Clinical trial NCT02265341
Conditions: Malignant Hepatobiliary Neoplasm
Sponsor: Mayo Clinic
Start date: 2014-12-01; Completion date: 2019-06-14
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial studies how well ponatinib hydrochloride works in treating patients with biliary cancer that has spread to other places in the body and that have alterations (fusions) in a gene known as fibroblast growth factor receptor 2 (FGFR2). Ponatinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the clinical benefit rate (confirmed complete or partial response or stable disease for 4 or more cycles) of ponatinib (ponatinib hydrochloride) in fibroblast growth factor receptor (FGFR) aberrant advanced biliary cancers.

SECONDARY OBJECTIVES:

I. To estimate progression free survival, overall survival, and cancer antigen 19-9 (CA19-9) response rate of these patients.

II. To estimate the adverse event profile of ponatinib.

TERTIARY OBJECTIVES:

I. Establish preliminary correlations between FGFR2 fusions and evidence of any clinical benefit.

II. Assess preliminary evaluation of FGFR2 pathway perturbation with ponatinib. III. To describe patient-reported health-related quality of life and symptoms.

OUTLINE:

Patients receive ponatinib hydrochloride orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for at least 2 years.

Arms: arm 1: Patients receive ponatinib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Ponatinib Hydrochloride intervention 3: Quality-of-Life Assessment
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 




 
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