nclu d i n g atrial fib rillatio n ( a n ab n or m al 
ra pi d or irre gu lar heart  r h yt h m w hic h ma y ca use lig h t- hea de dn ess, 
s h ort ness of bre at h or weak ness)  a n d a bn or m all y ra pi d or slo w heart  
rates, Narr owi n g  of bl o o d vessels restrictin g bl o o d flo w t o ar eas a wa y 
fr o m t he center o f t he b o dy s uc h  as le gs, arms, t oe s, fin g ers, ear l o bes, 
a n d pe n is, C on d itio n o f d ecrease d o xy g e n s up p l y t o t he areas aw a y fr o m 
t he ce nter of t he b o d y s uc h as le gs, ar ms, t oes, fin g ers, ear l o bes, a n d 
p e nis, M uscle pai n cau se d b y t o o little bl o o d fl o w d urin g wa lki n g or 
e xercise, Bl oo d clot i n a maj or vei n i n t he le gs or p elvis, F l us hi ng o r h ot 
flu s h (bec o mi n g v er y re d i n t he face, a n d ofte n ot her areas of t he s ki n. 
S o me tim e m a y be a feelin g of war m t h t hat s prea ds o ver t he b o d y m o st 
str o n gl y felt i n t he h ea d an d nec k re g i o n), O bstru cti o n of a bl o o d vessel 
i n t he l un g s res ulti n g i n fl ui d b uild- u p i n t he l un gs, P leu ral eff us i o n (a n 
a b n or mal b u ild u p o f flu i d i n t he li ni n g of t he lu n g s w hic h  ma y cau se 
c hest p ain, c o u g h , or sh or t ness of breat h), Blee din g s uc h as n ose blee ds o r 
pete c hiae (i n w hic h  tin y p ur p le or re d d o ts a pp ear o n t he s ki n d ue t o 
blee d i ng u n d er t he s kin ’s s urface), Vo ice i m pair me nt, s uc h as h oarse ness, 
I ncrease d pr ess ure of t he bl o o d vessels i n y o ur lu n g , w h ic h cau ses 
s y mpt o ms s uc h as s h ort ness o f breat h d urin g r o u tine ac tivit y (f o r 
e xa m ple, cli m bi n g t w o flig h ts of stairs), tired n ess, c hest p ain, a n d a 
racin g heart beat, I n flam m atio n of t he pa nc reas (a n or ga n i n t he a bd o me n 
w h ic h pr o d uces i ns uli n a n d certai n di g esti ve e nz y mes, e. g., a m ylase, 
w hic h  will  be released i nt o t he bl o o d, w he n t he pa n creas is d isease d or 
i nfla me d), w hi c h ma y aff ect t he fu n cti o n of t he pa ncreas a n d w hic h  ma y 
cau se pain i n  t he ab d o m e n ( belly ), s o meti me ca n be se vere a n d ma y 
i ncrease bl o o d s ugar , Sto m ac h aci d, or occasi o nall y bile fl ows  bac k  
(reflu xes) i nt o y o u r fo o d pi pe (es o p ha g u s), w hic h ca n cau se h eart bu r n, 
In flam m atio n of t he m uc o u s lini n g o f a n y of t he str uct ures i n t he m o ut h, 
i nclu d i n g c hee ks, g u ms, t o n g u e, lip s, t hr oat a n d r o of or flo or of t he 
m o ut h, I n di g esti o n or up set st omac h, Bl oati n g, A b d o mi n al d isc o mf ort, 
D r y m o ut h, A n i ncrease i n t he bl o o d of a s ub sta nce ( biliru bi n) pr o d u ce d 
b y t he liv er t hat c o ul d i nd icate li ver d isease a n d i n hi g h a m o u nts ca n 
cause y ell owi n g  of t he s ki n a n d e yes, I ncrease d e nz y mes i n t he bl o o d, 
al kaline p h o s ph atase ( A LP) a n d ga m ma - gl uta m yltran sferase ( G G T), S ki n 
pr o ble ms w hic h  ma y i nclu d e rash, m a y be itch y or pa i nf ul, dr y wit h 
fla kin g o r peelin g s ki n, s o meti me o v er large ar ea of y o ur b o d y ( de m atitis 
exf o liative); br u ise, re dnes s, c ha n ge or l ose col o r o f y o u r ski n, d ue t o 
blee di n g u n d er neat h t he s ki n; dar ke n i ng o r thic ke ni n g o f t he o uter la yer 
of y o ur s ki n, H air l oss, Itc hi ng, E x cessi ve s weati n g s o meti mes d u rin g 
slee p, Nec k pai n, C hest  pai n n ot d ue t o heart  disease, I m p ot e nce 
(ina b ilit y t o ac hie ve or main tai n a n erecti o n l o n g e n ou g h t o e n ga ge i n 
sex ual i nte rco urs e), Ch ills, Fl u li ke s y m pt o ms, w hic h  i nclu d e fev er, 
c hills, b o d y aces, na usea, l oss of a ppe tite, Feeli n g sic k or disc o mf ort, 
Bac terial inf ecti o n of t he tiss ue j ust b elo w t he s ki n s urface, Ery t he ma 
m u ltif or me (a ras h wit h s p o ts t hat ma y l o o k li ke a target ) 
 
Si de effects i nfreq ue n tl y re p orte d (Less  th a n 1 % o f p ati e nts) 
A se v ere i nfecti o n i n t he bo d y, s o meti me k n o w n as  bl o o d p ois o ni n g, 
w h ic h ca n ca use difficu lt y b reat hin g, c oa g u latio n of t he bl o o d, 
m alf u ncti o n of y o ur or ga n s a n d is us uall y treate d i n a n inte n sive care 
u n it of a h os pital, A co n d iti o n t hat occ urs after t he start of a nti-cance r 

5 2                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
treat me nt i n w hic h  t he d yi n g t u m or cells release t heir c o nte nts i nt o 
t he blo o d a n d cause c ha ng es t o i m p orta nt bl o o d c he micals a n d may 
cau se da ma ge t o or ga ns in clu d i n g t he ki d n e ys, heart a n d liver , Bl oo d 
v essels i nside y o u r sk u ll beco me bl o c ke d b y bl o o d cl ot, w hic h  is o ne 
of t he cau ses of stro k e, Bl oo d v essels i nsi de y o ur e yes bec ome 
bl o c ke d b y bl o o d cl o t, w hic h  ma y cau se se vere da ma ge t o y o ur e y es, 
y o u mi g h t n ot be a ble t o see clearl y a n d s o meti me e ve n blin d n ess 
c o ul d ha p pe n, P o or perip h eral circula tio n is a c o n ditio n i n w hic h  t he 
bl o o d v essels ca n n ot s up p l y e n o u g h bl o o d t o y o u r feet or leg; y o u 
w ill e x perie nce n u m b ness a n d cra m pi n g i n t he feet a n d l o wer le gs. 
Y o u m a y als o ha ve tin g lin g se nsati o n i n t he feet a n d t oes, Sp len ic 
i nfarctio n is a c on d itio n i n w hic h  o x y ge n s up p l y t o t he s plee n is 
inte rru pt e d, lea di ng t o p artial or c o m ple te i nfarcti o n (tiss ue deat h d ue 
to o x y g e n s h orta ge) i n the s plee n, Blee din g t h at ca n be  seri o us a n d 
ca n lea d t o deat h i ncl u di n g b lee din g i n  t he brai n or i n t he 
g astr oi nt esti nal tract (w hic h e xt e nds fro m t he m o ut h t o t he a nus), 
H e pat ot o xi cit y a c on d itio n i n w hic h y o ur li ver is da ma ge d a n d ca n 
n ot f u n cti o n well, Su d d e n, se vere i ncrease i n bl o o d press ure 
o cc urri n g i n i nd i vi du als wh o ha ve u ntr eate d hi gh bl o o d pre ss ure or 
ha ve st o p p e d taki n g a ntih y p erte nsi ve me dicatio n , Ery t he ma n o d os u m 
(a n infla m m ati o n of t he fat cells u n d er t he ski n t hat cau ses te nd er 
lesi o ns o n t he s ki n), F or ma tio n o f a n a bn or m al c on n ecti o n bet wee n 
i nter nal or ga n s i n t he bell y t hat are n ot n or m ally c o n n ecte d, Q T 
Pr ol o n g ati o n is a c ha n ge i n electr ocardi o g rap h y ( E C G). E C G  is a 
st ud y o f t he electrical s ystem o f t he heart  t hat ma y i ndic ate a n 
i ncrease d ris k of seri o us a bn or m alities i n t he heart's r h yt h m, 
H y p erse nsiti vit y 
 
 
1 5. 1 8 
Dr u g  pr oc ure me nt:  Dr u g will be pr o vi de d free of c har ge t o st u d y 
partici pa nts b y Aria d P har mace uticals . 
 
  
1 5. 1 9 N ursi n g G ui deli nes:  
1 5. 1 9 1  Res pirat or y s y m pt o ms are c o m m o n, i ncl u di n g U RI, c o u g h, a n d 
d ys p nea. I nstr uct patie nt t o re p ort t hese a n d treat 
s y m pt o maticall y. M o nit or f or effecti ve ness of i nter ve nti o n. 
1 5. 1 9 2  C o m m o n gastr oi ntesti nal s y m pt o ms see n i ncl u de: a n ore xia, 
decrease d a p petite, a b d o mi nal pai n, c o nsti pati o n, diarr hea, 
na usea, a n d v o miti n g. Treat s y m pt o maticall y a n d m o ni t or f or 
effecti ve ness of i nter ve nti o n  
1 5. 1 9 3 Patie nts ma y e x perie nce art hral gias a n d m yal gias. Treat wit h 
O T C pai n relie vers as all o we d i n pr ot oc ol. I nstr uct patie nt t o 
re p ort a n y pai n n ot relie ve d wit h t hese met h o ds. 
1 5. 1 9 4  M o nit or C B C w/ diff. I nstr uct patie nt t o re p ort a n y si g ns or 
s y m pt o ms of i nfecti o n a n d/ or u n us ual br uisi n g or blee di n g t o t he 
healt h care tea m.  
1 5. 1 9 5  M o nit or L F T’s. 
1 5. 1 9 6 War n patie nts of t he p ote ntial f or fati g ue a n d ast he nia.  
1 5. 1 9 7 Patie nts ca n e x perie nce t hr o m b osis, car diac/ vasc ular e ve nts, 
a n d/ or blee di n g i n t he brai n. I nstr uct patie nt t o see k e mer ge nc y 
hel p f or a n y ne ur ol o gical or car diac/ vasc ular s y m pt o ms.  

5 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 5. 1 9 8 Oral lesi o ns/ ulcers are u nc o m m o n, b ut ca n be se vere. I nstr uct 
patie nt o n g o o d oral h y gie ne. Visc o us li d ocai ne or ma gi c 
m o ut h was h ma y be hel pf ul.  
 
1 6. 0  
St atistic al C o nsi der ati o ns a n d Met h o d ol o g y  
 
1 6. 1 
O ver vie w:  T his pr ot oc ol will assess t he efficac y of p o nati ni b i n F G F R a berra nt 
a d va nce d biliar y ca ncers usi n g a t w o-sta ge p hase II st u d y desi g n. 
 
1 6. 1 1  Pri mar y E n d p oi nt:  T he pri mar y e n d p oi nt of t his trial is t he  cli ncal 
be nefit rate , w hic h i ncl u des c o nfir me d t u m or res p o nse ( C R or P R) or 
S D f or 4 or m ore c ycle .  A c o nfir me d t u m or res p o nse is defi ne d t o be 
eit her a C R or P R n ote d as t he o bjecti ve stat us o n 2 c o nsec uti ve 
e val uati o ns at least 8 wee ks a part.   Cli nical be nefit rate will be e val uate d 
usi n g all c ycles of treat me nt.  All patie nts meeti n g t he eli gi bilit y criteria 
w h o ha ve si g ne d a c o nse nt f or m, ha ve be g u n treat me nt, a n d ha ve n ot 
bee n dee me d a maj or treat me nt vi olati o n d uri n g t he first c ycle of 
treat me nt will be e va ula ble f or res p o nse. 
 
1 6. 2 
Statistical Desi g n  
 
1 6. 2 1 
T he lar gest cli nical be nefit w here t he pr o p ose d treat me nt re gi me n w o ul d 
be c o nsi dere d i neffecti ve i n t his p o p ulati o n is 5 %, a n d t he s mallest 
cli nical be nefit rate  t hat w o ul d warra nt s u bse q ue nt st u dies wit h t he 
pr o p ose d re gi me n i n t his patie nt p o p ulati o n is 2 0 %.  T he f oll o wi n g t w o-
sta ge Si m o n O pti m u m desi g n  uses 1 0 or  2 7 patie nts t o test t he n ull 
h y p ot hesis t hat t he tr ue c li nical be nefit ratei n a gi ven patie nt p o p ulati o n is 
at m ost 5 %. 
 
T he n ull c li nical be nefit rate of 5 % is base d o n res p o nse rates o bser ve d 
f or refract or y s oli d t u m ors wit h si n gle a ge nts i n a n u nselecte d/e m piric 
setti n g ( H orst ma n n, E. et al., 2 0 0 5). 
  
 
1 6. 2 1 1 S T A G E 1:  E nter 1 0 patie nts i nt o t he st u d y. If 0 s uccesses (i.e., 
patie nts dee me d as ha vi n g cli nical be nefit) are o bser ve d i n t he 
first 1 0 e val ua ble patie nts, we will c o nsi der t his re gi me n 
i neffecti ve i n t his patie nt p o p ulati o n a n d ter mi nate t his st u d y. 
Ot her wise, if t he n u m ber of s uccesses is at least 1 , we will 
pr ocee d t o Sta ge 2. 
1 6. 2 1 2  S T A G E 2: E nter a n a d diti o nal 1 7 patie nts i nt o t he st u d y. If 2 or 
fe wer s uccesses are o bser ve d i n t he first 2 7 e val ua ble patie nts, 
we will c o nsi der t his re gi me n i neffecti ve i n t his patie nt 
p o p ulati o n. If 3 or m ore s uccesses are o bser ve d i n t he first 2 7 
e val ua ble patie nts, we ma y rec o m me n d f urt her testi n g of t his 
re gi me n i n s u bse q ue nt st u dies i n t his p o p ulati o n. 
 
1 6. 2 1 3 N O T E:  Accr ual will be s us pe n de d bet wee n sta ges t o all o w 
patie nts t o bec o me e val ua ble f or t he pri mar y e n d p oi nt. 

5 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 6. 2 1 1 O ver Accr ual: If m ore t ha n t he tar get n u m ber of patie nts are 
accr ue d, t he a d diti o nal patie nts will n ot be use d t o e val uate t he 
st o p pi n g r ule or use d i n a n y decisi o n ma ki n g pr ocess.  A nal ys is 
i n v ol vi n g o ver accr ue d patients is disc usse d i n Secti o n 1 6. 3 1 3. 
1 6. 2 2 
Sa m ple Size:  T he t w o-sta ge st u d y desi g n t o be utilize d is f ull y descri be d 
i n Secti o n 1 6. 2 1.  A mi ni m u m of 1 0 a n d a ma xi m u m of 27 e val ua ble 
patie nts accr ue d o nt o t his st u d y u nless u n d ue a d verse e ve nts are 
e nc o u ntere d.  We a ntici pate accr ui n g a n a d diti o nal 3 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 h us, a m a xi m u m  of 3 0 p atie nts will be accr ue d o nt o t his st u d y  i n 
or der t o ha ve 2 7 e val ua ble patie nts a vaila ble f or t he statistical desi g n 
descri be d i n Secti o n 1 6. 2 1.   
1 6. 2 3  Accr ual Ti me a n d St u d y D urati o n:  T he a ntici pate d accr ual rate is 
a p pr o xi matel y 3 patie nts per m o nt h, base d o n p h ysicia n esti mate.  
T heref or e, t he accr ual peri o d f or t his p hase II st u d y is e x pe cte d t o be 1 6 
m o nt hs (i ncl u di n g a 6- m o nt h s us pe nsi o n i n accr ual t o perf or m t he Sta ge 
1 a nal ysis) .  T he fi nal a nal ysis ca n be gi n a p pr o xi matel y 2 2 m o nt hs after 
t he trial be gi ns, i.e., as s o o n as t he last patie nt has bee n o bser ve d f or 6 
m o nt hs.   
1 6. 2 4  P o wer  a n d Si g nifica nce Le vel:  Ass u mi n g t hat t he n u m ber of  s uccesses 
is bi n o miall y distri b ute d, t he si g nifica nce le vel is < 0. 1 5  a n d t he 
pr o ba bilit y of declari n g t hat t his re gi me n warra nts f urt her st u dies (i.e. , 
statistical p o wer) u n der vari o us cli nical be nefit  rates ca n be ta b ulate d as 
a f u ncti o n of t he tr ue cli nical be nefit rate  as s h o w n i n t he f oll o wi n g 
ta ble. 
If t he tr ue cli nical be nefit  rate is … 
0. 0 5 
0. 1 0 
0. 1 5 
0. 2 0 
0. 2 5 
T he n t he pr o ba bilit y of declari n g t hat t he 
re gi me n warra nts f urt her st u dies is … 
0. 1 2 
0. 4 3 
0. 7 0 
0. 8 5 
0. 9 3 
A n d t he pr o ba bilit y of st o p pi n g at Sta ge 1 is … 
0. 6 0 
0. 3 5 
0. 2 0 
0. 1 1 
0. 0 6 
1 6. 2 5  Ot her C o nsi derati o ns:  A d verse e ve nts, q ualit y/ d urati o n of res p o nse, a n d 
patter ns of treat me nt fail ure o bser ve d i n t his st u d y, as well as scie ntific 
disc o ve ries or c ha n ges i n sta n dar d care will be ta ke n i nt o acc o u nt i n a n y 
decisi o n t o ter mi nate t he st u d y.  
1 6. 3 
A nal ysis Pla n:  T he a nal ysis f or t his trial will c o m me n ce at pla n ne d ti me  p oi nts 
(see Secti o n 1 6. 2 3) a n d at t he ti me t he patie nts ha ve bec o me e val ua ble f or t he 
pri mar y e n d p oi nt.  S uc h a decisi o n will be ma de b y t he Statisticia n a n d St u d y 
C hair, i n acc or da nce wit h Ma y o Cli nic Ca ncer Ce nter ( M C C C) Sta n dar d 
O perati n g Pr oce d ures, a vaila bilit y of data f or sec o n dar y e n d p oi nts (e. g., 
la b orat or y c orrelates), a n d t he le vel of data mat urit y. 
1 6. 3 1  Pri mar y E n d p oi nt  

5 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 6. 3 1 1 Defi niti o n:  T he pri mar y e n d p oi nt of t his trial is t he cli nical 
be nefit rate as defi ne d i n Secti o n 1 6. 1 1. 
1 6. 3 1 2  Esti mati o n:  T he pr o p orti o n of cli nical be nefit rate  will be 
esti mate d b y t he n u m be r of  patie nts wit h cli nical be nefit 
(c o nfir me d C R, c o nfir me d P R, or S D f or 4 or m ore c ycles) 
di vi de d b y t he t otal n u m ber of e val ua ble patie nts.  A c o nfi de nce 
i nter val f or t he tr ue cli nical be nefit rate  will be calc ulate d usi n g 
t he a p pr oac h of D uff y a n d Sa nt ner   
1 6. 3 1 3 O ver Accr ual:  If m ore t ha n t he tar get n u m ber of patie nts are 
accr ue d, t he a d diti o nal patie nts will n ot be use d t o e val uate t he 
st o p pi n g r ule or use d i n a n y decisi o n ma ki n g pr ocesses; 
h o we ver, t he y will be i ncl u de d i n fi nal p oi nt esti mates a n d 
c o nfi de nce i nter vals. 
1 6. 3 2 
Defi niti o ns a n d A nal yses of Sec o n dar y E n d p oi nts  
1 6. 3 2 1  Pr o gressi o n- free s ur vi val ti me is defi ne d as t he ti me fr o m 
re gistrati o n t o t he earliest date of d oc u me ntati o n of disease 
pr o gressi o n.  If a patie nt dies wit h o ut a d oc u me n tati o n of disease 
pr o gressi o n t he patie nt will be c o nsi dere d t o ha ve ha d disease 
pr o gressi o n at t he ti me of t heir deat h .  I n t he case of a patie nt 
starti n g treat me nt a n d t he n ne ver ret ur ni n g f or a n y e val uati o ns, 
t he patie nt will be ce ns ore d f or pr o gressi o n 1 da y p ost-
re gistrati o n.  T he distri b uti o n of pr o gressi o n-free s ur vi val ti me 
will be esti mate d usi n g t he met h o d of Ka pla n- Meier ( 1 9 5 8). 
1 6. 3 2 2 S ur vi val ti me is defi ne d as t he ti me fr o m re gistrati o n t o deat h 
d ue t o a n y ca use.  T he distri b uti o n of s ur vi val ti me will be 
esti mate d usi n g t he met h o d of Ka pla n - Meier ( 1 9 5 8). 
1 6. 3 2 3 C A 1 9 - 9 res p o nse is defi ne d t o be a ≥5 0 % re d ucti o n fr o m 
baseli ne.  T he C A 1 9 -9 res p o nse rate will be esti mate d b y t he 
n u m ber of C A 1 9- 9 res p o nses di vi de d b y t he t otal n u m ber of 
e val ua ble patie nts.  A c o nfi de nce i nter val will be calc ulate d 
base d o n t he bi n o mial distri b uti o n. 
1 6. 3 2 4 A d verse E ve nts: All eli gi ble patie nts t hat ha ve i nitiate d treat me nt 
will be c o nsi dere d e val ua ble f or assessi n g a d verse e ve nt rate(s).  
T he ma xi m u m gra de f or ea c h t y pe of a d verse e ve nt will be 
rec or de d f or eac h patie nt, a n d fre q ue nc y ta bles will be re vie we d 
t o deter mi ne patter ns.  A d diti o nall y, t he relati o ns hi p of t he 
a d verse e ve nt(s) t o t he st u d y treat me nt will be ta ke n i nt o 
c o nsi derati o n. 
1 6. 3 3 
Tra nslati o nal A n al yses 
Rate of F G F R f usi o ns a n d ct D N A m utati o ns will be descri be d, a n d ass ociati o n 
wit h c o nfir me d t u m or res p o nse a n d/ or cli nical be nefit will be i n vesti gate d usi n g 
a Fis her’s e xact test.  Gi ve n t he s mall sa m ple size, all tra nslati o nal a nal yses are 

5 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
c o nsi dere d e x pl orat or y a n d n o a dj ust me nt f or m ulti plicit y will be e m pl o ye d.  
O ne -si de d p- val ues ≤0. 1 0 are c o nsi dere d statisticall y si g nifica nt t hr o u g h o ut. 
 
  
  
1 6. 3 4 A nal ysis of Patie nt - Re p orte d O utc o mes ( Q ualit y of Life a n d S y m pt o ms) 
 
Patie nt -re p orte d o utc o mes ( q ualit y of life a n d s y m pt o ms) will be assesse d pri or 
t o re vie w of treat me nt res p o nse a n d disc ussi o ns of patie nt’s ge neral healt h si nce 
last treat me nt e val uati o n.  Patie nt -re p orte d o utc o mes will i ncl u de t he E O R T C 
Q L Q - C 3 0, a 3 0-ite m patie nt-re p orte d q uesti o n naire a b o ut patie nt a bilit y t o 
f u ncti o n, s y m pt o ms relate d t o t he ca ncer a n d its treat me nt, o verall healt h a n d 
q ualit y of life, a n d percei ve d fi na ncial i m pact of t he ca ncer a n d its treat me nt.  2 8 
of t he 3 0 ite ms are meas ure d o n a 1 -4 scale ( 1 = n ot at all; 4 = ver y m uc h) wit h t he 
re mai ni n g t w o ite ms ( o verall healt h a n d o verall q ualit y of life) sc ore d o n a 1- 7 
n u meric a nal o g ue scale ( 1 = ver y p o or; 7 =e xcelle nt).  T he recall peri o d f or t he 
E O R T C Q L Q - C 3 0 is o ne wee k.  T he E O R T C Q L Q- C 3 0 is t he pr o d uct of m ore 
t ha n a decade of c olla b orati ve researc h a n d t o date, m ore t ha n 2 2 0 0 st u dies usi n g 
t he E O R T C Q L Q- C 3 0 ha ve bee n re gistere d wit h t he E O R T C ( Fa yers et al, 2 0 0 1 
[ E O R T C Sc ori n g Ma n ual]).  I n a d diti o n, patie nts will c o m plete t he ne wl y 
de vel o pe d E O R T C Q L Q- BI L 2 1.  T his E O R T C m o d ule assesse d q ualit y of life 
d o mai ns s pecific t o biliar y ca ncers usi n g 2 1 ite ms o n t he sa me 1 -4 scale as t he 
c ore q uesti o n naire.  T his q uesti o n naire is i n t he pr ocess of bei n g vali date d ( data 
f or m t his st u d y ma y be use d t o pr o vi de vali dati o n i nf or mati o n).  S ki n a n d b o wel 
s y m pt o ms will be assesse d usi n g t he S ki n de x- 1 6 a n d B o wel F u ncti o n 
Q uesti o n naire ( B F Q).  T he S ki n de x - 1 6 c o ntai ns 1 6 q uesti o ns eac h o n a 0- 1 0 
scale ( 0 = ne ver b ot here d, 1 0 =al wa ys b ot here d) assessi n g s ki ns pr o ble ms a n d has 
pre vi o usl y bee n vali date d ( C hre n et al, 2 0 0 1) .  T he B F Q, de vel o pe d a n d create d 
b y Ma y o Cli nic p h ysicia ns, i de ntifies patie nt -re p orte d pr o ble ms wit h vari o us 
as pects of b o wel f u ncti o n ( yes or n o res p o nse) t o hel p e val uate h o w b o wel 
d ysf u ncti o n affects n or mal acti vities a n d  q ua lit y of life ( Q O L). C o nte nt vali dit y 
of t his i nstr u me nt has bee n pre vi o usl y re p orte d ( At hert o n et al, 2 0 1 3).  We will 
use t he U niscale assess me nt of o verall q ualit y of life  ( Sl oa n, O’ Fall o n et al, 
1 9 9 8) o n a scale of 0- 1 0 ( 0 =as ba d as it ca n be, 1 0 =as g o o d as it ca n be) .  T his 
si n gle ite m is o ne of t he m ost wi del y use d q ualit y of life meas ures a n d has bee n 
s h o w n t o be pr o g n ostic f or s ur vi val a b o ve a n d be y o n d perf or ma nce stat us a n d 
ot her c o m m o n pr o g n ostic fact ors i n a ra n ge of ca ncer t y pes.  T he Was It W ort h  It 
( WI WI) q uesti o n naire is mi ni malist a n d efficie nt, as ki n g o nl y fi ve ke y q uesti o ns 
wit h tric h ot o m o us res p o nses a b o ut t he patie nt’s satisfacti o n wit h t he st u d y a n d 
li keli h o o d of rec o m me n di n g it t o ot her patie nts.   T his t o ol has bee n pil ot teste d 
i n a rece nt cli nical trial l o o ki n g at t he Q O L of patie nts partici pati n g i n p hase I 
cli nical trials at Ma y o Cli nic R oc hester a n d has de m o nstrate d t o be eas y t o 
c o m plete, u n dersta n da ble, a n d i m p orta nt t o patie nts.  It has als o bee n  use d t o 
assess patie nt satisfacti o n as a c o m pa ni o n pr ot oc ol ( N 0 3 9 2) t o N ort h Ce ntral 
Ca ncer Treat me nt Gr o u p ca ncer treat me nt p hase II a n d III cli nical trials.  
 
A pa per b o o klet  c o ntai ni n g all t he patie nt -re p orte d o utc o mes will be 
a d mi nistere d i n cli nic at baseli ne a n d e ver y c ycle, a n d eac h P R O will be sc ore d 
acc or di n g t o t he p u blis he d sc ori n g al g orit h m.  Scale sc ore traject ories o ver ti me 
will be e xa mi ne d usi n g strea m pl ots a n d mea n pl ots wit h sta n dar d de viati o n err or 
bars o verall.  C ha n ges fr o m baseli ne at eac h c ycle will be statisticall y teste d 
usi n g paire d t -tests, a n d sta n dar dize d res p o nse mea ns ( mea n of t he c ha n ge fr o m 

5 7                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
baseli ne sc ores at a gi ve n c ycle, di vi de d b y t he sta n dar d de viati o n of t he c ha n ge 
sc ores) will be i nter prete d (after a p pl yi n g Mi d del’s ( 2 0 0 2) a dj ust me nt) usi n g 
C o he n’s ( 1 9 8 8) c ut - offs:  < 0. 2 0 = tri vial; 0. 2 0- < 0. 5 0 = s mall; 0. 5 0- < 0. 8 0 = 
m o derate; a n d > =/ 0. 8 0  = lar ge.  C orrelati o n bet wee n o utc o mes will e m pl o y 
Pears o n a n d/ or S pear ma n c orrelati o ns at i n di vi d ual ti me p oi nts .   
 
1 6. 4 
Data & Safet y M o nit ori n g  
 
1 6. 4 1  T he pri nci pal i n vesti gat or(s) a n d t he st u d y statisticia n will re vie w t he 
st u d y at least t wice a year t o i de ntif y accr ual, a d verse e ve nt, a n d a n y 
e n d p oi nt pr o ble ms t hat mi g ht be de vel o pi n g.  T he Ma y o Cli nic Ca ncer 
Ce nter ( M C C C) Data Safet y M o nit ori n g B oar d ( D S M B) is res p o nsi ble 
f or re vie wi n g accr ual a n d safet y data f or t his trial at least t wice a year, 
base d o n re p orts pr o vi de d b y t he M C C C Statistical Office.  
 
1 6. 4 2  A d verse E ve nt 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 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 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 satisf y t he f oll o wi n g:  
 
•  
if 4 or m ore patie nts i n t he first 2 0 treate d patients ( or 2 0 % after 2 0 
patie nts ha ve bee n accr ue d) e x perie nce a Gra de 4 or hi g her n o n -
he mat ol o gic a d verse e ve nt.    
 
We n ote t hat we will re vie w Gra de 4 a n d 5 a d verse e ve nts dee me d 
“ u nrelate d” or “ u nli kel y t o be relate d”, t o verif y t heir attri b uti o n a n d t o 
m o n it or t he e mer ge nce of a pre vi o usl y u nrec o g nize d treat me nt-relate d 
a d verse e ve nt. 

5 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 6. 5 
Res ults R e p orti n g o n Cli nical Trials. g o v:  At st u d y acti vati o n, t his st u d y will ha ve 
bee n re gistere d wit hi n t he “ Cli ncial Trails. g o v” we bsite.  T he Pri mar y a n d 
Sec o n dar y E n d p oi nts (ie, “ O utc o me Meas ures”) al o n g wit h ot her re q uire d 
i nf or mati o n f or t his st u d y will be re p orte d o n Cli nical Trials. g o v.  F or p ur p oses of 
ti mi n g of t he Res ults Re p orti n g, t he i nitial esti mate d c o m pleti o n date f or t he 
Pri mar y E n d p oi nt of t his st u d y is 2 2 m o nt hs after t he st u d y o pe ns t o accr ual.  T he 
defi niti o n of “ Pri mar y E n d p oi nt C o m pleti o n Date” ( P E C D) f or t his st u d y is t he 
ti me t hat e ver y patie nt has eit her c o m plete d 4 c ycles of treat me nt  or e n de d acti ve 
treat me nt ( w hic he ver occ urs first). 
1 6. 6 
I nclusi o n of W o me n a n d Mi n orities 
1 6. 6 1 
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. 
1 6. 6 2 
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 treat me nt re gi me n i n s u bsets d efi 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.  T heref ore, 
alt h o u g h t he pla n ne d a nal ysis will, as al wa ys, l o o k f or differe nces i n 
treat me nt effect base d o n racial a n d ge n der gr o u pi n gs, t he sa m ple size is 
n ot i ncrease d i n or der t o pr o vi de a d diti o nal p o wer f or s u bset a nal yses. 
1 6. 6 3 
Base d o n pri or M C C C st u dies i n v ol vi n g si milar disease sites, we e x pect 
a b o ut 4 % of patie nts will be classifie d as mi n orities b y race a n d 5 0 % of 
patie nts will be w o me n.  E x pecte d s izes 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  
F e 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  
1 4  
1 4  
2 8  
Et h nic C ate g or y: T ot al of all s u bjects  
1 5  
1 5  
3 0  
R aci al C ate g or y  
A merica n I n dia n or Alas ka n Nati ve  
0  
0  
0  
Asia n  
0  
0  
0  
Blac k or Africa n A merica n  
1  
1  
2  
Nati ve Ha waiia n or ot her Pacific Isla n der  
0  
0  
0  
W hite  
1 4  
1 4  
2 8  
R aci al C ate g or y: T ot al of all s u bjects  
1 5  
1 5  
3 0  
 
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  

5 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
R aci al 
C ate g ories: 
A meric a n I n di a n o r 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 affilia ti 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.  
 
 
 
 
 
 

6 0                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
1 7. 0   
P at h ol o g y C o nsi der ati o ns/ Tiss ue Bi os peci me ns  
  
1 7. 1  
S u m m ar y T a ble of Rese arc h Tiss ue S peci me ns t o be C ollecte d f or t his Pr ot oc ol  
 
 
C orrel ati ve St u d y 
( Secti o n f or m ore 
i nf or m ati o n) 
M a n d at or y or 
O pti o n al  
T y pe of 
Tiss ue t o 
C ollect  
Bl oc k, 
Sli des, C ore, 
etc. ( # of 
e ach t o 
s u b mit) 
B aseli ne   
J ust 
pri or t o 
C ycle 2, 
D a y 1 1  
At 
P r o gress
i o n1 
P r ocess 
at site ? 
( Yes or 
N o)  
Te m per at ure  
 C o n diti o ns 
f or St or a ge 
/ S hi p pi n g  
 
W h ole E x o me 
Se q ue nci n g ( W E S); 
W h ole Met h yl o me 
Pr ofili n g ( R R B S)  
O pti o nal 
Fres h or 
Fr oze n   
 3- 6 c ores 
X 
 
 
X 
X 
N o  
 Freeze.  
 
 
I H C bi o mar kers 
O pti o nal 
F or mali n 
Fi xe d 
Paraffi n 
E m be d de d 
or fres h  
1 0 of sli des 
X 
 
 
X 
X 
N o  
A m bie nt,  
1. o nl y if arc hi val s peci me n was a vaila ble

6 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
C R F  
Acti ve -M o nit ori n g P h ase  
( C o m plia nce wit h T est Sc he d ule Secti o n 4. 0) 
 
At eac h e val uati o n d uri n g treat me nt  
R E CI S T Meas ure me nt
 
X  
C o nc o mita nt Me dicati o n  
X  
Ot her La b orat or y  
X (see Secti o n 4. 0)  
He mat ol o g y La b orat or y  
X (see Secti o n 4. 0)  
C he mistr y La b orat or y  
X (see Secti o n 4. 0)  
R esearc h Tiss ue S u b missi o n  
X (see Secti o n 1 7 . 0) 
Researc h Bl o o d S u b missi o n  
X (see Secti o n 1 4. 0)  
Patie nt Q uesti o n naire B o o klet  
X 2 
B o o klet C o m plia nce  
X 3 
E n d of Acti ve Treat me nt/ Ca ncel N otificati o n  
X  
N otificati o n F or m –  Gra de 4 or 5 N o n -A E R 
Re p orta ble E ve nts/ H os pitalizati o n  
At eac h occ urre nce (see Secti o n 1 0. 0)  
A D R/ A E R  
At eac h occ urre nce (see Secti o n 1 0. 0)  
1.  C o m plete at eac h e val uati o n d uri n g Acti ve Treat me nt (see Secti o n 4. 0).  
2. Patie nt q uesti o n naire b o o klet m ust  be use d; c o pies are n ot acce pta ble f or t his s u b missi o n.  T o be 
c o m plete d pri or t o treat me nt e ver y c ycle .   
3. T his f or m m ust be c o m plete d o nl y if t he patie nt q uesti o n naire b o o klet c o ntai ns a bs ol utel y N O 
patie nt pr o vi de d assess me nt i nf or mati o n.  
 
F oll o w -u p M ateri al(s)   
C R F  
E ve nt M o nit ori n g P h ase 1 
 
 
q. _ 6 _ 
m o nt hs 
u ntil P D  
 
 
 
At P D  
After 
P D q. 
_ _ 6 _ _ 
m os.  
 
 
 
Deat h  
 
 
 
Ne w Pri mar y  
E ve nt M o nit ori n g  
X 2 
X 2  
X  
X  
At eac h occ urre nce  
1.  If a patie nt is still ali ve 2 years after re gistrati o n, n o f urt her f oll o w- u p is re q uire d. 
2.  S u b mit c o p y of d oc u me ntati o n of res p o nse or pr o gressi o n t o t he M C C C  O perati o ns 
Office,  Atte nti o n: 
. 
 
1 9. 0  
B u d get  
 
  
1 9. 1 
C osts c har ge d t o patie nt:  r o uti ne cli nical care  
 
  
1 9. 2 
T ests t o be researc h f u n de d:  a m ylase a n d li pase bl o o d tests, Electr ocar di o gra ms,  
E C H Os, O pti o nal C yc le 2, Da y 1 tiss ue bi o ps y a n d st u d y dr u g, p o nati ni b. 
 
  
1 9. 3 
Ot her b u d get c o ncer ns:  n o ne 
 
2 0. 0 
Ref ere nce s 

6 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1.  
S hi n H R, Lee C U, Par k HJ, Se ol S Y, C h u n g J M, C h oi H C, A h n Y O, S hi ge mast u T. 
He patitis B a n d C vir us, Cl o n orc his si ne nsis f or t he ris k of li ver ca ncer: a case -c o ntr ol 
st u d y i n P usa n, K orea. I nter nati o nal j o ur nal of e pi de mi ol o g y 1 9 9 6; 2 5: 9 3 3- 4 0. 
2.  
Wata na pa P. C h ola n gi ocarci n o ma i n patie nts wit h o pist h orc hiasis. T he Britis h j o ur nal of 
s ur ger y 1 9 9 6; 8 3: 1 0 6 2- 6 4. 
3. 
Wata na pa P, Wata na pa W B. Li ver fl u ke -ass oc iate d c h ola n gi ocarci n o ma. T he Britis h 
j o ur nal of s ur ger y 2 0 0 2; 8 9: 9 6 2- 7 0. 
4.  
Ber g q uist A, E k b o m A, Olss o n R, K or nfel dt D, L o of L, Da nielss o n A, H ultcra ntz R, 
Li n d gre n S, Pr ytz H, Sa n d ber g- Gertze n H, Al mer S, Gra nat h F, Br o o me U. He patic a n d 
e xtra he patic mal i g na ncies i n pri mar y scler osi n g c h ola n gitis. J o ur nal of he pat ol o g y 
2 0 0 2; 3 6: 3 2 1- 7. 
5.  
Ber g q uist A, Gla u ma n n H, Perss o n B, Br o o me U. Ris k fact ors a n d cli nical prese ntati o n 
of he pat o biliar y carci n o ma i n patie nts wit h pri mar y scler osi n g c h ola n gitis: a case -c o ntr ol 
st u d y. He pat ol o g y 1 9 9 8; 2 7: 3 1 1- 6. 
6.  
B ura k K, A n g ul o P, Pas ha T M, E ga n K, Petz J, Li n d or K D. I nci de nce a n d ris k fact ors f or 
c h ola n gi ocarci n o ma i n pri mar y scler osi n g c h ola n gitis. T he A merica n j o ur nal of 
gastr oe nter ol o g y 2 0 0 4; 9 9: 5 2 3- 6. 
7. 
Claesse n M M, Vl e g gaar F P, T yt gat K M, Sierse ma P D, va n B u ure n H R. Hi g h lifeti me 
ris k of ca ncer i n pri mar y scler osi n g c h ola n gitis. J o ur nal of he pat ol o g y 2 0 0 9; 5 0: 1 5 8- 6 4. 
8.  
Visser B C, S u h I, Wa y L W, Ka n g S M. C o n ge nital c h ole d oc hal c ysts i n a d ults. Arc hi ves 
of s ur ger y 2 0 0 4; 1 3 9: 8 5 5 - 6 0; disc ussi o n 8 6 0- 2. 
9.  
Hsi n g A W, Z ha n g M, Ras hi d A, Mc Gl y n n K A, Wa n g B S, Ni wa S, Ortiz- C o n de B A, 
G oe dert JJ, Fra u me ni J F, Jr., O' Brie n T R, Ga o Y T. He patitis B a n d C vir us i nfecti o n a n d 
t he ris k of biliar y tract ca ncer: a p o p ulati o n- base d st u d y i n C hi na. I nter nati o nal j o ur nal of 
ca ncer. J o ur nal i nter nati o nal d u ca ncer 2 0 0 8; 1 2 2: 1 8 4 9- 5 3. 
1 0.  
K o ba yas hi M, I ke da K, Sait o h S, S uz u ki F, Ts u b ota A, S uz u ki Y, Arase Y, M uras hi ma 
N, C ha ya ma K, K u ma da H. I nci de nce of pri mar y c h ola n gi ocell ular carci n o ma of t he li ver 
i n ja pa nese patie nts wit h he patitis C vir us-relate d cirr h osis. Ca ncer 2 0 0 0; 8 8: 2 4 7 1- 7. 
1 1.  
Li u X F, Z o u S Q, Qi u F Z. Pat h o ge nesis of c h ola n gi ocarci n o ma i n t he p orta he patis a n d 
i nfecti o n of he patitis vir us. He pat o biliar y & pa ncreatic diseases i nter nati onal : H B P D 
I N T 2 0 0 3; 2: 2 8 5- 9. 
1 2.  
S hai b Y H, El- Sera g H B, Da vila J A, M or ga n R, Mc Gl y n n K A. Ris k fact ors of 
i ntra he patic c h ola n gi ocarci n o ma i n t he U nite d States: a case-c o ntr ol st u d y. 
Gastr oe nter ol o g y 2 0 0 5; 1 2 8: 6 2 0- 6. 
1 3.  
Welzel T M, Gra u bar d BI, El- Sera g H B, S hai b Y H, Hsi n g A W, Da vila J A, Mc Gl y n n K A. 
Ris k fact ors f or i ntra he patic a n d e xtra he patic c h ola n gi ocarci n o ma i n t he U nite d States: a 
p o p ulati o n- base d case -c o ntr ol st u d y. Cli nical gastr oe nter ol o g y a n d he pat ol o g y : t he 
official cli nical practice j o ur nal of t h e A merica n Gastr oe nter ol o gical Ass ociati o n 
2 0 0 7; 5: 1 2 2 1- 8. 
1 4.  
Ya ma m ot o S, K u b o S, Hai S, Ue nis hi T, Ya ma m ot o T, S h ut o T, Ta ke m ura S, T a na ka H, 
Ya ma za ki O, Hir o has hi K, T a na ka T. He patitis C vir us i nfecti o n as a li kel y eti ol o g y of 
i ntra he patic c h ola n gi ocarci n o ma. Ca ncer scie nce 2 0 0 4; 9 5: 5 9 2- 5. 
1 5.  
D o nat o F, Gelatti U, T a g ger A, Fa vret M, Ri ber o M L, Callea F, Martelli C, Sa vi o A, 
Tre visi P, Nar di G. I ntra he patic c h ola n gi ocarci n o ma a n d he patitis C a n d B vir us 
i nfecti o n, alc o h ol i nta ke, a n d he pat olit hiasis: a case-c o ntr ol st u d y i n Ital y. Ca ncer ca uses 
& c o ntr ol : C C C 2 0 0 1; 1 2: 9 5 9- 6 4. 
1 6.  
Lee C C, W u C Y, C he n G H. W hat is t he i m pact of c oe xiste nce of he pat olit hiasis o n 
c h ola n gi ocarci n o ma? J o ur nal of gastr oe nter ol o g y a n d he pat ol o g y 2 0 0 2; 1 7: 1 0 1 5- 2 0. 
1 7. 
Bec ker N, Lie be r ma n n D, Wesc h H, Va n Kaic k G. M ortalit y a m o n g T h or otrast-e x p ose d 
patie nts a n d a n u ne x p ose d c o m paris o n gr o u p i n t he Ger ma n T h or otrast st u d y. E ur o pea n 
j o ur nal of ca ncer 2 0 0 8; 4 4: 1 2 5 9- 6 8. 

6 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
1 8.  
Tra vis L B, Ha u pt ma n n M, Ga ul L K, St or m H H, G ol d ma n M B, N y ber g U, Be r ger E, 
Ja n o wer M L, Hall P, M o ns o n R R, H ol m L E, La n d C E, Sc h otte nfel d D, B oice J D, Jr., 
A n derss o n M. Site- s pecific ca ncer i nci de nce a n d m ortalit y after cere bral a n gi o gra p h y 
wit h ra di oacti ve t h or otrast. Ra diati o n researc h 2 0 0 3; 1 6 0: 6 9 1 - 7 0 6. 
1 9.  
Ra n di G, Fra n cesc hi S, La Vecc hia C. Gall bla d der ca ncer w orl d wi de: ge o gra p hical 
distri b uti o n a n d ris k fact ors. I nter nati o nal j o ur nal of ca ncer. J o ur nal i nter nati o nal d u 
ca ncer 2 0 0 6; 1 1 8: 1 5 9 1- 6 0 2. 
2 0. 
Bertra n E, Heise K, A n dia M E, Ferrecci o C. Gall bla d der ca ncer: i nci de n ce a n d s ur vi val 
i n a hi g h-ris k area of C hile. I nter nati o nal j o ur nal of ca ncer. J o ur nal i nter nati o nal d u 
ca ncer 2 0 1 0; 1 2 7: 2 4 4 6- 5 4. 
2 1.  
K ha n S A, T h o mas H C, Da vi ds o n B R, Ta yl or- R o bi ns o n S D. C h ola n gi ocarci n o ma. La ncet 
2 0 0 5; 3 6 6: 1 3 0 3- 1 4. 
2 2. 
Valle J, Wasa n H, Pal mer D H, C u n ni n g ha m D, A nt h o ne y A, Mara ve yas A, Ma d h us u da n 
S, I ves o n T, H u g hes S, Pereira S P, R o u g ht o n M, Bri d ge water J. Cis plati n pl us 
ge mcita bi ne vers us ge mcita bi ne f or biliar y tract ca ncer. T he Ne w E n gla n d j o ur nal of 
me dici ne 2 0 1 0; 3 6 2: 1 2 7 3- 8 1. 
2 3. 
T ur ner  N, Gr ose R. Fi br o blast gr o wt h fact or si g nalli n g: fr o m de vel o p me nt t o ca ncer. 
Nat ure re vie ws. Ca ncer 2 0 1 0; 1 0: 1 1 6- 2 9. 
2 4.  
Willia ms S V, H urst C D, K n o wles M A. O nc o ge nic F G F R 3 ge ne f usi o ns i n bla d der 
ca ncer. H u ma n m olec ular ge netics 2 0 1 2; 2 2: 7 9 5- 8 0 3. 
2 5. 
Mae da T, Ya gasa ki F, Is hi ka wa M, T a ka has hi N, Bess h o M. Tra nsf or mi n g pr o pert y of 
T E L -F G F R 3 me diate d t hr o u g h PI 3 - K i n a T-cell l y m p h o ma t hat s u bse q ue ntl y pr o gresse d 
t o A M L. Bl o o d 2 0 0 5; 1 0 5: 2 1 1 5- 2 3. 
2 6.  
Re n M, Qi n H, Re n R, Ti d well J, C o well J K. Src acti vati o n pla ys a n i m p orta nt ke y r ole i n 
l y m p h o ma ge nesis i n d uce d b y F G F R 1 f usi o n ki nases. Ca ncer researc h 2 0 1 1; 7 1: 7 3 1 2- 2 2. 
2 7.  
Re n M, Qi n H, Re n R, C o well J K. P o nati ni b s u p presses t he de vel o p me nt of m yel oi d a n d 
l y m p h oi d mali g na ncies ass ociate d wit h F G F R 1 a b n or malities. Le u ke mia : official j o ur nal 
of t he Le u ke mia S ociet y of A merica, Le u ke mia Researc h F u n d, U. K 2 0 1 2.  
2 8.  
Ric hel da R, R o nc hetti D, Bal di ni L, Cr o L, Vi g gia n o L, Marzella R, R occ hi M, Ots u ki T, 
L o m bar di L, Mai ol o A T, Neri A. A n o vel c hr o m os o mal tra nsl ocati o n t( 4; 1 4)( p 1 6. 3; q 3 2) 
i n m ulti ple m yel o ma i n v ol ves t he fi br o blast gr o wt h-fact or rece pt or 3 ge ne. Bl o o d 
1 9 9 7; 9 0: 4 0 6 2- 7 0. 
2 9.  
Cr oss N C, Reiter A. Fi br o blast gr o wt h fact or rece pt or a n d platelet- deri ve d gr o wt h fact or 
rece pt or a b n or malities i n e osi n o p hilic m yel o proliferati ve dis or ders. Acta hae mat ol o gica 
2 0 0 8; 1 1 9: 1 9 9- 2 0 6. 
3 0.  
Si n g h D, C ha n J M, Z o p p oli P, Ni ola F, S ulli va n R, Casta n o A, Li u E M, Reic hel J, P orrati 
P, Pelle gatta S, Qi u K, Ga o Z, Ceccarelli M, Riccar di R, Brat DJ, G u ha A, Al da pe K, 
G olfi n os J G, Za gza g D, Mi k kelse n T, Fi n occ hiar o G, Las orella A, Ra ba da n R, Ia var o ne 
A. Tra nsf or mi n g f usi o ns of F G F R a n d T A C C ge nes i n h u ma n gli o blast o ma. Scie nce 
2 0 1 2; 3 3 7: 1 2 3 1- 5. 
3 1. 
C hase A, Gra n d F H, Cr oss N C. Acti vit y of T KI 2 5 8 a gai nst pri mar y cells a n d cell li nes 
wit h F G F R 1 f usi o n ge nes ass ociate d wit h t he 8 p 1 1 m yel o pr oliferati ve s y n dr o me. Bl o o d 
2 0 0 7; 1 1 0: 3 7 2 9- 3 4. 
3 2.  
G ua g na n o V, Ka uff ma n n A, W o hrle S, Sta m m C, It o M, Bar ys L, P or n o n A, Ya o Y, Li 
F, Z ha n g Y, C he n Z, Wils o n CJ, B or das V, Le D o u get M, Gait her L A, B ora ws ki J, 
M o na ha n J E, Ve n katesa n K, Br u m me n d orf T, T h o mas D M, Garcia -Ec he verria C, 
H of ma n n F, Sellers W R, Gra us- P orta D. F G F R Ge netic Alterati o ns Pre dict f or 
Se nsiti vit y t o N V P -B GJ 3 9 8, a Selecti ve Pa n - F G F R I n hi bit or. Ca ncer disc o ver y 
2 0 1 2; 2: 1 1 1 8- 1 1 3 3. 
3 3. 
G oz git J M,  W o n g MJ, M ora n L, War d well S, M o he m ma d Q K, Narasi m ha n NI, 
S ha kes peare W C, Wa n g F, Clac ks o n T, Ri vera V M. P o nati ni b ( A P 2 4 5 3 4), a 

6 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
m ultitar gete d pa n -F G F R i n hi bit or wit h acti vit y i n m ulti ple F G F R -a m plifie d or m utate d 
ca ncer m o dels. M olec ular ca ncer t hera pe uti cs 2 0 1 2; 1 1: 6 9 0- 9. 
3 4. 
A ma n o R, Ya ma da N, D oi Y, Yas hir o M, O hira M, Mi wa A, Hira ka wa K. Si g nifica nce 
of kerati n oc yte gr o wt h fact or rece pt or i n t he pr oliferati o n of biliar y tract ca ncer. 
A ntica ncer researc h 2 0 1 0; 3 0: 4 1 1 5- 2 1. 
3 5.  
Wa n g P, D o n g Q, Z ha n g C, K ua n P F, Li u Y, J ec k W R, A n derse n J B, Jia n g W, Sa vic h 
G L, T a n T X, A u ma n J T, H os ki ns J M, Mis her A D, M oser C D, Y o urst o ne S M, Ki m J W, 
Ci b uls kis K, Getz G, H u nt H V, T h or geirss o n S S, R o berts L R, Ye D, G ua n K L, Xi o n g Y, 
Qi n L X, C hia n g D Y. M utati o ns i n is ocitrate de h y dr o ge nase 1 a n d 2 occ ur fre q ue ntl y i n 
i ntra he patic c h ola n gi ocarci n o mas a n d s hare h y per met h ylati o n tar gets wit h gli o blast o mas. 
O nc o ge ne 2 0 1 2. 
3 6. 
Peti ot A, C o nti FJ, Gr ose R, Re vest J M, H o di vala -Dil ke K M, Dic ks o n C. A cr ucial r ole 
f or F gfr 2-III b si g nalli n g i n e pi der mal de vel o p me nt a n d hair f ollicle patter ni n g. 
De vel o p me nt 2 0 0 3; 1 3 0: 5 4 9 3- 5 0 1. 
3 7.  
Utis pa n K, T h u wajit P, A bi k o Y, C har n g kae w K, Pa u pair oj A, C ha u-i n S, T h u wajit C. 
Ge ne e x pressi o n pr ofili n g of c h ola n gi ocarci n o ma- deri ve d fi br o blast re veals alterati o ns 
relate d t o t u m or pr o gressi o n a n d i n dicates peri osti n as a p o or pr o g n ostic mar ker. 
M olec ular ca ncer 2 0 1 0; 9: 1 3.  
3 8. 
Sirica A E. T he r ole of ca ncer -ass ociate d m y ofi br o blasts i n i ntra he patic 
c h ola n gi ocarci n o ma. Nat ure re vie ws. Gastr oe nter ol o g y & he pat ol o g y 2 0 1 2; 9: 4 4- 5 4. 
3 9.  
Fe n g S, Wa n g F, Mats u bara A, Ka n M, Mc Kee ha n W L. Fi br o blast gr o wt h fact or rece pt or 
2 li mits a n d rece pt or 1 accelerates t u m ori ge nicit y of pr ostate e pit helial cells. Ca ncer 
researc h 1 9 9 7; 5 7: 5 3 6 9- 7 8. 
4 0.  
Ric ol D, Ca p pelle n D, El Marj o u A, Gil- Diez - de-Me di na S, Gira ult J M, Y os hi da T, Ferr y 
G, T uc ker G, P o u p o n M F, C h o pi n D, T hier y J P, Ra d va n yi F. T u m o ur s u p pressi ve 
pr o perties of fi br o blast gr o wt h fact or rece pt or 2 -III b i n h u ma n bla d der ca ncer. O nc o ge ne 
1 9 9 9; 1 8: 7 2 3 4- 4 3. 
4 1.  
Eise n ha uer E A, T hera sse P, B o gaert J, Sc h wartz L H, Sar ge nt D, F or d R, Da nce y J, 
Ar b uc k S, G w yt her S, M o o ne y M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pla n R, 
Lac o m be D, Ver weij J.  Ne w res p o nse e val uati o n criteria i n s oli d t u m ors:  re vise d 
R E CI S T g ui deli ne ( versi o n 1. 1).  E ur J C a ncer 4 5( 2):  2 2 8- 2 4 7, 2 0 0 9. 
4 2.  
H orst ma n n E , Mc Ca be M S , Gr oc h o w L , et al. Ris ks a n d be nefits of p hase 1 o nc ol o g y 
trials, 1 9 9 1 t hr o u g h 2 0 0 2. N E n gl J Me d.  2 0 0 5 Mar 3; 3 5 2( 9): 8 9 5 - 9 0 4. 
4 3.  
C hre n M M, Lase k RJ, Sa ha y A P, Sa n ds L P. Meas ure me nt pr o perties of S ki n de x - 1 6: a 
brief q ualit y - of-life meas ure f or patie nts wit h s ki n diseases. J C uta n Me d S ur g. 2 0 0 1 
Mar - A pr; 5( 2): 1 0 5- 1 0. E p u b 2 0 0 1 Mar 2 1. P u b Me d P MI D: 1 1 4 4 3 4 8 1. 
4 4.   
At hert o n PJ, Hal yar d M Y, Sl oa n J A, Miller R C, De mi n g R L, T ai T H, Stie n KJ, 
Marte ns o n J A Jr. Assess me nt of patie nt -re p orte d meas ures of b o wel f u ncti o n bef ore a n d 
after pel vic ra di ot hera p y: a n a ncillar y st u d y of t he N ort h Ce ntral Ca ncer Treat me nt 
Gr o u p st u d y N 0 0 C A. S u p p ort Care Ca ncer. 2 0 1 3 A pr; 2 1( 4): 1 1 9 3- 9. d oi: 
1 0. 1 0 0 7/s 0 0 5 2 0- 0 1 2- 1 6 4 8- 8. E p u b 2 0 1 2 N o v 1 5. P u b Me d P MI D: 2 3 1 5 1 6 4 9 
4 5.    
T h y gese n K, Al pert J S, Jaffe A S,  et al. T hir d U ni versal Defi niti o n of M y ocar dial 
I nfarcti o n. Circ ulati o n. 2 0 1 2; 1 2 6 ( 1 6): 2 0 2 0- 2 0 3 5. 
4 6.  
East o n J D, Sa ver J L, Al bers G W, et al. Defi niti o n a n d e val uati o n of tra nsie nt isc he mic 
attac k: A Scie ntific State me nt f or Healt hcare Pr ofessi o nals Fr o m t he A merica n Heart 
Ass ociati o n/ A merica n Str o ke  
4 7.   
Ass ociati o n Str o ke C o u ncil; C o u ncil o n Car di o vasc ular S ur ger y a n d A nest hesia; C o u ncil 
o n Car di o vasc ular Ra di ol o g y a n d I nter ve nti o n; C o u ncil o n Car di o vasc ular N ursi n g; a n d 
t he I nter discipli nar y C o u ncil o n Peri p heral Vasc ular Disease. Str o ke. 2 0 0 9; 4 0 ( 6): 2 2 7 6-
2 2 9 3. 
 

6 7                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
A p pe n di x I  
E C O G Perf or m a nce St at us Sc ale  
 
S C O R E  
D E S C RI P TI O N  
0  
F ull y  acti ve,  a ble  t o  carr y  o n  all  pre -dis ease  perf or ma nce  wit h o ut 
restricti o n.  
1  
Restricte d i n p h ysicall y s tre n u o us acti vit y b ut a m b ulat or y a n d a ble 
t o  carr y  o ut  w or k  of  a  li g ht  or  se de ntar y  nat ure,  e. g.,  li g ht 
h o use w or k, offi ce w or k.  
2  
A m b ulat or y a n d ca pa ble of all self -care b ut u n a ble t o carr y o ut a n y 
w or k acti vities. U p a n d a b o ut m ore t ha n 5 0 % of w a ki n g h o urs.  
3  
Ca pa ble  of  o nl y  li mite d  self -care,  c o nfi ne d  t o  b e d  or  c h air  m ore 
t ha n 5 0 % of wa ki n g h o urs.  
4  
C o m pletel y  disa ble d.  Ca n n ot  carr y  o n  a n y  self -care.  T otall y 
c o nfi ne d t o be d or c hair.  
5  
Dea d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

6 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
 
Na me _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
Ma y o Cli nic N o _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
St u d y Na me/ N u m ber _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
A p pe n di x II: M E DI C A TI O N DI A R Y  
 
Patie nt I nstr ucti o ns 
 
•  
Please i n dicate o n t he cale n dar bel o w every da y t hat y o u ta ke y o ur st u d y  me dicati o n b y pl aci n g 
t he d ose ta ke n o n t he li ne u n der  t he date.  
•  
If y o u miss a d ose, place a c hec k “0 ” u n der t he date , b ut re me m ber t o ta ke y o ur prescri be d d ose at 
t he ne xt re g ularl y sc he d ule d ti me. 
•  
Bri n g all  b ottles a n d a n y u n us e d st u d y me dicati o n al o n g wit h t his diar y w he n y o u ret ur n f or y o ur 
ne xt a p p oi nt me nt.  
 
Me d icati o n(s) 
D ose  
P o nati ni b  
M G  
  
  
  
 
 
 
 
 
 
Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _                Partici pa nts Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 
 
Area B el o w O nl y T o B e C o m plete d o nl y b y C o or di nat or  
 
N u m ber of pills ret ur ne d _ _ _ _ _     
 
St u d y C o or di nat or I nit ials _ _ _ _ _ _ _ _ 
 
Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Discre pa nc y Yes _ _ _ _ N o _ _ _ _ _  
St u d y Dr u g  
D a y 1  
D a y 2  
D a y 3  
D a y 4  
D a y 5  
D a y 6  
D a y 7  
D ate  
 
 
 
 
 
 
 
P o nati ni b  
 
 
 
 
 
 
 
St u d y Dr u g  
D a y 8  
D a y 9  
D a y 1 0  
D a y 1 1  
D a y 1 2  
D a y 1 3  
D a y 1 4  
D ate  
 
 
 
 
 
 
 
P o nati ni b  
 
 
 
 
 
 
 
St u d y Dr u g  
D a y 1 5  
D a y 1 6  
D a y 1 7  
D a y 1 8  
D a y 1 9  
D a y 2 0  
D a y 2 1  
D ate  
 
 
 
 
 
 
 
P o nati ni b  
 
 
 
 
 
 
 
St u d y Dr u g  
D a y 2 2  
D a y 2 3  
D a y 2 4  
D a y 2 5  
D a y 2 6  
D a y 2 7  
D a y 2 8  
D ate  
 
 
 
 
 
 
 
P o nati ni b  
 
 
 
 
 
 
 

6 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
 
A p pe n di x III – Patie nt I nf or mati o n S heet  
 
T o or der b o o klets please e- mail 
 
 
P A TI E N T I N F O R M A TI O N S H E E T  
P ati e nt C o m plete d Q u alit y of Life B o o klet  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Y o u h a ve bee n gi ve n a b o o klet t o c o m plete f or t his st u d y.  T he b o o klet c o nt ai ns 
s o me q uesti o ns a b o ut y o ur ‘ q u alit y of life’ as a p atie nt recei vi n g tre at me nt f or 
c a ncer.  Y o ur a ns w ers will hel p us t o better u n derst a n d h o w t he tre at me nt y o u are 
recei vi n g is aff ecti n g t he w a y y o u feel.  
 
1.  T his b o o klet c o ntai ns si x sets of q uesti o ns: 
•  E O R T C Q L Q - C 3 0 ( 3 0 q uesti o ns) 
•  E O R T C Q L Q - BI L 2 1 ( 2 1 q uesti o ns) 
•  S ki n de x- 1 6 ( 1 6 q uesti o ns) 
•  B o wel F u ncti o n Q uesti o n naire ( 1 0 q u esti o ns) 
•  U niscale ( 1 q u esti o n) 
•  Was It W ort h It ( WI WI) ( 5 q uesti o ns ) 
 
2.  Directi o ns o n h o w t o c o m plete eac h s et of q uesti o ns are writte n o n t he t o p of e ac h 
set. 
 
3.  Please c o m plete t he b o o klet d uri n g y o ur s c he d ule d cli nical visit a n d ret ur n it t o 
y o ur n urse, p h ysicia n, or researc h c o or di nat or. 
 
T h a n k y o u f or t a ki n g t he ti me t o hel p us.  

7 0                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
A p pe n di x I V 
E O R T C Q L Q - C 3 0 ( Versi o n 3) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
W e are i ntereste d i n s o me t hi n gs a b o ut y o u a n d y o ur healt h. Please a ns wer all of t he q uesti o ns y o urself b y 
circli n g t he n u m ber t hat best a p plies t o y o u. T here are n o "ri g ht" or " wr o n g" a ns wers. T he i nf or mati o n t h at 
y o u pr o vi de will re mai n strictl y c o nfi de ntial.  
 
  
 
N ot at   
A 
Q uite  
Ver y  
  
 
All  
Little  
a Bit  
M uc h  
1.  D o y o u ha ve a n y tr o u ble d oi n g stre n u o us acti vities,  
 
li ke carr yi n g a hea v y s h o p pi n g ba g or a s uitcase? 
1  
2  
3  
4 
 
2.  D o y o u ha ve a n y tr o u ble ta ki n g a l o n g wal k?  
1  
2  
3  
4 
 
3.  D o y o u ha ve a n y tr o u ble ta ki n g a s h ort wal k o utsi de  
 
of t he h o use?  
1  
2  
3  
4 
 
4.  D o y o u nee d t o sta y i n be d or a c hair d uri n g t he da y?  
1  
2  
3  
4 
 
5.  D o y o u nee d hel p wit h eati n g, dressi n g, was hi n g  
 
y o urself or usi n g t he t oilet?  
1  
2  
3  
4 
 
D ur i n g t he p ast w ee k: 
N ot at   
A 
Q uite  
Ver y  
  
 
All  
Little  
a Bit  
M uc h  
6.  W ere y o u li mite d i n d oi n g eit her y o ur w or k or ot her  
 
dail y acti vities?  
1  
2  
3  
4 
 
7.  W ere y o u li mite d i n p urs ui n g y o ur h o b bies or ot her  
 
leis ure ti me acti vities? 
1  
2  
3  
4 
 
8.  W ere y o u s h ort of breat h?  
1  
2  
3  
4 
 
9.  Ha ve y o u ha d pai n?  
1  
2  
3  
4 
 
1 0.  Di d y o u nee d t o rest?  
1  
2  
3  
4 
 
1 1.  Ha ve y o u ha d tr o u ble slee pi n g?  
1  
2  
3  
4 
 
1 2.  Ha ve y o u felt wea k?  
1  
2  
3  
4 
 
1 3.  Ha ve y o u lac ke d a p petite?  
1  
2  
3  
4 
 
1 4.  Ha ve y o u felt na useate d?  
1  
2  
3  
4 
 
1 5.  Ha ve y o u v o mite d?  
1  
2  
3  
4 
 
 
D uri n g t he p ast w ee k:  
N ot at   
A 
Q uite  
Ver y  
  
 
All  
Little  
a Bit  
M uc h  
 
1 6.  Ha ve y o u bee n c o nsti pate d?  
1  
2  
3  
4 
 
1 7.  Ha ve y o u ha d diarr hea?  
1  
2  
3  
4 
 
1 8.  W ere y o u tire d?  
1  
2  
3  
4 

7 1                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
1 9.  Di d pai n i nterfere wit h y o ur dail y acti vities?  
1  
2  
3  
4 
 
2 0.  Ha v e y o u ha d diffic ult y i n c o nce ntrati n g o n t hi n gs,  
 
li ke rea di n g a ne ws pa per or watc hi n g tele visi o n? 
1  
2  
3  
4 
 
2 1.  Di d y o u feel te nse?  
1  
2  
3  
4 
 
2 2.  Di d y o u w orr y?  
1  
2  
3  
4 
 
2 3.  Di d y o u feel irrita ble?  
1  
2  
3  
4 
 
2 4.  Di d y o u feel de presse d?  
1  
2  
3  
4 
 
2 5.  Ha ve y o u ha d diffic ult y re me m beri n g t hi n gs?  
1  
2  
3  
4 
 
2 6.  Has y o ur p h ysical c o n diti o n or me dical treat me nt  
 
i nterfere d wit h y o ur fa mil y life? 
1  
2  
3  
4 
 
2 7.  Has y o ur p h ysical c o n diti o n or me dical treat me nt  
 
i nterfere d wit h y o ur s ocial acti vities?  
1  
2  
3  
4 
 
2 8.  Has y o ur  p h ysical c o n diti o n or me dical treat me nt  
 
ca use d y o u fi na ncial diffic ulti es?  
1  
2  
3  
4 
 
F or t he f oll o wi n g q uesti o ns ple ase circle t he n u m ber bet w ee n 1 a n d 7 t h at best  
a p plies t o y o u.  
 
2 9. H o w w o ul d y o u rate y o ur o verall healt h  d uri n g t he past wee k?  
 
  
1  
2  
3  
4  
5  
6  
7 
 
Ver y p o or   
 
 
 
 
 
E xcelle nt  
 
3 0. H o w w o ul d y o u rate y o ur o verall q ualit y of life  d uri n g t he past wee k?  
 
  
1  
2  
3  
4  
5  
6  
7 
     Ver y p o or   
 
 
 
 
 
E xcelle nt  
 
 
 
 

7 2                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
A p pe n di x V 
E O R T C Q L Q – BI L 2 1  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Patie nts s o meti mes re p ort t hat t he y ha ve t he f oll o wi n g s y m pt o ms or pr o ble ms. Please 
i n dicate t he e xte nt t o w hic h y o u ha ve e x perie nce d t hese s y m pt o ms or pr o ble ms d uri n g t he 
past wee k. Please a ns wer b y circli n g t he n u m ber t hat best a p plies t o y o u. 
 
D u ri n g t he p ast w ee k:  
N ot at   
A 
Q uite  
Ver y  
  
 
All  
Little  
a Bit  
M uc h  
 
3 1.  Ha ve y o u ha d tr o u ble wit h eati n g?  
1  
2  
3  
4 
 
3 2.  Ha ve y o u felt f ull u p t o o q uic kl y after be gi n ni n g t o eat?  
1  
2  
3  
4 
 
3 3.  Ha ve y o u ha d pr o ble ms wit h y o ur se nse of taste?  
1  
2  
3  
4 
 
3 4.  W ere y o u  restricte d i n t he t y p es of f o o d y o u ca n eat as a  
 
res ult of y o ur disease or treat me nt? 
1  
2  
3  
4 
 
3 5.  Ha ve y o ur s ki n or e yes bee n yell o w (j a u n dice d)?  
1  
2  
3  
4 
 
3 6.  Ha ve y o u ha d itc hi n g?  
1  
2  
3  
4 
 
3 7.  Ha ve y o u bee n w orrie d a b o ut y o ur s ki n bei n g yell o w?  
1  
2  
3  
4 
 
3 8.  Ha ve y o u bee n less acti ve t ha n y o u w o ul d li ke t o be?  
1  
2  
3  
4 
 
3 9.  Ha ve y o u felt ‘sl o we d d o w n’?  
1  
2  
3  
4 
 
4 0.  Ha ve y o u felt lac ki n g e ner g y?  
1  
2  
3  
4 
 
4 1.  Di d y o u ha ve pai n d uri n g t he ni g ht?  
1  
2  
3  
4 
 
4 2.  Ha ve y o u ha d pai n i n y o ur st o mac h area?  
1  
2  
3  
4 
 
4 3.  Ha ve y o u ha d pai n i n y o ur bac k?  
1  
2  
3  
4 
 
4 4.  Di d y o u ha ve a bl oate d feeli n g i n y o ur a b d o me n?  
1  
2  
3  
4 
 
4 5.  Ha ve y o u felt stresse d?  
1  
2  
3  
4 
 
4 6.  Ha ve y o u felt less a ble t o e nj o y y o urself?  
1  
2  
3  
4 
 
4 7.  Ha ve y o u w orrie d a b o ut y o ur healt h i n t he f ut ure?  
1  
2  
3  
4 
 
4 8.  Ha ve y o u w orrie d a b o ut y o ur fa mil y i n t he f ut ure?  
1  
2  
3  
4 
 
4 9.  T o w hat e xte nt ha ve y o u bee n tr o u ble d wit h si de effects  
 
fr o m y o ur treat me nt? 
1  
2  
3  
4 
 
5 0.  Ha ve y o u ha d diffic ulties wit h drai na ge t u bes/ ba gs?  
1  
2  
3  
4 
 
5 1.  Ha ve y o u w orrie d a b o ut l os i n g wei g ht? 
1  
2  
3  
4 

7 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
A p pe n di x VI  
S KI N D E X - 1 6 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Directi o ns:   Pleas e circl e t he n u m ber ( 0 - 6) best reflecti n g y o ur res p o nse t o t he f oll o wi n g 
t hat descri bes d uri n g t he p ast w ee k , h o w ofte n h a ve y o u b ee n b ot here d b y: 
 
1.  
Y o ur s ki n itc hi n g:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
2.  
Y o ur s ki n b ur ni n g or sti n gi n g:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
3.  
Y o ur s ki n h urti n g:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
4.  
Y o ur s ki n bei n g irrit ate d:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
5.  
T he persiste nce/rec urre nce of y o ur s ki n c o n diti o n:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
6.  
W orr y a b o ut y o ur s ki n c o n diti o n (f or e x a m ple, t h at it will s pre a d, get w orse, sc ar or 
be u n pre dict a ble, etc.):  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
7.  
T he a p pe ar a nce of y o ur s ki n:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
 

7 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
8.  
F r ustr ati o n a b o ut y o ur s ki n: 
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
9.  
E m b arr ass me nt a b o ut y o ur s ki n:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
1 0.  Bei n g a n n o ye d a b o ut y o ur s ki n: 
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b o t here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
1 1.  F eeli n g de presse d a b o ut y o ur s ki n:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
1 2.  T he effects of y o ur s ki n o n y o u r i nter acti o ns wit h ot hers (f or e x a m ple, i nter acti o ns 
wit h f a mil y, f rie n ds, cl ose rel ati o ns h i p, etc.): 
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
1 3.  T he effects of y o ur s ki n o n y o ur desire t o be wit h pe o ple:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
1 4.  Y o ur s ki n m a ki n g it h ar d f or y o u t o s h o w y o ur affecti o n: 
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
 
 
1 5.  T he effects of y o ur s ki n c o n diti o n o n y o ur d ail y acti vities:  
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al w a ys b ot here d 
 
 
1 6.  Y o ur s ki n m a ki n g it h ar d t o w or k or d o w h at y o u e nj o y:  
 

7 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0 
Ne ver b ot here d  
  
  
  
  
  
  
  
Al wa ys b ot here d 
A p pe n di x VII  
B o w el F u ncti o n Q uesti o n n aire  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Directi o ns:   E ac h of t he state me nt s or q uesti o ns bel o w descri b e s y m pt o ms or pr o ble ms 
w h ic h s o meti mes occ ur i n patie nts wit h y o ur t y pe of ca ncer.  Q u esti o ns 2- 1 0 ca n be 
a ns wer e d b y circli n g “ yes” or “ n o”.  
 
1. H o w m a n y b o wel m o ve me nts d o y o u h a ve e ac h d a y o n a ver a ge ? 
 
 
2. D o y o u s o meti mes h a ve t o get u p at ni g ht t o h a ve a b o wel m o ve me nt ? 
yes  
n o 
3. D o y o u s o meti mes l ose c o ntr ol of y o ur b o wel m o ve me nts ?  
yes  
n o 
4. D o y o u s o meti mes h a ve a n ot her b o wel m o ve me nt wit hi n 3 0 mi n of t he  
     pre vi o us o ne ?  
yes  
n o 
5. D o y o u s o meti mes we ar pr otecti ve cl ot hi n g or a p a d i n c ase y o u l ose  
     c o ntr ol of a  b o wel m o ve me nt ?  
yes  
n o 
6. Are y o u s o meti mes u n a ble t o tell t he differe nce bet wee n st o ol a n d g as ?  
yes  
n o 
7. Are y o ur b o wel m o ve me nts s o meti mes li q ui d i n c o nsiste nc y ?  
yes  
n o 
8. O nce y o u feel t he ur ge t o h a ve a b o wel m o ve me nt, d o y o u fi n d t h at y o u  
     m ust d o s o wit hi n 1 5 mi n t o a v oi d a n acci de nt ? 
yes  
n o 
9. D o y o u e ver h a ve cr a m pi n g wit h b o w el m o ve me nts ? 
yes  
n o 
         If yes, is y o ur cra m pi n g: 
 
 
         □ mil d  
 
 
         □ m o derate  
 
 
         □ se vere 
 
 
1 0. D o y o u e ver h a ve bl o o d i n y o ur b o wel m o ve me nt ?  
yes  
n o 
         If yes, c hec k t he descri pti o n t hat best descri bes t he a m o u nt of bl o o d i n y o ur    
         b o wel m o ve me nt:  
 
 
         □ o n t oilet tiss ue o nl y  
 
 
         □ mi xe d wit h or c oati n g b o wel m o ve me nt  
 
 
         □ e n o u g h t o t ur n water i n  t oilet b o wl re d 
 
 
 
 
 
 

7 6                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
 
A p pe n di x VIII  
U nisc ale  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Please circle t he n u m ber ( 0 -1 0) best reflecti n g y o ur res p o nse t o t he f oll o wi n g t hat descri bes y o ur 
feeli n gs d uri n g t he p ast wee k, i n cl u di n g t o d a y. 
 
1.  
H o w w o ul d y o u descri be y o ur o ver all Q u alit y of Life ? 
 
  
0  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0   
 
As ba d as   
  
  
  
  
  
  
  
  
As g o o d as 
  
it ca n be  
  
  
  
  
  
  
  
  
  
  
it ca n be 
 
 
If y o u h a ve n ot st arte d tre at me nt o n t his st u d y, 
ple ase st o p here.  T h a n k y o u f or t a ki n g t he 
ti me t o hel p us.  
 
If y o u h a ve st arte d tre at me nt o n t his st u d y, 
ple ase c o nti n ue t o t he ne xt p a ge.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

7 7                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
A p pe n di x I X 
W as It W ort h It ( WI WI) 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Partici pati n g i n a cli nical tri al / researc h st u d y is a pers o nal c h oice a n d a n i n di vi d ual 
e x perie nce. We w o ul d li ke t o get y o ur fee d bac k o n y o ur e x perie nce i n t his researc h 
st u d y. 
 
Directi o ns:   Please a ns wer eac h q uesti o n b y circli n g Y (f or yes), N (f or n o), or U (f or u ncertai n).  
 
 
1.  W as it w ort h w hile f or y o u t o p artici p ate i n t his rese arc h st u d y ?  (circle o ne) 
 
  
Y 
N 
U 
 
 
2.  If y o u h a d t o d o it o ver, w o ul d y o u p artici p ate i n t his rese arc h st u d y a g ai n ?  (circle o ne) 
 
  
Y 
N 
U 
 
 
3.  W o ul d y o u rec o m me n d p artici p ati n g i n t his rese arc h st u d y t o ot hers ?  (circle o ne) 
 
  
Y 
N 
U 
 
 
4.  O ver all, di d y o ur q u alit y of life c h a n ge b y p artici p ati n g i n t his rese arc h st u d y ?  (circle o ne) 
 
  
It i m pr o ve d 
It sta ye d t he sa me 
It g ot w orse 
 
 
5.  O ver all h o w w as y o ur e x perie nce of p artici p ati n g i n t his rese arc h st u d y ?  (circle o ne) 
 
 Better t ha n I e x pecte d   
The sa me as I e x pecte d  
W orse t ha n I e x pecte d  
 
 
 
 
 
 
T h a n k y o u f or t a ki n g t he ti me t o hel p us.  
 
 
 
 
 
 
 
 
 

7 8                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
 
A p pe n di x X 
C hil d - P u g h Cl assific ati o n 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
P ar a meter  
P oi nts Assi g ne d  
1  
2  
3  
Ascites  
A bse nt  
Sli g ht  
M o derate  
Bilir u bi n ( m g/ d L)  
≤2  
2 t o 3  
> 3  
Al b u mi n ( g/ d L)  
> 3. 5  
2. 8 t o 3. 5  
< 2. 8  
Pr ot h o m bi n Ti me  
 
 
 
     Sec o n ds o ver c o ntr ol  
1 t o 3  
4 t o 6  
> 6  
     I N R 
< 1. 7  
1. 8 t o 2. 3  
> 2. 3  
E nce p hal o pat h y  
N o ne  
Gra de 1 t o 2  
Gra de 3 t o 4  
M o difie d C hil d- P u g h Classificati o n of t he se verit y of li ver dis ease acc or di n g t o t he de gree of 
ascites, t he plas ma c o nce ntrati o ns of bilir u bi n a n d al b u mi n, t he Pr ot hr o m bi n ti me, a n d t he de gree 
of e nce p hal o pat h y. A t otal sc ore of 5 t o 6 is c o nsi dere d Gra de A ( well- c o m pe nsate d  disease); 7 - 9 
is Gra de B (si g nifica nt f u ncti o nal c o m pr o mise); a n d 1 0 t o 1 5 is Gra de C ( dec o m pe nsate d 
disease). T hese gra des c orrelate wit h o ne a n d t w o year s ur vi val;  Gra de A – 1 0 0 % a n d 6 5 %; 
Gra de B: 8 0 % a n d 6 0 %; a n d Gra de C – 4 5 % a n d 3 5 %. 
 
 
 
 
 
 
 
 
 
 

7 9                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
A p pe n di x XI: M E DI C A TI O N G UI D E Icl usi g
® 
(e ye-C L U E -si g) ( p o n ati ni b) T a blets  
W h at is t he m ost i m p ort a nt i nf or m ati o n I s h o ul d k n o w a b o ut Icl usi g ?  
Icl usi g c a n c a use seri o us si de effects, i ncl u di n g:  
Bl o o d cl ots or bl oc k a ge i n y o ur bl o o d vessels ( arteries a n d vei ns). Bl o o d cl ots or bl oc ka ge i n 
y o ur bl o o d vessels ma y lea d t o heart attac k, str o ke, or deat h. A bl o o d cl ot or bl oc ka ge i n y o ur 
bl o o d vessels ca n pre ve nt pr o per bl o o d fl o w t o y o ur heart, brai n, b o wels (i ntesti nes), le gs, e yes, 
a n d ot her parts of y o ur b o d y. Y o u ma y nee d e mer ge nc y s ur ger y or treat me nt i n a h os pital. Get 
me dical hel p ri g ht a wa y if y o u get a n y of t he f oll o wi n g s y m pt o ms:  
• 
c hest pai n or press ure  
• 
pai n i n y o ur ar ms, le gs, bac k, nec k or j a w  
• 
s h ort ness of breat h  
• 
n u m b ness or wea k ness o n o ne si de of y o ur b o d y  
• 
tr o u ble tal ki n g  
• 
hea dac he  
• 
dizzi ness   
• 
se vere st o mac h area pai n  
• 
decrease d visi o n or l oss of visi o n  
 
Bl o o d cl ots or bl oc ka ge i n y o ur bl o o d vessels ca n ha p pe n i n pe o ple wit h or wit h o ut ris k fact ors 
f or heart a n d bl o o d vessel disease, i ncl u di n g pe o ple 5 0 years of a ge or y o u n ger. T al k t o y o ur 
healt hcare pr o vi der if t his is a c o ncer n f or y o u.  
He art pr o ble ms. Icl usi g ca n ca use heart pr o ble ms, i ncl u di n g heart fail ure w hic h ca n be seri o us 
a n d ma y lea d t o deat h. Heart fail ure mea ns y o ur heart d oes n ot p u m p bl o o d well e n o u g h. Icl usi g 
ca n als o ca use irre g ular sl o w or fast heart beats a n d heart attac k. Y o ur healt hcare pr o vi der will 
c hec k y o ur heart f u ncti o n bef ore a n d d uri n g y o ur treat me nt wit h Icl usi g. Get me dical hel p ri g ht 
a wa y if y o u get a n y of t he f oll o wi n g s y m pt o ms: s h ort ness of breat h, c hest pai n, fast or irre g ular 
heart beats, dizzi ness, or feel fai nt.  
Li ver pr o ble ms. Icl usi g ca n ca use li ver pr o ble ms, i ncl u di n g li ver fail ure, w hic h ca n be se vere 
a n d ma y lea d t o deat h. Y o ur healt hcare pr o vi der will d o bl o o d tests bef ore a n d d uri n g y o ur 
treat me nt wit h Icl usi g t o c hec k f or li ver pr o ble ms. Get me dical hel p ri g ht a wa y if y o u get a n y of 
t hese s y m pt o ms of li ver pr o ble ms d uri n g treat me nt:  
• 
yell o wi n g of y o ur s ki n or t he w hite part of y o ur e yes (ja u n dice)  
• 
dar k “tea -c ol ore d” uri ne  
• 
slee pi ness  
 
Se e “ W h at are t he p ossi ble si de effects of Icl usi g ? ” f or i nf or mati o n a b o ut si de effects.  

8 0                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
W h at is Icl usi g ?  
Icl usi g is a prescri pti o n me dici ne use d t o treat a d ults w h o ha ve:  
•  
a s pecific t y pe of a b n or mal ge ne ( T 3 1 5I- p ositi ve) c hr o nic p hase, accelerate d p hase,  or 
blast p hase c hr o nic m yel oi d le u ke mia ( C M L), or T 3 1 5I- p ositi ve P hila del p hia 
c hr o m os o me p ositi ve ac ute l y m p h o blastic le u ke mia ( P h + A L L)  
•  
c hr o nic p hase, accelerate d p hase, or blast p hase C M L or P h + A L L w h o ca n n ot recei ve 
a n y ot her t yr osi ne ki nase i n hi bit o r ( T KI) me dici nes  
 
It is n ot k n o w n if Icl usi g is safe a n d effecti ve i n c hil dre n less t ha n 1 8 years of a ge.  
W h at s h o ul d I tell m y he alt hc are pr o vi der bef ore t a ki n g Icl usi g ? B ef ore y o u 
t a ke Icl usi g, tell y o ur he alt hc are pr o vi der if y o u:  
•  
ha ve a hist or y of bl o o d cl ots i n y o ur bl o o d vessels (arteries or vei ns)  
•  
ha ve heart pr o ble ms, i ncl u di n g heart fail ure, irre g ular heart beats, a n d Q T pr ol o n gati o n  
•  
ha ve dia betes  
•  
ha ve a hist or y of hi g h c h olester ol  
•  
ha ve li ver pr o ble ms  
•  
ha ve ha d i nfla m mati o n of y o ur pa ncreas ( pa ncreatitis)  
ha ve hi g h bl o o d press ure  
•  
ha ve blee di n g pr o ble ms  
•  
pla n t o ha ve a n y s ur gical pr oce d ures  
•  
are lact ose ( mil k s u gar) i nt olera nt. Icl usi g ta blets c o ntai n lact ose.  
•  
dri n k gra pefr uit j uice  
•  
ha ve a n y ot her me dical c o n diti o ns  
•  
are pre g na nt or pla n t o  bec o me pre g na nt. Icl usi g ca n har m y o ur u n b or n ba b y. Y o u s h o ul d 
n ot bec o me pre g na nt w hile ta ki n g Icl usi g. T ell y o ur healt hcare pr o vi der ri g ht a wa y if y o u 
bec o me pre g na nt or pla n t o bec o me pre g na nt.  
•  
are breastfee di n g or pla n t o breastfee d. It is n ot k n o w n if Icl usi g passes i nt o y o ur breast 
mil k. Y o u a n d y o ur healt hcare pr o vi der s h o ul d deci de if y o u will ta ke Icl usi g or 
breastfee d. Y o u s h o ul d n ot d o b ot h.  
 
Tell y o ur he alt hc are pr o vi der a b o ut all t he me dici nes y o u t a ke, i ncl u di n g prescri pti o n 
me dici nes a n d o ver -t he-c o u nter me dici nes, vita mi ns, a n d her bal s u p ple me nts. Icl usi g a n d 
ot her me dici nes ma y affect eac h ot her ca usi n g si de effects.  
K n o w t he me dici nes y o u ta ke. Kee p a list of t he m t o s h o w y o ur healt hcare pr o vi der a n d 
p har macist w he n y o u get a ne w me dici ne.  

8 1                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
H o w s h o ul d I t a ke Icl usi g ?  
•  
T a ke Icl usi g e xactl y as y o ur healt hcare pr o vi der tells y o u t o ta ke it.  
•  
Y o ur healt hcare pr o vi der ma y c ha n ge y o ur d ose of Icl usi g or tell y o u t o st o p ta ki n g 
Icl usi g.  
•  
D o n ot c ha n ge y o ur d ose or st o p ta ki n g Icl usi g wit h o ut tal ki n g t o y o ur healt hcare 
pr o vi der.  
•  
S wall o w Icl usi g ta blets w h ole. D o n ot cr us h or diss ol ve Icl usi g ta blets.  
•  
Y o u ma y ta ke Icl usi g wit h or wit h o ut f o o d.  
•  
If y o u miss a d ose of Icl usi g, ta ke y o ur ne xt d ose at y o ur re g ular ti me. D o n ot ta ke 2 
d oses at t he sa me ti me t o ma ke u p f or a misse d d ose.  
•  
If y o u ta ke t o o m uc h Icl usi g, call y o ur healt hcare pr o vi der or g o t o t he nearest h os pital 
e mer ge nc y r o o m ri g ht a wa y.  
 
W h at are t he p ossi ble si de effects of Icl usi g ? Icl usi g m a y 
c a use seri o us si de effects, i ncl u di n g:  
See “ W h at is t he m ost i m p ort a nt i nf or m ati o n I s h o ul d k n o w a b o ut Icl usi g ? ”  
•  
Hi g h bl o o d press ure . Y o ur bl o o d press ure s h o ul d be c hec ke d re g ularl y a n d a n y hi g h 
bl o o d press ure s h o ul d be treate d w hile y o u are ta ki n g Icl usi g. T ell y o ur healt hcare 
pr o vi der if y o u get hea dac hes, dizzi ness, c hest pai n or s h ort ness of breat h.  
•  
I nfl a m m ati o n of t he p a ncre as ( p a ncre atitis). S y m pt o ms i ncl u de s u d de n st o mac h- area 
pai n, na usea, a n d v o miti n g. Y o ur healt hcare pr o vi der s h o ul d d o bl o o d tests t o c hec k f or 
pa ncreatitis d uri n g tr eat me nt wit h Icl usi g.  
•  
Ne ur o p at h y. Icl usi g ma y ca use da ma ge t o t he ner ves i n y o ur ar ms, brai n, ha n ds, le gs, or 
feet ( Ne ur o pat h y). T ell y o ur healt hcare pr o vi der if y o u get a n y of t hese s y m pt o ms d uri n g 
treat me nt wit h Icl usi g:  
o  m uscle wea k ness, ti n gli n g, b ur ni n g, pai n, a n d l oss of feeli n g i n y o ur ha n ds a n d 
feet  
o  d o u ble visi o n a n d ot her pr o ble ms wit h e ye si g ht, tr o u ble m o vi n g t he e ye, 
dr o o pi n g of part of t he face, sa g gi n g or dr o o pi n g e yeli ds  
•  
Effects o n t he e ye. Seri o us e ye pr o ble ms t hat ca n lea d t o bli n d ness o r bl urre d visi o n ma y 
ha p pe n wit h Icl usi g. T ell y o ur healt hcare pr o vi der if y o u get a n y of t he f oll o wi n g 
s y m pt o ms: percei ve d flas hes of li g ht, li g ht se nsiti vit y, fl oaters, dr y or itc h y e yes, a n d e ye 
pai n. Y o ur healt hcare pr o vi der will m o nit or y o ur visi o n bef ore a n d d uri n g y o ur treat me nt 
wit h Icl usi g.  
•  
Se vere blee di n g. Icl usi g ca n ca use blee di n g w hic h ca n be seri o us a n d ma y lea d t o deat h. 
T ell y o ur healt hcare pr o vi der if y o u get a n y si g ns of blee di n g w hile ta ki n g Icl usi g 
i ncl u di n g:  
o v o miti n g bl o o d or if y o u r v o mit l o o ks li ke c offee- gr o u n ds  
 

8 2                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
 
o pi n k or br o w n uri ne  
o re d or blac k (l o o ks li ke tar) st o ols  
o c o u g hi n g u p bl o o d or bl o o d cl ots  
o u n us ual blee di n g or br uisi n g of y o ur s ki n  
o me nstr ual blee di n g t hat is hea vier t ha n n or mal  
o u n us ual va gi nal blee di n g  
o n ose blee ds t hat ha p pe n ofte n  
o dr o wsi ness or diffic ult y bei n g a wa ke ne d  
o c o nf usi o n  
o hea dac he  
o c ha n ge i n s peec h  
•  
Fl ui d rete nti o n. Y o ur b o d y ma y h ol d t o o m uc h fl ui d (fl ui d rete nti o n). Tell y o ur 
healt hcare pr o vi der ri g ht a wa y if y o u get a n y of t hese s y m pt o ms d uri n g treat me nt wit h 
Icl usi g:  
o s welli n g of y o ur ha n ds, a n kles, feet, face, or all o ver y o ur b o d y  
o wei g ht gai n  
o s h ort ness of breat h a n d c o u g h  
•  
L o w bl o o d cell c o u nts. Icl usi g ma y ca use l o w bl o o d cell c o u nts. Y o ur healt hcare 
pr o vi der will c hec k y o ur bl o o d c o u nts re g ularl y d uri n g treat me nt wit h Icl usi g. T ell y o ur 
healt hcare pr o vi der ri g ht a wa y if y o u ha ve a fe ver or a n y si g ns of a n i nfecti o n w hile 
ta ki n g Icl usi g.  
•  
T u m or L ysis S y n dr o me ( T L S). T L S is ca use d b y a fast brea k d o w n of ca ncer cells. T L S 
ca n ca use y o u t o ha ve:  
o ki d ne y fail ure a n d t he nee d f or dial ysis treat me nt  
o a n a b n or mal heart beat Y o ur healt hcare pr o vi der ma y d o bl o o d tests t o c hec k f or T L S.  
•  
P ossi ble w o u n d he ali n g pr o ble ms. If y o u nee d t o ha ve a s ur gical pr oce d ure, tell y o ur 
healt hcare pr o vi der t hat y o u are ta ki n g Icl usi g. Y o u s h o ul d st o p ta ki n g Icl usi g at least 1 
wee k bef ore a n y pla n ne d s ur ger y.  
•  
A te ar i n y o ur st o m ac h or i ntesti n al w all ( perf or ati o n). T ell y o ur healt hcare pr o vi der 
ri g ht a wa y if y o u get:  
o se vere pai n i n y o ur st o mac h-area (a b d o me n)  
o s welli n g of t he a b d o me n  
o hi g h fe ver  
 
T he m ost c o m m o n si de effects of Icl usi g i ncl u de:  
•  
s ki n ras h  
•  
c o nsti pati o n  
•  
st o mac h-area (a b d o me n) pai n  
•  
fe ver  
•  
tire d ness  
•  
j oi nt pai n  
•  
hea dac he  
•  
na usea  
•  
dr y s ki n  
 
T ell y o ur healt hcare pr o vi der if y o u ha ve a n y si de effect t hat b ot hers y o u or t hat d oes n ot g o 
a wa y.  
 

8 3                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
T hese are n ot all of t he p ossi ble si de effects of Icl usi g. F or m ore i nf or mati o n, as k y o ur 
healt hcare pr o vi der or p har macist.  
Call y o ur d oct or f or me dical a d vice a b o ut si de effects . Y o u ma y re p ort si de effects t o F D A at 
  
H o w s h o ul d I st ore Icl usi g ?  
St ore Icl usi g at r o o m te m perat ure bet wee n 6 8° F t o 7 7° F ( 2 0° C t o 2 5° C).  
Kee p Icl usi g a n d all me dici nes o ut of t he re ac h of c hil dre n.  
Ge ner al i nf or m ati o n a b o ut Icl usi g  
M e dici nes are s o meti mes prescri be d f or p ur p oses ot her t ha n t h ose liste d i n a Me dicati o n G ui de. 
D o n ot use Icl usi g f or a c o n diti o n f or w hic h it was n ot prescri be d. D o n ot gi ve Icl usi g t o ot her 
pe o ple, e ve n if t he y ha ve t he sa me s y m pt o ms y o u ha ve. It ma y har m  t he m.  
Y o u ca n as k y o ur healt hcare pr o vi der or p har macist f or i nf or mati o n a b o ut Icl usi g t hat is 
writte n f or healt h pr ofessi o nals.  
F or m ore i nf or mati o n, g o t o w w w.icl usi g.c o m or call 
  
W h at are t he i n gre die nts i n Icl usi g ?  
Acti ve i n gre die nt : p o nati ni b  
I n acti ve i n gre die nts: lact ose m o n o h y drate, micr ocr ystalli ne cell ul ose, s o di u m starc h 
gl yc olate (t y pe B), c oll oi dal silic o n di o xi de a n d ma g nesi u m stearate. T he ta blet c oati n g 
c o nsists of talc, p ol yet h yle ne gl yc ol, p ol y vi n yl alc o h ol a n d tita ni u m di o xi de.  
T his Me dicati o n G ui de has bee n a p pr o ve d b y t he U. S. F o o d a n d Dr u g 
A d mi nistrati o n.  
Ma n ufact ure d f or: A RI A D P har mace uticals, I nc. 2 6 La n ds d o w ne Street Ca m bri d ge, M A 0 2 1 3 9-
4 2 3 4  
Re vise d: Dece m ber 2 0 1 3  
Refere nce I D: 3 4 2 5 7 8 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

8 4                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
A p pe n di x XII:  Pr o hi bite d Dr u gs Affecti n g t he Q T I nter v al  
T he list of dr u gs t hat ca n be ass ociate d wit h T orsa des de P oi ntes or pr ol o n ge d Q T i nter val is s h o w n o n t he 
ta ble bel o w.  T his ca n als o be ca n be f o u n d o nli ne at htt p:// w w w.azcert. or g/ me dical -pr os/ dr u g -
lists/ b ycate g or y.cf m. 
T hree cate g ories of dr u gs are liste d o n t his we bsite.  C o nc o mita nt use of dr u gs i n t he first c ate g or y ( Dr u gs 
wit h Ris k of T orsa des de P oi ntes) is pr o hi bite d, a n d t h ese dr u gs are liste d bel o w.  A ge nts i n t he 2 
cate g ories of lesser ris k ( Dr u gs wit h P ossi ble Ris k of T orsa des de P oi ntes; a n d Dr u gs wit h C o n diti o nal 
Ris k of T orsa des de P oi ntes) s h o ul d be a v oi de d.  N ote: t hese are a vaila ble o n t he we bsite, b ut are n ot liste d 
i n t he ta ble bel o w. 
T a ble B- 1  
Dr u gs Ge ner all y Acce pte d b y t he Q T Dr u gs. or g A d vis or y B o ar d of t he 
Ariz o n a C E R T t o h a ve a Ris k of C a usi n g T ors a des de P oi ntes a n d 
Pr o hi bite d i n t his St u d y  
Ge neric N a me  
B r a n d N a me  
Cl ass/ Cli nic al Use  
A mi o dar o ne  
C or dar o ne ® 
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
A mi o dar o ne  
Pacer o ne ®  
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
Arse nic tri o xi de  
Trise n o x ® 
A nti -ca ncer / Le u ke mia  
Aste miz ole  
His ma nal ®  
A nti hista mi ne / Aller gic r hi nitis  
Be pri dil  
Vasc or ®  
A nti -a n gi nal / heart pai n 
C hl or o q ui ne 
Arale n ®  
A nti -malarial / malaria i n fecti o n 
C hl or pr o mazi ne  
T h orazi ne ®  
A nti - ps yc h otic/ A nti-e metic / sc hiz o p hre nia/ na usea  
Cisa pri de  
Pr o p ulsi d ® 
GI sti m ula nt / heart b ur n  
Clarit hr o m yci n  
Bia xi n ® 
A nti bi otic / bacterial i nfecti o n  
Dis o p yra mi de  
N or pace ® 
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
D ofetili de  
Ti k os y n ®  
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
D o m peri d o ne 
M otili u m ®  
A nti -na usea / na usea  
Dr o peri d ol  
I na psi ne ® 
Se dati ve; A nti -na usea / a nest hesia a dj u nct, na usea  
Er yt hr o m yci n  
Er yt hr oci n ® 
A nti bi otic; GI sti m ula nt / bacterial i nfecti o n; i nc rease 
GI m otilit y  
Er yt hr o m yci n  
E. E. S. ®  
A nti bi otic; GI sti m ula nt / bacterial i nfecti o n; i ncrease 
GI m otilit y  
Hal ofa ntri ne  
Halfa n ®  
A nti -malarial / malaria i nfecti o n  
Ge neric N a me  
B r a n d N a me  
Cl ass/ Cli nic al Use  

8 5                                                                    M C 1 3 4 5 
M C C C A d de n d u m 2 
 
Hal o peri d ol  
Hal d ol ® 
A nti - ps yc h otic / sc hiz o p hre nia, a gitati o n 
I b utili de 
C or vert ®  
A nti -arr h yt h mic / a b n or mal heart r h yt h m  
Le v o met ha d yl  
Orlaa m ®  
O piate a g o nist / pai n c o ntr ol, narc otic de pe n de nce 
Mes ori dazi ne  
Sere ntil ®  
A nti -ps yc h otic / sc hiz o p hre nia  
Met ha d o ne  
D ol o p hi ne ® 
O piate a g o nist / pai n c o ntr ol, narc otic de pe n de nce 
Met ha d o ne  
Met ha d ose ®  
O piate a g o nist / pai n c o ntr ol, narc otic de pe n de nce 
Pe nta mi di ne  
Pe nta m ®  
A nti -i nfecti ve / p ne u m oc ystis p ne u m o nia 
Pe nta mi di ne  
Ne b u Pe nt ® 
A nti -i nfecti ve / p ne u m oc ystis p ne u m o nia 
Pi m ozi de 
Ora p ®  
A nti -ps yc h otic / T o urette's tics  
Pr o b uc ol 
L orelc o ® 
A ntili pe mic / H y perc h olester ole mia  
Pr ocai na mi de  
Pr o nest yl ® 
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
Pr ocai na mi de  
Pr oca n ®  
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
Q ui ni di ne 
Car di o q ui n ®  
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
Q ui ni di ne 
Q ui na gl ute ® 
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
S otal ol  
Beta pace ®  
A nti -arr h yt h mic / a b n or mal heart r h yt h m 
S parfl o xaci n  
Za ga m ®  
A nti bi otic / bacterial i nfecti o n  
T erfe na di ne 
Sel da ne ®  
A nti hista mi ne / Aller gic r hi nitis  
T hi ori dazi ne  
Mellaril ®  
A nti -ps yc h otic / sc hiz o p hre nia