Clinical trial NCT02257541
Conditions: Advanced Gastrointestinal Stromal Tumor (GIST)
Keywords: BGJ398 Imatinib Mesylate 14-140
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2014-10-02; Completion date: 2019-03-25
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of a phase Ib clinical trial is to find the doses of drugs that are safe. Although BGJ398 has been given to patients safely on its own, it has never been given together with imatinib mesylate. In this study, we will test the safety of taking BGJ398 with imatinib mesylate. The investigators will learn this by closely checking for side effects that the patient may experience. Side effects can be seen in laboratory studies, on physical examination, or by asking the patient.Once a dose has been determined to be safe, a larger Phase II study will be done in patients with advanced GIST who have never received any prior treatments.

Detailed description:

Arms: arm 1: BGJ398 With Imatinib Mesylate In the phase Ib portion of the study, patients will receive imatinib at 400 mg once daily and BGJ398 at the standard 3+3 escalation doses for 21 days on, 7 days off (treatment schedule A).Using treatment schedule A, if dose level 1 to -2 is identified as the MTD and concern exists regarding therapeutic activity of BGJ398 at this dose level, expansions with higher dose levels (1 to 3) may be considered at the MSKCC PI's discretion, with modification of the treatment schedule. In this setting BGJ398 will be administered daily for one week followed by 3 weeks off and imatinib will be taken daily throughout the 4 week cycle period (treatment schedule B). In the phase II portion of the study, patients will receive imatinib at 400 mg once daily (standard of care first line imatinib dose) and BGJ398 at the RP2D and treatment schedule identified in the phase Ib portion of the study. One cycle is 28 days.
Interventions: intervention 1: BGJ398 intervention 2: Imatinib Mesylate
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
P a g e 1  o f 1 2 6  
 
M E M O R IA L S L O A N K E T T E R IN G  C A N C E R C E N T E R 
IR B #:  1 4 -1 4 0 A (7)  
A p p ro v e d : 2 4 -J A N -2 0 1 7  
 
 
 
A p h a s e I b/II stu d y  o f B GJ 3 9 8  in  co m b in a tio n  w it h im a ti nib  m e sy la t e in  p a tie n ts w it h u n tre a t e d 
a d v a n c e d g a stro in t estin a l stro m a l tu m o r (G IS T)  
 
P R O T O C O L  F A C E  P A G E  F O R  
M S K C C  T H E R A P E U TI C /D IA G N O S TI C P R O T O C OL  
P rin cip al I nv es tig a to r/D e p a rtm e n t: 
Willi a m  D . T a p , M D  
M e d icin e /S a rco m a  
C o -P rin cip al  
In v es tig a to r(s)/D e p a rtm e n t: 
P in g  C h i, M D , P h D  
M e d icin e /S a rco m a  
In v es tig a to r(s)/D e p a rtm e nt:  
S a n d r a P . D ’ An g el o , M D  
M ar y  Lo u is e K e o h a n , M D  
M rin al M.  G o u n d er,  M D 
M ar k A.  D icks o n , M D 
A le xa n d er  N . Sh o u sh tari,  M D  
Ci a ra M . K e lly , M B  B C h  B A O  (H o n s), M R C P I 
M er ce d es  C o n d y , N P,  F C C S,  A CL S, C B LS 
A n a Sj o b er g,  N P  
S i nc hu n  H w a n g , M D  
W o lfg a n g  A.  W e b er,  M D 
Jo s e p h P . Erin j eri, M D , P h D 
M .H . H ei n e m a n n , M D , FA C S 
Jas m in e  Fra n cis, M D  
Cr isti n a R. A n to n es cu , M D 
R o n al d  D e M at te o , M D , FA CS 
S a m u el Si n g er,  M D , FA C S 
H a n  X i a o, M D  
S re e  C h a las a n i, M D 
A fs h e e n Iq b al, M D 
L ore n M ich el,  M D 
Av ni M . D e s ai, M D 
Ja h a n  A g h al a r, M D 
Jo h n  Fi o r e, M D 
St u art Lich tm a n , M D  
St e v e n S u g ar m a n , M D 
J uli an a E n g , M D  
Ji a Li, M D  
W a n q in g  Iris Zh i, M .D ., P h . D 
A rl y n Ap o llo , M D  
P a m el a  D ru llin s ky , M D 
Z o e  G o ld b er g,  M D 
K e n n e th  N g , M D  
Tiff a n y  T ro so -Sa n d o v al,  M D 
P ar is a M o m t az, M D  
D a n i el M c F arl an d , D O  
 
A lice Z er v o u d a k is, M D 
S t e p h e n V e a ch , M D 
M e d icin e /S a rco m a  
M e d icin e /S a rco m a  
M e d icin e /S a rco m a 
M e d icin e /S a rco m a 
M e d icin e /S a rco m a 
M e d icin e /S a rco m a 
N u rsin g  
N u rsin g  
R a d io lo gy 
R a d io lo g y/M o l ec ular Im a g in g  &  T h er a p y 
R a d io lo g y/ In ter v e nt io n al  R a d io lo g y 
S u rg er y/ O p h t h alm ic O n co lo g y 
S u rg er y/ O p h t h alm ic O n co lo g y 
P at h o lo g y 
S u rg er y 
S u rg er y  
M e d icin e : B a skin g  Ri d g e 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c k 
M e d icin e : C o m ac k 
M e d icin e : C o m ac k 
M e d icin e : C o m ac k 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : W es tch es ter 
M e d icin e : W es tch es ter  
 
M e d icin e : W es tch es ter  
M e d icin e : W es tch es ter  
C o n s e ntin g  
P ro fess io n al(s )/D e p a rtm e n t: 
P in g  C h i, M D  P h D  
Willi a m  D . T a p , M D  
S a n d r a P . D ’ An g el o , M D  
M e d icin e /S a rco m a  
M e d icin e /S a rco m a  
M e d icin e /S a rco m a  


P a g e 2  o f 1 2 6  
 
M E M O R IA L S L O A N K E T T E R IN G  C A N C E R C E N T E R 
IR B #:  1 4 -1 4 0 A (7)  
A p p ro v e d : 2 4 -J A N -2 0 1 7  
 
 
M ar y  Lo u is e K e o h a n , M D 
M rin al M.  G o u n d er,  M D 
M ar k A.  D icks o n , M D  
H a n  X i a o, M D  
S re e  C h a las a n i, M D 
A fs h e e n Iq b al,  M D 
L ore n M ich el,  M D 
Av ni M . D e s ai, M D 
Ja h a n  A g h al a r, M D  
 
Jo h n  Fi o r e, M D 
St u art Lich tm a n , M D 
A rl y n Ap o llo , M D 
J uli an a E n g , M D  
Ji a Li, M D  
W a n q in g  Iris Zh i, M .D ., P h . D 
P a m el a  D ru llin s ky , M D  
Z o e  G o ld b er g,  M D 
K e n n e th  N g,  M D  
Tiff a n y  T ro so -Sa n d o v al,  M D 
P ar is a M o m t az, M D  
D a n i el M c F arl an d , D O 
A lic e Z e rv o u d a kis,  M D 
St e p h e n V e ac h,  M D  
M e d icin e /S a rco m a 
M e d icin e /S a rco m a 
M e d icin e /S a rco m a 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : B a skin g  Ri d g e 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c k 
 
M e d icin e :C o m m a ck 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c kM e d icin e:  C o m m a ck 
M e d icin e : C o m m a c k 
M e d icin e : C o m m a c k 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : R o ckv ill e C e n tre 
M e d icin e : W es tch es ter  
 
M e d icin e : W es tch es ter  M e d icin e: 
W e stc h ester  
 
 
 
P a rticia p tin g  In stitu tio n s 
P I’s N a m e  
S it e’s R o le  
D a n a F ar b er  C a n c er In stitu t e 
A n d r e w W a g n e r, M D  
D at a C o lle ctio n  
M D  A n d ers o n  C a n c er C e n ter  
N e e t a So m ai a h , M D  
D at a C o lle ctio n  
 
P le a s e N o t e: A  C o n se n tin g  P ro fe ssio n a l m u st h a v e  co m pl et e d  th e  m a n d a to ry  H u m a n  S u b je cts E d u ca tio n 
a n d  C e rtifica tio n  P ro g ra m . 
 
M e m o rial S lo a n -K e tteri n g  C a n c er C e n te r 
1 2 7 5  Y o rk  A ve n u e  
N e w  Y o r k, N e w  Y o rk 1 0 0 6 5  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e  3  o f 1 2 6  
 
 
T a b le  o f C o n te n ts 
 
 
 
1 .0  
P R O T O C OL S U M M A R Y  A N D /O R S C H E M A  ....................................................................................6  
2 .0  
O BJ E C TI V E S  A N D  S C IE N T IFIC  A IM S ................................................................................................9  
 
3 .0  
B A C K G R O U N D  A N D  R A TI O N A LE  .................................................................................................1 0  
3 . 1 
T ar g e tin g  E T V 1  i n GI ST  ...........................................................................................................1 0  
 
3 . 2 
B G J3 9 8  ...................................................................................................................................1 5  
 
3 . 2. 1 
O v e rv ie w  o f B GJ3 9 8  ........................................................................................................1 5  
3 . 3 
I m atin i b M e sy l at e (Gl e e v ec  S TI 5 7 1 ; N S C  # 7 1 6 0 5 1 )............................................................1 8  
 
3 . 3. 1 
O v e rv ie w  o f Im ati n i b m e sy lat e  .......................................................................................1 8  
3 . 3. 2 
Cl i nic al e x p erie nc e  wit h Im ati n i b m e sy l ate .....................................................................1 8  
 
3 . 3. 3 
P h ar m a co ki n e tics o f Im a tin i b m e sy l ate  ..........................................................................2 0  
4 .0  
O V E R V IE W O F  S T U D Y  D E SIG N /I NT E R V E N TI O N  ..........................................................................2 1  
 
4 . 1 
D esi g n .....................................................................................................................................2 1  
 
4 . 2 
In te rv e n tio n  ...........................................................................................................................2 2  
5 .0  
T H E R A P E U T IC /D IA G N O ST IC  A G E N T S  ..........................................................................................2 2  
 
5 . 1 
I m atin i b M e sy l at e (Gl e e v ec  S TI 5 7 1 ; N S C  # 7 1 6 0 5 1 )............................................................2 2  
5 . 1. 1 
M ec h a n ism  o f Actio n : .....................................................................................................2 2  
 
5 . 1. 2 
F or m u la tio n , Sto r ag e  a n d  P ac k a g i ng ...............................................................................2 2  
5 . 1. 3 
A d m in istr atio n  o f Im ati n i b m e sy l ate ...............................................................................2 3  
 
5 . 2 
B G J3 9 8  ...................................................................................................................................2 3  
5 . 2. 1 
M ec h a n ism  o f A ctio n : .....................................................................................................2 3  
 
5 . 2. 2 
F or m u la tio n , Sto r ag e  a n d  P ac k a g i ng ...............................................................................2 3  
 
5 . 2. 3 
A d m in istr atio n  o f B GJ3 9 8 ................................................................................................2 4  
6 .0  
C R IT E R IA  F O R  S U B JE C T  EL IG IB ILIT Y  .............................................................................................2 4  
 
6 . 1 
S u b j ect In clu sio n  Cr ite ri a .......................................................................................................2 4  
6 . 2 
S u b j ect E xclu sio n  Cr ite ria .......................................................................................................2 5  
 
7 .0  
R E C R U IT M E N T  P LA N  ....................................................................................................................2 6  
8 .0  
P R E T R E A T M E N T  E V A L UA T IO N  ....................................................................................................2 6  
 
9 .0  
T R E A T M E N T /IN T E R V E N TI O N  P LA N  .............................................................................................2 7  
 
9 . 1 
D o se  R a tio n a le:  ......................................................................................................................2 8  
9 . 2 
F ollo w -u p  fo r to xicities  ..........................................................................................................3 1  
 
9 . 3 
D o se  M o d ifica tio n ..................................................................................................................3 2  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e  4  o f 1 2 6  
 
 
9 . 3. 1 
I m atin ib : ..........................................................................................................................3 2  
 
9 . 3. 2 
B G J3 9 8 : ............................................................................................................................3 5  
9 . 4 
D ru g  In te r actio n s ...................................................................................................................4 3  
 
9 . 4. 1 
P e rm itte d co n co m it a nt th e r ap y  w it h Im a tin i b re q u iri ng  c au tio n  a n d / or ac tio n ............4 4  
1 0 .0  E V AL U A T IO N  D U R IN G  T R E A T M E N T/ IN T E R V E N TI O N  .................................................................4 7  
 
1 0 . 1  St a n d ar d  E v al u at io n  ...............................................................................................................4 7  
1 0 . 1.1  
St u d y  C al e n d ar (P h a se  I P o rtio n  St u dy )...........................................................................4 7  
 
1 0 . 1.2  
St u d y  C al e n d ar (P h a se  II P o rtio n  St u dy )..........................................................................5 2  
1 1 .0  T O X IC IT IE S /S ID E  E F FE C T S  ............................................................................................................6 0  
 
1 1 . 1 
A d v ers e  E ve nt s.......................................................................................................................6 0  
 
1 2 .0  C R IT E R IA  F O R  T H E R A P E U T IC  R E S P O N S E /O U T C O M E  A S S E S S M E N T  ...........................................7 4  
1 2 . 1 
A n tit um o r Effect –  So li d T u m o rs............................................................................................7 4  
 
1 2 . 1.1  
D efi n itio n s .......................................................................................................................7 4  
1 2 . 1.2  
D is e ase  P ar a m e ters  .........................................................................................................7 4  
 
1 2 . 1.3  
M e th o d s fo r E v al u at io n  o f M e as ur a b l e D ise as e  .............................................................7 5  
1 2 . 1.4  
P ri ma r y R es p o n s e Cr ite ri a (R E CI S T  1 .1 )...........................................................................7 6  
1 2 . 1.5  
S ec o n d ary  R e sp o n s e Crit er ia ( C H OI fo r C T a n d  E O R T C  fo r [1 8F] -F D G -P E T)  .....................7 6  
 
1 2 . 1.6  
N o t e v al u a b l e (N E )...........................................................................................................7 7  
1 2 . 1.7  
E arl y  d e a th .......................................................................................................................7 7  
 
1 2 . 1.8  
Sy m p to m atic  D e ter io r atio n .............................................................................................7 8  
1 2 . 1.9  
C o n firm a tio n  o f r esp o n se ................................................................................................7 8  
 
1 2 . 1.1 0   S p eci al n o te  o n tar g e t le sio n s th at  b e co m e  “to o  sm all  t o m e a s ure ” .............................7 8  
1 2 . 1.1 1   E v al u at io n  o f b est o ver all  res p o n s e w ith i n 3 2  w e e k s o f c o m bin at io n  tre a tm e nt b as e d  
o n  T a b l e 1 8 : .....................................................................................................................7 8  
 
1 2 . 1.1 2   D u r atio n  o f re sp o n se .......................................................................................................7 9  
1 2 . 1.1 3   D u r atio n  o f sta b l e dis e as e  ...............................................................................................7 9  
 
1 2 . 1.1 4   P ro g ress io n -F re e  S u rv i v al (P F S) .......................................................................................7 9  
 
1 2 . 1.1 5   O ver all  S u rv iv al ( O S)  ........................................................................................................7 9  
1 3 .0  C R IT E R IA  F O R  R E M O V A L FR O M  S T U D Y  ......................................................................................7 9  
 
1 4 .0  BI O S T A TI S T I CS ..............................................................................................................................8 0  
1 5 .0   R E S E A R C H  P A R T IC IP A N T  R E GI S T R A T IO N  A N D  R A N D O M IZ A TI O N  P R O C E D U R E S  .....................8 3  
 
1 5 . 1 
R es e a rc h P a rticip a n t R e gis tr atio n ..........................................................................................8 3  
1 5 . 1.1  
R e gistr at io n  fo r P artici p at in g  Sit es  ..................................................................................8 3  
 
1 5 . 2 
R a n d o m iza tio n  .......................................................................................................................8 4  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 5  o f 1 2 6  
 
 
1 6 .0  D A T A  M A N A G E M E N T  IS S U E S  ......................................................................................................8 4  
 
1 6 . 0.1  
D at a a n d  So u rc e D o cu m e n tati o n  fo r P artici p a tin g  Sit e s.................................................8 4  
1 6 . 0.2  
D at a a n d  So u rc e D o cu m e n tati o n  S u b m issio n  fo r P art icip ati n g  Sit es  .............................8 5  
 
1 6 . 0.3  D at a  a n d  S o u rce  D o c u m e nta tio n  S u b m issio n  T im eli n es  fo r P a rticip ati n g  S ite s .................8 5  
1 6 . 0.3 D at a  R e v ie w  a n d  Q u eri es  fo r P artici p a tin g  Sit e  D at a ..........................................................8 6  
 
1 6 . 1 
Q u a lit y Ass u r an c e ..................................................................................................................8 6  
1 6 . 1.1  Q u al ity A ss ura n c e fo r P art icip ati n g  Sit es  ............................................................................8 6  
 
1 6 . 2 
D at a a n d  S afe ty  M o n ito rin g ...................................................................................................8 7  
1 6 . 3 
R e g u l ato ry D o c um e nt at io n ....................................................................................................8 8  
 
1 6 . 3.1  
A m e n d m e nts  ...................................................................................................................8 8  
 
1 6 . 3.2  
A d d itio n al I R B C o rre s p o nd e nc e  ......................................................................................8 9  
1 6 . 3.3  
R e g u l ato ry D o c um e nt at io n  S u b m issi o n fo r P a rticip ati n g  Sit es  ......................................8 9  
 
1 6 . 4 
D o cu m e n t m ai n te n a n ce  ..................................................................................................9 0  
1 6 . 5 
N o n co m p li an c e ......................................................................................................................9 0  
 
1 7 .0  P R O T E C T IO N  O F H U M A N  S U B JE C T S ............................................................................................9 0  
1 7 . 1 
P ri va c y ....................................................................................................................................9 1  
 
1 7 . 2 
S eri o u s Ad ver se  E ve nt  ( SA E ) R e p o rtin g  .................................................................................9 1  
 
1 7 . 2.1  
R e p o rtin g  t o N o v artis b y M S K C C  .....................................................................................9 3  
1 7 . 3 
S eri o u s Ad ver se  E ve nt  ( SA E ) R e p o rtin g  fo r P artici p ati n g  Sit es  ..............................................9 4  
 
1 7 . 4 
S a f ety R e p o rts ........................................................................................................................9 4  
1 8 .0  I NF O R M E D  C O N S E N T  P R O C E D U R E S ............................................................................................9 5  
 
1 8 . 1 In fo rm e d  C o n se nt  P ro c e du r es fo r P artici p a tin g  Sit es  ................................................................9 5  
1 9 .0  R E F E R E N C E S  .................................................................................................................................9 6  
 
2 0 .0  A P P E N D I CE S  .................................................................................................................................9 8  
 
A p p e n d ix A: P er fo rm a n c e St atu s Criteri a ............................... ...........................................................9 9  
A p p e n d ix B: P ill D iar y  fo r IR B # 1 4 -1 4 0 : P A R T  A  ...............................................................................1 0 0  
 
A p p e n d ix C: P ill D iar y  fo r IR B # 1 4 -1 4 0 : P A R T  B ................................................................................1 0 4  
A p p e n d ix D : LIS T  O F C Y P 3 A 4  IN H I BIT O R S A N D  IN D U C E R S ( R e fer e nc e  fo r Im ati n ib ).......................1 0 8  
 
A p p e n d ix E: List o f co n co m it a nt m e d ic atio n s t o b e  u se d  w it h c au tio n  wit h B G J3 9 8  ......................1 1 0  
A p p e n d ix F: List o f pr o hib ite d m e d ic atio n s w it h B GJ3 9 8  ................................................................1 1 2  
 
A p p e n d ix G: S e lect  Hi g h -P h o s ph o ro u s Fo o d s a n d  S u g g es te d A lte rn at iv es  .....................................1 1 2  
A p p e n d ix H: O p h t h alm o lo gy  F o rm s .................................................................................................1 1 4  
 
S i gn a tu re  o f E xa m in e r:   
........................................1 1 4  
 
S i gn a tu re  o f E xa m in e r:   
..............................................................1 1 5  


P a g e 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
A p p e n d ix G: O p h t h alm o lo gy  F o rm s… … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … … .1 0 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. 0  
P R O T O C O L S U M M A R Y  A N D/ O R  S C H E M A  
 
A p h as e  Ib /II stu d y o f B G J3 9 8  in  co m b in a tio n  w ith  i m atin i b m es yl a te  i n p a ti en ts w ith 
u n tre a te d  a d v a n ce d g a stro in tes tin al  stro m al  tu m or  (G IS T ) 


P a g e 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
I n c urr e nt st a nd ar d o f c ar e, p ro lo n g e d effic a cy  o f im a tin i b m es y la t e is lim ite d i n  p ati e nts  wit h  lo cal ly 
a d v a n c e d/u n res e ct a ble  o r m e tast at ic G astr o in te sti na l Stro m al  T u m o rs ( GIST s).  I mp o rt a ntly, im ati n i b 
in d u c es m ai n ly cy to sta tic e ff ects i n t h e m a jo rity  o f p a ti e nts wit h  lim ite d  a p o p to tic eff e ct a n d  af fo rd s 
littl e, if a n y, h o p e  t o c ure  a  p ati e nt  wit h  lo c ally a d v a n c e d o r m e tast at ic d is e ase . A b o u t 5 0 %  o f 
p ati e nts  re s p o n d to  im ati n ib  i n t h e first-lin e  s ettin g , b u t n e arly  all p ati e nts  wit h  a d v a n c e d d is ea s e will 
d e v e lo p  im a tin ib -r esist a nce  wit h  a  m e d ia n  tim e  to  p ro g r essio n  o f 2 0 -2 4 m o n t hs aft e r in iti atio n  o f 
t h er ap y [1 -4 ]. S e co n d  a n d  t hir d lin e  o p tio n s h a ve  v e ry  lim ite d  effic a cy wit h  r esp o n s e r ate  o f 4 -1 0 % 
a n d  m e d ia n  P ro g r essio n  Fre e  S u rv iv al (P F S ) ra te s o f 4 -6  m o n t hs [5 -7 ]. 
 
T his  is  a  p h a se  Ib /II  st ud y  o f  a  F G F R  in h ib ito r  (B G J3 9 8 -N o v artis)  i n  co m b in ati o n  w it h  im ati n i b 
m e sy l ate  (G le e vec  - N o v a rtis) as  a  first lin e  th er a p y  in  p ati e nts  wit h  u n tr e ate d  lo c all y a d v a n c e d o r 
m e tast at ic GI ST.  T h e  st ud y  is d esi g n e d  to  s p ecifical ly t arg et  t h e F G F R  a n d M A P K  p at h w a y s i n 
co n ju n ctio n wit h  c-KI T  i n GIS T.  W e  b eli e v e  t h at t his n o vel  co m b in at io n str at e gy  will  p ro v e  t o b e  m o re 
eff e ctiv e  t h a n sin g l e a g e n t im ati n i b a n d  p ro v id e  a n  eff e ctiv e  th er a p e utic  r e gim e n  t h at will  h el p 
p ati e nts wit h  a d v a n c e d GIST . T h e c o m b in at io n  t he r ap y  will d o  t his b y t arg e tin g  th e  M A P K p at h w a y , a 
m a jo r p at h w ay  im p lica te d  i n t h e d e v e lo p m e nt  o f re sist an c e to  sin g l e a g e nt  im ati n ib , a n d  a  critic al 
lin e a g e  sp ecific  s urviv al  fa cto r o f GI S T  a n d  its p re c urso r I CC -E T V 1 . M o re o ver,  w e  b el ie v e  t h at t h e 
co m b in ati o n  th er a p y  will  sig n ific an tl y e n h a n c e a p o p to sis a n d  p o te nti a te  t h e e ffic ac y o f tre a tm e n t. 
W e  b eli e ve  t his stra te g y will  als o  eff e ctiv ely  a d d r ess m a n y o f t h e im a tin ib -re sist an c e m ec h a n ism s 
t h at ar e i n p art  m e d ia te d  b y  F G F R si g n al i ng . 
 
T h e  p ri m ary  g o al  o f th e  p h as e  I b st ud y  is t o ass e ss t h e to ler a b ility a n d  s af ety o f t h e co m b in at io n 
t h er ap y . O nc e t h e h ig h e st to l er ab le  d o s e is id e ntif ie d  o r t h e clin ic al d o s es o f im ati n i b (4 0 0  m g d ai ly) 
a n d  B G J3 9 8  (1 2 5  m g  q d  –  th r e e w e e ks o n  a n d  o n e  o ff) ar e  re ac h e d,  th e  p h a se  II p o rtio n  o f t h e st ud y 
will  b e  in iti at e d.  T h e  p rim ar y e n d p o in t o f t h e p h as e  II p o rtio n  is to  ass e ss R es p o n se  R a te  ( R R) 
(co m p l ete  re s p o ns e (C R)  +  p arti al r e sp o n s e (P R )) b y  R E CI S T  1 .1 . 
 
T h e  p h as e  I b p o rtio n  o f th e  st ud y  will  b e  p erf o rm e d  in  st a nd ar d  3 + 3  f ash io n . T h e  p h as e  I b p o rtio n o f 
t h e st ud y  will  b e  o p e n  t o a ll p ati e nts  wit h  lo c ally  a dv a n c e d o r m e tast at ic GI ST  w h o  h a v e  p ro g ress e d 
o n  im ati n ib .  A n  in iti al co h o rt o f t hre e  eli g ib l e p ati e nts  wit h  lo c ally a d v a n c e d o r m e tas tatic  GI S T  will 
in iti at e tr eat m e nt  w it h B G J3 9 8  a t 7 5  m g  d ai ly  (th r e e w e e ks  o n  a n d  o n e  o ff) a n d i m ati n i b at  4 0 0  m g 
d ai ly fo r 4  w e e k s ( 1 cy cl e). D e p e n d in g o n  t h e to xicity, d o s e le vels  o f im ati n i b (4 0 0  m g  d ai ly ) +  B G J3 9 8 
will  b e  in v es tig at e d as  o u tlin e d  b el o w  ( T ab l e 1) . As i m ati n i b 4 0 0  m g P O  Q D  is st a nd ar d o f c ar e fo r 
m e tast at ic GI S T , t his d o se will  r em ai n  co n st a nt ( b arrin g  in d ivi du al  d o s e m o d ific atio n s o u tlin e d  i n 
s ectio n  9 .2 a ). 
 
 
 
 
 
 
 
 
T a b le  1 : T h e  d o s e e sca la tio n  sch e m a:  
 
D o s e L e v el 
Im ati ni b  
B G J3 9 5  
 
-2  
4 0 0 m g  d a ily  
2 5  m g  q d  


P a g e 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
-1  
4 0 0  m g  d a ily  
5 0  m g  q d  
1  
4 0 0  m g  d a ily  
7 5  m g  q d  
2  
4 0 0  m g  d a ily  
1 0 0  m g  q d  
3  
4 0 0  m g  d a ily  
1 2 5  m g  q d  
 
 
A n y  a d v ers e  e ve nt  t h at m e e ts crit eri a i n s ectio n  9 . 1 th at  o cc urs p ri or to  t h e s eco n d  cy cl e (i.e.  b ef o r e 
C 2 D 1 ) will  b e  co n sid er e d  a  D o s e Lim itin g  T o xicity (DL T ) fo r t h e p u rp o ses  o f d o s e es cal a tio n  t o t h e 
n e xt d o s e le v el.  A n y  a d v e rs e e ve nt  t h at o cc urs a fte r th e  first cycle  m a y r e qu ir e a d o se  r e du ctio n  fo r 
t h e p ati e nt b u t will  n o t im p act  t h e ass e ssm e nt  o f d o s e l evel s af e ty . 
 
T h e  p h as e  II  p o rtio n  o f  t h e  st ud y  will  b e  u s e d  to  co n firm  t h e  s afe ty  a n d  to l er ab ility  o f  t h e 
co m b in ati o n  a n d  to  a ss ess a d d itio n al  effic a cy sig n als o f th e  co m b in ati o n  i n p at ie nts  wit h  u n tre at e d 
lo c all y a d v a n ce d o r m e t astatic  GI ST. R es p o n s e R a te  (R R)  b y  R E CI ST  1 .1  will  b e  th e  p ri m ary e n d p o in t. 
S ec o n d ary e n d p o in ts will in clu d e  R R  b y C h o i crite ri a a n d  E O R T C  criteri a  fo r p a rti al r es p on se  o n  F D G 
P E T  (2 5 %  r e du ctio n  i n P E T  S U V m ax)  3  w e e ks  (C 1 D 2 1 ) af ter  co m b in ati o n tr e at m e nt,  P F S , O S  a n d 
r ese cta b ility ra te s. A lso , th e  tri al will  b e  ric h i n m o lec u l ar co rr ela te s/e x plo r ato ry  e n d p o in ts t h at will 
in clu d e  M A P  ki n a se,  F G F R, a n d  KI T  sig n al i ng  p at h w a y  in h ib itio n , e v al u at io n  o f FG F 2  a n d  FG F R  l eve ls 
o n  t u m o r  tiss u e, FG F2  ser u m  le v els,  E T V 1  in h ib itio n  ass es se d b y  E T V 1  p ro te i n  le vel s, a n d  its  
tr an scrip tio n al  a ctiv ity  b a se d  o n  a  c usto m  E T V 1 -d e p e n d e nt  g e n e  sig n at u re.  T h is co m b in e d  a n alysis 
will  b e  critic al t o p ro p er ly d esi g n  fu t ur e clin ic al tria ls o f t his co m b in ati o n  i n p ati e nts wit h  lo c all y 
a d v a n c e d o r m e t ast atic GI ST.  
 
T h e  tri al ph a se  Ib /II sc he m a  is o u tlin e d b e lo w : (Sc h e m a  1 ): 
 
 
 
A ll p artici p a n ts o n  t h e P h as e  II p o rtio n  will  h a ve  a  2 -w e ek  l e a d i n o f im ati n i b al o n e.  Bl o o d  will  b e 
d r a w n at th e  e n d  o f th is p erio d  to  e sta b lis h ste a d y -sta t e tro u g h  im ati n i b se ru m  le v els. Aft er bl o o d  fo r 
im ati n i b le v els ar e o b t ain e d , B G J3 9 8  at t h e  re co m m e n d e d  P h as e  II d o se  (R P 2 D ) a n d  sc h ed u l e will  b e 
a d d e d  t o t h e r e gi me n.  T h e  in iti atio n  o f B G J3 9 8  will  n o t b e  co n tin g e nt  o n  t h e im ati n i b l ev el;  rat h e r, 


P a g e 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
B G J3 9 8  c a n b e  st arte d  af ter  t h e b lo o d d r a ws fo r im ati n i b le vels  ar e  p erf o rm e d.  T h e  st art o f th e  
co m b in ati o n  t h er ap y w ill b e  co n sid er e d C y cl e 1 , D a y 1 . 
 
2. 0       O BJ E C TI V E S  A N D S C IE N T IF IC  AI M S  
 
H y p o th e sis: T ar g e tin g  t h e M A P K  p at h w a y  a n d  F G F R  sig n al i ng  b y  co m b in in g  B G J3 9 8  a n d  im ati n i b will 
b e  a  s af e a n d  a  m o re  eff e ctiv e t h er a p e utic  str ate gy t h a n  im ati n i b al o n e  i n p at ie nts  wit h  u n tr ea te d 
lo c all y a dv a n ce d o r m e ta static GI S T.  
 
P rim a ry  O bj e ctiv e : 
 
P h as e  I b st ud y: t o a ss ess th e  s af ety  a n d  to l er ab ility o f tr ea tm e n t wit h  B G J3 9 8  (a n  F G F R  in h ib ito r) i n 
co m b in ati o n  wit h  im ati n i b a n d  t o d e te rm in e  t h e M T D  a n d  t h e r eco m m e n d e d  P h as e  II d o s e (R P 2 D ) 
a n d  sch e d u l e o f th e  co m b in ati o n  th e ra p y  i n lo c ally  a d v a n c e d o r m e t asta tic GI S T  p ati e nts.  
 
P h as e  II st ud y : to  as sess  th e  eff ic acy  (R R  =  co m p let e  r esp o n s e (C R)  +  p arti al  r es p on s e (P R))  a t 3 2 
w e e ks  o f  t h e  co m b in at io n  t h er ap y  o f  B G J3 9 8  a n d  i m ati n i b  i n  p ati e nts  wit h  u n tr e ate d  lo c ally 
a d v a n c e d o r m e t ast atic GI ST,  u sin g  R E CI S T  1 .1 . 
 
S ec o n d a ry  O b jec tiv e s: 
 
P h as e  I b st udy : t o ass e ss th e  p h ar m a co ki n e tics o f B G J3 9 8  a n d  im ati n i b; to  e stim a te  R R  ( C R +  P R)  b y 
3 2  w e e ks b y  b o t h R E CI ST  1 . 1 a n d  C H OI  crit eria , p ro g r essio n  fre e  s urviv al  (P F S) a n d  clin ic al b e n efit 
r at e (C R + P R + SD ) at  3 2  w e e ks  o f t h e co m b in ati o n  t h er a p y o f B G J3 9 8  a n d  im ati n i b i n  all lo c ally 
a d v a n c e d o r m e t ast atic GI ST  p ati e nts w h o  h a ve  rec e ive d p rio r t h er ap y  w it h im a tin i b. 
 
P h as e  II st ud y : t o ass e ss th e  R R  (C R  +  P R)  o f th e  co m b in ati o n  t h er ap y  o f B G J3 9 8  a n d  im ati n i b b y  C H OI 
crit eri a, a n d b y  E O R T C  criteri a  fo r p arti a l r es p on se  o n F D G  P E T  (2 5 %  r e du ctio n i n P E T  S U V m a x), P F S , 
o ver all  s urv iv al  ( OS), clin ical  b e n efit  r ate  ( CR + P R + S D)  at  3 2  w e e k s a n d r e s ect a bilit y r ates  i n p ati e n ts 
wit h u n tr ea te d  lo c all y a dv a n c e d o r m e ta st atic un tre a te d GI S T.  
 
C o rre la tiv e  O b je ctiv e : 
 
W e will  a n alyz e t h e m o l ecu l ar a n d  sig n al i ng  eff e cts o f im ati n i b i n co m b in at io n  wi th  B G J3 9 8  u sin g 
t um o r b io p s y sp ec im e ns co ll ecte d  p r e- a n d p o st-tr eat m e nt  ( C1 D 8 ), a n d (if f e asi b l e) u p o n d is e as e 
p ro g r essio n . Bi o p sies  will  b e  p erf o rm e d  o n  a m in im u m  o f 2 0  p at ie nts  fro m  t h e P h as e  II p o rtio n  o f th e 
st ud y  acr o ss all  sit es. I n a d d itio n , b lo o d  a n d  s er u m w ill b e  co ll ecte d  t hro u g h o u t t h e tri al. A ll o f t h es e 
s am p l es  will  b e  u se d  to  a n al yz e  t h e  p h a rm a co d y n a m ic  eff ects  o f  B G J3 9 8  in  co m b in ati o n  wit h 
im ati n i b o n  t h e fo llo wi n g  a n d  co rr ela t e w it h clin ic al re s p o ns e t o h el p  id e nti fy p ro m isin g  p ro g n o stic o r 
p r e dictive  b io m ar kers  fo r fu rt h er st udy : 
 
•  E T V 1  p ro tei n l e v el b y  w es ter n b lo t (W B ) 
•  E T V 1 -d e p e n d e nt  tr an scrip to m e  (e x press io n  p ro file  o f  E T V 1 -d e p e n d e nt  g e n e  t arg e ts)  b y 
n a n o strin g . 
•  Ex pr ess io n  o f  g e n es  im p lic ate d  i n  GI S T  p at h o g e n e sis  a n d  sig n al i n g,  in clu d in g  KI T,  E T V 1 , 
F G F R 1,  -2 , -3 , a n d -4 ; D U S P 6 , SP R Y 2 , a n d SP R Y 4 . 
•  C ell p ro lifer at io n  (K i-6 7 ) a n d  a p o p to sis (cle a ve d c as p a se -3 ) b y  IH C  


P a g e 1 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
•  M A P  ki n a se  p at h w a y  a n d  o t h er  p at h w a y s  d o w nst re a m  o f  KI T  sig n al i ng  u sin g  st a nd ar d 
a n tib o d i es (p h o s ph o -E R K,  p h o s ph o -KI T,  p h o s ph o -M E K,  p h o s ph o -A K T)  by  IH C  
•  KI T /P D G FR A  m u t atio n al  st atu s  i n  m atc h e d  t um o r  b io p s y  sp eci m e ns  co ll ecte d  p ri or  t o 
t h er ap y , a fte r co m b in at io n  t h er ap y a n d  u p o n  d is e as e pr o g r essio n . FG F R  a n d  F G F2  e xp ress io n 
o n  tu m o r sa m p l es b y  IH C a n d  F G F2  lig a n d  l ev els i n  co llec te d  s eru m  by  E LIS A.  
•  P ro te i n e xp re ssio n  o f FG F2 , s V E GF R 1 , s V E GF R 2 , V E G F -A,  -C,  -D , c KI T, P LG F, a n d  Ti e 2  i n t um o r 
tiss u es utilizin g  co m m erci a ll y a vai la b l e im m u n o ass a y  kits 
 
W e  will  als o  m o n ito r th e  eff e ct o f B G J3 9 8  o n  im at in i b s er u m l evels  b y  m e a su rin g  t h e ste a d y -st ate 
im ati n i b s eru m  tro u g h  le vels  at  t h e e n d o f th e  2 -w e e k  le a d  i n im ati n i b al o n e  p h as e  a n d  aft er  t h e 
co m b in ati o n  o f B G J3 9 8  a n d  im ati n i b th er a p y  a t w e e k 3  a n d  w e e k 5  ( C1 W 3  a n d  C 2 W 1 ). 
 
3. 0  
B A C K G R O U N D  A N D R A T I ON A LE  
 
3. 1  
T a rg e tin g  E T V 1  in  G IS T  
 
3 .1 .1 . K IT  in h ib iti on  b y T K Is in  G IS T : al th o u g h  eff e ctiv e , tu m o r re sista n c e in v a ria b ly  o ccu rs 
 
G astr o in tes tin al  stro m al  tu m o r (GI S T)  re p re s e nts o n e  o f th e  m o st co m m o n  s ub ty p es  o f h u m a n 
s arco m as. GI ST  is t ho u g h t to  ari se  fro m  th e  In ters titi al C ells  o f C aj al (I C Cs), w hic h  h ig h l y e xp r ess th e 
KI T  re c e pto r ty ro sin e  ki n a se  ( RT K)  [8 ]. T h e m a jo rity  o f GI S Ts  h ar b o r act iv ati n g  m u t atio n s i n t h e KI T 
R T K , a n d t o a  l ess er e xte nt  i n th e P D G F R A  R T K  a n d B R A F  s erin e /t hre o n in e  kin a se  [9 -1 1 ], a n d th es e 
m u t atio n s are  th o u g h t to  fu n ctio n  as  o n co g e n ic " driver"  m u t atio n s re q u ir e d fo r g ro w th  a n d  s urviv al 
o f GIS T.  T h es e  o b ser va tio n s h a v e pr o v id e d t h e  scie nt ific r atio n al e fo r th e  clin ic al s ucc ess o f usi ng 
ty ro sin e  kin a se  in h ib ito rs (T K Is), e .g . im a tin i b m es y la te  ( Gle e ve c® ), i n th e  m a n a ge m e nt  o f a dva n c e d 
GI S Ts.  
 
I m atin i b h as b e co m e  t h e first lin e  st a nd ar d  o f c ar e i n a d v a n c e d GIS T , w it h a re s p o ns e ra t e ( R R) o f 
a p p ro xim at e ly 4 5 -5 0 %  a n d  o ver all dis e a s e co n tro l i n 8 0 %  t o 8 5 %  o f p atie nts,  as  w ell  as a  m e d ia n 
p ro g r essio n  fre e  s urv iv al (P F S ) o f 2 0  to  2 4  m o n t hs [3 , 4 , 1 2 ]. D es pi te  t h e e ar ly  clin ic al s ucc ess, th e 
m a jo rit y o f p ati e nts  d e v e lo p  r esist a nce  to  im ati n i b wi th i n 2 -3  y e ars  o f tr ea tm e nt  [3 , 1 3 ]. T w o s e co n d 
lin e  t h er ap e ut ic o p tio n s e xist i n cu rr en t sta n d ar d  o f ca r e fo r GI S T p at ie nts  t h at ha v e  p ro g r esse d  o n  
4 0 0 m g  o f im a tin i b p er d a y.  O n e  str ate g y  e n tai ls i ncr ea sin g  th e  im ati n i b d o se  fro m  4 0 0 m g  to  8 0 0 m g 
d ail y , w h ic h h as  a  m e d ia n  tim e  t o pr o g re ssio n  ( TT P ) o f 1 2  w e e k s a n d  pr im ar ily  b e n efits  p ati e n ts wit h 
KI T  e xo n  9  m u t atio n s [4 , 1 3 , 1 4 ]. Alte rn at iv e ly , p atie n ts c a n sw itc h th er a p y  fro m  im ati n i b to  s un itin i b 
m al a te,  a n o t h er m u lti-tar g e te d  T K I t ha t in h ib its V E G F/P D G F R /KI T , w hic h  h as a  m e d ia n  T T P  o f 2 7 . 3 
w e e ks  [1 5 ]. R ec e n tly , th e  FD A a p p ro ve d re g o r afe n ib  a s a t hird -lin e  tre a tm e nt  fo r GI S T  b as e d  o n  a 
r an d o m ize d p la c e b o co n tro ll e d P h as e  III tri al i n w hic h  re g o r afe n ib  s ho w e d  a  3 .9  m o n t h im p ro v e m e nt 
i n P F S  o ver  a  p l ace b o  a n d  a  re s p o nse  r ate  o f 4 . 5 % [7 ]. T h e  lim it e d res p o n se  r ate  o f s un itin i b i n t h e 
s ec on d  lin e  se ttin g  a n d  th e  d o cu m e n te d l ac k  o f e ffica cy se e n  wit h T KIs i n t h e  th ird  lin e  s ettin g  cl e arly 
in d ic at e t h at a  g e n e r al dis e as e  r esist a nc e to  th is cl ass o f in h ib ito rs d e ve lo p s o n c e dis e as e  p ro g r essio n 
o cc urs o n  im ati n ib . D es pi te  th es e  clin ic al o b s erv at io n s, pr og r ess h as b e e n s lo w  i n i d en tify in g  a n d 
a p p l yi n g n o vel tre a tm e nt  str ate g i es fo r p ati e n ts w it h im ati n i b (a n d  h e n c e o t h er T KI)  r esist a nt dise as e . 
 
T h e  m ec h a n ism s o f im ati n ib  re sist an ce  i n GI S T  ar e  co m p l ex a n d  h et e ro g e n e o u s. A p p ro xim a te ly  5 %  o f 
p ati e nts h a v e  p rim a ry  re sist a nc e to  im ati n i b wit h  p ro gr essio n  o f dise as e  w ith i n tw o m o n t hs o f 
tr e atm e nt.  A b o u t 1 4 %  o f p ati e nts d e v e lo p  e arl y  r esista n c e to  im ati n i b af ter  a p p ro xim at e ly  4  m o n t hs 


P a g e 1 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
KI T wt 
KI T wt 
KI T ∆5 6 0  
 
P  M E K 
P  M E K 
P P M E K  
P  
E R K 
E R K 
E R K  
D e c re a s e d  IC C  s u rv iv a l  
N o rm a l IC C  d e v e lo p m e n t 
IC C  h y p e rp la s ia  a n d  G IS T  
 
Fi g u r e 1. Mo d el of t h e r ol e of E T V 1 i n I C C m ai nt e n a n c e a n d GI S T o n c o g e n e s i s. 
N o r mal  le v el  of  KIT a c tiv a tio n  b y  KI T lig a n d (re d  tri a n gle)  sta b iliz e s  E T V 1 tr a n s cri ptio n 
f a ct or t hr o u g h t h e MA P K p a t h w a y, a n d r e s ult s i n p hy s i olo g ic al  E T V 1 tr a ns c ri pti o n al o ut p u t 
criti c al  f or I C C d e v e lo p m e nt ( mi d d l e). I n t h e a b s e n c e  of E T V 1, t h ere i s d e cr e a s e d  I CC 
d e v e lo p m e nt, w hi c h  p he n o c o pi es g e n eti c l o s s  of  KIT s i g n allin g  (l eft). A ctiv a ti n g m ut atio n  
of KI T ( e. g. KI T ∆5 6 0 ) le a d s t o c o n stit uti v e  a ctiv a ti o n of t h e KI T- MA P K si g n a llin g p a t h w a y, 
i n cre a s e d  sta b iliz a ti o n a n d a u g me n t e d E T V 1 tr a ns c ri pti o n al o ut p u t t h at pr o m ot es 
t u m orig e n e si s (ri g ht). 
 
E T  
E T  
o f tre a t me nt.  T h e  m aj ority of p atie nts  d ev el o p r esista n c e t o i mati n i b af ter  ap p r oxim at ely  2- 3 ye ars  of 
tr e at me nt  [ 1 2]. S ec on d ary  m ut ati o ns ar e r ar e i n p rim ar y  r esist a nce , but ar e f o u n d i n ab o ut 5 0- 6 7 % o f 
p ati e nts  wit h s ec o n d ary r esist a n c e [1 6 , 1 7]. T h e r est of sec o n d ar y  resist a n c e has  u n k n o w n e tiol o g i es. 
Ot h er  c aus es  of s ec on d ar y  r esist a nc e ar e  still b ein g d e fin e d;  r ese arc h e rs at MS K C C r e c e ntly 
c orr elat e d a n i nt r atu m o r al im m u n e r esp o ns e w it h i m atin i b r esist anc e i n GI S T  [ 1 8].  M or e over,  rec e n t 
d at a s u g g est  t h at t h e GI S T st em/ pr o g e n it ors ar e KI T -l o w a n d KI T -in d e p e n d e nt  a n d t her e f or e 
i mati ni b-i n s e nsitiv e [1 9 ], w h ic h mig h t acc ou n t f or p art  of t h e re sist anc e m ec h a nis m s i n b o t h pri mar y 
a n d s ec o n d ary r e sist anc e s et tin g s. I n a d d iti o n, activat i o n of alt er n a tiv e si g n ali n g p at h w ays  s uc h as 
t h e M A P Ki n as e  p at h w a y a n d t h e PI 3 K p at h way h a v e als o  b ee n c orr elat e d wit h t h e d evel o p m e nt  of 
p ri m ary i m atin i b r esist a nc e [2 0 ]. I n s u m mar y, alth o u g h KI T  in h i bitor s h av e r ev ol utio niz e d t h e 
tr e at me nt  of a dv a n ce d GI ST,  t h e effic acy is n ot i nd ef i nit e a n d it is n ot c ur ativ e i n m ost a dv a nc e d GI S T  
p ati e nts  [ 3, 4, 1 2, 2 1 -2 4 ]. 
 
H er e,  w e  pr o p os e  a  
n o v el 
str ate gy  
t h at 
c o m bi nes   in h i bitio n o f 
b o t h 
KI T
 a n d  F G F 
sig n ali n g   p at h w a ys. 
T h e   g oal of s uc h d u al 
in h i bitio n   is    to   n ot 
o n l y   t arg et   KI T,   b u t 
als o  t h e  M A P  Ki n as e 
p at h w ay
 ( v i a  
F GF 
sig n al i n g).  W e  h ave 
r ece ntl y 
d iscov er e d 
t h at t h e M A P  Ki n as e 
p at h w ay   pl ays a m aj o r 
r ol e 
i n
 t h e
 
p at h o g e n esis
 a n d 
pr o p a g ati o n    of    GIS T 
by sta b ilizi n g E T V 1  [2 5 ]. E T V 1  is a lin e a g e  s p ecific s urvi v al f actor i n GI S T t h at co o p er at es wit h m u t a nt 
KI T  i n  o nc o g e nesis.   E T V 1  is  a  mast er r e gu l at or  of a n  I CC- GI S T- s p ecific tr ansc rip tio n  n et w o r k. T h e 
E T V 1 - de p e n d e nt  tr an scripti o n al   pr o gr a m is  f urt h er  r eg u l at e d  by acti vat e d KI T , w hic h  pr ol on g s  ET V 1 
pr ot e i n st a bility vi a its do w nstr e a m M A P  ki n as e si g n ali n g p at h w ay  a n d  str on g l y co o p er at es wit h  E T V 1 
t o pro m o t e t u m orig e n esis ( Fi g u r e 1) [2 6 ]. T h e f act t hat  E T V 1  is a lin e a g e - s p ecific tr an scrip tio n f act or 
r e qu ir e d f or t h e s urvival o f t h e I C C/ GI S T lin e a g e a n d m a y  d efin e t h e o pti mal  c ell ul ar c o nt ext f or KI T - 
m e d i ate d   o nc o ge n esis   in d icat es t h at E T V 1  m ay  al s o  b e critic al  f or t h e  s urvi v al  a n d  mai nt e n a n c e  of 
t h e i ntrin sic ally i mati n i b-r esist a nt, KI T -in d e p e n d e nt  ste m  cell / pr o ge n it ors i n GI S T a n d p osits E T V 1 as 
a  n o v el  t h er ap e u tic t arg e t i n  b ot h  i m atini b-s e nsiti v e a n d  - r esist a nt  GI ST.  W h il e it is c ha ll e ngi n g t o 
t arg et  tr ans crip tio n  f act ors, t h e o bs erv at i o n t h at  t he E T V 1   pr ot ei n  l evel  is st a bilize d   by act ive M A P 
ki n as e   sig n ali n g h as  pro v i d e d us wit h  t h e sci en tific  r atio n al e   t o  ex pl or e t h e t h er a pe utic   p ote nti al   of 
t arg eti n g E T V 1   pr otei n   st a bilit y  by  in h i bitin g t h e   MA P  ki n as e   sig n al i ng p at h w a y  i n b o t h  i m atini b- 
s e nsiti v e  a n d  -r esist a nt GI S Ts. T his   strat e gy if  s ucc essfu l,  s h all  by pass  t h e  diff ere nti al effic a cy  of 
i mati n i b  a nd  s u nitin i b  on  GI S T  t um o rs  wit h  diff ere nt  KI T  m ut a tio n al  st atus ,  a nd  p ot e nti ally  be 
eff e ctiv e f or all GI S Ts, i ncl u di n g t h os e of t h e GI S T st em/ pr o g e n it or p o o l. 


P a g e 1 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
3 .1 .2     G a stro in t estin a l S tro m a l T u m o rs O v er e x p re ss FG F 
 
T h e  F G F p at h w a y  h as r e ce ntl y  b e e n i d e ntifi e d  as a p o ssib l e m e d iat o r i n t h e d e v e lo p m e nt  o f GIS T 
r esist a nce  to  im ati n ib . P re clin ic al w o rk  h as  es ta b lish e d  F G F 2  as  b ei n g  h ig h ly o v er e x pr esse d  i n GI S T 
t um o rs as  co m p ar e d  to m u ltip l e o t h er m al i g na n ci es ( Fig u r e 2 a).  T h e  F G F  R e c e pto r ( F GF R)  is al so 
u p r e gu l at e d i n GI ST  w h e n  co m p ar e d  to  o t h er tu m o rs ( Fig u r e 2 b ). Sti m u l atio n  o f GI S T  c ells wit h  FG F2 
i n v itr o s ee m s t o act iv at e  th e  F G F  p at h w a y  a n d  d o w n stre a m  ef fec to rs o f t h e M A P  Ki n a se  p at h w a y  (p - 
E R K)  ( Fig u r e 2 c). S u b s e qu e nt  b lo c k ad e  o f F G F  sig n al i ng  wit h  B G J3 9 8  (N o v a rtis, p a n -F G F R  in h ib ito r) 
in h ib its FG F 2  sig n al i ng  a n d  i n F G F 2  stim u l ate d  ass a ys is a b l e to  al so  a b ro g at e  M A P K  sig n al i ng  ( Fig u r e 
2 d ).  In te r estin g ly,  im a tin i b  is  a b l e  t o  a b ro g a te  p -E R K  sig n al i ng  i n  F G F 2  n o n -stim u l ate d  ass a ys 
s ug g es tin g  t h at i n th e  a b se nc e o f FG F 2 , M A P  Ki n as e si g n al i ng  is m e d ia te d  b y K I T. H o w e ver,  i n FG F 2 
stim u l ate d  ass a y s, im ati n ib  is u n a b l e t o a b ro g a te  p -E R K,  s ug g e stin g  t h at th e  acti v ity o f t h e M A P 
Ki n as e  sy ste m  is d e p e n d e n t o n  F G F,  m o re  s o t h a n KI T sig n al i n g, i n F G F  d e p e n d e nt  t um o rs. T ak e n 
to g e th er,  t h ese  d at a  s ug g est  t h at a  n u m b er  o f GI ST  t um o rs h a v e  h ig h  e xp r essio n o f F G F 2  a n d 
s ub s e qu e nt act iv ity/ p e n et ra n c e o f th e  F G F  si gn al i ng  p at h w a y . 
 
 
 


P a g e 1 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 .1 .3     T h e  F G F P a th w a y M a y M e d ia t e Im a ti nib  R esis ta n c e vi a  M A P  K in a s e S ig n a lin g  
 
T o  fu rt h er e xp lo re  h o w  th e  F G F a n d  M A P  kin a se  p a th w a y s ar e  in terr el a te d  a n d  acti v e  i n GI S T,  GI S T 
c ell lin es  w e r e e xp o se d t o  im ati n i b i n c ult ur e fo r e xte n d e d p eri o d s o f tim e  ( Fig u r e 3 ). Aft er t hr e e d a ys 
o f e xp o s ure,  th e  F G F sig n al i ng  p at h w ay  b e co m es  act iv at e d  as  n o te d  b y ac q u ir e d e xp r essio n  o f F R S2 . 
At b as eli n e , p -E R K  is activa te d . H o w e ver,  its a ctiv it y is q u ic kly a b ro g a te d u p o n e x p os ure  to  im ati n ib . 
H o w e v e r,  p -E R K  a ctiv ity  is  r e activ at e d  wit h  p ro lo n g  e xp o s ure  t o  im ati n i b  w h e n  F G F  sig n al i ng 
acti v a te s ( da y  3 ).  S u b s eq u e nt  e xp o s ure  to  B G J3 9 8  n o t o n ly  s hu ts o ff F G F  sig n al i n g, b u t als o  p -E R K 
sig n al i n g. T his  stro n g ly s ug g es ts t h at re sist an ce  t o im ati n i b is m e d iat e d  b y  M A P  Ki n as e  sig n al i ng  v i a 
t h e F G F  p at h w a ys a n d  t ha t in h ib itio n  o f t h e F G F  p at h w a y wit h  B G J3 9 8 m a y n o t o n ly  o ver co m e 
r esist a nce  b u t p ro v id e  a m ec h a n is m to  a v o i d im ati n i b re sist an c e if t h e dru g s ar e g i ve n  i n co m b in at io n 
at  t h e st art o f t h er ap y . I n FG F  t um o rs, t h e act iv ity  o f t h e M A P  Ki n as e  p a t h wa y as  m e d ia te d  b y FG F 
sig n al i ng  m a y  p la y  a  ro l e i n c ellu l ar pr oli fer at io n  a n d  th e  d e v el o p m e n t o f im ati n i b r esist a nce.  
 
3 .1 .4     Im a tin ib  P l us B G J3 9 8  H a s G re a ter  A n ti pro lif era tiv e  E ffe cts in  G IS T  T h a n  B o th  Im a tin ib  a n d  
B G J3 9 8  A lo n e  
 
T h e  co m b in at io n   o f  im ati n i b  a n d 
B G J3 9 8 
m a y 
b e 
m o r e effici e nt  i n  
aff ecti n g  t h e  g ro w th   o f  GI S T  a s 
o p p o se d  to  im ati n i b  alo n e.  C ell u l ar 
p ro lif er atio n  ass a y s w er e  p erf o rm e d o n 
GI S T  c ell lin es  i n  t h e p r ese n c e a n d 
a b s e nc e o f FG F 2  stim u l atio n ( Fi g u r e 4 ). 
E v e n  is  th e  a b s e nc e   o f  F G F 2 
stim u l atio n ,  t h e   co m b in ati o n  o f 
im ati n i b 
p lu s 
B G J3 9 8  
w as 
m o r e 
effic ac io u s i n  killin g  b o t h GI S T -T 1  a n d 
GI S T -8 8 2  cells.  


P a g e 1 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
3 .1 .5     F G F R  In h ib iti on  is S u p e ri or t o 
M E K  i nhi bi tio n  in  F G F  St im u l ate d 
GI S T  S yst e ms  
 
S i nc e t h e act iv ity o f t h e FG F  sig n al i ng 
p at h w ay  i n   GIST,  fo r  b o t h 
p ro lif er atio n  a n d  t h e d e v e lo p m e nt o f 
r esist a nce,  a p p e ars  t o  b e  m e d iat e d 
b y  t h e M A P  Ki n as e  p a t hw a y,  fu rt he r 
in v es tig at io n s w er e  d o n e  to  s e e h o w 
B G J3 9 8  w o u l d  co m p a re   t o   th e 
acti v ity o f a  M E K  in h ib ito r (M E K 1 6 2  –  
N o v art is).    Elec tric al    im p e d a n c e 
ass a ys  w e r e p erf o rm e d o n  GI S T  c ell 
lin e  lin es  i n th e  p re s e nc e a n d  a bs e nc e 
o f FG F 2  stim u l atio n  ( Fig u r e 5 ). I n t h e 
a b s e nc e o f FG F2 , t h e co m b in ati o n o f 
im ati n i b   p lu s   M E K 1 6 2   se e m e d   to 
h a v e  si g n ific an t  s up eri o rity  o v er t h e 
co m b in ati o n o f im a tin i b p lu s B G J3 9 8 . 
T his  s u g g es ts t h at th e  M A P  K in as e 
p at h w ay  is a ctivel y  co n trib u tin g  t o  
GI S T      o n co g e n esis      at      b as eli n e,  
p o ssib l y t hr ou g h E T V 1  sig n al i ng a n d  t h at d u al  in h ib itio n wit h  a  M A P  Ki n a se  p at h w a y  in h ib ito r wi th 
im ati n i b se e m s to  h a ve  sig n ific an t sy n er g y  o ver  im ati n i b a lo n e.  T his  w ar ra n ts fu rt h er clin ic al 
in v es tig at io n s.  H o w e ve r,  in  t h e  p r ese n ce  o f  F G F 2  sti m u l atio n ,  th e  co m b in a tio n  o f  im ati n i b  a n d 
B G J3 9 8  se e m s t o h a v e  s up eri o rity  o v er  im a tin i b a n d  M E K  in h ib itio n . I n t h e c as e o f FG F 2  stim u l atio n , 
sig n ific an t sy n er g y , m o r e so  th a n  wit h im ati n i b a n d  M E K 1 6 2 , w as  n o te d i n  GI S T  cell  lin es  cells.  
 
3 .1 .6     S u m m a ry  
 
O v er all, t h e se  d at a s u g g est  t h at a s u b s et o f GI ST  r ely o f FG F  sig n al i n g. I n t h ese  tu m o rs, p ro lifer at io n 
a n d  im ati n i b re sist an c e is m e d ia te d  v i a t h e M A P K  p a t h w ay . B G J3 9 8 , a  p a n  F G F R  in h ib ito r, a p p e ars  t o 
a b ro g at e  F G F  a n d  M A P  K in as e  sig n al i ng  a n d  t h at d u al  in h ib itio n  o f KI T  w ith  a  F G F/ M A P  ki n as e 
p at h w ay  in h ib ito r h as  sig n ific an t syn er g istic eff e cts ov er  sin g l e a g e nt  im ati n i b a n d m a y  p ro v id e  a  w a y 
t o o v er co m e  im ati n i b resi st a nc e as  m e d iat e d t hr o u gh  t h e F G F  sig n al i n g. T h e  im p e d a n c e ass a y s al so 
s ug g est  t h at t h e co m b in at io n  o f im a tin i b a n d  B G J3 9 8  m a y  h a v e  cyto to xic eff e cts i n GI ST  as  o p p o se d 
t o t h e k n o w n  cy to st atic eff e cts o f im a tin i b a lo n e.  T h er e fo re , t arg e tin g  th e se  GI S T  t um o rs i n a n 
u p fro n t s ettin g  m a y  aff o r d t h e o p p o rt un ity to  g r e atly eff e ct o u tco m es  i n e xcess  o f w h at  is c urr e ntly 
s ee n  wit h  im ati n i b al o n e , i. e. p r ev e nt  im ati n i b r esista n c e a n d  p o ssib l y al lo w  fo r cy to to xic ef fe cts o n 
t h e c an c er c ells. I n s uch , w e  ar e  p ro p o sin g  ‘A  p h as e  Ib /II st ud y o f B G J3 9 8  in  co m b in at io n  wit h 
im ati n i b m es y la t e i n p ati e n ts wit h  u n tr e ate d  a d v a n ce d  g astr o in tes tin al  stro m al t u m o r (GI ST)’.  As  t h e 
tr u e p e n etr a n ce  o f FG F  sig n al i ng  i n GI ST  is c urr en tl y n o t k n o w n,  w e  ar e  p ro p o sin g  t his n o v el 
in v es tig a to r in iti ate d tri al a s a m e a ns  o f e st a blish in g  th e  s af ety  a n d  e ffic acy  o f im ati n i b pl u s B GJ 39 8  i n 
GI S T.  I n a d d itio n , t h e tri al will  b e  ric h i n co rr ela tiv e  e x p erim e nts  to  d e te rm in e  th e  tr u e p e n e tr an c e o f 


P a g e 1 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
F G F  sig n al i ng  i n GI S T,  a n d  h e nc e  in te g r al b io m a rk e rs t h at will  h el p  s elect  t h e p a ti e nt p o p u l atio n  w h o 
w o u l d b e n efit  fro m  FG F R i n h ib itio n . I n a d d itio n , as  F G F  sig n al i ng  a p p e ars  t o m e d ia te  M A P  Ki n a se 
sig n al i n g. T his  p ro j ect will als o  b e  d esi g n e d  to  e v al u a t e t h e o v er all eff e cts o f M A P  ki n as e  sig n al i ng  i n 
GI S T  b o t h i n th e  co n te xt o f E T V 1  a ctiv ity a n d  F G F  si gn a lin g  
 
Str at e g ic ally , w e  b eli e ve  th at  t his p ati e nt  p o p u l atio n  will  b e  t h e p u r est co n d itio n  fo r t h e p ro o f o f 
co n c e pt t h at t h e co m b in a tio n  r e gim e n  will  b e  a  m o re  eff e ctiv e  str at egy  t h a n sin g l e a g e nt  im ati n i b 
al o n e. W e  b eli e v e  t h at th is a p p ro ac h  w ill n o t o n ly aff e ct KI T,  F G F R , a n d M A P K  sig n al i n g, bu t als o  E T V 1 
p ro te i n st a bility an d  th e  F G F/ M A P K  p a t h w ays a bilit y to  i ncite  r esist a nc e to  im at in i b th er a p y . 
 
3. 2       B GJ 3 9 8  
 
3 .2 .1     O v er vi e w  o f B G J3 9 8  
 
B G J3 9 8  is a n  o r ally  b io -a v a il ab l e, s ele ctiv e  a n d  A T P  co m p e titiv e  p a n -fib ro b l ast g ro w th  fac to r re c e pto r 
( F GF R)  ki n a se  in h ib ito r w hic h  h as  d e m o n str ate d  a n ti-t um o r a ctiv ity i n p r eclin ica l, i n vitro  a n d  in -vivo 
t um o r m o d els  h ar b o rin g  F G F R  g e n etic  alt er a tio n s.  B GJ3 9 8  b el o n g s to  t h e p y ri mi di ny l a ry l u r e a 
c h em ical  cl ass  a n d  its  ch e m ic al n a m e  is 3 -(2 ,6 -D ich lo ro -3 ,5 -d im e th o xy p h e ny l)-1 -{6 -[4 -(4 -e th y l-1 - 
p ip er a zin -1 -y l)p h e nyl a m in o] -p y rim id in y l-4 -y l}-1 -m e t hyl ure a  p h o s ph at e (1 :1 ). 
 
As  o f S e p te m b e r 2 4 , 2 0 1 3 , 9 4  p at ie nts  h a v e  b e e n  e n ro ll e d to  t h e C G B J3 9 8 X 2 1 0 1 st u d y .  T h e  M T D  h as 
b e e n  i d en tifi e d as  1 2 5  m g  o n c e d ai ly  (q .d .). 
 
P l e ase  r efer  to  t h e I nves tigat o r’s B ro c hu r e fo r a dd itio n al i n fo rm ati o n  o n  B G J3 9 8 . 
 
3 .2 .2     N o n -clin ica l e xp e rie n c e 
 
At  t h e c ellu l ar l evel, B GJ 3 9 8  sel e ctive ly in h ib its th e  k in as e  a ctiv ity o f FG FR 1  FG FR 2 , F G FR 3 , a n d  FG F R 4 
as  m e as u r e d b y  in h ib itio n  o f r ece p to r a u to p h o s ph o ryl atio n  w it h I C5 0  val u es  o f 3  - 7  n M  fo r FG F R 1 , 
F G F R 2  a n d  F G F R 3,  a n d  1 6 8  n M  fo r F G F R 4 . I n c ellu la r ki n as e  sel e ctiv ity  ass a y s u sin g  a  p a n el  o f B a F3 
c ell lin es  r e nd e re d  IL-3  in d e p e n d e nt  b y  v ar io u s tyro sin e  ki n as es,  t h e m o st p o t en tl y in h ib it e d ki n as e, 
i n a d d itio n  to  th e  F G F Rs  w er e  V E G FR 2  a n d  FLT 1  w it h IC 5 0 s o f 1 5 1 0  n M  a n d  1 5 9 1  n M , re sp ec tiv e ly . 
C o n siste nt  w it h in h ib itio n o f F G F R  a u to p h o s ph o ry l atio n , B G J3 9 8  in h ib its F G F R  d o w nst re a m  sig n al i ng 
a n d  p ro lif er atio n  o f  h u m a n  c an c er  cell  lin es  h ar b o rin g  g e n etic  alt e rati o n s  o f  t h e  F G F Rs.  T h es e 
in clu d e,  a m o n g  o t h ers, l un g  a n d  br e ast  c an c er c ell lin es  wit h F G F R 1  g e n e a m p lific atio n , g astric c a ncer 
wit h  F G F R 2  ge n e  a m p lifica tio n , e n d o m e tria l c an c er wit h  F G F R 2  m u ta tio n s a n d b l ad d er  c an c er w it h 
F G F R 3  m u tati o n s o r FG F R 3  tr an slo c atio n s[2 7 ]. I n lin e  wit h  its cell u l ar act iv ity , B GJ3 9 8  s ho ws  a n ti- 
t um o r activ ity  i n m u ltip l e m o d els b e ari n g  F G F R  g e n e tic alt era tio n s[2 8 , 2 9 ]. 
 
3 . 2.2 .1  A n i m al d ru g  m et a b o lis m a n d  p h a rm a co ki n etics  
 
I n all  s p eci es te ste d , B G J3 9 8  e x hi bit e d a  h ig h  p l asm a  CL  a n d  a  l ar ge  Vss.  T h e  co m p o u n d  is h ig h ly 
b o u n d  t o p l asm a  p ro te in s (~  9 8 %)  b u t d o es  n o t p r efe re nti a lly d istrib u t e t o r e d b lo o d c ells. B G J3 9 8  is 
wi d el y  d istrib u te d  t o tissu es  i n t h e r at a n d h as  a  h igh a ffi nity t o m el a n i n co n ta in in g tiss u es.  I n vitro 
h e p atic  sy ste m s  m e ta b o lize  B G J3 9 8  p r e do m in a n tly  t o  2  p h a rm a co lo g ical ly  acti v e  m e ta b o lite s: 
B H S 6 9 7  a n d  B Q R 9 1 7 .    Bi otr a n sfo rm at io n  o f B G J3 9 8  t o b o t h m e t a bo lites  w a s o b s erv e d  i n h u m a n 
h e p at o cy te  c ult ure s. T h e  co m p o u n d  is a  P -g p  a n d  B C R P  s ub strat e  a n d  als o  in h ib its B C R P  m e d ia te d 
tr an s p ort wit h a n I C 5 0  v al u e  o f 0 .2 1 µ M . B GJ3 9 8  is a p o te nt r e v ersi b l e i nh ib ito r o f C Y P 3 A 4  ( Ki 0 .2 6 µ M ). 
T h e  co m p o u n d  al so  re ve rsib l y  in h ib its  C Y P 2 C 9  a n d  C Y P 2 C 1 9  wit h  Ki  o f  6 . 09 µ M  a n d  4 .1 µ M , 


P a g e 1 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
r es p ective ly  a n d  C Y P 2 C 8  w it h IC 5 0 o f 1 2 µ M . B G J3 9 8  is als o a  tim e  d e p e n d e nt  in h ib ito r o f CY P 3 A 4  wit h 
a  K I = 3 7 . 3 µ M a n d  K i na ct =  0 .0 5 4 7 m i n -1. I n a d d itio n  C Q M 1 5 7 , a  rec e n tly id e n tifi e d m e ta b o lit e i n 
circu l atin g  p l asm a  fro m  p a ti en ts, is a n in h ib ito r o f CY P 2 C 8,  C Y P 2 C 9  a n d  C Y P 3 A 4  (IC 5 0  l ess t h a n 1 0  µ M ) 
a n d  C Y P 2 C 1 9  (I C5 0  1 2  µ M ).   C Q M 1 5 7  is a ls o a n  in h ib ito r o f tr an sp o rters  P -g p , B C R P , O A T P 1 B 1  a n d 
O A T P 1 B 3  (I C5 0  less  t h a n 5  µ M ). 
A  d istrib u tio n  st ud y  fo llo w in g si n g l e d o s e a d m in istr atio n  o f [1 4C ]B G J3 9 8  i n r ats sh o w e d  e v id e n ce  t h at 
r ad io l ab el e d  co m p o n e n ts  ( B GJ3 9 8  a n d  /o r its m e ta b o lites)    cro ss th e b lo o d  b r ain  b ar ri er. 
C o n c e ntra tio n s o f B G J3 9 8  a n d  its act iv e  m e ta b o lit e B H S 6 9 7  w e r e al so  d e te cte d  i n r at b r ain  fo llo wi n g 
a si n g l e o ral a d m in istr atio n  o f 1 0  m g /k g  o f B GJ3 9 8 . 
 
3 . 2.2 .2  S a f ety ph ar m a co lo g y an d  toxi co lo g y 
 
B G J3 9 8  s ho w e d  n o  e v id e n c e o f i n vitro  g e n o to xicity in  A m e s a n d  c hro m o so m e  a b err ati o n  te sts a n d 
n o  e v id e nc e  o f  p h o to to xicit y  i n  a  3 T 3  p h o to -cyto to xicity  te st.  I n  vitro  saf et y  p h a rm a co lo gy 
ass es sm e nt o f B G J3 9 8  r ev e al e d  a  d ecr e as e  i n h u m a n  E t h er-à -g o -g o -r el ate d  g e n e  ( h E R G) c ha n n el 
acti v ity wit h a n I C 5 0  o f 2 . 0 µ M  (1 1 2 1 n g/ m l). 
 
I n viv o s afe ty p h a rm a co lo g y  st ud i es i n r ats a n d  d o g s d i d n o t re ve al  a n y eff e cts o n  c en tr al n e rvo u s o r 
r es pir ato ry  sy st em s a n d o n  h e m o d y n a m ic o r el e ctro ca rd io g r ap h ic p ara m e te rs, r es p ectiv el y . 
 
I n r e p e at e d d o s e (o r al g a va g e;  u p  to  4 -w e e ks)  to xicity  st ud i es, B G J3 9 8  d i d l e a d t o in cre as es  i n ser u m 
F G F 2 3  a n d  s er u m p h o s ph o ro u s as so cia te d  wit h  p a rti ally  r eversi b l e e cto p ic m in er ali zati o n  ( ki dn e y, 
lu n g , v asc u lar  a n d  d ig es ti v e sy ste m s) al o n g  w it h  l ar gely  re versi b le  c ha n g e s i n r e na l fu n ctio n 
p ar a m e ters  a n d  b o n e  g ro w th  p l at e t hicke n i ng  / r ete nti o n o f t h e p rim ar y  s po n g io s a i n r ats ( ≥ 1 0 
m g/ k g/ d a y) a n d  d o g s ( ≥ 1 0 m g /k g/d ay ). T h e se  eff e cts w er e  d e e m e d  t o b e  o n -ta rg et  eff e cts m e d ia te d 
b y  p h ar m a co lo g ic al i nh ib itio n  o f F G F R.  
 
I n r ats, co rn e al  c ha n g es  w er e  fo u n d  u p o n  4  w e e ks o f B G J3 9 8  tre a tm e nt  co n sistin g  o f irre versi b le , 
slig h t co rn e al  o p ac it y i n d o se -d e p e n d e nt  in cid e nc e , as ass ess e d  b y i n viv o o p h t ha lm o lo g y , a sso ciat e d 
wit h r e v ersi b l e, diffu se  e p ith eli al k er a to p at h y  at  th e  h ig h est  d o se  o f 1 0  m g/ k g.  I n th e  4 -w e e k  G LP  o r al 
to xicity st ud y  i n ra ts, th e  s ev er ely  to xic d o s e i n 1 0 %  ( ST D 1 0) w as  1 0  m g/ k g /d a y  w hic h  res ult e d  i n 
p r em at u re  d e a t h i n o n e  (1 /3 0 ) a n im al. D o s es o f 2 0  m g /k g /d a y i n ra ts le d  to  vas cu lo p at hy  ass o ci ate d 
wit h  m o rib u n d ity a fte r 6  a d m in istr atio n s. I n d o g s, th e  h ig h est  n o n -se v er e ly to xic d o s e ( HN S T D)  w as  
1 0  m g /k g /d a y l e ad in g  to  m in im al,  fu ll y re v ersi b l e re te nt io n o f t h e p ri m ary sp o n g io s a a n d m in im al 
in cr e as e i n m in e ral izati o n  in  l un g  a n d  k id n ey  w it ho u t o b s erv e d f u n ctio n al im p ai rm e nt.  
 
3 .2 .3     C li nica l e xp e rie n c e 
 
3 . 2.3 .1  Cl i nic al s af ety 
 
As  o f S e p te m b er  2 4 , 2 0 1 3 , 9 4  p at ie nts  h a ve  b e e n  e n ro ll e d to  t h e C G B J3 9 8 X 2 1 0 1  st ud y .   T h e  d o se 
es cal a tio n  p o rtio n  o f th e  stu d y  h as  b e e n  co m p l ete d  a n d  t h e M T D  h as  b e e n  id e n tifie d  as  1 2 5  m g  o n c e 
d ai ly ( q. d.), a d m in ist ere d c o n tin u o u sly .  B G J3 9 8  w a s a d m in ist ere d  to  4 3  p at ie nts  e v al u a te d  at  9 
d iffer e nt  d o s e le v el s, r an g in g  fro m  5  m g  p er  d a y  t o 1 5 0  m g  p er  d a y.  F o u r d o s e lim itin g  to xicitie s 
(D LTs)  w e re  r ep o rte d  d u rin g  t h e d o s e es cal a tio n  p o rtio n  a n d  o cc urre d  at  t h e 1 0 0  m g  ( n =1 ; g r ad e  3  
A S T /AL T  e le va tio n ), 1 2 5  m g  ( n= 1 ; h yp er p h o s ph at e m i a fo r >  1 4  d ay s), a n d  1 5 0  m g  ( n= 2 ; g r ad e  1 
co rn e al  to xicity  a n d  gr a d e  3  A S T /AL T  e le v at io n ) d o s e l ev els.  
 
As  o f S e p te m b er  2 4 , 2 0 1 3 , 5 1  p ati e nts  h a ve  b e e n e nr oll e d  t hu s f ar as  p art  o f o n e  o f 3  o n g o in g 
e xp a n sio n  co h o rts at  1 2 5  m g  d ai ly . O n e  co h o rt h as  e nr oll e d   1 2  p at ie nts  w it h F G F R 1  a m p lifi e d 


P a g e 1 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
a d v a n c e d o r m e tast a tic sq u a m o u s n o n -sm all  c ell lu n g c arci n o m a ; a  se co n d c o h o rt h as  e n ro ll e d 2 1 
p ati e nts  wit h  a n y  a d v a n ce d  so li d t um o r h ar b o rin g a n  F G F R  g e n etic  p at h w a y  alt e r atio n . B o t h o f t h ese 
co h o rts ar e  tr ea tin g  p ati e nts  o n  co n tin u o u s 2 8 -d ay  cy cl es. T h e  t hir d co h o rt h as e nr oll e d  1 8  p ati e nts 
a n y  so li d tu m o r wit h  a n y FG F R  g e n etic  p at h w a y  a lte rati o n o n  a  n e w  sc h ed u l e o f 3  w e e k s o n  d ru g , 1 
w e e k  o ff, r ep e a te d i n  2 8 -d a y  cy cl es. 
 
T h e  m o st fr eq u e nt  tre a tm e n t-e m er g e n t a d ver se  e v e n ts as o f th e  c ut-o ff d a te  s usp ec te d t o  b e  rel at e d 
t o B G J3 9 8  w e re  h y p er p h o sp h at e m i a ( 7 1.3 % ), d ecr e a se d a p p e tit e (2 6 .6 % ), f atig u e  (2 5 .5 % ), sto m atitis 
(2 4 .5 % ), al o p e ci a (2 1 .3 % ), ast h e nia (1 6 % ), a n d i ncr e ases  i n A S T  (1 1 .7 %)  a n d  A LT  (1 1 .7 % ). Th e  m aj o rity 
o f a dvers e  e v e nts  w e r e Gr a d e  1  a n d  2  a n d  re versi b l e u p o n  disc o n tin u ati o n  o f stu d y  dr u g . 
 
H y p er p h o s ph a te m i a h as  b e e n  s ee n  i n t h e m aj o rity o f p ati e nts  tr ea te d  at  d o ses  o f 1 0 0  m g  q .d . a n d 
h ig h er.  P h o s ph a te  el e vati o n s ar e  a  b io m ar ker  o f o n -tar g et  F G F R  p a t h wa y  in h ib itio n w h ic h m e d iat e s 
r e na l t ub u l ar p h o s ph a te  s ecr etio n  a n d  r e ab so rp tio n . T h e h y p e rp h o s ph at e m i a h as  b e e n m a n a g e d b y 
d i et ary p h o s ph a t e r estrictio n s, p h o s ph a te  lo w e rin g  th er a p y , a n d  d ru g  in te rru p tio n s. As  a  r es ult, a n 
alt er n a t e d o sin g  sc h ed u l e o f 1 2 5  m g 2 1  d a ys o n , 7  d ays  o ff i n a  2 8  d a y  cycle  is c urr e ntl y b ei n g 
in v es tig a te d as p a rt o f St ud y  B GJ 3 9 8 X 2 1 0 1 . 
 
3 . 2.3 .2  Pr el imi n a ry effi c acy of B G J3 9 8  
 
A m o n g  p ati e nts  i n th e  P h a s e 1  st ud y , a n ti-t um o r a ctivit y w a s n o te d  i n se ver al  tu m o r ty p es  wit h  FG FR  
g e n etic  a b err at io n s, i ncl ud in g  o n e  P R l a stin g  a p p ro xim at e l y 9  m o n t hs i n s qu a m o u s NS C LC.  
 
3 .2 .4     P h a rm a co k i ne tics 
I n St u d y  B GJ 3 9 8 X 2 1 0 1 , f ull P K  p ro file s w er e  o b t ain e d  o n  D a y  1 , D a y  1 5  a n d  D a y  2 8  aft e r th e  first d o se 
o f st ud y  d ru g .  As  t his st ud y  is o n g o in g , all  d a ta  p r es en te d  ar e c u rr en t as o f 2 4  Se pt e m b er  2 0 1 3  (r efer 
t o t h e I nves tig a to r B ro c hu re  fo r f urth er  d e tai ls). 
 
At  5  a n d  1 0  m g /d a y , p l asm a  co n ce ntr at io n s o f B GJ3 9 8  w e r e lo w  (<  3 .3  n g/ mL ) a n d  fr eq u e ntly  b e lo w 
t h e lo w er  lim it o f q u a n tific atio n .  Ex p o s ure  (C m ax  a n d  A U C)  w as  m e as u r ab l e in  all  tr e ate d  p ati e nts 
st arti n g at  2 0  m g /d ay.  
 
T h e  m e d ia n  a p p ar e n t T m a x v al u e  ac ro ss all d os e le v e ls te n d e d t o  b e  2 -3  h o u rs po st-d o s e. At t h e M T D 
(1 2 5  m g  q . d.), th e  m e d ia n C m ax  a n d  A U C 0 -2 4  w er e  ~ 8 0 . 8 n g/ m l an d  ~ 6 9 4  h .n g/ m l o n  D a y  1  a n d  ~ 2 4 5 
n g /m L a n d  ~ 3 3 4 2  h .n g/ m L o n  D a y  1 5 . At  1 2 5  m g  q . d. 3 w e e ks o n  1  w e e k o ff, m e d i a n C m ax  a n d  A U C 0 - 
2 4  w e re  ~ 7 1 .3  n g/ m L a n d  ~ 6 3 2  h . n g/m L o n  D a y  1  a n d  2 5 1  n g/ m L a n d  3 6 9 3  h . n g/m L o n  D ay  1 5 . 
 
T h e  in te r-p ati e nt  v ar ia b ility  w as  m o d er a te  t o h ig h f o r B GJ3 9 8  a n d %  co effici e n t o f var iat io n ( %  C V) 
r an g e d  fro m  5 0  –  7 5 %  a t th e  e xp a n sio n  co h o rt o f 1 2 5  m g  q d  o n  D a y  1 5 .  A ccu m u l atio n  w as o b s erve d 
wit h  d ai ly  d o sin g .  T h e  m e a n  A U C 0 -2 4  r atio s b e tw e e n  C ycl e  1  D a y  1  a n d  Cyc le  1  D a y  1 5  r an g e d  fro m  
1 . 5 t o 6 .5 , w hic h  in d ic ates  so m e  c ha n g e  i n B G J3 9 8  e x p os ure  fo llo wi n g  m u ltip l e d o sin g .  A t d o s es o f 
6 0 m g  a n d  a b o v e,  m o st in d i vi du al  p ati e nts  s ho w e d  in cr e ase d  e x p os ure o n  D a y 1 5  fo llo wi n g  m u ltip l e 
d o sin g  (~ 1 . 5 –  1 3  fo l d r ela tiv e  t o D a y  1  e x p os ure).  V e ry lim ite d  d at a  a re  a v ai la b l e fo r p a ti e nts w h o 
r ece iv e d  co n tin u o u s d o sin g  fo r 2 8  d ays  w it ho u t d o se  in te rru p tio n s ( 8 p ati e nts  at  d o s es 6 0  m g  a n d 
a b o v e,  o n ly 7  p ati e nts  w it h P K  d at a).  I n m o st o f th es e  p ati e nts  w h o  rec e iv e d  u n in te rru p te d  d o sin g , a 
fu rt h er in cr e ase  i n e x p os ure  b e y o n d  D ay  1 5  w as o b se rv e d.  T his is  b as e d o n  e it h er A U C 0 -2 4  e xp o s ure 
o n  D a y  2 8  o r co m p ar i ng  p r e d os e sa m p l es aft er  D a y  1 5  i n t h es e p ati e nts.   R ef e r to  t h e B G J3 9 8  
In v es tig a to r’s Br o c hu r e fo r fu rt h er d et ails. 


P a g e 1 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
I n m o st p a ti e nts, ac ro ss a ll st ud y d a y s a n d  d o s e le vels,  a ctive  m e ta b o lites  w e r e m e as ur a b l e. As a 
p erc e n t a g e o f p are nt  e xp o s ure,  B H S 6 9 7  w as d e te cte d  at  ~ 1 0 -1 5 %  a n d  B Q R 9 1 7  at  <  1 0 %. Fo llo wi n g  a n 
e xp lo ra to ry  a n a ly sis,  CQ M 1 5 7  w as  id e n tifi e d  as  a  m a jo r  p h a rm a co lo g ic ally  acti ve  m e ta b o lite  i n 
p l asm a  sa m p l es w it h i n v itr o p o te ncy  t h at w as  sim ila r t o B G J3 9 8 .  P r elim in ary  a n al ysis  i n circu l atin g 
p l asm a  fo llo wi n g  d o sin g  wit h  1 2 5  m g  o f  B G J3 9 8  o n  D a y  1  ( n= 8 ),  sh o w e d  p l asm a  e xp o s ures  to 
C Q M 1 5 7  r an g e d  fro m  3 %  t o  3 0 0 %  o f  p ar e n t  B G J3 9 8 .    O n  D a y  1 5  ( n =4 ),  e x po s ure  t o  C Q M 1 5 7 
r em ai n e d  t h e sa m e o r d e cr e as e d as  co m p ar e d  to  D a y 1  u n li k e B G J3 9 8  w hic h  sh o w e d  acc u m u l atio n 
fo llo wi n g  m u ltip l e do sin g . F or f urt h er i nfo rm at io n r e fer  to  th e  In ve stig a to r’s Bro c hu r e. 
 
3. 3       Im a tini b  M e sy la t e ( Gle e v e c    S T I5 7 1 ; N S C  # 7 1 6 0 5 1 ) 
 
3 .3 .1     O v er vi e w  o f Im a tin ib  m es y l at e 
 
I m atin i b m es y la t e is a  p ro tei n -ty ro sin e  ki n as e  in h ib ito r t h at in h ib its t h e Bc r-A b l ty ro sin e  ki n as e,  t h e 
co n stitu tiv e  a b n o rm al  ty ro sin e  ki n as e  cr e ate d  b y  t h e  P h il ad el p h i a  c hr o mo so m e  a b n o rm al ity  i n 
c hro n ic m y el o i d l eu ke mi a  (C M L). It in h ib its p ro life r atio n  a n d  in d u c es a p o p to sis in  Bc r-A b l p o sitiv e  cell 
lin es  as w e ll as fr es h l eu ke m ic cells fr o m  P h il ad el p h i a c hro m o so m e  p o sitiv e  (P h +)  c hro n ic m ye lo i d 
l eu ke m i a. Im ati n i b is al so  a n  in h ib ito r o f t h e r ece p to r ty ro sin e  ki n a ses  fo r p la te l et-d e ri ve d g ro w th 
f acto r (P D G F ) ste m  cell  f acto r ( S CF), co lo n y  stim u l atin g  f acto r ( C SF 1 R)  a n d  co ll ag e n  r ece p to rs (D D R ), 
c-Kit,  a n d i n h ib its P D G F - a n d S C F -m e d iat e d c ell u l ar e v e nts.  I n vitro , im ati n i b in h ib its p ro lif er atio n i n 
g astr o in tes tin al stro m al  t um o r (GI S T)  c ells, w h ic h e xp r ess a n  a ctiv a tin g  c-kit  m u tati o n . 
 
Gl e e v ec  is a p p ro ve d  i n t h e U S  fo r t h e tr e atm e nt  o f th e  fo llo wi n g i n d ic atio n s: n e w l y d i ag n o se d  a d u lt 
p ati e nts  wit h  P h +  C ML  i n ch ro n ic p h as e;  p ati e n ts wit h P h +  C ML  i n b l ast crisis, ac cel er a te d  p h as e  o r i n 
c hro n ic p h as e  af ter  f ailu re  o f in te rfer o n -al p h a  t h era p y ; p e d iatric  p a ti e nts wi th  P h +  c hro n ic p h as e 
C ML  w h o s e d ise as e  h as r e c urr e d aft er ste m  cell tr a n s pla n t o r w h o a re  r esist an t t o in te rfer o n -al p h a 
t h er ap y ; p at ie nts  wit h  K IT  ( CD 1 1 7 ) p o sitiv e  u n r esec ta b l e a n d / or m e ta st atic m al ig n a n t GI S T;  a d ju v a n t 
tr e atm e nt  o f a d u lt p a tie n ts fo llo wi n g  r esec tio n o f KI T  ( CD 1 1 7 ) p o sitiv e  GI S T;  p ati e n ts wit h 
r el ap s e d/refr ac to ry P h + a cu t e l ym p h o b l astic l eu ke m ia ( AL L); p ati e nts wit h u n res e cta b l e, r ec urre nt 
a n d / or 
m e ta sta tic 
d er m a to fib ro s arco m a 
p ro t ub er a n c e 
(D FS P ); 
p ati e nts  
wit h 
m yel o d y s plasti c/m yel o p ro lif er ativ e  d is e ases  (M D S/M P D ) as so cia te d  w it h p l at el et-d e ri ve d g ro w t h 
f acto r r ece p to r (P D G F R)  g e n e  re -ar ra n g e m e nt s; p at ie nts wit h  h y p er e o sin o p h ilic sy n d ro m e /c hro n ic 
e o sin o p h ilic l eu k e m i a ( H ES/C E L); a n d  p ati e nts wit h  a g g r essive  syste m ic m a sto cy to sis ( AS M ) wit ho u t 
t h e D 8 1 6 V c-Kit  m u ta tio n  o r wit h c-Kit  m u t atio n al st atu s un k n o w n.  
 
3 .3 .2     C li nica l e xp e rie n c e wi th  Im a tin ib  m e syl a t e 
 
Effic ac y  r es ults o f im ati n i b st ud i es i n le u k e m ia s h a v e  s h ow n  d r am a tic ra te s o f co m p l ete  r esp o n s es. 
T h es e  m a jo r o b j ective  clin ic al r es p on ses  c a n b e  o f var ia b l e d u r ab ility , l astin g  fro m  w e e k s t o m o re 
t h a n  a  y e ar.    T h e  p at h w a y s  o f  r esist a nc e  i n  le u k e m i a  ar e  b ei n g  a ctive ly  e x plo re d.    P o ssib l e 
m ec h a n ism s o f re sist an c e in clu d e  o v er e x pr essio n  o f t h e m u ta te d  B C R -A b l g e n e  a n d  v ar ia n ts, 
s ec on d a ry  g at e ke e p er m u t atio n s i n t h e a b l ki n as e  as  w e ll as  in cr e ase d  e xp ressi o n  o f al p h a  aci d 
g l yco p ro te in . 
 
T h o u s an d s o f p at ie nts  wi th  m e t asta tic o r u n re s ecta b l e GI S T  h a v e  n o w  b e e n  tr e ate d  wit h  im a tin ib . 
T h e  a p p ro xim at e  re s p o ns e r at e is 4 5 -5 2 %  [3 , 4 ].  J uxta - M e m b r an e  D o m ai n  m u ta tio n s i n t h e e x on  1 1 
r es p on d  b e st t o im ati n ib .  T h e  re s p o ns e r ate  fo r GIS T  p ati e nts w it h e xo n  9  m u t atio n s is ab o u t 3 0 % , a s 


P a g e 1 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
w e ll as  fo r p a ti e nts wit h G IS T  h ar b o rin g  m u t a nt P D G F R A . R es p o n s e ra te s a re  n e arl y  0  fo r GI ST wit h 
wil d  t yp e  c-k it. M u tati o n s in  th e  ki n a se  d o m ai n  a re  k n o w n  t o b e  u n r esp o n sive  (E xo n  1 7 ). 
 
I m atin i b w a s fo u n d  eff e ctiv e  i n p at ie nts wit h  th e  h yp er e os i no p h ilic sy n d ro m e, a n d  in v es tig at io n  in to 
t h e g e n e tic b as is o f t his d ise as e  re ve al e d  t h at m a n y  o f t h ese  p ati e n ts, a s w ell  as s o m e  wit h  sy st em ic 
m as to cy to sis, h ar b o r a  c hro m o so m al  d e le tio n  t ha t g iv es  ris e to  a n o n co g e n ic fu sio n  p ro te i n ( FI P1 L1 - 
P D G FR A)  inv o l vi n g th e  P D G F  r ece p to r. I ma tin i b is n o w  co n sid e re d  a  first-lin e  a g e nt  fo r m a n y 
m al i g na n ci es c ha ra cte rize d  b y a b err a n t p ro tei n  ty ro sin e  ki n a se  sig n al i ng  v i a A B L, c-kit,  a n d P D G F 
r ece p to r. 
 
O v er 1 2 , 00 0  a d u lts h a v e  re c eiv e d  im ati n i b at  d o s es ra n g in g  fro m  2 5 -1 0 0 0 m g  d ai ly .  D u rin g  a  P h as e I 
tri al, t h e m o st co m m o n l y re p o rte d  a dv ers e  e v e nts  (A E)  r ela te d  t o im a tin i b a d m in istr atio n  w e re  m il d 
t o m o d e rat e  n a u s ea , e d e m a  o f v ar io u s lo ca tio n s,  an d  m u sc ulo skel e t al sy m p to m s, all  o f w hic h 
a p p e ar e d  to  h a ve p o ssib l e d o se -re s p o ns e r el atio n s hip s. T h e  co rres p o n d in g  e v e n ts fro m  t h e p o o le d 
P h as e  II tri als (N o v a rtis 0 1 0 1 , 0 1 0 9 , 0 1 1 0 ) w e re  n a u s e a, vo m itin g , m u scl e cra m p s, e d e m a,  d i arrh e a 
a n d  h e a d ac h e.  S e ve ral  se ri o us  a d v e rs e  e ve n ts  ( SA E)  h a v e  b e e n  r e po rt e d,  7 7  wit h  a  s usp e cte d 
c au s ality rel at io n s hip  to  trial  d ru g .  T h e  m a jo rity o f SA Es  wit h  a  s usp e cte d  r ela tio n s hip  f ell in to  five 
b ro a d  c ate g o rie s a n d  o cc urr e d i n 1 .4 -3 . 3 % o f p at ie n ts: r ash ; liver  fu n ctio n  test ( LF T)  a b n o rm al iti es; 
m yel o s up p re ssio n ; u p p er  GI  h e m o rrh a g e;  flu i d r ete n tio n /re n al  f ailu r e/el e ctro ly t e im b al a n ce.  T h er e 
w e r e tw o  d e at hs  wit h  s usp ec te d  rel at io n s hip  to  tri al d ru g , d u e  t o liv er  f ailu r e (p o ssib l y i n asso ci atio n 
wit h e xce ssiv e  co n s u m ptio n  o f ace ta m in o p h e n ), a n d flu i d re te n tio n /re n al  i nsu ffici e nc y, re s pe ctiv el y . 
 
I n p ati e nts  wit h  C M L, t h e m a jo rity o f Gl e e v e c®  -tr e ate d  p ati e nts  e xp eri e n ce d  a d v er se  e v e n ts at  so m e 
tim e.  M o st e ve nts  w e re  o f m il d to  m o d er a te  g r ad e,  Im ati n i b w as  d isco n tin u e d  fo r a d v ers e  e v e nts  i n 
2 . 4 % o f n e w ly d i ag n o s e d C ML p a ti e nts, 4 %  i n ac cel er at e d  p h as e a n d  5 %  i n b l ast crisis. T h e  m o st 
fr eq u e ntly  r ep o rte d  a d v e rs e e v e nts  (re g a r dl ess o f re l atio n s hi p) w er e  e d e m a , n a u s e a, a n d  vo m itin g , 
m u scl e cr am p s, m u sc ulo skel e tal  p ai n , d i arrh e a  a n d  ra s h. E d e m a  w as  m o st fr eq u e ntl y  p er io rb it al o r i n 
lo w e r lim b s a n d  w a s m a n a g e d  wit h  d iu re tics, o t he r su p p o rtive  m e as ur e s, o r b y r e d u cin g  t h e d o s e o f 
Gl e e v e c® . 
 
I n p ati e nts  wit h  GI S T,  th e  m a jo rity  o f im ati n ib -tre at e d  p ati e nts  e xp er ie nc e d  A Es  at  so m e  tim e. 
A p p ro xim a te ly  6 0 %  o f p atie nts  r ep o rt e d a t l e ast o n e  g r ad e  3 /4  A E a t so m e  tim e  d u rin g  th e  st ud y , a n d 
im ati n i b w as d isco n tin u e d  d u e  t o A Es  i n 1 8  p ati e nts.  T h e  m o st fr eq u e nt ly  r e p orte d  A Es  w e r e e d e m a, 
n a u s e a, d i arrh e a,  a b d o m in al  p ai n , m u scl e cra m p s, fa tig u e,  a n d  r ash , m o st o f wh ic h w e r e o f m ild -to - 
m o d er at e  se v eri ty .  I m atin ib  w as  d isco n tin u e d  fo r A Es  i n 7  p ati e nts  (5 %)  i n b o t h d o s e le vels  (4 0 0  a n d  
8 0 0  m g/d ) st ud i ed .  S u p er fici al e d e m a, m o st fr eq u e n tl y p eri o rb it al o r lo w er  e xtre m ity , w as m a n a g e d 
wit h  d iu r etics, o t h er s up p o rtiv e  m e as u res,  o r b y re d u cin g  t h e d o se  o f im a tin ib .  S e v e re  (N C I-C T C A E 
Gr a d e  3 /4 ) s up erfici al  e d e m a  w as  o b s erv e d  i n 3  p at ie n ts (2 % ), in clu d in g  f aci al e d e m a  i n 1  p a ti e nt. 
Gr a d e  3 /4  p l eu r al eff us io n  o r asci tes  w as  o b ser v e d  i n 3  p ati e nts  (2 % ).  N in e  (6 %)  p ati e nts  (6 0 0 m g /d 
( n =6 ); 4 0 0 m g /d  ( n= 3 )) w e r e r ep o rt e d t o h a v e  g r ad e  3 /4  GI  o r in tra -t um o r al h e m o rrh a g e  d u rin g  th e 
st ud y  ( GI b l e e din g  ( n =5 ); in tr at um o r al b l e e din g  ( n =3) ; b o t h GI  a n d  in tr at um o r al b l e e din g  ( n =1 ).  T h e 
GI  lo c alizati o n o f th e  t um o r li ke l y co n trib u te d to  t his A E  i n t his p ati e nt  p o p u lati o n . N o n e  o f t he s e 
p ati e nts  h a d  t hro m b o cy to p e n ia  at  t h e tim e  o f h a e m o rrh a g e.  T h e  sm all  n u m b er  o f e v e nts  a n d  t h e 
v ar ia b ility i n b a seli n e  clin ic al p ro files  p recl u d e  co n clu sio n s to  ai d  t h e id e ntif icati o n o f p ati e nts  at 
in cr e ase d ri sk o f he m o rrh a g e  d u rin g  th er a p y wit h im a tin ib . 


P a g e 2 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
F or   fu rt h er   in fo rm at io n   r e ga rd in g   clin ic al   e x p eri en c e   wit h   Im a tin i b   m e sy l at e,   r ef er   to   t h e 
In v es tig a to r’s Br o c hu r e. 
 
3 .3 .3  
P h a rm a co k i ne tics o f Im a tin ib  m es y l at e 
 
3 . 3.3 .1  P h ar m a co ki n e tics o f I ma tin i b i n h e alt hy  s ub j ects a n d  p ati e nts  wit h  n o rm al  h e p a tic a n d  r e na l 
fu n ctio n  
 
T h e  p h ar m a co ki n e tics o f  Gl e ev e c®  h a v e  b e e n  e v a lu at e d  i n h e alt hy  s ub je cts a n d  i n p o p u l atio n 
p h ar m a co ki n e tic st ud i es i n o v er  9 0 0  p at ie nts.  Im ati n ib  is w e ll a b so rb e d  aft er  o ra l a d m in istr atio n  wit h 
C m ax  ac h i ev e d  wit hi n 2 -4 h o u rs p o st-d o se.  M e a n  a b so lu t e b io a v ai la b ility is 9 8 %.  F ol lo wi n g o r al 
a d m in istr atio n  i n h e alt hy  v o lu n te e rs, t h e el im in ati o n h al f-liv es  o f im ati n i b a n d  its m aj o r m e t a bo lite, 
t h e N -d es m e th y l d eri va tive,  w e re  a p p ro xim a te ly 1 8 a n d  4 0  h o u rs, r es pe ctivel y. M e a n  im ati n i b A U C 
in cr e ase d  p ro p o rtio n al ly w it h in cr e asin g  d o s e i n t h e ra n g e  2 5 m g  - 1 0 0 0 m g.  T h e re  w as  n o  sig n ific an t 
c ha n g e  i n t h e p h ar m a co k in e tics o f im ati n i b o n r e p e at e d d o sin g , a n d acc u m u lati o n is 1 .5 -3  fo l d at 
ste a d y  st ate  w h e n Gl e e ve c ® is d o s e d o n c e d ai ly . At cli n ic ally r ele v a n t co n c en tr atio n s o f im ati n ib , 
b in d in g  to  pl a sm a  pr o te in s i n i n vitro  e xp er im e n ts is a p p ro xim a te ly  8 9 -9 6 % , m o stl y to  al b u m in . 
 
A  p h ar m ac o ki n e tic st ud y  fo llo wi n g  co n tin u o u s o n ce  d ai ly  o r al a d m in istr atio n  o f im ati n i b h as  b e e n 
p erf o rm e d  i n tw o  GI S T  p at ie nts.  T h e  p r eli mi n ary re s ults s h ow e d  t h at t h e P K  p ro files  i n GIS T  p ati e nts 
ar e  sim il ar to  t h at o b ser ve d  i n C ML  p ati e nts.  I m atin ib  is r ap id l y a b so rb e d  a n d  a  C m ax  o f 2 . 9 μ g/m l 
w as  r e ac h e d at  ste a d y  st ate  fo llo wi n g  a  4 0 0  m g  d ai ly  d o s e.  T h e  te rm in al  lif e w a s 1 3 h  a n d  t h er e w as  
1 /5  fo l d d ru g  acc u m u l atio n  aft er  o n e  m o n t h d o sin g .  T h e  A U C  (0 -2 4 ) v al u es  w e r e 2 3 ,7 4 8  n g /h/ m l at 
ste a d y sta te  af te r a 4 0 0  m g  d o sin g , w h ic h is sim il ar to  t ho s e se e n i n  C M L p at ie nt s. 
 
T h e  te rm in al  h alf -lif e (t1 /2 ) av er a g e d  to  1 0  to  2 3  h o u rs (1 8  h o u rs fo r t h e p ar e n t an d  4 0  h o u rs fo r th e 
m a jo r m e ta b o lite  (se e  b el o w )) a n d t h er e  w a s a 2 -3  fo ld  acc u m u la tio n o f d ru g  at  ste a d y st ate.  T h e se 
d at a  ar e  co m p ati b l e wit h  a sc h e d u l e o f o n ce  d ai ly a d m in istr atio n . T h e  in cr e ase  in  m e a n  p l asm a  A U C 
v al u es  w a s p ro p o rtio n al  to  d o se  u p  t o 7 5 0  m g /d a y .   T h e  m e a n  p l asm a  A U C  (0 -2 4 ) at  ste a dy  sta t e 
fo llo wi n g  a  co n tin u o u s o n ce  d ai ly o r al d o s e o f 7 5 0  m g  w as  6 2 ,2 5 9  n g /h /m l. 
 
A  fo o d  ef fect  st ud y  h as  s h ow n  n o  sig n ific an t  d iff er e nc es  i n  a b so rp tio n  w h e n  im ati n i b  w a s 
a d m in ist ere d  eit h er  wit h  fo o d o r i n th e  f astin g  st at e.  S in c e t his a g e nt h as  p o te n ti al t o irrit ate  g astr ic 
m u co s a, it is t h eref o re  stro n g l y re co m m e n d e d  t h at th e  a g e nt  b e  t a ke n wit h  fo o d  to  d ecr e a se  risk  o f 
g astric irrit a tio n . 
 
I m atin i b is h e p atic al ly  m e ta b o lize d  a n d  el im in ati o n  is m ai n ly  i n th e  fe c es, p r e do m in a n tly as 
m e ta b o lites.  T h e  m a jo r m e ta b o lite  is t h e N -d es m e th y l at e d p ip erz i ne  d eri va tiv e , a n d  t his m e ta b o lite 
s h ow s i n v itr o p o te n cy  sim il ar t o t h at o f t h e p ar e n t d ru g . C Y P 3 A 4  is th e  m a jo r e n zy m e  r esp o n sib l e fo r 
m e ta b o lism  o f im ati n ib . Ot h er  cy to c hro m e  P 4 5 0  e n zy m es,  s uc h as  C Y P 2 D 6 , C Y P 2 C 9 , a n d  C Y P 2 C 1 9 , 
p l a y  a  m in o r  ro l e  i n  its  m e ta b o lism .  B ec a u s e  o f  th e  in h er e nt  risk  o f  eit h er  r e du c e d  a ctiv it y  o r 
e n h a n c e d to xicit y o f co n co m it a nt m e d ic atio n s a n d/ o r im a tin ib , d ru g s k no w n  t o b e  m e ta b o lize d  b y 
t h e sa m e  C Y P 4 5 0  iso e n zym es  as  im ati n i b s h o ul d b e  u s e d wit h  c au tio n  ( Ap p e n d ix C).  S p e ci al c are  h as 
t o b e  g ive n  to  th e  co n co m it a nt u s e o f p ar a ce ta m o l (a c eta m in o p h e n,  T y le n o l) w it h im ati n ib . A n y  u se 
o f t his d ru g  h as  t o b e  d o cu m e n te d  i n th e  m e d ic al re co rd s a n d / or c ap t ure d  o n t h e  a p p ro p ria t e c as e 
r e p ort fo rm . C a ses  o f r e acti v atio n  o f H e p atitis  B c a n  o cc ur i n p ati e n ts w h o a r e ch ro n ic c arriers o f t his 
v iru s after  re c eiv in g  a  B C R -A B L ty ro sin e  kin a se  in h ib ito r (T K I), s uc h as  im ati n ib . 


P a g e 2 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
3 . 3.3 .2  P h ar m a co ki n e tics o f Im a tin i b i n p ati e nts  wit h h e p a tic in s ufficie nc y  
 
A P h as e  I st ud y  t o in ves tigat e  t h e eff e cts o f im a tin i b i n p a ti e nts wit h  liv er  d y sfu n ctio n w as  co n d u cte d 
b y  N CI.  R es ults  s ho w e d  th at  e xp o s ure  to  b o t h im a tin i b a n d  C G P 7 4 5 8 8  w as c o m p ar a b l e b e tw e e n 
p ati e nts  wit h  m il d o r m o d er a te  h e p at ic in s ufficie n c y a n d  th o s e wit h  n o rm al  h e p a tic fu n ctio n . 
T h er e fo r e I ma tin i b c a n b e  a d m in ist ere d  t o p ati e n ts w it h v ar yi n g  d e gr e es o f h e p atic  im p ai rm e nt  w it h 
so m e  m o d ifica tio n s i n d o sin g  r eco m m e n d e d.  P at ie n ts wit h  m il d a n d  m o d er a te  h e p atic  im p ai rm e nt 
c a n b e  tr e ate d  at  a  st artin g  d o s e o f 4 0 0 m g /d a y , w h er e as,  p ati e n ts wit h  se v e re h e p atic  im p a irm e nt 
s h o ul d b e  tre a te d at  a  sta rtin g  d o s e o f 3 0 0  m g /d a y . 
 
3 . 3.3 .3  P h ar m a co ki n e tics o f Im a tin i b i n p ati e nts  wit h re n al  i nsu ffici e nc y 
 
I m atin i b a n d  its m e t a bo lites  ar e  n o t sig n ific an tly e xcr ete d  b y t h e ki d n e y .  A  m u ltic e nt er P K  st ud y i n 
p ati e nts  wit h  a d v a n ce d  m al i g na n ci es a n d  v aryi n g  d e gr e es  o f r e na l d y sfu n ctio n  h as  b e e n  co n d u cte d 
b y  U S  N ati o n al  C a n c er In stitu t e [S t ud y  P -5 3 4 0 ].  R es u lts s ho w  t h at im ati n i b is w ell  to ler a te d  o v er  a 
d o s e r an g e  o f 4 0 0 -8 0 0  m g i n  p ati e nts  wit h  m il d r e na l d y sfu n ctio n  (cre ati n in e  cle ar a n c e b e tw e e n  4 0 
a n d  5 9  m L/m in ), a n d a  d o s e r an g e  o f 2 0 0 -6 0 0  m g d a il y i n p ati e n ts w it h m o d e ra t e r e na l d y sfu n ctio n 
(cre ati n in e  cle ar a n c e b e tw e e n  2 0  a n d  3 9  m L/ min ). P K  r es ults sh o w e d  th a t t h e A U C a n d  C m ax  v al u es  i n 
t h e m ild , m o d er at e , a n d  se v e re  g ro u p s w e re  a p p ro xim at e ly 1 .5 -2 -fo l d t h at o f t h e n o rm al  g ro u p  at 
ste a d y -st at e.  T h e in cr e ase  i n im ati n i b e xp o s ure  w a s n o t as so ci ate d  wit h  a n y  in cr e ase d  clin ic ally 
sig n ific an t to xicity  o r  d ru g -r el at e d  A Es.     T h er e fo re,  i n  p ati e nts  wit h  m il d  o r  m o d er a te  r e na l 
in s uffici en cy , n o  d o s e m o d ific atio n  o f im ati n i b m e sy l ate  is r e qu ire d.  
 
F o r se ver e  re n al  d y sfu n ctio n  p ati e nts  (cr e ati ni ne  cl e ar a n c e < 2 0  m L/m in ), o n l y 2  p ati e n ts w e re 
e nr oll e d,  a n d  n o  p at ie nts  in  h e m o d i aly sis w e re  e n ro lle d  in t o t h e st ud y .  Lite r atu r e d at a  (P a p p as,  et  al  
2 0 0 5 ) sh o w e d  t h at 4 0 0  m g d ai ly  d o s e w as  w e ll to l era te d  i n a  p ati e nt  wit h  e n d  st a g e r e na l d is e as e o n 
h e m o d i aly sis. 
 
4. 0       O V E R V IE W  O F S T U D Y  D E SI G N/ IN T E R V E N T I ON  
 
4. 1       D e sig n  
 
T his  is a  m u lti-c e nter  sin g l e ar m  p h as e  I b/II tri al to  e v a lu at e  t h e clin ic al s afe t y a n d  effic a cy  o f im a tin i b 
a n d  B G J3 9 8  i n p ati e nts  wi th  lo c all y a d v a n ce d  o r m e ta st atic GI ST.  A ll p ati e nts  will  h a v e  a  d i ag n o sis o f 
GI S T.  P ati e n ts i n t h e P h a se  I b p o rtio n  o f t h e tri al ar e  re q u ir e d t o h a v e  lo c all y a d v a n c e d o r m e ta st atic 
GI S T  a n d  c a n b e  i n a n y  p h as e  o f tr ea tm e nt  t h at h as  p ro g r esse d o n  im ati n ib . P a ti e nts o n  t h e P h as e  II 
p o rtio n o f t h e st ud y  ar e  re q u ir e d t o h a v e  lo c ally  a d v a n c e d o r m e ta st atic GI S T  a n d  h a v e  n o t rec e iv e d 
a n y  p ri or sy ste m ic t h er ap y e xc e pt fo r a d ju v a n t im at in i b t h er ap y co m p le te d  m o r e t h a n 9 0  d a ys  p rio r 
t o e nr ollm e nt  ( un tr ea te d/ tr e atm e nt n a ïv e).  
 
T h e  p h as e  I b p o rtio n o f t h e st ud y  will  b e  a  st a nd ar d 3  +  3  d o s e e sc alat io n  w it h s am p l e size  r an g in g 
fro m  6 -3 0  p at ie nts.  P h a rm ac o ki n e tic sa m p lin g  fo r B JG 3 9 8  will o cc ur i n t his p h as e  o f t h e tri al. T h e 
p h as e  II p o rtio n  o f th e  st ud y  w ill ass ess R es p o n s e R a t e (C o m p l ete  a n d  P arti a l, R E C IS T  1 . 1) at  3 2  w e e ks 
as  its p rim a ry  e n d p o in t. T h e  tri al will  ass u m e  a  2 0 %  im p ro v e m e nt  i n t h e h isto ric al R R  o f im a tin i b 
al o n e , fro m  4 5 %  to  6 5 % .  T h e  p h as e  II s am p l e size  will  b e  4 4  p ati e n ts. At  t h e e n d o f t h e st ud y , if >  2 4 
p ati e nts  h a v e  h a d  a  d o cu m e n te d  r es p on se  b y R E CI ST  1 .1 , t h e st ud y will  b e  co n sid er e d  p o sitive  a n d  


P a g e 2 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
t h e tr ea tm e nt  r e gim e n  will  b e  co n sid e re d  w o rt hy o f fu rt h er in v e sti g atio n . T h e  stu d y  d esi g n  is b as e d 
o n  a n e x act Bi n o m i al test  a n d  h as a t yp e  I err o r o f 0 .0 8  a n d  a  ty p e  II erro r o f 0 . 1. 
 
4. 2       I nt erv e n tio n  
 
P ati e n ts w h o  m e e t t h e eligib ilit y criteri a  will  b e  tr ea te d  wit h  t h e co m b in at io n  th er a p y o f B G J3 9 8  a n d 
im ati n ib . I n t h e p h as e  I b p o rtio n  o f th e  st ud y , p at ie n ts will  rec e iv e  im ati n i b at  4 0 0  m g  o n ce  d ai ly a n d 
B G J3 9 8  at  t h e sta n d ar d  3 + 3  es cal a tio n  d o ses  fo r 2 1  d a ys  o n , 7  d ays  o ff (tr ea tm e n t sc h ed u l e A )( T ab l e 
1 ).  Usi n g  tre a tm e nt sc h e d u l e A,  if d o s e l ev el  1  to  -2  is id e ntifi e d  a s t h e M T D  a n d  co n c er n e xists 
r e ga rd in g  t h er ap e utic  a ctivit y o f B G J3 9 8  at  t his d o s e le v el, e x p an sio n s wit h  h ig h er  d o s e le v els  ( 1 to  3 ) 
m a y  b e  co n sid e re d  at  t h e M S K C C P I’s d iscr etio n , w it h m o d ifica tio n  o f t h e tre a tm e nt  sc h ed u l e.  I n t his 
s ettin g  B G J3 9 8  will  b e  a d m in ist ere d  d ai ly fo r o n e  w e e k  fo llo w e d  b y  3  w e e k s o ff an d  im ati n i b will  b e 
t a ke n  d ai ly  t hr ou g h o u t t h e 4  w e e k  cy cle  p er io d  (tre a tm e nt sc h e d u l e B ).  I n t h e p h as e  II p o rtio n  o f t h e 
st ud y , p ati e nts  will  re c eiv e  im ati n i b at  4 0 0  m g  o n c e d ai ly  (sta n d ar d  o f c ar e first lin e  im ati n i b d o s e) 
a n d B G J3 9 8  at  t h e R P 2 D  a n d tr e a tm e nt  sc h ed u l e id e n tifi e d i n t h e p h as e  I b p o rtio n o f t h e st ud y . O n e 
cy cl e is 2 8  d a y s.  If n o  p ro g r essio n o f t h e tu m o r is s ee n , p at ie nts  will  co n tin u e  o n t h er a p y . T h o s e 
p ati e nts  w h o  h a v e  p ro g r essio n  o f d ise as e will  p ro ce e d  d ir ectl y to  se co n d  lin e  th er a p y  as  p er  st a nd ar d 
o f c ar e.  Fo r P h as e  II, st ud y  p er so n n el  will  a tte m p t to  co ll ect s urvi v al  sta t us fo r all  p ati e nts  af ter  th e 
e n d -o f-st ud y  v isit e v e ry  3  m o n t hs v i a te le p h o n e,  e m a il, o r o t he r m e th o d  fo r u p to  3  y e ar s. 
 
5. 0       T H E R A P E U TI C/ D I AG N O S TI C  A G E N T S  
 
5. 1  
Im a tini b  M e sy la t e ( Gle e v e c S T I5 7 1 ; N S C  # 7 1 6 0 5 1 ) 
5 .1 .1  
M ec h a n is m o f A cti on : 
 
I m atin i b is a  sm all m o l ec ule  t h at h as  b e e n  d e m o n strat e d  t o b e  a  h ig h l y s el ectiv e  in h ib ito r o f cert ai n 
p ro te i n ty ro sin e  kin as es.  Sp ecific al ly , i ma tin i b is k n o w n  to  i nh ib it t h e k in a se  a ctio n  o f th e  fo llo wi n g : 
 
•  A b l a n d  t h e c him eric  B C R -A b l fu sio n  p ro te i n fo u n d  i n c erta in  l eu k e m i as s uch  as  c hro n ic 
m yel o i d le u k e m i a ( CM L). 
•  T h e  p l at ele t-d er iv e d g ro wt h  f act or re ce p to r (P D G FR).  
•  KI T,  th e  p ro d u ct o f th e  c-kit pr o to -o n co g e n e.  
•  A b l-r el at e d g en e  (A R G ). 
 
I m atin i b h as  b e e n  e xte ns iv ely  tes te d  i n P h il ad el p h i a c hr om o so m e -p o sitiv e  le u ke mi a  p ati e nts  w h e re 
t h e m ai n  t arg et  is in h ib itio n  o f t h e d y sre g u l at e d ki n a s e act iv ity a sso ciat e wit h  th e  c him er ic B C R -A b l 
fu sio n  p ro tei n  a n d  i n p ati e nts  wit h  g ast ro in te stin al  stro m al  t um o rs (GI ST)  i n w h ic h t h e m ai n t ar g et  is 
in h ib itio n  o f t h e dysr e gu l ate d ki n as e  ac tiv ity as so ci at ed  w it h activ ati n g  m u ta tio n s o f KI T.  
 
C as es  o f re act iv at io n  o f H e p atitis  B  ca n  o cc ur i n p ati e n ts w h o  ar e  c hro n ic c arrie rs o f t his v iru s aft e r 
r ece iv in g  a  B C R -A B L ty ro sin e  ki n as e  i nh ib ito r ( T KI), s uch  as  im a tin ib . 
 
5 .1 .2     F o rm u la tio n , S to ra g e  a n d  P a ck a g in g  
 
I m atin i b is a v ai la b l e i n 1 0 0 m g a n d  4 0 0  m g s co r e d c ap s ule . T h e  sto r ag e  co n d itio n s fo r st ud y d ru g will 
b e  d es crib e d i n  th e  p a ck a ge  in s ert, us u al ly  a t ro o m  te m p er at u re -2 5 ° C (7 7 °F). 


P a g e 2 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
5 .1 .3     A d m ini str atio n  o f Im a tin ib  m es y la t e 
 
I m atin i b will  b e  s up p li e d b y  N o v arti s. Im ati n i b is a vai la b l e i n 1 0 0  m g  a n d 4 0 0  m g  sco r e d c ap s ule . 
P r efe re n ti ally  a n d  u n l ess o t h er wise  clin ic ally  in d ic at ed , 4 0 0 m g  c ap s ule  will  b e  u s e d. T h e  in v e sti g ato r 
s h o ul d in str uct t h e p ati e nt  t o t ake  t h e st ud y  d ru g e xactl y  as  p r escrib e d  ( pr o mo te  co m p li an c e) a n d  to 
n o tif y th e  In ves tig a to r o f a n y d e v i atio n s. P at ie nts  will b e  in str uct e d t o re co r d th eir  d ai ly st ud y d ru g 
a d m in istr atio n  i n t h e p ati e nt  d i ary p ro v id e d  t o th e m . I m atin i b will  b e  d o s e d at  4 0 0  m g o n c e a  d ay  b y 
m o u t h. B ec a u se  o f t h e p o te nti al  fo r in te sti na l irrit atio n , t h e c ap s ule  sh o u l d b e  t a ke n  d u rin g  a  m e al 
a n d  wit h  a  l ar ge  g l ass o f w a ter  (8  o z) to  m in im ize  t h e c ha n c e o f irrit atin g  th e  e so p h a g e al  a n d/ o r 
g astric  m u co s a. P ati e n ts s h o ul d k e e p  n o rm al  e a tin g  h a b its; h o w e v er,  lo w -f at (i. e.  co n tin e nt al) 
b r e a kf ast is r eco m m e n d e d  a v o id in g  x a nth in e  ( e.g . c aff ein e)  o r g r ap e fru it co n t ain in g  fo o d  o r 
b e v er a ges.  M in im u m  o f 1 h s h o ul d  b e  al lo w e d  b e tw e e n  l ast d ru g  in t ake  a n d  g o in g  t o b e d.  If v o m itin g 
o cc urs, n o  a d d itio n al  tri al m e d ica tio n  sh o u l d b e  ta k e n  t h at d a y  i n a n  ef fo rt to  r e plac e  th e  m at e ria l 
t h at h as  b e e n  vo m ite d .  If a  d o s e o f im ati n i b is m isse d , t h e s ub j ect s h o ul d t ake  t h e d o se  as  so o n  a s 
p o ssib l e, b u t o n ly if t h er e ar e  1 2  o r m o r e h o u rs re m ai n in g  b ef o r e t h e n e xt d o se  is d u e.  If t h e n e xt 
d o s e is d u e  i n l ess t h a n 1 2  h o u rs, t h e s ub j ect sh o u l d s ki p t h e m isse d  d o s e a n d  ta k e  t h e n e xt d o s e as 
sc h ed u l ed . A st ud y m e d ica tio n  di a ry w ill b e  co m p l ete d  b y  th e  p ati e nts  fo r e ac h  d o s e o f Im ati n ib . 
 
In str uctio n s fo r d o s e m o d ific atio n s c a n b e  fo u n d  i n Se ctio n  9 . 
 
5. 2       B GJ 3 9 8  
 
5 .2 .1     M ec h a n is m o f A cti on : 
 
B G J3 9 8  is  a n  o ral ly  b io a v ai la b l e,  p o te nt  a n d  s ele cti v e  in h ib ito r  o f  th e  fib ro b l ast  g ro w t h  f acto r 
r ece p to rs ( F GF Rs).  T h e  FG F R  f am ily  o f rec e p to r ty ro sin e  ki n a ses  (R T K s) co n sists o f fo u r m e m b ers 
( F GF -R 1 , F GF -R 2 , F GF -R 3 , FG F -R 4 ), w hic h  se rve  as th e  h ig h  affi n it y re c e pto rs fo r 2 2  F G F lig a n d s. T h es e 
ar e  p l eio tro p ic g ro w t h f acto rs t h at co n tro l c ell p ro life r atio n , m ig r ati on , a n g io g e n esis,  a p o p to sis a n d 
d iffer e nti at io n a n d ar e  in v o lve d i n b o t h d e v e lo p m e n tal a n d a d u lt tiss u e h o m e o st asis. M o re  r ece ntly, 
c an c er e p i de m io lo g ic al a n d  m o lec ul ar  st ud ie s h a v e  r e p orte d  var io u s g e n e tic alt er at io n s in clu d in g 
g e n e  a m p lific atio n s, m u tat io n s a n d  c hro m o so m al  tr a n slo c atio n s, as  w e ll  as a b err a n t p ro te i n 
e xp r essio n  fo r t his fa m ily o f R T K s a n d  lig a n d s. F u rth er,  th eir  lin k  t o c an cer  d e p e n d e nc e  h as  b e e n  
es ta b lis h e d p r eclin ic all y b y m e a ns  o f lo ss o f fu n ctio n  a p p ro ac h es.  P re clin ic al re s e arc h st ud ie s h a ve 
s h ow n  t ha t B G J3 9 8  s elec tiv el y  s up p r esse s FG F R  sig n al i ng  a n d  p ro lif er atio n  i n ca n c er c ells wit h F G F R 
d e p e n d e ncy  a n d  r es p ectivel y , t h e tu m o r g ro w t h o f m o u se  a n d  r at xe n o g r aft m o d els  as so ci ate d  wit h 
a b err a n t F G F Rs  e xp r essio n /act iv at io n . I n a d d itio n  t o a d ir ect eff e ct o n  t h e tu m o r ce lls, B G J3 9 8  h as  a n 
eff e ct o n  e n d o t h elia l cells  b y  b lo cki n g b F G F -in d u ce d  a n g io g e n esis,  t hu s p ro v id in g  a n  alt er n a tiv e 
m ec h a n ism  to  in h ib it tu m o r g ro w th . O n t h is b asis,  tar g e te d  in h ib itio n o f F G F R s c a n b e  e x plo ite d  fo r 
t h er ap e utic g a i n. 
 
5 .2 .2     F o rm u la tio n , S to ra g e  a n d  P a ck a g in g  
 
B G J3 9 8  will  b e  p ro v id e d  b y  N o v a rtis as  film -co at e d  ca p s ule  fo r o r al u s e o f d o sa g e  stre n g t h o f 2 5 m g 
a n d  1 0 0 m g.  St u d y  d ru g  m u st b e  r ece ive d  b y  a  d es ig n at e d  p ers o n  at  th e  stu d y  sit e, h a n d l e d a n d 
sto re d  s af ely  a n d p ro p er ly , a n d  k e p t i n a  s ecu r e d lo ca tio n to  w h ic h o n ly  th e  in v e stig a to r a n d 
d esi g n at e d  assi st a nts  h a ve  ac cess.  U p o n  r ecei p t,  B G J3 9 8  sh o u l d  b e  sto re d  acc o rd in g  to  t h e 
in str uctio n s s pe cifi e d o n  th e  d ru g  l ab els.  St u d y  m e d icati o n  will  b e  d isp e ns e d  b y a n  a u t ho rize d  p ers o n 
at  t h e in ve stig a to r’s site.  


P a g e 2 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
5 .2 .3     A d m ini str atio n  o f B G J3 9 8  
 
B G J3 9 8  will  b e  t ake n  o r ally , u sin g  tr e at me nt  sc h ed u l e A  (o n ce  a  d a y  fo r 2 1  d ays  o n , 7  d ays  o ff) o r 
tr e atm e nt  sc h ed u l e B  (o n c e d ai ly fo r 7  d a ys  o n , 2 1  d a ys  o ff) r e pe ati n g  i n 2 8  d a y  cy cl es. P ati e n ts 
s h o ul d b e  in str ucte d to  ta ke  t h e d aily  d o se  o f B GJ3 9 8  in  th e  m o rn in g , at a p p ro xim at e l y t h e sa m e  tim e 
e ac h  d a y  (2 4  ±  2  h o u r in te rv a l). P ati e nts  sh o u l d co n s um e  a  lig h t b r ea kf ast e ac h  d a y  ( e.g ., n o n - 
g r ap efr u it-b as e d  ju ice , to a st a n d  ja m ). T h is sh o u l d b e  fo llo w e d  b y  a 2  h o u r fa st, a fte r wh ic h t h e d o ses 
o f st ud y  d ru g s h o ul d b e  t ake n . P ati e n ts s h o ul d co n tin u e  t o f ast fo r 1  h o u r af ter  th e  a d m in istr atio n  o f 
st ud y  dr u g . 
 
B G J3 9 8  sh o u l d b e  ta k e n  w it h a  l ar ge  g l ass o f w ater  ( ~2 5 0  mL ) a n d  co n su m e d ov er  a s sh o rt a t im e  as 
p o ssib l e. P a ti e nts sh o u l d b e  in str uct e d to  sw all o w  th e  c ap s ules  w h o l e a n d  n o t ch e w  t he m . If fo r a n y 
r e aso n  a  b r e akf ast w as  n o t co n s u me d  p ri or to  t aki n g t h e d o s e t h e p ati e n t s h o uld  t a k e t h e d o s e w it h 
a  fu ll g l ass o f w a ter,  a n d  co n tin u e  to  f ast fo r a n  h o u r aft er t a ki n g t h e d o s e. If th e  p ati e nt  fo rge ts to 
t a k e th e  sc h ed u l e d d o s e i n t h e m orn in g , he /s h e sh o u l d n o t t ake  t h e d o se  m o re  th a n  2  h o u rs after  th e 
u s ua l tim e a n d  s h o ul d co n tin u e  tr e atm e n t t h e n e xt d ay.  A n y  d o s es t h at a re m isse d  s h o ul d b e  skip p e d 
alt o g e t h er a n d sh o u l d n o t b e  r e plac e d  o r m a d e  u p  at  t h e n ext sc h ed u l e d d o sin g . 
 
If v o m itin g  o cc urs fo llo w in g  t h e d o sin g  o f st ud y  d ru g , re -d o sin g  is n o t p e rm itte d  t h at sa m e  d a y . 
D o sin g  s h o ul d  r esu m e  th e  n e xt  d a y. B G J3 9 8  is  ch ar act eriz e d  b y  p H -d e p e n d e nt  so lu b ility ,  a n d 
t h er efo r e, m e d icin al  p ro d u cts t h at alt er  t h e p H  o f t h e u p p er  g astr o -in te stin a l tr act m a y  alt er  t h e 
so lu b ility o f b o t h co m p o u n d s, a n d li m it b io a v ai la b ility . T h e se  a g e nts  in clu d e,  b u t ar e  n o t lim it e d to , 
p ro to n -p u m p  in h ib ito rs ( e.g ., o m e p r azo le),  H 2 -a n t ago n ists ( e.g ., r an itid in e)  a n d a n t aci ds. T h er e fo r e, 
B G J3 9 8  sh o u l d b e  d o se d  a t l e ast 2  h o u rs b e fo r e o r 1 0  h o u rs af ter  d o sin g  wit h  a  g astric  p ro tec tio n 
a g e nt.  P at ie nts  m u st a vo i d co n su m in g  S e v ille  o r an ges  o r ju ice , g r ap efr u it, g r ap e fru it ju ice,  g r ap efr u it 
h y b rid s, o r p u m m e lo s fro m  7  d ays  p rio r to  t h e first d o s e o f st ud y m e d ic atio n  t hr ou g h  t h e e n d  o f 
st ud y p artici p at io n . T his  is d u e  t o a  p o te n ti al C Y P 3 A 4  in te ra ctio n wit h  st ud y m e d ica tio n .  N o rm al 
o r an g es  a n d  o r an g e  ju ic e a r e al l ow e d . 
 
T h e  in ve sti g ato r o r res p o n sib l e sit e p er so n n el  s h ou l d in str uct t h e p ati e nt t o  t a k e th e  st ud y  d ru g 
e xact ly as  p res crib e d  t o p ro m o te  co m p li an c e. A ll d o sa g es  p r escrib e d  a n d  d isp e n s e d t o t h e p a ti e nt 
a n d  all  d o s e c ha n g es  o r m iss e d d o ses  d u rin g  t h e st ud y  m u st b e  re co rd e d.  A  stu d y  m e d ic atio n  d i ary 
will  b e  co m p le te d  b y t h e p ati e nts  fo r e ac h  d o se  o f B G J3 9 8 .   P ati e nts  will  b e  in str uct e d t o re t ur n 
u n u s e d stu d y  dr u g  to  th e  sit e at  th e  e n d  o f e ac h  cycle.  
 
6. 0       C RI T E RI A  F O R  S U BJ E C T  E LIG IBILI T Y  
 
6. 1       S u bj e ct I ncl usio n  C rit eria  
 
P ati e n ts e lig ib l e fo r in clu sio n  i n t his stu d y  h av e  to  m e e t a ll o f th e  fo llo wi n g  criter ia:  
 
In cl usi o n crit eria : 
 
•  P ati e n ts m u st h a v e  p a t ho lo g ic all y co n fir me d GI S T.  
•  I n th e  P h a s e I b p o rtio n , m u st h a v e  lo c all y a dv a n ce d o r m e tast at ic GI S T  a n d  h a v e  pr o g r esse d 
o n  im ati n ib . 
•  I n th e  P h a s e II p o rtio n , p atie nts  m u st b e  n e w ly  di a g n o s e d o r im a tin i b tr ea tm e nt  n aï v e  i n t h e 
a d v a n c e d/ me tas tatic se ttin g . P ri or a d ju va n t im a tin i b th er a p y  is allo w e d as lo n g  a s dis e as e 


P a g e 2 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
r ec urre nc e  w as  d o cu m e n te d  ≥9 0  d a ys  aft e r l ast d o se  o f im ati n i b a n d  im ati n i b h as  n o t y et 
b e e n  re st arte d.  
•  P ati e n ts m u st b e  at  le ast  1 8  ye ars  o f age.  
•  D is e ase  m u st b e  m e as ur a b le  b y R E CI ST  1 .1 . 
•  E C O G  P er fo rm a n c e St atu s 0  o r 1 . 
•  A d e q u at e  r en al,  h e p a tic, a n d h e m a to lo g ic f un ctio n as  th e  fo ll owi n g : S er u m  C r e atin in e  ≤ 1 .5 
m g /d L, T o t al S er u m  Bil iru b i n ≤ 1 .5  x u p p er  lim it o f no rm al ( U LN ) u n l ess du e  to  Gi l bert’s 
D is e ase , S eru m  A ST  (S G O T) a n d / or AL T  (S G P T) ≤ 2 .5  x UL N (o r ≤ 5 . 0 x U LN  if co n sid er e d d u e 
t o t um o r), A N C  ≥ 1 5 0 0 /m m
3, P l at ele ts ≥ 1 0 0 ,0 0 0 /m m
3, a n d  h e m o g lo b i n ≥ 1 0 g /d L. 
•  P ati e n ts o f c hil d be ari n g  p o te n ti al m u st h a v e  a  n e g at ive  b lo o d p r e gn a n c y te st wi th i n 1 4  d a y s o f 
tre a tm e nt.  P at ie nts  m u st a g r e e to  us e  a r eli a b l e b a rri er m e th o d  o f bi rt h co n tro l du rin g  a n d f o r 
3  m o n t hs fo llo wi n g  t h e l ast do se  o f stu d y  dr u g . 
•  P ati e nt  m u st h a v e  a d e q u a te  c ard i ac fu n ctio n  (l eft v e n tricu l ar e jec tio n fr a ctio n (LV E F ) ≥5 0 %  as  
d e te rm in e d by  a  m u ltig at e d  ac q u isitio n  (M U G A ) sc a n o r e c h oc ard io g ra m ; a n d Q T c in te rv al  
≤4 8 0  m s b y  F rid erici a ’s fo rm u l a (Q Tc F).  
•  P ati e nt  m u st b e  a b le  to  t ake  o r al m e d ic atio n s. 
•  P ati e n ts m u st sig n  a n i n fo rm e d  co n se nt d o c um e nt.  
 
6. 2  
S u bj e ct E x clu sio n  C rit eria  
 
P ati e n ts m e e tin g  a ny  o f t h e fo llo wi n g  crit eri a ar e  e xclu d e d fr o m  th e  stu dy : 
 
Excl u si o n crite ria : 
 
•  F or p h as e  I, pr io r i nto ler a n c e to  im ati n i b at  a  d o s e o f 4 0 0  m g  d a il y. 
•  F or  p h as e  II, a n y  rec e ip t o f cy to to xic, bi o lo g ic, o r im m u n e  t h er ap y ai m e d to  tre at  GI S T  e xce p t 
fo r a dju v a n t im ati n i b syste m ic t h er ap y  t h at co n clu d e d  at  l e ast 9 0  d a y s prio r to  re gistr at io n . 
F or P h a s e I, p ati e nts  ar e  el ig ib l e re g ar d l ess o f prio r th er a p y . 
•  C h ro n ic liver  d ise as e  ( e. g., cirrh o sis) 
•  K n o w n p o sitiv e  se ro lo gy  fo r HIV, act iv e  H e p atitis  B, a n d / or a ctive  H e p atitis C  i nfe ctio n . 
•  P ati e n ts h ave  a h isto ry o r cu rr en t e v id e nc e  o f C e n tr al S er o u s R e tin o p at hy  ( C S R) o r r etin al 
v ei n  o cclu sio n  (R V O)  o r m a jo r p r e disp o sin g f ac to rs to  CS R o r R V O (e. g . u n co n tro lle d 
g l au co m a  o r o c ular hy p e rte nsi o n ) i n t h e o p in io n  o f th e  st ud y o p h t h alm o lo g ist. 
•  H isto r y o f re tin al  d e g e n er a tiv e  dis e as e  
•  Acti v e  co rn e al d iso rd er  o r ke r ato p at hy  (e. g . co rn e al  a b r asio n , bu llo u s k e ra to p a th y) 
•  S e v e re  a n d/ o r u n co n tro lle d  m e d ic al dis e a se,  in clu d in g : 
o  U n co n tro ll e d dia b e te s m ellit us ( A 1 c > 8 ) 
o  C h ro n ic K id n e y  D is e ase  St a g e  III o r hi g her  (Cr e a tin in e  Cl e ar a n c e < 6 0 m L/ min /m
2  b y 
M o d ifie d  D iet  i n R e n al  D ise as e  (M D R D ) c alcu l atio n ) 
o  Acti v e , un co n tro lle d i n f ectio n  
•  K n o w n  act iv e  b r ain  m e t astasis  u n l ess th e y  h a v e  b e e n  tr e ate d  a n d  s ho w n d o c um e nt e d 
r ad io g r ap h ic sta b ility  fo r 2 8  d a y s. 
•  K n o w n  o th er  a ctiv e  m al i g na n c y (o t h er th a n  m al i g na n ci es w hic h  t h e in v es tig a to r d et e rm in es 
ar e u n li ke ly  to  i nterf er e  w ith  tr e atm e nt  a n d  s afe ty a n a l ysis). 
•  P ati e n ts h ave  clin ic ally  si gn ific an t c ard io v a sc ular d is ea s e, in clu d in g  a ny  o f th e  fo llo wi n g  


P a g e 2 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
o  A n y  hist o r y o f a c ut e co ro n ar y  sy n d ro m e  in clu d in g  m yo c ard i al i nfar ctio n , st a ble  o r 
u n st a ble  a n g in a, C A B G,  co ro n ar y  a n g io p l asty o r ste nt in g , o r kn o w n  o b str uctive  co ro n a ry 
art er y  dis e a se  
o  S y m p to m atic  ch ro n ic h e art  f ailu r e (N e w  Y o r k H e art  A sso ci atio n  Cr ite ria , Cl ass I I-IV)  
o  E v id e nc e  o f clin ic all y si gn ific an t c ard i ac ar r hy th m i as a n d / or co n d u ctio n  a b n o rm a liti es <  6 
m o n t hs prio r to  scre e n in g  e xc e pt atri a l fib rilla tio n  (A F) a n d  p ar o xy sm al s u p ra ve n tricu l ar 
t ac hycar d i a (P S V T ) 
•  A n y  hist o r y o f t hro m b o tic cer e br o v asc u lar  ac cid e nt  o r o t h er art eri al  th ro m b o sis 
•  U n co n tro ll e d arte ria l h y p e rte n sio n  (sy sto lic bl o o d  pr e ss ure  > 1 5 5  m m H g  o r dia sto lic >9 5 
m m H g)  d es pi te  a p p ro p ria te  m e d ic al th er a p y . 
•  H isto r y a n d / or c urre nt  e v id e nc e  o f u n co n tro lle d  e n d o crin e  al ter at io n s o f c alciu m/ p h o s ph a te 
h o m e o st asis, e.g ., p ar at h yro i d d iso rd ers,  h isto ry o f p ar at h y ro id ec t omy , tu m o r ly sis, t um o r al 
c alcin o sis, e tc. 
•  I mp ai r me nt  o f g astro in tes tin al f u n ctio n  o r ga stro in te stin al d is e as e (e. g ., u n co n tro ll e d 
u lc er ative  d is ea se ; u n co n tro ll e d na u s ea , v om itin g , dia rrh e a ; ch ro n ic m al a b so rp tio n 
sy n d ro m e).  
•  P ati e n ts w it h m aj o r s urg e ry  w it hin  3  w e e ks  p rio r to  stu d y  e n try  o r w h o  h a v e  n o t r eco v e re d 
fro m  si d e eff e cts o f s uc h p ro c e du r e. 
•  W o m e n  w h o  ar e  p re g n a n t o r l act atin g . 
•  S ex u a ll y a ctiv e  m al e s, u n le ss th e y  us e  a  co n d o m  d u rin g  i nt erco u rs e w hi le  ta kin g  th e  d ru g  a n d 
fo r 1 5  d a y s a fte r sto p p in g  tr e atm e n t. T h e y  s h o ul d n o t f at h er a c hil d i n t his p erio d . A co n d o m 
is r e qu ir e d to  b e  us e d  al so  b y  v a sec t om ize d  m e n i n  o rd er  t o pr e ve nt d eli v ery  o f th e  d ru g  v i a 
s em in al fl u id . 
•  P ati e n ts w it h an y sig n ific an t h isto ry o f n o n -a d h er e n ce  t o m e d ic al re g im e ns  o r wi th  i na b ility 
t o gr a n t re li ab l e i nfo rm e d  co n s e nt. 
 
 
7. 0       R E C R UI T M E N T  P LA N  
 
B o t h m e n  a n d  w o m e n  a n d  m e m b ers  o f all  r ac es a n d  e th n ic g ro u p s ar e  eli g ib l e fo r t his tri al. T h e 
clin ic al tri al will  b e  liste d o n  t h e clin c altri als. g ov  w e b sit e a n d  o n  t h e w e b sit es o f p artici p a tin g 
in stit utio n s. P at ie nts  will  b e  id e ntifi e d  t hr ou g h  in t ern al  r ef err als a n d  e xte rn al  r ef err als b y  M e d ical 
a n d  S u rg ic al  O nc o lo g ists  n ati o n al ly  a n d  i n te rn ati o n al ly .  P ati e nts  will  b e  re cru it e d  t hr ou g h  t h e 
S a rco m a  D is e ase  M a n a g e m e nt T e a m  o f t h e M e m o ri al S lo a n -K e tte rin g  C a n cer  C e nt e r, D a n a  Fa rb er 
C a n c er In stit ute  a n d  M D  A n d ers o n  C a n c er C e nt er.  T h e  S a rco m a  ser v ic e a n d t h e  S a rco m a  D is ea s e 
M a n a g e m e nt  T e a m  e a c h h o l d we e kl y in te rd e p a rtm e n t al m e e tin g s t o id e ntif y  st ud y p artici p a n ts fo r 
o p e n  clin ic al tri als. W e  wi ll als o  d iscu ss t h e tri al a n d  p ati e nt  r ecr uitm e nt  wit h  s ev er al  GI S T  p ati e nt 
s up p o rt g ro u p s. 
 
P ati e n ts  will  b e  r ecr uite d  t hr ou g h  t h e  S a rco m a  D is e as e  M a n a g e m e nt  T e a m  o f  t h e  p artici p ati n g 
in stit utio n s. 
 
8. 0       P R E T R E A T M E N T  E V A LU A T IO N  
 
P ati e n ts will  n e e d  t o h a v e  th e  fo llo wi n g  tes ts a n d  pr o ce d u r es p ri or to  e n teri n g  th e  st udy : 
 
W ith in  4  w e e k s o f stu d y  sta rt: 


P a g e 2 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
•  In fo rm e d C o n se nt  
•  T u m o r im a g in g - C T  C h es t/A b d o m e n /P el v is pr efer a b l e 
•  C o n firm a tio n  o f d ise as e  ( A b io p s y will  b e  re q u ir e d if p ati e nts  d o  n o t h a ve  e n o u g h  arc h i ve d 
tiss u e to  m a k e  tr ea tm e nt  d ecisi o n s).  A  p o rtio n  o f th is b io p s y will  b e  co ll ecte d  fo r r ese arc h 
p u rp o s es o n l y a fte r a p at h o lo g ic al d i ag n o sis h as b e e n  m a d e  a n d  in fo rm e d  co n se nt  h as  b e e n 
o b t ain e d.  
•  O p h t h al mo lo g y  e x am in a tio n  
•  T u m o r b io p sy : A fte r co n s en t, a n d  p ri or t o tre a tm e n t, 2 0  p at ie nts  e n ro ll e d o n  th e  P h as e  II 
p o rtio n  o f t h e st ud y  ac ro ss all  sites  will  h a ve  a  d e d ic ate d  o p e n  in cisio n al  o r co r e b io p sy o f 
t h eir d is e as e (se e  sec tio n 9 . 1 fo r d e t ail e d d es crip tio n  o f b io p sy s ele ctio n  p ro c ess). A fte r 
b io p si es  o n  2 0  p ati e n ts  ar e  o b t ain e d,  co n se nt  t o  a  b io p sy  will  n o t  b e  m a n d at e d  fo r 
e nr ol lm e nt.   H o w e v er,   co n s e nt   to   r ese arc h   b io p si es   i n   s ub s e qu e nt   p at i en ts   will   b e 
e nc o u r ag e d  if f un d in g  e xists. 
 
W ith in  2  w e e k s o f stu d y  sta rt: 
 
•  D e m o g r ap h ics 
•  B -H C G (if a p p lic ab l e) 
•  M e d ic al Histo ry 
•  C o n c urr e nt M e d ic atio n  
•  P h y sic al Ex a m  
•  V it al Sig n s 
•  H ei g h t 
•  W e ig h t 
•  P er fo rm a n c e St atu s (E C O G ) 
•  C B C wit h di ffer e nti al,  pl a te le ts 
•  Bl o o d  C h e m istry --C o m p re h e ns iv e  p a n e l- ( Al b um i n, to tal  b iliru b in , b ic arb o n at e , B U N , c alciu m , 
c hlo rid e,  cr e ati ni ne, s o d iu m , g lu co s e, p o ta ssiu m , to tal  p ro te in , so d iu m , a lk ali n e p h o s ph at as e , 
S G O T  [A S T ], S G P T  [A LT ]) p lu s L DH , cre a tin in e  p h o s ph o ki n as e  ( C K), m a g n e siu m , p h o s ph o ru s, 
a m y la s e, a n d  lip a se . 
•  T S H  
•  H e p atitis  B  s ero lo g y — ( He p  B  s urf ac e  a n ti g e n,  H e p  B  s urf ac e  a n tib o d y  a n d  H e p  B  co r e 
A n tib o d y ) 
•  E K G  
•  Ur i nal ysis  
•  B as eli n e  FD G  P E T  sc a n (P h a s e II stu d y  o n ly) 
•  Ec h oc ar d io g ra m  o r M U G A  
 
P l e ase  se e  St u d y  C al e n d ar in  S ec tio n  1 0 . 0 fo r m o r e in fo rm ati o n . 
 
9. 0       T R E A T M E N T/I N T E R V E N TI O N  P LA N  
 
Tr e a tm e nt  will  b e  a d m in ister e d  o n  a n o u t p ati en t b as is.  R e p o rte d  a dv ers e  e v e n ts a n d  p o te n ti al risks 
ar e  d es crib e d  i n S ecti o n  1 1 .  A p p ro p ria t e d o s e m o d ific atio n s o f im ati n i b a n d  B G J3 9 8  ar e  d es crib e d  i n 
s ectio n  9 . 2.  N o  in v e stig at io n al  o r co m m e rci al a g e nts o r t h er ap i es o t h er t h a n th o s e d es crib e d  b el o w 
m a y  b e  a d m in ist ere d w it h t h e i nt e nt to  tre at  t h e p atie nt's m al i g na n cy . 


P a g e 2 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
I m atin i b will  b e  s elf a d m in ist ere d  o r ally b y th e  p at ie nt  o n  a  d ai ly b asis  t hr ou g h o u t t h e tr e at me nt 
cy cl e. T h e  st a nd ar d  tre a tm e nt  d o se  is 4 0 0  m g P O  Q D . 4 0 0  m g  c ap s ule  will  b e  u se d  u n l ess o t h er wise 
s p ecifie d  b y  t h e tre a tin g p h y sici an . B G J3 9 8  will  b e  ta k e n  at  t h e R P 2 D  a n d  tr e atm e nt  sch e d u l e c h ose n 
fro m  t h e P h a se  I b p o rtio n  o f t h e tri al. T h e  R P 2 D  sel e cte d  m a y  b e  lo w e r t h a n t h e M T D  b as e d  o n P K 
d at a  a n d  clin ic al to le r an c e b e y on d  C y cl e 1 . B G J3 9 8  is t ake n  d ai ly  fo r a  d u r atio n  d e te rm in e d  b y  t h e 
tr e atm e nt  sc h ed u l e a p p ro p ria t e fo r t h e g ive n  d o s e le v el  . I n t h e e v e n t o f d o s e d el a y s o f B G J3 9 8 , D a y 
1  o f t h e fo llo wi n g  cycle  w ill b e  d efi n e d  as  t h e d ay  th at  B G J3 9 8  is r est arte d . A p ill d i ary fo r b o t h 
m e d ica tio n s will b e  p ro v id e d a n d r ec o rd e d ( Ap p e n d ix B). T his will b e  u s e d t o ass u r e co m p li an ce  wit h 
t h e re g im e n.  
 
O n  t h e P h as e  I b p o rtio n , th e  tim in g  o f p h ar m a co ki n e tic s am p l e co ll ectio n s will b e  d e p e n d e nt  o n  t h e 
tre a tm e nt  sch e d u l e o n to  w hic h t h at  p ati e nt  is e nr oll ed . F or tr e atm e nt  sc h ed u le  A p h ar m ac o ki n e tic 
s am p l es will  b e  d ra w n  o n C ycl e  1 , D ay  1  at  t h e fo llo wi n g  tim e p o in ts: 0 , 1 , 2 , 4 , 6 , 8 , a n d  2 4  h rs; a n d 
C ycl e  1 , D a y 2 1  at  t h e fo llo wi n g  tim e p o in ts: 0 , 1 , 2 , 4 , 6 , a n d 8  h o u rs.  F or  tre a tm e nt  sch e d u l e B 
p h ar m a co ki n e tic s am p le s will  b e  d r a w n o n  C yc le  1 , D a y  1  a t t h e fo llo wi n g  tim e p o in ts: 0 , 1 , 2 , 4 , 6 , 8 , 
a n d  2 4  h rs; C y cl e 1 , D a y 7 at  t h e fo llo wi n g  tim e p o in ts: : 0 , 1 , 2 , 4 , 6 , a n d  8  h o u rs,  Cyc le  1 , D ay  1 5  at 
tim e p o in t 0 h r a n d C y cl e 1 , D a y  2 1  at  tim e p o in t 0 h r. 
 
A fte r co n s e nt, a n d  p ri or to  tr ea tm e nt,  th e  first 2 0  p ati e nts  e n ro ll e d o n  t h e P h as e  II p o rtio n  o f th e 
st ud y  ac ro ss all  sites  will  h a v e  a  d e d ica te d o p e n  in cisio n al  o r co re  b io p s y o f th eir  d is e ase . A ll b io p sie s 
will  b e  p erf o rm e d  a t M S K C C  o r o t h er p artici p ati n g  in stit utio n s. B io p si es o n  s ub s e qu e nt  p ati e nts will 
n o t b e m a n d a te d,  b u t e n co u r ag e d  if a d d itio n al  fu n d in g  is id e ntifi e d . A  p ati e n t m a y b e  e xc us e d fro m 
t his bi op sy re q u ire m e n t if tissu e  is n ot ac cessi b le  o r if in v es tig a to r d ete rm in es  t ha t t h e p ati e nt sh o u l d 
n o t u n d er g o  t his b io p sy .  If t his o cc urs, a  b io p s y will  b e  m a n d at e d  i n a d d itio n al  p ati e nts  t o e ns u r e 
t h at at  l e ast 2 0  p artici p a n ts u n d er g o  a  b io p sy . U p o n  in iti atio n  o f tre a tm e n t, p at ie nts  w h o  u n d e rw e n t 
a  p r e-tr ea tm e nt  b io p sy  w ill u n d er g o  a  se co n d  b io p s y  after  o n e  w e e k ( C1 D 8 ) o f co m b in ati o n  o f 
B G J3 9 8  a n d  im ati n i b tr eat m e nt  a n d  at  tim e  o f d is e ase  p ro g ress io n . A ll p at ie nts  will  u n d er g o  b as eli n e 
st a gi ng  F D G  P E T  a n d  b o d y i m a g in g  a n d  r e p ea t F D G  P E T  sc a ns d u rin g  w e e k  t hre e  o f t h e co m b in at io n 
t h er ap y o f tr ea tm e nt  (C 1 D 2 1 ) as  p a rt o f st a nd ar d o f c are . Fo u r w e e ks o f tr e at me nt  (2 8  d a y s) will  b e 
co n sid er e d  o n e  cy cle.  I ma g in g  wit h  st a nd ar d  C T  sc a ns a n d  r es p on s e e v al u at io n s will  o cc ur e v ery  8 
w e e ks fo r t h e first 3 2  w e e k s r e ga rd less  o f tre a tm e n t in te rru p tio n  a n d  th e n  o n  D a y  1  o f e v e ry  3 r d 
cy cl e t h ere aft e r. 
 
A ll p artici p a n ts o n t h e  P h a s e II p o rtio n  will  h a v e  a  2 -w e e k  l e a d i n o f im ati n ib . B lo o d will  b e  d r a w n at 
t h e e n d o f t his p er io d  t o es t a blis h ste a d y -st at e im ati n ib  s er u m tro u g h  l evels.  A ft er b lo o d  fo r im ati n i b 
l ev els  ar e  o b t ain e d,  B G J3 9 8  at  t h e es ta b lis h e d P h a se  II d o s e a n d tr e a tm e nt  sch e d u l e will  b e  a d d e d  to 
t h e r e gi me n. T h e  st art o f th e  co m b in ati o n t h er a p y  w ill m ar k  t h e b e gi n n in g o f cycl e 1  (D a y  1  cy cl e 1 ). 
T h e  in iti atio n  o f B G J3 9 8  w ill n o t b e  co n tin g e nt o n  th e  im ati n i b le v e l; ra t h er, B G J3 9 8  c a n b e  st arte d 
aft er  t h e b lo o d  d r a w fro m  im ati n i b l evels  is p erf o rm e d . Bl o o d  will  b e  d r a w n a g ai n  a p p ro xim a te l y 3 -5 - 
w e e ks af ter  t h e in itiati o n  o f t h e co m b in at io n  t h er ap y  to  e st a blis h t h e ste a d y -st at e im ati n i b ser u m 
tro u g h  le v els i n  th e  p res e n c e o f B GJ3 9 8 . 
 
9. 1       D o se  R a tio n a le : 
P h a s e Ib : T h e  p rim ar y  e n d p o in t o f t h e p h as e  1 b  p o rtio n  o f t his st ud y  is t o d e te rm in e  th e  m a xim u m  
to l era te d  d o s e  (M T D )  a n d  t h e  R e c om m e n d e d  P h a s e  2  D o s e  (R P 2 D )  a n d  tre a tm e n t  sch e d u l e  o f 
B G J3 9 8  a d m in ister e d  i n co m b in at io n  wit h  im ati n i b i n p ati e nts  wit h  GI S T.    T h e  p h as e  I b will  b e 
p u rsu e d  i n st a nd ar d  3 + 3  fo rm at,  b a se d  o n  to xiciti es e nc o u n ter e d  d u rin g  th e  first cy cl e o f t h er ap y . 


P a g e 2 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
T h e  first t hr e e p ati e nts  w ill b e  e nr oll e d  at  D o se  le v el  1 (T a b le  1 , se e  s ectio n 1 ) u sin g  tr e at me nt 
sc h ed u l e A.  D o s e l evel  1  is c h os e n b as e d  o n  th e  st a nd ar d  o f c ar e im ati n i b d o se  o f 4 0 0  m g  d ai ly i n t h e 
a d v a n c e d GI ST  p ati e n t p o p u l atio n , a n d  a n  in te rm e d ia t e d o se  l evel  o f B G J3 9 8  (7 5  m g  d ai ly ). T his  d o se 
is b el o w  t h e B G J3 9 8  M T D  o f 1 2 5  m g  d ai ly  id e ntifi e d  in  p h as e  I tri als as  m o n o th er a p y .  B G J3 9 8  d o se 
l ev el 1  to  -2  will  b e  a d m in iste r e d u sin g  a  sc h ed u l e o f B GJ3 9 8  t ake n  d ai ly  fo r 3  w e e ks  fo llo w e d  b y  o n e 
w e e k  o ff an d  im ati n i b ta ke n  d a il y t hro u g h o u t th e  4  w e e k  cycle  p er io d  (tre a tm e n t sc h ed u l e A ). 
 
T h e  m ax im u m  p ac e  o f d o se  es cal a tio n  wit hi n e ac h  co h o rt is o u tlin e d  i n T a b le  2 . Ex p a n sio n s o f lo w er 
d o s e le v els  m a y  b e  m a d e  b as e d  o n  s af ety  a n d  to ler a n c e co n sid er at io n s at  t h e M S K C C P rin cip al 
In v es tig a to r’s d iscre tio n , a n d  t h e s el ecte d  R P 2 D m a y b e  lo w e r t h a n t h e M T D  d efi n e d  b el o w.  If d o se 
l ev el  1  is n o t fo u n d  to  b e  to l er ab l e, th e n t h e  n e xt co h o rt will  b e  e nr oll e d a t d o s e l ev el  -1 . If d o s e le vel  
-1  is n o t fo u n d  t o b e  to l era b l e, t h e n t h e n e xt co h o rt w ill b e  e n ro ll e d at d o se  le vel -2 . If d o s e le vel  -2  is 
n o t fo u n d  to  b e  to l er ab le,  t h e n t h e st ud y m a y  b e  te rm in at e d  b as e d  o n  d isc ussio n s wit h  th e  M S K C C 
P rin cip al I nv es tig a to r. If 0 -1 o f 6  p at ie nts  e xp eri e n c e a  DL T  o n  d o s e le v el 3 , t his w ill b e t h e R P 2 D . 
 
T a b le  2 : 
 
 
N u m b e r  o f  P a tie n ts  w ith  DL T  a t  a  
G iv e n  D os e L e v e l 
 
E sca la tio n  D e cisio n  R u le  
 
0  o u t o f 3 
 
E nt er  3  p ati e n ts at  th e  n e xt d o s e le vel.  
 
1  o u t o f 3 
 
E nt er at  l e ast 3  m o re  p ati e n ts at  t his d o se  le vel.  
•    If 0  o f t h es e a d d itio n al  3  p ati e nts  e xp e ri en c e 
DL T  (1/ 6  to t al), p ro ce e d  t o t h e n ext d o s e le v el.  
•    If  1  o r  m o r e  o f  t his  g ro u p  s uff er  D LT  (≥2 /6 
to t al),  t h e n  d o se  es ca lat io n  is  sto p p e d,  a n d 
t his d o s e is d ecl ar e d  t h e  M T D .    T hr e e  (3 ) 
a d d itio n al  p ati e n ts will  b e e nt er e d  a t t h e n e xt 
lo w e st  d o se  l ev el  if  o n ly  3  p ati e nts  w e r e 
tre at e d  pr e vio u sly  at  t h at d o s e. 
 
> 2  
D o se  es cal a tio n  will  b e  sto p p e d.  T his  d o s e l evel  
will  b e  d ecl a re d  t h e M T D .  T hr e e ( 3 ) ad d itio n al 
p ati e nts  will  b e  e n ter e d  at  t h e n e xt lo w e st d o se 
l ev el if o n l y 3  p at ie nts w e re  tr e ate d p re v io u sly  at 
t h at do se.  
 
< 1  o u t o f 6  at  h ig h e st d o se  le v el  b e lo w 
t h e M T D  
 
T his is g e n er al ly  t h e r eco m m e n d e d p h as e  2  d o se. 
At  l e ast  6 p ati e n ts m u st b e  e nt e re d  at  th e 
r eco m m e n d e d p h a se  2  d o se  (R P 2 D ). 
 
 
Usi n g  tr e atm e nt sc h e d u l e A, if d o se  le vel  1  t o -2  is i de n tifi e d as th e  M T D  a n d  co n c er n exists re g a r din g 
t h er ap e utic  act iv it y o f B G J3 9 8  at  th is d o s e le v el, e x pa n sio n s w it h hi g her  d o s e le v els (1  to  3 ) m a y  b e 
co n sid er e d  at  t h e M S K C C  P I’s discr etio n , wit h m o d ificati o n  o f th e  tre a tm e nt  sch e d u l e. I n t his se ttin g 
B G J3 9 8  w ill b e  a d m in ist er ed  d a il y fo r o n e  w e e k  fo llo w e d by  3  w e e ks o ff an d  im a tin i b w ill b e ta k e n  


P a g e 3 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
d ai ly  th ro u g h o u t th e  4  w e e k  cycl e p er io d  (tr e at me nt sc h ed u l e B). T h e  h ig h er  d o se  le v el  e xp a n sio n 
will  st art by  e nr olli n g  3  p at ie nts  in to  a  co h o rt, at  d o s e le v el  1 , usi n g  tr ea tm e nt sc h e d u l e B. 
 
W h e n  u sin g  tre a tm e nt  sch e d u l e  B  t h e m ax im u m  p ac e  o f  d o s e es cal a tio n  w it hin  e ac h  co h o rt  is 
o u tlin e d i n  T a b l e2 . 
 
 
 
U p o n  d o cu m e n t atio n  o f th e  R P 2 D  d o se  a n d  tre a tm e n t sc h ed u l e o f th e  co m b in a tio n , t h e p h a se  II tri al 
will  o p e n  a n d  all  s ub s e qu e nt  p ati e nts  e n ro ll e d will i n iti at e tr ea tm e nt  at  t h at d o s e a n d  tr e at me nt 
sc h ed u l e w it h an y s ub s e qu e nt d o se  m o d ific atio n s as o u tlin e d b el o w.  
 
T o xicity will  b e  as sess e d  u sin g  t h e N CI  C T C A E  (v ers io n 4 . 03 ) u n l ess o t h erwis e  sp e cifi e d. D o s e Lim itin g 
T o xicity (D LT)  is d efi n e d  as a n  u n e x p ect e d a dv ers e  e ve nt  ( A E) o r a b n o rm al  l ab o rat o ry  v al u e  as ses se d 
as at  l e ast p o ssib l y r el ate d t o  th e  st ud y  m e d ic atio n , w h ic h o cc urs ≤2 8  d a ys  (1  cycl e) fo llo wi n g  th e  first 
d o s e o f B G J3 9 8  (cycle  1 ), a n d  m e e ts a n y  o f  t h e crit eri a liste d  i n T a b le  3 . P l e ase  n o te  p l asm a 
ass es sm e nts  m ay  s ub stit ute  fo r se ru m  as ses sm e n ts p er  lo c al l ab o rat o r y st a nd a rd s. 
 
T a b le  3 : C rit eria  fo r d e fini n g  d o se -lim itin g  to xi citie s 
 
T O X IC IT Y  
DL T  C RI T E RI A  
H e m a to lo g y 
C T C A E gr a d e  4  n e utr o p e n ia l asti n g  m o re  t h a n 7  co n s ecu tiv e  d a ys  
C T C A E gr a d e  4  t hro m b o cy to p e n ia  
C T C A E Gr a d e  3  o r 4  n e utr o p e n ia w it h fe v er  (t em p er a tu r e ≥ 3 8 .5 ° C) 
S ki n  a n d  s ub c ut an e o u s 
tiss u e diso rd ers  
R as h , H F S R  ( H an d  F o o t Ski n R e ac tio n ) o r p h o to se ns itiv ity C T C A E  Gr a d e  3  >  7 
co n s ecu tive  d ays  d es p ite  
s ki n to xicity  tre a tm e nt  (as  p er  lo c al pr acti ce)  
R as h , HF S R o r ph o to se nsit iv it y C T C A E  Gr a d e  4  
E y e  d iso rd ers  
C S R  ( C e ntr al S e ro u s R e tin o p at hy)  C T C A E  Gr a d e  2  fo r >  1 4  co n s ecu tive  d a ys 
co n firm e d by  o p h t h alm o lo g ic e xa m in at io n  
C S R   ( C e ntral    S e ro u s    R e tin o p at h y )   C T C A E   Gr a d e  ≥   3 ,   co n firm e d   b y 
o p h t h al mo lo g ic e x am in a tio n  
R e tin al  d iso rd er  o th er  th a n  C S R  (re tin al  d e t ach m e nt /te ar,  re tin al v asc u lar 
d iso rd er,  r etin o p at hy o th er)  C T C A E  Gr a d e  ≥ 2  co n firm e d  b y  o p h t h alm o lo g ic 
e xa m in ati o n  
V is ua l d ist ur ba n c es wit h o u t o c ular  (r etin a l) c ha n g e s: Bl u rr e d v isio n , F las h in g  
li g hts, Flo a ters,  C o rn e al  a b n o rm al iti es C T C A E  Gr a d e  ≥ 3  
G astr o -in tes tin al  
≥  C T C A E  g r ad e  3  n a u s e a  o r  vo m itin g  ≥  4 8  h rs  d e s pit e  o p tim al  a n ti-e m e tic 
t h er ap y 
≥ C T C A E  gr a d e  3  di a rrh e a  ≥ 4 8  hrs d es p ite  o p tim al a n ti-d i arrh e a  tr ea tm e nt  
P a n cr ea titis ≥ C T C A E  g r ad e  3  
H e p at o -b ili ary 
≥ C T C A E  gr a d e  3  to t al bi liru b i n 
≥ C T C A E  g r ad e  3  A LT  (iso la te d  in cr ea s es i n A ST  w it ho u t co n co m it an t in cr e ases  


P a g e 3 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
i n AL T  will  n o t b e  co n sid e re d  d o se -lim itin g , b ec a us e  o f th e  n o n -s pe cific n at u re  
o f AS T)  
S er u m  a lk alin e  p h o s ph at a se  C T C A E  Gr a d e  4  >  7  co n se c uti v e d a ys  
In v es tig at io n s (M e t a bo lic) 
S er u m  Lip a se  a n d/ o r s eru m  a m y l ase  ( asym p to m ati c) C T C A E  g r ad e  3  fo r >  7 
co n s ecu tive  d ays  
S er u m  Lip as e  a n d / or se ru m  a m y la s e (as ym p to m atic)  C T C A E  g r ad e  4  
Sy m p to m atic  se ru m  lip as e  a n d / or ser u m  a m y l ase  ≥ C T C A E  g r ad e  3  
E C G Q T  In te rval  
Q Tc F i n ter v al  ≥ 5 0 1  m s o n  at  l e ast tw o s e p ar a te  E C Gs  
R e n al  
S er u m  cre a tin in e  >  2 x U LN  
S er u m  P h o s ph o ro u s t h at re q u ir es d o se  in terr u p tio n  o f B G J3 9 8  fo r > 1 4  d ays  o f 
first 2 1  d a y s o f C y cl e 1  
N o n -h e m a to lo g ic e v e nts  
≥ C T C A E  gr a d e  3 , e xce p t fo r th e  e xcl usio n s no te d b e lo w  
Ex ce pt io n s to  D LT  crite ri a 
Gr a d e  3  al o p eci a  
 
<  5  d a y s o f C T C A E gr a d e  3  fati g u e  
<  5  d a y s o f C T C A E gr a d e  3  e d e m a  
Gr a d e  3  la b o r ato ry  a b n o rm al itie s t h at ar e  res p o n sive  to  o ral  s up p le m e nt at io n 
o r de e m e d by  t h e in v es tig a to r t o b e  clin ic ally  i nsi g nifica n t 
C T C A E  v ers io n  4 .0 3  w ill b e  u s e d fo r all gr a d in g . 
O pti m al  t h er ap y  fo r v o m itin g  o r d i arrh e a  will  b e  b as e d  i n in stit utio n al  g u id eli n e s, wit h  co n sid er a tio n  o f th e 
p ro h ib it e d m e d ic atio n s liste d i n  th is pro to co l. 
 
 
P h a s e II: T h e  R P 2 D  d o ses  a n d  tr e atm e nt sc h e d u l e d ef in e d  i n t h e p h as e  I b clin ic al tri al will b e  u s e d t o 
co n d u ct th e  p h as e  II p ortio n  o f th e  st ud y . 
 
9. 2       F oll o w -u p  for t o xicitie s 
P ati e n ts w h o se  tr ea tm e nt  is in te rru p te d  o r p e rm a n e ntl y  d isco n tin u e d  d u e  t o a n  a d v ers e  e v e nt  o r 
clin ic all y sig n ific an t l ab o r ato r y v al u e  m u st b e  fo llo w e d  u n til r eso lu tio n  o r st a bilizati o n  o f t h e e v e nt. 
A p p ro p ria t e clin ic al e x p erts (e. g . o p h t h al mo lo g ist, c ard io lo g ist, d e rm a to lo g ist) sh o u l d b e  co n s ulte d  as 
d e e m e d  n ec e ss ary . A  d o s e in te rru p tio n  o f ≥ 2 8  d ays m ay  r e qu ir e th e  p ati e nt  t o b e  d isco n tin u e d  fro m 
t h e st ud y (w it h t h e e xce p tio n  o f pa ti e nts w h o  u n d er g o  s ur ge ry ; se e  sec tio n  1 3 ). P ati e n ts w ill co n tin u e 
t o b e  fo llo w e d fo r to xicity fo r 2 8  d a y s fo llo wi n g  th e  l ast d o se  o f stu d y m e d ic atio n . 
 
P ati e n ts  e xh ib itin g  h yp o m a g n es a e m i a,  h y p o c alca e m i a,  a n d/ o r  h y p o k al e m i a,  s h o ul d  r ecei ve 
el e ctro lyt e re p lac e m e nt  as  in d ic at e d b y  n at io n al  a n d i n stit utio n al  g u id eli n es  a n d  b e  fo llo w e d  u n til 
l ab o r ato ry val u es  h a ve  n o rm al ize d  o r as clin ic all y i nd ic at e d. 
 
P ati e n ts o n  t h e st ud y will b e  e xa m in e d  r e gu l arl y t o m o n ito r fo r t h e p o ssib l e d e v e lo p m e nt  o f C S R,  as 
t h e a p p e ar a n c e o f C S R h as  b e e n  ass o cia te d  wi th  B G J3 9 8  tre a tm e nt.  P a ti en ts will  r ece iv e  a 
o p h t h al mo lo g ic al v isit at  b as eli n e  a n d  4  w e e ks a fte r in iti atio n  o f t h e st ud y  d ru g . If a n  o c ular  e v e nt 
o cc urs,  p ati e n ts  will  u n d er g o  o p h t h al mo lo g ic al   ev al u ati o n  as   m a n d a te d  b y  t h e  st ud y 
o p h t h al mo lo g ist. Fo r p ati e n ts d e v el o p in g  a C S R o f a n y  g r ad e  it is re co m m e n d e d t o  fo llo w  u p  t h e C S R 
wit h a n o p h t h alm o lo g ic al e x a m e ver y  tw o  w e e ks fo r 8  w e e ks,  a n d  s ub s e qu e n tly  a t a p p ro xim a tely  a  4 - 


P a g e 3 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
w e e k  in te rval.  D o se  a d ju stm e nts  fo r o c ular  to xiciti es ar e  o u tlin e d  i n T a b le  1 1 . If o c ular  fin d in g s re - 
d e v e lo p aft er  r ec h alle n g e  wit h  d ru g , d ru g m a y  b e  p er m a n e nt ly  d isco n tin u e d  b a s e d o n e v al u at io n b y 
t h e st ud y o p h t h alm o lo g ist. 
 
A ll  p ati e nts  will  h a v e  b a seli n e  c ard i ac  ej e ctio n  fr actio n  e v al u at e d  b y  ec h o ca rd io g r a m  o r  M U G A 
st ud i es. If a  c ard i ac e v e nt  o cc urs, t h e p at ie nts  will  u n d e rg o  c ard i ac e v al u ati o n a s s ee n  a p p ro p ria t e b y 
t h e i nves tig a to r. 
 
9. 3       D o se  M o di fic atio n  
N o  d o se  r e du ctio n s  will  b e  p erf o rm e d  fo r  h e m at o lo g ic al  to xiciti es  Gr a d e  1  o r  2  a n d  n o n - 
h e m a to lo g ic al to xiciti es g ra d e  1 . N o  d o s e r e du ctio n  o f im ati n i b w ill o cc ur d u rin g  th e  first cy cle  fo r th e  
P h as e  I b p a ti e nts. 
 
9 .3 .1     Im a tin ib : 
 
P l e ase  r ef er to  T a b le  4  a n d 5  fo r d o s e r e du ctio n  ste ps a n d  crit eri a fo r in te rru p tio n  a n d  re -in iti atio n  o f 
im ati n i b fo r dr u g-r el ate d to xiciti es. 
 
T a b le 4 : D o s e M o d ifica tio n  A lg o rith m  fo r Im a tin ib  
 
D o se  Le v el  
I m atin i b D o se  
1  
4 0 0  m g  Q D  
-1  
3 0 0  m g  Q D  
-2  
2 0 0  m g  Q D  


P a g e 3 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
T a b le  5 : D o s e m o d ifica tio n s fo r a d v e rs e e v e n ts a ssoci a t e d wi t h im a tin ib  
H e m at o lo g ic to xicit y 
≥ G ra d e 3  
H o l d th er a p y  a n d  r esu m e  im ati n i b at  4 0 0  m g  Q D  aft e r r eco v ery  t o ≤ G ra d e  2 , 
if r eco v ery  o cc urs w it hin  1 4  d a ys  
If to xicity p ersis ts fo r 1 5 -2 8  d a ys  o r rec urs, h o l d th er a p y  a n d  re su m e  at  n e xt 
lo w e r d ose  le v el  aft e r r eco v e ry  to  ≤ Gr a d e  2 : 
l → 3 0 0  m g  Q D  
If r ec urr e nce  is se e n  a t t h e r e du c e d im ati n i b d o se,  h o ld  th er a p y  a n d  res u m e  
at  n e xt lo w e r d o se  le vel a fter  r eco v e ry  to  ≤ Gr a d e  2 . 
l → 2 0 0  m g  Q D  
If 4t h o cc urre nc e,  co n sid e rati o n s sh o u l d b e  h a d  t o re m o v e  s ub j ect fro m 
st ud y  if th e  to xiciti es a r e n o t m a n a g e a b le  w it h a p p ro p ria t e s up p o rtiv e 
m e as u res.  
N o t e: 
N o  d o se  r e du ctio n s w ill b e p erf o rm e d fo r gra d e  3  o r 4  a n e m i a. T h e  p at ie nt  m ay  rec e iv e  b lo o d 
tr an sfu sio n s. Use  o f e r yth ro p o ie ti n alf a (E P O)  is all o w e d at  th e  d iscre tio n  o f th e  tr e ati n g i nves tig a to r. 
G -C S F  o r G M -C S F  m ay  n o t b e  u s e d as a pr o p h y l actic b u t m a y  b e  us e d as  o th er w ise  clin ic all y i nd ic at e d 
t o s up p o rt b lo o d  co u n ts fo r p ati en ts i n t his stu d y . 
G e n e ra l n o n -h e m at o lo g ic to xi city  
Gr a d e  2 
(in to l er ab le  o r 
p ersisti n g  >  7  d a y s 
wit h o p tim al  
s up p o rtive  c are)  
H o l d t h er ap y  a n d  r esu m e  im ati n i b at  4 0 0  m g  Q D  aft e r r eco v ery  t o ≤ G ra d e  1 , 
if r eco v ery  o cc urs w it hin  1 4  d a ys  
If to xicity p ersis ts fo r 1 5 -2 8  d a ys  o r rec urs, h o l d th er a p y  a n d  re su m e  at  n e xt 
lo w e r d ose  le v el  aft e r r eco v e ry  to  ≤ Gr a d e  1 : 
l → 3 0 0  m g  Q D  
If r ec urr e nce  is se e n  a t t h e r e du c e d im ati n i b d o se,  h o ld  th er a p y  a n d  res u m e  
at  n e xt lo w e r d o se  le vel a fter  r eco v e ry  to  ≤ Gr a d e  1 . 
l → 2 0 0  m g  Q D  
If 4t h  o cc urre nc e,  co n sid e rati o n s sh o u l d b e  h a d  t o re m o v e  s ub j ect fro m 
st ud y  if th e  to xiciti es a r e n o t m a n a g e a b le  w it h ap p ro p ria t e s up p o rtiv e 
m e as u res.  


P a g e 3 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
≥ Gr a d e  3  
H o l d th er a p y  a n d  r esu m e  im ati n i b at  3 0 0  m g  Q D  aft e r r eco v ery  t o ≤ G ra d e  1 , 
if r eco v ery  o cc urs w it hin  1 4  d a ys  
If to xicity p ersis ts fo r 1 5 -2 8  d a ys  o r rec urs, h o l d th er a p y  a n d  re su m e  at  n e xt 
lo w e r d ose  le v el  aft e r re co v e ry  to  ≤ Gr a d e  1 : 
l → 2 0 0  m g  Q D  
If r ec urr e nce  is se e n  a t t h e r e du c e d im ati n i b d o se,  h o ld  th er a p y  a n d  res u m e  
at  n e xt lo w e r d o se  le vel a fter  r eco v e ry  to  ≤ Gr a d e  1 . 
l → 1 0 0  m g  Q D  
If 4t h o cc urre nc e,  co n sid e rati o n s sh o u l d b e  h a d  t o re m o v e  s ub j ect fro m 
st ud y  if th e  to xiciti es a r e n o t m a n a g e a b le  w it h ap p ro p ria t e s up p o rtiv e 
m e as u res.  
 
D o s e re -e sca la tio n  
E v e ry  a tte m p t t o re -e sc al ate  t h e d o s e o f stu d y tr ea tm e nt to  th e  in iti al d o s e le vel  s h o ul d b e  m a d e. 
T his a p p li es to  eit h er d o s e r e du ctio n s du e  to  h e m a to lo g ic al o r n o n -h e m a to lo g ica l to xiciti es. T h e  d o s e 
s h o ul d b e  re -es cal a te d  if t h e fo llo wi n g  crit eri a ar e  m et  wit hi n  4  w e e ks aft e r d ose  r e du ctio n : 
 
•  A ll ≥ Gr a d e  2  n o n -h e m a to lo g ic to xiciti es h a ve  r eso lv ed to  ≤ Gr a d e  1  
•  A ll ≥ Gr a d e  3  h e m a to lo g ic to xicities  h a v e  re so lve d to  ≤ Gr a d e  1  
•  Or alt e rn a tiv el y , all ≥ G r ad e  3  h e m a to lo g ic al a n d n o n -h e m a to lo g ic al to xiciti es h a ve  res o lve d  
t o ≤ Gr a d e  2  a n d ar e  m a n a g e a b le  w it h s up p o rtive  t he r ap y 
 
R e -es cal a tio n  o f im a tin i b sh o u l d b e  co n sid er e d  a n d  a re  e n co u r ag e d,  es p eci al ly  if a p a rticip a n t 
u n d er g o es  o n e  fu ll cycle  at  t h e m o d ifie d d o se  w it ho u t e xp eri e nci n g  t h e to xicity th at  c au s e d t h e d o s e 
r e du ctio n . 


P a g e 3 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
9 .3 .2     B G J3 9 8 : 
 
F or  p ati e n ts w h o  d o  n o t  to ler at e  t h e p ro to co l-sp ecifi e d  d o sin g  sc h ed u l e, d o s e a d ju stm e nts  a re 
p er m itte d  i n o rd er  t o al l ow  t h e p ati e nt  t o co n tin u e t h e  st ud y tr e atm e nt.  T h e s e c ha n g es  m u st b e 
r eco rd e d o n  t h e D o s ag e  A d m in istr atio n  R e co r d C R F.  
 
A ll d os e m o d ificat io n s s ho u l d b e  b as e d o n  t h e w o rst pr ec e di n g  to xicity . T h e fo llo wi n g  g u id eli n es  n e e d 
t o b e  a p p li e d: 
 
E ac h  p ati e nt  will  b e  al lo w e d  u p  t o 3  d o s e r e du ctio n s, p ro v id e d  t his is fe asi b l e b as e d  o n  th e  R P 2 D . 
P ati e n ts m u st d isco n tin u e  B G J3 9 8  if to xiciti es p ersist  fo llo wi n g  3  d o s e r e du ctio n s ( T ab l e 6 ) u n le ss a 
co n tin u at io n  is al lo w e d i n  d iscu ssio n  w it h t h e M SK C C  P I. 
 
F ol l owi n g  r eso lu tio n  o f to xicit y t o b as eli n e  o r ≤ g r ad e  1 , tr ea tm e nt  is r esu m e d a t eit h er  th e  sa m e  o r 
lo w e r d o s es o f st ud y  d ru g s as  p er  t h e crit eri a i n T a b le  6 .  If tr e atm e nt  is r esu m e d  at  t h e s am e  d o s es 
o f st ud y d ru g s, a n d  t h e sa m e  to xicity r ec urs wit h th e  s am e  o r w o rs e se v eri ty  re g ar d l ess o f d u r atio n , 
d o s es m u st b e  r e du c e d t o t h e n e xt lo w e r d o se  l evel  (T a b le  6 ). If tr e atm e nt  is re s u me d  at  t h e lo w e r 
d o se s o f st ud y  d ru g s, an d t h e s a m e  to xicity  r ec urs with t h e s a m e  o r w o rs e se v er ity , t h e p ati e nt m u st 
d isco n tin u e  st ud y  tre a tm e n t u n l ess a  co n tin u at io n  is al lo w e d i n  disc u ssio n  w it h th e  M S K C C  P I. 
 
If a  p ati e nt  r e qu ir es a  d o se  d el a y  o f >  1 4  co n sec uti ve  d a ys  o f B G J3 9 8  fro m  t h e in te n d e d  d ay  o f th e 
n e xt sc h ed u l e d d o se,  t h e n t h e p ati e nt  s h o ul d b e  d isco n tin u e d  fro m  t h e st ud y  tr e atm e nt  u n l ess a 
co n tin u at io n  is al lo w e d i n  d iscu ssio n  w it h t h e M SK C C  P I. 
 
I n e xce pti o n al  sit ua tio n s, st ud y  tre a tm e nt m ay  co n tin u e  e ve n  if t h e p ati e nt  ex p eri e nc e d  o n e  o f t h e 
tr e atm e nt  sto p p in g  ru l es.   T h e  d ecis io n  to  al l ow  fo r co n tin u ati o n  o f tr eat m e n t will  b e  m a d e  o n  a 
c ase -b y -ca s e b as is fo llo w in g  d iscu ssio n  b e tw e e n  th e  M SK C C  P rin cip al  In v e stig at o r  (M P I) a n d  t h e 
In v es tig a to r.    Sit u atio n s th at  m a y  al l ow  fo r co n tin u a tio n  o f tr e at me nt  in clu d e  b u t ar e  n o t lim ite d  t o 
t h e fo llo wi n g . A  d o se  d el a y o f > 1 4  d a y s h as o cc urr e d, b u t t h e p a ti e nt is cl ea rl y b e n efiti n g  fro m  st ud y 
tr e atm e nt  (i. e., st a ble  d ise as e,  p arti al  res p o n se,  o r co m p le te  res p o n se)  a n d  it is t h e inv es tig a to r’s 
o p in io n  t h at n o  s af ety co n c er ns ar e  p r ese nt,  af ter  d iscu ssio n  w it h t h e M P I, t h e p ati e nt  m a y re m a in 
o n  t h e st ud y  tre a tm e nt.  A t h ir d o r s ub s e qu e nt  re d u ctio n  (to  d o s e le v el  -3 ) i n d o s e m a y  b e  al lo w e d  if 
t h e p ati e nt  is cle ar ly  b e n efiti n g  fro m  st ud y  tre a tm e nt  (i. e., st a ble  d ise as e , p arti al  r es p on se,  o r 
co m p l ete  r esp o n se ) b u t is exp er ie nci n g  a dv ers e  e ve n ts t h at p r ev e nt  co n tin u e d  tr e atm e n t at  th e 
al re a dy  re d u c e d d o s e. 
 
F or  g u id a n c e r e ga rd in g  in terr u p tio n s i n B G J3 9 8  th er a p y d u e  t o a d v er se  e ve nt s, pl e as e se e  T a b le  7 . Of 
s p eci al n o t e is m a n a g e m e nt  o f h y p er p h o s ph at e m i a, a n  e xp e cte d o n -t arg et  d ru g e ff ect. S e e  t h e R e n a l 
s ectio n  o f T a b l e 8 fo r d o s e in te rru p tio n s fo r ac ute  ki d n e y  i nju ry acc o m p a n i e d by h y p er p h o s ph a te m i a. 
R e co m m e n d at io n s fo r p ro p h y l axis an d d o s e m o d ificati o n s fo r h y p er p h o s ph at e m i a ar e o u tlin e d i n 
T a b le  8 . Ex act  tim in g  o f sto p p in g /st arti n g B G J3 9 8  i n t h e se ttin g  o f el e v a te d  p h o s ph o ro u s le v els  will 
b e  l eft t o t h e ju d g m e nt o f t h e tr e atin g  p h y sici an , a n d d iffer e nc es  i n p h o s ph at e  m a n a g e m e nt will  n o t 
b e  co n sid e re d  p ro to co l d e v i atio n s. A  list o f h ig h -p h o s ph o ro u s fo o d s an d  s ug g es te d  a lte rn at iv es  is 
p ro v id e d  i n Ap p e n d ix F t o  g u id e  d iscu ssio n s r e ga rd in g a p p ro p ria t e d i et ary in t ake.  P l e as e n o t e p l asm a 
ass es sm e nts  m ay  s ub stit ute  fo r se ru m  as ses sm e n ts p er  lo c al l ab o rat o r y st a nd a rd s. 


P a g e 3 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
T a b le  6 : D o s e re d uc tio n  ta b le  
D o s e  le v el  
B G J 3 9 8  
 
D o s e  le v el  0  
R P 2 D  
S t artin g  d o s e  
D o s e  le v el  -1  
R P 2 D  m in u s  2 5 
m g  
 
D o s e  le v el  -2  
R P 2 D  m in u s  
5 0 m g  
 
D o s e  le v el  -3  
R P 2 D  m in u s  
7 5 m g  
A llo w e d  o n ly  if p a tie n t s is cl e a rly  b e n e fitin g  fro m 
s t ud y  tr ea tm e n t, b u t is e x p eri e n c in g  A E  th at 
pr e v e nt  c o n tin u e d  tre a tm e n t a t d o s e  le v el  -2 a n d 
a p p lic a b le  b a s e d  o n R P 2 D  
 
 
 
T a b le  7 : C rit eria  fo r in t erru p tio n  a n d  r e-in itia tio n  o f B G J3 9 8  tre a t me n t 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
C a rdi a c  di s o rd e rs  
C a rdi a c  - P rol o n g e d  Q T c  in te rv al  b y  
F ri d erici a ’s  F o rm u la  (Q T c F)  
 
Gr a d e  1 a n d  2  : Q T c F  4 8 1 -5 0 0  m s e c  
(a s ym pt o m at ic ) 
M a int a in  d o s e  le v el  of  B G J 3 9 8  
•  
E C G  a s s e s s m e n t s s h o u ld  b e  p er fo rm e d  for  2 
a d d itio n a l c y cl e s  at  th e  s a m e  fre q u e n c y  a s in 
c yc le  1 , o r a s  cl in ic a lly  in d ic at e d  If E C G 
a s s e s s m e n t s s h o w  n o  Q T c F  ≥ 4 8 1  m s e c , for 
s u b s e q u e nt  c y c le s  E C G  m o ni tori n g  w ill b e 
p e rfo rm e d  a s  p e r v is it s c h e d u le.  
•  
If E C G  a s s e s s m e n t s ar e  s till a b n or m al  (Q T c F  ≥ 
4 8 1  m s e c  a n d  ≤5 0 0  m s e c ), th e n  E C G 
m o ni t orin g  m u s t c o n tin u e  a t th e  s a m e 
fre q u e n c y  a s in  c yc le  1  for  a ll s u b s e q u e nt  
c yc le s . 
Gr a d e  3  : Q T c F  >  5 0 0 m s e c  a s 
id e nt ifie d  o n t h e  E C G  b y  th e 
in v e s tig a t or 
•  
H o ld  B G J 3 9 8.  
•  
M o n it or p at ie n t w ith  h o ur ly  E C G s  u n til t h e 
Q T c F  h a s  r etu rn e d  t o b a s e lin e . 
•  
P er fo rm  furt h er  m o ni t orin g  a s  c lin ic a lly 
in d ic at e d.  
•  
E x c lu d e  o th er  c a u s e s  of  Q T c F  pr o lo n g a tio n 
s u c h  a s  h y p o k a le m ia,  h y p o m a g n e s a e m ia  a n d 
d e cr e a s e d  b lo o d  o x y g e n at io n . 
•  
P a tie n t s s h o u ld  r ec e iv e  a p pr o pr ia t e e le c tro ly te 
re pl a c e m e n t a n d  s h o u ld  n o t r ec e iv e  furt h er 
B G J 3 9 8  u n til e le c tr oly t e s a re  d o c u m e n t e d t o b e 
w ith in  n o rm al  lim its . 
 
 
O n c e  th e  Q T c F  pr o lo n g a tio n  h a s  r es o lv e d , p a tie n t s 
m a y  b e  re -tr ea te d  a t on e  lo w er  d o s e  le v e l at  t h e 
in v e s tig a t or’s  d is cr et io n  


P a g e 3 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
 
•  
E C G  a s s e s s m e n t s s h o u ld  b e  p er fo rm e d  for  2 
a d d itio n a l c y cl e s  at  th e  s a m e  fre q u e n c y  a s in 
c yc le  1  or  a s  cl in ic a lly  in d ic at e d  
o  
If E C G  a s s e s s m e n t s s h o w  n o  Q T c F  ≥ 
4 8 1  m s e c , for  s u b s e q u e nt  c yc le s  E C G  
m o ni t orin g  w ill b e  p er fo rm e d  a s  p e r 
vi si t s c h e d u le.  
o  
If E C G  a s s e s s m e n t s ar e  s till a b n or m al 
(Q T c F  ≥ 4 8 1  m s e c  a n d  ≤5 0 0  m s e c ), 
t he n  E C G  m o ni t orin g  m u s t c o n tin u e  at 
t h e s a m e  fre q u e n c y  a s in  c y c le  1  or  a s 
c lin ic a lly  in d ic a te d , for  a ll s u b s e q u e n t 
c yc le s  
•  
P a tie n t s w h o  e x p e rie n c e  re c ur re n t Q T c F  ≥ 
5 0 0 m s e c  a ft er o n e  d o s e  re d u c tio n  w ill b e 
d is c o n tin u e d  fro m s t ud y. 
N B : If v e n tric u lar  a rrh y th m ia  o r T or s a d e s  d e  P o int e s  is 
o b s er v e d  in  a p a tie nt,  h e/ s h e  w ill b e  d is c o n tin u e d  fro m 
t h e s tu d y . 
W h e n e v er  Q T c F  ≥ 5 0 1 m s e c  is o b s er v e d , a  p la s m a 
s a m p le  for  d et e rm in a tio n  of  B G J 3 9 8  c o n c e n tra tio n 
s h o u ld  b e o b ta in e d  w ith  th e  tim e  o f s a m p le  c o lle c tio n 
n o te d.  
C a rdi a c  di s o rd e rs  - o th e rs  
Gr a d e  ≥ 3, or  c o n g e s tiv e  h e a rt fa ilur e  ≥ 2  
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
I nv e s ti g ati on s -H e m a tol o g y  
A N C  d e c re a s e d  (N e u tro p e ni a)  
Gr a d e  3  (A N C  <  1 .0  - 0 .5  x  1 0 9 / L) 
 
 
 
 
Gr a d e  4  (A N C  <  0 .5  x  1 0 9 /L ) 
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1 or  b a s e lin e , t he n  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8  
•  
If r es o l ve d  in >  7  d a y s , ↓ 1  d o s e  le v el  of  
B G J 3 9 8.  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  ≤ Gr a d e  
1,  ↓ 1  d o s e  le v el  of  B G J 3 9 8 . 
F e bri le  n e u tro p e ni a  
Gr a d e  3  (A N C  <  1 .0  x  1 0 9 /L , s in g le 
t em p e rat u re  o f > 3 8. 3 ° C o r a s u s t ain e d 
t em p e rat u re  o f ≥ 3 8 .0 ° C for  m or e  t ha n  o n e 
h o ur  ) 
 
 
 
Gr a d e  4  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1,  th e n  
•  
If r es o l ve d  b y  ≤ 7 d a ys , ↓ 1 d o s e  le v el  of  
B G J 3 9 8.  
•  
If n o t r es o lv e d  w ith in  7 d a y s  d is c o n tin u e  p a tie nt 
fro m s t ud y  dr u g  tre at m e n t. 
 
D is c o n tin u e  p a tie nt  fro m s t ud y  tr ea tm e n t. 
H e m o gl o b i n 
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 


P a g e 3 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
Gr a d e  3  (< 8 .0  m g/ d L  –  6 . 5 m g/ d L) 
Gr a d e  4  (<  6 .5  m g/ d L)  
1  or  b a s e lin e , th e n  m a int ai n  d o s e  le v e l 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  or  b a s e lin e , th e n  ↓ 1 d o s e  le v e l 
P l at elet  c o u nt  d e c re a s e d  
(T h ro m b o c y to p e ni a)  
Gr a d e  3  (P L T  <  5 0  - 2 5  x  1 0 9 / L ) w ith o u t 
b le e d in g  
 
 
 
 
Gr a d e  3  (P L T  <  5 0  - 2 5  x  1 0 9 / L ) w it h 
b le e d in g  or  
Gr a d e  4  (P L T  <  2 5  x  1 0 9 / L ) 
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  o r b a s e lin e  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in >  7  d a y s , ↓ 1  d o s e  le v el  of  
B G J 3 9 8  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  or  b a s e lin e , th e n  ↓ 1 d o s e  le v e l 
I nv e s ti g ati on s  –  R e n al  
S e ru m  c re a ti nin e  
M o n it or C r, C a,  a n d P i at  le a s t tw ic e  w e e k ly  u n til Cr 
im pr o v e s  or  s t ab iliz e s  
Gr a d e  1 a n d  C a  x  P i > 5 5  m g 2 / dl2  d e s p it e 
s e v e la m er  1 6 0 0  m g  T I D a n d  lo w - 
p h o s p h or o u s  d iet  for  at  le a s t 1 4  d a y s  
 
 
 
 
 
 
Gr a d e  2  (>  1 .5  - 3 .0  x  U L N)  a n d  C a  x  P i ≤5 5 
m g 2 / dL 2  
 
 
 
 
 
Gr a d e  2 a n d  C a  x  P i > 5 5  m g
2 / dl2  d e s p ite 
p h o s p h or u s  lo w er in g  th e ra p y  for  at le a s t 1 4 
d a y s  
 
Gr a d e  ≥ 3  (>  3 .0  x  U L N)  
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  o r b a s e lin e  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in >  7  d a y s , ↓ 1  d o s e  le v el  of  
B G J 3 9 8.  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  o r b a s e lin e  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in >  7  d a y s , ↓ 1  d o s e  le v el  of  
B G J 3 9 8.  
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t 
 
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
I nv e s ti g ati on s  –  H e p a ti c 
Bl o o d  bili ru bi n  (p ati e n ts  w it h G il b ert 
S y n d ro m e  th e s e  d o s e  m o difi c a ti on s 
a p p ly  t o c h a n g e s  in  d ire c t bili ru bi n  o n ly ) 
 
 
Gr a d e  2  (> 1 .5  –  3. 0  x U L N)  
 
 
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o CT C A E  Gr a d e  ≤ 
1  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in >  7  d a y s , ↓ 1  d o s e  le v el  of  
B G J 3 9 8.  


P a g e 3 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
 
Gr a d e  ≥ 3  (>  3 .0  x  U L N)  
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
 
 
N ot e : If C T C A E  Gr a d e  3  o r 4 h y p e rb iliru b in e m ia  is d u e 
t o h e m o ly s is , th e n  ↓ 1 d o s e  le v e l of  B G J 3 9 8  a n d 
c o n tin u e  tre at m e n t a t th e  d i s cret io n  of  th e  In v e s tig a tor.  
A S T  or  A L T  
Gr a d e  3  (>  5 .0  - 2 0 . 0 x U L N)  w ith o u t 
b iliru b in  e le v at io n  >  2 .0  x  U L N  
 
 
 
 
 
 
Gr a d e  4  (>  2 0. 0  x U L N)  w ith o ut  b iliru b in 
e le v a tio n  > 2. 0  x U L N  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  o r b a s e lin e  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in >  7  d a y s , ↓ 1  d o s e  le v el  of  
B G J 3 9 8.  
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
A S T  or  A L T  a n d  Bil iru bi n  
A S T  or  A L T  > 3. 0  –  5 .0  x U L N  a n d  to t al 
b iliru b in  > 2. 0  x U L N  w it ho u t liv er  m et a s t a sis 
or  e v id e n c e  o f d is e a s e  p ro gr e s s io n  in  th e 
liv er  
 
 
A S T  or  A L T  >  5. 0  x U L N  a n d  to tal  b iliru b in  >  
2. 0  x U L N  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  
•  
If r es o l ve d  in ≤ 7  d a y s , ↓ 1 d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in >  7  d a y s , d is c o n tin u e  p a tie nt  fro m 
s t ud y  tr ea tm e n t. 
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
L a b o rat o ry  / M et a b oli c  di s or d e rs  
A s y m pt o m a ti c a m y la s e  a n d/ or  lip a s e 
el e v ati o n  (N ot e:  n ot  b y  C T C A E  4 . 0) 
 
Gr a d e  1  (> U L N  –  2 . 0 x U L N)  
 
 
 
Gr a d e  2  (> 2 .0  x  U L N  –  5 .0  x U L N  w it h n o 
at trib ut a b le  c lin ic a l s ig n s  or s ym pt o m s ) 
 
 
 
 
Gr a d e  3  (>  2 .0  - 5 .0  x  U L N  w it h at trib u ta b le 
c lin ic al  si g n s  or  s ym pt o m s  O R >  5 .0  x  U L N 
w ith o u t cl in ic al  s ig n s  or  s y m pt o m s ) 
 
•  
C o n tin u e  B G J 3 9 8  d o s in g  
 
 
 
 
•  
M a y  c o n tin u e  B G J 3 9 8  d o si n g ; c o n s id e r w e e k ly 
la b or at o ry  m o ni t orin g  
 
 
 
•  
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  
Gr a d e  ≤ 2.  
•  
C o n s id er  ↓ 1  d o s e  le v el  of  B G J 3 9 8  
 
 
N ot e : A  C T s c a n  or  o th e r im a gi n g  s t ud y  t o a s s e s s  th e 
p a n cr e a s , liv e r, a n d  g a llb la d d er  s h o u ld  b e c o n s id er e d 
a ft er t h e fir st o c c ur re n c e  o f an y  C T C A E  ≥ Gr a d e  3 
a m y la s e  a n d/ o r lip a s e.  


P a g e 4 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
 
 
 
Gr a d e  4  (>  5 .0  x  U L N  w ith  c lin ic al  si g n s  or 
s ym pt o m s ) 
 
 
 
•  
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  
Gr a d e  ≤ 2.  
•  
↓ 1  d o s e  le v e l of  B G J 3 9 8  
•  
If r ec ur s , d is c o n tin u e  p at ie n t fro m s t ud y 
tr ea tm e n t 
H y p e rp h o s p h a te mi a  W ith o ut  E l ev at e d  
Cr e ati n in e  
S e e  T a b le  8 for  d et a ils . 
 
 
N ot e  th a t t h e “E le v at e d  cr e a tin in e”  s e c tio n  a b o v e  
pr o v id e s  g u id a n c e  w h e n  c re a tin in e  is e le v at e d.  
H y p e rc a lc e mi a  
S er u m  c a lc iu m  gr a d e  2  
 
 
 
 
 
 
 
S er u m  c a lc iu m  ≥ gr a d e  3  
 
H o ld  B G J 3 9 8  d o s e  u n til r es o lv e d  t o gr a d e  1  o r 
b a s e lin e : 
•  
if r es o l ve d  ≤ 7 d a ys  a ft er s u s p e n d in g  B G J 3 9 8,  
m a int ai n  d o s e  le v el  
•  
if r es o l ve d  >  7 d a ys  a ft er s u s p e n d in g  B G J 3 9 8,  
↓ 1  d o s e  le v e l 
 
D is c o n tin u e  p a tie nt  fro m t h e  st u d y  
N e rv o u s  s y s te m  di s o rd e rs  
P e ri ph e ra l N e u ro p at h y  
Gr a d e  2  
 
 
Gr a d e  ≥ 3  
 
 
O m it d o s e  o f B G J 3 9 8  u nt il re s o lv e d  to  C T C A E  Gr a d e  ≤ 
1,  th e n  ↓ 1 d o s e  le v e l of  B G J 3 9 8  
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  dr u g  tr ea tm e n t 
G I di s or d e rs  
P a n c re a titi s 
Gr a d e  2  
 
 
 
 
 
 
Gr a d e  ≥3  
 
 
O m it d o s e  o f B G J 3 9 8  u nt il re s o lv e d  to  C T C A E  Gr a d e ≤ 
1,  th e n  ↓ 1 d o s e  le v e l of  B G J 3 9 8  
If Gr a d e  2  r ec ur s  d e s p it e d o s e  r e du c tio n , d is c o n tin u e 
s t ud y  dr u g  tre a tm e n t 
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  dr u g  tr ea tm e n t 


P a g e 4 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
Di a rrh e a  
Gr a d e  1  
M a int a in  d o s e  le v el  of  B G J 3 9 8,  b u t in itiat e  a n ti- 
d iar rh e al  tr ea tm e n t 
 
Gr a d e  2  
 
•  
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  
Gr a d e  ≤ 1  
•  
O pt im i ze  a nt i-d iar rh e al  tr ea tm e n t, m a int a in 
d o s e  le v el  of  B G J 3 9 8.  
•  
F or  re o c c ur re n c e  o f diar rh e a  C T C A E  Gr a d e  2 , 
h o ld  d o s e  of  B G J 3 9 8  u n til r es o lv e d  t o C T C A E 
Gr a d e  ≤ 1,  ↓ B G J 3 9 8  b y  1 d o s e  le v el  
 
Gr a d e  3  
 
 
 
 
 
 
 
 
 
 
Gr a d e  4  
 
•  
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  
Gr a d e  ≤ 1  
•  
O pt im i ze  a nt i-d iar rh e al  tr ea tm e n t 
•  
↓ B G J 3 9 8  b y  1 d o s e  le v el  
•  
F or  re o c c ur re n c e  o f diar rh e a  C T C A E  Gr a d e  3 , 
d e s p ite  o pt im al  a n ti-d iar rh e al  tre at m e n t, 
d is c o n tin u e  p a tie nt  fro m s tu d y  tre at m e n t. 
 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
 
 
N ot e : A n tid iar rh e al  m e di c a tio n  is r e c o m m e n d e d  a t th e 
fir st s ig n  of a b d o m in a l cr a m p in g,  lo o s e  st o o ls  or o v ert 
d iar rh e a  
V o mi ti n g 
Gr a d e  2 n o t c o ntr o lle d  b y  o pt im al  a n ti- 
e m et ic  th er a p y  
 
Gr a d e  3 n o t c o ntr o lle d  b y  o pt im al  a n ti- 
e m et ic  th er a p y  or  Gr a d e  4  
 
H o ld  B G J 3 9 8  d o s e s  u n til ≤ gr a d e  1,  ↓ 1 d o s e  le v e l 
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  
E y e  Di s or d e rs  ( co n firm e d  b y  o p h th a lm o lo gi c  e x a m in a tio n ) 
R eti n al  di s o rd e rs  
Gr a d e  2  C S R  a n d  C S R -lik e  e v e n t s 
 
 
 
 
 
 
Gr a d e  3  C S R  a n d  C S R -lik e  e v e n t s a n d  a n y 
ot h er  g ra d e  3  e y e  d is or d er s  
 
 
 
 
≥ gr a d e  1  r etin a l v e in  o c c lu s io n , gr a d e  4  
C S R  a n d  C S R -lik e  e v e n ts , a n d  gr a d e  4  
H o ld  B G J 3 9 8  u nt il r es o lv e d  t o ≤ gra d e  1 b u t r efer  t h e 
p a tie n t t o a  r etin a l s p e ci a lis t for  e v a lu a tio n  
•  
If r es o l ve d  in  ≤ 1 4  d a ys , ↓ B G J 3 9 8  b y  1 d o s e  
le v el  
•  
If re s o l ve d  in >  1 4  d a ys , d is c o n tin u e  B G J 3 9 8  
 
 
H o ld  B G J 3 9 8  u nt il r es o lv e d  t o gr a d e  ≤ 1 . 
•  
If r es o l ve d  in ≤ 1 4  d a ys , ↓ B G J 3 9 8  b y  1 d o s e  
le v el  
•  
If r es o l ve d  in >  1 4  d a ys , d is c o n tin u e  B G J 3 9 8  


P a g e 4 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
W o rs t T o x ic ity  C T C A E  u si n g  th e  c ur re n t 
a c tiv e  C T C A E  v er s io n  
R e c o m m e n d e d  D o s e  M o d ific at io n s  a n y  tim e  d uri n g  a 
c yc le  o f th er a p y  
ot h er  e y e  d is or d er s  
D is c o n tin u e  B G J 3 9 8  
Ot h er  o c u la r/v i s u al to x ic ity  
≥ gr a d e  3  
H o ld  B G J 3 9 8  u nt il r es o lu tio n  to  ≤ g ra d e  1  
If r es o lut io n  in  ≤1 4  d a y s , ↓ 1  d o s e  le v e l, o t he rw is e 
d is c o n tin u e  B G J 3 9 8  
G e n e ral  di s o rd e rs  
F ati g u e  
Gr a d e  3  
 
 
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1  
•  
If r es o l ve d  in ≤ 7  d a y s , m a int a in  d o s e  le v el  of  
B G J 3 9 8.  
•  
If r es o l ve d  in  >  7  d a y s , d is c o n tin u e  p a tie nt  fro m 
s t ud y  tr ea tm e n t. 
Ot h er  c li nic al ly  s i gn ific a n t A E s  
Gr a d e  3  
 
 
 
Gr a d e  4  
H o ld  d o s e  of  B G J 3 9 8  u n til re s o lv e d  t o C T C A E  Gr a d e  ≤ 
1,  th e n  ↓ 1 d o s e  le v e l of  B G J 3 9 8.  
 
D is c o n tin u e  p a tie nt  fro m  s t ud y  tr ea tm e n t. 
A ll d o s e  m o di fic at io n s  s h o u ld  b e  b a s e d  o n  th e  w or s t pr e c e d in g  to x ic ity . O n c e  a  d o s e  h a s  b e e n 
re d u c e d  it w ill n ot  b e  in cr e a s e d  at  a  lat e r tim e  e v e n  if th er e  is  n o  to x ic ity . P a tie n t s w h o  r eq u ire  m or e 
t ha n  tw o  d o s e  re d u c tio n s  of  B G J 3 9 8  w ill b e  d is c o n tin u e d  fro m  s t ud y  dr u g  tre at m e n t. 
If a  p a tie n t re q u ire s  a  d o s e  d e la y  of  >  1 4  d a y s  fro m t h e  in te n d e d  d a y  of  th e  n e x t s c h e d u le d  d o s e  of  
B G J 3 9 8  th e n  s t ud y  tre at m e n t m u s t b e  st o p p e d.  
 
T a b le  8 : 
P ro p h yl a x is  a n d  Tr e a t me n t  re co m m e n d a tio n s  fo r  h y p e rp h o sp h a t e mia  wi th o u t 
ki d n e y  in ju r y: 
H y p e r p ho s p h a te m i a 
Pr o p h y la x i s 
( Pa tie nt s  re c e iv in g  
tr ea tm e nt  s c h e d u l e A ) 
Ini tia t e S e v e l am e r 8 0 0  m g  w it h m e al s  (u p  to  T I D) c o n c u rre n t w it h B G J 3 9 8 , u nl e s s  
o th e rw i se  c o n trai n di c a te d  b y  p a ti en t’s  c u rre n t m e d i ca l c o n d itio n . 
R e s tric t d i eta r y p h o s p h a te  in ta k e  to  6 0 0  –  8 0 0  m g /d a y , if B M I ≥ 2 1 k g /m
2 . 
H y p e r p ho s p h a te m i a 
Tr e a tm e nt  W it ho u t 
El e v a te d  C re a tin in e  
I N T E R V E N TI O N 
S e ru m  P i >  5 . 5 –  
7 .0 m g /d L : 
C o n ti nu e  s e v el a m e r 8 0 0  m g  w it h 2  m e a ls  p e r d a y  a n d  in c re a s e  th e  d o s e  o f 
s e v el a m e r w it h th e  l arg e s t m e a l t o 1 6 0 0 m g  (to ta l d a ily  d o s e =  3 2 0 0  m g ). 
S e ru m  P i 7. 1 m g  –  
9 .0 m g /d L  
In c re a s e  th e  d o s e  o f s e v e la m e r u p  to  1 6 0 0 m g  ( 2 ta bl e t s p e r m e al ) e v e r y 8  h o u r s a n d 
c o n ti n ue  s e v e la m e r t hro u g h  D a y  2 1  a n d  u n til S e ru m  Pi  is  < 5. 5 , w hi c h e v e r is  la te r. 
S e v el a m e r s h o u ld  b e  gi v e n  e v e n  o n  d a y s  B G J 3 9 8  is n o t ta k e n  u n til s e ru m  Pi  is  < 5 .5 . 
 
If s e ru m  P i ≤ 7 . 0 m g /d L  w ith in  7  d a y s , i n cre a s e  s e v el a m e r to  1 6 0 0  m g  T I D w it h n e x t 
c y cl e , if n o t a lre a d y  d o n e  s o . N o  i nte rru p tio n  o r a d j us tm e n t to  B G J 3 9 8  is  n e c e s s a ry . 
 
If S e ru m  Pi  > 7 . 0 m g /d L  f or lo n g e r t ha n  7  d a y s , h o ld  B G J 3 9 8  u n til s e ru m  P i is  < 5 . 5 
m g /d L . A s s e s s  if p a tie n t s w e r e t a kin g  S e v e l am e r 1 6 0 0  m g  T I D o n  D a y  1  o f m o s t 
re c e n t c y c l e. 


P a g e 4 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
-  If p a ti e nt w a s  N O T  ta k in g  S e v el a m e r 1 6 0 0  m g  T I D o n  D a y  1  o f th e  m o s t re c e n t 
c y cl e : 
o  
In c re a s e  S e v el a m e r to  1 6 0 0  m g  T I D f or e a c h  s u b s e q u e n t c y c le  
o  
N o  d o s e  re d u c ti on  in  B G J 3 9 8  is  n e c e s s a r y 
 
-  If p a ti e nt W A S t a ki n g  s e v el a m e r 1 6 0 0  m g  T I D o n  D a y  1  o f th e  m o s t re c e n t c y c l e: 
o  
D o s e  re d u c e  B G J 3 9 8  b y  1  l ev e l 
 
If s e ru m  p h o s p h o ro u s  d o e s  n o t re s o lv e  to  < 7 . 0 m g /d L  d e s p ite  p h o s p h o ro u s  lo w e ri ng 
th e ra p y  w ithi n  1 4  d a y s  o f firs t h el d  d o s e  o f B G J 3 9 8 , d is c o n tin u e  B G J 3 9 8  th e ra p y . 
A ll p a ti en t s w ill c o n ti nu e  to  b e  foll o w e d -u p  u n til re s o l utio n  to  s e ru m  p h o s p h o ru s  ≤ 5 .5  
m g /d L  o r b a s eli n e  o r s ta bi liz a tio n . 
S e ru m  P i 9 . 1 m g /d L  o r 
hi g h er  
R e c h e c k  s e ru m  Pi  a s  s o o n  a s  p o s si b le  to  ru le  o u t l ab o ra to r y e rro r. 
If c o n firm e d , h ol d  B G J 3 9 8  u n til S e ru m  Pi  < 7 . 0 m g /d L . In c re a s e  th e  d o s e  o f 
s e v el a m e r u p  to  1 6 0 0 m g  ( 2 t abl e ts  p e r m e al ) e v e r y 8  h o u rs  a n d  c o n ti n ue  s e v e la m e r 
th ro u g h  D a y  2 1 a n d  u n til S e ru m  Pi  is  < 5 .5 , w hi c h e v e r is  la te r. S e v el a m e r s h o u ld  b e 
gi v e n  e v e n o n  d a y s  B G J 3 9 8  is n o t ta k e n  u n til S e ru m  Pi  is  < 5. 5 . T h e n  a s s e s s : 
 
-  If p a ti e nt w a s  N O T  t a kin g  S e v el a m e r 1 6 0 0  m g  T I D o n  D a y  1  o f th e  m o s t re c e n t 
c y cl e : 
o  
In c re a s e  S e v el a m e r to  1 6 0 0  m g  T I D f or e a c h  s u b s e q u e n t c y c le  
o  
N o  d o s e  re d u c ti on  in  B G J 3 9 8  is  n e c e s s a r y 
 
-  If p a ti e nt W A S  ta ki n g  s e v el a m e r 1 6 0 0  m g  T I D o n  D a y  1  o f th e  m o s t re c e n t c y c l e: 
o  
D o s e  re d u c e  B G J 3 9 8  b y  1  l ev e l 
 
If s e ru m  p h o s p h o ro u s  d o e s  n o t re s o lv e  to  < 7 . 0 m g /d L  d e s p ite  p h o s p h o ro u s  lo w e ri ng 
th e ra p y  w ithi n  1 4  d a y s  o f firs t h el d  d o s e  o f B G J 3 9 8 , d is c o n tin u e  B G J 3 9 8  th e ra p y . 
A ll p a ti en t s w ill c o n ti nu e  to  b e  foll o w e d -u p  u n til re s o l utio n  to  s e ru m  p h o s p h o ru s  ≤ 5 .5  
m g /d L  o r b a s eli n e  o r s ta bi liz a tio n . 
 
 
9. 4       D r ug  In t era ctio n s 
I n g e n er al,  co n co m it an t m e d ic atio n s a n d  t h er ap i es d e e m e d  n ec e ss ar y fo r th e  s up p o rtive  c ar e a n d  
s af et y o f t h e p at ie nt  ar e  al lo w e d,  p ro v id e d  t h eir u s e is d o c um e nt e d  i n t h e p ati e n t r eco rd s a n d  o n  t h e 
a p p ro p ria t e c as e r ep o rt  fo rm . T h e  a d m in istr atio n  o f a n y  o th er  a n ti-ca n cer  a g e nts  in clu d in g , 
c h em o t h era p y a n d  b io lo g ic ag e nts  is n o t p e rm itte d . U s e o f e ryt hr op o i eti n al fa ( E P O)  is all ow e d  at  t h e 
d iscr etio n  o f t h e tr e atin g  in v es tig a to r. G -C S F  o r GM -C S F  m a y  n o t b e  u s e d as  a p ro p h y l actic m e as ur e 
b u t m a y  b e  u se d  as  o th e rwis e  clin ic ally  in d ic at e d to s u p p o rt b lo o d c o u n ts fo r p ati e nts  i n t his st ud y. 
T h e  u s e o f o th er  co n c urr en t in v e sti g atio n al d ru g s is n o t al l ow e d . 
 
S u b j ects s h o ul d r ecei ve  fu ll s up p o rtiv e  c ar e d u rin g  t h e st ud y , in clu d in g  tr an sfu sio n  o f b lo o d  a n d 
b lo o d  p ro d u cts, a n d  tre a tm e nt  wit h  a n tib io tics, a n al g esics,  s h ort co u rs e o f  ster o id s, o r 
b isp h o s ph o n at e s,  w h e n   a p p ro p ria te .  A n ti-e m e tics  (s uc h  as  p ro c hl orp er a zin e,  lo r aze p a m , 
o n d a n s etro n  o r o t h er 5 -H T  a n t a g on ists) m a y  b e  a d m in ist ere d  p ro p h y l actical ly i n t h e e v e nt o f n a u se a. 
A n tid i arrh e als,  s uc h as lo p er a m id e , m a y  b e  a d m in ister e d  as  n e e d e d  i n t h e e ve n t o f d i arrh e a . Or al 
co n tr ace pti v e  p ills are  p e rm itte d.  


P a g e 4 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
A ll  co n co m it an t  m e d ica tio n s  t a ke n  d u rin g  t h e  st ud y  will  b e  r eco rd e d  w it h  in d ic atio n ,  d o s e 
in fo rm a tio n , an d  d at e s o f a d m in istr atio n.  T h e  El e ctro n ic D at a  C a p t ur e sy ste m , M e d iD a t a R A V E,  m u st 
c ap t ur e th e  co n c urr e nt u s e o f all o t h er d ru g s, o v e r-th e -co u n ter  m e d ica tio n s, o r alt e rn at iv e  t h er ap i es. 
T h e  M S K C C  P rin cip al  Inv es tig at o r s h o ul d b e  al e rte d  if t h e p ati e nt  is ta ki n g  a n y  a g e nt  k n o w n  t o af fect 
(o r wit h th e  p o te n ti al t o af fec t) s ele cte d  P 4 5 0  iso e n zym es.  
 
A ll s ub j ects will  b e  a ske d to  p ro v id e  a  co m p le te  list o f p r escrip tio n  a n d  o ve r-t he -co u n te r m e d ic atio n s 
t h at h a v e  b e e n  t ak e n  wit h i n t h e 4  w e e k s p ri or to  scr e e nin g . T h e  in ves tig a to r m u st b e  in fo rm e d  as 
so o n  a s p o ssib le  a b o u t a n y n e w  m e d ica tio n (s) t ake n  fro m  t h e tim e  o f scr ee n in g u n til t h e co m p le tio n 
o f t h e p o st-tr ea tm e nt  fo llo w -u p  v isit. A d d itio n al ly , p ati e nt  n ico tin e  h isto ry  s h o ul d b e  r eco rd e d  as 
in d ic at e d o n  t h e e C R Fs.  
 
9 .4 .1     P e rm itte d  co n co m ita n t th e ra p y  w it h Im a tin ib  re q ui rin g  ca u tio n  a n d /o r a ctio n  
 
I m atin i b  a p p e ars  t o  b e  a  co m p e titive  in h ib ito r  o f  C YP 2 C p ,  C Y P 2 D 6 ,  C Y P 3 A 4 /5 ,  s ug g e stin g  t h at 
im ati n i b co u l d r e du c e t h e cl e ar an c e o f co -a d m in ist er e d d ru g s w h o se  m e ta b o lis m is d e p e n d e n t o n 
t h es e P 4 5 0  cyto c hro m e  iso e n zym e s. B ec a us e  o f th e  in h er e nt  risk o f eit h er  r e d u c e d acti v ity o r 
e n h a n c e d to xicit y o f co n co m it a nt m e d ic atio n s a n d/ o r im a tin ib , d ru g s k n o w n  t o b e  m e ta b o lize d  b y 
t h e s am e  P 4 5 0  iso e n zym es  as  im ati n i b  sh o u l d b e  u s e d wit h  c au tio n  (A p p e n d ix C).  A  n o n - 
co m p r e h en sive  list o f cy to c hr om e  C Y P 3 A 4  in h ib ito rs a n d i n d u c ers m ay  b e  fo u n d  i n Ap p e n d ix C .  F D A 
cl assific atio n  o f CY P 3 A 4  i nh ib ito rs c a n b e  fo u n d  a t: 
 
h ttp ://w w w .fd a. g ov / Dru g s/D e v el o p m e nt A p p ro v a lP ro c ess/ De v e lo p m e nt R e so u rces /D ru g In te r actio n sL 
a b eli n g /u cm 0 9 3 6 6 4 .h tm # cy p E n zym es  
 
A n o n -co m p r eh e nsi ve  list o f C YP 3 A 4  i nd u c ers is pr o v id e d i n  A p p e n d ix C. 
 
S p eci al  c ar e h as  to  b e  g ive n  t o t h e co n co m it a nt u se  o f a ce ta m in o p h e n  (p ar ac e t am o l, T y l en o l) wit h 
im ati n ib . A n y  u s e o f t his d ru g  h as  t o b e  d o cu m e n te d  i n t h e m e d ic al re co rd s a n d / or c ap t ure d  o n  th e 
a p p ro p ria t e c ase  r e p ort fo rm . P at ie nts  s h o ul d b e  w a rn e d  t o a v o id  o r r estrict th e  u s e o f o v e r-t h e- 
co u n te r a n d  pr escri p tio n  m e d icin es  co n t ain in g  a ce ta m in o p h e n ( p ar a ce ta m o l). 
 
S i nc e w arf ar in is  m e ta b o lize d  b y C Y P 2 C 9  a n d C Y P 3 A 4 , p ati e nts  w h o  r e qu ir e a n tico a g u l atio n s h o ul d 
r ece iv e  lo w -m o l ec ular  w e igh t o r st a nd ar d  h e p a rin , if p o ssib l e. 
 
P ati e n ts s ho u l d als o  a v o i d S e v ill e o r an g es  o r Se v ill e o ra n g es  d eri v at iv es,  g r ap efr u it o r gra p efr u it j uic e, 
st ar fr uit o r st ar fr uit j uic e a n d  o t h er fo o d s k n o w n  to  in h ib it CY P 3 A 4  w hi le  t a ki n g im ati n ib . 
 
D ru g s t h at m a y  in cre as e  im ati n i b p l asm a  co n c e ntra tio n s ( Ap p e n d ix C ):  C a u tio n  is r eco m m e n d e d 
w h e n  a d m in ist erin g  im ati n i b wit h  in h ib ito rs o f t h e cyto c hro m e  P 4 5 0  iso e n zym e  C Y P 3 A 4 f a m il y ( e.g ., 
k e to co n a zo l e,  itra co n a zo le,  er y t hro m y cin ,  a n d  cla rith ro m y cin ).  S u b st a nce s  t h at  in h ib it  C Y P 3 A 4 
acti v ity  m a y  d ecr e a s e m e t a bo lism  a n d  i n cr e as e im ati n i b  co n c e ntr atio n s.  T he r e w as  a  sig n ific an t 
in cr e as e i n e xp o s ure  to  im ati n i b w h e n  t h e co m p o u n d  w as  co -a d m in ister e d wit h  k e to co n a zo le,  a 
C Y P 3 A 4  in h ib ito r. 
 
D ru g s t h at m a y  d ec re as e  im ati n i b p l asm a  co n c e ntrat io n s ( Ap p e n d ix C ): S u b st an c es t h at ar e  in d u c ers 
o f C Y P 3 A 4  act iv it y m a y  in cr e as e m e ta b o lism  a n d  d ecr e a se  im ati n i b p l asm a  c o n c e ntra tio n s. C o - 
m e d ica tio n s t h at in d u c e  C YP 3 A 4  ( e.g ., d e xa m e th as o n e,  p h e n yto in , c arb a m a ze p i ne,  rifa m p ic in , 
p h e n o b ar b it al o r St. Jo h n' s W o rt) m a y  re d u c e e xp o s ure  to  im ati n ib . 


P a g e 4 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
D ru g s t h at m a y  h a ve  t h eir p l as m a co n c e ntr atio n  alt e re d  b y  im ati n i b ( Ap p e n d ix C ): Im ati n i b in cr e ases 
t h e m e a n  C m ax  a n d  A U C  o f sim v a st ati n ( a C Y P 3 A 4  su b str ate ) 2 - a n d  3 .5 -fo ld , r es p ectiv e l y, in d ic atin g 
in h ib itio n  o f C Y P 3 A 4  b y im ati n ib . P art ic ular  c au tio n  is r eco m m e n d e d  w h e n  a d m in ist erin g  im a tin i b 
wit h  C Y P 3 A 4 /5  s ub str ates  wit h  a  n ar r ow  t h er ap e u tic  wi n d o w  ( e.g .,  cy clo s p orin e  o r  p im o zid e). 
I m atin i b will  in cre as e  p l asm a  co n ce ntr at io n s o f o th er  C Y P 3 A 4  m e ta b o lize d d ru g s ( e.g ., tri azo lo - 
b e n zo d i aze p i nes,  d ih yd ro p y rid in e  c alciu m  c ha n n el  b lo ckers,  c ert ai n H M G -C o A  r e du ct as e in h ib ito rs, 
e tc.). 
 
9 .4 .2     P e rm itte d  co n co m ita n t th e ra p y re q u irin g  ca u tio n  a n d /o r a cti on  wi th  B G J3 9 8  
 
D ru g s t h at alt er  t h e p H o f th e  GI  tr act: B G J3 9 8  is c ha r act eriz e d b y  p H -d e p e n d e nt  so lu b ility , a n d 
t h er efo r e, m e d icin al  p ro d u cts t h at alt er  t h e p H  o f t h e u p p er  g astr o -in te stin a l tr act m a y  alt er  t h e 
so lu b ility o f b o t h co m p o u n d s, a n d li m it b io a v ai la b ility . T h e se  a g e nts  in clu d e,  b u t ar e  n o t lim it e d to , 
p ro to n -p u m p  in h ib ito rs ( e.g ., o m e pr az o le),  H 2 -a n t ago n ists ( e.g ., r an itid in e)  a n d a n t aci ds. T h er e fo r e, 
st ud y  d ru g (s)  s h o ul d  b e  d o s e d  a t  l ea st  2  h o u rs  b ef o r e o r  1 0  h o u rs  a fte r d o sin g  wit h  a  g as tric 
p ro te ctio n  a g e nt.  N o t e th a t so m e  p ro to n -p u m p  in h ib ito rs m a y  i nh ib it B CR P . 
 
C o rtico ster o id s: C h ro n ic d o sin g  o f co rtico ster o id s su c h as  d e x am e th a so n e  a n d  p r e dn iso n e  is k n o w n 
t o in d u c e C Y P 3 A  e n zy mes, t h er e by  in cr ea sin g  t h e risk o f r e du cin g  d ru g  e xp o s ure  t o s ub -t h er ap e utic 
l ev els.  I n a d d itio n  B G J3 9 8  is a n  i n v itro  in h ib ito r o f C YP 3 A 4  a n d  h as t h e  p o te n ti al t o in cre as e  t h e 
sy ste m ic  exp o s ure  o f co rtico ste ro id s t h at ar e m e ta b o lize d  b y  C Y P 3 A 4 . Sys te m ic co rtico ste ro i d 
tr e atm e nt  c a n b e  us e d  wi th  c au tio n  a n d  m in im ize d to  th e  e xte n t p o ssib l e. 
 
S u b str ate s a n d i nh ib ito rs: 
 
C Y P  s ub str ate s a n d i nh ib ito rs: 
 
B G J3 9 8  w as  sh o w n  to  in h ib it t h e cy to c hr o me  p 4 5 0  iso e n zym e  C Y P 3 A 4  i n  in -v itr o a ss a ys, t hu s, 
s ug g es tin g  a n  in cr e ase d  risk  o f d ru g  in te r actio n s w it h co n co m it a nt m e d ic atio n s th at  ar e  m e ta b o lize d 
b y  C Y P 3 A 4.     H o w e ver,  su c h  in te r actio n s  h a ve  n o t  b e e n  co n fir me d  i n  p ati e nts.     T h er e fo r e, 
in v es tig a to rs m a y a d m in iste r m e d ic atio n s t h at a re  kn o w n  to  b e  m e ta b o lize d  b y C Y P 3 A 4.   P at ie nts 
m u st b e  m o n ito re d  fo r p o te n ti atio n o f to xicit y a n d m a y  r e qu ir e d o se  titr atio n o r r e du ctio n o f t h e 
C Y P 3 A 4  s ub str ate.  I n p artic u l ar c au tio n is a d v is e d wh e n s u b str ate s wit h  a n ar r ow  t h er ap e utic  in d e x, 
s uc h as  al fe nt a n il, f en t a nyl, ast e m izo le,  cis ap rid e,  d ier g o ta m in e, er g o ta m in e, p im o zid e,  q u in id in e, 
siro lim u s, ta cro lim u s, a n d  te rf en a d in e  n e e d  t o b e  a d m in iste re d.  P le as e  r ef er to  A p p e n d ix D  fo r t h e 
list o f m e d ic atio n s to  b e  u se d wit h  c au tio n . 
 
C a u tio n  is a d v ise d  w h e n  B G J3 9 8  is co -a d m in ister e d  wit h  o p io i d  an al g esics.  In h ib itio n o f o p io i d 
m e ta b o lism  b y C Y P 3 A 4  ca n  l e a d  t o  o p io i d  to xicity, in clu d in g  f at al  r esp ira to r y d e pr ess io n , o r a n 
e n h a n c e d risk fo r  Q Tc p ro lo n g at io n . P a ti e nts re c eiv in g  B G J3 9 8  a n d  o p io i d a n al g esics  s h o ul d b e 
c ar ef ull y m o n ito r e d. Sy nth e tic o p io id s wit h  clin ic ally  r ele v a n t in te r actio n s w it h C Y P 3 A 4  in h ib ito rs 
in clu d e,  b u t ar e n o t lim ite d  t o, pro p o xy p h e n e,  f e nt an y l, alf en t a nyl a n d s uf e nt an il. Us e  o f alf e nta n y l, a 
s e nsitive  C Y P 3 A 4  s ubs tr at e wit h n ar ro w t h er a p e ut ic wi nd o w, s h o ul d b e a v o id e d  w h e n e v er  p o ssib l e. 
T h e  u s e o f m e t h ad o n e  a n d  l ev o m e t h ad y l sh o u l d als o  b e  a v o id e d  w h e n e v er  p o ssib l e.  R e fer  to  th e 
A p p e n d ix D  fo r t h e list o f m e d ica tio n s  t o b e  u s e d wit h c au tio n . N o t e t ha t t h e list m a y  n o t b e 
co m p r e h en sive.  


P a g e 4 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
H o rm o n al  co n tra c e ptiv es  m a y  b e  af fec te d  b y cy to ch ro m e  P 4 5 0  in te ra ctio n s a n d  ar e  t h ere fo r e n o t 
co n sid er e d  ef fec tiv e  fo r th is st ud y .   F or  al lo w e d  co n tr ace pti o n  m e th o d s p le as e  r ef er to  s ectio n  
1 1 . 4.1 .  H ig h l y e ffe ctiv e  co n tr ac e ptio n  s ho u l d b e  m a in t ain e d t hr o u g h o u t t h e stu d y . 
 
B G J3 9 8  is a  r ev ersi b l e in h ib ito r o f C Y P 2 C 8 , C Y P 2 C 9  a n d  C Y P 2 C 1 9 ; co a d m in istra tio n  o f m e d ica tio n s 
t h at a re  s ub stra te s o r in d u ce rs o f CY P 2 C ar e p e rm itt ed . B G J3 9 8  is a s ub str ate  o f CY P 3 A 4 .  T h er e fo r e 
m o d er at e  in h ib ito rs a n d  in d u c ers s h o ul d b e  u s e d w it h c au tio n  if n o  o t h er a lter n a tive  is a vai la b l e. 
Str o n g  i nh ib ito rs a n d  i nd u c ers ar e  pr o h ib it e d. 
 
P l e ase  r ef er to  A p p e n d ix D  fo r t h e list o f m e d ic atio n s t o b e  u s e d wit h  c au tio n  a n d  A p p e n d ix E  fo r 
d ru g s t h at ar e  p ro h ib ite d  t o b e  u s e d wit h  B G J3 9 8 . P l e ase  n o t e t h at t h e list m ig h t n o t b e 
co m p r e h en sive.  
 
Tr a n s p orter  s ub str ates:  I n  v itro  d at a  s ho w  t h at  B G J3 9 8  is  a n  in h ib ito r  o f  B C R P .    C Q M 1 5 7 ,  a 
m e ta b o lite  o f B G J3 9 8 , is a n  in h ib ito r o f tr an s p ort ers P -g p , B C R P , O A T P 1 B 1 , a n d  O A T P 1 B 3  (I C5 0  2 -4  
µ M ).    I n t h e a b se nc e  o f d at a  co n firm in g  w h et h er  tr an s p ort er in ter act io n s o cc urs i n v ivo , p ati e n ts 
r ece iv in g  m e d ic atio n s t ha t  ar e  s ub str ate  o f t h es e tr an s p orters  m u st b e  m o n ito r e d  fo r p o te nti al 
to xicity a n d  m a y  re q u ir e do s e titra tio n  o r r e du ctio n  o f t h e m e d ic atio n . 
 
N o n -e n zym e  In d u cin g  A n ti-e p il ep tic d ru g s ( n o n-EI A E D ): N o n -e n zym e  in d u cin g  a n ti-e p il ep tic 
m e d ica tio n  ( n o n -EI A E D )  su c h  as  v al p ro ic  aci d ,  le ve tira ce ta m  a n d  l a m o trig in e  ar e  al lo w e d  wit h 
c au tio n .  P at ie nts  w h o  w e re  p re v io u sly  o n  a  n o n -EI A E D  a n d  n e e d  to  c ha n g e  a n ti-co n v u ls an ts sh o u l d 
b e  st arte d  o n  a n ot h er  n o n -EI A E D  if at  all p o ssib l e. EI A E D s are  n o t p e rm itte d  (A p p e n d ix E).  
 
A n ti-e m e tics: A n ti-e m e tics ar e  al lo w e d  fo r t h e tre a tm e nt  o f n a u s e a o r vo m itin g .  It is re co m m e n d e d 
t o a v o i d u sin g  d ru g s t h at ar e  k n o w n  t o c au se  Q T  p ro lo n g ati o n .  N o t e t h at so m e  a n ti-e m e tics h a v e  a 
k n o w n  risk  fo r T o rs ad e  d o P o in tes,  a n d t h er e fo r e n e e d t o  b e  u se d  w it h c au tio n .  S e e  A p p e n d ix D fo r 
list o f d ru g s t h at n e e d to  b e  u s e d wit h c au tio n .  A p r e pit a nt is b o t h a s e ns itiv e  s ub str ate  a n d  a 
m o d er at e  C Y P 3 A 4  i nh ib ito r a n d  c a n b e  u se d wit h  c au tio n  if a n alte rn at ive  is no t a v ai la b l e. 
 
Q T /Q Tc  in ter v al p ro lo n g at io n  o r to rs ad e  d e  p o in te s m e d ic atio n s: M e d ic atio n s th at  h a v e  t h e p o te n ti al 
t o p ro lo n g t h e  Q T /Q Tc  in te rv al  o r in d u c e to rs ad e s d e  p o in t es ar e  al l ow e d wit h  ca u tio n .  In v es tig a to rs 
at  t h eir d iscr etio n  m a y co -a d m in ist er s uc h m e d ic atio n s, b u t p ati e nts  s h o ul d b e  c ar ef ull y m o n ito r e d. 
S e e  A p p e n d ix D  fo r list o f dr u g s th at  n e e d to  b e  u se d  wit h c a ut io n . 
 
9 .4 .3     P ro h ib ite d  co n co m ita n t th e ra p y  wi th  B G J3 9 8  
 
C Y P  i nh ib ito rs 
 
Str o n g  in h ib ito rs o f C Y P 3 A 4  s uc h as  th e  o n es  liste d  i n A p p e n d ix C  a re  p ro h ib it e d b ec a us e  B G J3 9 8  is a 
li ke l y s ubs tr at e o f  t his iso e n zym e.    C a u tio n  s h o u ld  b e  u s e d d u rin g  a d m in istr atio n o f m o d er a te 
in h ib ito rs. T h e  fo llo wi n g  fo o d  p ro d u cts a re  p ro h ib it ed : S e v ill e o r an g es o r ju ic e, gr ap efr u it, g r ap efr u it 
ju ic e, g r ap efr u it hy br i ds, an d  p u m m el o s. 
 
C Y P  in d u c ers: Str o n g  in d u c ers o f C Y P 3 A 4  a re  p ro h ib it e d b ec a us e  th eir  u s ag e  w o u l d li ke ly  d ec re as e 
t h e  e xp o s ure  o f  B G J3 9 8 .    T h er ef o re,  a g e nts  s uc h as  t ho s e  liste d  i n A p p e n d ix  E  ar e  p ro h ib it e d. 
C a u tio n  sh o u l d b e  u s e d d u rin g  a d m in istr atio n  o f m o d e r at e in h ib ito rs. 


P a g e 4 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
P h o s ph o ru s a n d  c alciu m : M e d ica tio n s t h at in cr e ase  t h e ser u m  le v els  o f p h o sp h o ru s a n d/ o r c alciu m 
ar e  p ro h ib ite d.  T h e se  in clu d e,  b u t ar e  n o t lim ite d  to , c alciu m , p h o s ph at e , v ita m in D , p ar at h y ro i d 
h o rm o n e  (P T H).  
 
H er b a l m e d ica tio n s: H er b a l p r e pa r atio n s/m e d ic atio n s ar e n o t al l ow e d  t hro u g h o u t t h e st ud y . T h e se 
h er b a l m e d ica tio n s in clu d e , b u t ar e  n o t lim ite d  to : St. Jo h n ’s w o rt, K a v a,  e p h e dr a ( m a  h u a n g ), g in g k o 
b ilo b a,  d e hy dr o e p ia n d ro ster o n e  (D H E A),  yo h im b e,  s a w p al m e tto , a n d g in s e ng . P ati e nts  s h o ul d sto p 
u sin g  th es e  h er b al  m e d ic atio n s 7 d ays p rio r t o first d o s e o f stu d y dr u g . 
 
E n zym e  In d u cin g  A n ti-e p il ep tic d ru g s ( EI AE D s): E n zy m e  in d u cin g  a n ti-e p il ep tic m e d ic atio n  is  n o t 
al lo w e d  ( ple a se  ref e r t o A p p e n d ix E).  P ati e n ts w h o  w e r e p re v io u sly  o n  a  n o n -EI A E D  a n d  n e e d t o 
p er m a n e nt ly  c ha n g e  a n tico n v u lsa n ts,  b u t  w h o  ca n n o t  c ha n g e  t o  a n o t h er  n o n -EI A E D  m u st  b e 
d iscu ss e d wit h  t h e M S K C C P I a n d  N o v arti s.  T h e se  p a ti en ts will  b e  ta k e n  o ff-st ud y  u n l ess it is felt  t h at 
t h e y h a ve  b e n efi te d fr o m  th e  t h er ap y fo llo wi n g  di sc ussio n  w it h t h e M S K C C  P I an d N o v a rtis. 
 
1 0. 0     E V A LU A TI O N  D U R IN G  T R E A T M E N T /IN T E R V E N T IO N  
 
1 0 . 1    St a n d a rd  E v a l ua tio n  
 
1 0 .1 .1    St u d y C a le n d a r (P h a s e I P or tio n  S tu d y)  
 
B as eli n e  clin ic al e v al u at io n s ar e t o b e  co n d u cte d  wit h in  2  w e e ks o f sta rtin g  pr o to co l th er a p y . 
R a d io lo g ic e v al u at io n s a n d s ur gic al bi o psi es m u st b e  d o n e  ≤4  w e e k s prio r to  t h e st art o f th e ra p y . 
 
In fo rm e d C o n se nt  c a n b e  o b t ain e d 3 0  d a ys  pr io r to  th e  st art o f stu d y th er a p y . 
 
A fte r p atie nts  h a v e  b e e n  o n  th e  co m b in ati o n  t h er ap y m o re  t h a n 4 cy cles,  th e  p a ti en t c a n i ncre as e 
t h e du r atio n  o f th e  e val u a tio n  by  t h e M D  a n d  R N to  e ve ry  8  o r 1 2  w e e ks at th e  in v es tig a to r’s 
d iscr etio n . T h e  b as ic l ab o rat o ry  a n d  E K G  as se ssm e nt  b e tw e e n e v al u at io n s c a n b e  p er fo rm e d lo c all y 
a n d  w ill b e o b t ain e d  e ver y  4  w e e ks fo r p ati en ts o n  th e  p h as e  I b p o rtio n  o f t h e st ud y . 
 
T a b le 9 : V isit E v a lu a tio n  Sc h e d u le  d u rin g  P h a s e Ib  


P a g e 4 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
P re - 
St u d y  
 
C y c l e 1  
 
C y c l e 2  
 
C y c l e 3  a n d b e y o n d  
 
 
 
Off S tu d y c  
 
W k  
1  
 
W k  
2  
 
W k  
3  
 
W k  
4  
 
W k  
5  
 
W k  
6  
 
W k  
7  
 
W k  
8  
 
W k  
9  
 
W k  
1 0  
 
W k  
1 1  
 
W k  
1 2 +  
Im a tin ib X  
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
B G J 3 9 8 Y A  
 
T r e atm e n t S c h e d u le  A  
 
 
Y A   
Y A   
Y A  
 
 
Y A   
Y A   
Y A  
 
 
Y A   
Y A   
Y A  
 
 
B G J 3 9 8 Y B  
 
T r e atm e n t S c h e d u le  B  
 
 
Y B  
 
 
 
 
Y B  
 
 
 
 
Y B  
 
 
 
 
 
In for m e d  c o n s e n t 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p h ic s  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e d ic a l h ist or y  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n c ur re n t M e d s  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
 
P h y s ic a l e xa m  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
X  
 
V ita l s ig n s  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
X  
 
H e ig h t 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W e ig h t 
 
X  
 
X   
 
X   
 
X   
 
 
X d   
 
 
 
X  
E y e  E xa m  g  
 
X  
 
 
 
 
X   
 
 
 
 
 
 
 
 
 
P er for m a n c e  s ta tu s  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
X  
C B C  w /d iff, p lts j 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
 
X   
X d   
 
 
 
X  
 
Ur in a ly s is  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d  c h e m ist ry  a , j 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   
 
X   
X d   
 
 
 
X  
 
H e p  B  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T S H  
 
X  
 
 
 
 
 
 
 
X   
X d   
 
 
 
 
E K G  
 
X  
 
 
 
X   
 
X   
 
 
X d   
 
 
 
 
E c h o  o r M U G A  
 
X  
 
 
 
 
X   
 
 
 
 
 
 
X e  
 
X  
 


P a g e 4 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
A d v er s e  e v e n t e v a lu a tio n   
 
X   
 
X   
 
X   
 
 
X d   
 
 
 
X  
 
R a d io lo g ic  e v a lu a tio n  
 
X  
 
 
 
 
 
 
 
 
X f  
 
 
X f 
 
T u m o r m e a s ur e m e n ts  
 
X  
 
 
 
 
 
 
 
 
X f  
 
 
 
 
B -H C G  
X b  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B G J 3 9 8  a n d  im a tin ib  P K 
L e v e ls  
 
 
h , i 
X  
 
 
h ,i 
X  
 
X h , i  
 
 
 
 
 
 
 
 
 
 
 
X : 
Im at i nib :  D o s e  a s a s s i gn e d ; P O  o n c e d a il y 
 
Y A :  B G J 3 9 8 : D o s e  a s a s s i gn e d ; P O  o n c e d a il y fo r 3 w e e k s o n a n d o n e  w e e k  o ff 
 
Y B :  B G J 3 9 8 : D o s e a s  a s s i gn e d ; P O  o n c e d a il y fo r o n e w e e k  o n a n d 3 w e e k s  o ff 
 
a : 
C o m p - A l bu m in , a lk a li n e p h o s p h a t as e , to ta l b iliru b in , b ic ar b o n a te , B U N , c a lc iu m, c h l ori de , 
c r e ati nin e , g lu c o s e ,  p o ta s s iu m, to ta l pr o te in , S G O T  [A S T ], S G P T  [A L T ], s o d iu m. In  a d d iti on , 
L D H , p h o s p h or u s , m a g n e s iu m, c re a ti n e k i na s e  ( CK ), a m y l as e , li pa s e.  
 
b : 
B l oo d  pr e g n a n c y  te s t (w o m e n o f c h ild b e ar in g p o te n tia l) o n c e a t b a s e lin e ; fur th e r te s ti n g a t th e 
d is c re ti o n o f th e  i nv e s ti ga to r w h il e o n s tu d y.  
c : 
Of f-st u d y e v a l ua ti o n p er fo rm e d 4  w e e k s  a fte r re m o v a l fro m  st u d y  w ith a w i nd o w  o f + /- 7 d a y s 
d : 
D a y 1 o f e a c h  c y c l e w h il e o n  st u d y.  A t th e  i nv e st i ga tor ’ s d is c r eti on , p a ti en ts  c a n r etur n  fo r 
R N /M D vi s its  a n d  g e t e v a l ua te d  e v er y 8 o r 1 2 w e e k s  af te r c y c l e 4 .  L a b or a tor y a s s e s s m e nt s  a n d  
E K G  a s s e s s m e nt s  b e tw e e n M D /R N v is its c a n  b e p er fo rm e d  l oc a ll y w ith r es u lts s e n t to  th e  st u d y 
s ite  
 
e :    T T E o r M U G A  w ill b e p er fo rm e d o n c e a t w e e k  1 6  a s  w e ll a s  a n y tim e  fe lt to b e  n e c e s s ar y b y  th e 
i nv e st i ga to r. M o d a litie s s h o u l d re m a i n c o n s ist e n t w h e n e v e r fe a s i ble . 
 
f: 
S c a n s s h o u l d b e p er fo rm e d e v er y 8 w e e k s  x  4  st ar ti n g af te r 2 c y c l e s ( e.g . C 3 D 1 , C 5 D 1 , C 7 D 1 , 
C 9 D 1 ), th e n e v er y 1 2 w e e k s  ( C 12 D 1 , C 1 5 D 1 , e t c). R a d i olo g ic  d o c u m e n ta ti o n m u s t b e pr o v i de d 
fo r p a ti ent s re m o v e d fro m  st u d y fo r pr o gr e s s iv e d is e a s e  w ith i n 2 8 d a y s  o f c lin ic a l a s s e s s m e n t o f 
pr o gr e s s i o n if n o  s c a n w a s  p er fo rm e d w ith i n 2 8 d a y s o f th e  tim e  o f t h at a s s e s s m e n t. 
 
g :  A t e y e e xa m s th e  fo llo w  te s ts s h o u l d b e c o m pl et e d :  
- 
s lit la m p  e xa m  
- 
d ila te d fu n d u s c o p i c e xa m  w ith p h o to s  
- 
o p tic a l c o h er e n c e  to m o gr a p h y te st i n g 
A  fo llo w -u p e y e e xa m  w ill o c c u r a t w e e k  4 ( C1 W 4 ) a n d /o r if th e p a tie n t d e v e l op s  n e w  o r w or s e n i n g 
o c u l ar s ym p to m s  
 
h : 
T h e  tim in g o f p h a rm a c o k i ne tic s a m p l e c o ll ec ti on s is  d e p e n d e n t o n th e  tr e atm e n t s c h e d u l e th e 
p a ti en t is e nr o lle d o n to .  F or tr ea tm e n t s c h e d u l e A  p h a rm a c o k i ne ti c s a m p l e c o ll ec ti on s s h o u l d b e 
dr a w n a t th e  fo llo w i n g tim e p o i nts : C y c l e 1 , D a y 1 p la s m a w ill b e  d ra w n  a t  0 , 1 , 2 , 4 , 6 , 8 , a n d 2 4 
h o ur s  af te r ta k i n g B G J 3 9 8 ; th e 0  a n d 2 4 h o u r tim e p o i nts  w ill b e dr a w n b e for e d o s i n g B G J 3 9 8 . 
C y c l e 1 , D a y 2 1 p la s m a w ill b e  dr a w n 0 , 1 , 2 , 4 , 6 , a n d 8 h o ur s  af te r d o s i n g B G J 3 9 8 . S e e T a b l e 
1 0 . A. T he s e a s s e s s m e nt s m u s t b e  d o n e o n th e  e xa c t d a te s  e xc e p t -3  /+ 1 d a y w i nd o w  fo r C 1 D 2 1 
tim e p o i nt. Ot h e r l ev e ls m a y b e dr a w n a s  c lin ic a ll y i nd ic a te d .  F or  tr ea tm e n t s c h e d u l e B 
p h ar m a c o k i ne tic s a m p l e c o ll ec ti on s s h o u l d b e dr a w n a t th e fo llo w i n g tim e p o i nts : C y c l e 1 , D a y 1 
p l as m a  w ill b e dr a w n a t  0 , 1 , 2 , 4 , 6 , 8 , a n d 2 4  h o ur s  a fte r ta k i n g B G J 3 9 8 ; th e 0  a n d 2 4 h o u r 
tim e p o i nts w ill b e dr a w n b e for e d o s i n g B G J 3 9 8 . C y c l e 1 , D a y 7 w ill b e dr a w n a t  0 , 1 , 2 , 4 , 6 , a n d  
8 h o ur s  af te r d o s i n g B G J 3 9 8 ; th e  0 h o u r tim e p o i nt w ill b e  dr a w n b e for e d o s i n g B G J 3 9 8  .  C y c l e 
1 , D a y 1 5 w ill b e dr a w n a t  0 hr . C y c l e 1 , D a y 2 1 w ill b e  dr a w n a t 0 hr .  S e e  T a b l e 1 0 .B . T he s e 
a s s e s s m e nt s m u s t b e  d o n e o n  th e  e xa c t d a te s e xc e p t -2  /0  d a y w i nd o w  fo r C 1 D 7 a n d  -3  /+ 1 d a y  


P a g e 5 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
w i nd o w  fo r C 1 D 1 5 a n d  C 1 D 2 1 tim e p o i nt. O th e r l ev e ls m a y  b e dr a w n  a s c li nic a ll y i nd ic a te d . 
 
i: 
F or tr ea tm e n t s c h e d u l e A  p l as m a  fo r im a tin i b l ev e l s w ill b e dr a w n c o n c urr e n tl y w ith B G J 3 9 8 
l ev e l s a t th e  fo llo w i n g tw o tim e  p o in ts : C 1 D 2 ( 24 h o ur s p o s t-firs t d o s e ) a n d C 1 D 2 1 . B o th tim e 
p o i nt s w ill b e dr a w n b e for e d o s i n g im a ti ni b o n  th a t d a y . C 1 D 2  m u s t b e d o n e o n th e  e xa c t d a te , 
a n d C 1 D 2 1  m a y b e dr a w n w ith i n a  -3 /+ 1  d a y  w i nd o w . Ot h e r l ev e l s m a y  b e dr a w n a s  c lin ic a ll y 
i nd ic a te d . 
 
F or tr e atm e n t s c h e d u l e B  p la s m a  f or im a tin i b l ev e l s w ill b e dr a w n c o n c urr e n tl y w ith B G J 3 9 8 l e v e ls  a t 
th e fo ll ow i n g thr e e tim e p o in ts : C 1 D 2 ( 24 h o ur s  p o s t-firs t d o s e ), C 1 D 7 a n d C 1 D 2 1 .  A ll tim e p o in ts 
w ill b e dr a w n b e for e d o s i n g im a ti nib o n th a t d a y .  C 1 D 2  m u s t b e d o n e o n th e  e xa c t d a te .  C 1 D 7 
c a n b e dr a w n w ith in a  -2 /0 d a y w i nd o w  a n d C 1 D 2 1 c a n  b e dr a w n  w ith i n a  -3 /+ 1  d a y  w i nd o w . 
Ot h e r l ev e l s m a y b e  dr a w n a s  c li nic a ll y i nd ic a te d . 
 
j. C B C a n d  B l oo d C h e m is try p er for m e d  o n D a y 1 o f e a c h  c y c l e m u s t b e r es u lte d  pr i or to  tr e atm e n t. 
 
A ll a s s e s s m e n ts ar e to  b e d o n e + /-3 d a y s  o f th e  s c h e d u l e d tim e p o i nts  u n le s s o th er w is e n o te d  a b o v e . 
R a d i olo g i c a s s e s s m e nt s  ( CT, P E T , T T E ) ar e  to b e  d o n e + /-7  d a y s fr om  th e  s c h e d u l e d a p p o i ntm e nt . 
 
 
 
 
T a b le  1 0 .A : P h a rm a co ki n e tic Ass es sm e nts  o f B GJ3 9 8  o n  T r e atm e n t Sc h e d u l e A 
 
 
Tr e a t me n t 
C y cle  
 
D a y  
 
P K S a m pl e # 
B G J3 9 8 (P la s ma ) 
T im e  
R el a tiv e  to  
D o s e 
1  
1  
1  
P re -d o s ea  
1  
1  
2  
1 h r ± 5  m i n 
1  
1  
3  
2 h r ± 5  m i n 
 
 
1  
 
 
1  
 
 
4  
 
4 h r ± 1 0 
m i n 
 
1  
 
1  
 
5  
6 h r ± 1 0  
m i n 
 
1  
 
1  
 
6  
8 h r ± 1 5  
m i n 
 
1  
 
2  
 
7  
2 4 h r ±  6 0 
m in a  
1  
2 1  
8  
P re -d o s e a  
1  
2 1  
9  
1 h r ± 5  m i n 
1  
2 1  
1 0  
2 h r ± 5  m i n 
1  
2 1  
1 1  
 
4 h r ± 1 0  


P a g e 5 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
m i n 
6 h r ± 1 0  
1  
2 1  
1 2  
m i n 
8 h r ± 1 5  
1  
2 1  
1 3  
m i n 
As cli n ic ally 
A n y 
A n y 
1 0 1 , 1 0 2 , e tc 
in d ic at e d 
a:  T h e s e le v els s h o u l d b e  d r a w n ju st p rio r to  a d m in istr atio n  o f B GJ3 9 8  pl u s im at in i b o n  th at  d a y 
N o te : C 1 D 2 1  w ill ha v e  a  -3  d a ys /+ 1  d a y  w in d o w,  th is wi nd o w  d iffers  fro m  all  o th er  P K  v isits 
T a b le  1 0 . B: P h a rm a co ki n e tic Ass es sm e nts  o f B GJ3 9 8  o n  T r e atm e n t Sc h e d u l e B  
 
 
Tr e a t me n t 
C y cle  
 
D a y  
 
P K S a m pl e # 
B G J3 9 8 (P la s ma ) 
T im e  
R el a tiv e  to  
D o s e 
1  
1  
1  
P re -d o s ea  
1  
1  
2  
1 h r ± 5  m i n 
1  
1  
3  
2 h r ± 5  m i n 
 
 
1  
 
 
1  
 
 
4  
 
4 h r ± 1 0 
m i n 
 
1  
 
1  
 
5  
6 h r ± 1 0  
m i n 
 
1  
 
1  
 
6  
8 h r ± 1 5  
m i n 
 
1  
 
2  
 
7  
2 4 h r ±  6 0 
m in a  
1  
7  
8  
P re -d o s e a  
1  
7  
9  
1 h r ± 5  m i n 
1  
7  
1 0  
2 h r ± 5  m i n 
 
1  
 
7  
 
1 1  
4 h r ± 1 0  
m i n 


P a g e 5 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
6 h r ± 1 0  
1  
7  
1 2  
m i n 
8 h r ± 1 5  
1  
7  
1 3  
m i n 
1  
1 5  
1 4  
P re -d o s eb  
1  
2 1  
1 5  
P re -d o s eb  
As  clin ic all y 
A n y 
A n y 
1 0 1 , 1 0 2 , e tc 
in d ic at e d 
b : T h e se  le v els  s ho u l d b e  d r a w n ju st p rio r to  a d m in istr atio n  o f t h e st ud y  dr u g s (B G J3 9 8  a n d/ o r 
im ati n ib ) o n  t h at d a y 
 
N o te : C 1 D 7  w ill h a ve  a  wi n d o w  o f -2 /0  d a y  w in d o w,  C 1 D 1 5  a n d  C 1 D 2 1  will  h a ve  a  -3 /+ 1  d a y  wi n d o w, 
t h es e wi n d o ws  d iffe r fro m  all o t h er P K  v isits 
 
 
 
 
1 0 .1 .2   St u d y C a le n d a r (P h a s e II P o rtio n  S tu d y)  
 
B as eli n e  clin ic al e v al u at io n s ar e t o b e  co n d u cte d  wit h in  2  w e e ks o f sta rtin g  pr o to co l th er a p y 
in clu d in g  a  b as eli n e  F D G -P E T pr io r to  th e  l e ad -i n p h a se  o f im a tin i b. R a d io lo g ic e val u ati o n s a n d 
s ur gic al bi o psi es m u st b e  d o n e  ≤4  w e e k s prio r to  t h e st art o f th e ra p y . T h er e  is a  2 -w e e k  l e a d i n o f 
im ati n i b a lo n e  a n d  t h e n BG J3 9 8  w ill b e  a d d e d to  im at in ib . 
 
In fo rm e d C o n se nt  c a n b e  o b t ain e d 3 0  d a ys  pr io r to  st u dy  start.  
 
A fte r p atie nts  h a ve  b e e n  o n  th e  co m b in ati o n  t h er ap y m o re  t h a n 4  cy cles,  th e  p a ti en t c a n i ncre as e 
t h e du r atio n  o f th e  e val u a tio n  by  t h e M D  a n d  R N to  e ve ry  8  o r 1 2  w e e ks at th e  in v es tig a to r’s 
d iscr etio n . T h e  b as ic l ab o rat o ry  a n d  E K G  as ses sm e nt  b e tw e e n e v al u at io n s c a n b e  p er fo rm e d lo c ally . 
 
 
 
T a b le 1 1 : Vi sit E v a lu a tio n  S ch e d u le  d u rin g  P h a s e II 
 
 
 
 
P re - 
St u d y  
 
 
 
W k  
 
-2  
 
C y c l e 1  
 
C y c l e 2  
 
C y c l e 3  a n d b e y o n d  
 
 
 
Off  
St u d y / 
 
E O T c  
 
 
W k  
1  
 
 
W k  
2  
 
 
W k  
3  
 
 
W k  
4  
 
 
W k  
5  
 
 
W k  
6  
 
 
W k  
7  
 
 
W k  
8  
 
 
W k  
9  
 
 
W k  
1 0  
 
 
W k  
1 1  
 
 
W k  
1 2 +  
Im a tin ib X  
 
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X  
 
X   


P a g e 5 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
B G J 3 9 8 Y  
 
T r e atm e n t s c h e d u le  to  b e 
d e ter m in e d  b y  th e  p h a s e 
Ib  p or tio n  o f th e  st u d y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In for m e d  c o n s e n t 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p h ic s  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M e d ic a l h ist or y  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n c ur re n t M e d s  
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
 
P h y s ic a l e xa m  
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
X  
 
Vi ta l s ig n s  
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
X  
 
H e ig h t 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
W e ig h t 
 
X  
 
 
X   
 
X   
 
X   
 
 
X d   
 
 
 
X  
E y e  E xa m  k  
 
X  
 
 
 
 
 
X   
 
 
 
 
 
 
 
 
 
P er for m a n c e  s ta tu s  
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
X   
 
 
X d   
 
 
 
X  
C B C  w /d iff, p lts m  
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
X   
 
X   
X d   
 
 
 
X  
 
Ur in a ly s is  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bl o o d  c h e m ist ry a , m 
 
X  
 
 
X  
 
X  
 
X  
 
X  
 
X   
 
X   
X d   
 
 
 
X  
 
H e p  B  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T S H  
 
X  
 
 
 
 
 
 
X   
 
 
X d   
 
 
 
 
E K G  
 
X  
 
 
 
 
X   
 
X   
 
 
X d   
 
 
 
 
E c h o  o r M U G A  
 
X  
 
 
 
 
 
X   
 
 
 
 
 
 
X e  
 
X  
 
A d v er s e  e v e n t e v a lu a tio n   
 
 
X   
 
X   
 
X   
 
 
X d   
 
 
 
X  
 
R a d io lo g ic  e v a lu a tio n  
 
X  
 
 
 
 
 
 
 
 
 
X f  
 
 
 
 
T u m o r m e a s ur e m e n ts  
 
X  
 
 
 
 
 
 
 
 
 
X f  
 
 
X f 
 
B -H C G  
X b  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


P a g e 5 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
F D G  P E T  s c a n  
 
X  
 
 
 
X g   
 
 
 
 
 
 
 
 
 
 
T u m o r Bi o p s y  
 
X  
 
 
X h   
 
 
 
 
 
 
 
 
 
X h  
 
R e s e ar c h  Bl o o d  Dr a w  
 
X i 
X i  
X i  
X i  
 
 
 
 
 
 
X j 
 
S ur v iv a l S ta tu s  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X l 


P a g e 5 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
K e y fo r T a b l e 1 0 : 
S c h e d u l e o f P h a s e  2  
E v a l ua ti on s  
X : 
Im at i nib :  D o s e  a s a s s i gn e d ; P O  o n c e d a ily  
 
Y : 
B G J 3 9 8 : D o s e  a s a s s i gn e d ; P O  o n c e d a il y  th e  tr e atm e n t s c h e d u l e w ill b e d e te rm i ne d b y  th e 
p h a s e Ib  p or ti o n o f th e  st u d y  
 
a : 
C o m p - A l bu m in , a lk a li n e p h o s p h a t as e , to ta l b iliru b in , b ic ar b o n a te , B U N , c a lc iu m, c h l ori de , 
c r e ati nin e , g lu c o s e ,  p o ta s s iu m, to ta l pr o te in , S G O T  [A S T ], S G P T  [A L T ], s o d iu m. In  a d d iti on , 
L D H , p h o s p h or u s , m a g n e s iu m, c re a ti n e k i na s e  ( CK ), a m y l as e , li pa s e.  
 
b : 
 B l oo d  pr e g n a n c y  te s t (w o m e n o f c h ild b e ar i n g p o te n ti al) o n c e a t b a s e lin e ; b l oo d  o r ur i n e 
pr e g n a n c y te s t a t th e  d is c r eti o n o f th e i n v e s ti ga to r w h il e o n  st u d y . 
 
c : 
Of f-st u d y e v a l ua ti o n p er fo rm e d 4  w e e k s  a fte r re m o v a l fro m  st u d y . 
 
d : 
D a y 1 o f e v er y c y c l e w h il e o n s tu d y .  A t th e  i nv e s ti ga tor ’s  d is c r eti on , p a ti ent s c a n re tu rn fo r 
R N /M D vi s its  a n d  g e t e v a l ua te d  e v er y 8 o r 1 2  w e e k s  a fte r c y c l e 4 .  L a b or a tor y a s s e s s m e nt s  a n d 
E K G  a s s e s s m e nt s  b e tw e e n M D /R N v is its c a n  b e p er fo rm e d  l oc a ll y w ith r es u lts s e n t to  th e  st u d y 
s ite  
 
e : 
 T T E or M U G A  w ill b e  p er fo rm e d  o n c e  a t w e e k  1 6 a s w e ll a s  a n y tim e  fe lt to b e n e c e s s ar y b y th e 
i nv e st i ga to r. M o d a litie s s h o u l d re m a i n c o n s ist e n t w h e n e v e r fe a s i ble . 
 
f: 
S c a n s s h o u l d b e p er fo rm e d e v er y 8 w e e k s  x  4  st ar ti n g af te r 2 c y c l e s ( e.g . C 3 D 1 , C 5 D 1 , C 7 D 1 , 
C 9 D 1) , th e n e v er y 1 2 w e e k s  ( C 12 D 1 , C 1 5 D 1 , e t c). R a d i olo g ic  d o c u m e n ta ti o n m u s t b e pr o v i de d 
fo r p a ti ent s re m o v e d fro m  st u d y fo r pr o gr e s s iv e d is e a s e  w ith i n 2 8 d a y s  o f c lin ic a l a s s e s s m e n t o f 
pr o gr e s s i o n if n o  s c a n w a s  p er fo rm e d w ith i n 2 8 d a y s  o f th e  tim e  o f t h at a s s e s s m e n t. 
 
g : 
 F D G  P E T  s c a n w ill b e  p er fo rm e d  a t b a s e lin e  ( pre -tr e atm e n t) a n d  d ur i n g w e e k  3  o f c o m bi n a ti o n 
th er a p y ( C 1 D 2 1 ). 
 
h : 
T u m o r b i op s y w ill b e  p er fo rm e d  pr e -tr e atm e nt , af te r w e e k  1 ( C1 D 8  ) o f th er a p y , a n d a t d is e a s e 
pr o gr e s s i o n fo r p a ti en ts w h o h a v e c o n s e n te d  fo r re s e ar c h  b i op s ie s i n c l ud i n g th e firs t tw e n ty 
m a n d a tor y p a ti ent s  a n d  a n y s u b s e q u e n t v o l un tar y p a ti ent s . A + /- 4  d a y w i nd o w w ill b e pr o v i de d 
fo r th e b i op s ie s to a c c o u n t fo r s c h e d u lin g . 
 
i: 
F o u r re s e ar c h  b l oo d  4 -8 m L v ia l s w ill b e o b ta i ne d  a t b a s e lin e  (w e e k  -2) , tw o w e e k s  af te r th e  s i ng l e 
a g e n t im a ti ni b l ea d i n  ( C 1 D1 o f c o m b i na ti o n th er a p y ), w e e k  3 ( C 1 D 1 5), w e e k  5 ( C 2 D1 ). A t l ea s t 
o n e  tu b e a t th o s e  tim e p o in ts w ill b e u s e d  fo r im a ti ni b tr o u gh  l ev e ls , a n d  tw o tu b e s  w ill b e  u s e d  
fo r c orr e l ativ e a n a ly s e s . Im a ti ni b le v e l s w ill b e pr i oritiz e d . 
 
j: 
T w o r es e ar c h b l oo d 4 -8 m L v ia l s fo r c orr e l ativ e a n a ly s e s  w ill b e  o b ta i ne d  a t th e  tim e  o f 
pr o gr e s s i o n. 
 
k : 
A t e y e e xa m s th e  fo llo w  te st s s h o u l d b e  c o m p l ete d  : 
- 
s lit la m p  e xa m  
- 
d ila te d fu n d u s c o p i c e xa m  w ith p h o to s  
- 
o p tic a l c o h er e n c e  to m o gr a p h y te st i n g 
A  fo llo w -u p e y e e xa m  w ill o c c u r a t w e e k  4 ( C1 W 4 ) a n d if th e  p a ti en t d e v e l op s  n e w  o r w or s e n i n g 
o c u l ar s ym p to m s . 
 
l: 
St u d y p er s o n n e l w ill a tte m pt  to c o n ta c t a ll e v a l ua b l e p a ti en ts e v er y 3  m o n th s  (± 2  w e e k s ) v i a 
te l ep h o n e , e m a il, et c to a s s e s s s u r viv a l st a tu s  fo r u p  to 3  y e ar s . 
 
m.  C B C  a n d B l oo d C h e m ist ry p erf or m e d o n  D a y 1 o f e a c h  c y c l e m u s t b e r es u lte d pr i or to  tr e atm e n t 
 
A ll a s s e s s m e n ts ar e to  b e d o n e + /-3 d a y s  o f th e  s c h e d u l e d tim e p o i nts  u n le s s o th er w is e n o te d . 
R a d i olo g i c a s s e s s m e nt s  ( CT, P E T , T T E ) ar e  to b e  d o n e + /-7  d a y s fr om  th e  s c h e d u l e d a p p o i ntm e nt . 


P a g e 5 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 0. 2     P A T H O LO G Y/ C O R R EL A T IV E/ S P E C I AL S T U D IE S  
 
T u m o r C o lle ctio n  a n d  S cre e n in g  
 
1 0 .2 .1   P re -tre a tm e n t d ia g n o sis co n firm a tio n : 
A ll p ati e nts  will  h a v e  h isto lo g ic al o r cyto lo g ic al co n firm at io n  o f a  d i ag n o sis a t t h eir tr ea tin g 
in stit utio n  p ri or t o tre a tm e nt.   If n ec e ss ar y a  p a tie n t m a y  h a ve  to  u n d er g o  a  b io p s y o f th eir 
d is e as e as  p er  st a nd ar d  clin ic al p r actic e to  e ns u r e th at  a  p ro p er  d i ag n o sis o f t h eir d is ea s e is 
m a d e.  Tiss u e  will  b e  o b t ain e d  fo r co rrel at ive  st ud i es o n l y aft er  a  d efi n itiv e  d ia g n o sis h as  b e e n 
m a d e  b y  p at h o lo gy  a n d  i nfo rm e d co n s e nt h as b e e n o b t ain e d.  
 
1 0 .2 .2   B io p s y sp e cim e n  co llec tio n  fo r co rrel a tiv e  stu di e s: 
F ollo wi n g  in fo rm e d  co n se n t, t h e first 2 0  p ati e nts  e n ro ll e d o n  t h e p h as e  II p o rtio n  will  u n d er g o 
m a n d a to ry re s e arc h b io p si es. A ll b io p si es will  b e  p erf o rm e d  at M S K C C  o r o th er  p artici p ati n g 
in stit utio n s.  T h e s e  p ati e n ts  will  u n d er g o  a  p re -tr ea tm e n t  bi o p sy  a n d  t h e n  a  p o st-tr ea tm e nt 
b io p s y (C 1 D 8 ) t h at will  b e  p erf o rm e d  a fte r w e e k 1  o f t h e co m b in ati o n  th er a p y . Bi op si es at  th e 
tim e o f p ro g ress io n  will b e  o p tio n al  b u t e nc o u r age d . A fter  2 0  p ai re d  b io p sy  s p ecim e ns  a re 
o b t ain e d,  t h e re m ai n d er  ar e  o p tio n al  a n d  e nc o u r ag e d  if a d d itio n al  fu n d in g  is id e ntifi e d . If a n 
o p e n  in cisio n al  b io p sy  is p erf o rm e d,  1  cm
3  o f tissu e  will  b e  fla s h fro ze n  a n d  0 . 5 t o 1 cm
3  will  b e 
fo rm al in  fix e d a n d  s en t to  p at h o lo g y fo r co rrel at ive  st ud i es.  A lter n a tiv el y , a  C T  g u id e d  co re 
b io p s y co u l d b e  p erf o rm e d .  C o r e b io p sy will  b e  p er fo rm e d  o f a  l esio n o f at  l e ast 2  c m b y  a  st ud y 
in te rv e n tio n al  r ad io lo g ist wit h  lo c al a n e st h esi a a n d  t hr ou g h  a  sin g l e e ntr a n c e sit e o n  t h e ski n 
s urf ac e, u p  t o five  tiss u e co r es o f t h e GI S T  will  b e  o b t ain e d.  F o u r co r es will  b e  fla s h fro ze n  a n d 
o n e  co r e will  b e  fixe d  i n fo rm al in  fo r co rr ela tive  p at h o lo g y . W e  b el ie v e  t h at b o th  a p p ro ac h es  will 
p ro v id e  s uffici e nt tiss u e to  d o  t h e p ro p o se d  st ud i es. A s m e nt io n e d  i n 1 0 .2 . 1, w e  m a y  als o  co llect 
tiss u e fro m  p ati e n ts r e qu ire d  t o u n d er g o  a p re -tre a tm e nt  b io p s y fo r co n firm at io n  o f d i ag n o sis. A 
p ati e nt  m a y  b e  e xc use d  fro m  t his r e qu ire m e n t if tiss u e is n o t d e e m e d  a cc essib l e o r fo r s afe ty 
r e aso n s a s d e ter m in e d  b y lo c al st ud y  inv es tig a tor . In  s uc h a  c as e, s ubs e q u e nt p ati e nts  will  b e 
a p p ro ac h e d  fo r a  m a n d a to r y b io p sy  u n til a  to t al o f 2 0  p ai re d  p ati e nt  b io p sie s ar e  o b t ain e d . 
Bi o p si es w ill n o t b e p er fo rm e d  o n  th e  P h a s e I p o rtio n  o f t h e pro to co l. 
 
1 0 .2 .3   R es e a rc h B lo o d : 
 
R es e a rc h b lo o d  will b e  d ra w n  o n  th e  P h as e  I b p o rtio n at  th e  tim e  p o in ts n o te d  i n T a b le s 1 0 . A a n d  
1 0 . B fo r B JG 3 9 8  a n d  im a tin i b p l asm a  le vels.  R es e a rc h b lo o d will  b e  o b t ain e d  o n  t h e P h as e  II 
p o rtio n  a t b as eli n e, 2  w e e ks  aft er  sin g l e a g e n t im a tin i b l e a d i n ( +/-3  d a ys) p ri or t o C ycl e 1 D a y 1 , 
a n d  at  C 1 D 1 5  a n d  C 2 D 1  aft er  t h e  co m b in at io n  th er a p y  st arte d  fro m  all  p a ti e nts.  A ll  b lo o d 
s am p l es s h o ul d b e  o b t ain e d  p rio r to  th e  d ai ly d o s e o f im ati n i b + /- B G J3 9 8 ; i.e.  a  tro u g h  le v el. 
R es e a rc h b lo o d  w ill b e  u se d  to  e v al u a t e t h e ste a d y -stat e  im ati n i b tro u g h  le v el.  
 
1 0 .2 .4   C ol le ctio n  o f S p e cim e n (s): 
T u m o r sa m p l es will b e c o llec te d  p re -tr ea tm e nt  fro m  t h e first 2 0  p ati e n ts e n ro lle d  o n  t h e P h a se  II 
p o rtio n o f t h e tri al w h o  h a v e  a cce ssib l e tu m o r fo r b io p sy a n d  will  st art im ati n i b d e  n o vo  fo r t his 
tri al. A lso , tiss u e will  b e  co ll ecte d  fro m  a n y  s ub s e qu e nt  p ati e nts w h o  re q u ir e st a nd ar d  o f c are 
b io p si es p ri or to  sy ste m ic tr e atm e nt, o r t ho se  p ati e n ts w h o  v o lu n te er  fo r re se arc h  b io p si es if 
fu n d in g  is a v ai la b le . 


P a g e 5 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 0 .2 .4   H a n d lin g  o f S p e cim e n s(s): 
 
F or e a c h sa m p l e i nd ic ate  th e  u n iq u e  p ati e nt  st ud y  id e n tific atio n  n u m b er,  hist o lo g y  di a g n o sis, a n d 
t h e d at e o f th e  s p ecim e n.  
 
1 0 .2 .5   S h i pp in g  o f S p ec im e n (s) 
 
F las h  fro ze n t u m o r fo r e xtracti o n  o f R N A a n d  D N A a n d  fo r pro te i n e xtr actio n : 
P in g  C h i, S arco m a B io lo g y  La b  
H u m a n  O n co lo g y  a n d  P at h o g e n esis  P ro g ra m 
M e m o rial S lo a n -K e tteri n g  C a n c er C e n te r 
Z u c ke rm a n  R e s e arc h B u ild in g  
Att n:  P in g  C hi  M D , P h D  
4 1 7  E  6 8 th  St., R m  Z 5 2 7  
N e w  Y o r k, N Y  1 0 0 6 5  
La b  P h o n e:  6 4 6 -8 8 8 -3 3 4 9  
La b  F ax:  6 4 6 -8 8 8 -3 4 9 4  
E m ai l: c hi p@ m skcc.o r g 
 
F res h t u m o r fixe d  i n fo rm a lin : 
Cr isti n a An to n es cu , M . D. 
M e m o rial S lo a n -K e tteri n g  C a n c er C e n te r 
D e p a rtm e n t o f P a t ho lo g y 
1 2 7 5  Y o rk  A ve., C -5 8 7  
N e w  Y o r k, N Y  1 0 0 6 5 -6 0 0 7  
T e l: 2 1 2 -6 3 9 -5 9 0 5  
E m ai l: a n to n esc @ m skcc .o rg  
 
P l asm a  fo r im ati n i b le v els  a n d  P l asm a fo r B GJ3 9 8  w ill b e  s hi p pe d to  M SK. M SK  w ill b atc h s hip  th e 
s am p l es to  W u Xi  A p p T e c C o . Ltd . 
 
 
A ll p artici p ati n g  sit es w ill n o tif y t h e M u ltic e nter  Tri al  R es e arc h  St aff  at  M S K C C  (E m ail: 
m e d m ctco re @ m s kcc.o r g)  w h e n s am p les  ar e  s hi pp e d  b y  co m p le tin g  a n d  e m ai lin g  t h e sa m p l e 
r e qu isitio n  fo rm . 
 
C o rr ela tive  st ud i es w ill b e  p erf o rm e d  o n  all  o b t ain e d  b io p s y sp ec im e ns d e t ail e d as th e  fo llo wi n g . 
 
1 .   M o le cu la r b a se d  co rre la ti ve  stu d ie s 
1 a . P h e n o ty pic ch a ra ct eriza ti on s b y im m u n o h ist och e mis try (IH C)  
F or  p at h w a y  r esp o n s e st ud i es, w e  will  ass e ss t h e b as e lin e  c ha r act eristics o f t h e M A P  kin a se , 
F G F,  a n d  KI T  p at h w a y  m e m b ers  i n FF P E  s am p les  co llec te d  fro m  all  p a ti e nts. P re v io u s st ud i es 
h a v e  d e m o n str ate d  t h e re lia b ilit y o f p a t h wa y  m e m b e rs KI T,  p K IT,  p E R K 1 / 2, p A K T, P T E N , p -S6 , 
p 4 E -B P 1 , p F R S 2 , F R S 2, p P R A S 4 0 , pST A T 3 , a n d  S T A T 3 , w h ic h w ill b e e v al u at e d  by  IH C. B as eli n e 
tiss u e c ha ra cte ristics will b e  d eri v e d  fro m  h isto lo g ic al c ha r acte rizat io n  fo r  KI T, C D 3 4  a n d 
D O G 1 . F GF2  a n d  F GF R w ill als o  b e  scre e n e d b y IH C  o n  all tu m o r sa m p l es. 


P a g e 5 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
1 b . G en etic c ha ra ct eriz atio n  of tu m o rs 
A ll t um o r s pe cim e ns  will  b e  g e n o typ e d  v i a st a nd ar d  s e qu e n o m  as sa y  fo r h o tsp o t m u t atio n s 
i n KI T,  P D G F R A  a n d  B R A F  t h at ar e  co m m o n ly m u t ate d  i n GI S T.  I n ad d itio n , w e will  p erf o rm 
m u ltip l ex cu sto m  e xo m e  ca p t ur e co u p le d wit h d e e p -se q u e nci n g  fo r ge n es  t ha t a r e fr eq u e nt ly 
im p lic ate d  i n GI S T  p at h o g e n esis,  in clu d in g  KI T,  P D G F R A,  B R A F , N F 1,  E T V 1 , P T E N , N RA S,  H R A S, 
K R A S a n d  p 5 3  m u t atio n al st atu s. 
 
1 c. Tr a n scrip t om e  ch a ra cte riz ati o n of tu m o rs 
As  a n  e xp lo r ato r y st ud y , w e  will  p er fo rm  c usto m  tra n scrip to m e  a n a ly sis o f a c ust o m  E T V 1 - 
d e p e n d e nt  g e n e  sig n at u re  i n GI S T [2 5 ] i n F F P E  s am p l es fro m  all  p at ie nts  u sin g n a n o strin g , 
b ec a us e  E T V 1 p ro te i n le vel  is v e ry  u n st a ble.  
 
1 d . P h ar m a co d yn a mic s tu d i es b y IH C,  W B a n d  im m u n o flu or e sc en c e 
F F P E  t um o r  tiss u e  a n d  p re -a n d  p o st-tr eat m e nt  tu m o r  fro ze n  sa m p l es  fro m  t h e  first  2 0 
p ati e nts  will  b e  e v al u a te d f o r in h ib itio n  o f E T V 1 a n d  t arg et  p at h w ay  in h ib itio n  (M A P  kin a se , 
F G F,  a n d  KI T  p at h w a ys).  A  v ar ie ty  o f p a t h w a y m a rk e rs o f t h e M A P  ki n a se  a n d  K IT  p at h w ay s, 
in clu d in g  KI T,  p KI T,  p E R K 1 /2 , p A K T,  P T E N , p -S 6,  p 4 E -B P 1 , p F R S 2 , F R S2 , p P R A S4 0 , p S T A T 3  a n d 
S T A T 3  will  b e  e v al u at e d  b y  IH C.  E T V 1  p ro tei n  l ev els  will  als o  b e  e val u at e d  b y b o t h w e ste r n 
b lo t a n d im m u n o flu o res c en c e o f fro ze n tiss u e s, si nce  t h er e is n o  IH C  gr a d e  E T V 1  a n tib o d y . 
 
1 e.  P h a rm a co d yn a mic  stu d i es b y tra n scrip to m e  
W e  will  p er fo r m c usto m  tr an scrip to m e  a n al ys es o f th e  E T V 1 -d e p e n d e n t g e n e  sig n at u re  i n 
GI S T  i n p re - a n d p o st-tr e atm e nt  b io p si es  t o a ss ess th e  in h ib itio n o f t h e E T V 1  tra n scrip tio n al 
acti v ity  a n d  co rrel at e  w it h r es p on s e. 
 
1 f. P h e n o ty pic c h a n ges  i n p re - a n d  p o st-tre a tm e nt  tu m o rs by I H C  
I n a d d itio n  to  t h e IH C o f p K I T, p A K T ,p E R K 1 /2 , e tc as o u tlin e d  i n 1 d i n p re - a n d  p o st-tr e at me nt 
b io p si es, w e  will  e xp lo re  t h e r el atio n s hip  b e tw e e n t h e  im m u n o st ain s wit h  t h e eff e cts o n 
t um o r g ro w th  as  ass a y e d b y  t h e p ro lifer at io n  m a rker,  K i-6 7 , a n d  t h e a p o p to sis/c ell d e at h 
m ar ker,  cle a v e d c as p a se  3 . 
 
1 g . S te a d y st ate  p la sm a  im a ti nib  tro u g h  l ev els 
T h e  ac u t e a n d  ste a d y  sta t e im ati n i b l ev el  will  b e  ass ess e d  i n all  P h as e  I b p ati e n ts (o n e 
s am p le /tim e p o in t). P at ie n ts e nr oll e d  o n to  tr e atm e n t sc h ed u l e A  will  h a ve  a  p la sm a  sa m p l e 
fo r im ati n i b le v els  d r a w n a t C 1 D 2  a n d  C 1 D 2 1  b e fo r e im ati n i b is d o se d o n  th o s e d a y s. P ati e n ts 
e nr oll e d  o n t o tr e at me nt  sc h ed u l e B  will  h a v e  a  p l asm a  sa m p l e fo r im a tin i b l ev el  d r a w n at 
C 1 D 2 , C 1 D 7  a n d  C 1 D 2 1  b ef o r e im ati n i b is d o s e o n  t ho s e d a ys.  T h e  ste a d y  st at e im ati n i b 
tro u g h l e v e ls will b e  o b t ain e d a n d e val u at e d i n t h e  tw o -w e e k  im a tin i b l e a d i n p h as e  ( on e 
s am p le /p ati e n t) a n d  i n t h e co m b in ati o n  t h er ap y p h a se  ( on e  s am p le /p at ie nt)  fro m  all p a ti e nts 
i n t h e P h as e  II p o rtio n o f th e  tri al. W e will  e v al u a te  th e  eff e cts o f B GJ3 9 8  o n  im ati n i b ste a d y 
st at e tro u g h  le v els by  co m p ar i ng  th es e  t wo  p h as es.  
 
1 i. B GJ 3 9 8 p h ar m a co ki n e tic ass e ssm e nt  
B G J3 9 8  l ev els  will  b e  ass e ss e d i n all  P h as e  I b p ati e nts  (1  s am p le  p er  tim e p o in t). P ati e n ts 
e nr oll e d  o n to  tre a tm e nt  sch e d u l e A  will  h a v e  p l asm a  s am p l es fo r B G J3 9 8  le vels  co ll ecte d  at  


P a g e 5 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
C 1 D 1  at  0 , 1 , 2 , 4 , 6 , 8  h o u rs; C 1 D 2  2 4  h r tim e  p o in t; a n d  C 1 D 2 1  at  0 , 1 , 2 , 4 , 6 , 8  h o u rs. 
P ati e n ts e nr oll e d o n t o tr eat m e nt  sc h ed u l e B  will h a v e  p l asm a s a m p l es fo r  B GJ3 9 8  l ev e ls 
co ll ecte d  at  C 1 D 1  at  0 , 1 , 2 , 4 , 6 , 8 h o u rs; C 1 D 2  2 4  h r tim e  p o in t aft er  th e  first d o s e o f 
B G J3 9 8 & im ati n ib ; C 1 D 7  at  0 , 1 , 2 , 4 , 6 , 8  h o u rs; C 1 D 1 5  at  0  h o u rs a n d  C 1 D 2 1  a t 0  h o u rs. 
 
1 i. F GF 2  s eru m/ p l asm a  le vels by  E LIS A  
A c o m m e rci ally a v ai la b le  E LIS A kit  fo r s er um/ p l asm a  F G F 2  ( Bio a g ily tix) will  b e  e v al u at e d i n all 
p ati e nts  at  b as eli n e , wit h  t h e in iti atio n  o f im a tin ib , aft er  im a tin i b l e a d i n a n d  s eri all y, af ter 
t h e  in iti atio n  o f  co m b in ati o n  t h er ap y .  F G F 2  le vels  will  b e  co rrel a te d  t o  p ri m ar y  a n d 
s ec on d a ry o u tco m es.  
 
2 .   S a m pl e col le ctio n s pr e - a n d  d u rin g  tre a t me n t 
2 a.  A rc hiv al  b io p sy FF P E  sa m p les  ( as a v ai la b l e, ~ 2 5  u n st ain e d  F FP E  se ctio n s o f st a nd ar d  5  µ m 
slid es,  O R  1 0 -2 0  u n st ain e d  F F P E  se ctio n s o f 1 0  µ m  slid es)  
2 b . F ro ze n p re -tre a tm e nt  co r e b io p sy sa m p le s (u p  to  fiv e  co r es) 
2 c. F ro ze n 1  w e e k  p o st-co m b in ati o n  tre a tm e nt  bi o p sy  sa m p l es ( u p to  fiv e  co r es) 
2 d . F ro ze n p o st-tre a tm e nt b io p s y o r s urg ic al sa m p l es at  d is e as e p ro g r essio n  (if p o ssib l e) 
2 e . W h o l e b lo o d  fo r r ese arc h  p u rp o s es. T h e se  sa m p l es will  p o ssib l y b e  u s e d fo r se ru m  F G F 2 
l ev els  a n d  scr e en in g  fo r o th er  p o te nti al  so lu b l e p ro tei n  b io m ar kers,  e tc. p re -tre a tm e nt 
a n d  1  o r 2 w e e k s aft e r tre a tm e n t a n d  p er io d ic ally, d a y  1  o f e ac h  cy cl e. 
 
3 .   Im a g in g  b a se d  co rre la tiv e  stu d ie s: 
F D G  P E T  p er  sta n d ar d  o f car e  will  b e o b t ain e d  p re -tre a tm e nt  a n d  t hre e  w e e k s (C 1 D 2 1 ) aft er 
in iti atio n o f t h e co m b in e d  im ati n i b a n d  B G J3 9 8  tre at m e nt  i n t h e P h as e  II p o rtio n . T h e se 
im a g es  will  b e  e v al u at e d  t o  d e te rm in e  w h e t h er  th e  F D G  P E T  st ud ie s  c a n  b e  u s e d  t o 
d e te rm in e  a n d  pr e d ict tre a tm e n t r esp o n s e. 
 
4 .   Im ati n ib  Le v e ls: 
As  im a tin i b is st a nd ar d o f c ar e fo r p ati e nts  wit h  u n tr e ate d  in o p er a b le  lo c all y ad v a n c e d o r 
m e tast at ic GI S T,  im a tin i b le v els  will b e  tes te d  to  e n su r e t h at B GJ3 9 8  d o e s n o t a ff ect im ati n i b 
s er u m le vels.  I n P h as e  Ib , im ati n i b l evels  will b e  te ste d o n C 1 D 2  (2 4  h o u r tim e p o in t aft er  th e 
first d o s e o f im a tin ib & B G J3 9 8 ) a n d  C 1 D 2 1  ( prio r to  d o sin g  o n  t h at d a y)  o n  b o t h tr ea tm e nt 
sc h ed u l es ( A a n d  B).  I n p h as e  Ib , o n  sc h ed u l e B,  im ati n i b l evel  will  als o  b e  te ste d  o n  C 1 D 7 
( prio r t o d o sin g o n t h at  d a y ). A ll p artici p a n ts o n t h e  P h as e  II p o rtio n will  u n d er g o  a  2 -w e e k 
l e a d i n o f sin g l e a g e nt  im ati n i b i n o rd er  t o e st a blish  a  ste a d y -st ate  s eru m  im ati n i b tro u g h 
l ev el.  Im ati n i b  l ev els  will  b e  r ec h eck e d  d u rin g  w e e k  3  a n d  w e e k  5  o f  th e  co m b in at io n 
t h er ap y . W e  will  co rrel a te  im a tin i b l ev els  to  p rim ar y  a n d  s eco n d ar y o u tco m e m e a s ures. 
I m atin i b le vels  w ill b e stra tifi e d i nt o q u artil es  a s do n e  p r ev io u sly [3 1 ]. 
5 . FG F 2  S e ru m  Le v e ls: 
P r eclin ic al d at a  s ug g es ts th at  F G F 2  le v els  m a y  co rre l at e wit h t h e  d e v e lo p m e n t o f im ati n i b 
r esist a nce  a n d  m a y p r e dict r es p on se  to  in h ib itio n w it h B G J3 9 8 . B lo o d  will  b e  co ll ecte d  at 
b as eli n e  (if n o t o n  im ati n ib ), aft er  t h e im a tin i b l e ad -in , a n d  d u rin g  w e e k  3  a n d  5  o f t h e 
co m b in ati o n  th er a p y . W e will  co rrel at e  F G F2  le v els  to  o u r p rim ary  a n d  se co n d a r y e n d p o in ts 
wit h  th e  h o p e  o f  e st a blis hin g  a n  in te g r al  b io m a r k er  fo r  B G J3 9 8  a n d  e val u ati n g  t h e 
p e n e tr an c e o f th e  FG F p a th w a y  i n GI S T.  If co lle cte d  b lo o d  s pe cim e n  is o n l y a d e q u at e  fo r 1 
ass a y,  im ati n i b le v els s h o u l d b e  p ri oritize d.  


P a g e 6 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
P l e ase  r efer e n ce  t h e l ab o rat o ry m a n u al f o r i nstru ctio n s o n  sa m p l e la b eli n g  a n d  sh ip p in g . 
 
1 1. 0     T O XI C I TIE S/ S ID E  E F F E C T S  
 
T o xicity gr a d in g  w ill b e p e rfo rm e d i n  a cco rd a n ce  w it h N CI C T C  vers io n  4 .0 3 , 
(h ttp ://cte p .c an cer. g o v/ p ro to co lD e v e lo p m e n t/el e ctro n ic _ a pp lic atio n s/ctc.h tm ). 
 
A d v ers e  e v e nt  ( A E) m o n ito rin g  a n d  re p o rtin g  is a  ro u tin e  p art  o f e v e ry  clin ic al tria l.  T h e  fo llo wi n g  list 
o f A Es (S e ctio n  1 1 .1 ) a n d  th e  c ha r acteristics  o f a n  o b ser v e d  A E (S e ctio n  1 1 . 2) will  d et e rm in e  w h et h er 
t h e e v e nt  re q u ir es e xp e d ite d r e p o rtin g  in  a d d itio n to  ro u tin e  re p o rtin g . 
 
1 1. 1     A d v e rs e E v e n ts 
1 1 .1 .1   Im a tin ib  M e syl a t e 
 
S e e  th e  p ac k a ge  in s ert fo r co m p l ete  list o f p o ssib l e a d ver se  e v e nts  re la te d  to  im a tin ib : 
 
T h e  m a jo rity  o f im ati n ib -tr e ate d p ati e n ts e xp er ie n ce d A Es at  so m e  tim e.  A p p ro xim a te ly  6 0 %  o f 
p ati e nts  re p o rte d  at  le ast  o n e  g r ad e  3 /4  A E  a t so m e  tim e  d u rin g  t h e  st ud y , a n d  im ati n i b w a s 
d isco n tin u e d  d u e  t o A Es  in  1 8  p at ie nts.  T h e m o st fr eq u e ntl y  re p o rte d  A Es w er e  e d e m a , n a u s e a, 
d i arrh e a,  a b d o m in al  p ai n , m u scl e cr am p s, f atig u e,  a n d  r ash , m o st o f w hic h  w er e  o f m il d-to -m o d er a te 
s ev erit y .  Im ati n i b w as  d isco n tin u e d  fo r A Es  i n 7  p ati e n ts (5 %)  i n b o t h d o se  le ve ls (4 0 0  a n d  8 0 0  m g /d ) 
st ud i ed .   S u p erfici al  e d e m a, m o st fre q u e ntly  p er io rb it al o r lo w e r e xtre m ity, w a s m a n a g e d  w it h 
d iu r etics, o th er  s up p o rtiv e  m e as u res,  o r b y  r e du cin g  t h e d o s e o f im a tin ib .  S e v e re  (N C I-C T C A E  Gr a d e  
3 /4 ) s up erfici al  e d e m a  w a s o b s erve d  i n 3  p ati e n ts (2 % ), in clu d in g  f aci al e d e m a  i n 1  p ati e nt.  G ra d e  
3 /4  p l eu r al eff us io n  o r asc ite s w as  o b ser v e d  i n 3  p ati e nts  (2 % ).  N in e  (6 %)  p ati e n ts (6 0 0  m g /d  ( n= 6 ); 
4 0 0  m g /d  ( n= 3 )) w e re  r ep o rt e d t o h a v e  g r ad e  3 /4  G I o r in tra -tu m o r al h e m o rrh a g e  d u rin g  t h e st ud y 
( GI b l e e din g ( n = 5 ); in tr atu m o ral  b l e e din g ( n = 3 ); b o th GI  a n d i n tr at um o r al b le e d i ng ( n = 1 ).  T h e  GI 
lo c alizat io n  o f t h e tu m o r li ke l y co n trib u te d  t o t his A E  i n t his p ati e nt  p o p u l atio n . N o n e  o f t he s e 
p ati e nts  h a d t hr o m b o cyto p e n ia  at  t h e tim e  o f h e m o rrh a g e.  T h e  sm all  n u m b e r o f e v e nts  a n d  t h e 
v ar ia b ility i n b a seli n e  clin ic al p ro files  p recl u d e  co n clu sio n s to  ai d  t h e id e ntif icati o n o f p ati e nts  at 
in cr e ase d  risk o f h e m o rrh a g e  d u rin g  th er a p y wit h im a tin ib . 
 
T a b le 1 2 : A d v e rs e e v e n ts g re a t er th a n  o r e q u a l to  1 0 % o f pa tie n ts w it h im ati n ib  tre a t me n t in  G IS T  
 
 
 
A ll C T C  G ra d e s  
 C T C 
G ra d e s  3  
/ 4  
 
 
4 0 0  m g  
( N =7 3 ) 
6 0 0  m g  
( N =7 4 ) 
4 0 0  m g  
( N =7 3 ) 
6 0 0  m g  
( N =7 4 ) 
Pr ef e rre d  T e rm  
n  (% ) 
n  (% ) 
n  (% ) 
n  (% ) 
F l uid  re te n tio n  
8 1  
8 0 (9 3 .2 ) 
7  
1 2  
S u p e rfici a l e d e m a  
8 1  
7 7  
6  
5  
P l e ura l e ffu s io n  o r A s ci te s  
1 5  
1 2  
3  
8  
Di a rrh e a  
5 9  
7 0  
3  
7  
N a u s e a  
6 3  
7 4  
6  
4  


P a g e 6 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
 
 
  
I R B# : 1 4 -1 4 0  A  (7 ) 
A ll C T C  G ra d e s  
 C T C 
G ra d e s  3  
/ 4  
F a tig u e  
4 8  
5 3  
1  
1  
M u s cl e  Cr a m p s  
4 7  
5 8  
 0  
0 
a b d o mi n a l P a in  
4 0  
3 7  
1 1  
4  
R a s h  a n d  re l ate d  t erm  
3 8  
5 3  
4  
3  
V o mi ti ng  
3 8  
3 5  
3  
5  
M u s c ul o s k e le ta l Pai n  
3 7  
3 0  
6  
1  
H e a d a c h e  
3 3  
3 9  
0  
0  
F l atu l en c e  
3 0  
3 4  
0  
0  
A n y  H e m o rrh a g e  
2 6  
3 4  
6  
1 1  
P y re x ia  
2 5  
1 6  
3  
0  
B a c k  P ai n  
2 3  
3 6  
6  
0  
N a s o p h a ry n gi tis  
2 1  
2 7  
0  
0  
In s o m n ia  
1 9  
1 8  
1  
0  
L a c rim a ti on  In c re a s e d  
1 6  
1 8  
0  
0  
D y s p e p s ia  
1 5  
1 5  
0  
0  
U p p e r re s pi ra to r y tra c t in fe c tio n  
1 4  
1 8  
0  
0  
Li v e r T o x i cit y 
1 2  
1 2  
6  
8  
Di z z i n e ss  
1 2  
1 1  
0  
0  
*A ll a d v er s e  e v e nt s  o c c ur rin g  in ≥ 1 0 %  of p a tie n t s r eg ar d le s s  of  s u s p e c t e d 
re la tio n s h ip  t o tre at m e n t 
 
 
A ls o re p o rt e d o n  Im a tin ib  M e syl a t e (S T I5 7 1 ) trial s b u t w it h th e  re la tio n sh ip  to  Im ati ni b  M e syl a t e 
(S T I5 7 1  still u n d e t er min e d : 
 
B L OO D  A N D LY M P H A T IC  SY S T E M D IS O R D E R S  - D isse m in at e d  in tr av a sc ular co a gu l atio n ; Fe br il e 
n e utr o p e n ia  
 
C A R D IA C  D IS O R D E R S  - C a rd i ac arr est; H e a rt f ailu re ; M y o c ard i al i nfar ctio n ; V e n tricu l ar arr h y th m i a 
 
E N D O C R I NE  D IS O R D E R S  - H y p o th y ro id ism  
 
E Y E  D IS O R D E R S - Bl u rr e d v isio n ; C o n ju n ctiv itis; P a p ille d e m a ; P h o to p h o b ia ; W a te rin g  e y es  
 
G A S T R O IN T E S T IN AL  D IS O R D E R S  - A b d o m in al d iste ns io n ; D u o d e n al  p er fo r atio n ; Es o p h a g e al fi st ula; 
Es o p h a g itis; G astr itis; G ast ro in te stin al u lc er4; Ile us;  P a n cr e atitis 
 
G E N E R AL  D IS O R D E R S A N D  A D MI N IS T R A T IO N  SI T E  C O N D I TIO N S  - F lu  lik e  sy m p to m s; G e n e ral 
d iso rd ers  a n d  a d m in istra tio n  site  co n d itio n s - Ot h er  (G u ill ain -B ar re  sy n d ro m e ); N o n -c ard i ac c he st 
p ai n  
 
H E P A T O B ILIA R Y  D IS O R D E R S  - H e p atic f ail u r e 
 
IM M U N E  S Y S T E M  D IS O R D E R S  - A ll erg ic re ac tio n ; A u to im m u n e  d iso rd er  


P a g e 6 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
I NV E S T IG A TI O N S  - C P K  in cre as e d ; G G T  i ncr e ase d;  Lip a s e in cr e ase d;  W e ig h t lo ss 
 
M E T A B O LIS M  A N D  N U T R ITI O N  D IS O R D E R S  - H y p er calc e m ia ; H y p er g ly c em i a; H yp o al b u m in e m ia ; 
H y p o c alc em i a; H yp o g lyce m i a; Hy p o m a g n e se m i a 
 
M U S C UL O S K EL E T AL  A N D  C O N N E C TI V E  T IS S U E D IS O R D E R S  - A v asc u lar n e cro sis; B ac k  p ai n ; B o n e 
p ai n ; G e n er ali ze d  m u scl e w e a k n es s; P ai n  i n e xtre m ity 
 
N E R V O U S  S Y ST E M D IS O R D E R S  - D e pr es se d l e v el  o f co n scio u s n ess; D y sge usi a ; E nc e p h al o p at h y ; 
H y d ro ce p h al u s; In tr acra n i al h em o rrh a g e ; Isc he m i a c ere br o v asc u lar;  P eri p h er al  m o to r n eu ro p at h y; 
P eri p h er al  s e nso r y n e ur o p at hy;  Seiz u r e; Tr e m o r 
 
P S Y C H IA T R IC  D IS O R D E R S  - A n xi ety ; C o n fu sio n ; D e pr e ssio n ; In so m n i a 
 
R E N AL  A N D U R IN A R Y  D IS O R D E R S  - A c ut e ki d n ey  i nju ry; H e m a t uria;  P ro te in u ria;  R e n al  a n d  ur i nary 
d iso rd ers  - Ot h er  (ki d n e y  sto n es)  
 
R E P R O D U C TI V E  S Y S T E M  A N D  B R E A S T  D IS O R D E R S  - Irr e gu l ar m e nstr u at io n  
 
R E S P IR A T O R Y , T H O R A C IC  A N D  M E D IA S T IN AL  D IS O R D E R S  - A d u lt res pi ra to r y d istre ss sy n d ro m e; 
A ll erg ic rh in itis; H y p o xi a; P h ar y n g o l ary n g e al p ai n ; P n e u m o n itis; P u lm o n a ry  hy p e rte n sio n ; R e s pir ato ry 
h e m o rrh a g e 5; V o ic e alt e ra tio n  
 
S K IN  A N D  S U B C U T A N E O U S  TI S S U E D IS O R D E R S  - D r y skin ; P u rp u r a 
 
V A S C UL A R  D IS O R D E R S - H y p o te nsi o n ; T h ro m b o e m b o lic e ve nt;  V asc u litis 
 
N o t e: Im ati n i b M e sy l at e (STI 5 7 1 ) i n co m b in at io n  w it h o t h er a g e nts  co u l d c au se  a n  e x acer b a tio n  o f an y 
a d vers e  e ve nt cu rre nt ly  k n o w n to  b e  c au se d by  t h e oth er  a g e n t, o r th e  co m b in ati o n  m ay  re s ult i n 
e v e n ts ne v er  p re v io u sly as so ci ate d wit h  e ith er  a g e n t. 
 
1 1 .1 .2   B G J3 9 8  
 
1 1 . 1.2 . 1 Ad v er se  E v e nts,  D o s e Lim itin g  T o xiciti es, a n d R e as o n s fo r D isco n tin u at io n  o f B GJ3 9 8  
 
F ro m  2 1  D e ce m b er  2 0 0 9  t o 2 4  S e p te m b er  2 0 1 3  ( da t a c uto ff da te ), 9 4  p ati e n ts re c eiv e d at  le ast  o n e 
d o s e o f B G J3 9 8  i n t h e clin ical st u d y  C B G J3 9 8 X 2 1 0 1  a n d  ar e i ncl u d e d  i n th e  c urre n t s af ety  se t. Th e 
m o st co m m o n  a d v er se  e v e n ts o f all s e ver it y gr a d es  (C T C A E  v . 3.0 .) s usp e cte d  to  b e  r el ate d  to  B G J3 9 8 
( T a ble  1 3 , b el o w),  w e re  hy p er p h o s ph at e m i a (7 1 % ), d ecr e a se d a p p e tite  (2 7 % ), fa ti gu e  (2 6 % ), 
sto m atit is (2 5 % ), a n d a lo p e ci a (2 1 % ). All o t h er ad ver se  e v e nts  w e r e re p o rt e d i n le ss th a n  2 0 %  o f 
p ati e nts. O v er all,  m o st a dv ers e  e v e nts  re p o rte d h a ve  b e e n  m il d to  m o d e rat e  i n se v er ity . T w e n ty -six 
(2 7 .7 %)  p ati e nts  e xp eri e n ce d at  le ast  o n e  g r ad e  3  o r 4  e v e nt s u s pe cte d  t o b e  rel a te d  to  B G J3 9 8 . 
 
As o f 2 3  S e p te m b er  2 0 1 3 , fo u r D LTs  h a ve  b e e n  re p o rte d i n  C y cle  1  d u rin g  d o se  e sc al atio n . O n e gr a d e  
3  e ve nt  o f A S T /A LT  el e v at io n  w as  re p o rt e d i n th e  1 0 0 m g  co h o rt. I n th e  1 2 5 m g  co h o rt, o n e  p at ie nt 
e xp eri e n ce d hy p er p h o s ph a te m i a fo r gr e a ter  t h a n 1 4  d a ys  d es p ite  a d e q u a te  th er a p y  th at  res ult e d  i n 
st ud y  dr u g  i nt erru p tio n . I n t h e 1 5 0 m g  co h o rt, o n e  p at ie nt e a c h exp eri e nc e d  g r ad e  1  co rn e al to xicit y 
a n d  gr a d e  3  A ST /A LT  e le v a tio n s, th e  l atter  le a d in g  to  st ud y  tre a tm e nt i n terr u p tio n  a n d  d o s e 
r e du ctio n . Ele v e n  o t h er D LTs  o cc urre d i n  6  p at ie nts  e n ro ll e d i n th e  first o f tw o  d o s e e xp a n sio n 
co h o rts rec e iv in g  B GJ 3 9 8  1 2 5  m g  d a ily , co n tin u o u s sch e d u l e. Fiv e  p a ti e nts e x pe ri en c e d 


P a g e 6 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
h y p er p h o s ph a te m i a th at  re q u ir e d disco n tin u at io n  o f st ud y  dr u g  d es p it e o p tim al  p ro p h y l actic 
tr e atm e nt  w it h ph o s ph at e  b in d ers  a n d  di et ar y  p h o s ph at e  re strictio n s. Th e  sixt h p ati e nt  e xp eri e n ce d 
Gr a d e  3  i ncr e ases  i n A S T  a n d  AL T.  
 
At t h e  tim e  o f d at a cu to ff, 0  o f 1 8  p at ie nts  rec e iv in g  1 2 5  m g  d a ily  3  w e e ks  o n , 1  w e e k  o ff ha d 
e xp eri e n ce d a  D LT.  
 
As o f 2 3  S e pt e m b er  2 0 1 3 , a m o n g  th e 9 4  p ati e nts  e n ro ll e d o n  th e  stu d y  a n d  a v a il ab l e fo r a n a ly sis, 1 2 
p ati e nts a re  still r ecei v in g  st ud y m e d ic atio n . Of t h e 8 2  p ati e nts  w h o  di sco n tin u e d  tr e atm e n t, 5 6 
(6 8 %)  di d  so  fo r pro g r essio n  o f dis ea s e. T e n  p at ie nts  (1 0 .6 %)  di sco n tin u e d  tr eat m e nt  d u e  to  a d ver se 
e v e n ts, in clu d in g p eri p h er a l n eu ro p at h y  (5 m g  d o s e le vel ), pu lm o n ar y  e m b o lism  (1 0 m g  d o s e le vel), 
g al l bl ad d er  r em o v al (2 0 m g), p u n ct ate  co rn e al  e p it h elio p at hy  (6 0 m g  d o se  le v el ), cu t a n eo u s lesi o n 
g ro w th  (1 0 0 m g  d o s e le v el)  a n d  bi lat e r al re tin al d e ta c h m e nt (1 0 0 m g  d o s e le vel).  N eit h er th e  re tin al 
d e tac h m e nt n o r th e  p u n ctat e  co rn e al  e p ith el io p at hy  w as  co n sid er e d  a  DL T  si nc e th e y  o cc urr e d afte r 
t h e first cy cl e o f th er a p y . T w o  p a ti e nts di e d  w h il e o n  st ud y , b o t h du e  to  di se as e  pr o g r essio n . T w e lv e  
p ati e nts dis co n tin u e d d u e  to  w it hd r a w al o f co n s en t, o n e  p ati e nt d u e  to  a d m in istrati v e  pr o b le m s, a n d 
o n e  p at ie nt d u e  t o pr o to co l d ev i atio n . 
 
As o f t h e d at a cu to ff da te,  6 7 e ve nts  o f h y p er p h o s ph a te m i a a m o n g  2 5  p ati e nts  w er e  re p o rte d at 
d o s e le vels gr e a te r t h a n 6 0 m g . T w e n ty  o f th es e  e v e n ts l e d to  st ud y  dr u g  i nt erru p tio n /d o s e 
r e du ctio n . P h o s ph a t e bi n d in g  th er a p y w as  a d m in iste re d f o r 3 8  o f th e se  e ve n ts. T h e  e v e nts  o f 
h y p er p h o s ph a te m i a w e re  re v e rsib l e fo llo wi n g  stu d y  tre a tm e nt i n terr u p tio n  a n d  in stit utio n  o f 
p h o s ph at e  bi n d in g  th er a p y. M o st o f th es e  e v e nts  w e re  s usp e cte d  to  b e  re la te d  to  st ud y  tre a tm e nt. 
N o  clin ic al ad v er se  e v e n ts w e r e as so ci ate d wit h  t h ese  e v e nts.  
 
A lt ho u g h  o cc asio n al  n o n -d o se -rel at e d  i ncre as e s fro m  b as eli n e  w er e  o b s erve d  i n E C G i nt e rv al 
p ar a m e ters,  in clu d in g  Q T c, n o  a d vers e  e ve nts  w e re  a sso ci ate d w it h t h ese  E C G fi n d in g s. N o  clin ic all y 
sig n ific an t fin d in g s o f Q T  p ro lo n g at io n  h a ve  b e e n  o b se rv e d to  d a te . M o n ito rin g  o f b o t h p o te n tial Q T - 
p ro lo n g at io n  a n d  l eft v e nt ricu l ar f un ctio n  a re  o n g o in g  a m o n g  th e  p at ie nts  e nr ol le d  i n t h e e x p an sio n 
co h o rts o f C B G J3 9 8 X 2 1 0 1 . 
 
1 1 . 1.2 . 2 S eri o u s A d v e rs e E ve nts  
 
As o f 2 3  S e p te m b er  2 0 1 3 , 4 6  ser io u s a dvers e  e ve nts  h a v e  b e e n r e p o rte d  ( T a ble  1 4 , b el o w ), i n 2 8 
p ati e nts  o n  stu d y C B G J3 9 8 X 2 1 0 1 . Se ve nt e e n s e ri o us a d v ers e  e v e nts  i n 9  p a ti e nts w e r e r e po rt e d t o 
b e  s usp ec te d to  B G J3 9 8  ( Ta b l e 1 5 , b elo w ). 
 
S ix e v e nts w e r e r e po rt e d a s s usp ec te d,  u n e xp e cte d , seri o u s a d ver se  r ea ctio n s (SU S A Rs)  a n d  r es ulte d 
i n  t h e  d istrib u tio n  o f  In v es tig a to r  N o tific atio n s.  T h es e  e ve nts  in clu d e  t wo  e v e n ts  o f  c ard i ac 
d y sfu n ctio n  wit h  left  v e nt ricu l ar ej e ctio n  fr actio n  (LV E F)  d ecr e as e s, a n d  o n e  e ve nt  e ac h  o f g r ad e  1 
r ev e rsib l e ac u t e re n al  in ju r y, g r ad e  4  h e p at ic f ailu r e 6 m o n t hs a fte r l ast d o s e o f d ru g , g r ad e  3 
h y p erc al ce m i a, a n d  gr a d e  4  hy p o p h o s ph a te m i a a n d  h yp o c alc ae m i a. 
 
T h e  e ve n ts o f c ard i ac d y sfu n ctio n  w it h LV E F  d ec re a se  o cc urre d  in t w o  d iffer e n t m al e  p at ie nts  wit h 
a d v a n c e d lu n g  S CC . T h e  first p ati e nt,  w h o  r ecei ve d  1 0 0  m g  q d  o f B G J3 9 8 , ex peri e nc e d  a  >  2 0 % 
d ecr e a se  i n LV E F  (6 6 %  to  4 2 %)  aft er r e cei v in g  B G J3 9 8  fo r ap p ro xim a tel y  1 0  m o n t hs. Ass o ci at e d wit h 
t his d ecr e a s e we r e l eft v e n tricu l ar t hro m b u s a n d  b il ater al  p l eu r al eff us io n s. T h e p ati e nt  d isco n tin u e d 
st ud y  tre a tm e nt six  d a y s la te r d u e t o p ro g r essive  d ise as e.  T h e s e co n d  p ati e n t, e n ro ll e d to  th e  1 2 5 m g 
q d  d o s e e xp a n sio n  co h o rt, e xp eri e n ce d  a  g r ad e  3  d e cr e as e i n LV E F  ( > 2 0 %  d e cr e as e fro m  b a seli n e ; 
7 3 %  t o 5 3 % ) aft er  a p p ro xim a tel y  3  m o n t hs o f st ud y  dr u g . D ru g  a d m in istr atio n  w as  in te rru p te d  fo r 1 4  


P a g e 6 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
d a ys  fo llo wi n g  t his e v e nt.  D u e  t o im p ro v e m e nt  i n LV E F  t o 5 8 %,  B G J3 9 8  w as  r est arte d  at  1 0 0 m g  q d 
a n d  LV E F  r et urn e d  to  b a s elin e  (7 1 %)  a p p ro xim a te ly 2  m o n t hs l at er. T h e p ati e n t d isco n tin u e d  st ud y 
t hr e e w e e ks  la te r du e  to  p ro g r essive  d ise as e . 
 
M o re  r ece ntly, t h e  first p a ti e nt e n ro ll e d o n t h is clin ical  tri al d e v e lo p e d  a  seri o u s u n e xp ec te d  S A E,  a 
Gr a d e  3  N o n -S T El e v at io n M I (N S T E M I) o n D a y  7  wi th  co n co m it an t G ra d e  4  C P K  el e v at io n  o n  D a y  6 . 
T h e p ati e nt  is a 6 4  y e a r o ld g e ntl e m a n , fo rm er  sm o ker  wit h H T N a n d d i ab e tes  m ellit us T y p e  II, wit h 
p ro g r essiv e  GI S T  w h o  h a d p ro g r esse d o n  im ati n i b a n d  s un itin i b a n d  w as  r ece iv in g  im ati n i b 4 0 0  m g 
d ai ly  p lu s B G J3 9 8  7 5 m g  d ai ly , 3  w e e ks  o n  / 1  w e e k  o ff. H e m o g lo b i n at  scre e n in g  w as  1 2 . 8 g /d L a n d 
h a d  d ecr e as e d  to  9 . 5 o n  D a y  1  ( pre -tre a tm e n t) a n d  9 . 0 g /d L o n  D a y 2 . T h er e w as n o  h e m a to ch ezi a  o r 
o t h er sig n s o f b l e e din g . B y  D a y  5 , t h e p at ie nt  h a d w o rse n i ng  f atig u e  a n d  d y sp n e a  o n  e xe rtio n ; i n 
r etro s p ect, t h e p ati e nt  h a d  e xp eri e n ce d  sim il ar sy m p to m s w hi le  o n  s un itin ib . O n  D a y  6 , N o v e m b er  
1 8 , 2 0 1 4 , t h e he m o g lo b i n w as  8 . 6 a n d  th e  p ati e nt w a s tr an sfu s e d 2 u n its o f P R B Cs. C P K  w as  2 0 1 1  U /L 
(3 8 -1 7 4 ). E K G  s ho w e d  n o rm al  sin u s rh y th m , n e w  T  w a v e  inv ers io n  i n V 1 -V 4, T w a v e  fla tte n i ng  i n V 5. 
C alc i um  w as  n o rm al a n d  p h o s ph o ru s gr ad e  1  ( 4.9  m g/d l (2 .5 -4 .2  m g /d l)). 
 
T h e  p ati e nt  w as  h o s pit alize d  o n  D a y  7 , N o v e m b er  1 9 , 2 0 1 4  a n d  w as  d i ag n o s e d w it h g r ad e  3  N S T E MI. 
C ar d i ac e nzym e s w er e  el e vat e d ( T ro p o n i n I 1 .6 7  n g /m l (0 -0 .6 4  n g/ m l)), E C G  sh o w e d fl a tte n i ng i n V 4, 
co n tin u e d  T WI  i n V 1 -V 3 ; u n st a ble  b as eli n e  i n III l e ad in g  t o iso l at e d 1  m m  S T  el e v a tio n . H e  w as 
tr e ate d  m e d ic ally wit h  h e p ar in  A S A,  P l avix, b e ta  b lo cker,  sta tin s a n d  w as  tra n sfu s e d wit h  2  u n its 
P R B C.  Ec h o c ard io g r a m sh o w e d  a  st a ble  e jec tio n  fracti o n  w it ho u t w all m o tio n  a b n o rm al ities,  a n d 
st a ble  a p p e ar a n ce  o f co n ce n tric l eft ve ntric u l ar hy p er tro p h y  a n d  m il d di a sto lic d ysfu n ctio n . 
 
T h e  p ati e n t w a s ta k e n o ff st ud y fo r S A E  o n D a y  7 ; la st d o se  o f im ati n ib  w as  o n  th e  e v e n i ng  o f D a y 6 
a n d  l ast d o s e o f B G J3 9 8  w as  m o rn in g  o f D ay  7 . T h e  p ati e nt  w as  d isch ar g e d  o n N o v e m b er  2 2 , 2 0 1 4 . 
T h e  e v e nt  w as  co n sid e re d  p o ssib ly rel at e d t o  im a tin i b a n d  B G J3 9 8  d u e  to  th e  te m p o r al as so cia tio n 
b e tw e e n  sy m p to m s a n d  a d m in istr atio n  o f st ud y d ru g s b al a n c e d a g ai n st th e  h isto r y o f st a ble  a n g in a 
o n  s un itin ib . 
 
1 1 . 1.2 . 3 D e at h s o n  St u d y  C B G J3 9 8 X 2 1 0 1  
 
T w o  p a ti e nts, b o t h wit h  a d v a n c e d lu n g  S C C , d i e d w hi le  t a ki n g B G J3 9 8 . O n e p ati e n t w h o  w as  e n ro ll e d 
t o t h e 5 0  m g  b i d d o se  e sc al atio n c o h o rt d i e d at  h o m e  o n C 2 D 5 . T h e  d e a th w as  as ses se d  b y  t h e 
in v es tig a to r as d u e  t o u n d erl yi n g  d is e ase  a n d  n o t r elat e d  to  st ud y m e d icati o n . T h e  se co n d  p a ti e nt, 
e nr oll e d  to  t h e 1 2 5  m g  d o s e e xp a n sio n  co h o rt, w as  d i ag n o s e d wit h  p n e u m o g e n ic s e psis o n  C 1 D 2 7 
a n d  w as  h o sp it alize d  o n  t h e s am e  d ay.  St u d y m e d icat io n  w as  in te rru p te d  o n  C 1 D 2 8  a n d  t h e p ati e nt 
d i e d o n  C 2 D 1 . Th e  e v e nt  w as ass e ss e d as n o t re l ate d to  B G J3 9 8 . 
 
T w o  p ati e nts d i e d w it hin  2 8  d ays o f t h eir l ast d o se o f B GJ3 9 8 . O n e  p a ti e nt wit h sq u a m o u s c arcin o m a 
o f u n k n o w n  o rig i n w as  e n ro ll e d to  th e  d o se  e xp a n sio n  p art  o f t h e st ud y  (1 2 5  m g  q d , co n tin u o u sly) 
a n d  r ece ive d  st ud y  m e d icati o n  fo r 1 5  w e e k s b ef o re  d isco n tin u in g  tr e atm e n t d u e  to  p ro g ress iv e 
d is e as e. T h e  p at ie nt  d i e d fo u r d a ys  l at er d u e  to  p ro gr essio n  o f d ise as e . T h e  d e at h  w as  ass e ss e d as 
n o t rel at e d  to  st ud y  m e d icati o n . T h e  sec o n d  p ati e nt wit h  lu n g  S C C  w as  e nr ol le d  t o t h e 1 2 5  m g  d o se 
es cal a tio n  co h o rt.  A d m in istr atio n  o f  B G J3 9 8  w as  d isco n tin u e d  o n  w e e k  1 3  d u e  t o  p ro g ressi ve 
d is e as e.  Ei g h te e n  d a ys  a fte r  st ud y  d ru g  w as  d isco n tin u e d,  t h e  p at ie nt  d i e d  d u e  t o  d is e ase 
p ro g r essio n . T h e d e at h  w a s asse sse d as n o t re l ate d to  stu d y  m e d ica tio n . 


P a g e 6 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
T a b le 1 3: Tr e a t me n t em e r ge n t a d v er s e e ve n ts s us p ect e d t o b e  dr u g  r el at ed, b y pr ef e rre d t er m a n d 
tre a t me n t gr o u p  
 
 
 


P a g e 6 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
T a b le  1 3 , co n t.: T re a t me n t e m e rg e n t a d v e rs e e v e n ts su sp e ct e d t o b e  dr u g  re la te d , b y  pr ef e rre d 
t er m a n d  tre a tm e n t g ro u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T a b le 1 4 : S e rio u s a d v e rs e e v e n ts b y  pr ef e rre d  t er m a n d  tre a t me n t g ro u p , re g a rd le ss o f re la tio n sh ip  
    t o B G J3 9 8  
 
 
 
 
P re fe rre d  te rm  
 
1 0  m g  
N = 3 
n  (% ) 
 
4 0  m g  
N = 6 
n  (% ) 
1 0 0 
m g 
N = 6  
n  (% ) 
 
1 2 5  m g  
N = 4  
1  n  
1 5 0 
m g 
N = 6  
n  (% ) 
5 0 m g 
B ID 
N = 4  
n  (% ) 
3  w k s 
o n  
1  w k 
o ff 
A ll 
p a tie n ts 
N = 9 4  
n  (% ) 
P a tie n ts  w ith  a t le a s t 
o n e  A E  
1 (3 3 .3)  
1 (1 6 .7)  
2 (3 3 .3)  
1 6 (3 9 .0)  3 (5 0 .0)  
1 (2 5 .0)  
4 (2 2 .2)  
2 8 (2 9 .8)  


P a g e 6 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
G e n e ra l p h y s ic a l 
h e a lth  d e te ri ora ti o n 
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
3 (7 .3)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
3 (3 .2)  
P n e u m o n ia  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
2 (4 .9)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
3 (3 .2)  
D y s p n o e a  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
2 (2 .1)  
F a tig u e  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 ( 0 .0 ) 
1 (2 5 .0)  
0 (0 .0)  
2 (2 .1)  
In fe c tio n  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
2 (4 .9)  
0 ( 0 .0 ) 
0 (0 .0)  
0 (0 .0)  
2 (2 .1)  
A c c id e n ta l o v e rd o s e  
0 (0 .0)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
0 ( 0 .0 ) 
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
A d re n a l in s u ffic ie n c y  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
A n xie ty  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 5 .0)  
0 (0 .0)  
1 (1 .1)  
A s th e ni a  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
 
 
 
Pr ef e rre d  te r m 
1 0  m g  
N = 3 
n  (% ) 
4 0  m g  
N = 6 
n  (% ) 
1 0 0  m g  
N = 6 n  
(% ) 
1 2 5  m g 
N = 4 1  n 
(% ) 
1 5 0  m g  
N = 6 n  
(% ) 
5 0 m g 
BI D N = 4 
n  (% ) 
3  w k s 
o n  
1  w k  o ff 
N = 1 8  n  
(% )  
 
A ll 
p a tie nt s 
N = 9 4  
n  (% ) 
Br o n c h itis  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (5 .6)  
1 (1 .1)  
C a rdi a c  fa il ur e 
0 (0. 0)  
0 (0 .0)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
C er v i c al ro o t p ai n  
0 (0. 0)  
0 (0 .0)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
C o n fu s i on a l s ta t e 
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
C o n s tip a tio n  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
D e c re a s e d  a p p e tite  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
D e h y d ra tio n  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
D i s ea s e  p ro g re s s i o n 
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
D y s p h a g ia  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
E j e cti on  fra c ti on  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
G ra n d  m a l c o n v u lsi o n  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
H a e m o p ty si s  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
H e a d a c h e  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 ( 2 5 .0 ) 
0 (0 .0)  
1 (1 .1)  
H y p e rc a lc a e mi a  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (5 .6)  
1 (1 .1)  
K e ra titis  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
M u s c ul a r w e a k n e s s  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
M u s c ul o s k e le t al p a in  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
N o n -c a rdi a c  c h e s t p a in  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
P ai n  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (5 .6)  
1 (1 .1)  
P n e u m o ni tis  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
P n e u m o th o ra x  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
P ul m o n a r y e m b o lis m  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 ( 0 .0 ) 
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
R e n a l fai lu r e a c u te  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
R e s pi ra to r y d is tre s s  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
R e s pi ra to r y fa il ur e 
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
S e p s is  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
St o m a titis  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
S u p e ri or v e n a  c a v a  
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
T i bia  fra c tu r e 
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (5 .6)  
1 (1 .1)  
V o mi ti n g 
0 (0. 0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  


P a g e 6 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
 
P re fe rre d  te rm  
 
1 0  m g  
N = 3 
n  (% ) 
 
4 0  m g  
N = 6 
n  (% ) 
 
1 0 0  m g  
N = 6 n  
(% ) 
 
1 2 5  m g  
N = 4 1 
n  (% ) 
 
1 5 0  m g  
N = 6 n  
(% ) 
5 0 m g 
B ID 
N = 4  
n  (% ) 
o n  1  w k 
o ff 
N = 1 8  
n  (% ) 
A ll 
p a tie n ts 
N = 9 4  
n  (% ) 
P a tie n ts  w ith  a t le a s t 
o n e  A E  
1 ( 3 3 .3 ) 
1 ( 1 6 .7 ) 
2 ( 3 3 .3 ) 
1 6 ( 3 9 .0 ) 
3 ( 5 0 .0 ) 
1 (2 5 .0)  
4 ( 2 2 .2 ) 
2 8 (2 9 .8)  
F a tig u e  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
1 (2 5 .0)  
0 (0 .0)  
2 (2 .1)  
In fe c tio n  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
A d re n a l in s u ffic ie n c y  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
A n xie ty  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 5 .0)  
0 (0 .0)  
1 (1 .1)  
C a rd i ac  fa ilu re  
0 (0 .0)  
0 (0 .0)  
1 (1 6 .7)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
C o n fu s i o na l s ta te  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
C o n s ti pa tio n  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
D e c re a s e d  a p p e tite  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 5 .0)  
0 (0 .0)  
1 (1 .1)  
D e h y d ra ti o n 
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
E je c tio n  fra c tio n 
d e c re a s e d  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 2 .4 ) 
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
H e a d a c h e  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 5 .0)  
0 (0 .0)  
1 (1 .1)  
H y p e rc a lc a e m ia  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (5 .6)  
1 (1 .1)  
K e ra titis  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
M u s c u la r w e a k n e s s  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 5 .0)  
0 (0 .0)  
1 (1 .1)  
R e n a l fa ilu re  a c u te  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
S to m a titis  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (2 .4)  
0 (0 .0)  
0 (0 .0)  
0 (0 .0)  
1 (1 .1)  
 
 
 
T a b le 1 5 : S e rio u s a d v e rs e e v e n ts b y  pr ef e rre d  t er m a n d  tre a t me n t g ro u p , a t le a st p o ssib ly  re la t e d 
t o B G J3 9 8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A d v e rs e E v e n ts C o n sid e re d  to  b e  E x p e ct e d fo r R e p o rtin g  P u rp o se s 
 
T a b le s 1 3  a n d  1 5  a b o v e  pr e s e nt t h e m o st co m m o n  s usp ec te d A E s a n d  S A Es  re p o rte d  i n t h e 9 4 
p ati e nts cu m u l ativ e ly  tre a te d wit h B G J3 9 8  a s o f 2 3  S e p te m b er  2 0 1 3 . Th e  s usp e cte d Gr a d e  3  a n d  4 
a d v ers e  e ve nts  w ill b e  co n sid er e d to  b e  e xp e cte d  fo r re p o rtin g  p u rp o ses  a n d  a re  p r ese n te d  i n T a b le  
1 6 . D u e  t o th e  lim ite d cli n ical e xp er ie nc e  a v ai la b l e to  d at e  wit h B G J3 9 8 , it is still diffic ult to  i d en tify 
e v e n ts po te n ti ally  d u e  t o th e  d ru g . T h er efo r e, a ny  e ve nt pr e v io u sly  re p o rte d s h o u l d b e  co n sid e re d to 
b e  e xp e cte d  re g a r dl ess o f e v e nt  gr a d e,  u n le ss th e  r ep o rt e d dia g n o sis up o n  m e d ic al re v i e w is 
ass ess e d  to  b e  o f un e x p ecte d s e v eri ty o r o f sig n ific an tl y g r e ater  s pe cificity . It sh o u l d b e  stre ss e d th a t 
m a n y o f t h e liste d  A Es  h a ve  b e e n  re p o rte d  o n l y o n  a  sin g l e o cca sio n  m a kin g  a n a cc ura t e a ss essm e nt 
o f c a us alit y ve ry  di fficu lt. D u e  t o th e  im p recisi o n  o f ca u s ality as ses sm e n ts it sh o u l d n o t b e  ass u m e d 
t h at all o f th es e  e ve nts  a re  in d e e d  th e  res ult  o f th er a p y  w it h B GJ3 9 8 . M o re o ver,  th e  ass e ssm e nt  o f 
c au s ality is p artic u l arly  di ffic ult i n critic ally  ill p a ti e nts w h er e  co n fo u n d in g  f acto rs ar e  p r ese nt rel ati n g 
m ai n l y t o co m p lica tio n s o f t h e un d erl yi n g  dis e as e  a n d  t o t h e us e o f co n co m it an t m e d ica tio n s. 


P a g e 6 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
T a b le 1 6 : S u sp e ct e d gr a d e  3  a n d  4  B G J3 9 8  A d v e rs e E v e n ts co n sid e re d  to  b e  e x p ect e d fo r re p o rtin g 
p u rp o se s 
M e d D R A  s y s te m  o rg a n  c la s s  
Pr ef e rre d  te rm  (P T ) 
 
C ar d ia c  d is or d er s  
C a rdi a c  f ailu re , L e ft v e ntr ic u lar 
d y s fu n c tio n  
E n d o c rin e  di s or d e rs  
A d re n al  i n suff i cie n c y  
 
E y e  d is or d er s  
D ry  e y e,  K e rati ti s, Vi s u al 
im p ai rm e n t 
G a s tr oint e s tin al  d is or d er s  
S t om at itis , O ral  p a i n 
G e n er al  d is or d er s  a n d  a d m in is tr atio n  s ite  
c o n d itio n s  
 
A s t he n ia,  F ati g u e  
H e p a to bili a ry  d is or d e rs  
H e p a ti c fa il ur e (fat a l) 
 
 
 
 
 
 
 
 
 
I n v es tig at io n s  
 
Al a n in e  a m in o tr an s fer a s e 
in cr e a s e d , A m yla s e  in cr e a s e d , 
A s p a rt ate  a m in o tr an s fer a s e 
in cr e a s e d , Bl o o d  p h o s p h o ru s 
i n cre a s e d , E je c ti o n fra ct io n 
d e cr e a s e d,  G a m m a - 
gl u ta m y ltra n s fe ra s e  in c re a s e d , 
L ip a s e  in cr e a s e d  
 
 
 
 
 
M e ta b o lis m  a n d  n ut ritio n  d i sor d er s  
 
D e cr e a s e d  a p p et ite, 
D e h y d rati o n,  H y p e rc a l ca e mi a, 
H y p e rk a la e mi a , 
H y p o n atr a e mi a , 
H y p er p h o s p h a ta e m ia,  
M u s c ul o s k e let al  a n d  c o n n e c tiv e  ti ss u e  
di s or d e rs  
 
M y al gi a  
 
N er v o u s  s ys t e m d is or d er s  
H e a d a c h e , N e u ro p at h y  
p e rip h e ra l 
P s y c hi atr ic  di s o rd e rs  
A n x i ety  
u ri n ary  di s or d e rs  
R e n al  i nju ry  
R e s pi rat o ry , th o ra c ic  a n d  m e di a s tin al  di s o rd e rs  
P ul m o n a ry  o e d e m a  
 
 
 
S ki n  a n d  s u b c u ta n e o u s  ti ss u e  d is or d e rs  
A lo p e c ia , O n y c h o ly s i s, P al m a r-
pl a n ta r ery th ro d y s a e st h e s ia  
s y n d ro m e  
E v e n t s in  b o ld  in di c a t e a n  e v e n t th at  is  n e w ly  in cl u d e d  s in c e  th e  p re v io u s  e d itio n  o f th e  
I n v es tig at o r' s B ro c h ur e  
 
 
P l e ase  r efer  to  t h e I nves tigat o r’s Br o c hu r e fo r de t ails o f all A E s. 
 
1 1. 2  
A d v e rs e E v e n t C h a ra cter istics 
 
1 1 .2 .1   D efi n itio n  o f a n  A E  


P a g e 7 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
A n y  u n to w ar d  m e d ic al o ccu rr en c e i n a  s ub j ect o r clin ic al i nve sti g atio n  s ub j ect, t em p o r ally  as so cia te d 
wit h th e  us e  o f a m e d icin al  pr o d u ct, w h et h er  o r no t co n sid er e d rel a te d to  th e  m e d icin al  p ro d u ct. 
 
N o te : A n  A E  c a n th e ref o r e b e  a n y  u n fa v o r ab le  a n d  u n in te n d e d si g n  (in clu d in g  a n  a b n o rm al l a b o r ato r y 
fin d in g ), sy m p to m , o r dise as e  ( n e w o r e xac er b a te d ) te m p o r ally  as so ciat e d  w it h t h e us e  o f a m e d icin al 
p ro d u ct. F o r m ar k e te d m e d icin al p ro d u cts, th is al so  i ncl u des  f ailu r e to  pr o d u ce  e x p ecte d b e n efits, 
a b u se,  o r m isu s e. Ex a m p les  o f e ve n ts m e e tin g  th e  d efi n itio n  o f a n A E  i ncl u de:  
 
•  Ex a cer b a tio n  o f a c hro n ic o r in te rm itte n t p re -e xistin g  co n d itio n  i ncl u din g  e ith er  a n i n cr e ase  i n 
fr eq u e ncy  a n d / or gr a d e  o f th e  co n d itio n  
 
•  N e w  co n d itio n s de te cte d  o r dia g n o se d af ter  st ud y  tre a tm e nt a d m in istra tio n  e ve n t h o u g h it  m a y 
h a v e  b e e n p re se nt pr io r to  t h e st art o f th e  stu d y Si g n s, sym p to m s, o r th e  clin ic al se q u el a e  o f a 
s usp ec te d i n ter a ctio n  
 
•  S i g ns, sy m p to m s, o r th e  clin ic al se q u el a e  o f a  s usp e cte d  i nt era ctio n  
 
•  S i g ns, sy m p to m s, o r th e  cli nic al se q u el a e  o f a  s usp e cte d o v er d o s e o f e ith er  st ud y  tre a tm e nt  o r a 
co n co m it a nt m e d ica tio n  (o v er d o s e p er  s e w ill n o t b e  re p o rte d as a n A E /SA E).  
 
“La ck  o f e ffic acy ” o r “f ailu re  o f e xp e cte d  p h ar m a co lo gic al actio n ” p er  s e is n o t to  b e  r e p orte d  as  a n 
A E o r SA E. H o w e ver,  a n y  sig n s a n d sym p to m s a n d/ o r clin ic al se q u el a e  r es ultin g  fro m  “la c k o f 
effic ac y” will b e  r e p orte d a s a n A E o r SA E,  if th e y  f ulfill th e  d efi n itio n  o f a n A E  o r SA E.  
 
T h e  sig n s a n d  sy m p to m s a n d / or clin ical s e q u el a e  res u ltin g  fro m  l ac k o f e ffica c y will  b e  re p o rte d if 
t h e y f ulfill t h e d efin itio n  o f a n  A E o r S A E. A lso , “l ac k o f effic ac y” o r “f ailu r e o f e x pe cte d 
p h ar m a co lo g ic al ac tio n ” a ls o co n stitu te s a n  A E  o r SA E . 
 
E v e nts  th at  d o  n o t m e e t th e  d efi n itio n  o f a n A E i n clu d e:  
 
•  M e d ic al o r s ur gic al pro ce d u r e ( e.g ., e nd o sco p y , a p p e n d ec to m y ); th e  co n d itio n  t h at l e a ds t o th e  
p ro c e du r e is a n  A E.  
 
•  S it u atio n s w h er e  a n  u n to w ar d m e d ic al o cc urre nc e  d i d n o t o cc ur (so ci al a nd/ o r co nv e n ie nc e  
a d m issio n  to  a  h o s pit al). 
 
•  A n ticip at e d  d a y -to -d a y  flu ct u atio n s o f pre -e xistin g  dis e as e( s) o r co n d itio n (s) p res e n t o r d e te cte d  a t 
t h e st art o f th e  stu d y th at  d o  n o t w o rse n.  
 
•  T h e  d ise as e /d iso rd er  b e in g  stu d i ed , o r e xp ec te d  pr o g r essio n , si gn s, o r sym p to m s o f th e  
d is e ase /d iso rd er  b ei n g  stu d i ed , un l ess m o re  se v er e  th a n  e x p ecte d fo r th e  s ub je ct’s co n d itio n . 
 
1 1 .2 .2   D efi n itio n  o f a  S A E  
 
A s eri o u s a d vers e  e v e nt is  a n y  u n to w ar d  m e d ic al o ccu rr en c e t ha t, at  a ny  d o se : 
 
a . R e sul ts in  d e a t h 
 
b . Is lif e-th re a t en in g  


P a g e 7 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
N O T E: T h e  te rm  'life -t hre a te n i n g' i n t h e d efin itio n  o f 'seri o u s' re f ers t o a n e v e nt  in  w h ic h th e  s ub j ect 
w as  at  risk o f d e a th  at  th e  tim e  o f t h e e v e nt. It  d o es  n o t ref e r t o a n e ve nt,  w h ic h h y p o t he tic all y m ig h t 
h a v e  ca u s e d d ea t h, if it w e r e m o re  se v e re.  
 
c. R e q u ire s h o sp ital iza tio n  o r pr o lo n g a tio n  o f exi stin g  h o sp ita liza tio n  
 
N O T E:  I n g e n er al,  h o s pit alizati o n  si gn ifies  t h at t h e su b j ect h as  b e e n  d e tai n e d ( u su al ly  i nvo lvi n g a t 
l e ast a n  o ver n i g ht st ay ) at  th e  h o s pit al o r e m er g e n cy w ar d f o r o b ser va tio n  a n d/ o r tre a tm e nt  t h at 
w o u l d n o t h a ve  b e e n a p p ro p ria t e i n t h e ph y sicia n ’s o ffic e o r o u t-p ati e nt  se ttin g . Co m p lic atio n s th a t 
o cc ur d u rin g  h o s pit alizati o n  ar e  A Es.  If a  co m p lic atio n  pr ol o n g s h o s pit alizat io n  o r f ulfills an y o t h er 
s erio u s crit eria , th e  e ve nt is se rio u s. W h e n in  d o u b t a s to  w h e t h er “h o s pit alizat io n ” o cc urr e d o r wa s 
n ec e ss ary , th e  A E  s h o ul d b e  co n sid er e d seri o u s. 
 
H o s pit alizat io n  fo r e le ctive  tr e atm e nt  o f a  p re -e xistin g  co n d itio n  th at  d i d n o t w o rse n fr o m  b a seli n e  is 
n o t co n sid e re d a n S A E.  
 
d . R e su lts in  d isa b ility/i n ca p a cit y 
 
N O T E:  T h e  te rm  dis a b ility  m e a ns  a s u b st a nti al dis r u ptio n  o f a p ers o n ’s a bility to  co n d u ct n o rm al l if e 
fu n ctio n s. T his d efi n itio n  is n o t in te n d e d to  i ncl u de  e xp eri e nc es  o f rel at ive ly m in o r m e d ic al 
sig n ific an c e s uc h as  u n co m p lic ate d  h e a d a ch e,  n a u se a,  v o m itin g , dia rrh e a,  in flu e n za, a n d  ac cid e nt al 
tr au m a  ( e.g . s prai n e d a nk le ) w hic h  m ay  i nt erfer e  o r pre v e nt  e ve ry d a y  life  fu n ctio n s bu t d o  n o t 
co n stitu t e a  s ub st a nti al di sru p tio n . 
 
e . Is a  co n g e n ita l a n o m a ly /b irt h d e fe ct. 
 
M e d ic al o r sci e ntific ju d g m e nt  s h o ul d b e  e xe rcise d i n  d eci d i ng  w h e th er  re p o rtin g  is a p p ro p ria te  i n 
o t h er sit ua tio n s, s uc h as im p o rt an t m e d ic al e v e nts  th a t m a y  n o t b e  im m e d iat e ly  life -t hr e ate n i ng  o r 
r es ult i n d e a t h o r h o s pital izati o n  b u t m a y  je o p ar d ize  th e  s ub j ect o r m a y  re q u ir e m e d ic al o r s ur gic al 
in te rv e n tio n  t o pr e v e nt  o n e  o f th e  o th er  o u tco m es  liste d  i n t h e a b o v e  d efi n itio n . T h es e  s ho u l d al so 
b e  co n sid er e d seri o u s. Ex a m p l es o f su c h e ve nts  ar e  in v asi ve  o r m al i g na n t c an ce rs, i nt e nsive 
tr e atm e nt  i n a n e m e rg e ncy  ro o m  o r at  h o m e  fo r alle rg ic bro n ch o s pa sm , blo o d  d yscr asi as o r 
co n v u lsio n s th a t d o  n o t re su lt i n h o s pit alizat io n , o r de v e lo p m e nt  o f dru g  d e p e n d e nc y  o r dr ug  a b u s e. 
 
f. A ll gr a d e  4  la b o ra to ry  a b n o rm al itie s 
 
S A Es  will  b e  re co rd e d a n d  re p o rte d as d e t ail e d i n sec tio n  1 7 . 2. 
 
1 1 .2 .3   La b o r ato ry  a n d  O th er  S a fe t y Asse ss me n t A b n o rm a lities  R e p o rt e d a s A E s a n d  S A Es  
 
A n y  a b n o rm al l a b o r ato ry test  res ults ( h e m a to lo gy , clin ic al ch e m istry , o r urin al ys is), o r o t h er s afe ty 
ass es sm e nts  (e. g ., E C Gs, ra d io lo g ic al sc a ns, v it al sig n s m e as u re m e nts)  i ncl u din g  th o s e t h at w o rse n 
fro m  b as eli n e,  a n d  e ve nts  felt  to  b e  clin ic ally si gn ific an t i n th e  m e d ic al an d  scie nt ific j ud g m e nt  o f th e 
in v es tig a to r a r e to  b e  re co rd e d as a n A E  o r SA E,  i n a cco rd a n c e wit h th e  d efi n itio n s pro v id e d.  
 
H o w e v e r, a ny clin ic all y si gn ific an t sa fe ty a ss essm e nts  th at  ar e a sso ci at e d wit h  t h e u n d erl yi n g  dis e a se, 
u n l ess ju d g e d by  t h e i nves tig at o r to  b e  m o re  se ver e  t h a n e x p ecte d  fo r th e  s ub j ect's co n d itio n , ar e 
n o t to  b e  r ep o rt e d as  A Es  o r SA Es.  


P a g e 7 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
R ef e r t o S ec tio n  1 7 .2  o n  crite ria , tim e  fra m e  a n d  pr o ce ss o n  re p o rtin g  a b n o rm al iti es t ha t ar e 
q u al ifi e d as  S A Es.  
 
1 1 .2 .4   D ise a se -R e la t e d E v e n ts a n d /o r D ise a se -R e la te d  O u tco m es  N o t Q u a lify in g  a s S A Es  
 
A n  e v e n t t h at is pa rt o f t h e n at u r al co u rs e o f t h e dis ea s e u n d er  st ud y  (i.e.,  dis e a se  p ro g re ssio n  o r 
h o s pit alizat io n  d u e  to  di se as e  p ro g ress io n ) d o es  n o t n e e d  to  b e  re p o rte d  as  a n  SA E. D e a t h du e  to 
d is e as e u n d er  st ud y  is to  b e  r eco rd e d i n  t h e E D C  sy ste m . H o w e v er,  if th e  u n d erl y in g  dis e as e  (i.e., 
p ro g r essio n ) is gre a ter  th a n  th at  w hic h  w o u l d n o rm a lly b e  e xp e cte d  fo r th e  s ubj ec t, o r if th e 
in v es tig a to r co n sid e rs th at  t h er e w as  a  c au s al rel at io n s hip  b et w e e n t re a tm e nt  w it h stu d y 
tr e atm e n t(s) o r pro to co l d esi g n /p ro c e du r es a n d  th e  d is e as e p ro g r essio n , th e n th is m u st b e  r ep o rte d 
as a n S A E.  
 
1 1 .2 .5   Ti m e  P e rio d  a n d  F re q u e nc y o f D ete cti ng  A Es a n d  S A E s 
 
T h e  inv es tig a to r o r sit e st aff is re sp o n sib l e fo r de te ctin g , do cu m e nti n g  a n d  re p o rtin g  e v e n ts th at 
m e et  th e  d efi n itio n  o f a n A E  o r S A E.  
 
A Es will b e  co ll ecte d f ro m  th e  tim e  th e  first d o se  o f stu d y  tr ea tm e nt is  a d m in ist er e d u n til 2 8  d a ys 
fo llo wi n g  disc o n tin u ati o n  o f stu d y  tr e atm e n t r e ga rd les s o f in itia tio n  o f a n e w  c an cer  t h er ap y  o r 
tr an sf er to  h o s pic e. 
 
A fte r disco n tin u at io n  o f stu d y  tre a tm e nt,  t h e in ves tig a to r will  m o n ito r all A E s/S A E s th at  a re  o n g o in g 
u n til r eso lu tio n  o r st a biliza tio n  o f th e  e ve nt  o r un til th e  s ub j ect is lo st t o fo llo w -u p . At a ny tim e  af ter 
tr e atm e nt  disc o n tin u ati o n  t h e i nves tig a to r m a y  re p o rt a n y  a d v er se  e v e n t t h at t hey  b el ie ve  p o ssib ly 
r el at e d t o st ud y tr e at me nt.  
 
R ef e r t o S ec tio n  1 7 .2  o n  crite ria , tim e  fra m e  a n d  pr o cess  o n  re p o rtin g  a b n o rm al iti es t ha t ar e 
q u al ifi e d as  S A Es.  
 
1 1 .2 .6   C T C A E  te rm (A E  d e scrip tio n ) a n d  g r ad e:  
 
T h e  d es crip tio n s a n d  gr a d in g  sc al es fo u n d  i n t h e re v ise d N CI C o m m o n  T e rm in o lo g y  Crit er ia f o r 
A d v ers e  E ve nts  ( C T CA E ) ve rsio n  4 .0  will  b e  u tilize d  fo r A E r e p o rtin g . All a p p ro p ria t e tre a tm e nt  ar e as 
s h o ul d h av e  ac cess  t o a co p y  o f th e  C T C A E  v e rsio n  4 .0 3 . A c op y o f th e  C T C A E  ve rsio n  4 .0  c a n b e 
d o w nl o a d e d f ro m  th e  C T E P  w e b s it e 
h ttp ://cte p .c an c er.g o v /p ro to co lD e vel o p m e n t/e lec tro n ic _ a pp lic atio n s/ctc.h tm . 
 
1 1 .2 .7   A ttrib u tio n o f t he  A E:  
 
− 
D efi n it e –  T h e  A E  is cl ea rly rel a t e d t o th e  st ud y  tr e atm e nt.  
 
− 
P ro b a b l e –  T h e  A E  is likely rel a t e d to  th e  stu d y tr ea tm e nt.  
 
− 
P o ssib l e –  T h e  A E  m ay  b e rel a t e d to  th e  stu d y tr ea tm e nt.  
 
− 
U n li ke l y –  T h e  A E  is d o u b tfu lly rel a t e d t o th e  st ud y tre at m e nt.  
 
− 
U n r el at e d –  T h e  A E  is cl ea rly NO T  rel a t e d to  t h e st ud y  tr e atm e nt.  


P a g e 7 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 1. 3  
Pr e g n a n c y T e sti ng , P re v e n tio n  a n d  R e p o rti ng  
 
1 1 .3 .1   P re g n a n c y T e stin g  a n d  Pr e v e n ti on  
 
T h e  n e e d  fo r a  scre e n in g  p re g n a n cy test  d e p e n d s o n  w h e th er  a f em al e s u b ject  is o f c hil d be ari n g 
p o te n ti al o r n o n -c hild b e ar in g  p o te n ti al. 
 
A  fe m al e o f no n -ch ild b e a ri ng  p o t en tia l (i.e., p h y sio lo gic all y in c ap a b l e o f b e co m in g  pr e g n a n t) is 
d efi n e d as a ny  fe m al e  w h o  h as h a d  a  h y ste re cto m y , bilat e r al o o p h o r ecto m y  (o v ar i ecto m y ) o r 
b il ate r al tu b al l i gat io n , o r is p o st-m e n o p a u s al. 
 
A p r actic al d efi n itio n  a cce p ts m e n o p a u se  af ter  1  y e ar  wit h o u t m e ns es  w it h a n a p p ro p ria t e clin ic al 
p ro file,  e. g ., ag e  a p p ro p ria te,  > 4 5  y e a rs i n th e  a b s e nce  o f h o rm o n e  re p l ace m e nt t her a p y  (H R T). I n 
q u es tio n a b l e c as es, th e  su b j ect m u st h a ve  a  fo llicl e stim u l atin g  h o rm o n e  ( FS H ) v al u e  > 4 0  m IU /m L 
a n d  a n es tr ad io l v al u e  <  4 0 p g /m L (< 1 4 0  p m o l/L). 
 
A  fe m al e o f chi ld -b e a rin g  p o t en tia l is d efin e d  as  a n y  f em a le  w h o  d o es  n o t m e e t t h e criteri a  o f n o n - 
c hild b e ari n g  p o te n ti al as  d es crib e d i n  th e  p re v io u s p a ra g r ap h . 
 
If a fe m al e  s ub j ect is o f c hild b e ari n g  p o te n ti al, s h e m u st h a v e  a  b lo o d  β -H C G p re g n a n c y te st 
p erf o rm e d  wit hi n  1 4  d a y s o f th e  first d o se  o f stu d y tre a tm e nt. S u b j ects wit h p os itiv e  p re g n a n cy te st 
r es ult m u st b e  e xclu d e d f ro m  th e  st ud y . S u b j ects w it h n e g ati v e  pr e g n a n c y te st re s ult m u st a g re e  to 
u s e a n  e ffec tive  co n trac e p tio n  m e th o d  as  d es crib e d b el o w  fro m  1 4  d ays  pr io r to  t h e first d o se  o f 
st ud y  tre a tm e nt  u n til 3  m o n t hsfo llo wi n g  th e  l ast d o s e o f st ud y  tre a tm e n t. 
 
Acc e pt a b l e co n tr ac e ptiv e  m e th o d s, w h e n u se d  co n siste n tl y a n d  i n acco rd a n c e wit h b o t h t h e pr o d u ct 
l ab el a n d  th e  in str uctio n s o f th e  p h y sici an , ar e as  fo llo w:  
 
•  A n  i ntr au te rin e  d e v ic e w it h a do cu m e n te d f ail u r e ra t e o f l ess th a n  1 %  p er  ye ar.  
 
•  V as e cto m ize d p a rt n er w h o  is ste rile  pr io r to  th e  fe m al e  s ub j ect’s e n try a n d  is th e  so le  
s exu al p art n e r fo r th at  fe m al e.  
 
•  C o m p le t e a b stin e nc e  fro m  se xu al i n terc o u rse  fo r 1 4  d a ys  b e fo r e e xp o s ure  to  
in v es tig at io n al p ro d u ct, t hr ou g h  th e  d o sin g  p er io d , an d  fo r at l e ast 2 1  d a y s afte r t h e l ast d o se 
o f inv es tig at io n al p ro d u ct. 
 
•  D o u b l e-b ar ri er co n tr ac ep tio n : co n d o m  a n d  o cclu sive  c a p (d i ap h r ag m  o r c erv ic al/ va u lt c ap s) 
wit h a  v a g in al s p e rm icid al  a g e nt (fo a m /g e l/cre a m /su p p o sito ry ). 
 
•  I mp l an ts o f le v o n o rg es trel w h e re  n o t co n tr ain d ic ate d f o r t his p atie nt p o p u l atio n o r p er  
lo c al pra ctic e 
 
•  In j ect a ble  p ro ges te ro n e  w h er e  n o t co n tr ai n dic at e d fo r th is p ati e nt p o p u l atio n  o r p er lo c al 
p r actic e. 
 
•  Est ro g e n ic v a g in al r i ng  
 
•  P erc ut a n e o u s co n tra c e ptiv e p a tc h es 


P a g e 7 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
If a fe m al e  s ub j ect is s usp e cte d  to  b e  pr e g n a n t d u rin g  t h e st udy , a b lo o d p re g n a n c y test  m u st 
b e  p erf o rm e d.  If pr eg n a n cy is co n fir me d, s u b j ect m u st st op  st ud y  tr e at me nt im m e d iat e ly a n d 
t h e pr eg n a n cy m u st b e  r ep o rt e d ac co rd in g  to  pr o ce d u r es d es crib e d i n  S e ctio n 1 2 .0  
 
1 2. 0  
C RI T E RI A  F O R  T H E R A P E U T IC  R E S P O N S E/ O U T C O M E  A S S E S S M E N T  
 
1 2. 1  
A n titu m or  E ffe ct –  S o lid  T u m o rs 
D u rin g  th e  tr e atm e n t p er io d , p ati e nts will  b e  e v al u at e d  pr io r to  tre a tm e n t a n d  re -e v al u a te d f o r 
r es p on s e e v e ry  8  w e e ks  fo r fo u r sca n s. P ati e n ts w ill th e n b e im a g e d a p p ro xim at e ly  e v e ry 1 2  w e e k s 
u n til dis e as e p ro g r essio n  is n o te d . If a p ati e nt  h as a d u r ab l e re sp o n s e o f >  2  y e ar,  p ati e nts ca n  b e 
im a g e d  e ver y  6  m o n t hs. R e s p o ns e a n d  p ro g r essio n  wi ll b e e v al u at e d  i n th is stu d y u sin g  th e  n e w 
in te rn ati o n al  crit eria pr o p o s e d by t h e re v ise d R e sp o n se  E val u ati o n  Cr ite ri a i n S olid  T u m o rs (R E CI S T) 
g u id eli n e  (v e rsio n  1 .1 ) [3 2 ]. C h a n g es  i n th e  l ar ge st d ia m e ter  ( un id im e ns io n al m e as u r em e nt)  o f t h e 
t um o r l esio n s a n d t h e sh o rte st d ia m e te r i n t h e c as e o f m al i g na n t ly m p h  n o d es  a re  u s e d i n t h e 
R E CI S T. C H OI res p o n se  criteri a as  o u tlin e d i n  GI S T  will  b e  u s e d as a s e co n d a ry  re sp o n s e [3 3 ]. I n 
a d d itio n , p ati en ts will  b e  e v al u at e d  b y  F D G -P E T  p rio r t o tr e atm e n t a n d  re -e v al u a te d  fo r r esp o n s e 3 
w e e ks  af ter  th e  co m b in ati o n  tr e atm e nt  b as e d  o n  th e  E O R T C crit eria [3 4 ]. T his will  als o  b e  us e d as 
s ec on d a ry  re s p o ns e. 
 
1 2 .1 .1   D efi n itio n s 
 
E v al u a b l e fo r to xicity . A ll P h as e  I b p ati e n ts w ill b e  e v a lu a b l e fo r to xicity  fro m  th e  tim e  o f th eir fi rst 
tr e atm e nt  w it h im a tin i b p lu s B G J3 9 8 . All P h as e  II pa tie nts  will  b e  e v al u a b l e fo r to xicity  fro m  th e  tim e 
o f th eir  first tr ea tm e nt  wi th  im ati n i b a lo n e.  
 
E v al u a b l e fo r effic a cy .  O n ly  th o s e p a ti e nts w h o  h a ve  m e as ur a b le  d is e ase  p r ese n t at  b a seli n e  a n d 
h a v e  rec e iv e d a t l ea st o n e d o s e o f im ati n i b pl u s B G J3 9 8 t h er a p y w ill b e co n sid e re d e val u a b l e fo r 
effic ac y . T h e s e p at ie nts  wi ll ha v e  t h eir res p o n se  cl assifi e d ac co rd in g  to  th e  d efi n itio n s st at e d b el o w. 
P ati e n ts o n  th e  P h a se  II p o rtio n  w h o  a re  ta k e n  o ff stu d y  pr io r t o r ecei v in g  th eir  first d o se  o f B GJ3 9 8 
fo r re as o n s o t h er th a n  p ro g r essiv e  d is e ase  a re  co n sid er e d  r e pla ce a b le  fo r t h e pu rp o s es o f e v al u ati n g 
p ri m ary a n d  se co n d ar y  e n d p o in ts. 
 
E v al u a b l e N o n -T ar g et  D ise as e  R es p o n se.  P ati e n ts w h o  h a ve  le sio n s pres e n t at  b as eli n e  t ha t ar e 
e v al u a b l e bu t d o  n o t m e e t t h e d efin itio n s o f m e as ur a b l e dis e ase , h ave  re c eiv e d  at  l e ast o n e  cy cl e o f 
t h er ap y , a n d h a ve  h a d  th e ir dis e as e re -e v al u a te d will  b e  co n sid er e d e v al u a b l e fo r n o n-t arg e t d is e ase. 
T h e  r esp o n s e ass e ssm e nt is b as e d o n  th e  pr es e n ce,  a b s e nc e, o r un e q u ivo c al pr o g r essio n  o f t h e 
l esio n s. 
 
1 2 .1 .2   D ise a s e P a r am et e rs 
 
M e as ur a b l e dis e a se.  M e a su r ab l e l esio n s ar e d efi n e d  as th o se  t ha t c a n b e  acc u ra tel y  m e as ur e d  i n a t 
l e ast o n e  d im e ns io n  (lo n g e st d i am e ter  to  b e  r eco rd e d  fo r n on -n o d al l es io n s a n d sh o rt ax is fo r n od al 
l esio n s) as  > 2 0  m m  by  ch e st x-r ay, as > 1 0  m m  w it h C T sc a n o r M RI,  o r > 1 0  m m  w it h c alip ers  b y 
clin ic al e xa m . All  tu m o r m e as ur e m e nts  m u st b e  re co rd e d i n  m illim e te rs (o r d ec im al fr a ctio n s o f 
c e ntim e ters).  
 
N o n -m e a s ura b l e dis ea s e. A ll o t h er l esio n s (o r site s o f dis e as e ), i ncl ud in g  sm all  le sio n s (lo n g est 
d i a me ter  < 1 0  m m  o r p at h o lo g ic al lym p h n o d es  wit h ≥ 1 0  t o < 1 5  m m  sh o rt a xis), a r e co n sid er e d  n o n - 
m e as ur a b le  d is e ase.  B o n e  l esio n s, le p to m e n i n ge al d ise as e , a scites,  p l eu r al/p eri car d i al e ffu sio n s, 


P a g e 7 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
l ym p h a n g itis c utis/p u lm o n itis, i nfla m m a to ry  br e a st d ise as e , a n d a b d o m in al  m as ses  (n o t fo llo w e d  b y 
C T  o r M RI), a re  co n sid er e d  as n o n -m e as ur a b l e. 
 
T ar g et  lesi o n s. All  m e as ur a b l e l esio n s u p to  a  m a xim u m  o f 2  l esio n s p er o rg a n  a n d  5  l esio n s i n to t al, 
r e pres e n ta tiv e  o f all i n v o lve d o rg a n s, s ho u l d b e  i d en tifi e d as  t arg et  lesi o n s a n d  rec o rd e d a n d 
m e as u re d at  b a seli n e.  T a rg et  l esio n s sh o u l d b e  sel e cte d o n  t h e ba sis o f t h eir size  (l esio n s w it h t h e 
lo n g est  di a m e te r), b e  re pr e s e nt ativ e  o f all in vo l ve d  o rg a n s, bu t i n a d d itio n  s h o uld  b e  t ho s e t ha t l en d 
t h em sel ves  to  re pr o d u cib l e re p e a te d  m e as ur e m e nts.  It m a y  b e  th e  c as e th at,  o n  o cc asio n , t h e 
l ar gest  le sio n  d o es  n o t l en d  itse lf t o re p ro d u cib l e m e a su r em e n t i n w h ic h circu m sta n c e t h e n ext 
l ar gest  le sio n  w hic h  c a n b e  m e as u re d r e p ro d u cib ly sh o u l d b e  s ele cte d . A  s u m o f th e  d i am e ters 
(lo n g est  fo r n o n -n o d al  l esio n s, sh o rt a xis fo r n o d al l e sio n s) fo r all t arg et  l esio n s will  b e  c alc ulat e d  a n d 
r e p orte d as  t h e b aseli n e  su m  di a m e ters.  If ly m p h  n o d es  ar e  to  b e  in clu d e d i n  th e  s um , t h e n o n l y t h e 
s h ort a xis is a d d e d i n t o th e  s um . T h e  b a seli n e  su m  di a m e ters  will  b e  u se d as ref e r e nc e to  f urt h er 
c ha r act eriz e a ny  o b je ctive  t um o r r e gre ssio n  i n t h e m e as u r ab l e dim e nsi o n  o f t h e d is e as e. 
 
N o n -t arg et  les io n s.  All o th er  l esio n s (o r site s o f dise a se)  i ncl u din g  a ny  m e a s ura b l e l esio n s o v er  a n d 
a b o v e  t h e 5  t arg et  l esio n s sh o u l d b e  id e ntif ie d as n o n -t arg et  lesi o n s a n d  s ho u l d a ls o b e  re co rd e d a t 
b as eli n e.  M e as u re m e nts  o f th es e  l esio n s are  n o t r e qu ir ed , bu t t h e pr es e n c e, a b se nc e,  o r i n r are 
c as es u n e q u iv ocal p ro g res sio n  o f e ac h  s ho u l d b e  n o t ed  th ro u g h o u t fo llo w -u p . 
 
1 2 .1 .3   M et h o d s fo r E va lu a tio n  o f M e as u r abl e  D ise a s e 
 
A ll m e a s ure m e nts  s ho u l d b e  t ake n a n d  re co rd e d  i n m e tric n o t atio n  usi n g  a  ru ler  o r c alip e rs. All 
b as eli n e  e v al u at io n s sh o u l d b e  p er fo rm e d as  clo sely  a s po ssib l e to  th e  b e g i n nin g  o f tre a tm e nt  a n d 
n e v er  m o r e th a n  4  w e e ks  b ef o r e th e  b e g i n nin g  o f th e  tr e atm e nt.  
 
T h e  sa m e  m e th o d  o f ass e ssm e nt  a n d  th e  s am e  tec h n iq u e  s h o ul d b e  u se d to  ch a ract e rize  e ac h 
id e ntifi e d a n d  re p o rt e d l esio n  at  b a seli n e  a n d  d u rin g  fo llo w -u p  p o rtio n  o f st ud y . Im a g in g -b as e d 
e v al u at io n  is p ref e rr e d to  e v al u ati o n  by  clin ic al e xa m in ati o n  u n l ess th e  lesi o n (s) b ei n g  fo llo w e d 
c an n o t b e  im a g e d b u t a re  a ss ess ab l e by  clin ic al e xa m . 
 
Cl i nic al l esio n s.  Cl i nic al les io n s w ill o n l y b e  co n sid e re d  m e as u r ab l e w h e n t h e y  a re  s up erfici al (e. g ., 
s ki n no d u l es a n d  p a l pa b l e ly m p h  n o d es)  a n d ≥1 0  m m  d i a me ter  as  ass e ss e d usi ng  c ali pers  (e. g ., ski n 
n o d u l es). I n t h e ca s e o f sk in  l esio n s, d o cu m e n tati o n  by  co lo r p h o to g r ap h y , i ncl ud in g  a  ru l er to 
es tim at e  th e  size  o f th e  l esio n , is re co m m e n d e d.  
 
C h est  x-ra y . Les io n s o n  ch est  x-ra y  a re  a cc e pt a ble  as  m e as ur a b le  l esio n s w h e n th e y  a re  cl ea rl y 
d efi n e d a n d  s urro u n d e d b y a e r ate d l u n g . H o w e v er,  C T  is pre fer a b l e. 
 
C o nv e nti o n al  C T  a n d  M RI.  T his g u id eli n e  h as d efi n e d  m e as ur a b ility o f le sio n s o n  C T  sc a n b a se d  o n  th e 
ass u m p tio n  th at  C T  slic e t hic k n ess is 5  m m  o r less.  If C T  sc a ns h a v e  slic e th ic k ne ss gr e ater  t h a n 5  
m m , t h e m in im u m  siz e fo r a m e as ur a b l e lesi o n  s h o ul d b e  twic e  t h e slice  t hick n e ss. M RI  is al so  
acc e p t a ble  i n c ert ai n sit u atio n s (e. g . fo r b o d y  sc a ns). 
 
Us e  o f M RI r e m ai n s a co m p l ex issu e.  M RI  h as e xce lle n t co n trast,  s pa ti al, a n d  t em p o r al re so lu tio n ; 
h o w e v er,  th e re  ar e  m a n y  im a g e  a c qu isitio n  v ar ia b le s in v o lv e d i n  M RI,  w hic h  gr e atl y  im p act  im a ge 
q u al ity , l esio n  co n s pic uity , a n d  m e as u re m e nt.  F u rth e rm o r e, t h e a v ai la b ilit y o f M RI is v a ria b l e 
g lo b al ly . As  w it h C T,  if a n  M RI is p erf o rm e d, t h e  tec h n ic al s p ecifica tio n s o f t h e sc an n in g  se q u e nc es  


P a g e 7 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
u s e d s h ou l d b e  o p tim ize d fo r th e  e v al u at io n  o f th e  ty p e  a n d  sit e o f dis e a se.  F u rth er m o r e, as  wit h C T , 
t h e m o d al ity  u se d at  fo llo w -u p  s ho u l d b e  t h e sa m e  a s w as  u s e d at  b a seli n e  a n d  th e  l esio n s sh o u l d b e 
m e as u re d /as ses se d o n  th e  s am e  p u ls e se q u e nc e.  It is b e y o n d  t h e sco p e  o f th e  R E CI S T  g u id eli n es  to 
p r escrib e  sp ecific  M RI p u lse  s e qu e n ce  p ar a m e ters  fo r all sc a n n ers,  b o d y  p arts,  a n d  dis e as es.  Id e all y, 
t h e sa m e  ty p e  o f sc an n er  sh o u l d b e  u s e d a n d t h e im a g e  ac q u isitio n  pr o to co l sh o u l d b e  fo llo w e d as 
clo s ely  as  p o ssib le  to  pr io r sc a ns. B o d y  sc an s sh o u l d b e  p er fo rm e d w it h bre a th -h o l d sc an n in g 
te c hn iq u es,  if p o ssib l e. 
 
1 2 .1 .4   P rim a ry  R es p o n s e C rit eria  (R E C IST  1 .1 ) 
 
1 2 . 1.4 . 1 E v al u a tio n  o f T ar get  Les io n s 
C o m p l et e R e sp o n s e (C R ): D is ap p e a ra n c e o f all t arg et  lesi o n s. A n y  p at h o lo g ical l ym p h  n o d e s 
(w h e th er  tar g e t o r n o n-ta rg e t) m u st h a v e  re d u ctio n  in  s ho rt a xis to  < 1 0  m m . 
 
P arti al  R es p o n s e (P R ): A t le ast  a  3 0 %  d ec re as e  i n t h e su m  o f th e  di a m e te rs o f ta rg et  l esio n s, t a ki n g as 
r ef ere n ce  th e  b as e lin e  s u m di a m e te rs. 
 
P ro g ressi v e  D is e ase  (P D ): A t l e ast a  2 0 %  in cr ea s e i n t h e su m  o f th e  d ia m e te rs o f tar g et  l esio n s, t aki n g 
as r ef e re nc e  th e  sm al lest  su m  o n  stu d y  (t his i nclu d es  t h e b as elin e  s u m if th at  is th e  sm al lest  o n 
st ud y ).  I n a d d itio n  to  th e  rel ati v e  in cr ea s e o f 2 0 %,  th e  s u m m u st al so  d e m o n strat e  a n a b so lu t e 
in cr e as e o f a t l ea st 5  m m . (N o te : t h e a pp e a ra n c e o f o n e  o r m o r e n e w  lesi o n s is als o  co n sid e re d 
p ro g r essio n s). 
 
St a b l e D ise as e  (S D ): N eit h e r s uffici en t s hrin ka g e  to  q u al if y fo r P R n o r s uffici en t in cr e as e to  q u al ify fo r 
P D , ta ki n g  a s re fer e nc e  th e  sm al lest  su m  di a m e te rs w h il e o n  st ud y . 
 
1 2 . 1.4 . 2 E v al u a tio n  o f N o n -T ar g et  Les io n s 
C o m p l et e R e sp o n s e (C R ): D is ap p e ar a n c e o f all n o n -t arg et  l esio n s a n d n o rm al izat io n  o f tu m o r m a rk e r 
l ev el.  All l y m p h n o d es  m u st b e  n o n -p at h o lo g ic al i n size  (< 1 0  m m  s h ort axis).  
 
N o te :  If t um o r m ar kers  a re  i niti ally  a b o v e  t h e u p p er  n o rm al l im it, th e y  m u st n o rm al ize  fo r a p ati e nt 
t o b e  co n sid er e d i n  co m p le t e clin ic al r esp o n s e. 
 
N o n -C R /N o n -P D : P e rsist en c e o f o n e  o r m o re  n o n -t arget  l esio n (s) a n d/ o r m ai n te n a n c e o f tu m o r 
m ar ker  le vel  a b o v e  t h e n o rm al l im its. 
 
P ro g ressi v e  D is e ase  (P D) : A p p e ar a n c e o f o n e  o r m o r e n e w  l esio n s a nd / or u n e q u ivo cal p ro g ress io n  o f 
e xistin g  n o n -t arg et  les io n s.  U n e qu ivo c al pro g r essio n  sh o u l d n o t n o rm al ly tru m p  tar g et  l esio n  st atu s. 
It m u st b e  re pr e se nt at iv e  o f o v er all di se as e  st atu s ch a n g e,  n o t a  sin g l e lesi o n  i ncre as e . 
 
A lt ho u g h a  cle ar p ro g ress io n o f “n o n -t arg e t” l esio n s o n l y is e xce p tio n al,  t h e o p in io n o f th e  tr ea tin g 
p h y sici a n s ho u l d pr e v ail i n  s uc h circu m st a nce s, a n d th e  p ro g re ssio n  st atu s s ho u l d b e  co n fir me d at  a 
l at er tim e  by  t h e re v ie w  p a n el ( or M SK C C  P rin cip al I nv es tig a to r). 
 
1 2 .1 .5   S ec o n d a ry R e sp o n s e Cri te ria  (C H O I fo r C T  a n d  E O R T C  fo r [1 8F ]-F D G -P E T ) 
 
C H OI crit eri a  d e ter m in es  re s p o ns e b a se d  o n  ch a n g es  in  siz e a n d tu m o r d e ns ity  (T a b l e 1 7 ) [3 3 ]. T his  is 
o f p artic ular  im p o rt an ce  i n GI S T,  as tu m o rs o fte n i n itia ll y re sp o n d  to  se lec tive  K I T in h ib itio n  w it h 
in fla m m a tio n  a n d  a  p ar a d o xic al in cr ea s e i n size  w it h a d ecr e a se  i n d e ns ity  pr io r to  d ecr e asi n g  i n size.  


P a g e 7 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
T a b le 1 7 : C H O I C rit eria : 
 
 
 
T o e v al u a t e fo r e arl y  t um o r re s p o nse  b as e d  o n  FD G -P E T,  t h e E O R T C  crite ri a [3 4 ]. T h e  E O R T C  FD G -P E T  
r es p on s e criteri a is d efi n e d  as  t h e fo llo wi n g : 
 
P ro g ressi v e  m e t a bo lic dis e as e  (P M D ) is cl assifie d as a n  i ncr e as e i n [1 8F] -F D G t u m o r S U V o f gre a ter 
t h a n 2 5 %  wit hi n  th e  tu m o r re g io n  d efi n e d o n  th e  b a s elin e  sc a n, v isib l e i ncre as e  i n t h e e xte n t o f [1 8F] - 
F D G  tu m o r up t ake  (> 2 0 %  in  th e  lo n g est  d im e ns io n ) o r th e  a p p e ar a n c e o f ne w  [1 8F] -F D G u p t ak e i n 
m e tast at ic l esio n s. 
 
St a b l e m e ta b o lic d ise as e  ( S MD ) is cla ssifie d as  a n i n cre as e  i n tu m o r [1 8F] -F D G SU V o f less  t h a n 2 5 %  o r 
a d ecr e a se  o f le ss th a n  1 5 %  a n d  n o  v isib l e i ncr e ase  i n e xte nt  o f [1 8F] -F D G t u m o r u p t a k e (> 2 0 %  i n t h e 
lo n g est  d im e ns io n ). 
 
P arti al  m e ta b o lic r esp o n s e (P M R)  is d efi n e d as  a  r e du ctio n  o f a  m in im u m  o f 2 5 %  in  tu m o r [1 8F] -F D G 
S U V aft e r 4  w e e ks  o f tr e atm e nt.  
 
C o m p l et e m e ta b o lic res p o n s e (C M R)  is d efi n e d as  co m p l ete  r eso lu tio n  o f [1 8F] -F D G  u p t ake  wit hi n  th e 
t um o r vo lu m e  so  t h at it w a s i nd istin g u ish a b l e fro m  su rro u n d in g  n o rm al tiss u e.  
 
1 2 .1 .6   N o t e v a lu a bl e  (N E ) 
 
W h e n n o  im a g in g/ m e as ur e m e nt  is d o n e  at  all at  a  p a rtic ular t im e  p o in t, t h e p atie n t is co n sid er e d n o t 
e v al u a b l e (N E)  a t t h at tim e  p o in t. 
 
1 2 .1 .7   E a rly  d e a t h 
 
If t h e p atie nt h as N O  re p e a t t um o r ass es sm e nts  fo llo wi n g  i niti atio n  o f st ud y t he r ap y  r es ultin g  fro m 
t h e d e at h o f t h e p atie nt d u e  to  dis e a se  o r tre a tm e n t, it is co n sid er e d  e ar ly  d e at h.  


P a g e 7 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 2 .1 .8  S y m p to m a tic D e t eri ora ti on  
 
P ati e n ts w it h glo b al d e ter io r atio n  o f h e alt h  st atu s re q u iri ng  disc o n tin u ati o n  o f tre a tm e nt  wit h o u t 
o b j ectiv e  e v id e nc e  o f dis e a s e p ro g ress io n at  t h at tim e  will b e  rec o rd e d as  “sy mp to m atic 
d e ter io r atio n ”. E ve ry eff o rt s ho u l d b e  m a d e  to  d o c um e nt o b jec tiv e  p ro g r essio n  e v e n af ter 
d isco n tin u at io n  o f tr eat m e n t. 
 
1 2 .1 .9   C o nfi rm a tio n  o f re sp o ns e  
 
C o m p l et e o r p arti a l res p o n s e m a y  o n ly b e  cl aim e d if th e  crit eria f o r e ac h  ar e  m et  at  a  s ubs e q u e nt 
tim e  p o in t (≥ 4 w e e ks  la te r) i n stu d i es wit h a  pr im a ry  e n d p o in t t h at i ncl u de  re s p o ns e ra te . W h e n 
r es p on s e r ate  is a se co n d a ry  e n d p o in t, co n firm a tio n  is N O T r e q u ir ed . 
 
1 2 .1 .1 0  S p e cia l n o t e o n  ta rg et  le sio n s th a t b e co m e  “to o  sm a ll to  m e a s ure ” 
 
W h il e o n  stu d y , all lesi o n s ( n od al a n d  n o n -n o d al)  re co rd e d at  b as eli n e  sh o u l d h av e  t h eir act u al 
m e as u re m e nts  re co rd e d at  e ac h  s ub s e qu e nt e v al u at io n , e v e n w h e n  ve r y sm all  (e .g . 2 m m ). H o w e ver, 
so m e tim e s, l esio n s o r ly m p h  n o d es  w hic h  ar e  re co rd e d  as  t arg e t l esio n s a t b as el in e  b e co m e  so  f ain t 
o n  C T  sc a n t ha t t h e r a dio lo g ist m a y  n o t fe e l co m fo rta b l e assi gn in g  a n e xa ct m e a s ure  a n d  m a y  re p o rt 
t h e m as  b ei n g  “to o  sm all  to  m e as u re .” W h e n th is o ccu rs, it is im p o rt an t t h at a v al u e  b e  re co rd e d o n 
t h e D 2 M  fo rm . If it is th e  o p in io n  o f t h e r a dio lo g ist th at  t h e les io n  h a s likel y  dis a p p e ar e d, t h e 
m e as u re m e nt s h o u l d b e  re co rd e d as  0  m m . If t h e les io n  is b el ie v e d to  b e  p res e n t a n d  is f ai ntly  se e n 
b u t to o  sm all  t o m e as ur e,  a d e fa u lt v a lu e  o f 5  m m  s ho u l d b e  assi g n e d.  
 
1 2 .1 .1 1  E v a l ua ti on  o f b e st o v e ra ll re sp o n s e wi th in  3 2  w e e ks  o f c o mb in a tio n  tre a t me n t b a se d  o n  
T a bl e  1 8 : 
 
T a b le 1 8 : 
 
T ar g et  lesi o n s 
N o n -t arg et  les io n s 
N e w  l esio n s 
O v er all  re sp o n s e 
C R  
C R  
N o  
C R  
C R  
N o n -C R /n o n -P D  
N o  
P R  
C R  
N o t e v al u a te d  
N o  
P R  
P R  
N o n -P D  o r n o t all  
e v al u a te d  
N o  
P R  
S D  
N o n -P D  o r n o t all  
e v al u a te d  
N o  
S D  
N o t all  e v al u a te d  
N o n -P D  
N o  
N E  
P D  
A ny  
Y e s o r N o  
P D  
A ny  
P D  
Y e s o r N o  
P D  
A ny  
A ny  
Y es  
P D  
 
 
*  If a C R is  tru l y m e t at  first tim e  p o in t, t h e n a ny  d ise a s e se e n at  a s u b s e qu e nt  tim e  p o in t, e v e n 
d is e as e m e e tin g  P R crite ri a re l ative  t o b a s elin e,  m a k e s th e  d is ea s e P D  at  t h at p o in t (sin c e dis e a se 
m u st h a v e  a p p e ar e d a fte r C R). H o w e v er,  so m e tim es  “C R”  m a y  b e  cl aim e d w h e n  s ub s e qu e nt sc a n s 
s ug g est  sm all l es io n s w e re  li ke l y still p r ese nt a n d  i n fa ct t h e p ati e nt  h a d  P R  o r S D , no t C R at  th e  first 


P a g e 7 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
tim e  p o in t. U n d er  t he s e circ u mst a nces,  t h e o rig in al C R s h o u l d b e  ch a n g e d to  P R  o r S D a n d  th e  b est 
r es p on s e is P R  o r SD . 
 
1 2 .1 .1 2  D u ra tio n  o f re sp o n s e 
 
D efi n e d a s th e  tim e  m e as u r em e nt crite ri a a re  first m e t fo r C R /P R  u n til t h e first d at e  th a t r ec urre nt  o r 
p ro g r essiv e  d ise as e  is o b je ctiv e ly  d o cu m e nt e d  (t a ki n g as  r efer e n ce  fo r pr o g ressi ve  d is e ase  t h e 
sm al le st m e as u re m e nt re co rd e d  o n  stu dy ). 
 
1 2 .1 .1 3  D u ra tio n  o f sta bl e  d ise a s e 
 
M e as u re d fr o m  t h e st art o f th e  tre a tm e nt  u n til t h e crite ri a fo r pro g r essio n  ar e  m e t, ta ki n g  as 
r ef ere n ce  th e  sm al le st su m  o n  stu d y  (if t h e b aseli n e  su m  is t h e sm al les t, t his is t h e re fe r e nc e fo r 
c alcu l atio n  o f P D ). Fo r th e  P h as e  II p o rtio n , st art o f tre a tm e nt is  d efi n e d as  th e  st art o f th e  im ati n i b 
l e ad -i n p eri o d . 
 
1 2 .1 .1 4  P ro g re ssio n -F re e  S u rvi va l (P F S)  
 
P F S  is d efi n e d  as  th e  p er io d  fro m  st art o f stu d y  tre a tm e nt u n til r ec urre nt  o r pro g r essiv e  o f dis e a se 
(P O D ) is o b jec tivel y  d o cu m e nt e d (t aki n g as  ref e re nc e  fo r pro g r essiv e  d ise as e  th e  sm al le st 
m e as u re m e nt re co rd e d  o n  st ud y ), d e at h,  o r d ate  o f la st co n t act. Fo r t h e P h as e  II p o rtio n , sta rt o f 
tr e atm e nt  is d efi n e d  as  th e  start  o f t h e im ati n i b le a d -i n p eri o d . 
 
1 2 .1 .1 5  O v er a ll S u rvi v a l (O S ) 
 
O S is d efi n e d a s th e  o b ser ve d l e n g t h o f lif e fro m  st ud y e n try to  d e at h  o r th e  d a t e o f l ast co n tact.  
 
 
1 3. 0  
C RI T E RI A  F O R  R E M O V A L F R O M S T U D Y  
 
P ati e n ts w ill b e  re m o v e d f ro m  stu d y  w h e n a n y o f th e  crit eri a liste d  b e lo w  a p p li es. T h e  re a so n  fo r 
st ud y  re m o v al  a n d  th e  d a te  t h e pa ti e nt w as  re m o v e d  m u st b e  d o c um e nt e d i n  t h e E D C sy ste m . 
P ati e n ts o n  th e  P h a se  II stu d y  m a y  b e  re p l ace d if t h ey c o m e  o ff st ud y  fo r re as o n s o t h er t h a n 
p ro g r essiv e  d ise as e p ri or to  re c eiv in g  th eir fir st d o s e o f B GJ3 9 8 . Un l ess o t h er wise  st ate d, p at ie nts  will 
b e  in clu d e d i n  th e  s af ety  a n d / or effic a cy  a n a lysis as d es crib e d i n  S e ctio n  1 4 . 
 
A d o s e i nt erru p tio n o f ≥ 2 8  d a ys  will r e q u ir e th e  p a tie n t t o b e d isco n tin u e d f ro m  t h e st ud y  (w it h t h e 
e xc e ptio n  o f p atie nts  w h o  u n d er g o  s ur ge ry ). Lo c al pr oc e d u re s (e. g. s u r ge ry, e m b o lizati o n ) ar e 
p er m itte d  o n  th is tri al a) if clin ic all y in d ic ate d o r b) if  res p o n s e to  th e ra p y  co nv e rts t h e p ati e nt i n t o a 
s ur gic al c an d id at e . All dr ugs w ill b e h el d  fo r at le ast  o n e  w e e k  pr io r t o th e  lo c al pr oc e d u r e. P a ti e nts 
will  r esu m e  t h er ap y  w h e n  d e e m e d cli n ic ally  s afe,  b u t n o  so o n er  th a n  1  w e e k  a n d  n o  l ater  t h a n 5 
w e e ks  af ter  th e  p ro c e du r e. If a p ati e n t f alls o u t o f t his wi n d o w,  co n sid er at io n  s ho u l d b e  h a d  fo r 
wit h d r a w al fro m  th e  st ud y b as e d o n  clin ic al re a so n s fo r th e  d el a y . P ati e n ts w h o  h a v e  h a d  a  lo c al 
p ro c e du r e w ill b e all o w e d  to  re m ai n  o n  th e  st ud y  if th e y  h a v e  m e as ur a b l e dise a se  ( R E CIST  1 .1 ) a fte r 
t h e pro c e du r e. P at ie nts  w h o  ar e  re n d e re d d is e ase  fre e  will  b e  t ake n  o ff t h e stu d y  a n d  c a n b e 
co n sid er e d  fo r a dj u v a n t im ati n i b p er s ta n d ar d  o f ca r e. C o n v ers io n  to  res e ct a bility  r ate  will  b e  a 
s ec on d a ry  e n d p o in t. 


P a g e 8 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
D u ra tio n  o f T h e ra p y : I n th e  a b s e nce  o f tre a tm e nt d e la ys  d u e  t o a dv e rs e e ve nts,  tr e atm e nt  m a y 
co n tin u e  u n til o n e  o f th e  fo llo wi n g  criteri a a p p li es: 
 
•  D is e ase  p ro g r essio n , 
•  In te rcu rr en t illn ess  t ha t p re v e n ts f urth er  a d m in istr atio n  o f tre a tm e nt,  
•  U n acc e p t a ble  a d vers e e ve n ts(s), 
•  P ati e nt  d eci d e s to  wit h d ra w  fro m  th e  st ud y , o r 
•  G e n er al  o r s pe cific c ha n g e s i n t h e p atie nt's co n d itio n  re n d er  t h e p ati e nt  u n acc e p ta b l e fo r 
fu rt h er tre a tm e nt i n  t h e ju d g m e nt  o f th e  inv es tig a to r. 
•  In a b ilit y o f th e  p a ti e nt t o co m p ly  w it h t h e re q u ire m e n t o f t h e pro to co l fo r tre a tm e nt  o r 
e v al u at io n . 
 
D u ra tio n  o f Fo llo w  U p:  P a ti en ts will  b e  fo llo w e d  fo r to xiciti es 4  w e e k s a fte r la st d o s e o r un til d e at h, 
w hic h e ver  o cc urs first. P at ie nts  re m o ve d f ro m  stu d y  fo r un ac ce pt a b l e ad v er se  e ve nts  will  b e 
fo llo w e d  u n til re so lu tio n  o r sta b ilizati o n  o f t h e ad v er se  e v e nt.  F or  P h a se  II, stu d y  p ers o n n el  w ill 
att e m p t t o co llect  s urv iv al  st atu s fo r all pa ti e nts aft er  t h e e n d -o f-st ud y v isit e v ery  3  m o n t hs via 
te l ep h o n e,  e m ai l, o r o th er  m e th o d  fo r u p to  3  y e ars.  
 
1 4. 0     BI O S T A TI S T IC S  
 
T his  is a  m u lti in stit utio n si n g l e ar m  p h as e  Ib/ II tri al t o e v al u at e  th e  clin ic al sa f ety  a n d  effic a cy o f 
im ati n i b a n d  B G J3 9 8  i n p ati e nts  wit h  a d v a n c e d G a stro in tes tin al  Stro m al  T u m o rs.   P at ie nts  i n t h e 
P h as e  I b p o rtio n  o f th e  trial  ar e  r e qu ir e d to  h a v e  m e tast a tic a n d  o r lo c ally a d v a n c e d GI ST  t h at h as 
b e e n  tre at e d wit h  im ati n ib . P ati e n ts o n  t h e P h a se  II p o rtio n  o f  t h e st ud y  a re  r e qu ir e d  t o h a ve 
a d v a n c e d GIS T  a n d  n o t h a ve  r ecei v e d a ny pr io r sy st em ic t h er ap y  ( un tr e ate d /tre at m e nt n aï ve).  
 
P h a s e 1 b  P or tio n  S tu d y  D e si gn  a n d E n d p o in t A sse ssm e n t 
 
T h e  p ri m ary e n d p o in t o f th e  p h as e  1 b  p o rtio n o f t his st ud y  is t o d e ter m in e  th e  m ax im u m  to ler at e d 
d o s e (M T D ) a n d tr e a tm e n t sc h ed u l e o f B G J3 9 8  a d m in iste r e d i n co m b in at io n wit h i m ati n i b i n p ati e nts 
wit h  GI S T.  T h e  p h as e  I b will  b e  p u rsu e d  i n st a nd ar d  3 + 3  fo rm a t, b as e d  o n to xicities  e nc o u n ter e d 
d u rin g  th e  first cy cl e o f th e r ap y . 
 
T h e  d o se  e sc al atio n  sc he m a  is liste d  i n T a b l e 1 . D o s e es cal a tio n will  p ro c ee d  wit hi n  e ac h c o h o rt 
acc o rd in g  t o T a b le  2 . T h e fi rst t hr e e p ati e nts  will  b e  e nr oll e d  at  D o s e Le vel  1 . If d o s e l ev el  1  is n o t 
fo u n d  t o b e  to l er ab le,  t he n  t h e n e xt co h o rt will  b e  e nr oll e d  a t d o se  le v el  -1 .  If d o s e le vel  -1  is n o t 
fo u n d  t o b e  to l er ab l e, th e n  t h e n e xt co h o rt will  b e  e nr oll e d  at  d o s e le v el  -2 . If d o s e le vel  -2  is n o t 
fo u n d  t o b e  to l er ab le , th e n  t h e st ud y m ay  b e  te rm in at e d  b a se d  o n  d isc ussio n s wit h  t h e M S K C C 
P rin cip al  Inv es tig a to r. If 0 o r 1  o f 6  p a ti e nts e xp eri e n c e a  D LT  o n  d o se  le vel  3 , th is will  b e  th e  R P 2 D 
u n l ess a l o w er  d o se  is s ele cte d  b as e d o n  c hro n ic to le r an c e o f th e  co m b in at io n a n d p h ar m ac o kin e tic 
d at a.  Lo w er  d o s e l evels  m a y  b e  e xp a n d e d  a n d  a n  R P 2 D  lo w e r t h a n th e  M T D  m a y  b e  s elec te d  b as e d 
o n  s af ety  a n d  c hro n ic to le ra n c e co n sid er a tio n s b y th e  M S K C C  P rin cip al  In ve stig a to r. If d o s e le v el  1  to  
-2  is id e ntifi e d  as t h e M T D  a n d  co n c er n e xists re g a rd in g  t h er ap e utic  a ctiv ity o f B GJ3 9 8  at  t his d o s e 
l ev el,  e x p an sio n s w it h h ig h er  d o s e l ev els  ( 1 to  3 ) m a y  b e  co n sid e re d  at  t h e M S K C C  P I’s d iscr etio n , 
wit h  m o d ific atio n  o f t h e tre a tm e nt  sc h ed u l e.    W h e n t h e R P 2 D  is fo u n d , a n y  p ati e nts  fro m  t h e P h as e 
I b p o rtio n  o f th e  st ud y  w h o  re m ai n  o n  th er a p y  b el o w  th e  M T D  m a y  h a v e  t h eir B G J3 9 8  d o s e in cre as e d 
t o t h e M T D  at  t h e tr e atin g  p h y sicia n ’s discre tio n.  


P a g e 8 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
T h e  s eco n d ar y e n d p o in ts o f t h e p h a se  1 b  p o rtio n  a re  (1 ) R es p o n s e R at e ( R R) d efi n e d  b y R E CI ST  1 .1 
crit eri a a n d  b y C H OI  criter ia,  (2 ) P ro g r essio n  F re e  S u rv i v al (P F S ), (3 ) Cli nic al B e n efit  R a te  ( CB R)  at  3 2 
w e e k s, a n d  (4 )  B GJ3 9 8  p h ar m a co kin e tic p ar a m e te rs, s uc h as  ar e a  u n d er  t h e  c urve  ( AU C)  a n d 
m ax im u m  co n c en tr atio n  ( Cm ax ). R R  will  b e  e stim a te d  as  t h e p ro p o rtio n  o f p ati e nts  w h o  h a ve 
co m p l ete  r esp o n s e o r p a rti al r es p on se  fo r e a c h crit eri o n. P F S will  b e  c alcu l at e d u sin g  K a p la n -M e ier 
es tim at e  a m o n g  all  p ati e n ts e nr ol le d  at  e ac h  d o s e le v e l. P ati e n ts w h o  h a v e  n o t e x p erie n ce d  t h e 
e v e nt o f in te rest  b y  t h e e n d  o f t h e st ud y will b e  ce n so r e d at  th e  tim e  o f t h e last  fo llo w -u p . P l asm a 
co n c e ntr atio n s o f B G J3 9 8  will  b e  a n a lyze d at  m u ltip le  tim e  p o in ts a n d  e x pr esse d  as a  m e a n  + /- S E.  
 
T h e  p h as e  I b p o rtio n  o f th e  st ud y  will  h a v e  a  m in im u m  sa m p l e size  o f 6  p at ie n ts a n d  a  m ax im u m  o f 
3 0 .  W e  e xp e ct to  ac cru e  a p p ro xim a te ly  2  p a ti e nts e a c h m o n t h, a n d  h e nc e  e xp e ct to  fin is h t h e p h a se  
1 b  p o rtio n  o f th e  st ud y  i n a p p ro xim a te ly  9 -1 5  m o n t hs. 
 
E v al u a b l e p ati e nts fo r s af ety  a n a ly sis in clu d e  all p a ti e nts w h o  h a ve  r ece iv e d o n e  d o s e o f im ati n i b pl u s 
B G J3 9 8 . P at ie nts  w h o  sto p  t h er ap y b ef o r e C y cl e 2 , D a y  1  fo r r ea so n s o t h er t h a n to xicity will  b e 
r e plac e d  i n t h e P h as e  I st ud y  fo r t h e p u rp o s es o f e va lu ati n g  t h e DL T.  E v al u a b l e p ati e nts  fo r effi ca cy 
in clu d e  all  p ati e nts  w h o  h a v e  re c eiv e d o n e  d o s e o f im ati n i b p lu s B G J3 9 8 . P a ti e nts w h o  a re  m issin g  a n 
ass es sm e nt  o f re sp o n s e p o st b as eli n e will  b e  co n sid e re d n o n -r esp o n d ers  fo r t h at tim e  p o in t. 
 
P ati e n ts o n t h e  P h a se  I p o rtio n  o f t h e st ud y  will  n o t b e  in clu d e d  i n t h e fin al  ef fic ac y a n a lysis d u e  to 
d iffer e nc es  i n t h e eli g ib ility crit eri a i n t h e tw o  p h as e s. 
 
P h a s e 2  P o rtio n  S tu d y  D es ig n  a n d  E n d p o in t A sse ssm e n t 
 
T h e  p ri m ary e n d p o in t o f th e  p h as e  II p o rtio n  o f t h e st ud y  is to  as sess  R es p o n se  R at e  ( C R+ P R,  R E CI S T  
1 . 1) a fte r 3 2  w e e k s o f co m b in ati o n t h er a p y . I n o rd er  t o d e tect  a  2 0 %  im p rov e m e nt  i n t h e R R  o v er 
im ati n i b al o n e  ( un acc e p ta b l e r at e o f 4 5 %;  a cce p ta b l e r at e o f 6 5 % ), 4 4  P h a se  II p ati e nts  will  b e 
e nr oll e d. At  t h e e n d  o f th e  st ud y , if > 2 4  p a ti e nts h a v e  h a d  a  d o c um e nt e d res p o n s e b y  R E CI S T  1 .1 , th e 
st ud y  will  b e  co n sid er e d  p o sitiv e  a n d  th e  tre a tm e nt r e g im e n  will  b e  co n sid er e d  w o rt hy o f fu rt h er 
in v es tig at io n . T h e  st ud y  d e sig n  is b as e d  o n  a n  e xa ct B in o m i al te st a n d  h as  a  o n e -sid e d  ty p e  I e rro r o f 
0 . 0 8 a n d  a  typ e  II e rro r o f 0 . 1. 
 
W e  e x p ect to  ac cru e  2  p a ti en ts e a c h m o n t h, a n d  h e n c e e xp ect  t o fin is h t h e p h as e  2  p o rtio n o f t h e 
st ud y  i n 2 4  m o n t hs. 
 
R es p o n se  r at e ( R E CI S T 1 .1 ) will  b e  d e te rm in e d  as  th e  p ro p o rtio n  o f p at ie nts  e v al u a b l e fo r ef fica cy 
( d efin e d  as  p a ti e nts wh o  rec e iv e  a t l ea st o n e  d o se  o f t h e co m b in at io n  r e gim e n)  w h o  h a ve  co m p l et e 
r es p on s e o r p a rti al r esp o n s e d efi n e d  b y t h e R E CIST  1 .1  wit h a  o n e -sid e d  9 0 %  co n fid e nc e  in te rv al  ( CI) 
p ro v id e d.  P a ti e nts m issin g  p o st b as eli n e  ass e ssm e nt  o f r es p on se  will  b e  co n sid er e d  n o n -r esp o n d ers 
fo r th e  p ri ma ry e n d p o in t a t th at  tim e p o in t. 
 
T h e  ste a d y sta t e  s eru m  i m ati n i b tro u g h  l evels  will  b e  o b t ain e d  a n d  e val u at e d  i n t h e tw o -w e e k 
im ati n i b l e a d i n p h as e  (t w o sa m p le s/p at ie nt)  a n d  i n t h e co m b in at io n  t h e r ap y p h as e  ( 2 
s am p l es/p ati e n t) fro m  all p ati e nts  i n th e  P h a se  II p o rtio n o f t h e tri al. W e  will  e v al u at e  t h e eff e cts o f 
B G J3 9 8  o n  im a tin i b ste a d y  sta t e tro u g h  le vels  b y  co m p ar i ng  t h e v al u es  a t th es e  t wo  tim e  p o in ts 
( b efo re  a n d  aft er  l e a d i n p eri o d ). W e  will  co m p ar e  th e  r an g es  w e  o b t ai n wit h th e  r an g es  r e p orte d  b y 
D e m e tri e t al JC O  2 0 0 9  a n d  ass e ss w h et h er  t h e e ffe cts ar e  co n sid er e d  s ub t h er ap e u tic, t h er ap e utic,  o r 


P a g e 8 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
s up r a-t h er ap e utic.  T his  a n al ysis  m ay  in fo r m fu t ur e tria ls wit h  t his co m b in ati o n  a n d  will  n o t c ha n g e 
t h e do se  t ha t will  b e  g ive n in  th e  co m b in ati o n  re gi m e n . 
 
T h e  se co n d a ry  e n d p o in ts o f th e  p h as e  2  p o rtio n  i nclu d e:  
(1 )  R R  b y  C H OI cri teri a.  It will  b e  d e ter m in e d as th e  p ro p o rtio n  o f p atie nts  e val u a b l e fo r e ffic acy w h o 
h a v e  co m p l ete  re s p o ns e o r p arti a l r esp o n s e d efi n e d b y  th e  C H OI cr ite ri a wit h a  tw o -sid e d  9 5 %  CI 
p ro v id e d.  
(2 )  R R  b y E O R T C cri teri a.  It will  b e  d e ter m in e d as  t h e pro p o rtio n  o f p ati e n ts e v al u a b le  fo r e ffica cy 
w h o  h a ve  co m p le t e res p o n s e o r p arti al res p o n se  d efi n e d by  th e  E O R T C  crit eri a w it h a tw o -sid e d  
9 5 %  CI p ro v id e d.  
(3 )  P ro g ress io n  fr e e s urvival  a n d  O v er all  S u rv ival. P F S a n d  O S  will b e  c alcu l ate d us in g a  K a p la n -M ei er 
es tim at e  a m o n g  all p a ti e nts e n ro lle d.  T h e y  ar e  d efi n e d  fro m  th e  sta rt o f im ati n i b tr e atm e nt, i.e . 
t h e le a d  i n p eri o d  is i nclu d e d i n  t his e n d p o in t. P ati e n ts o n t h e  P h as e  II p o rtio n w h o  sto p  stu d y 
p ri or to  re c eiv in g  a  d o s e o f B G J3 9 8  fo r r ea so n s u n r el ate d t o p ro g ressi o n  (e. g . in to l er an c e t o 
im ati n ib ) will  b e  c e nso r e d at  t h e tim e  o f wit h d r a w al. P ati e n ts w h o  h a ve  n o t h a d  t h e e v e nt  o f 
in te r est b y  t h e e n d  o f t h e st ud y  w ill b e  c e nso re d at  t h e tim e  o f l ast fo llo w -u p.  
(4 )  R es e ct a bilit y r ate . It will  b e  c alcu l at e d b y  th e  p ro p o rtio n  o f P h a se  II p at ie nts  w h o  h a v e  co m p le te d  
1  cy cl e o f tr e at me nt  w h o  h a v e  res e ctio n  o f th eir d ise a s e w it h a tw o -sid e d 9 5 %  CI  p ro v id e d.  
 
F or  th e  p u rp o se  o f e x plo r ato r y st ud ie s, th e  p h as e  2  p o rtio n  in clu d es  t h e p h e n o ty p ic (b y IH C),  g e n et ic, 
tr an scrip to m ic, e p i ge n eti c,  an d  p h ar m ac o d y n a m ic ch ar act eriz at io n  o f t h e tu m o rs as  co rrel at iv e 
e n d p o in ts.     T w e n ty  p at ie nts  ar e  p l an n e d  to  h a v e  m a n d a to ry  p ai re d  b io p si es  ( pre  a n d  p o st 
tr e atm e n t), a n d t h e  r em a in in g p ati e nts  will  p rov id e  o p tio n al  b io p sies  if fu n d in g is  id e ntifi e d . T his 
s am p l e size  p rov id es  8 0 %  p o w e r to  d e te ct a  st a nd a rd ize d  d iffer e nc e  o f 0 .5 5  a ss u mi n g 2  sid e d  o n e 
s am p l e p aire d t  te st at  1 0 %  si gn ific an c e le v el.  T h e  v ar ia b l e o f i nt ere st will  b e  c ha n g e  i n pr o tei n l e v els.  
 
T h e  a n al ys is of th e  e x plo r ato r y st ud i es is pl a n n e d as fo llo ws.  
1 )   E T V 1  p ro tei n l e vel b y  w es ter n b lo t (W B ) as a  co n tin u o u s v ar ia b le . T h e  c ha n g e  o f E T V 1  p ro tei n 
l ev el  (b e fo r e v s. afte r t h e co m b in at io n  th er a p y ) w ill b e  r eco rd e d a s up , do w n, a n d  n o -c ha n g e 
(c at eg o ric al res p o n se ). It w ill b e t ab u l at e d w it h t h e pe rc e nt ag es  pr o v id e d.  It will  b e  co rrel a te d 
wit h r es p o n s e usi n g  th e  Fish er’s  e xact  te st. 
 
2 )   E T V 1 -d e p e n d e nt tr an script o m e  (e xp r essio n  p ro file  o f E T V 1 -d e p e n d e nt g e n e  tar g e ts) b y 
n a n o strin g . T h e e xp re ssio n  ch a n g e  o f E T V 1  ta rg et  g e n es  ( b efo r e v s. aft er  th e  co m b in ati o n 
t h er ap y ) will  b e  co rr el ate d  wit h  clin ic al res p o n se  u sin g  th e  Wilc o xo n  ra n k  tes t. T h e o u tco m e  w ill 
b e  a co m p o site  sco re  ( b ase d  o n  g e n e  e x pressi o n  le vel  a n d  di rec tio n al it y o f t h e ch a n g es ), a n d it is 
co n tin u o u s v ar ia b le.  
 
3 )   C ell p ro lifer at io n  (K i-6 7 ) a n d  a p o p to sis (cle a v e d c as pa se -3 ) b y  IH C.  D es crip tive  statistics  will  b e 
p ro v id e d.  T h es e  var ia b les  a r e co n tin u o u s. 
 
4 )   M A P  ki n as e  p at h w a y  a n d  o t h er p ath w a y s d o w n str ea m  o f K IT  a n d  F G F si g n al i ng  u sin g  sta n d ar d 
a n tib o d i es (p h o s ph o -E R K,  p h o s ph o -KI T,  p h o s ph o -M E K,  p h o s ph o -A K T,  e tc) b y IH C. D e scrip tive 
st atistics w ill b e  p ro v id e d.  
 
5 )   KI T /P D G F R A  m u t atio n al s ta t us i n m a tc h e d t um o r bio p s y s pe cim e ns co ll ecte d  pr io r t o th er a p y , 
aft er  co m b in ati o n  th er a p y a n d  u p o n  dis e as e  pr o g ress io n . F GF R a n d  F G F2  e x pres sio n  o n  t um o r 


P a g e 8 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
s am p l es by  IH C a n a ly ze d as  a  b in ar y  co v ar ia te  a n d  F G F 2  lig a n d  l ev els i n  co lle cte d  se ru m  by  E LIS A  
a n al yz e d  as  a  co n tin u o u s co v ar ia te . 
 
6 )   P ro te i n e x pr essio n  o f F GF 2 , s V E G F R1 , s V E G FR 2 , V E G F -A,  -C,  -D , c KIT,  PL G F , a n d  T ie 2  i n t um o r 
tiss u es utilizin g  co m m erci a ll y a vai la b l e im m u n o ass a y  kits. T his will  b e  a  co n tin u o u s v ar ia b l e. 
 
7 )   Ex pr ess io n  o f g e n es  im p licat e d  i n GIS T  p a t ho g e n esis  a n d  si gn al i n g, i ncl u din g  K I T, E T V 1 , F GF R 1 , -2 , 
-3 , a n d -4 ; D U S P 6 , SP R Y 2 , a n d  S P R Y 4  w ill b e  a n al y ze d  as a  co n tin u o u s co v ar ia te.  C h a n g es  b ef o re 
a n d  aft e r tre a tm e n t will  b e  ass e sse d a n d  co rr ela te d  wit h cli n ic al re sp o n s e. 
 
I n m o st o f th e  a b o v e  stu di e s, w e  ar e  in te re ste d  i n lo o kin g  at  ch a n g es  i n e xp r essio n  l ev e ls, pro te i n 
m e as u re m e nts,  o r m u t atio n  stat us b e fo re  a n d  af ter  tre a tm e nt.  T h e  co rr ela tiv e  e n d p o in ts 
d es crib e d a b o v e  w ill b e  co rr el at e d wit h res p o n se  ( bi na r y o u tc om e  d efi n e d  as C R + P R usi n g  R E C IS T  
1 . 1). T h es e  a n a ly ses  a re  ex p lo r ato r y i n n a t ur e a n d n o  a d ju stm e n t fo r m u ltip l e co m p ar iso n s w ill 
b e  m a d e.  
 
 
 
1 5. 0  
R E S E A R C H  P A R TI C IP A N T  R E GI S T R A T I ON  A N D R A N D O M IZ A T IO N  P R O C E D U R E S  
 
1 5. 1  
R e s ea rc h P a rticip a n t R e g istra ti o n 
 
C o n firm  e lig ib ility as  d efi n e d  i n t h e se ctio n  e n titl e d Crite ri a fo r P ati e n t/S u b j ect El ig ib ility . 
 
O bt ai n  i nfo rm e d  co n se nt,  b y  fo llo wi n g  p ro c e du res  d e fin e d i n  se ctio n  e ntitl e d I n fo rm e d C o n s e nt 
P ro c e du r es. 
 
D u rin g  th e  re gistr at io n  p ro c ess re gist e rin g  i nd ivi du als  will  b e  re q u ir e d to  co m p l ete  a  p ro to co l s p ecific 
Eli g ib ilit y C h e cklist. 
 
A ll pa rticip a n ts m u st b e  r egist ere d  t hr ou g h  th e  P ro to co l P artici p a n t R e gistr a tio n  (P P R)  Off ic e a t 
M e m o rial S lo a n -K e tteri n g  C a n c er C e n te r. P P R is  a v ai la b l e M o n d a y  t hr ou g h  Fr i da y  fro m  8 :3 0 a m  –  
5 :3 0 p m  at  6 4 6 -7 3 5 -8 0 0 0 . R e gistr at io n s m u st b e  s ub m itte d  v i a th e  P P R  El e ctro n ic R e gistr at io n  S yste m  
(h ttp ://p p r/).  T h e  co m p l ete d si g n at u re  p a g e  o f th e  w ritt e n co n s e nt/R A  o r v e rb al scri p t/R A, a 
co m p l ete d Eli g ib ilit y C h ec k list a n d o t h er rel e v a n t d o cu m e nts  m u st b e  u p lo a d e d  via t h e  P P R E lec tro n ic 
R e gistr at io n  S yste m . 
 
1 5 .1 .1   R e gi stra tio n  fo r P a rticip a tin g  S it es 
 
C e ntr al r e g istr atio n  fo r th is stu d y will  t ake  p l ace  at  M e m o rial S lo a n -K e tteri n g  C a n c er C e n te r (M S K C C).  
 
T o  co m p l ete  r e gistra tio n  a n d  e nr oll  a  p artici p a n t fro m  a n o t h er in stitu tio n , t h e st ud y  st aff a t t h at sit e 
m u st co n ta ct th e  d esi g n a t ed  re s e arc h st aff a t M S K C C  to  n o tif y h im /h er  o f th e  p a rticip a n t r e gistrati o n . 
T h e  sit e st aff th e n  n e e d s to  e m ail  r e gistr atio n/ eli g ib ilit y d o c um e nts  to  t h e M u ltic e nt er Tri al C o re  at 
M S K C C a t m e d m ctco re @ m s kcc.o r g. 
 
T h e  fo llo wi n g  d o c um e nts  m u st b e  s e nt fo r e a c h e n ro llm e nt  wit hi n  2 4  h o u rs o f th e  in fo rm e d  co n s e nt 
fo r m b ei n g  si gn e d:  
•  T h e  co m p le te d  o r p arti ally co m p l ete d M SK C C  eli g ib ility  c h ecklist 


P a g e 8 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
•  T h e  sig n e d i n fo rm e d co n se n t a n d  H IP A A  A u th o rizati o n  fo rm  
•  S u p p o rtin g  so u rce  d o cu m e n t atio n  fo r eli g ib ility q u es tio n s (l ab o r ato ry r es ults, p at h o lo g y  re p o rt, 
r ad io lo g y  r e p orts, M D  n o te s, p h y sic al exa m  s he e ts, m e d ic al h isto ry, p ri or tr e at me nt r ec o rd s, a n d 
E K G  r ep o rt) 
 
U p o n  re cei p t, t h e res e arc h  st aff at M S K  w ill co n d u ct a n  i nt eri m re v i e w o f all d o cu m e nts.  If th e 
eli g ib ilit y ch e cklist is n o t co m p l ete  o r so u rc e d o cu m e n t atio n  is m issin g , th e  p arti cip a n t will  b e 
r e giste r e d P E N D IN G a n d  th e  sit e w ill b e  r esp o n sib l e fo r se n d in g  th e  co m p l ete d r e g istr atio n 
d o c um e nts  wit hi n  3 0  d a y s o f th e  co n s e nt. 
 
If t h e e xter n a l re g istra tio n  s ub m issi o n is co m p l ete , th e  p artici p ati n g  sit e IR B h as  g r an te d  a p p ro v al fo r 
t h e pro to co l, a n d  th e  sit e is i n g o o d  sta n d in g , th e  M SK  r ese arc h  st aff will  s e n d t h e co m p l ete d 
r e gistr atio n  d o c um e nts  to  th e  M S K  P P R  Offic e  fo r p art icip a n t e nr ol lm e nt as  st ate d i n  se ctio n  1 5 .1 . 
 
 
O nc e th e  p artici p a n t is r e giste r e d, t h e p articip a n t will  b e  assi g n e d a n u m b er  i n th e  M SK  Cl i nic al 
R es e a rc h D a t a b as e ( CR D B).  T his n u m b er  is u n iq u e  t o th e  p artici p a n t a n d  m u st b e  w ritte n o n  all d a t a 
a n d  co rre s p o nd e n ce  fo r th e  p artici p a n t. T h is pro to co l pa rticip a n t n u m b er  will  b e  r ela y e d b a ck  to 
st ud y  staff  at  t h e re gist e rin g  sit e v i a e -m ail  a n d  w ill se rv e  as  th e  e n ro llm e nt co n firm at io n . 
 
1 5. 2  
R a n d o mi za tio n  
 
N O T  A P PL I CA BL E  
 
1 6. 0  
D A T A  M A N A G E M E N T  IS S U E S  
 
A R es e a rc h St u d y  A ssist a nt ( R SA ) will  b e  assi g n e d  t o th e  st ud y . T h e  re sp o n sib ilitie s o f t h e R S A in clu d e 
p ro j ect co m p li an ce,  d at a  co ll ectio n , a bstr actio n  a n d  e n try , d at a re p o rtin g , re g u la to r y m o n ito rin g , 
p ro b l e m re so lu tio n  a n d  pr io ritizat io n , a n d co o rd in at e  t h e activ ities  o f th e  pr o to co l st ud y  te a m . 
 
T h e  d at a  co llec te d f o r th is st ud y  w ill b e  e n te r e d in t o a se c ure  d at a b as e  (M e d iD a ta R A V E).  So u rc e 
d o c um e nt at io n  w ill b e  a v a il ab l e to  s up p o rt th e  co m p u te rize d p a tie nt r e co rd . 
 
1 6 .0 .1   D a ta  a n d  S o u rc e D o cu m e n ta tio n  fo r P a rticip a tin g  S ites  
 
D a t a 
T h e  p artici p ati n g  sit e(s) wi ll e nte r da t a re m o tel y  i nto  a n i n te rn e t-b a se d El e ctro n ic D a ta C a pt u r e 
sy ste m , te rm e d  M e d iD a ta  R A V E . St an d ar d ize d El e ctro n ic C as e  R e p o rt Fo rm s (e C R Fs) a n d  d at a  e ntr y 
g u id eli n es  h a ve  b e e n  g e n e rat e d  fo r th is st ud y . Th e  site  staff  will  r ecei ve  M e d i Dat a  R A V E tr ai n in g  pr io r 
t o e nr ollin g  its first p a ti e nt t hr ou g h  a  seri es  o f e -M o d u l es. T h e p a rticip ati n g  Si te  P I is r esp o n sib l e fo r 
e ns u rin g  th es e  fo rm s a r e co m p le te d a cc ura tely  a n d  i n a  tim e ly  m a n n er.  P artici p a tin g  site s will  b e 
r es p on sib l e fo r fillin g  o u t th es e  e C R Fs a n d  s ub m itti n g t h e m to  M SK C C  p er  th e  d e sig n at e d  tim eli n es.  
 
S o u rce  D oc u m e n ta tio n  
S o u rc e d o cu m e nt a tio n  ref e rs t o o rig in al re co rd s o f o b se rv at io n s, clin ic al fin d in g s a n d  e v al u at io n s th a t 
ar e s u b s e qu e nt ly  re co rd e d  as d at a. S o u rc e d o cu m e nt a tio n  sh o u l d b e  co n siste nt  w it h d at a e n ter e d 
in t o e C R Fs.  R el e v a n t so u rce  d o cu m e n t atio n  to  b e  re v ie w e d b y  th e  stu d y m o n ito r th ro u g h o u t th e 
st ud y  i ncl u de s: 


P a g e 8 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
•  B as eli n e  m e a s ures  t o ass ess pre – p ro to co l dis e a se  stat u s (e x. C T, P E T S ca n , EK G, E C H O,  M U G A , 
e tc.) 
•     Tr e a tm e nt  re co rd s 
•     Gr a d e  3 -5  to xiciti es/a dv er se  e v e nts  n o t pr e v io u sly s ub m itte d w it h SA E  R e p o rts 
•     R es p o n se  d esi g n at io n  
 
S o u rc e d o cu m e nt a tio n  sh o u l d in clu d e  a  m in im u m  o f tw o  id e ntif iers  to  al lo w  fo r d at a  v e rific atio n . 
M S K  will  m ai n t ai n th e  co n fid e nti a lity o f an y  s ub je ct-id e ntifi a b l e i nf orm a tio n  it m ay  e n co u n te r. 
 
 
1 6 .0 .2   D a ta  a n d  S o u rc e D o cu m e n ta tio n  S u b m issio n  fo r P a rticip a tin g  S it es 
 
P artici p ati n g si tes  s h o ul d en te r d at a  d ir ectly in t o M e d i D ata  R A V E . S o u rce  d o cu m e nt a tio n s h o u l d b e 
s e nt  to  M SK C C  a t  t h e co n t act  p ro v id e d  b e lo w.  S u b m issi o ns s h o ul d in clu d e  a  co ver  p a g e  listi n g 
r el ev a n t re co rd s e nc lo s e d p er  p artici p a n t. 
 
C o n ta ct fo r su b m issio n  o f S o u rce  D oc u m e n ta tio n  
E M A IL: m e d m ctco re @ m skcc.o r g to  t h e a tte nt io n  o f th e  M u ltice nt er  T ria l C o r e R es e arc h  St aff 
 
 
1 6 .0 .3  D a ta  a n d  S o u rc e D o cu m e n ta ti on  S u b m issio n  T im el in es  fo r P a rticip a tin g  Si te s 
 
 
D at a  a n d  so u rce  d o c um e nt ati o n  t o s up p o rt d at a  sh o u l d b e  tr an sm itte d  to  M SK C C  ac co rd in g  t o t h e 
fo llo wi n g  ch ar t: 
 
D a ta  a n d  S o u rc e Su b m issio n  R e q u ire m e n ts a n d  T im e lin es  fo r T h e r ap e u tic S tu di es  
 
 
 
B as eli n e  
 
Ev e ry Cy cl e 
 
S A E  
 
Off  S t ud y 
S U B MI S SIO N  S CH E D UL E  
 
S o u rc e D o c um e nt at io n  
Wit h i n 2 4  h o u rs 
(se e  se cti o n 1 5. 1 .1)  
 
 
 
Wit h i n 1 4  d a y s o f visit 
Wit h i n 4 8  h o u rs 
of  e v e n t (se e 
s ecti o n 1 7 .3); 
u p d a te s to  b e 
su b m itte d  a s 
a v ail a b l e 
 
 
Wit h i n 1 4  d a y s o f 
visit 
 
 
e C R Fs  
 
Wit h i n 7 d a y s o f 
visit 
R e q u ir e d Fo rm s 
B a s elin e  F or ms  
X  
 
 
 
Cy cl e Fo rm s  
X  
 
 
Off  S t ud y Fo rms   
 
 
X  
C o n co mit a n t 
M e d ica ti on s 
F o rm  
 
X  
 
X  
 
X  
 
X  
A d v ers e Ev e n t F or m   
X  
X  
 
S e rio u s A d v ers e Ev e nt  
F o rm  
 
 
 
X  
 


P a g e 8 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 6 .0 .3  D a ta  R e vi e w  a n d  Q u e ries  fo r P a rticip a tin g  S ite D a ta  
 
R es e a rc h st aff at  M S K C C  w ill re v ie w  d a t a a n d  so u rc e d o c um e nt at io n  as  it is s ub m itte d.  D at a  will  b e 
m o n ito re d a g ai n st so u rce  d o c um e nt at io n  a n d  disc re p a n ci es will  b e  s en t as q u e rie s to  th e 
p artici p ati n g  site s. Q u er ies  will  b e  se nt by  M SK  R e s e arc h st aff twi ce  a  m o n t h. 
 
P artici p ati n g  sit es s ho u l d res p o n d  to  d at a  q u eri es  w ith i n 1 4  d a y s o f re c ei pt. 
 
 
1 6. 1  
Q u a lit y A ssur a n c e 
 
W e e kl y  re gistr at io n  re p o rts w ill b e g e n er a te d to  m o n ito r p atie nt ac cru als a n d  co m p l ete n ess  o f 
r e gistr atio n  d at a.  R o u tin e  d at a q u al it y re p o rts will  b e  g e n er at e d  t o ass e ss m issin g  d at a a n d 
in co n sist en ci es.  A ccr ua l ra te s a n d e xte n t a n d  ac cu ra cy  o f e v al u at io n s a n d fo llo w -u p  w ill b e 
m o n ito re d p er io d ic all y t hro u g h o u t t h e st ud y  p er io d  a n d  p o te n ti al pr o b le m s will  b e  b ro u g h t to  t h e 
att e nt io n  o f th e  stu d y te a m  fo r disc ussio n  a n d  a ctio n  
 
R a n d o m -sa m p le  d at a q u al it y a n d  p ro to co l co m p li an ce  a u d its w ill b e  co n d u cte d  b y  th e  stu d y te a m , a t 
a m in im u m  o f tw o  tim es  p er  y e ar,  m o r e fre q u e ntl y  if in d ic at e d. 
 
1 6 .1 .1  Q u a lit y Assu r an c e fo r P a rticip a tin g  S it es 
 
 
M o n ito rin g  
 
E ac h d a t a co lle ctio n  sit e w ill b e m o n ito r e d p eri o d ic ally by  M S K C C o r a  d esi g n a te d  co n tr act re s e arc h 
o rg a n izati o n  ( C R O). M o n ito rin g  v isits will  b e  co n d u cte d e ver y  4 -8  w e e ks,  d e p e n d e nt u p o n  th e 
p ro to co l a n d  p ati e nt  ac cru al a n d  ac tiv ity . T h e  m o n ito r a n d  th e  p art icip ati n g  sit e will  id e ntif y  a 
m u t u ally a g re e a b le  tim e  fo r e ac h  m o n ito rin g  v isit. At  l e ast 1 0  b u sin e ss d ays a h ea d  o f th e  visit, t h e 
m o n ito r will  se n d  th e  sit e a  n o tifica tio n  le tter  t h at d e tai ls th e  d a te  a n d  e xp e ct atio n s o f th e  v isit. 
M o n ito rin g  m ay  b e  co n d u cte d  re m o te ly o r in -p er so n . T h e  m o n ito r m u st b e  al lo w e d  a cc ess t o all 
p ro to co l re g u l ato r y a n d  s ou rc e d o cu m e n ts to  a ss ess co m p li an ce  w it h t h e pr o to co l, f ed er al 
r e gu l atio n s a n d G C P s. T h e  m o n ito r will  as sess  all d at a  fo r co m p l ete n ess  o f so u rce  d o cu m e n ts a n d  to 
co n firm  d at a b ei n g  re co rd e d  i n t h e e C R Fs is a cc ura te. If m o n ito rin g  w ill b e d o n e  re m o te ly , sit es m u st 
a g r e e i n a d v a n c e t o pr o v id e  so u rc e d o cu m e nts  as  r eq u ir ed . D u rin g  o n sit e v isits, t h e m o n ito r will  a lso 
in s p ect a n d  re v ie w  th e  f aciliti es a n d  i nv estig at io n al p ro d u ct sto r ag e  ar e a.  T h e  p a rticip ati n g  sit e w ill 
m ai n t ai n a cc urat e  re co rd s o f dis p en sin g  o f stu d y  dr u g s fo r dr ug  a cco u n ta b ility . D ru g  ac c ou n t a bility 
will  b e  re v ie w e d  at  m o n ito rin g  v isits. St ud y  dr u g  a n d  b o ttle s m u st b e  re t ain e d u n til t h e m o n ito r 
p erf o rm s dru g  a cco u n t a bilit y o f th e  st ud y dr u g (s). 
 
T h e  sit e  Inv es tig a to r(s)  a n d / or  a n  a u t ho rize d  m e m b er  o f  t h e  In v e stig a to r’s  st aff  s h o ul d  al l ow 
s uffici e nt tim e  d u rin g  m o n ito rin g  v isits to  d iscu ss fin d in g s. T h e  In v es tig at o r(s) o r a n  a u t ho rize d 
m e m b er  o f t h e Inv es tig a to r’s st aff will m a k e  a n y n ec e ss ary co rrec tio n s d u rin g  a n d  b e tw e e n 
m o n ito rin g  v isits. 
 
 
A u d itin g  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
C o u n cil an d  In stit utio n al R e v i e w B o ar d . 
P a g e  8 7  o f 1 2 6  
 
 
E ac h  p artici p ati n g  site  acc ru in g  p artici p a n ts t o t his p ro to co l will b e  a u d ite d  b y  M S K  fo r p ro to co l a n d 
r e gu l ato ry  co m p li an c e, d a ta  v erific at io n  a n d  so u rc e d o c um e nt at io n .  A u d its o f s el ecte d  p artici p a n t 
r eco rd s m a y  b e  co n d u cte d  o n -sit e o r r em o te ly. 
 
A u d its will  b e  co n d u cte d  a n n u al ly  at  m in im u m , a n d m o re  o fte n if si g n ific an t a n d / or r e p ea te d  fin d in g s 
ar e  id e ntifi e d  d u rin g  m o n ito rin g  v isits.  T h e  n u m b er  o f p artici p a n ts a u d it e d w ill b e  d e te rm in e d  b y  t h e 
o u tco m e  o f m o n ito rin g  v isits a n d  co m p le xity o f th e  p ro to co l. 
 
E ac h a u d it w ill b e  su m m ar ize d a n d  a  fin al r e p o rt will  b e  s e nt to  th e  P I at  th e  a u d ite d p a rticip ati n g  site 
wit hi n  3 0  d a ys of th e  a u d it. T h e re p o rt w ill in clu d e  a  su m m a ry  o f fin d in g s, p articip a n t-s p ecific ca s e 
r ev ie w,  re co m m e n d a tio n s o n  a ny  p erf o rm a n ce  a n d/ o r s h ortco m in g s a n d re q u e st fo r co rr ectiv e 
acti o n , w h e n n e c essa ry. W h e n c o rrec tiv e  act io n  is re q u ir ed , th e  p a rticip ati n g  site  m u st re p ly w ith i n 
4 5  d a y s o f rec e ip t o f th e  a u d it re p o rt w it h t h eir co rre ctiv e  ac tio n  pl a n . 
 
 
1 6 . 1.2   R es p o n se  R e v ie w  
 
 
 
S i nc e t h er ap e u tic eff ic ac y is a sta te d  pr im ary  o b jec tive  fo r th e  P h a se  II p o rtio n  o f th is stu dy , all 
sit es P h as e  II pa rticip a n ts’ res p o n se s ar e s ub j ect to  re vi e w b y M SK’s  T h er a p e utic  R es p o n se  R e v ie w 
C o m m itte e  (T R R C).  R a d io lo g y , a dd itio n al l a b  re p o rts a n d  p o ssib ly b o n e  m ar ro w  b io p si es a n d / or 
as p ira te s will  n e e d  to  b e  o b t ain e d fr o m  t h e p articip a tin g  site s fo r M S K  T R R C re v ie w  a n d 
co n firm at io n  o f re sp o n s e a ss essm e nt.  T h es e  m at e ria ls m u st b e  se nt to  M S K pro m p tl y u p o n 
r e qu es t. 
 
 
1 6. 2  
D a t a a n d  S a fe t y M o ni t ori ng  
 
T h e  D at a  a n d  S a fe ty  M o n ito rin g  ( DSM ) P l an s a t M e m o ria l Sl oa n -K e tte rin g  C a n ce r C e nte r w er e 
a p p ro v e d  by  th e  N at io n al C a n c er In stit ute  i n S e p te m b er  2 0 0 1 . T h e  p l an s a dd re ss th e  n e w  p o lici es s et 
fo rt h b y th e  N CI  i n t h e d o cu m e nt  e ntit le d “ Po lic y o f th e  N ati o n al  C a n c er In stit ute  fo r D a t a a n d  S af e t y 
M o n ito rin g  o f Clin ic al Tri a ls” w h ic h c a n b e  fo u n d a t: 
h ttp ://c an certri als . nci.n ih .g o v /r ese arc h e rs/d sm /in d e x.h tm l.  T h e  D S M  P l an s at  M S K C C w er e 
es ta b lish e d a n d  a re  m o n ito r e d b y  th e  Offi ce  o f Clin ic al R e se arc h . T h e  M SK C C  D a ta a n d  S af e ty 
M o n ito rin g  P l an s c a n b e  fo u n d  o n  th e  M S K C C  In tr an et  at: 
h ttp ://in sid e 2/ clin res e arc h /D o cu m e nt s/M S K C C % 2 0 D a t a% 2 0 a n d % 2 0 S a fe ty% 2 0 M o n ito rin g% 2 0 P l an s. 
p d f. 
 
T h er e  a re  se v er al d iff ere nt  m ec h a n ism s b y w hic h  clin ic al tri als are  m o n ito re d fo r d at a, s af e t y a n d 
q u al ity . T h e re  a re  in stitu tio n al p ro c esses  i n pl a ce  fo r q u al ity ass ur a n ce  ( e.g ., p ro to co l m o n ito rin g , 
co m p li an c e a n d  d a ta verif ic atio n  a u d its, th e ra p e utic res p o n se , a n d staff  e d u c atio n  o n  clin ic al 
r ese arc h  Q A) a n d  d e p a rtm e nt al p r oc e du r es fo r q u al ity co n tro l, plu s th e re  a re  t wo  i nstitu tio n al 
co m m itte es  t ha t ar e  re sp o n sib l e fo r m o n ito rin g  th e  a ctiv ities  o f o u r clin ic al tri als pr o g ra m s. T h e 
co m m itte es:  D a t a a n d  S a fe t y M o n ito rin g  C o m m itte e  (D S M C)  fo r P h a se  I an d  II clin ic al tria ls, an d  t h e 
D at a a n d  S afe ty  M o n ito rin g  B o ar d  (D S M B)  fo r P h as e  III cli nic al tria ls, r e p ort to  t h e Ce n ter’s  R es e a rc h 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 8 8  o f 1 2 6  
 
 
D u rin g  th e  p ro to co l de v e lo p m e nt  a n d  re vie w  pr o cess,  e ac h  p ro to co l w ill b e  as se ss e d fo r its le v el  o f 
ris k a n d d e g re e  o f m o n ito rin g  re q u ir ed . E ver y  typ e  o f p ro to co l (e. g ., N I H sp o n so re d, i n -h o u s e 
s p o nso re d, i n d u stri al sp o n so r ed , N CI co o p er a tive  g ro u p , e tc.) w ill b e a d d r esse d  a n d  th e  m o n ito rin g 
p ro c e du r es w ill b e  e st a blish e d at  th e  tim e  o f pro to co l ac tivati o n . 
 
1 6. 3     R e g ul a tor y  D o c um e n t atio n  
 
P ri or to  im p le m e nti n g  th is p ro to co l at M S K C C , th e  p ro to co l, in fo rm e d  co n s e nt fo rm , H I P A A 
a u t ho rizati o n a n d a n y  o t h er in fo rm ati o n p e rt ain in g t o  p artici p a n ts m u st b e  a p p ro v e d b y  t h e M S K C C 
In stit utio n al  R e v ie w  B o a rd / Priv acy  B o ar d  (IR B /P B). P rio r  t o im p le m e nti n g  th is p ro to co l a t th e 
p artici p ati n g  sit es, a p p ro val  fo r t h e M S K C C  I R B/P B a p p ro v e d  p ro to co l m u st b e  o b t ain e d  fro m  t h e 
p artici p ati n g  site ’s I R B. 
 
T h e  fo llo wi n g  d o cu m e n ts m u st b e  p ro v id e d  to  M S K C C  b e fo r e t h e p a rticip ati n g  sit e c a n b e  in iti at e d 
a n d  b e g in  e n ro llin g  p artic ip a n ts: 
•     P artici p ati n g  Sit e IR B  a p p ro v al(s)  fo r t h e p ro to co l, a p p e n d ic es, in fo rm e d  co n s en t fo r m a n d  H I P A A 
a u t ho rizati o n  
•     P artici p ati n g  Si te  I R B a p p ro ve d co n s e nt fo rm  
•     P artici p ati n g  Si te  1 5 7 2  
•     P artici p ati n g  Si te  I R B m e m b ers h ip  list 
•     P artici p ati n g  Si te  I RB ’s F ed er al Wi d e  Ass u r an c e n u m b er  a n d O H R P  R e g istr atio n n u m b er  
•     C u rric ul um  v it a e a n d  m e d ical l ic e ns e fo r e ac h  in v e sti g ato r a n d co n se nti n g  pr o fe ssio n al  
•  D o cu m e n t atio n  o f H u m a n  S u b j ect R es e a rc h C ertific a tio n  tr ain in g  fo r in v es tig a to rs a n d  k e y  st aff 
m e m b ers  at  t h e P artici p at in g  Sit e  
•     G o o d  Cli n ic al P r actice  T r ai nin g  fo r th e  P rin cip al  In ve stig at o r a n d C o -Inv es tig a to r 
•     C o n flict o f In ter e st fo rm s fo r P arti cip ati n g  Si te  Inv es tig at o rs o n  th e  1 5 7 2  
•     P artici p ati n g  sit e l ab o r ato ry  c ertific atio n s a n d n o rm a ls 
 
U p o n  r ece ip t o f th e  r e qu ir e d d o c u m en ts, M S K C C  will  fo rm al ly  co n t act t h e sit e a n d  g r an t p er m issi o n 
t o p ro ce e d w it h e nro llm e n t. 
 
P artici p ati n g  site s t h at ar e co n s ultin g  a n d/ o r co n d u ctin g  s p ecim e n o r d at a a n al y sis s h o ul d s ub m it th is 
p ro to co l to  th eir  I R B acco rd in g  t o lo c al g u id eli n es.  C o p i es o f an y  sit e I R B co rr esp o n d e nc e  s h o ul d b e 
fo r w ard e d  to  M SK C C.  P art icip ati n g  sit es t h at a re  co n d u cti n g s p ecim e n  a n al ysis m u st p ro v id e  a  1 5 7 2 
t o M S K C C. 
 
 
1 6 .3 .1   A m e n d m e n ts 
 
E ac h  c ha n g e  t o th e  p ro to co l d o cu m e n t m u st b e  o rg a n ize d  a n d  d o c u m e nt e d b y  M S K C C  a n d  first 
a p p ro v e d  b y t h e M S K C C  IR B /P B.  U p o n  r ecei p t o f M S K C C  I RB / PB  a p p ro v al,  M SK C C  will  im m e d iat e ly 
d istrib u t e all n o n -e xp e d it ed  a m e n d m e nts  to  th e  p art icip ati n g  site s, fo r s ub m issio n  to  th eir l o c al I R Bs. 
 
P artici p ati n g  site s m u st o b t ai n a p p ro v al  fo r all  n o n  e x p e dite d  a m e n d m e nts  fro m  t h eir IR B  wit hi n 4 5  
c al e nd ar  d ays  o f M S K C C  IR B /P B  r ele asi n g  t h e p ro to co l. If th e  a m e n d m e nt  is th e  r esu lt o f a  s afe t y 
issu e  o r m a k e s eli g ib ility crit eri a m o r e r estrictiv e,  sit es will  n o t b e  p er m itte d  t o co n tin u in g e nr olli n g 
n e w  p artic i pa n ts un til th e  p artici p ati n g  sit e I R B a pp ro val h as b e e n g ra n te d . 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 8 9  o f 1 2 6  
 
 
 
T h e  fo llo wi n g  d o cu m e nts m u st b e  p rov id e d  t o M S K C C  fo r e a c h a m e n d m e n t wit hi n  t h e st at e d 
tim eli n es:  
•     P artici p ati n g  Si te  I R B a p p ro v al  
•     P artici p ati n g  Si te  I R B a p p ro ve d i n fo rm e d co n s e nt fo rm  a n d  H IP A A  a ut h o rizati o n  
 
 
1 6 .3 .2   A d di tio n a l IR B  C o rre s p on d e n c e 
 
C o n tin u in g  R e v ie w  A p p ro v a l 
T h e  C o n tin u in g  R e v ie w  A p p ro v al  le tter  fro m  th e  p artici p ati n g  sit e’s  IR B  a n d  t h e  m o st  c urr e nt 
a p p ro v e d  v e rsio n o f th e  in fo rm e d  co n s e nt fo rm  sh o u l d b e  s ub m itte d  t o M SK C C  w it hin  7  d a ys o f 
e xp ira tio n . F a ilu r e t o s ub m it t h e re -a p p ro v al  i n t h e st at e d tim eli n e w ill r es ult in  s usp e nsi o n  o f n e w 
p artici p a n t e n ro llm e nt.  
 
D e v ia tio n s a n d  Vi o la tio n s 
A p ro to co l d e v i atio n o n t h is st ud y  is d efi n e d  as  a  r e qu est  to  tr ea t a  r ese arc h  p ar ticip a n t w h o  r e qu ires 
alt er at io n  i n t h eir st ud y  p la n . If a  d e v i atio n  fro m  t his p ro to co l is p ro p o s e d fo r a p o te n ti al o r existin g 
p artici p a n t at  M S K C C  o r a p artici p ati n g  sit e, a p p ro v al fr o m  t h e M SK C C  I RB / PB  is r e qu ir e d p ri or to  t h e 
acti o n . P artici p a tin g  sit es s h o ul d co n t act t h e M S K C C  P I w h o  will  i n t ur n se e k  a p p ro v al  fro m  t h e 
M S K C C  I RB /P B.  D e v i atio n  r e q u es ts fro m  eli g ib ility crit eri a will  n o t b e  p e rm itte d  fo r res e arc h 
p artici p a n ts. 
 
A  p ro to co l v io l atio n  is a n y c ha n g e  o r d e p a rt ure  fro m  th e  r ese arc h  p ro to co l th at  o cc urr e d wit h o u t 
p ri or a p p ro v al  fro m  t h e M S K C C  I R B/P B.  F or  p ro to co l v io la tio n s t ha t ar e  id e ntif ie d  aft er  t he y  o cc ur, 
t h e p artici p ati n g  sit e sh o u ld  r e p ort t o M SK C C  w it hin 1 4  d a y s o f l e arn in g o f th e  e v e n t. T h e  M S K C C  P I 
will  i n tu r n re p o rt th e  v io la tio n  to  t h e M S K C C IR B /P B.  
 
P artici p ati n g  site s  s h o ul d  r e p ort  d e v i atio n s  a n d  v io l atio n s  to  t h eir  in stit utio n ’s  I R Bs  as  so o n  as 
p o ssib l e p er  t ha t sit e’s in stit utio n al  g u id eli n es.  A p p ro v al s/a ck n o wl e d g m e nts  fro m  t h e p artici p ati n g 
sit e I R B fo r pr o to co l de v i atio n s a n d v io la tio n s s h o ul d b e  s ub m itte d  t o M S K C C as  rec e iv e d.  
 
Ot h e r co rre sp o n d e n ce  
P artici p ati n g  site s sh o u l d su b m it o t h er co rres p o n d e n c e to  t h eir in stit utio n ’s IR B  acc o rd in g  t o lo c al 
g u id eli n es,  a n d  s ub m it co p i es o f th at  co rr esp o n d e nc e  t o M S K C C. 
 
 
1 6 .3 .3   R e g u la to ry D o cu m e n ta tio n  S u b m issio n  fo r P a rticip a tin g  S it es 
 
P artici p ati n g  sit es s ho u l d su b m it all a fo re m e nti o n e d re g u l ato ry  d o c um e nt at io n  to  M S K  v i a th e 
M u ltic e nter  Off ic e a t th e  e -m ail p ro v id e d b el o w. S u b m issi o ns sh o u l d i ncl u de  th e  p ro v id e d 
P artici p ati n g  Si te  S u b m issio n  F o rm  a s a co ver  p a g e  listin g  all e nc lo s e d d o cu m e n ts. 
 
R e g u l ato ry  C o n t act: 
E m ai l: M u ltic ntrp ro c @m skcc.o r g to  t h e a tte nt io n  o f 1 4 -1 4 0  D o c um e nt S u b m issio n  
 
F or q u es tio n s re g a r din g  re g u l ato r y d o cu m e nt a tio n  s ub m issi o ns, pl e ase  c all 6 4 6 -8 8 8 -0 9 2 4 . 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 9 0  o f 1 2 6  
 
 
 
F or p r oto co l rel a te d q u es tio n s, pl e ase  co n t act y ou r M S K St u d y  C o o rd in at o r. 
 
 
 
 
1 6 .4  
D o cu m e n t m a in t en a n c e 
 
T h e  M S K C C  P I a n d  t h e P ar ticip ati n g  Sit e P I will  m ai n ta i n a d e q u at e  a n d  acc u rat e  rec o rd s to  e n a b le  t h e 
im p le m e nt a tio n  o f t h e pro to co l to  b e  f ull y d o c um e nt e d  a n d  th e  d at a  to  b e  s ubs e q u e ntl y  verifi e d.  
 
T h e  p artici p ati n g  sit es will  e ns u r e t h at all  p art icip ati n g  sit e IR B  co rr esp o n d e nc e (I R B  a p p ro v al  le tte rs 
r ef ere n cin g  p ro to co l v ers io n  d at e  a n d  a m e n d m e nt  n u m b er,  I R B a p p ro v e d  p ro to co l, a p p e n d ic es, 
in fo rm e d  co n s e nt fo rm s, d e v i atio n s, v io la tio n s, an d  a p p ro v al o f co n tin u in g  r ev ie ws)  is m ai n t ain e d  i n 
t h e r e gu l ato ry b in d er  o n  sit e a n d  s e nt to  M SK C C.  T h e  r e gu l ato ry  b in d er  o n  site  will  b e  r ev ie w e d  b y 
t h e M SK C C  d e sig n at e d  st ud y  m o n ito r at m o n ito rin g  v isits. 
 
A  r e gu l ato ry b in d er  fo r e a c h sit e will  al so  b e  m ai n tai n e d  at  M S K C C;  t his b in d er  m a y b e  p a p er  o r 
el e ctro n ic. 
 
A fte r  st ud y  clo s ure,  t h e p artici p ati n g  sit e  wi ll m a in t ai n all  so u rc e  d o c um e nts  a n d  st ud y  r el ate d 
d o c um e nts  fo r 7  y e ars.  
 
1 6. 5  
N o n co m p lia n c e 
 
If a p articip ati n g  sit e is n o n co m p li an t w it h t h e pr o to co l d ocu m e nt,  accr u al p riv ile g es  m a y  b e 
s usp e n d e d a n d/ o r co n tr act p a y m e nts  m a y  b e  w ith h e ld , un til t h e o u tsta n d in g  issu es  h a v e  b e e n 
r eso lve d.  
 
1 7. 0  
P R O T E C T IO N  O F H U M A N  S U BJ E C T S  
 
P artici p at io n  i n t his tria l is v o lu n t ary . T h e p ati e n ts w ill b e  e xp l ain e d t h e  e xte nt  o f t h e ris ks, b e n efits, 
to xiciti es/sid e  eff e cts, a lte rn ati v e s/o p tio n s fo r tr ea tm e nt, fi n a n ci al co sts/b u rd e n s, a n d th e  v o lu n t ary 
n at u re  o f th e  st ud y . All p a ti en ts will  b e  r e qu ire d to  sign  a  st ate m e nt  o f in fo rm e d  co n s e nt, w h ic h 
m u st co n fo rm  to  I R B g u id eli n es.  
 
In clu sio n  o f W o m e n a n d  M in o riti es: M e m o rial S lo a n -K e tte rin g  C a n c er C e nt er  h as  file d f o rm s: H H S 
4 4 1  (civ il rig h ts), HH S ( h a n d ic ap p e d i n d i vi du al), 6 3 9 -A  (s ex discr im in ati o n ), a n d  6 8 0  ( ag e 
d iscrim in at io n ); w e  al so  ta ke  d u e  n o tic e o f th e  N I H p o lic y co n c er nin g  i ncl usio n  o f w o m e n  a n d 
m in o riti es i n clin ic al re se a rc h p o p u l atio n s. P a ti e nts o f all r ac e s, b o t h m a le  a n d  fe m al e,  w ill b e 
acc e p te d  i nt o th e  p ro to co l. T h e  p ro p o se d st u d y p o p u lati o n  is as d e scrib e d i n  sec tio n  6 .0  a n d  7 . 0. 
 
Ex clu sio n  o f Lac tati n g  o r P re g n a n t W o m e n : Lac tati n g  a n d  pr e g n a n t w o m e n ar e a ls o e xcl ud e d b e c au s e 
o f po te n ti al a nti -p ro lifer at iv e  eff e cts o f B G J3 9 8  a n d/ o r im ati n i b t h at m ay  b e  h a rm fu l to  th e  
d e v e lo p in g  fe t us o r n u rsin g  i nfa n t. 
 
In clu sio n  o f C h ild r e n i n R e se arc h : T his p ro to co l/p ro je ct d o e s no t in clu d e  p at ie nts  y o u n g er  t h a n th e 
a g e  o f 1 8 . Alt h o u g h  s arco m as a re  th e  m o st co m m o n  so li d tu m o r i n c hild r e n, p e d i atric GI S Ts  a r e 
r el ativ ely  rar e. I n  a d d itio n , p e d iatric GI S Ts  o fte n  d o  n o t r esp o n d  to  im ati n i b as  t he y  te n d  to  n o t h a v e  


P a g e 9 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
m u t atio n s i n cKI T.  P e d iatr ic GI S T p ati e n ts w o u l d b e  b e tter  s erv e d e n ro llin g  o n  clin ic al tria ls 
s p ecific ally d esi g n e d fo r th e  g e n et ic a b n o rm al ities  o f th eir t u m o r. 
 
B e n efit s: It is p o ssib l e th at  t his tr ea tm e nt  will  r es ult i n s hri nk a g e  o f th e  tu m o r o r in  a  st a bilizat io n  o f 
a n  o t h erwis e  pr o g re ssin g  dis e as e. It  is n o t k n o w n,  o f co u rs e, w h et h er  t he s e o r a n y  o t h er fa v o r ab l e 
e v e n ts w ill o cc ur. It is n o t k n o w n  w h et h er  th is tre a tm e nt w ill aff ect  th e  o v er all s u rv i v al o f t h e 
p ati e nts.  
 
C o sts: T h e  p ati e n t will  b e  res p o n sib l e fo r t h e co sts o f st a nd ar d  m e d ic al c are,  in clu d in g  all  d ru g 
a d m in istr atio n  fe es  a n d  all  h o s pit alizat io n s, e v e n fo r co m p licati o n s o f tr ea tm e nt.  B G J3 9 8  a n d 
I m atin i b will b e  p ro v id e d  to  th e  p ati e nt  w ith o u t c ha rg e. R e se arc h -o n ly  bi o ps ies  a n d  l ab o r ato r y te sts 
will  n o t b e  c ha rg e d to  th e  p ati e nt.  R es e a rc h te sti n g p erf o rm e d  o n  tiss u e will  n o t b e  c ha rg e d  t o th e 
p ati e nt.  
In c e ntiv e s: N o  i nc en tiv es  w ill b e o ffer e d  t o p ati e nt s/su b j ects fo r p articip ati o n  i n th e  st ud y . 
A lte rn ati ves:  F o r p ati e nts  wit h l o c ally a d v a n ce d  a n d/ o r m e tast at ic GI S T  a lte rn at iv e  tr e at me nts  m ay  
in clu d e  im ati n i b o ff st ud y  p er  st a nd ar d  o f c are  o r o t he r clin ic al tria ls. 
 
C o n fid e nti a lity : E ver y  e ffo rt will  b e  m a d e  to  m ai n t ai n p ati e nt co n fid e nti a lity . R e se arc h a n d  h o s pit al 
r eco rd s ar e  co n fid e nt ial.  P a ti e nt’s n a m e  o r a ny  o th er  p ers o n al ly  i d en tify in g  i nfo rm a tio n  w ill n o t b e 
u s e d i n re p o rts o r pu b lic atio n s re s ultin g  fro m  t his stu d y . T h e Fo o d  a n d  D ru g  A d m in istr atio n  o r o th er 
a u t ho rize d a g e nc ies  (e. g ., q u al ifi e d m o n ito rs fro m  M SK C C o r co ll ab o ra tin g  i nstitu tio n s) m a y  re v ie w 
p ati e nts’ re co rd s a n d p at h o lo g y  slid es, as re q u ir ed . 
 
1 7. 1  
Pr iv a c y 
 
M S K C C’s  P riv a cy  Off ic e m a y  all o w  th e  u s e a n d  disc l osu r e o f pro tec te d h e alt h  i nfo rm ati o n  p u rsu a n t to 
a c o m pl e te d a n d  si gn e d  R e s e arc h Au th o rizati o n  fo rm . T h e  u s e a n d  disc lo s ure  o f p ro te cte d  h e alt h 
in fo rm a tio n  will  b e  lim ite d  t o t h e in d ivi du als d es crib e d  i n t h e R es e arc h  A u t ho rizati o n  fo rm . A 
R es e a rc h Au t ho rizat io n  fo rm  m u st b e  co m p l ete d  b y  th e  P rin cip al I n v es tig a to r a n d  a p p ro ve d by  t h e 
I R B an d  P riv a cy  B o ar d  (I RB /P B).  
 
1 7. 2  
S e rio u s A d v e rs e E v e n t (S A E)  R e p o rti ng  
 
A n  a dv e rse  e v e nt  is co n sid er e d s e rio u s if it res ults i n  A N Y  o f t h e fo llo wi n g  o u tc o me s: 
•  D e a th  
•  A lif e-t hr e ate n i ng  a dv e rs e e v e nt  
•  A n  a dv e rse  e v e nt  th at  res u lts i n in p ati e nt  h o s pit alizat io n  o r pr o lo n g at io n  o f e xistin g 
h o s pit alizat io n  
•  A p ersist e n t o r sig n ific an t in c ap acity  o r s ub sta n ti al d isru p tio n  o f th e  a b ility t o co n d u ct 
n o rm al  lif e f un ctio n s 
•  A co n g e n it al a n o m a ly/ b irt h d ef e ct 
•  I mp o rta n t M e d ic al E v e nts  (I M E) t h at m a y  n o t re s ult i n d e a th , b e life  t hre at e n in g , o r 
r e qu ir e ho s pital izati o n  m a y b e  co n sid er e d  s erio u s w h e n , b as e d u p o n  m e d ical j u d g m e nt,  


P a g e 9 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
t h e y m a y  je o p ar d ize  t h e pa ti e nt o r s ub je ct a n d  m ay  re q u ir e m e d ic al o r s ur gic al 
in te rv e n tio n  t o pr e v e nt  o n e  o f th e  o u tco m es  liste d  i n t his d efin itio n  
N o te : H o s pit al ad m issio n  fo r a pla n n e d p ro ce d u r e/d ise as e  tr e at me nt is  n o t co n sid er e d a n  
S A E.  
 
 
S A E  r e p ortin g is r e q u ir e d a s s o o n as  t h e p articip a n t sig n s co n s e nt. S A E  re p o rtin g  is r e qu ir e d 
fo r 3 0 -d a ys after  t h e p artic ip a n t’s l ast in v e stig ati o n al  tr e atm e nt  o r in ter v e nt io n . A n y  e v e nts 
t h at o cc ur after  th e  3 0 -d a y  p eri o d  a n d  th a t ar e  at  le ast  p o ssib ly r el ate d to  p ro to co l tre a tm e nt 
m u st b e  r ep o rt ed . 
 
If a n S A E  r e qu ir es s ub m issio n  to  th e  I R B o ffice  p er  IR B  S O P  R R -4 0 8  ‘ Re p o rtin g  o f S er io u s 
A d v ers e  E v e nts’,  th e  S A E  re p o rt m u st b e  s en t to  th e  IR B  wit hi n  5  c ale n d ar d a y s o f t h e e v e n t. 
T h e  I R B re q u ir es a Cli n ic al R es e a rc h D a t a b as e ( CR D B)  S A E r e p o rt b e  s ub m itte d  e lec tro n ic all y 
t o t h e S A E Offic e  as  fo llo w s: 
 
F or I N D /ID E  tri als: R e p o rts t h at i ncl u de  a  Gr a d e  5  S A E  s h o ul d b e  se nt to 
s a e gra d e 5 @ m skcc .o rg .  All o t h er r e p orts sh o u l d b e  s en t t o  s ae m s kin d @ m skcc.o rg . 
 
F or all  o t h er tria ls: R e p o rts t h at i ncl u de  a  Gr a d e  5  S A E  s h o ul d b e  se nt to 
s a e gra d e 5 @ m skcc .o rg .  All o t h er r e p orts sh o u l d b e  s en t t o  s a e@ m skcc .o r g. 
 
T h e  r ep o rt sh o u l d co n t ai n th e  fo llo wi n g  i nfo rm ati o n : 
F iel d s po p u l at e d fro m  C R D B:  
•  S u b j ect’s in iti als 
•  M e d ic al re co r d n u m b e r 
•  D is e ase /h isto lo g y  (if a pp lica b l e) 
•  P ro to co l nu m b er  a n d  titl e 
 
D at a n e e d in g  to  b e  e nt e r ed : 
 
•  T h e  d at e  th e  a d v e rs e e v e nt  o cc urre d  
•  T h e  a dv ers e  e ve nt  
•  T h e  g r ad e  o f t h e e ve n t 
•  R el at io n s hip  o f t h e ad v er se  e v e nt to  t h e tre a tm e nt  (d ru g , d ev ice , o r in te rve nt io n ) 
•  If t h e A E w as  e xp e cte d  
•  T h e  se v er ity o f t h e A E 
•  T h e  in te rve nt io n  
•  D e tai le d t e xt t h at i ncl u des  t h e fo llo wi n g  
o  A e xp l an at io n  o f h o w  t h e A E  w as  h a n d l e d 
o  A d escri p tio n o f th e  s ub j ect’s co n d itio n  
o  In d ic atio n  if th e  s ub j ect re m ai n s o n  th e  stu d y 
•  If a n a m e n d m e n t will  n e e d  t o b e  m a d e  to  t h e pro to co l a n d / or co n se nt fo rm  


P a g e 9 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
•  If t h e S A E is a n U n a n ticip a te d P ro b le m  
 
T h e  P I’s si gn at u re  a n d  th e  d at e  it w as  sig n e d ar e  re q u ir e d o n  t h e co m p l ete d r e p o rt. 
 
F or I N D /ID E  p ro to co ls: 
T h e  C R D B  S A E  re p o rt sh o u l d b e  co m p le te d  as  p er  a b o v e  in stru ctio n s. If a pp ro p ria te , th e 
r e p ort w ill b e fo rw a rd e d  t o th e  FD A b y t h e S A E st aff th ro u g h  th e  IN D  Off ice  
 
 
1 7 .2 .1   R e p o rtin g  to  N o v a rtis b y  M S K C C  
 
R e p o rtin g  R es p o n sib ility: 
 
A n y  s erio u s a d ver se  e ve n ts t h at o cc ur fro m  t h e first d o se  o f st ud y  tre a tm e nt  u n til 3 0  d ays  aft e r 
r ece iv in g  t h e l ast d o se  o f st ud y  m e d ic atio n , w h e th er  o r n o t rel at e d to  t h e st ud y  d ru g , m u st b e 
r e p orte d  b y t h e inv es tig a to r at  M S K C C  to  N o v art is. In  a d d itio n , a n y S A Es  t h at o cc ur as  a  re s ult o f 
p ro to co l s p ecific di a g n o stic pr oc e d u res  o r in te rve n tio n s m u st als o  b e  re p o rte d.  
 
E ac h  s erio u s a d v e rs e e ve n t ( bu t n o t p r e gn a n cies) m u st b e  r ep o rt e d b y t h e  inv e stig at o r a t M SK C C  to 
N o v art is w it hin  2 4  h o u rs o f l e arn in g  o f its o cc urre n ce,  e v e n  if it is n o t f elt to  b e  tre a tm e n t-r elat e d . 
F ollo w -u p  in fo rm at io n  a b o u t a  p r ev io u sly r ep o rt e d seri o u s a d ve rs e e ve nt  m u st als o b e  r e p ort e d to 
N o v art is w it hin  2 4  h o u rs o f re c eiv in g  it. If t h e  se ri o us a dv ers e  e ve nt  h as n o t b e e n  p r evio u sly 
d o c um e nt e d  (n e w  o cc urre n c e) a n d  it is th o u g h t t o b e r el at e d  to  st ud y  d ru g  (o r th er a p y ), th e  M e d ic al 
S a f ety Ex p ert  o f t h e Cl i nica l S a f ety  &  E p i de m io lo gy  (C S & E)  D e p a rtm e nt  m a y  co n t act th e  inv es tig a to r 
t o o b t ai n fu rt h er in fo rm a tio n . If w arr a n te d,  a n  in v es tig a to r a lert  m a y  b e  iss u ed , to  in fo r m all 
in v es tig a to rs inv o lve d  i n a n y  st ud y  wit h  t h e sa m e  d ru g  (o r th er a p y) t ha t t his s erio u s a dv ers e  e ve n t 
h as b e e n r e p o rte d.  
 
R e p o rtin g  P ro c e du re s: 
 
T h e  M SK C C  p rin cip al i n ves tig at o r h as th e  o b lig at io n  to  re p o rt all seri o u s a dv e rs e e v e n ts to  th e  M S K C C 
I R B, F D A ( all co rr esp o n d e n c e w it h t h e F D A  m u st g o  t hr ou g h  th e  M S K C C  IN D  O ffice)  a n d  N o v artis 
P h ar m a c e utic als Cl i nic al Sa f ety  &  E p i de m io lo g y  (C S& E ) D e p a rtm e n t. 
 
S A Es  will  b e  re p o rt e d t o N o v artis  o n ce  r ep o rt e d to  th e  M S K C C IR B usi n g  th e  M SK C C C R D B  S A E  R e p o rt 
F or m . 
 
A ll se rio u s a d v e rs e e v e n ts m ust  b e  re p o rt e d b y  fac sim ile  w ith in  2 4  h o u rs o f l ea rn in g  o f t h e 
o cc urre n ce  t o th e  lo ca l N o v a rtis C lini ca l S a fe t y &  E p i d em io lo g y  (C S & E ) D e p a rtm e n t. F a x: 1 -8 7 7 -7 7 8 - 
9 7 3 9 . 
 
T h e  inv es tig a to r m u st th e n  e n s ure  t ha t t h e fo rm  a n d  co vers h e e t a re  acc u ra te l y a n d  fu ll y co m p le te d 
wit h fo llo w -u p  i nfo rm at io n  a n d  f ax th o s e to  N o v artis  CS & E  D e p a rtm e n t wit hi n 5  c al e nd ar d a ys o f 
r ece iv in g  it. T h e o rig in al a n d  th e  d u p lic at e co p ies  o f th e  C R D B  S A E  R e p o rt Fo rm , N o v art is S A E 
co vers h e e t, a n d t h e fa x co n firm at io n  s h ee t m u st b e  re tai n e d at  M SK C C . 
 
F ollo w -u p  i nfo rm at io n  s ho u l d d escri b e  w h e th er  th e  e v e nt h as  re so lve d  o r co n tin u es,  if an d  h o w  it 
w as  tre a te d,  w h e t h er t h e b lin d  w as br o k e n  o r n o t, a n d  w h e th e r th e  p ati e nt  co n tin u e d o r 
d isco n tin u e d st ud y  p artic ip ati o n . 


P a g e 9 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 7. 3  
S e rio u s A d v e rs e E v e n t (S A E)  R e p o rti ng  for  P ar ticip a ti n g Si te s 
 
R es p o n sib ility o f P artici p at in g  Sit es  
•  P artici p ati n g  sit es ar e  res p o n sib l e fo r r ep o rtin g  all  S A Es  to  th eir  lo c al I R B p er  lo cal g u id eli n es.  
L oc al I R B S A E a p p ro v als/ a ck n o w le d g m e n ts m u st b e  se n t t o M S K  u p o n  rec e ip t. 
•  P artici p ati n g  sit es ar e  res p o n sib l e fo r s ub m itti n g th e  SA E  R e p o rt Fo r m to  M S K  wit hi n  4 8  
h o u rs o f l e ar ni ng  o f th e  ev e nt.  
•  W h e n a  d e a t h is un fo r ese e n  a n d  i nd ic at es p art icip a n ts o r o th ers  a re  at  in cr e ase d ris k  o f 
h ar m , p articip ati n g  site s sh o u l d n o tify  th e  M S K  P I as so o n  as p o ssib l e bu t wit hi n  2 4  h o u rs o f 
t h e tim e  t h e sit e b ec o m es  a w ar e  o f t h e e v e n t. 
 
S A E  co n ta ct in fo rm at io n  fo r th e  C o o rd in ati n g  C e n ter  is liste d  b el o w: 
M u ltic e nter  Tr ials C o r e St aff 
M S K C C  Cl i nic al T ria ls Off ice  
1 1 1 4  Fi rst A v e n u e  7 th  F lo o r 
N e w  Y o r k, N Y  1 0 0 6 5 
( F) 6 4 6 -2 2 7 -2 4 8 2  
E m ai l: m e d m ctco re @ ms kcc . or g 
 
Willi a m  T a p,  M D  
M e m o rial S lo a n  K e tteri n g  C a n c er C e n ter  
3 0 0  E 6 6 t h Str e et  
N e w  Y o r k, N Y  1 0 0 6 5  
( O) 6 4 6 -8 8 8 -4 1 6 3   ( F) 6 4 6 -8 8 8 -4 2 5 2  
E m ai l: t a p w@ m skcc .o r g 
 
R es p o n sib ility o f M S K C C  
•  T h e  M S K C C R e se arc h  St aff  is r esp o n sib l e fo r s ub m ittin g  all  S A Es  to  t h e M S K C C  IR B /P B  as s p ecifi e d 
i n 1 7 .2  a n d  to  N o v a rtis as d es crib e d i n  1 7 .2 . 1 
•  T h e  M S K C C  P I is r es p on sib le  fo r in fo rm in g  all  p artici p ati n g  sit es a b o u t all  d e a th s a n d  u n e xp ec te d 
S A Es  t h at a re  eit h er  p o ssib l y, p ro b a b ly , o r d efi n it ely rel at e d  to  t h e st ud y in te rv e n tio n  wit hi n 3 0 
d a ys  o f r ecei v in g  t h e st am p e d S A E  fro m  th e  M S K C C I R B /P B.  
•  A n y  r e p ort p er tai n in g  t o a  g r ad e  5  e v e n t will  b e  d istrib u te d  t o t h e p artici p ati n g  sit es as  so o n  as 
p o ssib l e. 
 
1 7. 4  
S a fe t y R e p o rts 
 
M S K  m u st s ub m it e xte rn al  s af et y re p o rts t o th e  M S K  I R B/P B a cco rd in g  to  i nstit utio n al g u id eli n es. All 
e xte rn al  s af ety  re p o rts w ill b e  m a d e  a v ai la b l e to  t h e p artici p ati n g  sites. F o r th o s e s af ety  re p o rts th at 
r e qu ir e a n a m e n d m e nt,  th e  p artici p ati n g  site s will  rec ei v e  a  s pe ci al al ert. 
 
P artici p ati n g  sit es ar e  res p o n sib l e fo r s ub m itti n g s afe ty  re p o rts t o th eir lo c al I R B p er  t h eir lo ca l I R B 
g u id eli n es. All l o c al I R B a pp ro v al s/a ck n o wl e d g m e nts  o f s af ety  re p o rts m u st b e  se n t t o M S K  u p o n 
r ece ip t. 


P a g e 9 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
1 8. 0  
IN F O R M E D  C O N S E N T  P R O C E D U R E S  
 
B ef o re  p ro to co l-sp ecifi e d  p ro c e du re s ar e c arri e d o u t, co n s e ntin g  p ro f essio n als  w ill exp l ain  f ull d et ails 
o f th e  p ro to co l an d  st ud y  p ro c e du re s as w e ll a s th e  risks  inv o lve d to  p art icip a n ts p ri or to  th eir 
in clu sio n  i n t h e stu d y . P art icip a n ts will  a lso  b e  in fo rm e d  th at  t he y  a re  fre e  to  wit h d r a w fro m  t h e 
st ud y  at  a ny  tim e. All p arti cip a n ts m u st si g n a n I R B /P B -a p p ro v e d  co n se nt fo rm  i nd ic atin g  th eir 
co n s e nt to  p artic i pa te . T his co n se nt fo r m m e e ts t h e re q u ir em e nts  o f th e  C o d e  o f F e d er al R e g u l atio n s 
a n d  th e  In stit utio n al R e vie w  B o ar d/ P riva c y B o ar d  o f th is C e nte r. T h e  co n s en t fo rm  will  in clu d e  th e 
fo llo wi n g : 
 
1 .   T h e  n at u re  a n d o b jec tiv es,  p o te n ti al risks a n d  b e n efits  o f t h e i nt e nd e d st u d y . 
2 .   T h e  l en g t h o f st ud y  a n d  th e  li ke ly  fo llo w -u p  re q u ir ed . 
3 .   A lte rn ati ves  t o t h e pro p o s ed  stu d y . (T h is w ill in clu d e  a v ai la b l e st a nd ar d  a n d  i nve sti g atio n al 
t h er ap i es. I n a d d itio n , p atie nts  will  b e  o ff ere d a n  o p tio n  o f s up p o rtiv e  c ar e fo r th er a p e utic 
st ud i es.) 
4 .   T h e  n a m e  o f th e  inv es tig a to r(s) re sp o n sib l e fo r th e  p ro to co l. 
5 .   T h e  rig h t o f th e  p artici p a n t to  acc e p t o r r ef use  st ud y  in te rve nti o n s/in te ra ctio n s a n d  to 
wit h d r a w fro m  p artic i pa tio n  at  a ny  tim e.  
 
B ef o re  a n y pr o to col -s p ecific p ro ce d u r es ca n  b e  c arrie d  o u t, t h e co n s e ntin g  p ro fe ssio n al  will  fu lly 
e xp l ain  th e  as p ec ts of p ati e n t p ri v acy  co n c er nin g  res e a rc h s p ecific in fo rm at io n . I n a d d itio n  to  si gn in g 
t h e I R B In fo rm e d C o n s e nt, all p ati e nts  m u st a g re e  to  th e  R e se arc h A u th o rizati o n  co m p o n e n t o f th e 
in fo rm e d  co n s e nt fo rm . 
 
E ac h p a rticip a n t a n d  co n s en tin g  pr of ess io n al  will  sig n  t h e co n s e nt fo rm . Th e  p art icip a n t m u st re c eiv e 
a c o p y o f th e  si gn e d i n fo rm e d c o n se nt fo rm . 
 
1 8 . 1 In fo rm e d  C o n s e nt Pr o ce d ur e s fo r P a rticip a tin g  S it es 
 
T h e  inv es tig a to rs liste d  o n  t h e C o n s e ntin g  P ro fess io n a ls Lists at  e ac h p a rticip ati n g  sit e m a y  o b t ai n 
in fo rm e d co n s e nt a n d  c ar e fo r th e  p artici p a n ts ac co rd in g  to  go o d  clin ic al pr actic e a n d  pr o to co l 
g u id eli n es.  
 
 
A n o t e w ill b e  p l ac e d i n t h e m e d ical r e co r d d o cu m e nt in g  th at  in fo rm e d  co n se nt  w as  o b t ain e d fo r th is 
st ud y , a n d th a t t h e p artic ip a n t ac k n o wl e d ges  t h e risk o f p articip a tio n . 


P a g e 9 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 9. 0  
R E F E R E N C E S  
 
1 . 
D e m e tri, G.D ., Id e nti fic atio n  a n d  tre a tm e nt  of  ch e m o resi st an t in o p e ra b le o r m et a sta tic GIST: 
ex p e ri en c e w it h t h e sel e ctive tyr o si n e ki na se i n h ib it or im ati n i b m e syla t e (S T I5 7 1 ). E ur  J 
C a n c er, 2 0 0 2 . 3 8  S u p p l 5 : p . S 52 -9.  
2 . 
D e b ie c-R yc hter,  M ., et  al.,  Us e  of c-K IT /P D G F R A m ut a ti on a l an a lysis t o p re d ict th e cl i nic al 
res p o n s e to im ati n i b i n p a tie nts  w it h ad va n c e d g a stro i nt esti na l stro m al t u m o u rs e nt e re d  o n 
p h a s e I an d  II stu d i es of th e  E O R T C  S oft  T issu e a n d  B o n e S a rco m a G ro u p . E ur  J C an c er, 2 0 0 4 . 
4 0 (5 ): p.  6 8 9 -9 5.  
3 . 
V er w e ij, J., e t al.,  Pr o g res sio n -fre e su rviva l i n g a stro i ntes tin a l stro m al  tu m o u rs wi th  hi g h -d os e 
i m atin ib : ra n d o mis e d  tria l. La n c et, 2 0 0 4 . 3 6 4 (9 4 4 0 ): p.  1 1 2 7 -3 4.  
4 . 
Bl a n k e , C.D ., e t al ., P h a s e III ra n d o mi ze d, i n te rg ro u p  tria l ass essi n g im ati n i b m esy la t e a t tw o  
d os e l ev els  i n p a ti e nts w it h u n res ect a b l e o r m e ta st atic g a stro i nte stin a l stro m al  tu m o rs 
ex p re ssin g  th e  kit rec e p to r tyrosi n e  ki n a se : S 0 0 3 3 . J Cl in  O n co l, 2 0 0 8 . 2 6 (4 ): p.  6 2 6 -3 2 . 
5 . 
P ar k, S. H ., et  al.,  So ra f en i b in  p a ti e nts wit h m et ast a tic g a stro i nte stin a l stro m al  tu m o rs w h o 
fa il e d tw o o r m o re p rio r tyrosi n e k in a s e in h ib ito rs: a p h a s e II st ud y of K o re a n  g a stro i nt esti na l 
stro m al t u m o rs st ud y g ro u p . In v est  N e w  D ru g s, 2 0 1 2 . 3 0 (6 ): p.  2 3 7 7 -8 3 . 
6 . 
M o n t em u rro , M ., et  al., So r af en i b as  t hir d- o r f ou rth -lin e tre a tm e nt  of a d va n c e d 
g a stro i nte stin a l stro m al  tu m o ur  a n d  p re tre a tm e nt i n clu d in g  b o t h i m atin i b a n d  su n itin ib , an d 
n il otin ib : A re tro s p ectiv e an a lysis. E ur  J C an cer,  2 0 1 2 . 
7 . 
D e m e tri, G.D ., e t al.,  Effi ca cy a n d  sa f ety of re g o ra fe n ib  f or a d va n c e d g a stro i nt estin a l stro m al 
t u m ou rs aft e r f ailu re  of i m a ti nib  a n d  su n itin i b (G R I D): a n  i nt ern a ti on a l, m ulti ce n tre, 
ra n d o mis e d, p l ac eb o -co n tro ll ed , ph a s e 3  tria l. La n ce t, 2 0 1 2 . 
8 . 
H u izin g a, J .D ., et al.,  W /kit g e n e re q u ire d f o r i nte rstitia l c ells of C aja l an d  fo r i nte stin a l 
p a c e ma k er a ctivity. N at u re , 1 9 9 5 . 3 7 3 ( 65 1 2 ): p.  3 4 7 -9.  
9 . 
H ei n rich , M . C., et  al.,  P D G FR A a ctiv ati n g m u t atio n s i n g a stro i nte stin a l stro m al  tu m o rs. 
Sc ie nc e,  2 0 0 3 . 2 9 9 (5 6 0 7 ): p . 7 0 8 -1 0 . 
1 0 . 
H ir ota, S.,  et  al ., G a i n-of -fu n ctio n  m u t atio n s of  c-kit  i n h u m a n  g a stro i nte stin a l stro m al 
t u m ors. Sc ie n ce,  1 9 9 8 . 2 7 9 (5 3 5 0 ): p.  5 7 7 -8 0 . 
1 1 . 
A g ar a m,  N .P ., et al.,  N ov el  V 6 0 0 E  B R A F  m u t atio n s i n im ati n i b-n a iv e an d  im a ti nib -resi st an t 
g a stro i nte stin a l stro m al  tu m o rs. G e n es  C hr o m o so m es  C a nc er,  2 0 0 8 . 4 7 (1 0 ): p.  8 5 3 -9.  
1 2 . 
D e m e tri, G.D ., e t al.,  Effi ca cy a n d  sa f ety of im ati n i b m esyl a t e i n a d va n c e d g a stro in t esti na l 
stro m al t u m o rs. N  E n g l J M e d, 2 0 0 2 . 3 4 7 (7 ): p.  4 7 2 -8 0.  
1 3 . 
H ei n rich , M . C., et  al.,  C o rre la ti o n of k in a s e g e n o typ e a n d  cli nic al ou tco m e  i n th e  N or th 
A m e ric an  I nte rg ro u p  P h a s e III Tr ia l of im ati n i b m esyl a te f or  tre a tm e nt  of a d va n ce d 
g a stro i nte stin a l stro m al  tu m o r: C AL G B 1 5 0 1 0 5  S t ud y b y C an c er a n d  Le u k e m i a G ro u p  B  a n d 
S o u t h we st O n co lo g y G ro u p . J Cli n  O n co l, 2 0 0 8 . 2 6 (3 3 ): p.  5 3 6 0 -7.  
1 4 . 
D e b ie c-R yc hter,  M ., et  al.,  KI T  m u t atio n s a n d  d o s e se lecti o n  f or im ati n i b i n p a tie n ts w it h 
a d va n c e d g a stro i nt esti na l stro m al  t u m our s. E ur  J C a n cer,  2 0 0 6 . 4 2 (8 ): p.  1 0 9 3 -1 0 3 . 
1 5 . 
D e m e tri, G.D ., e t al.,  Effi ca cy a n d  sa f ety of s un itin i b i n p a ti e nts wit h a d va n c e d 
g a stro i nte stin a l stro m al  tu m o ur  a fter  f ailu re of im ati n ib : a ra n d o m is e d co n tro ll e d tria l. 
La n c et, 2 0 0 6 . 3 6 8 (9 5 4 4 ): p.  1 3 2 9 -3 8.  
1 6 . 
H ei n rich , M . C., et  al.,  M o le cu la r c orrel a t es of i m ati n i b resi st an c e i n g a stro i nt estin a l stro m al 
t u m ors. J Cli n  O n co l, 2 0 0 6 . 2 4 (2 9 ): p.  4 7 6 4 -7 4.  
1 7 . 
A n to n es cu , C. R., e t al ., A cq u ire d resi st an c e to im ati n i b i n g a stro i ntes tin a l stro m al  t u m or 
o ccu rs t hro u g h  s ec on d a ry g e n e m ut ati o n . Cl in  C a n c er R es,  2 0 0 5 . 1 1 (1 1 ): p.  4 1 8 2 -9 0.  


P a g e 9 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 8 . 
B a lac h a n d r an , V. P., et  al.,  Im ati n i b p o t e ntia te s a n titu m or  T  c ell res p o n ses  i n g a stro i nt esti na l 
stro m al t u m o r th ro u g h  th e  in h ib itio n  of I d o.  N at  M e d,  2 0 1 1 . 1 7 (9 ): p.  1 0 9 4 -1 0 0 . 
1 9 . 
B ar d sl ey , M . R., et  al ., Kitl o w  ste m  c ells ca u s e res ista n c e t o K it/p la t ele t-d e rive d g ro wt h f a cto r 
a lp h a  i nh ib it ors i n mu rin e g a stro i nte stin a l stro m al t u m or s. G a stro e nt e ro lo g y , 2 0 1 0 . 1 3 9 (3 ): p.  
9 4 2 -5 2 . 
2 0 . 
B a u er,  S ., e t al ., KI T  o n co g e n ic sig n a lin g  m ec h a n ism s in  im a ti nib -res ista n t g a stro in t esti na l 
stro m al t u m o r: P I3 -ki n a se/ A K T  is a cru ci al su rviva l pa th w ay.  O nc o g e n e,  2 0 0 7 . 2 6 (5 4 ): p.  
7 5 6 0 -8.  
2 1 . 
F le tc h er, J.A . an d  B .P . R ub in , KI T  m ut ati o n s i n GIS T . C u rr O pin  G e n et  D e v , 2 0 0 7 . 1 7 (1) : p.  3 -7.  
2 2 . 
H ei n rich , M . C., et  al.,  Ki n a se m u t atio n s a n d  im a ti nib  res p o n s e i n p a ti en ts wit h m et ast a tic 
g a stro i nte stin a l stro m al  tu m o r. J Cli n  O nc o l, 2 0 0 3 . 2 1 (2 3 ): p.  4 3 4 2 -9.  
2 3 . 
R eic h a r dt, P ., et  al.,  G a stro in t esti na l stro m al t u m o rs I: p a t ho lo g y, pa t ho b io lo g y, prim a ry 
t h era p y, an d  su rg ic al issu es . S e m i n O nc o l, 2 0 0 9 . 3 6 (4 ): p.  2 9 0 -3 0 1 . 
2 4 . 
V er w e ij, J., e t al.,  I ma ti nib  m esyl a t e (ST I-5 7 1  Gl iv ec, G l e ev ec) is a n  a ctiv e ag e nt  for  
g a stro i nte stin a l stro m al  tu m o ur s, b u t d o es  n o t yiel d  res p o n s es i n o t h er sof t-tissu e sa rco m as 
t ha t a re  u n s el ect e d f or a  m o lec u la r ta rg e t. Re s ults fro m  a n  E O R T C  S o ft T issu e a n d  B o n e 
S a rco m a  G ro u p  p h a s e II stu d y. E ur  J C an c er, 2 0 0 3 . 3 9 (1 4 ): p.  2 0 0 6 -1 1.  
2 5 . 
C h i, P ., et  al.,  E T V 1  is a  lin e a g e su rviva l fa cto r th a t c oo p e ra t es w it h K I T i n g a stro in t esti na l 
stro m al t u m o u rs. N at u re,  2 0 1 0 . 4 6 7 (7 3 1 7 ): p.  8 4 9 -5 3.  
2 6 . 
A n d ers e n , R. J., e t al ., R e gr e ssio n  of c a stra te -rec ur re nt  p rost at e  ca n c er b y a sm a ll-m ol e c ul e 
in h ib it or of t h e a mi n o -te rm in u s d o m a in  of th e a n d ro g e n  rec e p to r. C a n cer  C ell,  2 0 1 0 . 1 7 (6 ): p.  
5 3 5 -4 6 . 
2 7 . 
W e sc he , J., K . H a g lu n d , a n d E. M. H a u g ste n,  Fi bro b la st g ro wt h f a cto rs a n d  t h eir re c ep t ors i n 
ca n c er. Bi oc h e m  J, 2 0 1 1 . 4 3 7 (2 ): p.  1 9 9 -2 1 3 . 
2 8 . 
G u a g n a n o , V., e t al ., F G F R  g e n etic  alt e ra ti on s pr e d ict f or s en sitivity t o NV P -B G J3 9 8 , a 
s el ectiv e p a n -FG F R i n h ib ito r. C a n c er D isco v , 2 0 1 2 . 2 ( 12 ): p.  1 1 1 8 -3 3 . 
2 9 . 
K o n ec n y , G. E.,  e t al.,  A ctivity of t h e fi b ro b la st g ro wt h fa cto r rec e p t or i nh ib it ors d o vitin i b 
( T KI2 5 8 ) a n d  N V P -B G J3 9 8  in  h u m a n  e n d o m e tria l ca n c er c ells. M o l C an cer  T h er,  2 0 1 3 . 1 2 (5 ): 
p . 6 3 2 -4 2 . 
3 0 . 
Li, M ., e t al.,  B E A M in g  u p  for  d et e cti o n a n d  q u a n tific ati o n of ra re se q u e n ce v a ria n ts. N at  
M e th o d s, 2 0 0 6 . 3 (2 ): p.  9 5 -7.  
3 1 . 
D e m e tri, G.D ., e t al.,  I ma ti nib  pl a sm a  l ev els ar e c o rrel a t e d w it h cli nic al b en efit i n p a ti e nts 
wit h u n re s ect ab l e/m e ta sta tic g a stro i ntes tin a l stro m al  t u m ors. J Cli n  O n co l, 2 0 0 9 . 2 7 (1 9 ): p.  
3 1 4 1 -7.  
3 2 . 
Eis e n h a u er,  E. A ., et  al ., N e w  res p o n s e ev a lu a ti o n crit eri a i n s olid  tu m o ur s: revi se d  R E CI ST  
g u id eli n e (v ersi o n 1 .1 ). E ur  J C a nc er,  2 0 0 9 . 4 5 (2 ): p.  2 2 8 -4 7 . 
3 3 . 
C h o i, H., et  al.,  C o rrel a tio n  of co m p u t e d to m o gr a p h y a n d  p o sitro n  e mi ssi o n t o mo g ra p h y i n 
p a ti e nts w it h m et ast a tic g a stro i nte stin a l stro m al t u m o r tre at e d  a t a  sin g l e i nstit utio n  w it h 
i m atin i b m e syla t e: p ro p os a l of n e w  co m p u t e d to m o g ra p h y res p o n s e crite ria . J Cl in  O n co l, 
2 0 0 7 . 2 5 (1 3) : p.  1 7 5 3 -9.  
3 4 . 
Y o u n g , H., e t al ., M e as u re m e nt  of clin ic al an d  su b clin ic al t u m ou r res p o n se usi n g  [ 18 F ]- 
flu or o d e o xy gl uco s e a n d  p o sitro n  e mi ssi o n to m o g ra p h y:  revi e w  a n d  1 9 9 9  E O R T C 
rec o m m e n d a ti on s. E u ro p e a n  O rg a n iz ati o n f or R e s e arc h a n d  Tr e a tm e nt  of  C a n c er ( EO R T C) 
P E T  S t ud y G ro u p . E ur  J C a n c er, 1 9 9 9 . 3 5 (1 3 ): p.  1 7 7 3 -8 2.  


P a g e 9 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
2 0. 0  
A P P E N DI C E S  
 
A p p e n d ix A: K P S -E C O G  C o n v e rsio n  C h a rt 
 
A p p e n d ix B : P ati e n t Or a l M e d ica tio n  D ia ry  
 
A p p e n d ix C:  LIS T  O F  C Y P 3 A 4  a n d  C Y P 2 B 6  IN H I BI TO R S A N D  IN D U C E R S  (Im ati ni b ) 
A p p e n d ix D:  List o f co n co m ita n t m e d ica tio n s to  b e  u se d  w it h ca u tio n  w it h B G J3 9 8  
A p p e n d ix E: L ist o f pro h ib it e d m e d ica tio n s wi t h B G J3 9 8  
 
A p p e n d ix F: List o f se le ct H i g h-p h o sp h o ro u s fo o d s a n d  su g g e st e d alt e rn a ti ve s 
 
A p p e n d ix G : O p h th a lm o lo g y  E x a m  F o rm s 


P a g e 9 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
A p p e n d ix  A : P er fo rm a n ce  St a tu s C rit eria  
 
 
 
 
 
E C O G  P erf o rm a n ce  S ta tu s S ca le  
 
K a rn o fs k y P erf o rm a n ce  Sc a le  
Gr a d e  
D es crip tio n s 
P er ce nt  
D es crip tio n  
 
 
 
0  
 
N o rm al  ac tiv ity .  Fu ll y a ctiv e,  a b l e t o 
c arr y o n  all p re -d ise as e  p e rfo rm a n c e 
wit h o u t re strictio n . 
 
1 0 0  
N o rm al,  n o  co m p l ai nts, n o e v id e n ce  o f 
d is e as e. 
 
9 0  
A b l e to  c arry  o n  n o rm al a cti vity; m in o r 
sig n s o r sy m p to m s o f dis e a s e. 
 
 
 
1  
Sy m p to m s, bu t a m b u l ato ry. 
R es tricte d  i n p h y sic ally stre n u o u s 
acti v ity , bu t a m b u l ato ry  a n d  a b le  to 
c arr y o u t w o rk o f a lig h t o r s e d e nt ary 
n at u re  ( e.g ., lig h t h o u se w o rk,  o ffic e 
w o rk). 
 
8 0  
N o rm al  ac tiv ity  w it h effo rt; s o m e si gn s 
o r sy m p to m s o f dise as e . 
 
7 0  
C ar es fo r self, u n a b l e to  c arr y o n 
n o rm al  ac tiv ity  o r to  d o  ac ti v e w o rk.  
 
 
 
2  
I n b e d < 5 0 %  o f t h e tim e.  A m b u l ato ry 
a n d  c ap a b l e o f all sel f-c ar e, b u t 
u n a b l e to  c arry o u t a ny  w o r k 
acti v ities.  U p  a n d  a b o u t m o r e t h a n 
5 0 %  o f w a kin g  h o u rs. 
 
6 0  
R e q u ir es o cc asio n al a ssista n c e, b u t is 
a b l e to  c are  fo r m o st o f his/h er  n e e ds.  
 
5 0  
R e q u ir es co n sid er a b l e assi st a nc e a n d  
fr eq u e nt  m e d ic al c ar e. 
 
 
 
3  
 
I n b e d > 5 0 %  o f t h e tim e.  C a p a b l e o f 
o n l y lim ite d s e lf-c are,  co n fin e d t o 
b e d o r c ha ir m o re  t h a n 5 0 %  o f 
w a k in g  h o u rs. 
 
4 0  
D is ab l ed , re q u ir es s pe ci al car e a n d  
assist a n c e. 
 
3 0  
S e v e rely  dis a b le d, h o s pit alizati o n  
in d ic at e d. D e a th  n o t im m in e nt.  
 
 
 
4  
 
1 0 0 %  b e dr i d de n.  C o m p let el y 
d is ab l ed . C a n n o t c arry o n  a n y  se lf- 
c ar e.  T o tal ly  co n fin e d  t o b e d o r 
c ha ir. 
 
2 0  
V er y  sick, h o s pit alizat io n  in d ic at e d. 
D e a th  n o t im m in e nt.  
 
1 0  
M o rib u n d , f atal p ro c esses  p ro g r essin g  
r ap id l y. 
5  
D e a d.  
0  
D e a d.  


P a g e 1 0 0  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
A p p e n d ix  B : P ill D ia ry  f or IR B  # 1 4 -1 4 0 : S C H E D UL E  A  
 
 
N a m e :  
 
 
M R N :  
 
 
A p h a s e I b/II stu d y  o f B GJ 3 9 8  in  co m b in a tio n  w it h im a ti nib  m e sy la t e in  p a tie n ts w it h 
u n tre a t e d a d v a n c e d g a stro in t esti na l stro m a l tu m or ( G IS T)  
 
 
 
 
T o ta l D a ily  
D o s e 
C a p su le 
S tre n g t h 
(m g ) 
N u m b e r o f 
C a p su le 
G iv e n  
 
P ill B o ttle s 
R et u rn e d ?  
 
N u m b e r o f 
C a p su le 
R et u rn e d  
 
 
Im ati n ib  
 
 
 
 
 
Y  o r N  
 
 
 
B G J3 9 8  
 
 
 
 
 
Y  o r N  
 
 
(A b o v e  t o b e  C o m p le te d  b y  R N)  
P L E A S E  FI L L  O U T  A N D  B RI N G  T HI S  S H E E T  A T Y O U R  N E X T  V IS IT . 
 
S P E C IA L  I NS T R U C T IO N S  
•  
Im at in ib  s h o u ld  b e t a k e n  o ra lly  w it h fo o d.  B G J 3 9 8  s h o u ld  b e  ta k e n  in  th e  m or n in g  2 
h o ur s  a ft er a  lig ht  b re a k fa s t. N o  fo o d  s h o u ld  b e  c o n s u m e d  for  1  h o ur  a ft er ta k in g  t h e 
c a p s u le.  B o t h s h o u ld  b e  ta k e n  w ith  a lar g e  g la s s  of  w at e r ( 8o z ). 
•  
D o  n o t c h e w  or  cr u s h  th e  c a p s u le  . 
•  
D o  n o t d rin k  gr a p e fru it ju ic e  or  t ak e  h e rb a l s u p p le m e n ts  s u c h  a s  S t. J o h n’ s  W ort  w h ile 
t ak in g  th e s e  m e di c at io n s . 
•  
T a k e  im at in ib  o n c e  a  d a y , n o  le s s  th a n  tw e lv e  h o ur s  b e t w ee n  e a c h  d o s e.  If a  d o s e  of 
im at in ib  is m is s e d , pl e a s e  ta k e  th e  d o s e  a s  s o o n  a s  p o s s ib le,  b u t o n ly  if th er e  ar e 1 2 
or  m o re  h o ur s  r em a in in g  b e for e  t h e n e x t d o s e.  
a.   If th e  d o s e  is d u e  in  le s s  th a n  1 2  h o ur s , s ki p  t h e m is s e d  d o s e  a n d  ta k e  th e  n e x t 
d o s e  a s  s c h e d u le d . 
 
•  
T a k e  B G J 3 9 8  o n c e  a  d a y  in  th e  m or n in g . If a  d o s e  o f B G J 3 9 8  is m is s e d , ta k e  a s  s o o n 
a s  p o s s ib le  w it hi n 2  h o u rs  of  th e  m is s e d  d o s e.  If 2  h o ur s  p a s s e s , s ki p  th e  m is s e d 
d o s e  a n d  ta k e  th e  n e x t d o s e  a s  s c h e d u le d.  
 
•  
If v o m itin g  o c c ur s  a ft er t ak in g  e ith er  im at in ib  o r B G J 3 9 8 , e v e n  if it a p p e a rs  th e  w h o le 
c a p s u le h a s  b e e n  re g u rg it ate d , d o  n ot  t ak e  a  re p la c e m e n t d o s e.  R e s u m e  a t th e  n e x t 
s c h e d u le d  d o s e.  
a.   If c o n s is t en t v o m itin g  o c c ur s  p le a s e  n o tify  th e  st u d y  in v e s tig a tor  
 
A ll m is s e d  d o s e s  s h o u ld  b e  r ec or d e d  in  th is  p ill d ia ry . 


P a g e 1 0 1  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
 
 
D A Y  
 
 
M E DI C A T IO N  
 
 
D A T E  
 
 
T IM E  
N U M B E R  of  
m g 
c a p s ul e s  
ta k e n  
N U M B E R  of  
  
 m g 
c a p s ul e s 
ta k e n  
 
 
E x a m p le  
 
I m ati ni b 
 
 
0 1 /0 1/ 2 0 1 0  
 
9: 0 0 A M  or P M  
 
1  
 
B G J 3 9 8  
9: 0 0 A M  
 
1  
D a y  1  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  2  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  3  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  4  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  5  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  6  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  7  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  8  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  9  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 0  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
I m ati ni b 
 
 
 
 


P a g e 1 0 2  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 1  
B G J 3 9 8  
 
 
 
 
D a y  
1 2  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 3  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 4  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 5  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 6  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 7  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 8  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 9  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 0  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 1  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 2  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 3  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 4  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
I m ati ni b 
 
 
 
 
 


P a g e 1 0 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
2 5  
B G J 3 9 8  
 
 
 
 
D a y  
2 6  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 7  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 8  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
 
 
 
 
P ati e nt  S i gn at u re: _   
 
D at e:   
 
 
C o n s e n ti n g P ro fe s si o n al /R e s e a rc h  R N  S i gn at u re:    
 
D at e:   
 
 
C o n s e n ti n g P ro fe s si o n al /R e s e a rc h  R N  C o m m e n ts:  


P a g e 1 0 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
A p p e n d ix  C : Pill D ia ry  f or IR B  # 1 4 -1 4 0 : S C H E D UL E  B  
 
 
N a m e :  
 
 
M R N :  
 
 
A p h a s e Ib /II stu d y  o f B GJ 3 9 8  in  co m b in a tio n  w it h im a ti nib  m e sy la t e in  p a tie n ts w it h 
u n tre a t e d a d v a n c e d g a stro in t esti na l stro m a l tu m or ( G IS T)  
 
 
 
 
T o ta l D a ily  
D o s e 
C a p su le 
S tre n g t h 
(m g ) 
N u m b e r o f 
C a p su le 
G iv e n  
 
P ill B o ttle s 
R et u rn e d ?  
 
N u m b e r o f 
C a p su le 
R et u rn e d  
 
 
Im ati n ib  
 
 
 
 
 
Y  o r N  
 
 
 
B G J3 9 8  
 
 
 
 
 
Y  o r N  
 
 
(A b o v e  t o b e  C o m p le te d  b y  R N)  
P L E A S E  FI L L  O U T  A N D  B RI N G  T HI S  S H E E T  A T Y O U R  N E X T  V IS IT . 
 
S P E C IA L  I NS T R U C T IO N S  
•  
Im at in ib  s h o u ld  b e t a k e n  o ra lly  w it h fo o d.  B G J 3 9 8  s h o u ld  b e  ta k e n  in  th e  m or n in g  2 
h o ur s  a ft er a  lig ht  b re a k fa s t. N o  fo o d  s h o u ld  b e  c o n s u m e d  for  1  h o ur  a ft er ta k in g  t h e 
c a p s u le.  B o t h s h o u ld  b e  ta k e n  w ith  a lar g e  g la s s  of  w at e r ( 8o z ). 
•  
D o  n o t c h e w  or  cr u s h  th e  c a p s u le  . 
•  
D o  n o t d rin k  gr a p e fru it ju ic e  or  t ak e  h e rb a l s u p p le m e n ts  s u c h  a s  S t. J o h n’ s  W ort  w h ile 
t ak in g  th e s e  m e d ic at io n s . 
•  
T a k e  im at in ib  o n c e  a  d a y , n o  le s s  th a n  tw e lv e  h o ur s  b e t w ee n  e a c h  d o s e.  If a  d o s e  of 
im at in ib  is m is s e d , pl e a s e  ta k e  th e  d o s e  a s  s o o n  a s  p o s s ib le,  b u t o n ly  if th er e  ar e 1 2 
or  m o re  h o ur s  r em a in in g  b e for e  t h e n e x t d o s e.  
b.   If th e  d o s e  is d u e  in  le s s  th a n  1 2  h o ur s , s ki p  t h e m is s e d  d o s e  a n d  ta k e  th e  n e x t 
d o s e  a s  s c h e d u le d . 
 
•  
T a k e  B G J 3 9 8  o n c e  a  d a y  in  th e  m or n in g . If a  d o s e  o f B G J 3 9 8  is m is s e d , ta k e  a s  s o o n 
a s  p o s s ib le  w it hi n 2  h o u rs  of  th e  m is s e d  d o s e.  If 2  h o ur s  p a s s e s , s ki p  th e  m is s e d 
d o s e  a n d  ta k e  th e  n e x t d o s e  a s  s c h e d u le d.  
 
•  
If v o m itin g  o c c ur s  a ft er t ak in g  e ith er  im at in ib  o r B G J 3 9 8 , e v e n  if it a p p e a rs  th e  w h o le 
c a p s u le  h a s  b e e n  re g ur g ita t ed , d o  n ot  ta k e  a  r ep la c e m e n t d o s e.  R e s u m e  a t th e  n e x t 
s c h e d u le d  d o s e.  
b.   If c o n s is t en t v o m itin g  o c c ur s  p le a s e  n o tify  th e  st u d y  in v e s tig a tor  
 
A ll m is s e d  d o s e s  s h o u ld  b e  r ec or d e d  in  th is  p ill d ia ry . 


P a g e 1 0 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
 
 
D A Y  
 
 
M E DI C A T IO N  
 
 
D A T E  
 
 
T IM E  
N U M B E R  of  
m g 
c a p s ul e s  
ta k e n  
N U M B E R  of  
  
 m g 
c a p s ul e s 
ta k e n  
 
 
E x a m p le  
 
I m ati ni b 
 
 
0 1 /0 1/ 2 0 1 0  
 
9: 0 0 A M  or P M  
 
1  
 
B G J 3 9 8  
9: 0 0 A M  
 
1  
D a y  1  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  2  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  3  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  4  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  5  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  6  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  7  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  8  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  9  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 0  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
I m ati ni b 
 
 
 
 


P a g e 1 0 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 1  
B G J 3 9 8  
 
 
 
 
D a y  
1 2  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 3  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 4  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 5  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 6  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 7  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 8  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
1 9  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 0  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 1  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 2  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 3  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 4  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
I m ati ni b 
 
 
 
 
 


P a g e 1 0 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
2 5  
B G J 3 9 8  
 
 
 
 
D a y  
2 6  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 7  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
D a y  
2 8  
I m ati ni b 
 
 
 
 
B G J 3 9 8  
 
 
 
 
 
 
 
P ati e nt  S i gn at u re: _   
 
D at e:   
 
 
C o n s e n ti n g P ro fe s si o n al /R e s e a rc h  R N  S i gn at u re:    
 
D at e:   
 
 
C o n s e n ti n g P ro fe s si o n al /R e s e a rc h  R N  C o m m e n ts:  


P a g e 1 0 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
Ac e ta mi n o p h e n  
Ac e ta zo la mi d e 
A mi o d a ro n e 
A ml o d ip in e 
A m p re n a vir 
A n as tro zo le 
A p re p ita n t 
A ta za n a vir 
A tor v as ta ti n 
A zel a stin e 
A zith ro m y ci n 
B e ta m e th as o n e 
B or te zo mi b 
B ro m o cript in e 
C af fei n e 
C eri v ast at in 
C hl o r am p h e n icol 
C hl o rzo xa zo n e 
Ci m e tid in e 
Ci p ro fl ox aci n 
Ci sa p rid e 
Cl ari t hro m y ci n 
Cl e m as tin e 
Cl o fa zi min e 
Cl o tri ma zol e 
Cl o za p in e 
C oc ai n e 
C o n i v apt a n  
C yc l op h os p h a mi d e 
C yc l osp ori n e 
D a n a zol  
D as a tin i b (1) 
D el a vir d in e 
D esi p r am in e 
D ex m e d e to m id in e 
D i aze p a m  
D icl ofe n ac  
D ih y d ro er g o ta mi n e  
D iltia ze m 
D isu lfir a m 
D o ce tax el 
D o xor u b ici n 
D o xycyclin e  
D ro sp ire n o n e 
E fa vir e nz 
E n o xaci n 
E nt ac a p o n e 
Er g ot a m in e 
Er y t hro m y ci n 
E t hin yl es tr ad i ol 
E to p osi d e 
F el o d ip in e 
F e nt a n yl 
Fl u co n a zol e 
Fl u o xe tin e 
Fl u v as ta ti n 
Fl u v ox a mi n e 
F o s a mp re n a vir 
Gl y b u rid e  
Gr a p e fru it ju ice  (2) 
H al o p eri d ol 
H y d ral a zin e 
Ifo sfa m id e  
I m atin ib 
I nd in a vir 
Irb es a rta n 
Iso n i azid 
Isr ad ip in e 
Itrac o n a zol e 
K e to co n a zo le 
L an s op ra zol e 
Lid o cai n e  
L om u stin e  
L os arta n  L o v asta tin 
M e flo q u in e 
M es tra n ol 
M e th a d o n e 
M e th i m az ol e 
M e th o xs al e n 
M e th ylp re d n is olo n e 
M e tro n id a zo le 
M ico n a zol e 
M id a zol a m 
M ife p risto n e 
M irta za p in e 
M ito xa nt ro n e 
M o d a fin il 
N e fa zo d o n e 
N el fin a vir  
N e vir a p in e 
N icar d ip in e 
N ife d ip in e 
N is old ip in e 
N iza tid in e 
N or flo xaci n 
Ol a nz a p in e 
O m e p r azol e 
Or p h e n a d rin e 
O xy b ut y ni n 
P a ro xe tin e 
P e n ta mi d in e 
P e r go lid e 
P h e n cyclid in e 
Pil o car p in e 
Pi m o zid e 
P ra v as ta ti n 
P re d n is olo n e  
P ri m a q uin e  
P ro g es ter o n e 
P ro p o fol 
P ro p o xyp h e n e 
Q ui n id in e 
Q ui n in e 
Q ui n u p ristin 
R a b e p ra zol e 
R a n ol a zin e 
Ri sp eri d o n e 
Rit o n a vir 
S a q u in a vir 
S el e gili n e 
S er tr alin e 
Sil d e n a fil 
Sir o li mu s 
S u lco n a zol e 
T acr oli m u s 
T a m o xife n 
T elit h ro m y ci n 
T e n ip osi d e 
T es to ster o n e 
T e tr acyc lin e 
Ti cl op id in e 
Tr a n ylcy p ro m in e 
Tr a zo d o n e 
Tr o l ea n d o m y ci n 
V al p ro ic aci d 
V e n la faxi n e 
V er a p a mil 
Vi n b l astin e 
Vi n cristin e 
Vi n or e lb in e 
V oric o n a zol e 
Z a firlu kast 
Zi p r asid o n e  
 
 
 
 
 
 
A p p e n d ix  D : LIS T  O F  C Y P 3 A 4  IN H IB IT O R S  A N D IN D U C E R S  (R e fe re n c e for  Im a tini b ) 
C Y P 3 A 4  I nh ib ito rs 


P a g e 1 0 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
C Y P 3 A 4  I nd u c ers 
A mi n o gl u te t hi mid e  
C ar b a m az e p in e 
F o sp h e n yt o in 
N a fcilli n 
N e vir a p in e  
O xcar b a ze p in e 
P e n to b a rb ital 
P h e n o b a rb ital  
P h e n ytoi n  
P ri mid o n e 
Rif a b u ti n 
Rif a m p i n 
Rif a p e n tin e  
S t. Jo h n ’s w ort (3)  
 
 
N o te : A d a p te d  fro m  C y to ch ro m e  P 4 5 0  E n zym e s: S u b str ates , In h ib ito rs, a n d  In d u c ers. I n: La cy 
C F, A rm stro n g  LL, G o ld m a n  M P , La n c e LL e ds.  D ru g  In fo rm ati o n  H a n d b o o k  1 5 th  e d . H u d so n , 
O H;  Le xiC o m p  In c. 2 0 0 7 : 1 8 9 9 -1 9 1 2 . 
 
O n ly m aj o r s ub str ates  a n d  eff e ctiv e  i nd u c ers a re  list ed . Ad d itio n al i n fo rm at io n  fo r dr ug 
in te r actio n s w it h cy to c hr om e  P 4 5 0  iso e n zym e s c a n b e  fo u n d  a t 
h ttp ://m e d icin e. u u p u i.e d u /fl ock h art/. 
 
List o f C Y P 3 A 4  a n d  C Y P 2 B 6  s ub str ate s. 
 
C y t oc hr o m e  
C at e g o ry  
S u b s tr at e 
C Y P 3 A 4 ,5 , 7 
A n ti arrh y th m ic s  
q ui n i din e →3 -O H ( n o t C Y P 3 A 5) 2 , d ro n e d a ro n e 1  
 
A n ti his ta mi n e s  
B e n z o di a z e p i ne s  ( CN S  
a g e n ts ) 
a s te mi z ol e 2 , e b a s ti ne 1 , [ te rfe n a di n e ]1, 2  
al p ra z o la m , b ro tiz ol a m
1 , d i az e p a m →3 O H,  mi d a z ol a m
1 , 
tri az ol a m
1  
C a l ciu m  C h a n n e l B lo c k e r s 
a ml o di p i n e, d ilti az e m , fe l od i pi ne 1 , n ife d ipi n e , n i so l dipi n e 1 , 
ni tre n di p i n e, v e ra p a mi l 
Pr o te a s e  In hi b ito rs  
b o c e p re v ir, b re c a n a v ir1 , c a p ra v iri n e1 , d a ru n a v ir1 , in d in a v ir1 , 
l o pin a v ir1 , rito n a v ir, s a q u in a v ir1 , te la p re v ir, ti pra n a v ir1  
H M G  C o A R e d u c ta s e  
In hi b ito rs  
a to rv a s ta ti n1 , l ov a s ta tin 1 , s im v a s ta tin 1  
Im m u n e  M o d ul a to r s 
c y cl o s p o ri ne 2 , e v e ro li mu s 1 , si roli m u s 1 ,2 , ta c ro lim u s 2  
A n ti bio tic s  
cl a rith ro m y ci n , e ry th ro m y ci n  (n o t C Y P 3 A 5 ), tel ith ro m y ci n  
A n tip s y c h o tic s  
a ri pip ra z ol e , h a lo p e ri do l, lu ra s id o n e 1 , p e ro s p iro n e 1 , 
pi m o z id e 2 , q u e ti ap i ne 1  
T y ro si n e  K i na s e  In h ibi to r s 
(a n tic a n c e r) 
d a s a ti nib 1 , i ma tin i b, n e ra ti nib 1  nil o ti nib  
O pi oi d s  
al fe n ta n il1, 2 , f e nta n y l2 , m e th a d o n e , l ev o m e th a d y l1  
Er g o t d e riv a tiv e s  (f or 
mi g ra i ne s ) 
di e rg o ta m i ne  (di h y d ro e rg o ta m in e )2 , e rg o ta m in e 2  
C or ti co s te roi d s  
b u d e s o n i de 1 , flu tic a s o n e 1  
Er e c tile  D y s fu n c ti on  A g e n ts  
sil d e n a fil1 , v a rd e n a fil1  
A n tie m e tic s  
a p re p ita n t1 , c a s o pi ta n t1  
O th e r s 
al p h a -di h y d ro e rg o c ry p tin e 1 , a p l av iro c 1 , b u s pi ro n e 1 , c i sa p rid e 2, 
c o ni v a p ta n 1 , d a rife n a c in 1 , el e tri pta n 1 , e p l ere n o n e 1 , 
l u me fa n tri ne 1 , m a ra v iro c 1 , q ui n i n e, ri d afo ro li mu s 1 , ta m o x ife n , 
ti ca g rel o r1 , to lv a p ta n 1 , tra z o d o n e , v i criv iro c 1 , v i n cri sti ne  
C Y P 2 B 6  
A l ky l atin g  A g e n ts  
(a n tic a n c e r): 
 
c y cl o p h o s p h a mi d e , ifo s fa m i de , thi o te p a  
O th e r s 
B u p ro p io n 1 , e fa v ire n z 1 , m e th a d o n e  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 1 0  o f 1 2 6  
 
 
C y t oc hr o m e  
C at e g o ry  
S u b s tr at e 
1  S e n s itiv e  s u b s tra te s : D ru g s  w h o s e  pl a s m a  A U C v al u e s  h a v e  b e e n  s h o w n  to  i n cre a s e  5 -fol d  o r hi g h e r w h e n  c o - 
a d m in is te re d  w it h a  p o te n t i nhi bi to r. 
2  S u b s tra te s  w it h n a rro w  t h era p e u tic  in d e x  ( NT I): Dr u g s  w h o s e  e x p o s u re -re s p o n s e  in d ic a te s  t ha t in c re a s e s  in 
th ei r e x p o s u r e l ev e ls  b y  t he  c o n c o mi ta n t u s e  o f p o te n t i nh i bito r s m a y  l ea d  to  s e ri ou s  s a fe t y c o n c e rn s  (e .g ., 
T o rs a d e s  d e  P o i nte s ). 
T hi s  lis t o f C Y P s u b s tra te s  w a s  c o m p il ed  fro m  th e  I nd i an a  U ni v e rsi t y S c h o o l o f M e d i ci ne ’s  “ Cli nic a lly  R el e v a n t” 
T a bl e ; fro m  th e  F D A ’s  “ G uid a n c e  f or I nd u s try , Dr u g  I nte ra c tio n  S t u die s ” a n d  fro m  t he  U ni v e rsi t y o f W a s hi n g to n ’s 
Dr u g  I nte ra c ti on  D a ta b a s e . T h e  f oll ow i ng  w e b si t e m a y  b e  f urth e r u s e fu l a s  a  re fe re n c e  to  a v oi d  p o te n tia l d ru g - 
d ru g  in te ra c tio n s : h ttp ://m e d i cin e .iu p ui .e d u /c li n ph a rm /d d is /ta bl e .a s p . 
 
A p p e n d ix  E : List o f co n co mi ta n t m e d ic atio n s to  b e  u s e d wi th  c au tio n  wi t h B GJ 3 9 8  
 
List o f C Y P 4 5 0  su b stra t es a n d  o th e r m e d ica tio n s t o b e  us e d  w it h ca u tio n  
 
 
S u b stra t es o f B C R P to  b e  a d m in ist er e d wi t h ca u tio n  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 1 1  o f 1 2 6  
 
 
 
 
 
 
List o f Q T  p ro lo n g in g  d ru g s 
 
 
Pr o hi bi te d  m e di c ati o n s  c a u si n g  Q T c  pr ol o n g ati o n  
A n tia rrh y th m ic:  
A n tic a n c e r: 
A n ti biot i c: 
A n ti a ng in al:  
a m io d ar o n e  
ar s e ni c  trio x id e  
a zi t hr om yci n  
b e pr id il 
d is o p y ra m id e  
v a n d e ta n ib  
c lari thr o m yc in*  
A n ti ps y c h o ti c: 
d o fet ilid e  
A n ti hi sta mi n e:  
e ry t hr om yc in*  
c h lor p ro m a z in e  
fle c a in id e  
a s t em iz o le * 
m o x iflo x a c in  
h a lo p e rid o l* 
ib u tilid e  
t erfe n a d in e * 
s p a rflo x a c in  
m e s ori d a zi n e  
pr o c a in a m id e  
A n ti ma l ari al: 
A n ti n au s e a:  
p im o z id e  
q u in id in e*  
c h lor o q u in e  
d o m p e rid o n e  
t hio rid a z in e  
 
s ot al o l 
 
h a lo fa n trin e  
dr o p er id o l 
O pi at e 
a g o ni s t: 
A n tilip e mi c : 
A n ti-i nfe c tiv e:  
G I s ti mu l a nt: 
le v o m et h a d y l 
pr o b u c o l 
p e n ta m id in e  
c is a p rid e*  
m et h a d o n e  
A n ti d ep re s s a n t: 
 
 
 
c it alo p ra m  
 
 
 
Pl e a s e  n ot e : *C Y P 3 A  s u b s trat e  
S o u r ce:  A riz o n a  C e n t er for E d u c a tio n  a n d  R e s e a r ch  o n  T h e ra p e u tic s  ( CE R T ), Dr u g s  th a t p ro lo n g  th e 
Q T int e rv a l a n d/ o r in d u c e  T or s a d e s  d e  P o in te s , h ttp: //w w w. a z c ert. or g/ m e di c a l-pr o s / dr u g-lis ts / dr ug - 
lis ts .c f m 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 1 2  o f 1 2 6  
 
 
A p p e n d ix  F : List o f p ro hi bi t e d m e d ic atio n s wi th  B GJ 3 9 8  
 
List o f C Y P 3 A i n h ib ito rs a n d  i nd u c ers t h at ar e  p ro h ib ite d  
 
 
EI A E D s t h at are  p ro h ib ite d  
 
 
S tro n g  C Y P 3 A  
i nd u c er s  
M o d e rat e  C Y P 3 A  
i nd u c er s  
c ar b a m a z e p in e  
fe lb a m at e  
p h e n o b a rb ital  
t opi ra m at e  (> 2 0 0 
m g/ d a y) 
p h e n y to in  
o x c ar b a z e p in  
fo s p h e n y to in  
e s lic ar b a z e p in  
pri m id o n e  
ru fin a m id e  
 
 
A p p e n d ix  G : Se le ct H ig h -P h o sp h o ro u s Fo o d s a n d  S u g g e ste d  A lt er na tiv e s 
 
 
H i gh -P h o sp h o ro u s B e v e ra g e s: B e e r, Ales,  D a rk  C o l as ( Co ca -C o l a, D ie t C o ke , P e p si, etc.), C h o co la t e 
d rin ks,  C o co a,  C a n n e d I ce d  T e a,  Ot h er  d rin ks  m a d e  wi th  m ilk 
 
A lt er nat i ve  B e v e ra g e s: Gi n g er  al e,  Le m o n -lim e  so d a (S p rit e, 7 -U p ); N o n d ai ry  cre a m er  
 
H i gh -P h o sp h o ro u s D ai ry  P ro d u cts: C o w’s  M ilk, C he e se,  C o tta g e  ch e es e , C h o co la te , Ice  Cr e a m , 
P u d d in g , Y o g u rt, Cr e a m  So u p s 
 
A lt er nat i ve s to  D a iry : C re a m  C h e es e , N o n d ai ry  Cr e a m er,  P o p sicles,  S h er b e t. D iffe r e nt bra n d s o f Ri ce , 
A lm o n d , a n d  S o y M ilk  h a v e  v a ry in g  a m o u n ts o f ph o sp h o ro u s, s o in d ivi du al n u tritio n  l ab els  s h o ul d b e 
co m p ar e d . 
 
H i gh -P h o sp h o ro u s P ro t ein s: C ar p , Cr a y fis h, F is h ro e,  Li ve r a n d o t he r o rg a n  m e a ts, Oy ste rs, S ar d in es  
 
A lt er nat i ve  P ro t ein s: B e e f, C h ic k e n, P o rk 
 
Ot h e r H ig h -P h o sp h o ro u s Fo o d s: Br a n c e re als,  w h o le  gr ai ns, nu ts, d ri e d b e a ns ( b lac k  b e a ns, 
c hic k p e as, lim a  b e a ns, soy b e a ns, l e nti ls, s plit p e a s) 


P a g e 1 1 3  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
A lt er nat i ve s: Cr e a m  o f w h e at,  s hre d d e d w h e at,  rice  o r co r n c ere a ls; g re e n  b e a n s, m ixe d  v e g e ta b l es 
 
 
 
 
 
A d a p te d  fro m  N a tio n al  Ki d n e y  Fo u n d ati o n ,  h tt p://w w w. ki d n e y .o rg /a to z/co n te n t/p h o s ph o ru s.cf m 


P a g e 1 1 4  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
A p p e n d ix  H : O p h th a lm o lo g y  F or m s 
 
 
1 4 -1 4 0  S cre e ni n g  O p h th al m ol o g y  E xa m in ati o n  
 
 
S u b j ect N a m e:    
 
 
M R N :  
 
 
 
O p h th a lm o lo g y  E x a m in a ti on  
 
 
D at e  o f Ex a m in at io n : 
 
 
_  _ /_  _  _  /_  _  _  _  
 
 
d d  /  m m m  /   y yy y  
P le a s e e v a lu a t e fo r b e lo w : 
Y es  
N o  
C o m m e n ts 
D o es  th e  p ati e n t h a v e  a  h isto r y o f re tin al  d e g e n er a tive  d is e ase ?  
 
 
 
D o es  th e  p ati e n t h a v e  p r ed isp o sin g  f acto rs t o C S R  o r R V O (i. e.  
u n co n tro lle d g la u co m a  o r o c ular hy p ert e n sio n? ) 
 
 
 
D o es  th e  p ati e n t h a v e  a h isto r y o r cu rr en t e v id e nc e  o f r eti n al vei n  
o cclu sio n  (R V O) ?  
 
 
 
D o es  th e  p ati e n t h a ve  a h isto r y o r cu rr en t e v id e nc e  o f C e ntr al  
S er o u s R e tin o p at hy  ( C S R)?  
 
 
 
D o es  th e  p ati e n t h a v e  a ctive  co rn e al d iso rd e r?  
 
 
 
D o es  th e  p ati e n t h a v e  a ctive  k e rat o p a t hy?  
 
 
 
 
 
 
Si g n a tu re of  E xa m i ne r:   
 
 
Pr in te d N a m e:    
 
D at e:    
 


P a g e 1 1 5  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
1 4 -1 4 0  O p h th al m ol o g y  F ol lo w -u p  E xa m  
 
N a m e:    
 
 
 
M R N :  
 
 
 
O p h th a lm o lo g y  E x a m in a ti on  
 
 
D at e  o f Ex a m in at io n : 
 
 
_  _ /_  _  _  /_  _  _  _  
 
 
d d  /  m m m  /   y yy y  
P le a s e e v a lu a t e fo r b e lo w : 
Y es  
N o  
C T C A E  
G ra d e  
R e lat e d  to  
stu d y  dr u g ?  
C o m m e n ts: 
Y E S  
N O  
 
D o es  th e  p ati e n t h a v e  a h isto r y o f re tin al  d e g e n er a tive 
d is e as e ? 
 
 
 
 
 
 
 
D o es  th e  p ati e n t h a v e  p r ed isp o sin g  f acto rs t o C S R  o r R V O 
(i. e. u n co n tro ll e d gla u co m a  o r o c ular h y p er te nsi o n ? ) 
 
 
 
 
 
 
 
D o es  th e  p ati e n t h a v e  a h isto r y o r cu rr en t e v id e nc e  o f 
r eti n al vei n  o cclu sio n  (R V O ) ? 
 
 
 
 
 
 
D o es  th e  p ati e n t h a v e  a h isto r y o r cu rr en t e v id e nc e  o f 
C e ntr al S e ro u s R e tin o p at hy  (C S R) ?  
 
 
 
 
 
 
D o es  th e  p ati e n t h a v e  a ctive  co rn e al d iso rd e r?  
 
 
 
 
 
 
D o es  th e  p ati e n t h a v e  a ctive  k e rat o p a t hy?  
 
 
 
 
 
 
 
 
 
Si g n a tu re of  E xa m i ne r:   
 
 
Pr in te d N a m e:    
 
D at e:    
 


P a g e 1 1 6  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
 
 
 
A p p e n d ix  I: L ab  M a n u a l 
 
 
 
 
M e m or ial Sl o a n K ett e ri n g C a nc er C e n te r 
 
 
 
 
 
 
R e se arc h  S a m p le  Pr o ce ssin g  In str uctio ns  a n d P a rticip ati n g  
Sit e  S h i p pin g  F or ms 
 
 
 
 
 
 
 
M S K  IR B  1 4 -1 4 0 : A  P h as e  Ib /II St u d y  of B G J 3 9 8 in 
C o m b in at io n  w it h I m ati ni b M e syl at e  i n P ati e nts  w it h 
U n tr e at e d A d v a n c e d G astr o in te stin al  Str o m al  T u m or  (G I S T) 


P a g e 1 1 7  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
P h as e  I b: R e s ea rc h B lo o d  C o lle ctio n  
 
•  P h ar m a co k in e tic S a m p le s for  B GJ 3 9 8  
•  P h ar m a co k in e tic S a m p le s for  I m atin i b 
R es e a rc h b lo o d  w ill b e  d ra w n o n  t h e P h as e  I b p o rtio n  at  th e  tim e  p o in ts n o te d i n  pr o to co l T a b le  1 0 . 
 
S u p p lie s fo r e a ch  sa m pl e  c olle ctio n  a n d  sto ra g e : 
 (1 ) 8  m L K 3 -E D T A t u b es –  p ro v id e d  by  sit e 
 (2 ) 1 . 8 m L N U N C  2 D  co d e d  t ub es  fro m  T h e rm o  –  p ro v id e d by  t h e sit e 
R ef e r en c e fo r tu b es:  3 7 4 5 0 2 N O V (1 D /2 D  co d e d  t ub es)  o r 3 7 4 5 0 2 ( 4 8 0  tu b e s/1 0  b a g s). At 
tim e p o in ts * w h e re  b lo o d  is b ei n g  co llec te d f o r B GJ 3 9 8  a n d  im ati n i b te sti n g (3 ) 1 .8 m L N U N C  
2 D  co d e d t u b es  will  b e  pr o v id e d (  *  Sc h e d u l e A:  C 1 D 2  0 h r & C 1 D 2 1  0 h r; Sc h e d u l e B:  C 1 D 2  
0 h r, C1 D 7  0 h r,C 1 D 2 1  0 h r) 
 
P h a s e I C o lle ctio n  P ro ce d u re s a n d  O n -S it e S to ra g e  fo r B G J3 9 8  A N D  Im ati n ib  P K s: 
1 .   Us e  (1 ) 8 m L K 3 -E D T A t u b e  fo r co ll ectio n  at  e ac h  tim e p o in t. 
2 .   A ll blo o d  s am p les  will  b e  ta k e n  by  eit h er  di rect  ve n i p u nct ur e o r a n in d w elli n g  c ath e ter 
in s erte d i n  a  fo re a rm  vei n . 
3 .   I mm e d iat e ly  a fte r blo o d  d ra w,  inv ert  g e ntl y  se ver al  tim es  to  e n s ure  m ixin g  o f co n te n ts. Av o i d 
p ro lo n g e d b lo o d  sa m p l e co n te n t w it h t h e r ub b er  sto p p er.  
4 .   P l ac e th e  t ub e  u p rig h t i n a  te st t ub e  r ack  s urro u n d e d  b y  ic e o r cryo b lo ck  u n til ce n trifu g ati o n . 
5 .   Wit hi n  3 0  m in u te s, c e ntrifu g e  t h e sa m p l e b e tw e e n  3 -5 oC fo r 1 0  m in u tes  at  a p p ro xim at e ly 
2 0 0 0 g . 
6 .   I mm e d iat e ly  a fte r ce ntrif u g ati o n , 2  ali q u o ts o f a b ou t 0 . 5 m L o f th e  co llec te d p la sm a s h o u l d 
b e  tr an sf erre d i n to  l ab e le d  1 . 8 m L N U N C 2 D  co d e d  tu b es  fro m  T h e rm o . At  l e ast 0 . 5 m L o f 
p l asm a i n t h e first tu b e  a n d  th e  re m ai n in g  pl a sm a i n to  th e  re m ai n in g t u b e s. 
7 .   I mm e d iat e ly  fre e ze  t h e t ub es  o ver  dr y  ic e (so lid  c arb o n di o xid e)  th e n ke e p f ro ze n  at  ≤-1 5 oC.  
 
 
La b e lin g  a n d  S h ip p in g  In stru ctio n s: 
1 .   La b el  sa m p l es w it h M S K C C  I D, d a te  o f co ll ectio n , a n d st ud y  tim e  p o in t. 
2 .   P artici p ati n g  sit es w ill s hip  s p ecim e n to  M S K. A ll s hip m e nts  s ho u l d b e  di rec te d to  th e  a d d r ess 
liste d  o n  th e  tiss u e s am p le  s hi pm e nt fo rm . S a m p l es sh o u l d b e  s hi p pe d f ro ze n w it h dry  ice  b y 
co u ri er s o th at  t h e p ack a g e  c a n b e  tr acke d a p p ro p ria tel y  (sp ecific al ly , F ed er al E xp r ess o r 
U P S).  
3 .   N o tif y th e  R es e arc h  a n d  La b o r ato r y St aff at M SK C C (l iste d  o n  th e  r e qu isitio n ) w h e n s a m p les 
ar e s hi p p e d.  
4 .   M S K  will  b atc h s h ip  s am p le s to  th e  a p p ro p ria t e l ab . 
 
 
M S K S h ip p in g  pr o ce d u re s fo r B G J3 9 8 : 
 S a m p l es are  to  b e  b atc h  s hi p pe d m o n t hly  t o W u Xi  v i a W o rl d C o u ri er. 
M S K  S h ip p in g  pr o ce d u re s fo r Im a tin ib : 
 S a m p l es are  to  b e  b atc h  s hi p pe d  m o n t hlyto  W u Xi  v i a W o rl d C o u ri er. 


P a g e 1 1 8  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
P h as e  I b P K  S a m p le  for  B GJ 3 9 8  
S h ip m e n t F o rm  (For P ar ticip a tin g  S it es) 
 
1 .  C o m p le te  th is re q u isitio n  fo rm  a n d  i ncl u de  o n e  fo r e a ch  s am p le  shi p p e d . 
2 .  La b el all s a m p le s w it h M S K C C ID , d a t e o f co lle ctio n, a n d  stu d y  tim e  p o in t. 
3 . B GJ s a m p les  ar e  to  b e  s hi p pe d  b atc h e d  e ver y  m o n t h to : 
 
Bi o A n aly tic S e rv ic es D e p a rtm e nt 
W u Xi  A p p te c C o m .,Lt d. N o . 22 8 , 
F u T e Z h o n g  R o a d  
W ai G a o Qi a o  Fr e e  T r ad e  Z o n e, 
S h a n g h ai, C h in a, 2 0 0 1 3 1  
 
4 . N o tif y th e  R es e arc h  St aff  at  M S K C C  sa m p l es ar e  s hi pp e d by  e m ai lin g  th e  co m p l ete d 
r e qu isitio n  fo rm  to : Willi a m  T a p , M D  (t a p w@ m skcc.o r g), C h lo e  M cf ad y e n 
(m cf ad y ec @ m skcc .o r g )), a n d  M S K  M u ltic en te r Gro u p  In b o x (m e d m ctco re @ m skcc.o r g). 
 
P le a s e co m pl et e  a ll fie ld s b e lo w : 
 
P a rticip a n t In fo rm ati o n  (S ch e d u le  A ) 
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:   
C o n t en ts –  S a m p le  In fo r ma tio n  
D a t e o f 
C o lle ctio n : 
(M M  D D  Y Y Y Y)  
P h a s e I S tu d y  T im e P o in t: 
D a t e o f 
C o lle ctio n : 
(M M  D D  Y Y Y Y)  
P h a s e I S tu d y  T im e P o in t: 
 
  C ycl e  1  D a y  1  (P re -d o s e) 
 
  C ycl e  1  D a y  2 1  (P re -d o se)  
 
  C ycl e  1  D a y  1  (1  h o u r) 
 
  C ycl e  1  D a y  2 1  ( 1 h o u r) 
 
  C ycl e  1  D a y  1  (2  h o u rs) 
 
  C ycl e  1  D a y  2 1  ( 2 h o u rs) 
 
  C ycl e  1  D a y  1  (4  h o u rs) 
 
  C ycl e  1  D a y  2 1  ( 4 h o u rs) 
 
  C ycl e  1  D a y  1  (6  h o u rs) 
 
  C ycl e  1  D a y  2 1  ( 6 h o u rs) 
 
  C ycl e  1  D a y  1  (8  h o u rs) 
 
  C ycl e  1  D a y  2 1  ( 8 h o u rs) 
 
  C ycl e  1  D a y  2  (2 4  h o u rs) 
 
 
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )  
 


P a g e 1 1 9  o f 1 2 6  
M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
 
 
 
 
P a rticip a n t In fo rm ati o n  (S ch e d u le  B ) 
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:   
C o n t en ts –  S a m p le  In fo r ma tio n  
D a t e o f 
C o lle ctio n : 
(M M  D D  Y Y Y Y)  
P h a s e I S tu d y  T im e P o in t: 
D a t e o f 
C o lle ctio n : 
(M M  D D  Y Y Y Y)  
P h a s e I S tu d y  T im e P o in t: 
 
  C ycl e  1  D a y  1  (P re -d o s e) 
 
  C ycl e  1  D a y  7  (P re -d o s e) 
 
  C ycl e  1  D a y  1  (1  h o u r) 
 
  C ycl e  1  D a y  7  (1  h o u r) 
 
  C ycl e  1  D a y  1  (2  h o u rs) 
 
  C ycl e  1  D a y  7  (2  h o u rs) 
 
  C ycl e  1  D a y  1  (4  h o u rs) 
 
  C ycl e  1  D a y  7  (4  h o u rs) 
 
  C ycl e  1  D a y  1  (6  h o u rs) 
 
  C ycl e  1  D a y  7  (6  h o u rs) 
 
  C ycl e  1  D a y  1  (8  h o u rs) 
 
  C ycl e  1  D a y  7  (8  h o u rs) 
 
  C ycl e  1  D a y  2  (2 4  h o u rs) 
 
 
 
 
 
 
 
 
 
  C ycl e  1  D a y  1 5  ( 0 h o u rs) 
 
 
 
  C ycl e  1  D a y  2 1  ( 0 h o u rs) 
 
 
 
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )  
 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 0  o f 1 2 6  
 
 
P h as e  I b P K  S a m p le  for Im a tin ib  
S h ip m e n t F o rm  (For P ar ticip a tin g  S it es) 
 
1 .  C o m p le te  th is re q u isitio n  fo rm  a n d  i ncl u de  o n e  fo r e a ch  s am p le  shi p p e d . 
2 .  La b el all s a m p le s w it h M S K C C ID , d a t e o f co lle ctio n, a n d  stu d y  tim e  p o in t. 
3 . I m atin i b sa m p l es ar e  t o b e  s hi p pe d  b atc h e d  m o n t hly to : 
 
Bi o A n aly tic S e rv ic es D e p a rtm e nt 
W u Xi A p p te c C o m .,Lt d. N o . 22 8 , 
F u T e Z h o n g  R o a d  
W ai G a o Qi a o  Fr e e  T r ad e  Z o n e, 
S h a n g h ai, C h in a, 2 0 0 1 3 1  
 
4 . N o tif y th e  R es e arc h  St aff  at  M S K C C  w h e n  s am p les  a re  s hi p pe d by  e m ai lin g  th e  co m p l ete d 
r e qu isitio n  fo rm  to : Willi a m  T a p , M D  (t a p w@ m skcc.o r g), () C h lo e  M cf ad ye n 
(m cf ad y ec @ m skcc .o r g ), a n d  M S K  M u ltic en te r Gro u p  In b o x (m e d m ctco re @ m skcc.o r g). 
 
P le a s e co m pl et e  a ll fie ld s b e lo w : 
 
P a rticip a n t In fo rm ati o n  (S ch e d u le  A ) 
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:   
C o n t en ts –  S a m p le  In fo r ma tio n  
D a t e o f C o lle ctio n : 
(M M  D D  Y Y Y Y ) 
P h a s e I S tu d y  T im e P o in t: 
 
  C ycl e  1  D a y  2  (2 4  h o u rs p o st-first d o se  / P re -d o s e o n  D a y  2 ) 
 
  C ycl e  1  D a y  2 1  (P re -d o se)  
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )  
 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 1  o f 1 2 6  
 
 
 
 
P a rticip a n t In fo rm ati o n  (S ch e d u le  B ) 
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:   
C o n t en ts –  S a m p le  In fo r ma tio n  
D a t e o f C o lle ctio n : 
(M M  D D  Y Y Y Y ) 
P h a s e I S tu d y  T im e P o in t: 
 
  C ycl e  1  D a y  2  (2 4  h o u rs p o st-first d o se  / P re -d o s e o n  D a y  2 ) 
 
  C ycl e  1  D a y  7  (P re -d o s e) 
 
  C ycl e  1  D a y  2 1  (P re -d o se)  
 
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )  
 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 2  o f 1 2 6  
 
 
P h as e  II: R e s ea rc h B lo o d  C o lle ctio n  
 
P h ar m a co k i ne tic S a m pl e s for Im a tin ib  a n d  FG F  S e r um  L ev e ls 
 
S u p p lie s fo r e a ch  sa m pl e  c olle ctio n  a n d  sto ra g e : 
 (2 -4 ) 4 -8  m L K 3 -E D T A  tu b es –  p ro v id e d b y  site  
 (2 ) 1 . 8 m L N U N C  2 D  co d e d  t ub es  fro m  T h e rm o  –  p ro v id e d by  site  
R ef e r en c e fo r tu b es:  3 7 4 5 0 2 N O V (1 D /2 D  co d e d  t ub es)  o r 3 7 4 5 0 2  (4 8 0  tu b e s/1 0  b a g s) 
 
P h a s e II C ol lec tio n  pr o ce d u re s fo r Im a tin ib  P Ks  a n d  FG F S e ru m  R es e a rch  bl o o ds : 
1 .   Us e  (4 ) 4 -8 m L K 3 -E D T A t u b es  fo r co ll ectio n  a t tim e p o in ts: W e e k -2 , C 1 D 1 , C 1 D 1 5 , C 2 D 1 . U s e 
(2 ) 4 -8 m L K 3 -E D T A t u b es  at  th e  tim e  o f pr o g ressi o n . 
2 .   A ll blo o d  s am p les  will  b e  ta k e n  by  eit h er  di rect  ve n i p u nct ur e o r a n in d w elli n g  c ath e ter 
in s erte d i n  a  fo re a rm  vei n . 
3 .   At s p ecifi e d  tim e p o in ts, co ll ect a  2 m L bl o o d  sa m p l e i n t ub es  wit h  th e  s p ecific co a g u l an t K 3 - 
E D T A  
4 .   I mm e d iat e ly  a fte r blo o d  d ra w,  inv ert  g e ntl y  se ver al  tim es  to  e ns u r e m ixin g  o f co n te n ts. Av o i d 
p ro lo n g e d b lo o d  sa m p l e co n te n t w it h t h e r ub b er  sto p p er.  
5 .   P l ac e th e  t ub e  u p rig h t s urro u n d e d by  ice  o r cry o b lo ck  u n til ce n trifu g at io n . 
6 .   Wit hi n  3 0  m in u te s, c e ntrifu g e  t h e sa m p l e b e tw e e n  3 -5 oC  fo r 1 0  m in u tes  at  a p p ro xim at e ly 
2 0 0 0 g . 
7 .   I mm e d iat e ly  a fte r ce ntrif u g ati o n , 2  ali q u o ts o f a b ou t 0 . 5 m L o f th e  co llec te d p la sm a s h o u l d 
b e  tr an sf erre d i n to  l ab e le d  1 . 8 m L N U N C 2 D  co d e d  tu b es  fro m  T h e rm o . At  l e ast 0 . 5 m L o f 
p l asm a i n  t h e first tu b e  a n d  th e  re m ai n in g  pl a sm a i n to  th e  se co n d  tu b e.  
8 .   I mm e d iat e ly  fre e ze  t h e t ub es  o ver  dr y  ic e (so lid  c arb o n di o xid e)  th e n ke e p f ro ze n  at  ≤-1 5 oC.  
 
 
La b e lin g  a n d  S h ip p in g  In stru ctio n s: 
1 .   La b el s a m p l es w it h M S K C C  I D, d a te  o f co ll ectio n , a n d st ud y  tim e  p o in t. 
2 .   P artici p ati n g  sit es w ill s hip  s p ecim e n to  M S K. A ll s hip m e nts  s ho u l d b e  di rec te d to  th e  a d d r ess 
liste d  o n  th e  tiss u e s am p le  s hi pm e nt fo rm . S a m p l es sh o u l d b e  s hi p pe d f ro ze n w it h dry  ice  b y 
co u ri er s o th at  t h e p ack a g e  c a n b e  tr acke d a p p ro p ria tel y  (sp ecific al ly , F ed er al E xp r ess o r 
U P S).  
3 .   N o tif y th e  R es e arc h  a n d  La b o r ato r y St aff at M SK C C (l iste d  o n  th e  r e qu isitio n ) w h e n s a m p les  
ar e s hip p e d.  
4 .   M S K  will  b atc h s h ip  s am p le s to  th e  a p p ro p ria t e l ab . 
 
 
M S K  S h ip p in g  pr o ce d u re s fo r Im a tin ib : 
 S a m p l es are  to  b e  b atc h  s hi p pe d  m o n t hly t o W u Xi v i a W o rl d C o u ri er . 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 3  o f 1 2 6  
 
 
P h as e  II R e s ea rc h B lo o d s 
S a m p le  S h ip m e n t F o rm  (F or  P a rticip a tin g  S it es) 
 
1 .  C o m p le te  th is re q u isitio n  fo rm  a n d  i ncl u de  o n e  fo r e a ch  s am p le  shi p p e d . 
2 .  La b el all s a m p le s w it h M S K C C ID , d a t e o f co lle ctio n, a n d  stu d y  tim e  p o in t. 
3 . A ll s am p l es ar e  to  b e  s hi pp e d  b atc h e d  q u art er ly  to : 
 
M e m o rial S lo a n  K e tteri n g  C a n c er C e n ter  
A T T N :C h lo e  M cf ady e n,  5 th  fl oo r 
1 6 0  E a st 5 3 rd  Str e e t 
N e w  Y o r k, N Y  1 0 0 2 2  
 
4 . N o tif y th e  R es e arc h  St aff  at  M S K C C  w h e n  s am p les  a re  s hi p pe d by  e m ai lin g  th e  co m p l ete d 
r e qu isitio n  fo rm  to : Willi a m  T a p , M D  (t a p w@ m skcc.o r g), C h lo e  M cf ad y e n 
(m cf ad y ec @ m skcc .o r g ), , a n d  M S K  M u ltic en te r Gro u p  In b o x (m e d m ctco re @ m skcc.o r g). 
 
P le a s e co m pl et e  a ll fie ld s b e lo w : 
 
P a rticip a n t In fo rm ati o n  
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:  
 
C o n t en ts –  S a m p le  In fo r ma tio n  
D a t e o f 
C o lle ctio n : 
(M M  D D  Y Y Y Y)  
P h a s e II S tu d y  T im e P o in t: 
 
  W e e k -2  (0  h o u r) 
 
  C ycl e  1  D a y  1  (0  h o u r) 
 
  C ycl e  1  D a y  1 5  ( 0 h o u r) 
 
  C ycl e  2  D a y  1  (0  h o u r) 
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )  
 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 4  o f 1 2 6  
 
 
P h as e  II: R e se arc h  Bi o p sie s 
R esearch bl o o d  will  be  dr aw n o n t he  P h ase II p or ti o n at t he tim e p oi n ts n oted i n pr ot o col. S ee 
p rot oc ol s ectio n 1 0. 2. 2 a n d 1 0. 2. 4 for  col lectio n an d p rep aratio n i nstr u ctio ns. S ee 1 0. 2. 4 for 
H an dl in g  o f S pecim et n a n d 1 0. 2. 5 for  S hi p p in g  of  S p ecim ens.  P artici patin g  sites s h o uld 
co m p lete t he fol lo wi n g  req uis io n an d i ncl u de  wit h s hi p m ent.  All s hi p m en ts s h o uld be  dir ecte d 
t o the  ad dr ess listed o n t h e tiss ue s am p le s hi p me nt fo rm.  S am p les s h o uld be  s hi p ped b y 
co uri er s o t hat the  p ack a g e can b e track ed ap p r op riately  (s pecifically , F ed eral Ex p ress or 
U P S ). N otify  t he Resea r ch an d  L ab o rat ory  S taff at M S K C C  (liste d o n t he req uis itio n) w h en 
sam p les are s hi p ped.  


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 5  o f 1 2 6  
 
 
P h as e  II B io p s y C o lle ctio n  ( Fl as h F ro z e n S pe cim e n)  
S a m p le  S h ip m e n t F o rm  
 
1 . C o m p le t e t his re q u isitio n  fo rm  a n d  i ncl u de  w it h s am p le.  
2 .  La b el all s a m p le s w it h M S K C C ID  a n d  d a te  o f co lle ctio n . 
3 . A ll s am p l es ar e  to  b e  s hi pp e d  b atc h e d  a p p ro xim a tel y  e v e ry 6 m o n t hs to : 
 
A ttn : P in g  C h i, M D , P h D - Sa rco m a  Bi o lo g y  La b  
M e m o ria l S lo a n  K e tt erin g  C a n ce r C e n t er 
4 1 7  E a st 6 8 t h S tre e t, Z u ck e rm a n  Z 5 2 7  
N e w  Y o rk,  N Y  1 0 0 6 5  
6 4 6 -8 8 8 -3 3 4 9  
 
4 . N o tif y th e  R es e arc h  St aff  at  M S K C C  w h e n  s am p les  a re  s hi p pe d by  e m ai lin g  th e  co m p l ete d 
r e qu isitio n  fo rm  to : P in g  C h i, M D , P h D  (c hi p@ m skcc .o r g), Willi a m  T a p , M D 
(t a p w@ m s kcc.o rg ), C h l oe  M cf ady e n (m cf ad yec @ m skcc.o r g ), a n d  M SK  M u ltic en te r Gro u p 
In b o x (m e d m ctco re @ m s kcc.o r g). 
 
P le a s e co m pl et e  a ll fie ld s b e lo w : 
S a m pl e In fo rm a tio n  
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:  
 
D a t e o f C o lle ctio n:  
 
S tu d y  T im e P o in t: 
(ch e ck  o n e ) 
  P re tr e at me nt  
  C ycl e  1  D a y  8  
  P ro g r essio n  
Or g a n /S it e o f C ol le ctio n : 
 
H isto lo g y  D ia g n o sis: 
 
Bi o p sy  P ro ce d u re  &  A m o u n t o f T issu e : 
  O p e n  In cisio n al B io p sy :    
 cm 3  
  I m ag e -G u id e d  C o re  B io p sy : #  C o r es:   
 
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )  
 


M E M O RI A L  S L O A N -K E T T E RI N G  C A N C E R  C E N T E R  
I R B P R O T O C O L  
I R B# : 1 4 -1 4 0  A  (7 ) 
P a g e 1 2 6  o f 1 2 6  
 
 
P h as e  II Bio p s y C o lle ctio n  ( F orm al in -Fix e d  S p e ci m en)  
S a m p le  S h ip m e n t F o rm  
 
1 .  C o m p le te  th is re q u isitio n  fo rm  a n d  i ncl u de  wit h  sa m p l e. 
2 .  La b el all s a m p le s w it h M S K C C ID  a n d  d a te  o f co lle ctio n . 
3 . A ll s am p l es ar e  to  b e  s hi pp e d  b atc h e d  a p p ro xim a tel y  e v e ry 6  m o n t hs to : 
 
A ttn : C ristin a  A n to n e scu , M D M e m o ria l 
S lo a n  K e tt erin g  C a n ce r C e n t er 
D e p a rt me n t o f P ath o lo g y  
1 2 7 5  Y o rk  A v e n u e , C -5 8 7  
N e w  Y o rk,  N Y  1 0 0 6 5  
2 1 2 -6 3 9 -5 9 0 5  
 
4 . N o tif y th e  R es e arc h  St aff  at  M S K C C  w h e n  s am p les  a re  s hi p pe d by  e m ai lin g  th e  co m p l ete d 
r e qu isitio n  fo rm  to : Cr istin a  A n to n e sc u, M D  (a n to n e sc @m skcc.o r g), Willi a m  T a p , M D 
(t a p w@ m s kcc.o rg ), C h l oe  M cf ady e n (m cf ad yec @ m skcc.o r g ), a n d  M SK  M u ltic en te r Gro u p 
In b o x (m e d m ctco re @ m s kcc.o r g). 
 
P le a s e co m pl et e  a ll fie ld s b e lo w : 
S a m pl e In fo rm a tio n  
In stitu tio n : 
 
P a rticip a n t In itia ls: 
 
M S K C C -A ssi gn e d P a rtici p an t ID:  
 
D a t e o f C o lle ctio n:  
 
S tu d y  T im e P o in t: 
(ch e ck  o n e ) 
  P re tr e at me nt  
  C ycl e  1  D a y  8  
  P ro g r essio n  
Or g a n /S it e o f C ol le ctio n : 
 
H isto lo g y  D ia g n o sis: 
 
Bi o p sy  P ro ce d u re  &  A m o u n t o f T issu e : 
  O p e n  In cisio n al B io p sy :    
 cm
3  
  I m ag e -G u id e d  C o re  B io p sy : #  C o r es:   
 
S h ip m e n t In fo rm a tio n  
S e n d e r’s C o n ta ct In fo rm a tio n  
S h ip p in g  D at e  
 
N a m e  
 
S h ip p in g  
M e th o d  
 
E m a il 
 
Tr a ck in g  
N u m b e r 
 
T e le p h o n e   
 
 F or M SK C C U s e O N LY :    D a t e re c eiv e d at  M SK C C:  _  _  / _  _  / _  _  _  _  (M M  D D  Y Y Y Y )