Conditions: Advanced Solid Tumors
Keywords: Advanced solid tumors Asian subjects Developmental Phase I
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 12
Healthy volunteers: no

Brief summary:
This is a Phase I, non-randomized, open-label, multiple dose study of pexidartinib in Asian subjects with advanced solid tumors. The study will be conducted in a dose escalation to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary antitumor activity of pexidartinib.

Detailed description:

Arms:
arm 1: Pexidartinib capsules administered twice daily in the morning and evening. Each cycle of treatment is 28 days in duration. The cycle of treatment is continued until disease progression, unacceptable toxicity, or consent withdrawal.

Interventions: intervention 1: Pexidartinib
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_000.pdf: 
C o nfi d e nti al 
P a g e  1  of  9 1  
C  LI  NI  C  A  L  S  T  U  D  Y  P  R  O  T  O  C  O  L   
A  P  H  A S  E  1  S  T  U  D  Y   O F  SI  N  G  L  E   A  G  E  N  T 
P  E  XI  D  A  R  TI  NI  B I  N   A SI  A N  S  U  B J  E  C  T S    WI  T  H 
A  D  V  A  N  C  E  D   S  O  LI  D   T  U   M  O  R S  
P  L 3 3 9 7-  A-  A 1 0 3 
V  E  R SI  O  N  5. 0  ,  2 5 F  E  B  2 0 2 0  
 
V  E  R SI  O  N   4. 0,  1 3  A P  R    2 0 1 8 
V  E  R SI  O  N   3. 0,  2 7  D  E  C    2 0 1 7 
V  E  R SI  O  N  2. 1  , 2 7  F  E  B  2 0 1 7  
V  E  R SI  O  N   2. 0 , 2 1  O  C  T    2 0 1 6 
V  E  R SI  O  N  1.  2 , 0 7  J  U  L   2 0 1 6 
  V  E  R SI  O  N  1. 1,  1 1    M  A  Y   2 0 1 6 
V  E  R SI  O  N  1. 0,  1 1  J  A  N   2 0 1 6 
 
 
D  AII  C  HI  S  A  N  K  Y  O   
 
 
 
C  O  N FI  D  E  N  TI  A  LI  T  Y  S  T  A  T  E   M  E  N  T   
I nf or  m ati o n  c o nt ai n e d i n t his  d o c u  m e nt is  pr o pri et ar y t o   D aii c hi  S a n k y o.   T h e 
i nf or  m ati o n is  pr o vi d e d t o  y o u i n  c o nfi d e n c e   w hi c h is r e q u est e d  u n d er  a n  a gr e e d  u p o n 
a n d si g n e d   C o nfi d e nti alit y  a n d   Dis cl os ur e   A gr e e  m e nt.    D o  n ot  gi v e t his  d o c u  m e nt  or  a n y 
c o p y  of it  or r e v e al  a n y  pr o pri et ar y i nf or  m ati o n  c o nt ai n e d i n it t o  a n y t hir d  p art y ( ot h er 
t h a n t h os e i n  y o ur  or g a ni z ati o n   w h o  ar e  assisti n g  y o u i n t his   w or k  a n d  ar e  b o u n d  b y t h e 
C o nfi d e nti alit y  a n d   Dis cl os ur e   A gr e e  m e nt)   wit h o ut t h e  pri or   writt e n  p er  missi o n  of  a n 
a ut h ori z e d r e pr es e nt ati v e  of   D aii c hi  S a n k y o.


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2  of  9 0 
I  N  V  E S  TI  G  A  T  O  R   A  G  R  E  E   M  E N  T   
A  P  H  A S  E  1  S  T  U  D  Y   O F  SI  N  G  L  E   A  G  E  N  T 
P  E  XI  D  A  R  TI  NI  B I  N   A SI  A N  S  U  B J  E  C  T S    WI  T  H 
A  D  V  A  N  C  E  D   S  O  LI  D   T  U   M  O  R S  
S p o ns o r   A p p r o v al:  
T his  cli ni c al st u d y  pr ot o c ol  h as  b e e n r e vi e  w e d  a n d  a p pr o v e d  b y t h e   D aii c hi  S a n k y o 
r e pr es e nt ati v e list e d  b el o  w. 
 
  
      
 
     P ri nt   N a  m e   
     Si g n at u r e   
 
     Cli ni c al  St u d y  L e a d    
     
 
     Titl e   
     D at e (  D  D    M  M   M   Y  Y   Y  Y)   
 
I n v esti g at o r’s  Si g n at u r e:  
I  h a v e f ull y  dis c uss e d t h e  o bj e cti v es  of t his st u d y  a n d t h e  c o nt e nts  of t his  pr ot o c ol   wit h 
t h e  S p o ns or’s r e pr es e nt ati v e. 
I  u n d erst a n d t h at i nf or  m ati o n  c o nt ai n e d i n  or  p ert ai ni n g t o t his  pr ot o c ol is  c o nfi d e nti al 
a n d s h o ul d  n ot  b e  dis cl os e d,  ot h er t h a n t o t h os e  dir e ctl y i n v ol v e d i n t h e  e x e c uti o n  or t h e 
et hi c al r e vi e  w  of t h e st u d y,   wit h o ut   writt e n  a ut h ori z ati o n fr o  m  t h e  S p o ns or.  It is, 
h o  w e v er,  p er  missi bl e t o  pr o vi d e i nf or  m ati o n t o  a s u bj e ct i n  or d er t o  o bt ai n  c o ns e nt.  
I  a gr e e t o  c o n d u ct t his st u d y  a c c or di n g t o t his  pr ot o c ol  a n d t o  c o  m pl y   wit h its 
r e q uir e  m e nts, s u bj e ct t o  et hi c al  a n d s af et y  c o nsi d er ati o ns  a n d  g ui d eli n es,  a n d t o  c o n d u ct 
t h e st u d y i n  a c c or d a n c e   wit h t h e   D e cl ar ati o n  of   H elsi n ki, I nt er n ati o n al   C o u n cil f or 
H ar  m o nis a  ti o n  gui d eli n es  o n   G o o d   Cli ni c al  Pr a cti c e (I  C  H  E 6),  a n d  a p pli c a bl e r e gi o n al 
r e g ul at or y r e q uir e  m e nts. 
I  a gr e e t o   m a k e  a v ail a bl e t o  S p o ns or  p ers o n n el, t h eir r e pr es e nt ati v es  a n d r el e v a nt 
r e g ul at or y  a ut h oriti es,   m y s u bj e cts’ st u d y r e c or ds i n  or d er t o  v erif y t he  d at a t h at I  h a v e 
e nt er e d i nt o t h e  c as e r e p ort f or  ms.  I  a  m  a  w ar e  of   m y r es p o nsi biliti es  as  a  Pri n ci p al 
I n v esti g at or  as  pr o vi d e d  b y t h e  S p o ns or. 
I  u n d erst a n d t h at t h e  S p o ns or   m a y  d e ci d e t o s us p e n d  or  pr e  m at ur el y t er  mi n at e t h e st u d y 
at  a n y ti  m e f or   w h at e v e r r e as o n; s u c h  a  d e cisi o n   will  b e  c o  m  m u ni c at e d t o   m e i n   writi n g.  
C o n v ers el y, s h o ul d I  d e ci d e t o   wit h dr a  w fr o  m  e x e c uti o n  of t h e st u d y, I   will  c o  m  m u ni c at e 
m y i nt e nti o n i  m  m e di at el y i n   writi n g t o t h e  S p o ns or.   
 
<  <I ns ert   N a  m e  >  >   
      
 
     P ri nt   N a  m e  
     Si g n at u r e  
 
 
<  <  I ns ert  Titl e>  >   
      
 
     Titl e   
     D at e (  D  D    M   M   M   Y  Y  Y  Y)   
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3  of  9 0 
P  R  O  T  O  C  O  L  S  Y  N  O P SI S  
Pr ot o c ol   N u  m b er:      
P L 3 3 9 7 -  A-  A 1 0 3 
I n v esti g ati o n al  Pr o d u ct:     
P L  X 3 3 9 7  
A cti v e I n gr e di e nt  (s)/I  N  N:     P e xi d arti ni b  
St u d y  Titl e:  
A  P h as e   1  St u d y  of  Si n gl e   A g e nt  P e xi d arti ni b i n   Asi a n 
S u bj e cts  Wit h    A d  v a n c e d  S oli d  T u  m ors 
St u d y  P h as e:  
P h as e   1 
I n di c ati o n   U n d er 
I n v esti g ati o n: 
P e xi d arti ni b   will  b e  e v al u at e d i n s u bj e cts   wit h  a d v a n c e d 
soli d t u  m ors. 
St u d y   O bj e cti v es:  
Pri  m ar y   O bj e cti v e s:  
•     T o  ass ess t h e s af et y  a n d t ol er a bilit y  of  p e xi d arti ni b 
i n   Asi a n s u bj e cts wit h   a d v a n c e d  s oli d t u  m ors 
•     T o  d et er  mi n e t h e r e c o  m  m e n d e d  P h as e   2  d os e 
(  R P 2  D) of  p e xi d arti ni b i n   Asi a n s u bj e cts   wit h 
a d v a n c e d s oli d t u  m ors 
S e c o n d ar y  O bj e cti v e  s: 
•     T o  ass ess t h e  p h ar  m a c o ki n eti cs ( P  K)  pr o fil e  of 
p e xi d arti ni b  a n d its   m et a b olit e  
•     T o  ass ess  t h e  p h ar  m a c o d y n a  mi cs ( P  D)  eff e ct  of 
p e xi d arti ni b   o n   C S F- 1  a n d  a di p o n e cti n i n  pl as  m a 
•     T o  e v al u at e t h e  pr eli  mi n ar y  effi c a c y  of  p e xi d arti ni b  
•     T o  e v al u at e  o bj e cti v e r es p o ns e r at e (  O  R  R) (t h e s u  m 
of  c o  m pl et e r es p o ns e [ C  R  ] r at e  a n d p arti al r es p o ns e 
[P  R ] r at e) 
•     T o  e v al u at e  dis e as e  c o ntr ol  r at e (D  C  R  ) (t h e s u  m  of 
C  R r at e,  P  R r at e,  a n d st a bl e  dis e as e   [S  D ] r at e) 
•     T o  e v al u at e r es p o ns e  d ur ati o n 
•     T o  e v al u at e  d ur ati o n  of  S  D 
•     T o  e v al u at e t i  m e t o r es p o ns e 
•     T o  e v al u at e  p er c e nt a g e  of  c h a n g e i n t ar g et l esi o n(s)  
E x pl or at or y  O bj e cti v e  s: 
•     T o  e x p l or e t h e  eff e ct  of   U  G T 1  A 4  g e n ot y p e  o n 
p e xi d arti ni b  P  K 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4  of  9 0 
•    T o  e x pl or e  a n y  p ossi bl e  c orr el ati o n  of  g e n o  mi c s t o 
p e xi d arti ni b  s af et y 
St u d y   D esi g n:  
T his is  a  P h as e   1,  n o n-r a n d o  mi z e d,  o p e n-l a b el, 
m ulti pl e  - d os e st u d y  of  p e xi d arti ni b i n   Asi a n s u bj e cts   wit h 
a d v a n c e d  s oli d t u  m ors.   T h e st u d y   will  b e  c o n d u ct e d i n  a 
d os e -es c al ati o n   3 + 3  d esi g n.   T his st u d y  c o  m pris es  2  d os e 
l e v els (  C o h ort  1  a n d   C o h ort 2)  t o  ass ess t h e s af et y  a n d 
t ol er a bilit y, R P 2  D,  P  K  a n d  P  D,  a n d  pr eli  mi n ar y  a ntit u  m or 
a cti vit y  of  p e xi d arti ni b.  
•     C o h ort  1:  6 0 0   m g/ d ( 2 0 0   m g i n t h e   m or ni n g, 
4 0 0   m g i n t h e  e v e ni n g) 
•     C o h ort  2:  1 0 0 0   m g/ d   ( 4 0 0   m g i n t h e   m or ni n g  a n d 
6 0 0   m g i n t h e  e v e ni n g ) f or t h e first 2  w e e ks  .  
T h er e aft er, t h e   d os e   will  b e r e d u c e d t o  8 0 0 m g/ d   
( 4 0 0   m g i n t h e   m or ni n g  a n d  4 0 0 m g i n t h e 
e v e ni n g ). 
St u d y   D u r ati o n: 
First s u bj e ct  e nr oll e d : 2  Q  2 0 1 6 
L ast s u bj e ct l ast  visit  (i n cl u di n g f oll o  w- u p): a p pr o xi  m at el y 
2 0 2 0  
S u bj e cts    w h o  c o nti n u e t o  d eri v e  cli ni c al  b e n efit fr o  m 
tr e at  m e nt i n t h e  a bs e n c e  of s u bj e ct’s  c o ns e nt   wit h dr a  w al, 
dis e as e  pr o gr essi o n,  or  u n a c c e pt a bl e t o xi cit y   m a y  c o nti n u e 
a n ot h er  c y cl e  of  tr e at  m e nt  at t h e i n v esti g at or’s  dis cr eti o n. 
St u d y  C e nt er  s  a n d  L o c ati o n:   O n e   st u d y sit e i n  T ai  w a n is  pl a n n e d. 
S u bj e ct  Eli gi bilit y   Crit eri a:     I n cl usi o n   Crit eri a: 
S u bj e cts   m ust s atisf y  all  of t h e f oll o  wi n g  crit eri a t o  b e  
i n cl u d e d i n t h e st u d y: 
1.    A g  e s h o ul d  b e  ≥   2 0 y e ars.  
2.    S u bj e cts  m ust  h a v e  a  p  at h ol o gi c all y  d o c u  m e nt e d s oli d 
t u  m or t h at  h as r el a ps e d fr o  m,  or is r efr a ct or y t o 
st a n d ar d tr e at  m e nt,  or f or   w hi c h  n o st a n d ar d tr e at  m e nt 
is  a v ail a bl e. 
3.    W o  m e n  of  c hil d b e ari n g  p ot e nti al   m u   st  h a v e  a  n e g ati v e 
s er u  m  pr e g n a n c y t est   wit hi n t h e  1 4- d a y  p eri o d  pri or t o 
tr e at  m e nt  all o c ati o n. 
4.    M e n  a n d   w o  m e n   of  c hil d b e ari n g  p ot e nti al  ar e  p er  mitt e d 
i n t h e st u d y as  l o n g  as t h e y  c o ns e nt t o  a v oi d  g etti n g 
t h eir  p art n er  pr e g n a nt  or  b e c o  mi n g  pr e g n a nt 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5  of  9 0 
t h e  ms el ves, r es p e cti v el y,  b y  usi n g  a  hi g hl y  eff e cti v e 
c o ntr a c e pti o n   m et h o d,  as  d es cri b e d  b el o  w, t hr o u g h o ut 
t h e st u d y  a n d f or  u p t o  9 0  d a ys  aft er  c o  m pl eti o n.  
Hi g hl y  eff e cti v e   m et h o ds  of  c o ntr a c e pti o n i n cl u d e 
h or  m o n al   m et h o ds  ass o ci at e d   wit h i n hi biti o n  of 
o v ul ati o n, i ntr a- ut eri n e  d e vi c e , s ur gi c al st erili z ati o n 
(i n cl u di n g  p art n er’s  v as e ct o  m y), or s e x u al  a bsti n e n c e.  
5.    W o  m e n  of  n o n- c hil d b e ari n g  p ot e nti al   m a y  b e i n cl u d e d 
if t h e y  ar e  eit h er s ur gi c all y st eril e  or  h a v e  b e e n 
p ost  m e n o p a us al f or  ≥  1  y e ar.     W o  m e n   w h o  h a v e 
d o c u  m e nt ati o n  of  at l e ast  1 2   m o nt hs  of s p o nt a n e o us 
a  m e n orr h e a  a n d  h a v e  a  f olli cl e-sti  m ul ati n g  h or  m o n e 
(F S  H)  l e v el  >  4 0 mI  U/  m L   will  b e  c o nsi d er e d 
p ost  m e n o p a us al. 
6.    All  ass o ci at e d t o xi cit y fr o  m  pr e vi o us  c a n c er t h er a p y 
m ust  h a v e  b e e n r es ol v e d (t o   ≤  Gr a d e   1  or  b as eli n e) 
pri or t o  a d  mi nistr ati o n  of  p e xi d arti ni b. 
7.    E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p  S c al e  of 
P erf or  m a n c e  St at us ( E  C  O  G  P S)  of  0  or  1.  
8.    Lif e  e x p e ct a n c y  ≥  3    m o nt hs, i n t h e  o pi ni o n  of t h e 
i n v esti g at or. 
9.    A d e q u at e  h e  m at ol o gi c,  h e p ati c,  a n d r e n al f u n cti o n 
d efi n e d  b y: 
•    A b  s ol ut e  n e utr o p hil  c o u nt  ≥  1. 5  ×  1 0 9/ L 
•    Pl at el et  c o u nt  ≥  1 0 0  ×  1 0 9/ L 
•    Al a ni n e  a  mi n otr a nsf er as e (  A L T)   or  as p art at e 
a  mi n otr a nsf er as e (  A S T)  ≤  1. 5  ×  u p p er li  mit  of 
n or  m al (  U L  N)  (if li v er   m et ast as es  ar e  pr es e nt 
or s u bj e cts   wit h  h e p at o c ell ul ar  c ar ci n o  m a, 
≤   3  × U L  N)   
•    Al b u  mi n  ≥  3   g/ d L  
•    T ot al  bilir u bi n  ≤  1. 5  ×   U L  N  
•    H e  m o gl o bi n  >  9   g/ d L  
•    S er u  m  cr e ati ni n e  ≤  1. 5  ×   U L  N  or  c al c ul at e d 
cr e ati ni n e  cl e ar a n c e  >   6 0 m L/  mi n  usi n g t h e 
C o c k cr oft-  G a ult f or  m ul a   
1 0.  A d e q u at e tr e at  m e nt   w as h o ut  p eri o d  b ef or e r e gistr ati o n 
d efi n e d  as:  
•    M aj or s ur g er y:   ≥  4   w e e ks ( 2  w e e ks f or l ess 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6  of  9 0 
i n v asi v e s ur g er y, s u c h  as  c ol ost o  m y) 
•    R a di ati o n t h er a p y ( e g,   w h ol e  br ai n 
r a di ot h er a p y): ≥  4   w e e ks (if  p alli ati v e 
st er e ot a cti c r a di ati o n t h er a p y,  ≥   2 w e e ks)   
•    C h e  m ot h er a p y  or i  m  m u n ot h er a p y (i n cl u di n g 
t ar g et e d t h er a p y   wit h  a nti b o d y or s  m all 
m ol e c ul e, r eti n oi d t h er a p y,  a n d  h or  m o n al 
t h er a p y): 4  w e e ks   or  5  h alf -li v es  of t h e  a g e nt, 
w hi c h e v er is s h ort er   (if t h e r e gi  m e n  h as 
c o nt ai n e d  nitr os o ur e as  or  mit o  m y ci n     C, 
≥   6 w e e ks)   
•    Ot h er i n v esti g ati o n al  d  r u g t h er a p y: ≥   4 w e e ks   
1 1.  Willi n g n ess  a n d  a bili   t y t o  pr o vi d e   writt e n i nf or  m e d 
c o ns e nt  pri or t o  a n y st u d y- r el at e d  pr o c e d ur es  a n d t o 
c o  m pl y   wit h  all st u d y r e q uir e  m e nts.  
E x cl usi o n   Crit eri a  
S u bj e cts  w h o   m e et  a n y  of t h e f oll o  wi n g  crit eri a   will  b e 
dis q u alifi e d fr o  m  e nt eri n g  t h e st u d y: 
1.    R efr a ct or y  n a us e a  a n d  v  o  miti n g,   m al a bs or pti o n, 
e xt er n al  bili ar y s h u nt,  or si g nifi c a nt s  m all  b o  w el 
r es e cti o n t h at   w o ul d  h a v e  pr e cl u d e d  a d e q u at e 
a bs or pti o n. 
2.    Pr es e n c e  of  a   m e di c al  or  ps y c hi atri c  c o n diti o n t h at, 
i n t h e  o pi ni o n  of t h e i n v esti g at or,   m a d e t h e s u bj e ct 
i n a p pr o pri at e f or i n cl usi o n i n t his st u d y. 
3.    Pr e vi o us  us e  of  p e xi d arti ni b  or  a n y  bi ol o gi c 
tr e at  m e nt t ar g eti n g c ol o n y  sti  m ul ati n g f a ct or - 1 
(C S F  - 1)  or t h e r e c e pt or f or  c ol o n y-sti  m ul ati n g 
f a ct or-1 ( C S F 1  R  );  pr e vi o us  us e  of  or al t yr osi n e 
ki n as e i n hi bit ors,  e g, i  m ati ni b  or  nil oti ni b,  is 
all o  w e d.  
4.    Cli ni c all y  a cti v e  pri  m ar y  c e ntr al  n er v o us s yst e  m 
t u  m ors  or  br ai n   m et ast asis,  d efi n e d  as  u ntr e at e d a n d 
s y  m pt o  m ati c,  or r e q uiri n g t h er a p y   wit h st er oi ds  or 
a nti c o n v uls a nts t o  c o ntr ol  ass o ci at e d s y  m pt o  ms. 
5.    A cti v e  or  c hr o ni c i nf e cti o n   wit h  h e p atit  is   C  or 
k n o  w n  p ositi v e  h e p atitis   B  s urf a c e  a nti g e n,  or 
k n o  w n  a cti v e  or  c hr o ni c i nf e cti o n   wit h  h u  m a n 
i  m  m u n o d efi ci e n c y  vir us. 
6.    K n o  w n  a cti v e t u b er c ul osis.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7  of  9 0 
7.    W o  m e n   w h o  ar e  br e astf e e di n g.    
8.    A s cr e e ni n g  Fri d eri ci a  c orr e ct e d   Q T i nt er v al 
(  Q T c F) ≥   4 5 0 ms (  m e n)  or   ≥  4 7 0  ms (  w o  m e n).   
9.    A   m e di c al  hist or y  or  c o  m pli c ati o ns  of  cli ni c all y 
si g nifi c a nt l u n g  dis e as e ( e g, i nt erstiti al  p n e u  m o ni a, 
p n e u  m o nitis,  p ul  m o n ar y fi br osis,  a n d s e v er e 
r a di ati o n  p n e u  m o nitis). 
1 0.  A  hist or y  of s y  m pt o  m ati c  c o n g esti v e  h e art f ail ur e 
([C  H F  ];   N e  w   Y or k   H e art Ass o ci ati o n [  N  Y  H  A] 
Cl ass es   II t o I  V)  or s eri o us  c ar di a c  arr h yt h  mi a 
r e q uiri n g tr e at  m e nt. 
1 1.  A  hist or y  of   m y o c ar di al i nf ar cti o n  or  u nst a bl e 
a n gi n a   wit hi n  6   m o nt hs  b ef or e  e nr oll  m e nt. 
1 2.  A n  u n c o ntr oll e d i nf e cti o n r e q uiri n g i ntr a v e n o us 
i nj e cti o n  of  a nti bi oti cs,  a ntivir als,  or  a ntif u n g als. 
D os a g e  F or  m,   D os e  a n d 
R o ut e  of   A d  mi nistr ati o n:   
P e xi d arti ni b,  as  a   2 0 0-m g    c a ps ul e f or  m ul ati o n f or  or al 
a d  mi nistr ati o n.    P e xi d arti ni b will  b e t a k e n t  wi c e  d ail y 
(  BI  D)  a p pr o xi  m at el y  1 2  h o urs ( h) a p art  i n t h e   m or ni n g  a n d 
e v e ni n g .  D os es   will  b e t a k e n i n t h e f asti n g st at e (  n o f o o d 
f or  1  h b ef or e  a n d  2   h  aft er  d osi n g,   wit h  a l o  w-f at s n a c k if 
n e e d e d ).  E a c h  c y cl e  of tr e at  m e nt   will  b e  2 8  d a ys  i n 
d ur ati o n .   T h e c y cl e  of tr e at  m e nt   will  b e  c o nti n u e d  u ntil 
dis e as e  pr o gr essi o n,  u n a c c e pt a bl e t o xi c it y, or  c o ns e nt 
wit h dr a  w al  . 
Pl a n n e d  S a  m pl e  Si z e:      
9 t o  1 5  s u bj e cts 
St atisti c al   A n al ys es:      
K e y  S af et y  P ar a  m et ers:   
S af et y  p ar a  m et ers   will i n cl u d e  d os e- li  miti n g t o xi citi es 
(D L Ts  ), s eri o us  a d v ers e  e v e nts ( S  A Es), tr e at  m e nt-e  m er g e nt 
a d v ers e  e v e nts ( T E  A Es ),  p h ysic al  e x a  mi n ati o n fi n di n gs 
(i n cl u di n g  E  C  O  G  P S),  vit al si g n   m e as ur e  m e nts, st a n d ar d 
cli ni c al l a b or at or y  p ar a  m et ers,  el e ctr o c ar di o gr a  m ( E  C  G) 
p ar a  m et ers ,  a n d  E  C  H  O/  M  U  G  A fi n di n gs.  All   T E  A Es   will 
b e  gr a d e d  a c c or di n g t o t h e  N ati o n al   C a n c er I nstit ut e 
C o  m  m o n  T er  mi n ol  o g y   Crit eri a f or   A d v ers e  E v e nt 
(  N  CI-C T  C  A E)     V ersi o n  4. 0. 
K e y  P h ar  m a c o ki n eti c   P ar a  m et ers:  
Pl as  m a  c o n c e ntr ati o n  d at a   will  b e  a n al y z e d  usi n g 
n o n -c o  m p art  m e nt al   m et h o ds.    P e a k  dr u g  c o n c e ntr ati o n 
(C  m a x  ), ti  m e  of   m a xi  m u  m  o bs er v e d  c o n c e ntr ati o n (T m a x  ) 
a n d  ar e a  u n d e r t h e  pl as  m a-c o n c e ntr ati o n -ti  m e  c ur v e fr o  m 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8  of  9 0 
ti  m e 0  t o  8 h ( A  U  C 0- 8 h) of  p e xi d arti ni b  a n d its   m et a b olit e 
will  b e  esti  m at e d  o n   D a y  s  1  a n d  1 5. 
K e y  Effi c a c y  P ar a  m et ers:   
T u  m or r es p o ns e   will  b e  e v al u at e d  usi n g  R es p o ns e 
E v al u ati o n   Crit eri a I n  S oli d  T u  m ors ( R E  CI S T  )   Versi o n  1. 1.   
S u bj e cts   will  b e  cl assifi e d i nt o t h e  b est  of t h e f oll o  wi n g 
t u  m or r es p o ns e  c at e g ori es:   C  R,  P  R,  S  D,  pr o gr essi v e 
dis e as e,  or  n ot  e v al u a bl e.   All  effi c a c y  v ari a bl es   will  b e 
pr es e nt e d i n  listi n gs b y  s u bj e ct.   T h e  n u  m b er  a n d 
p er c e nt a g e  of  s u bj e cts i n  e a c h r es p o ns e  c at e g or y   will  b e 
s u  m  m ari z e d  al o n g   wit h t h e  n u  m b er  a n d  p er c e nt a g e  of 
s u bj e cts   wit h  a n  o bj e cti v e r es p o ns e (  C  R  or  P  R)  a n d  a  D  C  R 
(C  R  or  P  R  or  S  D  ).   E x a ct  bi n o  mi al  9 5  %  c o nfi d e n c e 
i nt er v als (  CIs; 2-si d e d)   will  b e  pr o vi d e d f or  e a c h  c at e g or y 
r es p ons e  a n d t h e  b est  O  R  R  . 
K e y  P h ar  m a c o d y n a  mi c  P ar a  m et ers:   
Pl as  m a  P  D  v ari a bl e : C S F  - 1  a n d  a di p o n e cti n. 
T h e  P  D   v ari a bl e  c o n c e ntr ati o n  v al u es will  b e list e d  b y 
c o h ort.   S u  m  m ar y t a bl es  of  v al u es  at  e a c h ti  m e  p oi nt   will 
b e  cr e at e d f or  t h e P  D  v ari a bl e (  C S F - 1 a n d  a di p o n e cti n ), 
d et ails  of   w hi c h   will  b e  a d d e d i n t h e  S t atisti c al A  n al ysis 
P l a n (S  A P ). 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  9  of  9 0 
T  A  B  L  E   O F   C  O  N  T  E  N  T S   
I  N  V  E S  TI  G  A  T  O  R   A  G  R  E  E   M  E  N  T  ..................................................................................  2 
P  R  O  T  O  C  O  L  S  Y  N  O P S I S  .................................................................................................  3 
T  A  B  L  E   O F   C  O  N  T  E  N  T S   .................................................................................................  9 
LI S  T   O F I  N  -T  E  X  T   T  A  B  L  E S   ........................................................................................  1 5 
LI S  T   O F I  N  -T  E  X  T  FI  G  U  R  E S   ......................................................................................  1 6 
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N  S ........................................................................................  1 7  
1.  
I  N  T  R  O  D  U  C  TI  O  N .......................................................................................  1 9 
1. 1.  
B a c k gr o u n d ....................................................................................................  1 9  
1. 2.  
I nt e n d e d   Us e   U n d er I n v esti g ati o n .................................................................  2 0 
1. 3.  
N o n cli ni c al  St u di es   ........................................................................................  2 0 
1. 4.  
Cli ni c al  St u di es   ..............................................................................................  2 0 
1. 4. 1.  
P L  X 1 0 8- 0 1:   U S  P h as e  1  St u d y ......................................................................  2 5  
1. 5.  
St u d y   R ati o n al e  ..............................................................................................  2 7 
1. 6.  
Ris ks  a n d   B e n efits f or  St u d y  S u bj e cts ...........................................................  2 8  
1. 6. 1.  
U p d at e d   Ris k I nf or  m ati o n .............................................................................  2 9  
2.  
S  T  U  D  Y   O  B J  E  C  TI  V  E S   A  N  D  H  Y P  O  T  H  E SI S   ...........................................  3 1 
2. 1.  
St u d y   O bj e cti v es  ............................................................................................  3 1 
2. 1. 1.  
Pri  m ar y   O bj e cti v es  ........................................................................................  3 1 
2. 1. 2.  
S e c o n d ar y   O bj e cti v es  ....................................................................................  3 1 
2. 1. 3.  
E x pl or at or y   O bj e cti v es ..................................................................................  3 1  
2. 2.  
St u d y   H y p ot h esis  ...........................................................................................  3 1 
3.  
S  T  U  D  Y   D  E SI  G  N  .........................................................................................  3 2 
3. 1.  
O v er  a ll   D esi g n ...............................................................................................  3 2 
3. 2.  
Dis c u  ssi o n  of  St u d y   D esi g n ...........................................................................  3 3 
3. 3.  
D ur ati o n  of t h e  St u d y .....................................................................................  3 3  
3. 4.  
D ur ati o n  of  S u bj e ct  P arti ci p ati o n ..................................................................  3 3  
4.  
S  T  U  D  Y  P  O P  U  L  A  TI  O N ..............................................................................  3 4  
4. 1.  
I n cl usi o n   Crit eri a ...........................................................................................  3 4 
4. 2.  
E x cl usi o n   Crit eri a  ..........................................................................................  3 5 
5.  
S  T  U  D  Y   T  R  E  A  T   M  E  N  T  ...............................................................................  3 6 
5. 1.  
Assi g ni n g  S u bj e cts t o  Tr e at  m e nts   a n d   Bli n di n g  ............................................  3 6 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 0  of  9 0 
5. 1. 1.  
Tr e at  m e nt   Gr o u ps ..........................................................................................  3 6  
5. 1. 2.  
M et h o d  of  Tr e at  m e nt   All o c ati o n    ...................................................................  3 6 
5. 1. 3.  
Bli n di n g .........................................................................................................  3 6  
5. 1. 4.  
E  m er g e n c y   U n b li n di n g  Pr o c e d ur e .................................................................  3 6 
5. 2.  
St u d y   Dr u g  .....................................................................................................  3 6 
5. 2. 1.  
D es cri pti o n   .....................................................................................................  3 6 
5. 2. 2.  
L a b eli n g  a n d  P a c k a gi n g  .................................................................................  3 7 
5. 2. 3.  
Pr e p ar ati o n  .....................................................................................................  3 7 
5. 2. 4.  
A d  mi nistr ati o n   ...............................................................................................  3 7 
5. 2. 5.  
St or a g e  ...........................................................................................................  3 7 
5. 2. 6.  
Dr u g   A c c o u nt a bilit y ......................................................................................  3 7  
5. 3.  
C o ntr ol  Tr e at  m e nt ..........................................................................................  3 8  
5. 4.  
D os e  -li  miti n g  T o xi citi es ................................................................................  3 8 
5. 5.  
R e c o  m  m e n d e d  P h as e  2   D os e .........................................................................  3 9  
5. 6.  
D os e  L e v el  Es c al ati o n   ...................................................................................  3 9 
5. 7.  
D os e I nt err u pti o ns  a n d   R e d u cti o ns ................................................................  4 1  
5. 7. 1.  
R e n al I  m p ai  r  m e nt ..........................................................................................  4 3 
5. 8.  
M et h o d  of   Ass essi n g  Tr e at  m e nt   C o  m pli a n c e ................................................  4 3  
5. 9.  
Pri or  a n d   C o n c o  mit a nt   M e di c ati o ns ..............................................................  4 3  
5. 9. 1.  
H or  m o n al   C o ntr a c e pti v es ..............................................................................  4 4  
5. 9. 2.  
A ci d  -r e d u ci n g   A g e nts ....................................................................................  4 4 
5. 1 0.  
S u bj e ct  Wit h dr a  w al/  Dis c o nti n u ati o n    .............................................................  4 5 
5. 1 0. 1.  
R e as o ns f or    Wit h dr a  w al ................................................................................  4 5  
5. 1 0. 2.  
Wit h dr a  w al  Pr o c e d ur es    ..................................................................................  4 5 
5. 1 0. 3.  
S u bj e ct   R e pl a c e  m e nt  .....................................................................................  4 5 
6.  
S  T  U  D  Y  P  R  O  C  E  D  U  R  E S  .............................................................................  4 7 
6. 1.  
S cr e e ni n g  .......................................................................................................  4 7 
6. 1. 1.  
D a y    – 2 8 t o   D a y – 1 .........................................................................................  4 7  
6. 1. 2.  
D a y   – 2 1  t o   D a y – 1 .........................................................................................  4 7  
6. 1. 3.  
D a y   – 1 4  t o   D a y – 1 .........................................................................................  4 7  
6. 1. 4.  
D a y   – 7  t o   D a y – 1 ...........................................................................................  4 8  
6. 2.  
R a n d o  mi z ati o n ...............................................................................................  4 8  
6. 3.  
Tr e at  m e nt  P eri o d  ...........................................................................................  4 8 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 1  of  9 0 
6. 3. 1.  
C y cl e    1 ...........................................................................................................  4 8 
6. 3. 1. 1.  
C y cl e  1,   D a y    1 (  C 1  D 1;    W e e k  1) ....................................................................  4 8 
6. 3. 1. 2.  
C y cl e   1,   D a y   2 (  C 1  D 2;    W e e k  1) ....................................................................  4 8 
6. 3. 1. 3.  
C y cl e   1,   D a y   8 (  C 1  D 8;    W e e k 2)  ±  2  d a ys  .....................................................  4 9 
6. 3. 1. 4.  
C  y cl e  1,   D a y   1 5 (  C 1  D 1 5;    W e e k 3)  ±  2  d a ys  .................................................  4 9 
6. 3. 1. 5.  
C y cl e  1,   D a y    2 2 (  C 1  D 2 2;    W e e k  4)  ±  2  d a ys .................................................  4 9 
6. 3. 2.  
C y cl e  2   ...........................................................................................................  5 0 
6. 3. 2. 1.  
C y cl e  2,   D a y    1 (  C 2  D 1;    W e e k  5)  ±  2  d a ys .....................................................  5 0 
6. 3. 2. 2.  
C y cl e  2,   D a y    8 (  C 2  D 8;    W e e k  6)  ±  2  d a ys .....................................................  5 0 
6. 3. 2. 3.  
C y cl e  2,   D a y    1 5 (  C 2  D 1 5;    W e e k  7)  ±  2  d a ys .................................................  5 0 
6. 3. 2. 4.  
C y c  l e  2,   D a y  2 2 (  C 2  D 2 2;    W e e k  8)  ±  2  d a ys .................................................  5 0 
6. 3. 3.  
C y cl e  3   ...........................................................................................................  5 1 
6. 3. 3. 1.  
C y cl e  3,   D a y    1 (  C 3  D 1;    W e e k  9)  ±  2  d a ys .....................................................  5 1 
6. 3. 3. 2.  
C  y cl e  3,   D a y   8 (  C 3  D 8;    W e e k  1 0)  ±  2  d a ys ...................................................  5 1 
6. 3. 3. 3.  
C y cl e  3,   D a y    1 5(  C 3  D 1 5;    W e e k  1 1)  ±  2  d a ys ................................................  5 1 
6. 3. 4.  
C y cl e  4   ...........................................................................................................  5 1 
6. 3. 4. 1.  
C y cl e  4,   D a y    1 (  C 4  D 1;    W e e k  1 3)  ±  7  d a ys ...................................................  5 1 
6. 3. 4. 2.  
C y cl e  4,   D a y    1 5 (  C 4  D 1 5;    W e e k  1 5)  ±  7  d a ys ...............................................  5 2 
6. 3. 5.  
C y cl e  5  a n d t h er e aft er ( b ef or e  e nt eri n g  e xt e nsi o n  p art)   ................................  5 2 
6. 3. 5. 1.  
C y cl e  5,   D a y    1 (  C 5  D 1 +;    W e e k  1 7)  a n d t h er e aft er ( b ef or e  e nt eri n g 
e xt e nsi o n  p art)  ±  7  d a ys .................................................................................  5 2  
6. 3. 6.  
Tr e at  m e nt   Visits   D uri n g  E xt e nsi o n  p art  ........................................................  5 2 
6. 3. 6. 1.  
E v er y  4    w e e ks  ±  7  d a ys .................................................................................  5 2 
6. 3. 6. 2.  
E v er y  1 2  w e e ks   ±  7  d a ys ...............................................................................  5 2  
6. 4.  
E n d  of  Tr e at  m e nt ...........................................................................................  5 3  
6. 5.  
F oll o  w- u p .......................................................................................................  5 3  
6. 6.  
P h ar  m a c o g e n o  mi c s a  m pl e  c oll e cti o n  visit  .....................................................  5 4 
7.  
E F FI  C  A  C  Y   A S S  E S S   M  E  N  T S   .....................................................................  5 5 
7. 1.  
T u  m or I  m a gi n g  ..............................................................................................  5 5 
7. 2.  
Effi c a c y  E n d p oi nts .........................................................................................  5 5  
7. 2. 1.  
Pri  m ar y  Effi c a c y  E n d p oi nts ...........................................................................  5 5  
7. 2. 2.  
S e c o n d ar y  Effi c a c y  E n d p oi nts .......................................................................  5 6  
7. 2. 3.  
E x pl or at or y  Effi c a c y  E n d p oi nts ....................................................................  5 6  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 2  of  9 0 
7. 2. 4.  
A p pr o pri at e n ess  of  S el e ct e d  Effi c a c y  E n d p oi nts...........................................  5 6  
8.  
P  H  A  R   M  A  C  O  KI  N  E  TI  C/ P  H  A  R   M  A  C  O  D  Y  N  A   MI  C 
A S S  E S S   M  E  N  T S   ...........................................................................................  5 7 
8. 1.  
P h ar  m a c o ki n eti c   E n d p oi nt(s) .........................................................................  5 7 
8. 2.  
P h ar  m a c o d y n a  mi c  E n d p oi nts ........................................................................  5 8  
8. 3.  
Bi o  m ar k er  E n d p oi nts .....................................................................................  5 8  
8. 4.  
I  m  m u n o g e ni cit y .............................................................................................  5 8 
8. 5.  
P h ar  m a c o g e n o  mi c   A n al ysis  ...........................................................................  5 8 
9.  
S  A F  E  T  Y   E  V  A  L  U  A  TI  O  N   A  N  D   R  E P  O  R  TI  N  G  .........................................  5 9 
9. 1.  
A d v ers e  E v e nt   C oll e cti o n  a n d   R e p orti n g ......................................................  5 9  
9. 2.  
S af et y  E n d p oi nt  E v e nts ..................................................................................  6 0  
9. 3.  
E v e nts  of  S p e ci al I nt er es t ..............................................................................  6 0 
9. 3. 1.  
C o  m bi n e d  El e v ati o ns  of   A  mi n otr a nsf er as es  a n d   Bilir u bi n ...........................  6 0  
9. 4.  
A d v ers e  E v e nt   ................................................................................................  6 0 
9. 4. 1.  
D efi niti o n  of   A d v ers e  E v e nt ..........................................................................  6 0  
9. 4. 2.  
S eri o us   A d v ers e  E v e nt  ...................................................................................  6 0 
9. 4. 3.  
S e v erit y   Ass ess  m e nt  ......................................................................................  6 1 
9. 4. 4.  
C a us alit y   Ass ess  m e nt   ....................................................................................  6 1 
9. 4. 5.  
A cti o ns t o  b e  T a k e n   R e g ar di n g t h e   St u d y   Dr u g  ............................................  6 2 
9. 4. 6.  
Ot h er   A cti o ns t o  b e  T a k e n f or  E v e nt .............................................................  6 2  
9. 4. 7.  
A d v ers e  E v e nt   O ut c o  m e ................................................................................  6 2  
9. 5.  
S eri o us   A d v ers e  E v e nts   R e p orti n g – Pr o c e d ur e  F or I n v esti g at ors  ..................  6 3 
9. 6.  
N otif yi n g   R e g ul at or y   A ut h oriti es, I n v esti g at ors,   a n d I nstit uti o n al 
R  e vi e  w  B  o ar d  ................................................................................................  6 3 
9. 7.  
E x p os ur e I n   Ut er o   D uri n g   Cli ni c al  St u di es ...................................................  6 4  
9. 8.  
Cli ni c al  L a b or at or y  E v al u ati o ns ....................................................................  6 4  
9. 9.  
Vit al  Si g ns   .....................................................................................................  6 5 
9. 1 0.  
El e ctr o c ar di o gr a  ms  ........................................................................................  6 6 
9. 1 1.  
P h ysi c al  E x a  mi n ati o ns  ...................................................................................  6 6 
9. 1 2.  
Ot h er  E x a  mi n ati o ns   .......................................................................................  6 6 
9. 1 2. 1.  
E c h o c ar di o gr a  m .............................................................................................  6 6  
9. 1 2. 2.  
Pr e g n a n c y  T est  ...............................................................................................  6 7 
1 0.  
O  T  H  E  R   A S S  E S S   M  E  N  T S   ...........................................................................  6 8 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 3  of  9 0 
1 1.  
S  T  A  TI S  TI  C  A  L    M  E  T  H  O  D S .......................................................................  6 9  
1 1. 1.  
A n al ysis  S ets   ..................................................................................................  6 9 
1 1. 1. 1.  
E nr oll e d   A n al ysis  S et ....................................................................................  6 9  
1 1. 1. 2.  
Effi c a c y   A n al ysis  S et  .....................................................................................  6 9 
1 1. 1. 3.  
D os e  -li  miti n g  T o xi cit y  E v al u a bl e  S et ...........................................................  6 9 
1 1. 1. 4.  
S af et y   A n al ysis  S et  ........................................................................................  6 9 
1 1. 1. 5.  
P h ar  m a c o ki n eti c   A n al ysis  S et  .......................................................................  6 9 
1 1. 1. 6.  
P h ar  m a c o d y n a  mi cs  A n al ysis  S et   ...................................................................  6 9 
1 1. 2.  
G e n er al  St atis  ti c al   C o nsi d er ati o ns .................................................................  6 9 
1 1. 3.  
St u d y  P o p ul ati o n   D at a ...................................................................................  7 0  
1 1. 4.  
St atisti c al   A n al ys es  ........................................................................................  7 0 
1 1. 4. 1.  
Effi c a c y   A n al ys es  ..........................................................................................  7 0 
1 1. 4. 2.  
P h ar  m a c o ki n eti c/ P h ar  m a c o d y n a  mi c   A n al ys es  ..............................................  7 1 
1 1. 4. 2. 1.  
P h ar  m a c o ki n eti c   A n al ys es  .............................................................................  7 1 
1 1. 4. 2. 2.  
P h ar  m a c o d y n a  mi c   A n al ys es  ..........................................................................  7 1 
1 1. 4. 2. 3.  
Bi o  m ar k er   A n al ys es   .......................................................................................  7 1 
1 1. 4. 3.  
S af et y   A n al ys es  .............................................................................................  7 1 
1 1. 4. 3. 1.  
A d v ers e  E v e nt   A n al ys es   ................................................................................  7 2 
1 1. 4. 3. 2.  
Cli ni c al  L a b or at or y  E v al u ati o n   A n al ys es ......................................................  7 2  
1 1. 4. 3. 3.  
Vit al  Si g n   A n al ys es   .......................................................................................  7 2 
1 1. 4. 3. 4.  
El e ctr o c ar di o gr a  m   A n al ys es  ..........................................................................  7 2 
1 1. 4. 3. 5.  
P h ysi c al  E x a  mi n ati o n   A n al ys es  .....................................................................  7 2 
1 1. 4. 3. 6.  
E x pl or at or y  S af et y  A n al ys es   .........................................................................  7 3 
1 1. 4. 4.  
Ot h er   A n al ysis   ...............................................................................................  7 3 
1 1. 5.  
I nt eri  m   A n al ys es ............................................................................................  7 3 
1 1. 6.  
S a  m pl e  Si z e   D et er  mi n ati o n  ...........................................................................  7 3 
1 1. 7.  
St atisti c al   A n al ysis  Pr o c ess  ...........................................................................  7 3 
1 2.  
D  A  T  A I  N  T  E  G  RI  T  Y   A  N  D   Q  U  A  LI  T  Y   A S S  U  R  A  N  C  E   .............................  7 4 
1 2. 1.  
M o nit ori n g  a n d I ns p e cti o ns ...........................................................................  7 4  
1 2. 2.  
D at a   C oll e cti o n   ..............................................................................................  7 4 
1 2. 3.  
D at a   M a n a g e  m e nt   ..........................................................................................  7 5 
1 2. 4.  
St u d y   D o c u  m e nt ati o n  a n d  St or a g e ................................................................  7 6  
1 2. 5.  
R e c or d   K e e pi n g   .............................................................................................  7 6 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 4  of  9 0 
1 3.  
FI  N  A  N  CI  N  G   A  N  D I  N S  U  R  A  N  C  E  ..............................................................  7 8 
1 3. 1.  
Fi n a n c es  .........................................................................................................  7 8 
1 3. 2.  
R ei  m b urs e  m e nt, I n d e  m nit y,  a n d I ns ur a n c e   ...................................................  7 8 
1 4.  
P  U  B  LI  C  A  TI  O  N  P  O  LI  C  Y  ...........................................................................  7 9 
1 5.  
E  T  HI  C S   A  N  D   S  T  U  D  Y   A  D   MI  NI S  T  R  A  TI  V E I  N F  O  R   M  A  TI  O  N   ............  8 0 
1 5. 1.  
C o  m pli a n c e  St at e  m e nt,  Et hi cs  a n d   R e g ul at or y   C o  m pli a n c e .........................  8 0  
1 5. 2.  
S u bj e ct   C o nfi d e nti alit y  ..................................................................................  8 0 
1 5. 3.  
I nf or  m e d   C o ns e nt ..........................................................................................  8 0 
1 5. 4.  
R e g ul at or y   C o  m pli a n c e .................................................................................  8 1  
1 5. 5.  
Pr ot o c ol   D e vi ati o ns .......................................................................................  8 1  
1 5. 6.  
S u p pl y  of  N e  w   I nf or  m ati o n   Aff e cti n g t h e   C o n d u ct  of t h e  St u d y ..................  8 2 
1 5. 7.  
Pr ot o c ol   A  m e n d  m e nts ...................................................................................  8 2  
1 5. 8.  
St u d y  T er  mi n ati o n  .........................................................................................  8 3 
1 5. 9.  
S af et y  M o nit ori n g   C o  m  mitt e e   .......................................................................  8 3 
1 5. 1 0.  
A d dr ess   List  ...................................................................................................  8 3 
1 6.  
R  E F  E  R  E  N  C  E S   ............................................................................................  8 4 
1 7.  
A P P  E  N  DI  C  E S   ..............................................................................................  8 5 
1 7. 1.  
S c h e d ul e  of  E v e nts ........................................................................................  8 5  
1 7. 2.  
El e ctr o ni c   D at a   C a pt ur e  S yst e  m  ....................................................................  8 8 
1 7. 3.  
C  Y P 3  A 4 I n hi bit ors  a n d I n d u c ers   ...................................................................  8 9 
1 7. 4.  
A d dr ess  List   ...................................................................................................  9 0 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 5  of  9 0 
LI S  T   O F I  N  -T  E  X  T   T  A  B  L  E S   
T a bl e   1. 1: 
S u  m  m ar y  of   Cli ni c al  St u di es   wit h  P e xi d arti ni b  as  of  3 1 J ul  2 0 1 5 ...........  2 1  
T a bl e   5. 1: 
D os e  -es c al ati o n   Crit eri a   B as e d  o n   D L T  ...................................................  4 0 
T a bl e   5. 2: 
D os e   M o difi c ati o n   G ui d eli n es f or  Tr e at  m e nt-  e  m er g e nt  T o xi citi es  ..........  4 1 
T a bl e   5. 3: 
A d diti o n al  Li v er  E v al u ati o n .....................................................................  4 2  
T a bl e   5. 4: 
R e c o  m  m e n d e d   D os a g e   R e d u cti o ns f or  P e xi d arti ni b   wit h 
C o n c o  mit a nt   Us e  of   M o d er at e  or  Str o n g   C  Y P 3  A I n hi bit ors  or 
U  G T I n hi bit ors   ..........................................................................................  4 4 
T a bl e   8. 1: 
P h ar  m a c o ki n eti cs  S a  m pli n g  Ti  m e  P oi nts  .................................................  5 7 
T a bl e   8. 2: 
P h ar  m a c o ki n eti cs  P ar a  m et ers  ...................................................................  5 8 
T a bl e   9. 1: 
Cli ni c al  L a b or at or y  E v al u ati o ns ...............................................................  6 5  
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 6  of  9 0 
LI S  T   O F I  N  -T  E  X  T  FI  G  U  R  E S   
Fi g ur e  3. 1:  
St u d y  S c h e  m ati c  ........................................................................................  3 2 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 7  of  9 0 
LI S  T   O F   A  B  B  R  E  VI  A  TI  O  N  S 
A  B  B  R  E  VI  A  TI  O  N   
D  E FI  NI  TI  O  N   
A E   
a d v ers e  e v e nt  
A L T   
al a ni n e  a  mi n otr a nsf er as e  
A  M L   
a c ut e   m y el oi d l e u k e  mi a  
A S T   
as p art at e  a  mi n otr a nsf er as e  
A  U  C 0-  X h 
ar e a  u n d er t h e  pl as  m a -c o n c e ntr ati o n -ti  m e  c ur v e fr o  m ti  m e  z er o 
t o X   h o urs  (  X  d e n ot es t h e  n u  m b er) 
A  U  Ci nf   
ar e a  u n d e r t h e  pl as  m a-c o n c e ntr ati o n -ti  m e  c ur v e fr o  m ti  m e  z er o 
t o i nfi nit y 
C  DI S  C   
Cli ni c al   D at a I nt er c h a n g e  St a n d ar ds   C o ns orti u  m   
C  H F   
c o n g esti v e  h e art f ail ur e  
CI   
c o nfi d e n c e i nt er v al  
C  m a x   
p e a k  dr u g  c o n c e ntr ati o n  
C  R   
c o  m pl et e r es p o ns e  
C S F  -1  
c ol o n y -sti  m ul ati n g f a ct or-1  
C S F 1  R   
r e c e pt or  of  c ol o n y-sti  m ul ati n g f a ct or-1  
C T   
c o  m p ut e d t o  m o gr a p h y  
C  X  D  X   
C y cl e   X   O n   D a y   X (  X  d e n ot es t h e  n u  m b er)   
C  Y P   
c yt o c hr o  m e  P 4 5 0  
D  C  R   
dis e as e  c o ntr ol r at e  
D L T   
d os e -li  miti n g t o xi cit y 
E  C  G  
el e ctr o c ar di o gr a  m  
E  C  H  O  
e c h o c ar di o gr a  m  
E  C  O  G  P S      
E ast er n  C o o p er ati v e   O n c ol o g y   Gr o u p  S c al e  of  P erf or  m a n c e 
St at us  
e  C  R F  
el e ctr o ni c  C as e   R e p ort  F or  m   
E  D  C  
El e ctr o ni c   D at a   C a pt ur e  
EI  U  
e x p os ur e i n  ut er o  
F S  H  
f olli cl e-sti  m ul ati n g  h or  m o n e 
G  C P   
G o o d   Cli ni c al  Pr a cti c e    
G  G T   
g a  m  m a  gl ut a  m yl tr a nsf er as e  
GI S T   
g astr oi nt esti n al str o  m al t u  m or  
G L P   
G o o d  L a b or at or y  Pr a cti c e   
H  Cl   
h y dr o c hl ori d e   
I  B 
I n v esti g at or’s   Br o c h ur e 
I  C F 
I nf or  m e d   C o ns e nt  F or  m 
I  C  H 
I nt er n ati o n al   C o u n cil f or   H ar  m o nis ati o n 
I g 
I  m  m u n o gl o bi n 
I L 
i nt erl e u ki n 
I  N  R 
I nt er n ati o n al   N or  m ali z e d   R ati o 
I  R  B 
I nstit uti o n al R e vi e  w   B o ar d   
I T  D 
i nt er n al t a n d e  m  d u pli c ati o ns 
L  H  
l ut ei ni zi n g  h or  m o n e 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 8  of  9 0 
A  B  B  R  E  VI  A  TI  O  N   
D  E FI  NI  TI  O  N   
M  RI   
m a g n eti c r es o n a n c e i  m a gi n g   
M T  D   
m a xi  m  u  m  t ol er at e d  d os e 
M  U  G  A   
m ulti  -g at e d  a c q uisiti o n  
N  CI  -C T  C  A E       
N ati o n al   C a n c er I nstit ut e  -C o  m  m o n  T er  mi n ol o g y   Crit eri a f or 
A d v ers e  E v e nts   
N  Y  H  A   
N e  w   Y  or k   H e art   Ass o ci ati o n  
O  R  R   
o bj e cti v e r es p o ns e r at e  
O T  C   
o v er -t h e-c o u nt er  
P  D  
p h ar  m a c o d y n a  mi cs  
P  K  
p h ar  m a c o ki n eti cs  
P  G x  
p h ar  m a c o g e n o  mi cs  
P PI  
pr ot o n  p u  m p i n hi bit ors  
P  R  
p arti al r es p o ns e  
P  V  N S  
pi g  m e nt e d  vill o n o d ul ar s y n o vitis  
Q T c   
Q T i nt er v al  c orr e ct e d f or   h e art r at e  
Q T c F   
Fri d eri ci a  c orr e ct e d   Q T i nt er v al  
R  A  N  K  -L      
r e c e pt or  a cti v at or  of  n u cl e ar f a ct or  k a p p a-B li g a n d   
R E  CI S T   
R es p o ns e  E v al u ati o n   Crit eri a I n  S oli d  T u  m ors   
R  N  A   
ri b o n u cl ei c  a ci d 
R P 2  D   
r e c o  m  m e n d e d  P h as e 2  d os e  
S  A E  
s eri o us  a d v ers e  e v e nt  
S  A P  
St atisti c al   A n al ysis  Pl a n  
S  A  V E  R  
S eri o us   A d v ers e  E v e nt   R e p ort  
S  D  
st a bl e  dis e as e  
S  M  C  
S af et y   M o nit ori n g   C o  m  mitt e e  
S  O  C  
S yst e  m   Or g a n   Cl ass  
S  U S  A  R  
s us p e ct e d  u n e x p e ct e d s eri o us  a d v ers e r e a cti o n  
T E  A E  
tr e at  m e nt-e  m er g e nt  a d v ers e  e v e nt  
T  G  C T  
t e n os y n o vi al-gi a nt  c ell t u  m o r 
T  m a x  
ti  m e  of   m a xi  m u  m  o bs er v e d  c o n c e ntr ati o n 
T T  R  
ti  m e t o r es p o ns e 
U L  N   
u p p er li  mit  of  n or  m al  
U S   
U nit e d  St at es   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  1 9  of  9 0 
1.      
I  N  T  R  O  D  U  C  TI  O  N 
1. 1.      B a c k g r o u n d 
P L  X 3 3 9 7 ( p e xi d arti ni b) is  a  n o v el,  or all y  a cti v e, s  m all   m ol e c ul e i n hi bit or t h at t ar g ets 
F  ms (r e c e pt or f or  c ol o n y -sti  m ul ati n g f a ct or- 1 [  C S F 1  R],  als o  k n o  w n  as   m a cr o p h a g e 
c ol o n y- sti  m ul ati n g f a ct or ,  as   w ell  as t h e  n e  wl y  d es cri b e d li g a n d i nt erl e u ki n [I L]- 3 4),   Kit 
(t h e r e c e pt or f or st e  m  c ell f a ct or),  a n d  o n c o g e ni c  Flt 3 (t h e r e c e pt or f or  Flt 3 li g a n d),  b ut 
r e  m ai ns  hi g hl y s el e ctiv e  v ers us  ot h er  ki n as es.   T h e  p ot e nt i n hi biti o n  of t h es e  3  ki n as es 
c a n  b e  e x pl oit e d t o  att a c k t u  m ors  vi a   m ulti pl e   m e c h a nis  ms.   F or  e x a  m pl e, s o  m ati c 
a cti v ati o n  of   Kit  a n d  Flt 3  h as  b e e n   w ell- d o c u  m e nt e d i n   m ulti pl e  c a n c ers.    B e y o n d t h e 
dir e ct  d e p e n d e n c e  of t u m ors  o n t h es e  o n c o g e ni c  dri v ers,  F  ms  a n d   Kit  ar e r e g ul at ors  of 
m a cr o p h a g es,  ost e o cl asts,   mi cr o gli a,  a n d   m ast  c ells t h at  ar e  k e y  c o  m p o n e nts  of  v ari o us 
t u  m or   mi cr o e n vir o n  m e nts t h at s u p p ort  c a n c er  gr o  wt h, s ur vi v al, i n v asi o n,  a n d   m et ast asis.  
T h er ef or e,  p e xi d a rti ni b  h as t h e  p ot e nti al t o  a nt a g o ni z e  c a n c er  b y t h e f oll o  wi n g 
m e c h a nis  ms:   
•     Dir e ctl y i n hi biti n g  o n c o g e ni c  dri v ers s u c h  as  o n c o g e ni c   Kit  a n d  Flt 3   m ut a nt 
pr ot ei ns 1 , 2 
•     I n hi biti n g  p ar a cri n e l o o ps  b et  w e e n str o  m al  c ells  a n d t u  m ors3 , 4  
•     Bl o c ki n g   mi gr ati o n  a n d  a n gi o g e n esis 5 , 6 , 7 
•  R e pr o gr a  m  mi n g t u  m or i  m  m u n e   mi cr o e n vir o n  m e nt  
•     D  isr u pti n g  ost e ol yti c   m et ast as es8 , 9 
A n i  m p ort a nt r ol e f or t u  m or i nfiltr ati n g   m a cr o p h a g es i n t u  m or  pr o gr essi o n  h as  p oi nt e d t o 
F  ms  as  a  k e y t ar g et  i n   m ulti pl e t u  m or t y p es.5   T h e  pr o-t u  m ori g e ni c r ol e  of 
c ol o n y- sti  m ul ati n g f a ct or - 1 (C S F  - 1)  a n d  F  ms is str o n gl y s u p p ort e d  b y  a   w e alt h  of st u di es 
d e  m o nstr ati n g t h at   C S F - 1 l e v els  pr e di ct  a  p o or  o ut c o  m e i n  a  v ari et y  of  o n c ol o g y 
i n di c ati o ns, i n cl u di n g  br e ast,  o v ari a n,  n o n-s  m all c ell l u n g,  a n d  c ol or e ct al  c a n c ers.  
T r e at  m e nt  of  br e ast  c a n c er  x e n o gr afts   wit h  a ntis e ns e  a nti b o di es  or s  m all i nt erferi n g 
ri b o n u cl ei c  a ci d (  R  N  A) t o   C S F- 1 s u p pr ess es t u  m or  gr o  wt h.   T h e   m e c h a nis  m f or t his 
i n hi biti o n r el at es i n  p art t o  a  p ar a cri n e l o o p t h at li n ks   C S F- 1-s e cr eti n g t u  m or  c ells   wit h 
e pi d er  m al  gr o  wt h f a ct or -s e cr eti n g   m a cr o p h a g es .3   F urt h er  m or e,  a  gr o  wi n g  b o d y  of 
lit er at ur e  h as  n o  w li n k e d   m a cr o p h a g es t o  a n gi o g e n esis.5  It  h as  n o  w  b e e n r e c o g ni z e d t h at 
v ari o us  c h e  m ot h er a pi es  or r a di ot h er a p y   m a y  c a us e t u  m or  c ells t o  h y p ers e cr et e   C S F- 1 
a n d/ or I L - 3 4, r es ulti n g i n  a c c u  m ul ati o n  of t u  m or-ass o ci at e d   m a cr o p h a g es .1 0  I n  a ni  m al 
m o d els,  c o  m bi n ati o n  c h e  m ot h er a p y   wit h  p e xi d arti ni b r es ults i n s u bst a nti all y  e n h a n c e d 
effi c a c y.   P e xi d arti ni b  c a us es  m o d ul ati o n  of t u  m or-  ass o ci at e d   m a cr o p h a g es  a n d/ or 
m y el oi d  - d eri v e d s u p pr ess or  c ells t h at   m a y p ot e nti all y  b e  b e n efi ci al  i n  e n h a n ci n g 
a nti t u  m or r es p o ns es   w h e n  us e d i n  c o  m bi n ati o n   wit h i  m  m u n e  c h e c k p oi nt i n hi bit ors. 
T h e  pr o- t u  m ori g e ni c  a n d  c h e  m ot h er a p y-r esist a n c e r ol e  of t u  m or-ass o ci at e d   m a cr o p h a g es 
is  n ot li  mit e d t o  br e ast  c a n c er  a n d   m a y i n cl u d e  a d diti o n al t u  m or t y p es s u c h  as   m el a n o  m a, 
pr ost at e  c a n c er , a n d  p a n cr e ati c  c a n c er,  a  m o n g  ot h ers.     A c c or di n gl y,  p e xi d arti ni b h as 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 0  of  9 0 
d e  m o nstr at e d t h er a p e uti c  effi c a c y  as  a si n gl e  a g e nt  a n d i n  c o  m bi n ati o n   wit h 
c h e  m ot h er a p y  or r a di ati o n i n  n o n cli ni c al   m o d els  of  p a n cr e ati c 1 1  a n d  pr ost at e c a n c er .1 2  
T h e  effi c a c y  of  ost e o cl ast  a nt a g o nists s u c h  as  bis p h os p h o n at es i n  pr e v e nti n g  b o n e 
fr a ct ur es  a n d  p ai n r es ulti n g fr o  m  ost e ol yti c   m et ast as es  h as  b e e n r e c o g ni z e d f or s o  m e 
ti  m e.1 3  Ost e o cl asts r e q uir e t h e  p ar all el  a cti v ati o n  of t h e   r e c e pt or  a cti v at or  of  n u cl e ar 
f a ct or  k a p pa- B li g a n d   (R  A  N  K  - L)  a n d  F  ms  p at h  w a ys f or  a cti vit y  a n d s ur vi v al.  R e c e ntl y, 
R  A  N  K  - L  a nt a g o nists  h a v e  d e  m o nstr at e d  effi c a c y t o  pr e v e nt  b o n e  d estr u cti o n i n 
n o n cli ni c al   m o d els,  a n d  d e n os u  m a b is  n o  w  a   U nit e d  St at es (  U S)  F o o d  a n d   Dr u g 
A d  mi nistr ati o n  - a p pr o v e d   R  A  N  K- L-t ar g eti n g  a nti b o d y.9    As  a  p ot e nt i n hi bit or  of  F  ms, t h e 
a nti -ost e o cl ast  eff e cts  of  p e xi d arti ni b  t h at  ar e s e e n i n  vitr o  a n d i n  vi v o  pr o vi d e  a n 
alt er n ati v e   m e c h a nis  m t o  bl o c k  b o n e  d estr u cti o n  a n d  c o ns e q u e nt  p ai n. 
T u  m or r es p o ns es i n  p ati e nts   wit h  a c ut e   m y el oi d l e u k e  mi a (  A  M L)  usi n g i n hi bit ors  of 
m ut a nt  Flt 3   h a v e  b e e n r e p ort e d,  alt h o u g h  n o n e  of t h es e i n hi bit ors  h a v e  b e e n  a p pr o v e d t o 
tr e at   A  M L.2  P e xi d arti ni b  pr ef er e nti all y i n hi bits  o n c o g e ni c  Flt 3  i nt er n al t a n d e  m 
d u pli c ati o ns ( I T  D)  v ers us t h e   wil d t y p e  pr ot ei n,   w hi c h   m a y tr a nsl at e i nt o  a  hi g h er 
t h er a p e uti c i n d e x t h a n  c urr e ntl y  a p pr o v e d t h er a pi es.   T u  m or  c o ntr ol  d u e t o  bl o c k a d e  of 
Kit   m ut ati o ns  h as  b e e n  v ali d at e d t hr o u g h t h e  est a blis h e d  effi c a c y  of i  m ati ni b  a n d 
s u niti ni b ( b ot h   wit h i n hi bit or y  a cti vit y  a g ai nst s el e ct e d  Kit  -m ut at e d t u  m ors) i n 
g astr oi nt esti n al str o  m al t u  m ors (  GI S T) .1 
1. 2.      I nt e n d e d   Us e   U n d e r I n v esti g ati o n  
P e xi d arti ni b   will  b e  e v al u at e d i n s u bj e ct s wit h    a d v a n c e d s oli d t u  m ors. 
1. 3.      N o n cli ni c al  St u di es   
W h e n s cr e e n e d i n  vitr o  a g ai nst  a  br o a d  p a n el  of  2 3 0  ki n as es,  p e xi d arti ni b s h o  ws  p ot e nt 
a n d s el e cti v e i n hi biti o n  a g ai nst its i nt e n d e d t ar g ets:   C S F 1  R,   Kit,  a n d  a cti v at e d  Flt 3.   
P e xi d arti ni b  als o  bl o c ks  ost e o cl ast  diff er e nti ati o n  a n d  c ell  gr o  wt h  of   C S F- 1- d e p e n d e nt 
c ell li n es.    P e xi d arti ni b  h as s h o  w n t h e  a bilit y t o  bl o c k   C S F 1  R  a cti vit y i n  a  v ari et y  of i n 
vi v o   m o d els.   P e xi d arti ni b s h o  ws  d os e- d e p e n d e nt i n hi biti o n  of s pl e n o  m e g al y i n  a n 
e n gi n e er e d  C S F 1  R  - d e p e n d e nt   m o us e   m o d el.    A d diti o n all y, p e xi d arti ni b  s h o  ws a  p ot e nt 
i n hi bit or  of t h e  pr olif er ati o n  of  Flt 3-I T  D- d e p e n d e nt   m o d els or   Kit - d e p e n d e nt   m o d els. 
A d diti o n al  d et ail e d i nf or  m ati o n r e g ar di n g t h e  n o n cli ni c al  p h ar  m a c ol o g y  a n d t o xi c ol o g y 
of  p e xi d arti ni b  c a n  b e f o u n d i n t h e  I n v esti g at or’s   Br o c h ur e (I  B). 
1. 4.      Cli ni c al  St u di es   
P e xi d arti ni b  h as  b e e n  e v al u at e d i n   m ulti pl e  cli ni c al st u di es ( T a bl e   1. 1); a s  of 3 1 J ul  2 0 1 5, 
t h e s af et y  a n d  p h ar  m a c o d y n a  mi cs ( P  D) eff e cts  of  p e xi d arti ni b  h as  b e e n  e v al u at e d i n 
1 0  cli ni c al st u di es,  of   w hi c h  3  h a v e  b e e n  c o  m pl et e d :  st u d y  P L  X 1 0 8-0 3 i n  p ati e nts   wit h 
r el a ps e d  or r efr a ct or y   H o d g ki n’s l y  m p h o  m a, st u d y  P L  X 1 0 8- 0 4 i n r e c urr e nt  gli o bl ast o  m a 
m ultif or  m e (  G  B  M),  a n d st u d y  P L  X 1 0 8- 0 6 i n  p ati e nts   wit  h  a d v a n c e d   m et ast ati c  pr ost at e 
c a n c er.   I n  a d diti o n, si n gl e- d os e st u di es  P L  X 1 0 8- 1 1  a n d  P L  X 3 3 9 7-  A-U 1 1 4   w er e 
c o  m pl et e d i n  h e alt h y s u bj e cts.    S e v e n  o n g oi n g st u di es  ar e  e v al u ati n g  p e xi d arti ni b i n 
p ati e nts   wit h  a d v a n c e d i n c ur a bl e s oli d t u  m ors f o c usi n g  o n  pi g  m e nt e d  vill o n o d ul ar 
s y n o vitis ( P  V  N S) ( P L  X 1 0 8- 0 1  a n d  P L  X 1 0 8- 1 0), r el a ps e d  or r efr a ct or y   A  M L 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 1  of  9 0 
( P L  X 1 0 8- 0 5),  c o  m bi n ati o n t h er a p y i n  a d v a n c e d i n c ur a bl e s oli d t u  m ors ( P L  X 1 0 8- 0 7,   wit h 
p a clit a x el;  P L  X 1 0 8 - 1 4,   wit h  p e  m br oli z u  m a b), i n  n e  wl y  di a g n os e d  gli o bl ast o  m a 
m ultif o  r  m e (  G  B  M) ( P L  X 1 0 8- 0 8,   wit h t e  m o z ol o  mi d e  a n d r a di ati o n),  a n d i n 
B  R  A F  -m ut at e d   m et ast ati c   m el a n o  m a ( P L  X 1 0 8  - 0 9,   wit h  v e  m ur af e ni b). 
T a bl e  1. 1:      S  u  m  m a r y  of   Cli ni c al  St u di es   wit h  P e x i d a rti ni b  as  of  3 1  J ul  2 0 1 5 
St u d y   N u  m b e r/  
St a rt   D at e a/ St at us/ 
C o u nt r y   
D osi n g   R e gi  m e n       
St u d y  P o p ul ati o n      
E n r oll  m e nt b  
P L  X 1 0 8 -0 1/  
0 1  O ct   2 0 0 9/  
O n g oi n g/   
U S   
P e xi d arti ni b  2 0 0  m g   Q  D 
( St arti n g  d os e);   R P 2  D: 
1 0 0 0  m g/ d ( a d  mi nist er e d 
as   BI  D)  
A d ults   wit h  a d v a n c e d, 
i n c ura bl e, s oli d t u  m ors; 
o n g oi n g  e xt e nsi o n  c o h ort 
f o c us e d  o n  Pi g  m e nt e d 
Vill o n o d ul ar  S y n o vitis   
( P  V  N S) 
Pl a n n e d : u p t o  5 0  p ati e nts 
i n t h e  d os e  es c al ati o n 
p h as e;  7 0  p ati e nts i n  6 
e xt e nsi o n  c o h orts  a n d  u p 
t o  3 0  a d diti o n al  p ati e nts i n 
a s p e cifi c  c o h ort  
A ct u al  : 1 3 4  
P L  X 1 0 8 -0 3/  
0 2  M ar   2 0 1 1/  
C o  m pl et e/   
U S   
P e xi d arti ni b,  or al,  c a ps ul e 
( 1 0 0 m g  p er  c a ps ul e)  at 
9 0 0  m g/ d   
A d ults   wit h r el a ps e d  or 
r efr a ct or y   H o d g ki n’s 
l y  m p h o  m a 
Pl a n n e d : 3 0  
A ct u al  : 2 0  
P L  X 1 0 8 -0 4/  
1 3  D e c   2 0 1 1/  
C o  m pl et e/   
U S   
P e xi d arti ni b,  or al,   BI  D 
c a ps ul e ( 1 0 0  m g  or 
2 0 0  m g  p er  c a ps ul e)  at 
1 0 0 0  m g/ d   
P ati e nts   wit h r e c urr e nt 
gli o bl ast o  m a   m ultif or  m e  
Pl a n n e d : 4 0  
A ct u al  : 3 8  
P L  X 1 0 8 -0 5/  
1 4  N o v   2 0 1 1/  
O n g oi n g/   
U S   
P e xi d arti ni b  or al,   BI  D, 
c a ps ul e  
T h e  d os e l e v el  of 
p e xi d arti ni b i n  P art  2   w as 
d et er  mi n e d t o  b e 
3 0 0 0  m g/ d  a d  mi nist er e d   
BI  D   
A d ults   wit h r el a ps e d  or 
r efr a ct or y  Flt3- I T  D 
p ositi v e  a c ut e   m y el oi d 
l e u k e  mi a 
Pl a n n e d : 9 0  
A ct u al  : 9 0  
P L  X 1 0 8 -0 6/  
2 5  M a y   2 0 1 2/  
N o  a cti v e  p ati e nts/   
U S   
P e xi d arti ni b  or al,   BI  D, 
c a ps ul e  at  1 0 0 0  m g/ d   
P ati e nts   wit h  pr o gr essi v e 
C  R P  C,  b o n e   m et ast a s es 
a n d  hi g h   C T  C  c o u nts  
Pl a n n e d : 2 0  
A ct u al  : 6 
P L  X 1 0 8 -0 7/  
1 5  M a y   2 0 1 2/  
O n g oi n g/   
U S   
P e xi d arti ni b,  or al,   BI  D, 
c a ps ul e  at  6 0 0  m g/ d, 
8 0 0  m g/ d,  1 0 0 0   m g/ d, 
1 2 0 0  m g/ d,  a n d  1 6 0 0   m g/ d   
P a clit a x el, I  V,  o n c e 
w e e kl y,  8 0   m g/  m 2 
P ati e nts   wit h  a d v a n c e d, 
i n c ur a bl e s oli d t u  m or; 
o n g oi n g  e xt e nsi o n  c o h ort 
f o c us e d  o n r el a ps e d  or 
r efr a ct or y  o v ari a n 
c a n c er,  pri  m ar y 
p erit o n e al  c a n c er,  or 
f all o pi a n t u b e  c a n c er  
Pl a n n e d : 9 0  
A ct u al  : 5 4  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 2  of  9 0 
T a bl e   1. 1   S u  m  m a r y  of   Cli ni c al  St u di es   wit h  P e xi d a rti ni b  as  of  3 1  J ul  2 0 1 5 
( c o nti n u e d) 
St u d y   N u  m b e r/  
St a rt   D at e a/ St at us/ 
C o u nt r y   
D osi n g   R e gi  m e n       
St u d y  P o p ul ati o n      
E n r oll  m e nt b  
P L  X 1 0 8 -0 8/  
1 8  J ul 2 0 1 3/  
O n g oi n g/   
U S   
P h as e  1 b : p e xi d arti ni b, 
or al,   BI  D,  8 0 0  m g/ d  or 
1 0 0 0  m g/ d;   
6 0  G y  of r a di ati o n t h er a p y 
o v er  a p pr o xi  m at el y 
6  w e e ks;   
t e  m o z ol o  mi d e  7 5 m g/  m 2 
P  O  o n c e  d ail y f or  a p pr o x. 
6  w e e ks;   
4- w e e k  n o tr e at  m e nt 
p eri o d;  a n d,  a dj u v a nt 
t e  m o z ol o  mi d e  1 5 0 m g/  m 2 
o n c e  d ail y  o n   D a ys   1-5  of 
e a c h  2 8 -d a y  c y cl e  
P h as e   2: R P 2  D fr o  m 
P h as e  1 b  
N e  wl y  di a g n os e d 
gli o bl ast o  m a  
Pl a n n e d : 7 9  
A ct u al  : 6 5  
P L  X 1 0 8 -0 9/  
2 3  O ct   2 0 1 3/  
C o  m pl et e/   
U S,  Fr a n c e, 
G er  m a n y   
D os e   Es c al ati o n  P h a s e : 
p e xi d arti ni b  8 0 0  m g/ d  a n d 
v e  m ur af e ni b  7 2 0  m g  or al, 
BI  D;  p e xi d arti ni b 
8 0 0  m g/ d  a n d  v e  m ur af e ni b 
9 6 0  m g,  or al   BI  D; 
p e xi d arti ni b  1 0 0 0  m g/ d 
a n d  v e  m ur af e ni b  9 6 0  m g, 
or al   BI  D  
E xt e nsi o n  c o h ort : R P 2  D 
(  BI  D) 
V 6 0 0  -m ut at e d   B  R  A F 
U nr es e ct a bl e  or 
M et ast  ati c   M el a n o  m a  
Pl a n n e d : 9 0  
A ct u al  : 1 3  
P L  X 1 0 8 -1 0/  
0 8  A pr   2 0 1 5/  
O n g oi n g/   
U S,   C a n a d a, 
D e n  m ar k,  Fr a n c e, 
G er  m a n y,   H u n g ar y, 
It al y,   N et h erl a n ds, 
P ol a n d,   U nit e d 
Ki n g d o  m,  S p ai n, 
a n d   A ustr ali a  
D o u bl e  bli n d  p h as e  : 
p e xi d arti ni b  1 0 0 0  m g/ d 
( 4 0 0 m g  a  m  a n d  6 0 0   m g 
p  m)  or  p l a c e b o f or first 
2  w e e ks  a n d  8 0 0   m g/ d 
(4 0 0  m g   BI  D)  or  pl a c e b o 
f or  2 2 w e e ks  . 
E xt e nsi o n  c o h ort : O p e n 
l a b el  p e xi d arti ni b  at 
m a xi  m u  m st arti n g  d os e  of 
4 0 0  m g  BI  D  . 
P  V  N S/ gi a nt  c ell t u  m or 
of t h e t e n d o n  
s h e at h (  G  C T -T S),  als o 
k n o  w n  as t e n os y n o vi al 
gi a nt  c ell t u  m ors 
(l o c ali z e d  a n d  diff us e 
t y p es) 
Pl a n n e d : 1 2 6  
A ct u al  : 5 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 3  of  9 0 
T a bl e   1. 1   S u  m  m a r y  of   Cli ni c al  St u di es   wit h  P e xi d a rti ni b  as  of  3 1  J ul  2 0 1 5 
( c o nti n u e d) 
St u d y   N u  m b e r/  
St a rt   D at e a/ St at us/ 
C o u nt r y   
D osi n g   R e gi  m e n       
St u d y  P o p ul ati o n      
E n r oll  m e nt b  
P L  X 1 0 8 -1 4/  
0 6  J ul 2 0 1 5/  
O n g oi  n g/  
U S   
D os e  -es c al ati o n  P h a s e 
( P art 1) : P e  m br oli z u  m a b  
2 0 0  m g I  V  e v er y  3   w e e ks 
i n  c o  m bi n ati o n   wit h a 
st arti n g  d os e of 
p e xi d arti ni b  at  6 0 0  m g/ d, 
wit h s e q u e nti al  es c al ati o ns 
t o 8 0 0  a n d  1 0 0 0  m g/ d  . 
E x p a nsi o n  P h as e ( P art  2) : 
P e  m br oli z u  m a b  2 0 0  m g 
I  V  e v er y  3 w e e ks   i n 
c o  m bi n ati o n   wit h  or al 
p e xi d arti ni b  a d  mi nist er e d 
as  a s plit  d os e  at t h e   R P 2  D  
of  p e xi d arti ni b . 
D os e  -es c al ati o n  P h a s e : 
A d v a n c e d s oli d t u  m ors, 
all  c o  m ers  
E x p a nsi o n  P h as e : T h e 
f oll o  wi n g t u  m or t y p e s: 
M el a n o  m a 
(tr e at  m e nt-n aï v e)  
M el a n o  m a ( pri  m ar y 
pr o gr essi v e)  
M  el a n o  m a (s e c o n d ar y 
pr o gr essi v e)  
N o n  -s  m all -c ell l u n g 
c a n c er (s al v a g e,  all 
c o  m er s)  
O v ari a n  c a n c er   
Tri pl e -n e g ati v e  br e ast 
c a n c er  
S q u a  m o us  c ell  c a n c er  of 
t h e  h e a d  a n d  n e c k 
Bl a d d er  c a n c er   
P a n cr e ati c  d u ct al 
a d e n o c ar ci n o  m a  
G astri c  c a n c er   
G astr oi nt e sti n al str o  m al 
t u  m or 
L ei o  m y os ar c o  m a  
C h ol a n gi o c ar ci n o  m a   
D os e  -es c al ati o n  P h a s e : U p 
t o  2 4; 
E x p a nsi o n  P h as e : U p t o 
4 7 5   wit h  2 8 t o  4 8  s u bj e cts 
p er t u  m or t y p e  
A ct u al  : 3 
P L  X 1 0 8 -1 1/  
0 3  J ul 2 0 1 4/  
C o  m pl et e/   
U S   
S u bj e cts r a n d o  mi z e d t o 
r e c ei v e tr e at  m e nts i n  1  of 
3 s e q u e n c es  of   A  B  C, 
B  C  A,  or   C  A  B  :  Tr e at  m e nt 
A  : 6 0 0 -m g si n gl e  d os e  of 
p e xi d arti ni b  u n d er f ast e d 
c o n diti o ns;  
Tr e at  m e nt   B : 6 0 0 -m g 
si n gl e  d os e  of  p e xi d arti ni b 
u n d er f e d  c o n diti o ns 
(  wit hi n  3 0 mi n ut e s  aft er 
hi g h -f at  br e a kf a st); 
Tr e at  m e nt   C : 4 0  m g 
es o  m e pr a z ol e 
a d  mi nist er e d   Q  D f or 
4  d a ys, f oll o  w e d  b y  4 0  m g 
es o  m e pr a z ol e 
a d  mi nist er e d  2  h  pri or t o  a 
6 0 0 -m g  si n gl e  d os e  of 
p e xi d arti ni b  u n d er f ast e d 
c o n diti o ns.  
H e alt h y s u bj e cts       
Pl a n n e d : 2 7  
A ct u al  : 2 7   
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 4  of  9 0 
T a bl e   1. 1   S u  m  m a r y  of   Cli ni c al  St u di es   wit h  P e xi d a rti ni b  as  of  3 1  J ul  2 0 1 5 
( c o nti n u e d) 
St u d y   N u  m b e r/  
St a rt   D at e a/ St at us/ 
C o u nt r y   
D osi n g   R e gi  m e n       
St u d y  P o p ul ati o n      
E n r oll  m e nt b  
P L  X 3 3 9 7 -A  -U 1 1 4/   
2 0  N o v   2 0 1 4/  
C o  m pl et e/   
U S   
Tr e at  m e nt   A:  
p e xi d arti ni b  4 0 0  m g 
(J-3 3 9 7 -A E)   
F asti n g  
Tr e at  m e nt   B:  
Si n gl e  d os e  p e xi d arti ni b 
4 0 0  m g (J  -3 3 9 7 -A F)   
F asti n g  
Tr e at  m e nt   C:  
Si n gl e  d os e  p e xi d arti ni b 
4 0 0  m g (J  -3 3 9 7 -A F)   
F e d  
H e alt h y s u bj e cts       
Pl a n n e d : 3 0  
A ct u al  : 3 0  
S o ur c e : T a bl e  2 3,   D S  U  R,  2 0 1 5   V ersi o ns  4. 0  a n d   D S  U  R  a d d e n d u  m (  V ersi o n  4. 1).  
BI  D  = t  wi c e  d ail y;   C  R P  C  =   C  astr ati o n -r esist a nt  pr ost at e  c a n c er; C T  C  =   Cir c ul ati n g  T u  m o ur   C e  ll;  h  = h o urs;  I  V  = 
i ntr a v e n o us; Q  D  =  o n c e  d ail y;   R P 2  D  = r e c o  m  m e n d e d  p h as e  2  d os e;   U S  =   U nit e d  St at es  . 
a     St art  d at e is t h e fi rst  visit f or t h e first  p ati e nt.   
b     A c cr u al is  b as e d  o n t h e t ot al  n u  m b er  of  p ati e nts  e nr oll e d  as  of   3 1  J ul 2 0 1 5.  
N o s af et y si g n als   i n  vit al si g ns,  p h ysi c al  e x a  mi n ati o ns,  or el e ctr o c ar di o gr a  ms ( E  C  Gs ) 
(i n cl u di n g  c ar ef ul  e v al u ati o n  of  p ot e nti al E  C  G    Q T  pr ol o n g ati o n) h a v e  b e e n i d e ntifi e d.   At 
d os es  of  >  1 0 0 0   m g/ d, tr a nsi e nt  a n d r e v ersi bl e i n cr e as es i n  al a ni n e  a  mi n otr a nsf er as e 
(  A L T)  a n d/ or as p art at e  a  mi n otr a nsf er as e (  A S T)  h a v e  b e e n  o bs er v e d i n  a p pr o xi  m at el y 
h alf  of t h e  p ati e nts.   Si  mil ar i n cr e as es i n   A L T  a n d   A S T   w er e s e e n i n t h e  1 3 -  we e k r at 
st u d y,  b ut  n ot i n t h e  d o g st u d y.    A  m o n g s oli d t u  m or  p ati e nts, t h e   m ost  c o  m  m o n  a d v ers e 
e v e nts ( A Es  ) ( oc c urri n g i n  ≥   20  %  of  all  p ati e nts tr e at e d   wit h  p e xi d arti ni b ) o bs er v e d  h a v e 
b e e n f ati g u e,  n a us e a,  d e cr e as e d  a p p etit e,  h air  c ol or  c h a n g e ( d e pi g  m e nt ati o n) ,  v o  miti n g, 
di arr h e a , h e a d a c h e ,  a n d a n e  mi a.   I n t h e   A  M L st u d y, t h e   m ost  c o  m  m o n   A Es r e p ort e d h a v e 
b e e n  di a rr h e a,  n a us e a, f ati g u e, f e bril e  n e utr o p e ni a, v o  miti n g,  d e cr e as e d  a p p etit e,  a n e  mi a, 
c o u g h,  h y p o k al e  mi a,  a n d i n cr e as es i n   A S T . 
A d  mi nistr ati o n  of si n gl e  d os es  of  6 0 0   m g   p e xi d arti ni b  wit h  a  hi g h f at   m e al r es ult e d i n 
i n cr e as e d p e a k  dr u g  c o n c e ntr ati o n (  C m a x  ) b y  5 3  %  a n d   A  U  C 0- 2 4 b y   9 5  % c o  m p ar e d  wit h 
t h e f ast e d st at e i n  h e alt h y s u bj e cts ( P L  X 1 0 8- 1 1).  M a xi  m u  m  pl as  m a  c o n c e ntr ati o ns   w er e 
o bt ai n e d  at  a   m e di a n  T  m a x  of  4   h o urs ( h)  p ost d os e,  a p pr o xi  m at el y  1  h l at er t h a n  o bs er v e d 
i n t h e f ast e d st at e.  M e a n  h alf  -lif e v al u es   w er e  c o  m p ar a bl e,  2 6  a n d  3 0  h, f oll o  wi n g 
a d  mi nistr ati o n  of  6 0 0   m g  p e xi d arti ni b  i n t h e f e d  a n d f ast e d st at es, r es p e cti v el y. 
C o a d  mi nistr ati o n  of  p e xi d arti ni b   wit h  es o  m e pr a z ol e r es ult e d i n  d e cr e as e d  e x p os ur e  of 
p e xi d arti ni b  as t h e   m e a n   C  m a x  a n d   A  U  C 0- 2 4 f or p e x i d arti ni b   w er e  4 0  %  a n d  3 8  %, 
r es p e cti v el y; l o  w er   w h e n  c o  m p ar e d wit h   a d  mi nistr ati o n  of  p e xi d arti ni b   al o n e,  all i n t h e 
f ast e d st at e ( P L  X 1 0 8- 1 1). 
D et ails  o n t h e  cli ni c al  e x p eri e n c e   wit h  p e xi d arti ni b    c a n  b e f o u n d i n t h e I  B. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 5  of  9 0 
1. 4. 1.      
P  L  X 1 0 8- 0 1:   U S  P h as e  1  S t u d y 
P L  X 1 0 8- 0 1 is  e v al u ati n g  p ati e nts   wit h  a d v a n c e d, i n c ur a bl e, s oli d t u  m ors i n   w hi c h t h e 
t ar g et  ki n as es  ar e li n k e d t o  dis e as e  p at h o p h ysi ol o g y.   T his st u d y is  b ei n g  c o n d u ct e d i n 
2  p arts:  a n i niti al  d os e -es c al ati o n  p art t o i d e ntif y  a r e c o  m  m e n d e d  P h as e   2  d os e (  R P 2  D), 
a n d  a n  e xt e nsi o n  p art t o  o bt ai n  pr eli  mi n ar y  effi c a c y  d at a i n  p ati e nts   wit h s el e ct e d t u  m or 
t y p es.   T h e  d os e-es c al ati o n  p art  of t h e st u d y  h as  b e e n  c o  m pl et e d  a n d  1 0 0 0   m g/ d, 
a d  mi nist er e d  as  a  t  wi c e  d ail y (BI  D  ) r e gi  m e n,   w as s el e ct e d  as t h e   m a xi  mu  m  t ol er at e d 
d os e  (  MT  D)  a n d   R P 2  D f or f urt h er  e v al u ati o n i n t h e  e xt e nsi o n  c o h orts. 
D os e  - es c al ati o n  Pa rt  
F ort y - o n e  p ati e nts  e nr oll e d i n  7  d os e- es c al ati o n  c o h orts r e c ei v e d st u d y  dr u g, i n cl u di n g  3, 
6,  6,  6,  7,  6,  a n d  7  p ati e nts i n   C o h orts  1 ( 2 0 0  m g   o n c e  d ail y [ Q  D  ]),  2 ( 3 0 0 m g   Q  D)  , 
3 ( 4 0 0   m g   Q  D),  4 ( 6 0 0   m g   Q  D),  5 ( 9 0 0  m g/ d   Q  D  or   BI  D  ),  6 ( 1 2 0 0 m g/ d   BI  D  ),  a n d 
7 ( 1 0 0 0   m g/ d  BI  D  ).    D os es fr o  m  2 0 0   m g t hr o u g h  9 0 0 m g/ d   w er e  a d  mi nist er e d  as   Q  D, 
w h er e as  1 0 0 0  a n d  1 2 0 0   m g  d os es   w er e  a d  mi nist er e d  as   BI  D.    T h e  1 0 0 0   m g/ d  d os e, 
a d  mi nist er e d  as  a   BI  D r e gi  m e n,   w as s el e ct e d  as t h e   M T  D  a n d   R P 2  D.  
O v er all, r e as o ns f or st u d y  dis c o nti n u ati o n   w er e  dis e as e  pr o gr essi o n ( 2 9 [ 7 0. 7  %]  p ati e nts), 
i n v esti g at or  d e cisi o n ( 5 [ 1 2. 2  %]  p ati e nts),   A E ( 4 [ 9. 8  %]  p ati e nts),  p ati e nt  d e cisi o n 
( 2 [ 4. 9  %]  p ati e nts),  a n d  pr ot o c ol  vi ol ati o n ( 1 [ 2. 4  %]  p ati e nt).  T h e   m aj orit y  of  p ati e nts 
c o  m pl et e d  at l e ast  1  c y cl e  of tr e at  m e nt; r e as o ns f or  dis c o nti n u ati o n  pri or t o  c o  m pl eti o n  of 
C y cl e   1   w er e  dis e as e  pr o gr essi o n ( 1   p ati e nt  e a c h i n   C o h orts  3,  5,  a n d  7), i n v esti g at or 
d e cisi o n ( 1  p ati e nt  e a c h i n   C o h orts  2,  4,  a n d  5),   A E ( 1  p ati e nt  e a c h i n   C o h orts  4,  6,  a n d  7), 
a n d  pr ot o c ol  vi ol ati o n ( 1  p ati e nt i n   C o h ort  5).  
P ati e nts  e nr oll e d i n t h e  d os e- es c al ati o n  p h as e  h a d  1 8  diff er e nt  c at e g ori es  of  pri  m ar y 
t u  m or t y p es  at  b as eli n e,   wit h  pri  m ar y t u  m or t y p es r e p ort e d  b y  >  1 p ati e nt i n cl u di n g r e ct al 
or  c ol or e ct al ( 6   p ati e nts),  c ol o n  a n d l ei o  m y os ar c o  m a ( 4  p ati e nts  e a c h),  br e ast,  o v ari a n, 
pr ost at e,  a n d  u n k n o  w n  pri  m ar y  ori gi n ( 3  p ati e nts  e a c h),  a n d  p a n cr e ati c,  n o n -s  m all  c ell 
l u n g  c a n c er,  b o n e,  a n d  e n d o  m etri al ( 2  p ati e nts  e a c h).    A  hi g h er  pr o p orti o n  of f e  m al e 
p ati e nts ( 6 1. 0  %) t h a n   m al e  p ati e nts ( 3 9. 0  %)  e nr oll e d i n t h e st u d y.   T h e   m aj orit y  of 
p ati e nts   w er e    W hit e ( 9 7. 6  %)  a n d  n ot   His p a ni c  or  L ati n o ( 9 2. 7  %).   T h e   m e a n  a g e  o v er all 
w as  5 8. 3  y e ars   wit h  a r a n g e  of  2 2 t o  7 9   y e ars.     All  p ati e nts  h a d  a n  E ast er n   C o o p er ati v e 
O n c ol o g y   Gr o u p  S c al e  of  P erf or  m a n c e  St at us ( E  C  O  G  P S)   of  0  or  1  at s cr e e ni n g,  as 
r e q uir e d  p er  pr ot o c ol. 
F ort y ( 9 7. 6  %)  p ati e nts  e x p eri e n c e d  ≥   1   A E  d uri n g t h e  d os e-es c al ati o n  p h as e;  1  p ati e nt i n 
C o h ort  5 ( 9 0 0   m g/ d)  di d  n ot  e x p eri e n c e   A Es.   T h e   m ost  c o  m  m o n   A Es ( >  1 0  %  o v er all 
i n ci d e n c e), irr es p e cti v e  of r el ati o ns hi p t o st u d y  dr u g,   w er e  n a us e a ( 4 6. 3  %),  d e cr e as e d 
a p p etit e ( 4 3. 9  %),  a n e  mi a  a n d f ati g u e ( 4 1. 5  %  e a c h),  v o  miti n g ( 3 9. 0  %),  d e h y dr ati o n 
( 2 4. 4  %),  di arr h e a ( 2 2. 0  %),  h air  c ol or  c h a n g es ( 1 9. 5  %),  b a c k  p ai n,  di z zi n ess,  d ys p n e a, 
a n d  p yr e xi a ( 1 7. 1  %  e a c h),  u p p er  a b d o  mi n al  p ai n,  c o nsti p ati o n,  a n d  h e a d a c h e ( 1 4. 6  % 
e a c h),  a n d   A S T i n cr e as e d,  d ys g e usi a,  a n d   m us c ul os k el et al  p ai n ( 1 2. 2  %  e a c h). 
Si x ( 1 4. 6  %)  p ati e nts  e x p eri e n c e d  a t ot al  of  9  d os e- li  miti n g t o xi cit y (D L T  )   A Es, i n cl u di n g 
1  p ati e nt i n   C o h ort  2 ( 3 0 0  m g   Q  D,   [I nt er n ati o n al   N or  m ali z e d   R ati o { I  N  R}  i n cr e as e d  a n d 
h e  m at uri a ]),  2  p ati e nts i n   C o h ort  4 ( 6 0 0 m g   Q  D,   [l y  m p h o c yt e  c o u nt  d e cr e as e d]  a n d 
[h y p o n atr e  mi a ]),  2  p ati e nts i n   C o h ort  6 ( 1 2 0 0   m g/ d   BI  D, [  A S T i n cr e as e d]  a n d [ a n e  mi a, 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 6  of  9 0 
n e utr o p e ni a,  a n d s y n c o p e]),  a n d  1  p ati e nt i n   C o h ort  7 ( 1 0 0 0   m g/ d   BI  D,  [  A S T i n cr e as e d]).  
All  b ut t  w o   of t h e   D L T   A Es   w er e  c o nsi d er e d  p ossi bl y  or  pr o b a bl y r el at e d t o st u d y  dr u g; 
h e  m at uri a  ( 3 0 0 m g   Q  D,   C o h ort  2)  a n d  h y p o n atr e  mi a (  C o h ort  4,  6 0 0   m g   Q  D  )   w er e 
c o nsi d er e d  u nli k el y r el at e d t o st u d y  dr u g.   T h e   D L T  d os e   w as  d et er  mi n e d t o  b e r e a c h e d 
at  1 2 0 0  m g/ d (  C o h ort  6), r es ulti n g i n  a n   M T  D  a n d   R P 2  D  of  1 0 0 0   m g/ d (  C o h ort   7).  
A  m o n g t h e  3 5  p ati e nts i n t h e  d os e-  es c al ati o n  p h as e  of  St u d y  P L  X 1 0 8- 0 1   wit h  e v al u a bl e 
effi c a c y i nf or  m ati o n,  n o  p ati e nt  a c hi e v e d  a  c o  m pl et e r es p o ns e (  C  R),  1 ( 2. 9  %)  p ati e nt 
a c hi e v e d  a  p arti al r es p o ns e ( P  R),  8 ( 2 2. 9  %)  p ati e nts  a c hi e v e d st a bl e  dis e as e  ( S  D),  2 2 
( 6 2. 9  %)  p ati e nts  h a d  pr o gr essi v e  dis e as e,  a n d  4 ( 1 1. 4  %)  p ati e nts   w er e  n ot  e v al u a bl e f or 
t h e  b est t u  m or r es p o ns e.  A  c o nfir  m e d  P  R   w as  a c hi e v e d  b y  o n e  p ati e nt,  a  4 0   y e ar   ol d 
f e  m al e   wit h m u c o e pi d er  m oi d  c ar ci n o  m a    of t h e s ali v ar y  gl a n d i n   C o h ort  7 ( 1 0 0 0   m g/ d, 
M T  D).    St a bl e  dis e as e   w as r e p ort e d i n  1  p ati e nt  e a c h (r a n g e:  1 6. 7  % t o  2 0. 0  %) i n 
C o h ort  2 ( 3 0 0   m g   Q  D),  6 ( 1 2 0 0   m g/ d),  a n d  7 ( 1 0 0 0   m g/ d,   M T  D);  2    p ati e nts ( 4 0. 0  %) i n 
C o h ort  4 ( 6 0 0   m g   Q  D);  a n d  3   p ati e n ts ( 5 0. 0  %) i n   C o h ort  5 ( 9 0 0   m g/ d).   T h e  pr o p orti o n 
of  p ati e nts   wit h  S  D    w as  n ot  d os e r el at e d i n t h e  d os e-es c al ati o n  p h as e  of t h e st u d y.  
I n  e a c h  d os e- es c al ati o n  c o h ort,  p ati e nts r e c ei v e d p e xi d arti ni b   o n t h e   m or ni n g  of C y cl e    1.  
O n   D a y    1 (  C 1  D 1)  a n d  o n   D a y  1 5 (  C 1  D 1 5),  p ati e nts  u n d er  w e nt  p h ar  m a c o ki n eti c (P  K ) 
s a  m pli n g.   F or   Q  D  d osi n g,  P  K s a  m pl es   w er e  c oll e ct e d  pri or t o  d osi n g  a n d  at  0. 5,  1,  2,  4,  8, 
a n d  2 4  h f oll o  wi n g  d osi n g.   F or   BI  D  d osi n g,  P  K s a  m pl es   w er e  o bt ai n e d  pr e d os e i n t h e 
m or ni n g  a n d  1,  2,  4,  7   h  p ost d o s e  o n   C 1  D 1  a n d   C 1  D 1 5.   T h e s e c o n d  d os e   w as t h e n 
a d  mi nist er e d  a n d  a  1 - h  p ost s e c o n d-d os e s a  m pl e ( 8   h  aft er t h e first  d os e)  a n d  a  2 4- h  p ost 
first- d os e s a  m pl e   w as  o bt ai n e d.  I n t h e  e xt e nsi o n  c o h ort,  P  K s a  m pl es   w er e  o bt ai n e d 
pr e d os e  a n d  at  1,  2,  4,  a n d  6  h  p ost d os e  o n t h e   m or ni n g  of   C 1  D 1 5. 
F or t h e  d os e r a n g e  of  2 0 0 t o  1 2 0 0   m g/ d, t h e   m e di a n  T  m a x  o n   D a y  1   w as  2. 0  h  a n d   C  m a x 
v al u es r a n g e d fr o  m  1 3 5 0 t o  5 2 5 0  n g/  m L;  o n   D a y  1 5, t h e   m e di a n  T  m a x   w as  2. 0  h  a n d 
C  m a x  v al u es r a n g e d fr o  m  2 0 3 0 t o  9 2 2 0  n g/  m L.    N ot  o nl y   w as  T  m a x r e a c h e d  q ui c kl y 
aft er  d osi n g,  b ut it   w as  als o r el ati v el y  c o nsist e nt  a cr oss  c o h orts   wit h   m e di a n  v al u es 
r a n gi n g fr o  m  0. 9 7 5 t o  2. 0 3  h.  Si  mil ar t o   C  m a x,   m e a n   A  U  C 0- 2 4 esti  m at es  g e n er all y 
i n cr e as e d   wit h t h e i n cr e asi n g  d os e;   m e a n   A  U  C0- 2 4 esti  m at es r a n g e d fr o  m  2 5 5 5 0  n g• h/  m L 
i n t h e  2 0 0   m g   Q  D  c o h ort t o  1 4 7 0 0 0  n g• h/  m L i n t h e  1 2 0 0 m g/ d   c o h ort. 
A  c o  m p aris o n  of  c o n c e ntr ati o n  v ers us ti  m e  d at a f or i n di vi d u al   p ati e nts  b et  w e e n   D a y   1 
a n d   D a y  1 5 s u g g ests s o  m e  p ot e nti al f or  p e xi d arti ni b  t o  a c c u  m ul at e  aft er 1 5  d a ys  of 
d osi n g.   T h us, t h e   m e a n  P  K   C  m a x  a n d   A  U  C 0- 6 v al u es   w er e  hi g h er f or  D a y    1 5 t h a n f or 
D a y    1.   T h e  a c c u  m ul ati o n r ati o  pr o vi d es  a n  ass ess  m e nt  of  h o  w   m u c h  a  dr u g  a c c u  m ul at es 
d uri n g  a  d osi n g r e gi  m e n  b et  w e e n   w h e n  d osi n g st arts  a n d  at st e a d y st at e.   T h e 
a c c u  m ul ati o n r ati o  f or   m e a n   A  U  C  d uri n g 1  d osi n g i nt er v al f or   D a y  1  c o  m p ar e d  wit h 
D a y    1 5   w as  a p pr o xi  m at el y  2. 
R e d u cti o ns i n t h e   C  D 1 4 +/  C  D 1 6 +  c ell  p o p ul ati o ns  h a v e  als o  b e e n  o bs er v e d i n   m ost 
p ati e nts tr e at e d t o  d at e.   S er u  m   C S F -1 l e v els  h a v e i n cr e as e d i n   m ost  p ati e nts  aft er 
i niti ati o n  of  p e xi d arti ni b  d osi n g,  as   w o ul d  b e  a nti ci p at e d fr o  m  F  ms i n hi biti o n, r es ulti n g i n 
r e d u c e d  cl e ar a n c e  of t h e li g a n d.  I  m p ort a ntl y,  hi g h er  pl as  m a p e xi d arti ni b   c o n c e ntr ati o ns 
ar e  ass o ci at e d   wit h  hi g h er  el e v ati o ns  of   C S F - 1, s u p p orti n g  a  c o n c e ntr ati o n- d e p e n d e nt 
p at h  w a y i n hi biti o n.   Uri n ar y   N  -t el o p e pti d e  c o n c e ntr ati o ns s h o  w e d  a 
c o n c e ntr ati o n - d e p e n d e nt  d e cr e as e fr o  m  b as eli n e,  c o nsist e nt   wit h  ost e o cl ast i n hi biti o n.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 7  of  9 0 
Cli ni c all y r el e v a nt i n cr e as es i n  a di p o n e cti n   w er e  als o  o bs er v e d,   wit h  2- t o  3- f ol d 
i n cr e as es fr o  m b as eli n e  g e n er all y  o bs er v e d i n  p ati e nts tr e at e d  at  d os e l e v els  of  9 0 0  m g/ d 
a n d  hi g h er. 
D os e   E xt e nsi o n  P a rt 
T h e  c o h ort- e xt e nsi o n  p art  of t h e st u d y is  o n g oi n g  a n d fi n al  a n al ysis  of  effi c a c y  d at a  h as 
n ot  b e e n  c o  m pl et e d.   As  of   3 1 J ul  2 0 1 5,  6 6  p ati e nts  h a v e  b e e n  e nr oll e d i nt o t h e  e xt e nsi o n 
c o h orts:  1)   m u c o e pi d er  m oi d  c ar ci n o  m a  of t h e s ali v ar y  gl a n d,  2) t e n os y n o vi al- gi a nt  c ell 
t u  m or (T  G  C T ),  3)   GI S T,  4)  a n a pl asti c t h yr oi d  c ar ci n o  m a,  5) s oli d t u  m ors   wit h 
d o c u  m e nt e d   m ali g n a nt  pl e ur al  or  p erit o n e al  eff usi o ns,  a n d  6)   mis c ell a n e o us t u  m or t y p es.  
T h e  c urr e nt f o c us  of t h e  e xt e nsi o n- c o h ort is t o  e v al u at e  p e xi d arti ni b  i n t h e tr e at  m e nt  of 
T  G  C T .  As  of   3 1  D e c    2 0 1 4,  3 1  p ati e nts  h a v e  b e e n  e nr oll e d i n t h e T  G  C T   c o h ort. 
A n  a n al ysis   w as  p erf or  m e d  usi n g  d at a  as  of  3 1   D e c    2 0 1 4 (d at a  c ut   p erf or  m e d  o n 
2 7  F e b   2 0 1 5) f or  3 1 p ati e nts   wit h  T  G  C T tr e at e d   wit h  p e xi d arti ni b  at  1 0 0 0    m g/ d  gi v e n  as 
a s plit  d os e.    M e di a n  e x p os ur e f or t his  c o h ort   w as  2 5 4  d a ys,  a n d t h e l o n g est tr e at  m e nt 
d ur ati o n   w as  7 4 8  d a ys . 
Of t h e  3 1 i nt e nt-  t o-tr e at (I T T)  p atie nts,  2 9   w er e  e v al u a bl e (i. e.,  h a d  a  b as eli n e  a n d  at l e ast 
o n e  p ost- b as eli n e   M  RI) f or r es p o ns e  b y   R es p o ns e  E v al u ati o n   Crit eri a I n  S oli d  T u  m ors 
(R E  CI S T  )  1. 1  p er l o c al r e a di n g,  a n d  1 4  h a d  a  P  R, f or  a n  o bj e cti v e r es p o ns e r at e (  O  R  R)  of 
4 5  % ( 9 5  %   CI : 2 7 – 6 4  %)  a n d   4 8  % ( 9 5  %   CI: 2 9 – 6 7  %) f or t h e I T T  a n d  e v al u a bl e  p ati e nts, 
r es p e cti v el y.    A n  a d diti o n al  1 3 p ati e nts  h a d  S  D  at t h e ti  m e  of t h e  a n al ysis f or  a  dis e as e 
c o ntr ol r at e (  D  C  R   = P  R  +  S  D)  of  8 7  % ( 9 5  %   CI : 7 0 – 9 6  %)  a n d  9 3  % (  CI : 7 7  – 9 9  %) f or t h e 
I T T  a n d  e v al u a bl e  p ati e nts, r es p e cti v el y. 
A d diti o n al  d et ail e d i nf or  m ati o n r e g ar di n g t h e  cli ni c al  p h ar  m a c ol o g y  a n d t o xi c ol o g y  of 
p e xi d arti ni b  c a n  b e f o u n d i n t h e  I  B. 
1. 5.      St u d y   R ati o n al e 
As t his is t h e first ti  m e  p e xi d arti ni b   will  b e st u di e d i n   a n  Asi a n  c o u ntr y,   t h e 
d os e- es c al ati o n  p art  of t h e st u d y   will  c o nfir  m t h e s af et y  a n d t ol er a bilit y  of  1 0 0 0  m g/ d i n 
s u bj e cts   wit h  a d v a n c e d s oli d t u  m ors.   T h e  d os e  es c al ati o n   will  st art fr o  m  6 0 0 m g/ d    a n d 
will  b e  es c al at e d t o  1 0 0 0     m g/ d  as t h e  hi g h est  d os e l e v el f or  2   we e ks  a n d t h e n r e d u c e d t o 
8 0 0  m g/ d   c o nti n u o usl y. 
S el e cti o n  of t h e  p e xi d arti ni b   d os e  of  1 0 0 0   m g/ d  as t h e  hi g h est  d os e  a n d t h e s plit- d os e 
a d  mi nistr ati o n s c h e d ul e is  b as e d  o n  d at a fr o  m  p ati e nts  wit h s oli d t u  m ors, i n cl u di n g t h e 
c o h ort  of  p ati e nts   wit h  T  G  C T    w h o r e c ei v e d p e xi d arti ni b  i n  St u d y P L  X 1 0 8- 0 1,  a  P h as e  1 
st u d y.  I n t h e  d os e-es c al ati o n  p art   of t h at st u d y,  2 s u bj e cts r e c ei vi n g  1 2 0 0 m g/ d  , 
a d  mi nist er e d  as  a s plit  d os e,  e x p eri e n c e d  D L Ts  of   a n e  mi a,  n e utr o p e ni a,  a n d s y n c o p e i n 
1  p ati e nt  a n d  el e v at e d   A S T i n t h e  ot h er.   F or t his r e as o n,  1 0 0 0  m g/ d   gi v e n  as  a s plit  d os e 
w as s el e ct e d  as t h e   M T  D   a n d t h e   R P 2  D  f or  T  G  C T. 
D at a fr o  m t h e   T  G  C T   c o h ort i n  St u d y  P L  X 1 0 8- 0 1,  a  P h as e  1 st u d y, s u g g ests t h at s o  m e 
p ati e nts  m a y r e q uir e  d os e   m o difi c ati o n.    T h er ef or e, t h e  d os e r e gi  m e n  h as  b e e n  c h a n g e d  t o 
1 0 0 0  m g/ d  as   t h e i niti al  d os e, f oll o  w e d  b y  8 0 0 m g/ d  aft er  2   w e e ks.   
F or  d et ail e d i nf or  m ati o n r e g ar di n g t h e  St u d y  P L  X 1 0 8- 0 1 st u d y, r ef er t o t h e I  B. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 8  of  9 0 
T his st u d y   will  e v al u at e t h e s af et y, t ol er a bilit y,  a n d  P  K  pr ofil e i n   Asi a n  s u bj e cts wit h 
a d v a n c e d s oli d t u  m ors. 
E xt e nsi o n  p art  of  t h e st u d y   will  all o  w s u bj e cts   w h o r e c ei v e d  p e xi d arti ni b  as  p art  of  a 
cli ni c al  st u d y t o  c o nti n u e tr e at  m e nt.  T h e  b e n efits  of tr a nsiti o ni n g s u bj e cts  i nt o  e xt e nsi o n 
p art  ar e t o:  
•     R e d u c e  c o  m pl e xit y  of  F  oll o  w - u p,  all o  wi n g s u bj e cts t o  c o nti n u e r e c ei vi n g t h e 
st u d y  dr u g  a n d fa cilit at e t h eir  p arti ci p ati o n.  
•     C o nti n u e t o   m o nit or  a n d  c oll e ct l o n g-  t er  m s af et y  d at a.  
1. 6.      Ris ks  a n d   B e n efits f o r  St u d y  S u bj e cts   
T h e s af et y  of  p e xi d arti ni b  h as  b e e n  e v al u at e d i n s u bj e ct s   wit h  a r a n g e  of t u  m or t y p es, 
i n cl u di n g s oli d t u  m ors,  h e  m at ol o gi c   m ali g n a n c y,  a n d i n  c o  m bi n ati o n   wit h 
c h e  m ot h er a p e uti c  a g e nts.   T h e s el e cti o n  of  1 0 0 0   m g/ d  as t h e i niti al  d os e t o  b e  e v al u at e d 
i n t h e s e v er al st u di es w as  b as e d  u p o n t h e s af et y  d at a fr o  m  St u d y  P L  X 1 0 8- 0 1  a n d t h e 
s af et y  of  1 0 0 0 m g/ d   w as f urt h er  e v al u at e d   i n s e v er al  cli ni c al st u di es . 
I n t h e   G o o d  L a b or at or y  Pr a cti c e (  G L P) r e p e at- d os e t o xi c ol o g y st u di es  c o nsisti n g  of  u p t o 
1 3  w e e ks  of  p e xi d arti ni b  d osi n g, t est  arti cl e  -r el at e d   A Es   w er e  n ot e d i n t est es 
(t esti c ul ar-s p er  m at o g o ni a r e d u cti o n),  o v ari es ( o v ari a n f olli c ul ar  d e g e n er ati o n), li v er,  b o n e 
a n d  b o n e   m arr o  w,  h e  m at ol o g y,  a n d l y  m p h oi d  c h a n g es; t h es e  c h a n g es  ar e  c o nsist e nt   wit h 
t h e  p h ar  m a c ol o gi c al   m e c h a nis  m  of  a cti o n  of p e xi d arti ni b.    All t est  arti cl e -r el at e d fi n di n gs 
w er e  p arti all y  or f ull y r e v ersi bl e.   P ot e nti  al  d os e-r el at e d  c h a n g es i n  b o n e   m arr o  w f u n cti o n 
c a n  b e   m o nit or e d  b y  p eri p h er al  bl o o d  c ell  c o u nt  a n d  diff er e nti al  c o u nts.    B e c a us e  of t h e 
eff e cts  o n r e pr o d u cti v e  or g a ns, s u bj e cts   will  b e   m o nit or e d f or  c h a n g es i n l ut ei ni zi n g 
h or  m o n e ( L  H), f olli cl e- sti  m ul ati ng  h or  m o n e ( F S  H),  a n d  ot h er s e x- s p e cifi c  h or  m o n e 
l e v els. 
Eff e cts  o n  e  m br y o f et al  d e v el o p  m e nt  h a v e  b e e n  o bs er v e d i n  b ot h r at  a n d r a b bit 
t o xi c ol o g y st u di es.   S u bj e cts i n t h e st u d y   will  b e r e q uir e d t o  us e  a d e q u at e  birt h  c o ntr ol 
d uri n g t h e st u d y  a n d f or  9 0  d a ys  aft er t h e l ast  d os e  of st u d y  dr u g  a d  mi nist er e d.  
Fi n di n gs i n t h e  n o n cli ni c al  c a ni n e s af et y  p h ar  m a c ol o g y st u d y s u g g est t h at  p e xi d arti ni b  
m a y  h a v e  a  n e g ati v e i n otr o pi c  eff e ct.   S u bj e cts   will  b e   m o nit or e d f or  c h a n g es i n  ej e cti o n 
fr a cti o n   wit h  c ar di a c  e c h o c ar di o gr a  ms ( E  C  H  Os). 
I n t h e cli ni c al   e v al u ati o n t o  d at e,  a  m o n g s oli d t u  m or  p ati e nts, t h e   m ost  c o  m  m o n  a d v ers e 
e v e nts (  A Es) (o c c urri n g i n  ≥   20  %  of  all  p ati e nts tr e at e d   wit h  p e xi d arti ni b ) o bs er v e d  h a v e 
b e e n f ati g u e,  n a us e a,  d e cr e as e d  a p p etit e,  h air  c ol or  c h a n g e ( d e pi g  m e nt ati o n) ,  v o  miti n g, 
di arr h e a , h e a d a c h e ,  a n d a n e  mi a.   I n t h e   A  M L st u d y, t h e   m ost  c o  m  m o n   A Es r e p ort e d  h a v e 
b e e n  di arr h e a,  n a us e a, f ati g u e, f e bril e  n e utr o p e ni a,  v o  miti n g,  d e cr e as e d  a p p etit e,  a n e  mi a, 
c o u g h,  h y p o k al e  mi a,  a n d i n cr e as es i n   A S T.   I n s o  m e i nst a n c es, t h e i n cr e as e i n li v er 
e n z y  m es   m a y r e q uir e  d os e  h ol d  or   m o difi c ati o n.    D osi n g   m o difi c ati o n  g ui d a n c e is 
i n cl u d e d   wit hi n t h e  pr ot o c ol f or   A E   m o nit ori n g (T a bl e   5. 2).   Li v er f u n cti o n ( cli ni c al 
c h e  mistr y), r e n al f u n cti o n ( cli ni c al  c h e  mistr y),  a n d  h e art  el e ctr o p h ysi ol o g y (  Q T i nt er v al 
c orr e ct e d f or  h e art r at e [  Q T c]  e v al u ati o n)   will   b e   m o nit or e d  d uri n g t his st u d y. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  2 9  of  9 0 
B as e d  o n t h e tr e at  m e nt  -e  m er g e nt  a d v ers e  e v e nt ( T E  A E ) r e p orts  of i n cr e as e d I  N  R 
o bs er v e d i n  p ati e nts r e c ei vi n g  c o n c o  mit a nt   w arf ari n,  c ar ef ul   m o nit ori n g is r e q uir e d 
d uri n g tr e at  m e nt   wit h  p e xi d arti ni b .     Warf ari n  d os es s h o ul d  b e  a dj ust e d if  a n i n cr e as e i n 
I  N  R is  n ot e d. 
P e xi d arti ni b is  a  n o v el,  or all y  a cti v e, s  m all   m ol e c ul e i n hi bit or t h at t ar g ets   C S F 1  R,   Kit, 
a n d  o n c o g e ni c  Flt 3,  b ut r e  m ai ns  hi g hl y s el e cti v e  v ers us  ot h er  ki n as es.   T h e  p ot e nt 
i n hi biti o n  of t h es e  3 ki n as es  c a n  b e  e x pl oit e d t o  att a c k t u  m ors  vi a   m ulti pl e   m e c h a nis  ms.  
P e xi d arti ni b  h as s h o  w n  a p ot e nt i n hi bit or  of t h e  pr olif er ati o n  of  t h es e t ar g et- d e p e n d e nt 
m o d els. 
I n s u  m  m ar y,  gi v e n t h e  a c c e pt a bl e s af et y  pr ofil e  of t h e p e xi d arti ni b  at t h e s el e ct e d  d os e 
l e v els,  a n d  n o n cli ni cal  d at a  a n d  P h as e  1  d at a i n  p ati e nts   wit h  T  G  C T , t h e  p ot e nti al f or  a 
p ositi v e  b e n efit/ris k  pr ofil e is  ass u  m e d i n t h e  P h as e  1 st u d y. 
1. 6. 1.      
U p d at e d   Ris k I nf o r  m ati o n 
D uri n g t h e  c o n d u ct  of t his st u d y, i  m p ort a nt s af et y i nf or  m ati o n r e c ei v e d fr o  m  o n e  o n g oi n g 
D aii c hi  S a n  k y o  p h as e III  p e xi d arti ni b st u d y ( E  N LI  V E  N)  o n i n di c ati o n  of  P  V  N S   or  gi a nt 
c ell t u  m or  of t h e t e n d o n s h e at h   wit h  d ail y  d os e  of  1 0 0 0  m g/ d a y f or t h e first t  w o   w e e ks 
t h e n  8 0 0   m g/ d a y.  I n t h e  o n g oi n g  E  N LI  V E  N st u d y, t  w o  S eri o us   A d v ers e  E v e nts ( S  A Es) 
of  h y p er bilir u bi n e  mi a  c o n c urr e nt   wit h tr a ns a  mi n as e i n cr e as e   w er e i d e ntifi e d r e c e ntl y.   
T h er e   w er e  a n  esti  m at e d  8 0  p ati e nts   w h o  h a d  b e e n  e x p os e d t o  p e xi d arti ni b i n  E  N LI  V E  N 
st u d y.  T h e i niti al  c as e,  a  7 5  y e ar  ol d   w o  m a n   wit h f e  w ris k f a ct ors,  e x p eri e n c e d 
h y p er bilir u bi n e  mi a f or  2. 5   m o nt hs ( o n g oi n g), r e q uiri n g st u d y  dr u g   dis c o nti n u ati o n, 
h os pit ali z ati o n  a n d t  w o li v er  di al ysis  pr o c e d ur es.    A li v er  bi o ps y s h o  w e d  c h ol est asis  a n d 
d u ct o p e ni a.   T h e s e c o n d  c as e,  a  5 2  y e ar  ol d   m al e   wit h f e  w ris k f a ct ors,  h a d  gr a d e  4 li v er 
e n z y  m e i n c r e as e  c o n c urr e nt   wit h  h y p er bilir u bi n e  mi a,   w hi c h r es ol v e d  o n st u d y dr u g  
dis c o nti n u ati o n   wit h o ut f urt h er   m e as ur es.   B ot h  c as es   w er e  n ot r e  -c h all e n g e d   wit h t h e 
st u d y dr u g . 
Fi v e  c as es  of t his  p att er n  of li v er  d ysf u n cti o n  h a v e  b e e n  o bs er v e d i n  ot h er  p e xi d arti ni b 
tri als,  b ot h i n   m o n ot h er a p y  a n d  c o  m bi n ati o n t h er a p y. I n t ot al t h er e  ar e  n o  w  7 
c h ol est ati c/  mi x e d t y p e  of li v er  d ysf u n cti o n  c as es r e p ort e d  a  m o n g  a p pr o xi  m at el y  5 5 0 
s u bj e cts.    A  m o n g t h e fi v e  c as es i n cl u di n g  o n e  c as e fr o  m i n t his  P L 3 3 9 7-  A-  A 1 0 3 st u d y, 
pr ol o n g e d  h y p er bilir u bi n e  mi a ( >  8   m o nt hs,  o n g oi n g)  o c c urr e d i n  o n e  c as e  a n d t  w o  ot h er 
c as es t o o k  2 - 3   m o nt hs t o r es ol v e.    All  c as es  o c c urr e d  b et  w e e n  1 4  a n d  5 7  d a ys  of t h e st art 
of  p e xi d arti ni b tr e at  m e nt, s u g g esti n g  a  hi g h er ris k   wit hi n t h e first  8   w e e ks  of tr e at  m e n t.  
T hr e e  of t h e  7  c as es  h a d li v er  bi o ps y s h o  wi n g  c h ol est asis  a n d  d u ct o p e ni a.  
I n r es p o ns e t o t h e  u p d at e d s af et y i nf or  m ati o n, t h e st u d y s af et y   m o nit ori n g  c o  m  mitt e e 
( S  M  C)   m e eti n g   w as  h el d t o r e vi e  w r el e v a nt  d at a  of t his st u d y.   T h e  S  M  C r e c o  m  m e n d e d 
s af et y   m eas ur es t h at  c h a n g e d t h e  c o n d u ct  of t his st u d y t o  e n h a n c e t h e  pr ot e cti o n  of 
s u bj e cts.   T h e f oll o  wi n g  a cti o ns  h a v e  b e e n  pr o vi d e d i n st u d y   m e  m os iss u e d  o n 
0 7  O ct    2 0 1 6  a n d  1 4 O ct    2 0 1 6: 
-     E nr oll  m e nt  of  a n y  n e  w  n o n- m ali g n a nt t u  m or i n cl u di n g  T  G  C T  p ati e nts   w as 
st o p p e d.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 0  of  9 0 
-     F or  n o n-  m ali g n a nt t u  m or i n cl u di n g  T  G  C T  p ati e nts i n s cr e e ni n g, t h e s cr e e ni n g 
s h o ul d  b e st o p p e d  a n d  dis c uss   wit h  p ati e nts  a b o ut  alt er n ati v e tr e at  m e nt  of t h eir 
dis e as e.  
-     F or  all  p ati e nts   wit h  o n g oi n g  p e xi d arti ni b tr e at  m e nt, t h e  p ati e nt  of t h e  n e  w s af et y 
fi n di n gs s h o ul d  b e i nf or  m e d  at t h eir  n e xt  visit/ c o nt a ct.  Aft er t h e  c o ns ult ati o n, if it 
is  d e e  m e d t o  b e i n t h eir  b est i nt er est t o  c o nti n u e tr e at  m e nt, t h e  p ati e nt s h o ul d  b e 
r e- c o ns e nt e d.    If  t h e   u p d at e d  i nf or  m e d   c o ns e nt  f or  m  (I C F)  is   n ot   a v ail a bl e,  
d o c u  m e nt   t his  dis c ussi o n i n t h e  p ati e nt’s r e c or d   a n d  c oll e ct  t h e si g n e d  u p d at e d 
I  C F w h e n  a v ail a bl e.   
-     E nr ol  m e nt  of  p ati e nts   wit h   m ali g n a nt t u  m or is  all o  w e d.   T h e   e nr ol  m e nt  b as e d  o n 
st u d y i n cl usi o n/ e x cl usi o n  crit eri a   w o ul d  b e  c o nti n u e d  a n d t h e  p ati e nt  of t h e  n e  w 
s af et y fi n di n gs s h o ul d  b e i nf or  m e d.  If t h e  u p d at e d I C F is  n ot  a v ail a bl e,  d o c u  m e nt 
t his  dis c ussi o n i n t h e  p ati e nt’s r e c or d  a n d  c oll e ct t h e si g n e d  u p d at e d I  C F w h e n 
a v ail a bl e.  
-     As t h e  c as es  of s e v er e  c h ol est ati c li v er  d ysf u n cti o n   w er e  o bs er v e d i n  c y cl es  1  a n d 
2  of t h e st u d y  dr u g ,  S p o ns or r e q u est f oll o  wi n g   m e as ur es t o  b e t a k e n i  m  m e di at el y 
t o   m a k e s ur e  p ati e nt s af et y is   w ell-  m o nit or e d. 
o    I n cl u d e   G a  m  m a  gl ut a  m yl tr a nsf er as e (  G  G T) t est i n li v er f u n cti o n t est 
p a n el ( T a bl e  9. 1  of t h e  pr ot o c ol) 
o    I n cr e as e li v er f u n cti o n t est fre q u e n c y t o   w e e kl y fr o  m   C y cl e  1   D a y  1 t o 
C y cl e  3   D a y  1 5  a n d t h e n  bi  w e e kl y  u ntil   C y cl e  5   D a y  1 
 
U p d at e d  h e p ati c s af et y ris k i nf or  m ati o n  as  of   D e c e  m b er  2 0 1 7;  pl e as e  c o ns ult t h e I  B f or 
m or e i nf or  m ati o n:    H  e p at ot o xi cit y is  a n i  m p ort a nt  a d v ers e  dr u g r e a cti o n.  El e v ati o ns  of 
li v er tr a ns a  mi n as es  a n d bilir u bi n   h a v e  b e e n  o bs er v e d i n st u di es   wit h  p e xi d arti ni b, 
t o g et h er   wit h  c ases  of  dr u g i n d u c e d  c h ol est asis.  C as es  of  c h ol est asis  h a v e  b e e n  o bs er v e d 
i n t h e first  8   w e e ks,  h a v e  g e n er all y r es ol v e d   wit h tr e at  m e nt  dis c o nti n u ati o n,  b ut i n s o  m e 
c as es  h a v e  b e e n s e v er e,   wit h  a  pr otr a ct e d  c o urs e r e q uiri n g li v er  di al ysis  a n d, i n  1  c as e, 
tr a ns pl a nt ati o n. H e p at ot o xi cit y   m a y  b e f at al.   O n e f at al  c as e   wit h  o n g oi n g  c h ol est ati c li v er 
i nj ur y  at t h e ti  m e  of  d e ath  h as  b e e n r e p ort e d.   M o nit or  p ati e nts  cl os el y  as  d efi n e d i n t h e 
pr ot o c ol.  Pr ot o c ol  d efi n e d  d os e r e d u cti o ns  a n d  dis c o nti n u ati o ns  of  p e xi d arti ni b, i n cr e as e d 
fr e q u e n c y  of l a b or at or y   m o nit ori n g,  a n d r e p orti n g  of fi n di n gs s h o ul d  b e f oll o  w e d (r ef er t o 
S e cti o n  5. 7 ). I n  a d diti o n, r e c h all e n g e   wit h  p e xi d arti ni b s h o ul d  n ot  b e  att e  m pt e d   wit h o ut 
pri or  dis c ussi o n   wit h t h e  S p o ns or’s   M e di c al   M o nit or. 
 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 1  of  9 0 
2.      
S  T  U  D  Y   O  B J  E  C  TI  V  E S   A  N  D  H  Y P  O  T  H  E SI S   
2. 1.      St u d y   O bj e cti v es  
2. 1. 1.      
P ri  m a r y   O bj e cti v es  
•     T o  ass ess t h e s af et y  a n d t ol er a bilit y  of  p e xi d arti ni b i n   Asi a n s u bj e cts   wit h 
a d v a n c e d s oli d t u  m ors 
•     T o  d et er  mi n e t h e  R P 2  D  of  p e xi d arti ni b   i n   Asi a n s u bj e cts   wit h a d v a n c e d  s oli d 
t u  m ors 
2. 1. 2.      
S e c o n d a r y   O bj e cti v es  
•     T o  ass ess t h e  P  K  pr ofil e  of  p e xi d arti ni b  a n d its   m et a b olit e  
•     T o  ass ess  t h e  P  D  eff e ct  of  p e xi d arti ni b  o n   C S F- 1  a n d  a di p o n e cti n l e v el i n  pl as  m a 
•     T o  e v al u at e t h e  pr eli  mi n ar y  effi c a c y  of  p e xi d arti ni b  
•     T o  e v al u at e  O  R  R   r at e (t h e s u  m  of   C  R r at e  a n d  P  R r at e) 
•     T o  e v al u at e   D  C  R (t h e s u  m  of   C  R r at e,  P  R r at e,  a n d  S  D r at e)   
•     T o  e v al u at e r es p o ns e  d ur ati o n 
•     T o  e v al u at e  d ur ati o n  of  S  D 
•     T o  e v al u at e ti  m e t o r es p o ns e ( T T  R)  
•     T o  e v al u at e  p er c e nt a g e  of  c h a n g e i n t ar g et l esi o n(s)  
2. 1. 3.      
E x pl o r at o r y   O bj e cti v es   
•     T o  e x pl or e t h e  eff e ct  of   U  G T 1  A 4  g e n ot y p e  o n  p e xi d arti ni b  P  K 
•     T o  e x pl or e  a n y  p ossi bl e  c orr el ati o n  of  g e n o  mi cs t o  p e xi d arti ni b s af et y  
2. 2.      St u d y   H y p ot h esis  
P e xi d arti ni b  will  b e s af e  a n d   w ell  -t ol er at e d  a n d  e x hi bits a c c e pt a bl e  P  K  pr o p erti es i n 
As  i a n s u bj e cts   wit h  a d v a n c e d s oli d t u  m ors.  S u bj e cts    w h o  h a v e  n ot  pr o gr ess e d   w hil e 
r e c ei vi n g p e xi d arti ni b  will  c o nti n u e t o   t ol er at e  a n d t o b e n efit fr o  m  l o n g er  a d  mi nistr ati o n 
of t h e st u d y  dr u g i n t h e  e xt e nsi o n  p art .  S e e  S e cti o n   1 1. 6 f or s a  m pl e si z e  d et er  mi n ati o n. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 2  of  9 0 
3.      
S  T  U  D  Y   D  E SI  G  N  
3. 1.      O v e r  a ll   D esi g n 
T his is  a  P h as e   1,  n o n-r a n d o  mi z e d,  o p e n-l a b el, m ulti pl e  - d os e st u d y  of p e xi d arti ni b  i n 
Asi a n s u bj e cts   wit h   a d v a n c e d s oli d t u  m ors.   T h e st u d y   will  b e  c o n d u ct e d i n  a 
d os e- es c al ati o n   3 + 3  d esi g n.   T his st u d y  c o  m pris es  2 d os e l e v els  (  C o h ort  1  a n d   C o h ort 2) 
t o  ass ess t h e s af et y  a n d t ol er a bilit y, R P 2  D,  P  K  a n d  P  D,  a n d  pr eli  mi n ar y  a nt  it u  m or 
a cti vit y  of  p e xi d arti ni b.  
•     C o h ort  1:  6 0 0   m g/ d ( 2 0 0   m g i n t h e   m or ni n g,  4 0 0   m g i n t h e  e v e ni n g) 
•     C o h ort  2:  1 0 0 0   m g/ d   ( 4 0 0   m g i n t h e   m or ni n g  a n d  6 0 0   m g i n t h e  e v e ni n g) f or t h e 
first  2 w e e ks  .  T h er e aft er, t h e   d os e   will b e r e d u c e d t o  8 0 0  m g/ d   ( 4 0 0   m g i n t h e 
m or ni n g  a n d  4 0 0   m g i n t h e  e v e ni n g). 
F or  t h e  d et ail e d  d os e l e v el  es c al ati o n   m et h o d  a n d t h e d efi niti o n  of   D L T, r ef er t o 
S e cti o n   5. 6 a n d   Fi g ur e  3. 1.   D os e r e d u cti o ns  a n d i nterr u pti o ns f or t o xi cit y   will  b e 
p er  mitt e d  a c c or di n g t o  pr e -s p e cifi e d  g ui d eli n es ( S e cti o n   5. 7). 
Fi g u r e  3. 1:     
St u d y  S c h e  m ati c  
 
D L T   =  d os e -li  miti n g t o xi cit y; M T  D   =  m  a x i  mu  m  t ol er at e d d os e ;  S  M  C  =  S af et y   M o nit ori n g   C o  m  mitt e e. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 3  of  9 0 
P e xi d arti ni b   will  b e  a d  mi nist er e d  or all y i n  c a ps ul e f or  m.   P e xi d arti ni b  will  b e s u p pli e d i n 
2 0 0   m g  c a ps ul es  a n d   will  b e t a k e n   BI  D  a p pr o xi  m at el y  1 2  h  a p art  i n t h e   m or ni n g  a n d 
e v e ni n g .  D os es   will  b e t a k e n i n t h e f asti n g st at e (  n o f o o d f or  1  h  b ef or e  a n d  2  h  aft er 
d osi n g,   wit h  a l o  w- f at s n a c k if  n e e d e d).  E a c h  c y cl e  of tr e at  m e nt   will  b e  2 8  d a ys  i n 
d ur ati o n.   S u bj e cts   will  c o nti n u e st u d y  visit i n  d os e  es c al ati o n  p art  till t h e c ut -off  d at e 
(T h e  c ut -off  is d efi n e d  as  t h e  d at e aft er  all s u bj e cts  h a v e  eit h er  dis c o nti n u e d t h e st u d y  or 
c o  m pl et e d  at l e ast  4  c y cl es .   S u bj e cts   w h o  ar e still  o n g oi n g i n t h e st u d y  aft er t h e  c ut-off 
d at e  a n d  w h o  ar e   r es p o n di n g  or st a bl e  aft er  p e xi d arti ni b  d uri n g t h e d os e  es c al ati o n  p ar t 
will   e nt er  e xt e nsi o n  p art  t o r e c ei v e  e xt e n d e d tr e at  m e nt  of  p e xi d arti ni b.  T h e  c y cl e  of 
tr e at  m e nt   will b e  c o nti n u e d  u ntil  dis e as e  pr o gr essi o n,  u n a c c e pt a bl e t o xi cit y,  or  c o ns e nt 
wit h dr a  w al  . 
3. 2.      Dis c ussi o n  of  St u d y   D esi g n   
T his st u d y   will  e v al u at e t h e s af et y, t ol er a bilit y,  a n d  P  K  pr ofil e i n   Asi a n s u bj e cts   wit h 
a d v a n c e d s oli d t u  m ors  as  c urr e ntl y  n ot   m u c h s af et y  d at a  ar e  a v ail a bl e i n t h es e s u bj e cts.   
P e xi d arti ni b  c a ps ul es ( 2 0 0  m g str e n gt h)   will  b e  a d  mi nist er e d.   
T h e  d os e- es c al ati o n  pl a n  is s el e ct e d  o n t h e  b asis  of  d at a fr o  m  St u d y  P L  X 1 0 8- 0 1,  a  U S 
P h as e   1,  o p e n-l a b el,  2- p art st u d y  of si n gl e  a g e nt p e xi d arti ni b  i n s u bj e cts   wit h  a d v a n c e d, 
i n c ur a bl e, s oli d t u  m ors ( P art  1)  a n d i n s u bj e cts   wit h s el e ct e d t u  m ors ( P art 2).   T h e i niti al 
d os e- es c al ati o n  p art  of t h e  st u d y ( P art  1) st u di e d t ot al  d ail y  or al  d os es fr o  m  2 0 0 m g 
t hr o u g h  1 2 0 0 m g.     T  w o s u bj e cts r e c ei vi n g  1 2 0 0   m g/ d,  a d  mi nist er e d  as  a s plit  d os e, 
e x p eri e n c e d   D L T t o xi citi es:   a n e  mi a,  n e utr o p e ni a,  a n d s y n c o p e i n  1 s u bj e ct  a n d  el e v at e d 
A S T i n t h e  ot h er.    O n e  of  7   s u bj e cts r e c ei vi n g  1 0 0 0   m g/ d,  a d  mi nist er e d  as  a s plit  d os e, 
e x p eri e n c e d  a   D L T  of   A S T i n cr e as e d.    T h us,  a   R P 2  D  of  1 0 0 0 m g/ d  as  a s plit  d os e   w as 
a d  mi nist er e d i n t h e  e xt e nsi o n  c o h orts ( P art  2)  of t his si n gl e  a g e nt st u d y.   A n i nt eri  m 
a n al ysis fr o  m t h e  e xt e nsi o n  c o h ort   wit h t h e l o n g est  d ur ati o n  of tr e at  m e nt (  m e di a n 
d ur ati o n  of  2 1 9  d a ys,  n  =  1 7  s u bj e cts) s h o  w e d t h at  a p pr o xi  m at el y  h alf  of t h e s u bj e cts 
r e q uir e d  a  d os e r e d u cti o n t o  at l e ast  8 0 0 m g/ d  as  a s plit  d os e   wit hi n t h e first   2  c y cl es.   
Bi o  m ar k er  d at a  h as s u g g est e d t h at  d os e  s  at  or  b el o  w 4 0 0  m g/ d  ar e l ess li k el y t o  h a v e   P  D  
a cti vit y.    T h us, i n  c o nsi d er ati o n  of  d at a fr o  m si n gl e  a g e nt p e xi d arti ni b ,  6 0 0 m g/ d  as  a 
s plit  d os e is s el e ct e d  as t h e i niti al  d os e   wit h  a n  all o  w a n c e f or  d e - es c al ati o n t o  4 0 0 m g/ d 
as  a s plit  d os e.  
3. 3.      D u r ati o n  o  f t h e  St u d y 
T h e s t u d y d ur ati o n  is  e x p e ct e d t o l ast  a p pr o xi  m at el y 4  y e ars fr o  m t h e ti  m e t h e first  
s u bj e ct is  e nr oll e d u ntil t h e l ast s u bj e ct is  off t h e st u d y  (i n cl u di n g  F oll o  w-u p  visit) . 
3. 4.      D u r ati o n  of  S u bj e ct  P a rti ci p ati o n   
T h e  n u  m b er  of tr e at  m e nt  c y cl es is  n o t fi x e d i n t his st u d y.   S u bj e cts   w h o  d eri v e cli ni c al 
b e n efit fr o  m tr e at  m e nt i n  t h e a bs e n c e  of  s u bj e ct’s  c o ns e nt  wit h dr a  w al,   dis e as e 
pr o gr essi o n,  or  u n a c c e pt a bl e t o xi cit y   m a y  c o nti n u e  a n ot h er  c y cl e  of tr e at  m e nt  at t h e 
i n v esti g at or’s dis cr eti o n . 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 4  of  9 0 
4.      
S  T  U  D  Y  P  O P  U  L  A TI  O  N   
S u bj e cts   m ust si g n  a n d  d at e t h e  I  C F  pr o vi d e d  b y t h e st u d y sit e  b ef or e  a n y st u d y-s p e cifi c 
q u alifi c ati o n  pr o c e d ur es  ar e  c o n d u ct e d. 
4. 1.      I n cl usi o n   C rit e ri a  
S u bj e cts   m ust s atisf y  all  of t h e f oll o  wi n g  crit eri a t o  b e i n cl u d e d i n t h e st u d y:  
1.    A g  e s h o ul d  b e  ≥   2 0 y e a rs. 
2.    S u bj e cts  m ust  h a v e  a  p  at h ol o gi c all y  d o c u  m e nt e d s oli d t u  m or t h at  h as r el a ps e d fr o  m, 
or is r efr a ct or y t o st a n d ar d tr e at  m e nt,  or f or   w hi c h  n o st a n d ar d tr e at  m e nt is  a v ail a bl e. 
3.    W o  m e n  of  c hil d b e ari n g  p ot e nti al   m ust  h a v e  a  n e g ati v e s er u  m  pr e g n a n c y t est   wit hi n 
t h e  1 4- d a y  p eri o d  pri or t o tr e at  m e nt  all o c ati o n. 
4.    M e n  a n d   w o  m e n   of  c hil d b e ari n g  p ot e nti al  ar e  p er  mitt e d i n t h e st u d y  as  l o n g  as t h e y 
c o ns e nt t o  a v oi d  g etti n g t h eir  p art n er  pr e g n a nt  or  b e c o  mi n g  pr e g n a nt  t h e  ms el v es, 
r es p e cti v el y,  b y  usi n g  a  hi g hl y  eff e cti v e c o ntr a c e pti o n   m et h o d,  as  d es cri b e d  b el o  w, 
t hr o u g h o ut t h e st u d y  a n d f or  u p t o  9 0 d a ys  aft er  c o  m pl eti o n.    Hi g hl y  eff e cti v e 
m et h o ds  of  c o ntr a c e pti o n i n cl u d e:  h or  m o n al   m et h o ds  ass o ci at e d   wit h i n hi biti o n  of 
o v ul ati o n, i ntr a- ut eri n e  d e vi c e , s ur gi c al st erili z ati on (i n cl u di n g  p art n er’s  v as e ct o  m y) , 
or s e x u al  a bsti n e n c e.  
5.    W o  m e n  of  n o n- c hil d b e ari n g  p ot e nti al   m a y  b e i n cl u d e d if t h e y    ar e  eit h er s ur gi c all y 
st eril e  or  h a v e  b e e n  p ost  m e n o p a us al f or  ≥  1  y e ar.      W o  m e n   w h o  h a v e  d o c u  m e nt ati o n 
of  at l e ast  1 2    m o nt hs  of s p o nt a n e o us  a  m e n orr h e a  a n d  h a v e  a n  F S  H l e v el 
>  4 0   mI  U/  m L   will  b e  c o nsi d er e d  p ost  m e n o p a us al. 
6.    All  ass o ci at e d t o xi cit  i es fr o  m  pr e vi ous  c a n c er t h er a p y   m ust  h a v e  b e e n r es ol v e d (t o 
≤  Gr a d e   1  or  b as eli n e)  pri or t o  a d  mi nist r ati o n  of  p e xi d arti ni b. 
7.    E  C  O  G  P S  of  0  or  1. 
8.    Lif e  e x p e ct a n c y  ≥   3   m o nt hs, i n t h e  o pi ni o n  of t h e i n v esti g at or. 
9.    A d e q u at e  h e  m at ol o gi c,  h e p ati c,  a n d r e n al f u n cti o n  d efi n e d  b y: 
•     A  bs ol ut e  n e utr o p hil  c o u nt  ≥   1. 5  ×  1 09/ L 
•     Pl at el et  c o u nt  ≥   1 0 0  ×  1 09/ L 
•     A L  T  or  A S  T  ≤   1. 5  × u p p er li  mit  of  n or  m al (  U L  N)  (if li v er   m et ast as es  ar e  pr es e nt 
or s u bj e cts   wit h  h e p at o c ell ul ar  c ar ci n o  m a,  ≤   3  × U L  N)   
•     Al b u  mi n  ≥    3 g/ d L  
•     T ot al  bilir u bi n  ≤   1. 5  ×   U L  N 
•     H e  m o gl o bi n  >  9   g/ d L  
•     S er u  m  cr e ati ni n e  ≤   1. 5  ×   U L  N or  c al c ul at e d  cr e ati ni n e  cl e ar a n c e  >  6 0  m L/  mi n 
usi n g  t h e C o c k cr oft-  G a ult f or  m ul a   
1 0.  A d e q u at e tr e at  m e nt   w as h o ut  p eri o d  b ef or e r e gistr ati o n  d efi n e d  as: 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 5  of  9 0 
•     M aj or s ur g er y:   ≥  4   w e e ks ( 2   w e e ks f or l ess i n v asi v e s ur g er y, s u c h  as   c ol ost o  m y) 
•     R a di ati o n t h er a p y   ( eg,   w h ol e  br ai n r a di ot h er a p y):  ≥   4 w e e ks (if  p alli ati v e 
st er e ot a cti c r a di ati o n t h er a p y,  ≥   2 w e e ks)   
•     C h e  m ot h er a p y  or i  m  m u n ot h er a p y (i n cl u di n g t ar g et e d t h er a p y   wit h  a nti b o d y  or 
s  m all   m ol e c ul e, r eti n oi d t h er a p y,  a n d  h or  m o n al t h er a p y):  4   w e e ks  or  5  h alf -li v es 
of t h e  a g e nt,   w hi c h e v er is s h ort er (if t h e r e gi  m e n  h as  c o nt ai n e d  nitr os o ur e as  or 
mit o  m y ci n   C,  ≥   6  w e e ks)   
•     Ot h er i n v esti g ati o n al   dr u g t h er a p y :  ≥  4 w e e ks   
1 1.  Willi n g n ess  a n d  a bilit y t o  pr o vi d e   writt e n i nf or  m e d  c o ns e nt  pri or t o  a n y st u   d y -r el at e d 
pr o c e d ur es  a n d t o  c o  m pl y   wit h  all st u d y r e q uir e  m e nts. 
4. 2.      E x cl usi o n   C rit e ri a   
S u bj e cts   w h o   m e et  a n y  of t h e f oll o  wi n g  crit eri a   will  b e  dis q u alifi e d fr o  m  e nt eri n g  t h e 
st u d y:  
1.    R efr a ct or y  n a us e a  a n d  v o  miti n g,   m al a bs or pti o n,  e xt er n al  bili ar y s h u nt,  or si g n  ifi c a nt 
s  m all  b o  w el r es e cti o n t h at   w o ul d  h a v e  pr e cl u d e d  a d e q u at e  a bs or pti o n. 
2.    Pr es e n c e  of  a   m e di c al  or  ps y c hi atri c  c o n diti o n t h at, i n t h e  o pi ni o n  of t h e  i n v esti g at or, 
m a d e t h e s u bj e ct   i n a p pr o pri at e f or i n cl usi o n i n t his st u d y. 
3.    Pr e vi o us  us e  of  p e xi d arti ni b  o r  a n y  bi ol o gi c tr e at  m e nt t ar g eti n g   C S F- 1  or t h e   C S F 1  R; 
pr e vi o us  us e  of  or al t yr osi n e  ki n as e i n hi bit ors,  e g, i  m ati ni b  or  nil oti ni b,  is all o  w e d.  
4.    Cli ni c all y  a cti v e  pri  m ar y  c e ntr al  n er v o us s yst e  m t u  m ors  or  br ai n   m et ast asis,  d efi n e d 
as  u ntr e at e d  a n d s y  m pt o  m ati c ,  or r e q uiri n g t h er a p y   wit h st er oi ds  or  a nti c o n v uls a nts t o 
c o ntr ol  ass o ci at e d s y  m pt o  ms. 
5.    A cti v e  or  c hr o ni c i nf e cti o n   wit h  h e p atitis   C  or   k n o  w n  p ositi v e  h e p atitis   B  s urf a c e 
a nti g e n ,  or  k n o  w n  a cti v e  or  c hr o ni c i nf e cti o n   wit h  h u  m a n i  m  m u n o d efi ci e n c y  vir us. 
6.    K n o  w n  a cti v e t u b er c ul osis. 
7.    W o  m e n   w h o  ar e  br e astf e e di n g. 
8.    A s cr e e ni n g  Fri d eri ci a  c orr e ct e d   Q T i nt er v al (  Q T c F)  ≥    4 5 0 ms (  m e n)  or  ≥    4 7 0 ms 
(  w o  m e n). 
9.    A   m e di c al  hist or y  or  c o  m pli c ati o ns  of  cli ni c all y   si g nifi c a nt l u n g  dis e as e ( e g, 
i nt erstiti al  p n e u  m o ni a,  p n e u  m o nitis,  p ul  m o n ar y fi br osis,  a n d s e v er e r a di ati o n 
p n e u  m o nitis). 
1 0.  A  hist or y  of s y  m pt o  m ati c  c o n g esti v e  h e art f ail ur e (  [C  H F  ];   N e  w   Y or k   H e art 
Ass o ci ati o n [  N  Y  H  A]   C  l ass es II t o I  V)  or s eri o us  c ar di a c  arr h yt h  mi a r e q uiri n g 
tr e at  m e nt. 
1 1.  A  hist or y  of   m y o c ar di al i nf ar cti o n  or  u nst a bl e  a n gi n a   wit hi n  6   m o nt hs  b ef or e 
e nr oll  m e nt. 
1 2.  A n  u n c o ntr oll e d i nf e cti o n r e q uiri n g i ntr a v e n o us i nj e cti o n  of  a nti bi oti cs,  a nti vir als,  or 
a ntif u n g als. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 6  of  9 0 
5.      
S  T  U  D  Y   T  R  E  A  T   M  E  N  T  
F or  d et ails  a n d  h a n dli n g  of t h e  st u d y  dr u g, r ef er t o t h e I  B  a n d t h e   m a n u al f or   m a n a g e  m e nt 
of t h e  st u d y  dr u g  a v ail a bl e i n t h e  St u d y   R ef er e n c e   M a n u al . 
T h e  i n v esti g at or m ust  e ns ur e t h at t h e   st u d y  dr u g   will  b e  us e d  o nl y i n  a c c or d a n c e   wit h t h e 
pr ot o c ol. 
5. 1.      Assi g ni n g  S u bj e cts t o   T r e at  m e nts  a n d   Bli n di n g   
5. 1. 1.      
T r e at  m e nt   G r o u ps   
T his st u d y  c o  m pris es  2  d os e l e v el s (  C o h ort  1  a n d   C o h ort  2) t o  ass ess t h e s af et y  a n d 
t ol er a bilit y, R P 2  D,  P  K  a n d  P  D,  a n d  pr eli  mi n ar y  a ntit u  m or  a cti vit y  of  p e xi d arti ni b. 
•     C o h ort  1:  6 0 0   m g/ d ( 2 0 0   m g i n t h e   m or ni n g,  4 0 0   m g i n t h e  e v e ni n g) 
•     C o h ort  2:  1 0 0 0   m g/ d   ( 4 0 0   m g i n t h e   m or ni n g  a n d  6 0 0 m g i n   t h e  e v e ni n g) f or t h e 
first  2   w e e ks.  T h er e aft er, t h e   d os e   w o ul d  b e r e d u c e d t o  8 0 0 m g/ d   ( 4 0 0   m g i n t h e 
m or ni n g  a n d  4 0 0   m g i n t h e  e v e ni n g) 
P e xi d arti ni b   will  b e  a d  mi nist er e d  or all y i n  c a ps ul e f or  m.   P e xi d arti ni b  will  b e s u p pli e d i n 
2 0 0   m g  c a ps ul es  a n d   will  b e t a k e n   BI  D  a p pr o xi  m at el y  1 2  h  a p art  i n t h e   m or ni n g  a n d 
e v e ni n g .  D os es   will  b e t a k e n i n t h e f asti n g st at e (  n o f o o d f or  1  h  b ef or e  a n d  2  h  aft er 
d osi n g,   wit h  a l o  w- f at s n a c k if  n e e d e d).  E a c h  c y cl e  of tr e at  m e nt   will  b e  2 8  d a ys i n 
d ur ati o n.   T h e  c y cl e s of t r e at  m e nt   will b e  c o nti n u e d  u ntil  dis e as e  pr o gr essi o n, 
u n a c c e pt a bl e t o xi cit y,  or  c o ns e nt   wit h dr a  w al. 
Tr e at  m e nt  d ur ati o n  of  p e xi d arti ni b  is pr es e nt e d i n  S e cti o n   3. 3. 
5. 1. 2.      
M et h o d  of   T r e at  m e nt   All o c ati o n    
T h e s t u d y  d esi g n h as  b e e n  d es cri b e d  i n S e cti o n   3. 
5. 1. 3.      
Bli n di n g   
T h e st u d y  is  o p e n-l a b el  a n d  n o  bli n di n g   will  b e  p erf or  m e d. 
5. 1. 4.      
E  m e r g e n c y   U n b  li n di n g P r o c e d u r e  
N ot  a p pli c a bl e.   
5. 2.      St u d y   D r u g  
5. 2. 1.      
D es c ri pti o n   
P e xi d arti ni b  is  a  h y dr o c hl ori d e (H  Cl  ) salt   wit h  a   w hit e t o  off -w hit e  cr yst alli n e s oli d 
a p p e ar a n c e.    Pe xi d arti ni b  H  Cl     will  b e s u p pli e d  as a 2 0 0   m g  c a ps ul e f or  m ul ati o n 
J- 3 3 9 7-  A F (2 0 0  m g fr e e  b as e  e q ui v al e nt) f or  or al  a d  mi nistr ati o n    c o nt ai ni n g t h e f oll o  wi n g 
e x ci pi e nts:  P ol o x a  m er  4 0 7,   m a n nit ol,  cr os p o vi d o n e,  a n d   m a g n esi u  m  st e ar at e. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 7  of  9 0 
T h e  i n v esti g at or m ust  e ns ur e t h at t h e   st u d y  dr u g   will  b e  us e d  o nl y i n  a c c or d a n c e   wit h t h e 
pr ot o c ol. 
5. 2. 2.      
L a b eli n g  a n d  P a c k a gi n g 
P e xi d arti ni b   will  b e s u p pli e d  b y  t h e S p o ns or.   P e xi d arti ni b  c a ps ul es ( 2 0 0  m g str e n gt h)  ar e 
m a n uf a c  t ur e d,  p a c k a g e d,  a n d l a b el e d  a c c or di n g t o G o o d   M a n uf a ct uri n g  Pr a cti c e   a n d 
G o o d   Cli ni c al  Pr a cti c e (  G  C P  ).  T h e  p a c k a gi n g   will  b e  cl e arl y l a b el e d  “ F or   Cli ni c al  St u d y 
Us e   O nl y  ,”  a n d   will s h o  w t h e  dis pl a y  n a  m e  of t h e st u d y  dr u g , t h e st u d y  dr u g 
m a n uf a ct uri n g  c o d  e, st or a g e  c o n diti o n,  a n d  ot h er r e q uir e d i nf or  m ati o n i n  a c c or d a n c e   wit h 
l o c al r e g ul ati o ns. 
5. 2. 3.      
P r e p a r ati o n 
P e xi d arti ni b  is  a n  a nti c a n c er  dr u g,  a n d  as   wit h  ot h er  p ot e nti al t o xi c  c o  m p o u n ds,  c a uti o n 
s h o ul d  b e  e x er cis e d   w h e n  h a n dli n g  p e xi d arti ni b .  S p e cifi c i nstr u cti o ns  o n  pr e p ar ati o n  a n d 
dis p e ns ati o n   will  b e  pr o vi d e d i n t h e  S t u d y P h ar  m a c y   M a n u al.  
5. 2. 4.      
A d  mi nist r ati o n   
P e xi d arti ni b s h o ul d  b e t a k e n  BI  D   a p pr o xi  m at el y  1 2   h  a p art.   E a c h  d os e is t o  b e t a k e n 
wit h   8  o u n c es ( a p pr o xi  m at el y  2 4 0   m L)  of   w at er.   P e xi d arti ni b  s h o ul d  b e gi v e n  i n t h e 
f asti n g st at e (n o f o o d f or  1  h  b ef or e  a n d  2  h  aft er  d osi n g,   wit h  a l o  w- f at s n a c k if  n e e d e d).  
E a c h  c y cl e  of tr e at  m e nt   will  b e  2 8  d a ys  i n  d ur ati o n.  T h e  c y cl e  of tr e at  m e nt   will  b e 
c o nti n u e d  u ntil  dis e as e  pr o gr essi o n,  u n a c c e pt a bl e t o xi cit y,  or  c o ns e nt   wit h dr a  w al. 
W h e n  a n  o d d  n u  m b er  of  c a ps ul es is t o  b e t a k e n i n  a  d a y, t h e l ar g er  n u  m b er  of  c a ps ul es 
s h o ul d  b e t a k e n  as t h e  e v e ni n g  d os e.   F or  e x a  m pl e,  6 0 0  m g/ d  =  3   c a ps ul es ( 1  c a ps ul e  i n 
t h e   m or ni n g,  2  c a ps ul es i n t h e  e v e ni n g).     W h e n  a n  e v e n  n u  m b er  of  c a ps ul es is t o  b e t a k e n 
i n  a  d a y, t h e   m or ni n g  a n d  e v e ni n g  d os es s h o ul d  b e t h e s a  m e ( e g,  8 0 0 m g/ d    =  4 c a ps ul es 
( 2  c a ps ul es i n t h e   m or ni n g,  2  c a ps ul es i n t h e  e v e ni n g)  or  4 0 0 m g/ d    =  2 c a ps ul es 
( 1  c a ps ul e i n t h e   m or ni n g,  1  c a ps ul e i n t h e  e v e ni n g). 
5. 2. 5.      
St o r a g e 
Dr  u g s u p pli es   m ust  b e st or e d i n  a s e c ur e, li  mit e d  a c c ess st or a g e  ar e a  at  2 0 °  C t o  2 5°  C, 
wit h   e x c ursi o n  p er  mitt e d t o  1 5°  C t o  3 0°  C.  If st or a g e  c o n diti o ns  ar e  n ot   m ai nt ai n e d  p er 
s p e cifi e d r e q uir e  m e nts,  t h e S p o ns or  or  c o ntr a ct r es e ar c h  or g a ni z ati o n  s h o ul d  b e  c o nt a ct e d. 
5. 2. 6.      
D r u g   A c c o u nt a bilit y   
W h e n  a  dr u g s hi p  m e nt is r e c ei v e d, t h e i   n v esti g at or  or  d esi g n e e   will  c h e c k t h e  a  m o u nt  a n d 
c o n diti o n  of t h e  dr u g,  c h e c k f or  a p pr o pri at e l o c al l a n g u a g e i n t h e l a b el,  dr u g  e x pir ati o n 
d at e,  a n d si g n t h e   R e c ei pt  of  S hi p  m e nt  F or  m  pr o vi d e d. 
I n  a d diti o n, t h e i n v esti g at or  or  d esi g n e e s h all  c o nt a ct  S p o ns or  as s o o n  as  p ossi bl e if t h er e 
is  a  pr o bl e  m   wit h t h e s hi p  m e nt. 
A   Dr u g   A c c o u nt a bilit y   R e c or d   will  b e  pr o vi d e d f or t h e   st u d y  dr u g.   T h e r e c or d   m ust  b e 
k e pt  c urr e nt  a n d s h o ul d  c o nt ai n t h e  d at es  a n d  q u a ntiti es  of  st u d y dr u g r e c ei v e d ; t h e 
s u bj e ct’s i d e ntifi c ati o n  n u  m b er  a n d/ or i niti als  or s u p pl y  n u  m b er  as  a p pli c a bl e, f or   w h o  m 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 8  of  9 0 
t h e st u d y  dr u g   w as  dis p e ns e d;  t h e  d at e  a n d q u a ntit y  of  st u d y  dr u g  dis p e ns e d  a n d 
r e  m ai ni n g,  as   w ell  as t h e i niti als  of t h e dis p e ns er. 
At t h e  e n d  of t h e st u d y,  or   as   dir e ct e d,  all  u n us e d st u d y  dr u g   will  b e r et ur n e d t o  a 
d esi g n e e  as i nstr u ct e d  b y t h e  S p o ns or.   St u d y  dr u g   will  b e r et ur n e d  o nl y  aft er t h e s t u d y 
m o nit or  h as  c o  m pl et e d  a fi n al i n v e nt or y t o  v erif y t h e  q u a ntit y t o  b e r et ur n e d.   T h e r et ur n 
of st u d y  dr u g   m ust  b e  d o c u  m e nt e d  a n d t h e  d o c u  m e nt ati o n i n cl u d e d i n t h e s hi p  m e nt.   At 
t h e  e n d  of t h e st u d y,  a fi n al st u d y  dr u g r e c o n cili ati o n st at e  m e nt m ust  b e  c o  m pl et e d  b y t h e 
i n v esti g at or or  d esi g n e e  a n d  pr o vi d e d t o t h e  S p o ns or. 
All st  u d y  dr u g i n v e nt or y  f or  ms m ust  b e   m a d e  a v ail a bl e f or i ns p e cti o n  b y  a    S p o ns or 
a ut h ori z e d r e pr es e nt ati v e  or  d esi g n e e  a n d r e g ul at or y  a g e n c y i ns p e ct ors.   T h e  in v esti g at or 
or  d esi g n e e  is r es p o nsi bl e f or t h e  a c c o u nt a bilit y  of  all  us e d  a n d  u n us e d st u d y s u p pli es  at 
t h e st u d y sit e. 
5. 3.      C o nt r ol   T r e at  m e nt   
N ot   a p pli c a bl e . 
5. 4.      D os e  -li  miti n g   T o xi citi es 
A   D L T is  d efi n e d  as  a n y  dr u g-  r el at e d  T E  A E t h at  o c c urs  d uri n g t h e first  2 8 d a ys  of 
tr e at  m e nt i n  e a c h s u bj e ct t h at   m e ets t h e f oll o  wi n g N  CI  -C T  C  A E   V  ersi o n   4. 0 crit eri a:  
•     F or  h e  m at ol o gi c al  t o xi cit y,  a   D L T is  d efi n e d  as f oll o  ws: 
−     Gr a d e  4  a n e  mi a   
−     Gr a d e  4  n e utr o p e ni a l asti n g  >  7   d a ys  
−     Gr a d e  ≥  3 f e bril e  n e utr o p e ni a   
−     Gr a d e  4  pl at el et  c o u nt  d e cr e as e d    
−     Gr a d e  ≥  3  pl at el et  c o u nt  d e cr e as e l asti n g  >  7   d a ys  or  ass o ci at e d   wit h 
bl e e di n g 
•     F or  h e p ati c   m aj or  o r g a n t o xi cit y,  a   D L T is d efi n e d   as f oll o  ws: 
−     Gr a d e   4   A L T  or   A S T i n cr e as e d  
−     A L  T  or   A S T  ≥   3  × U L  N, if  a c c o  m p a ni e d   wit h    ≥   2  × U L  N   i n t ot al 
bilir u bi n  
−     A L  T  or   A S T  >  5  ×  U L  N l asti n g  >  1 4   d a ys  
•     N o n  -h e  m at ol o gi c al t o xi cit y,  a   D L T is  d efi n e d  as f oll o  ws:  
−     Gr a d e  ≥   3  n o n- h e  m at ol o gi c al,  n o n-h e p ati c   m aj or  or g a n t o xi cit y  
−     I n a bilit y t o  c o  m pl et e  at l e ast  7 5  %  of t h e  pr es cri b e d  d os e  of  p e xi d arti ni b i n 
t h e first  c y cl e  as  a r es ult  of  dr u g-r el at e d  T E  A E 
T h e f oll o  wi n g  T E  A E is   N  O T  c o nsi d er e d  a   D L T: 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  3 9  of  9 0 
•     Gr a d e    3  n a us e a,  v o  miti n g  or  di arr h e a t h at  h as r es ol v e d   wit hi n  7 d a ys   wit h  o pti  m al 
pr o p h yl a xis  a n d/ or tr e at  m e nt 
•     Gr a d e    3 f ati g u e t h at  h as r es ol v e d t o   Gr a d e  <  2   wit hi n  7 d a ys  
•     Gr a d e  ≥ 3  al k ali n e  p h os p h at as e t h at is r el at e d t o  u n d erl yi n g   m ali g n a n c y ( e g,  b o n e 
m et ast asis)   
•     L a b or at or y  d at a  a b n or  m aliti es  d et er  mi n e d t o  b e tr a nsi e nt  b y t h e  i n v esti g at or or 
is ol at e d l a b or at or y fi n di n gs  n ot  ass o ci at e d   wit h si g ns  or s y  m pt o  m 
•     Gr a d e    3/ 4 l y  m p h o cyt e  c o u nt  d e cr e as e  
5. 5.      R e c o  m  m e n d e d  P h as e  2   D os e   
E a c h tr e at  m e nt  c y cl e   will  b e  2 8   d a ys i n  d ur ati o n.   T h e M T  D   will  b e  d efi n e d  as t h e  d os e  at 
w hi c h  ≤  1  of  6   s u bj e cts e x p eri e n c e d  a   D L T  d uri n g   C y cl e  1.   T h e   R P 2  D   will  b e 
d et er  mi n e d  b as e d  o n t h e   M T  D. 
If   D L T is  o bs er v e d i n  2  of  6 s u bj e cts i n   C o h ort  2, th e  S af et y   M o nit ori n g 
C  o  m  mitt e e  ( S  M  C) will  dis c uss  a b o ut   w h et h er t h e  n u  m b er  of s u bj e cts i n   C o h ort  2  c o ul d 
b e  e x p a n d e d t o  a t ot al  of  9 s u bj e cts  or  n ot.  If  a  d e cisi o n t o  e x p a n d   C o h ort  2 t o  9  s u bj e cts 
is t a k e n  b y  S  M  C, t h e n   MT  D    w o ul d  b e  c o nsi d er e d  as  d os e  at   w hi c h ≤  2  of  9  s u bj e cts 
e x p eri e n c e d  a   D L T  d uri n g   C y cl e  1.  
5. 6.      D os e   L  e v el  Es c al ati o n  
T hr e e t o  6  s u bj e cts   will  b e  e nr oll e d i n  2  d os e l e v els (  C o h ort  1  a n d   C o h ort 2).     A t ot al  of  9 
t o  1 5 s u bj e cts   will  b e  e nr oll e d.    D os e-es c al ati o n   Crit eri a   B as e d  o n   D L T is  d es cri b e d i n 
T a bl e   5. 1. 
C o h ort  1: 
S u bj e cts i n   C o h ort  1   will  b e  a d  mi nist er e d  6 0 0   m g/ d ( 2 0 0   m g i n t h e   m or ni n g,  4 0 0  m g i n 
t h e  e v e ni n g).  If  a   D L T is  o bs er v e d i n  1  of  3 s u bj e cts,  at l e ast  6 s u bj e cts   will  b e tr e at e d i n 
C o h ort  1.  If  a   D L T is  o bs er v e d i n  0  of  3 s u bj e cts  or l  of  6 s u bj e cts i n   C o h ort  1,   C o h ort  2 
will  b e i niti at e d.  If  a   D L T is  o bs er v e d i n  3  or   m or e  of  6 s u bj e cts i n   C o h ort  1,   C o h ort  1 
will  b e t er  mi n at e d  a n d   C o h ort  2   will  n ot  b e  o p e n e d. 
•     If a  D L T is  o bs er v e d i n   ≥   2  of  3 s u bj e cts  or ≥   2  of  6 s u bj e cts i n   C o h ort  1, t h e 
S  M  C  will  dis c uss   w h et h er   a l o  w er  d os e ( e g,  4 0 0  m g/ d)   s h o ul d  b e  o p e n e d  or  n ot. 
C o h ort  2: 
S u bj e cts i n   C o h ort  2   will  b e  a d  mi nist er e d  1 0 0 0  m g/ d (  4 0 0   m g i n t h e   m or ni n g,  6 0 0  m g i n 
t h e  e v e ni n g).   F or t h e first 2  w e e ks, s u bj e cts   will t a k e   4 0 0   m g i n t h e   m or ni n g  a n d  6 0 0  m g 
i n t h e  e v e ni n g.  T h er e aft er , t h e  e v e ni n g  d os e   w o ul d  b e r e d u c e d t o  4 0 0 m g (t ot al 
8 0 0   m g/ d).   S u bj e cts   w h o   will  h a v e  a  d os e r e d u cti o n  d uri n g t h e first  2  w e e ks   will 
c o nti n u e t h eir tr e at  m e nt  at t h e r e d u c e d  d os e l e v el.  If  a   D L T is  o bs er v e d i n  0  or l  of 
3 s u bj e cts i n   C o h ort  2,   C o h ort  2   will  b e  e x p a n d e d t o  6 s u bj e cts.  If  a   D L T is  o bs er v e d i n 
2  or  3  of  3 s u bj e cts i n   C o h ort  2,  t h e S  M  C   will  dis c uss t o r e - o p e n   C o h ort  1  a n d  e x p a n d  u p 
t o  a t ot al  of  6 s u bje cts  if   C o h ort 1  e v al u at e d  3  s u bj e cts or  e v al u at e t h e i nt er  mitt e nt  d os e 
( 8 0 0 m g/ d).    If  a   D L T is  o bs er v e d i n  2  of  6 s u bj e cts i n   C o h ort  2, t h e  S  M  C   will  dis c uss 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 0  of  9 0 
w h et h er t h e  n u  m b er  of s u bj e cts i n   C o h ort  2  c o ul d  b e  e x p a n d e d t o  a t ot al  of  9 s u bj e cts  or 
e v al u at e  t h e i nt er  mitt e nt  d os e ( 8 0 0 m g/ d)  .  If a   D L T is  o bs er v e d i n  ≥   3 of  6  s u bj e cts i n 
C o h ort   2, t h e  S  M  C   will  dis c uss t o r e - o p e n   C o h ort  1  a n d  e x p a n d  u p t o  a t ot al  of  6 s u bj e cts 
if   C o h ort 1  e v al u at e d  3  s u bj e cts  or  e v al u at e t h e i nt er  mitt e nt  d os e ( 8 0 0  m g/ d).   
 
T a bl e  5. 1:     
D os e  - es c al ati o n   C rit e ri a   B as e d  o n   D  L  T 
C o h o rt  1 
I n ci d e n c e  of 
D  L  Ts   
D e cisi o n    
D e cisi o n, if   C o h o rt  1 is   E  x p a n d e d t o 
T  ot al  6  S u bj e cts  
0  of  3  
C o h ort  2   will  b e  o p e n e d  . 
R ul e s   w h e n   C o h ort   1 is r e -o p e n e d : 
•     I n ci d e n c e  of   D L T s is  0 of  6  or  1  of  6 : 
T h e   M T  D  h as  b e e n  d et er  mi n e d  as 
C o h ort   1.  
•     2  of  6  or  3  of  6:   M T  D  h as  b e e n 
e x c e e d e d  at   C o h ort  1 .a 
1  of  3  
C o h ort  1   will  b e  e x p a n d e d t o t ot al 
6  s u bj e cts. 
•     I n ci d e n c e  of   D L T s is  1 of  6:   C o h ort  2 
will  b e  o p e n e d  . 
•     2  of  6,  3  of  6,  or  4  of  6:  M T  D  h as  b e e n 
e x c e e d e d  at   C o h ort  1 .a 
2  of  3  or  3  of  3      
T h e   M T  D  h as  b e e n  e x c e e d e d  at 
C o h ort   1 .a  
- 
D L T  =  d os e  -li  miti n g t o xi cit y;   M T  D  =   m a xi  mu  m  t ol er at e d  d os e. 
a     If D L T is  o bs er v e d i n   >  2  of  3 s u bj e cts  or  >  2  of  6 s u bj e cts i n   C o h ort  1 , t h e S M  C   will  dis c uss   w h et h er   a l o  w er 
d os e  l e v el ( e g,  40 0  m g/ d)   s h o ul d  b e o p e n e d  or  n ot.  
C o h o rt  2 
I n ci d e n c e  of 
D  L  Ts   
D e cisi o n   
D e cisi o n, if   C o h o rt   2  is E x p a n d e d   t o 
T ot al   6  S u bj e cts  
0  of  3  or  1  of  3      
C o h ort   2   will  b e  e x p a n d e d t o t ot al 
6  s u bj e cts. 
•     I n ci d e n c e  of   D L T s is  0 of  6  or  1  of  6: 
T h e   M T  D  h as  b e e n r e a c h e d . 
•     2  of  6  s u bj e cts h a v e   D L T i n   C o h ort  2, 
t h e n  S  M  C   will  dis c uss t o  e x p a n d  u p 
t o  a t ot al  of  9 s u bj e cts  or  e v al u at e t h e 
i nt er  mitt e nt  d os e ( 8 0 0   m g/ d). 
•     ≥  3  of  6 s u bj e cts i n   C o h ort  2, t h e  S  M  C 
will  dis c uss t o r e  -o p e n   C o h ort  1  a n d 
e x p a n d  u p t o  a t ot al  of  6 s u bj e cts if 
C o h ort  1  e v al u at e d  3 s u bj e cts  or 
e v al u at e t h e i nt er  mitt e nt  d os e 
( 8 0 0 m g/ d).   
2  of  3  or  3  of  3      
If   C o h ort 1  e v al u at e d  3  s u bj e cts, t h e 
S  M  C   will  dis c uss t o  r e-o p e n   C o h ort  1 
a n d  e x p a n d  u p t o  a t ot al  of  6 s u bj e cts 
or  e v al u at e t h e i nt er  mitt e nt  d os e 
( 8 0 0 m g/ d)  . 
 
D L T  =  d os e  -li  miti n g t o xi cit y;   M T  D  =   m a xi  mu  m  t ol er at e d  d os e;  S  M  C  =  S af et y   M o nit ori n g   C o  m  mitt e e. 
D os e r e d u cti o ns  a n d i nt err u pti o ns f or t o xi cit y   will  b e  p er  mitt e d  a c c or di n g t o  pr es p e cifi e d 
g ui d eli n es ( T a bl e  5. 2  a n d   T a bl e  5. 3). 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 1  of  9 0 
 
5. 7.      D os e I nt e r r u pti o ns  a n d   R e d u cti o ns   
R e d u cti o ns  or i nt err u pti o ns   of  t h e  d os e f or t o xi cit y   m a y t a k e  pl a c e  at  a n y ti  m e d uri n g t h e 
st u d y a c c or di n g t o t h e  g ui d eli n es  pr es e nt e d  i n T a bl e   5. 2 a n d  T a bl e   5. 3.  D os e   
r e d u cti o n/i nt err u pti o n g ui d eli n es  f or  h e  m at ol o gi c  a n d  n o n-h e  m at ol o gi c tr e at  m e nt -r el at e d 
T E  A Es  ar e  b as e d  o n s e v erit y.     D os e i nt err u pti o ns  c a n  b e i  m pl e  m e nt e d  at t h e  dis cr eti o n  of 
t h e i n v esti g at or t o   m a n a g e i nt ol er a bl e  or  cli ni c all y si g nifi c a nt t o xi cit y. If  a  d os e 
i nt err u pti o n is r e q uir e d, st u d y  ass ess  m e nts s h o ul d  b e  p erf or  m e d  as s c h e d ul e d, irr es p e cti v e 
of t h e st u d y  dr u g  d el a y,   wit h t h e  e x c e pti o n  of  P  K  ass ess  m e nts,   w hi c h s h o ul d  b e  d ef err e d 
u ntil tr e at  m e nt is r es u  m e d. I nt err u pti o ns  d u e t o t o xi cit y l asti n g  > 1 4  d r e q uir e tr e at  m e nt 
dis c o nti n u ati o n  u nl ess t h e   m e di c al   m o nit or  a p pr o v es  c o nti n u ati o n.  
D os e r e d u cti o ns s h o ul d  b e  a p pli e d i n i n cr e  m e nts  of  2 0 0   m g/ d (  1  c a ps ul e),  wit h   a 
mi ni  m u  m    d os e  of  4 0 0 m g/ d.     S u bj e cts  u n a bl e t o t ol er at e  4 0 0 m g/ d (  2  c a ps ul es)   will  b e 
dis c o nti n u e d  fr o  m tr e at  m e nt. 
If t o xi cit y r e q uir es  a  d osi n g  d el a y  or i nt err u pti o n f or   m or e t h a n  3 c o ns e c uti v e   w e e ks, t h e 
s u bj e ct will  b e   wit h dr a  w n fr o  m t h e st u d y    d u e t o t oxi cit y.  D os e  -  m o difi c ati o n  g ui d eli n es 
f or tr e at  m e nt-e  m er g e nt  t o xi citi es  as   w ell  as  g ui d eli n es f or t h eir m a n a g e  m e nt  ar e 
pr es e nt e d i n  T a bl e   5. 2 a n d  T a bl e   5. 3.  T h es e  p ar a  m et ers  a r e  o nl y  a  g ui d e  a n d  ar e  n ot 
i nt e n d e d t o s u p ers e d e t h e  cli ni c al j u d g  m e nt  of t h e  i n v esti g at or.    All  a dj ust  m e nts s h o ul d 
b e  c o  m  m u ni c at e d t o t h e  S p o ns or.  R e c h all e n g e   wit h  a r e d u c e d  d os e  of  p e xi d arti ni b   m a y 
r es ult i n  a r e c urr e n c e  of i n cr e as e d s er u  m tr a ns a  mi n as es,  bilir u bi n,  or   A L P.    M o nit or li v er 
t ests   w e e kl y f or t h e first   m o nt h  aft er r e c h all e n g e. 
 
T a bl e  5. 2:     
D os e    M o difi c ati o n   G ui d eli n es f o r   T r e at  m e nt  -e  m e r g e nt  T o xi citi es   
E v e nt       
S e v e rit y  
P e xi d a rti ni b   D os a g e    M o difi c ati o ns  
H e p at o xi cit y   
I n cr e as e d 
A L T  a n d/ or 
A S T   
> 3 t o  5  ×   U L  N  
•      Wit h h ol   d  a n d   m o nit or li v er t ests   w e e kl y.  
•      If   A S T  a n d   A L T  ≤ 3  ×   U L  N   wit hi n  4   w e e ks, r es u  m e  at 
r e d u c e d  d os e. 
•      If   A S T  or   A L T  n ot  ≤ 3  ×   U L  N i n  4   w e e ks,  p er  m a n e ntl y 
dis c o nti n u e  p e xi d arti ni b.  
> 5 t o  1 0  ×   U L  N  
•      Wit h h ol d  a n d   m o nit or li v er t ests t  wi c e   w e e kl y.    
•      If   A S T  a n d   A L T  ≤ 3 ×   U L  N   wit hi n  4   w e e ks, r es u  m e  at 
r e d u c e d  d os e. 
•      If   A S T  or   A L T  n ot  ≤ 3  ×   U L  N i n  4   w e e ks,  p er  m a n e ntl y 
dis c o nti n u e  p e xi d arti ni b.  
> 1 0  ×   U L  N  
•      P er  m a n e ntl y  dis c o nti n u e  p e xi d arti ni b.  
•      M o nit or li v er t ests t  wi c e   w e e kl y  u ntil   A S T  or   A L T  ≤ 5  × 
U L  N, t h e n   w e e kl y  u ntil  ≤ 3  ×   U L  N.   
I n cr e as e d 
A L P a a n d 
G  G T   
A L P  > 2  ×   U L  N   wit h   G  G T 
> 2  ×   U L  N  
•      P er  m a n e ntl y  dis c o nti n u e  p e xi d arti ni b.    M o nit or li v er 
t ests t  wi c e   w e e kl y  u ntil   A L P  ≤ 5 ti  m e s   U L  N, t h e n 
w e e kl y  u ntil  ≤ 2   ×   U L  N.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 2  of  9 0 
E v e nt       
S e v e rit y  
P e xi d a rti ni b   D os a g e    M o difi c ati o ns  
I n cr e as e d 
bilir u bi n  
T  B  >  U L  N t o  < 2  ×   U L  N  
or  
D  B  >  U L  N  a n d  < 1. 5  × 
U L  N   
•      Wit h h ol d  a n d   m o nit or li v er t ests t  wi c e   w e e kl y.    
•      If  a n  alt er n at e  c a us e f or i n cr e a s e d  bilir u bi n is  c o nfir  m e d 
a n d  bilir u bi n  <  U L  N   wit hi n  4   w e e ks, r es u  m e  at r e d u c e d 
d os e.  
•      If  bilir u bi n  n ot  <  U L  N i n  4   w e e ks,  p er  m a n e ntl y 
dis c o nti n u e  p e xi d arti ni b.  
 
T  B  ≥ 2  ×   U L  N  
or  
D  B  > 1. 5  ×   U L  N   
•      P er  m a n e ntl y  dis c o nti n u e  p e xi d arti ni b.  
•      M o nit or li v er t ests t  wi c e   w e e kl y  u ntil  bilir u bi n  ≤  U L  N.    
A d v e rs e   R e a cti o ns  o r   Ot h e r   L a b o r at o r y   A b n o r  m aliti es   
A n y       
S e v er e  or i nt ol er a bl e  
•      Wit h h ol d  u ntil i  m pr o v e  m e nt  or r es ol uti o n.    
•      R es u  m e  at  a   r e d u c e d  d os e  u p o n i  m pr o v e  m e nt  or 
r es ol uti o n. 
A L T  =  al a ni n e  a  mi n otr a nsf er a s e;   A L P  =  al k ali n e  p h o s p h at as e;   A S T  =  as p art at e  a  mi n otr a nsf er as e;   D  B  = 
dir e ct  bilir u bi n;   G  G T  =  g a  m  m a -gl ut a  m yl tr a nsf er as e;  T  B  = t ot al  bilir u bi n;   U L  N  =  u p p er li  mit  of 
n or  m al . 
a     C o nfir  m   A L P  el e v ati o ns  a s li v er is o z y  m e fr a cti o n.   
 
T a bl e  5. 3:     
A d diti o n al   Li v e r   E v al u ati o n   
E v al u ati o n   
C o  m  m e nts   
I n cr e as e fr e q u e n c y  of t esti n g li v er  c h e  mistri es t o 
t  wi c e  p er   w e e k, i n cl u di n g I  N  R,  a n d  c o nti n u e  u ntil 
li v er  c h e  mistri es  h a v e  st a bili z e d,  a n d t h e n r e d u c e t o 
w e e kl y  u ntil li v er  c h e  mistri es r et ur n t o  n or  m al  or 
b as eli n e . 
I n v e sti g ati o n al tr e at  m e nt m a y  b e st art e d  aft er li v er 
f u n cti o n t ests r e c o v er t o   Gr a d e 0 t o  1  or  b as eli n e 
l e v el,  a n d i n  c o ns ult ati o n   wit h   M e di c al   M o nit or. 
D et ail e d  hist or y f o c usi n g  o n   m e di c ati o ns  a n d 
s u bst a n c es  us e d:  al c o h ol,  c h a n g e i n   m e di c ati o n 
d os a g es,  n e  w   m e di c ati o ns  a d d e d,  att e nti o n t o  us e  of 
a c et a  mi n o p h e n,   O T  C   m e di c ati o n  us e,  a n d 
r e cr e ati o n al  dr u g  us e.   C h e c k f or  c h a n g e i n  di et or 
us e  of  di et ar y s u p pl e  m e nts,   wit h  p arti c ul ar  att e nti o n 
t o  d os e  a n d  d ur ati o n  of  a n y  h er b al  pr o d u ct. 
S us p e ct   m e di c ati o ns   will  b e  dis c o nti n u e d  or 
s u bstit ut e d f or if  p ossi bl e.  
D et ail e d   m e di c al  hist or y  a n d  p h ysi c al  e x a  mi n ati o n 
s e e ki n g  n e  w  a b n or  m aliti e s.  
E v al u at e  a b n or  m aliti es f o u n d.  
F ull s er ol o gi c al  e v al u ati o n f or  h e p atitis  A,   B,   C,  a n d 
E (I g  G  a n d I g  M).   C h e c k f or  a ut oi  m  m u n e  h e p atitis 
wit h s er ol o gi c al l a b or at or y st u di es.   
If  vir al  h e p atitis  or  a ut oi  m  m u n e  h e p atitis s u g g e st e d, 
h a v e  p ati e nt  e v al u at e d  b y  h e p at ol o g ist. 
Li v er  ultr as o u n d  p erf or  m e d t o  e v al u at e li v er  a n d 
bili ar y tr e e.  
E v al u at e  a n y  a b n or  m aliti es f o u n d.  
C h e c k  hist or y f or  e x p os ur e t o  c h e  mi c al  a g e nts.       
R e  m o v e  c h e  mi c al  e x p os ur e  a n d  h a v e  p ati e nt  s e e n 
b y  h e p at ol o gist.  
O bt ai n  h e p at ol o g y  c o ns ult if li v er f u n ct  i o n 
c o nti n u es t o ris e  b e y o n d  1 4  d.  
C o nt a ct   M e di c al   M o nit or.   
W e  r e q u est t h at  c as es  b e  dis c uss e d   wit h t h e    M e di c al    M o nit o r  as  d efi n e d i n t h e 
p r ot o c ol   w h e n e v e r i n v esti g ati o n al  p r o d u ct is  b ei n g  h el d f o r li v e r f u n cti o n t est 
a b n o r  m alit y.  
 
F or s us p e ct e d  c as es  of  c h ol est ati c li v er i nj ur y  ( e g, a  mi n otr a nsf er as e i n cr e as e  c o n c urr e nt 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 3  of  9 0 
wit h  h y p er bilir u bi n e  mi a,  or li v er  bi o ps y s u g g esti n g  c h ol est asis  a n d/ or  d u ct o p e ni a), 
p ati e nts   will  b e f oll o  w e d t o  ass ess l o n g -t er  m  o ut c o  m e.   A d diti o n al  di a g n osti c  a n d f oll o  w-
u p  pr o c e d ur es   mi g ht  b e i  m pl e  m e nt e d  as  a p pr o pri at e t o f ull y  ass ess t h e  e v e nt.  
 
5. 7. 1.      
R e n al I  m p ai r  m e nt   
A r e d u c e d  d os e  of  6 0 0   m g/ d a y ( 2 0 0   m g i n t h e   m or ni n g  a n d  4 0 0   m g i n t h e  e v e ni n g)  or 
4 0 0   m g/ d a y ( 2 0 0   m g i n t h e   m or ni n g  a n d  2 0 0   m g i n t h e  e v e ni n g) is r e c o  m  m e n d e d i n  st u d y 
s u bj e cts wit h   mil d t o s e v er e r e n al i  m p air  m e nt   ( c al c ul at e d  cr e ati ni n e  cl e ar a n c e  b et  w e e n  1 5 
t o  8 9   m L/  mi n  usi n g t h e   C o c k cr oft-G a ult f or  m ul a).   
5. 8.      M et h o d  of   Ass essi n g   T r e at  m e nt   C o  m pli a n c e    
At t h e st u d y  visits i n di c at e d i n t h e  S c h e d ul e  of  E v e nts (  A p p e n di x    1 7. 1),  p e xi d arti ni b   will 
b e  dis p e ns e d t o s u bj e cts.   T h e  a p pr o pri at e st u d y  p ers o n n el   will  d o c u  m e nt  a n d   m ai nt ai n 
r e c or ds  of st u d y dr u g  dis p e nsi n g t o  e a c h s u bj e ct  a n d  a n y r et ur ns  at  e a c h st u d y  visit.  
S u bj e cts   will  c o  m pl et e  a  d osi n g  di ar y t o r e c or d t h e  n u  m b er  of  c a ps ul es/ d at e/ti  m e t a k e n 
d uri n g  e a c h  d osi n g  c y cl e.   At  e a c h   st u d y visit, s u bj e cts   will  b e  ass ess e d f or  c o  m pli a n c e 
wit h st u d y   dr u g  a d  mi nistr ati o n, i e, r et ur n  all  b ottl es ( us e d/ u n us e d)  at l e ast  o n c e  e v er y 
c y cl e.   F urt h er  d et ails   c a n  b e f o u n d i n t h e  St u d y   R ef er e n c e   M a n u al. 
5. 9.      P ri o r  a n d   C o n c o  mit a nt    M e di c ati o ns 
D uri n g t h e st u d y, if t h e  us e  of  a n y  c o n c o  mit a nt tr e at  m e nt  b e c o  m es  n e c ess ar y ( e g, f or 
tr e at  m e nt  of  a n   A E), t h e tr e at  m e nt   m ust  b e r e c or d e d  o n t h e s u bj e ct’s s o ur c e  d o c u  m e nt 
a n d  el e ctr o ni c   C as e   R e p ort  F or  m ( e  C  R F) , i n cl u di n g t h e r e as o n f or tr e at  m e nt,  n a  m e  of t h e 
dr u g,  d os a g e,  d at e,  a n d r o ut e  of  a d  mi nistr ati o n.    All   m e di c ati o ns i n cl u di n g  pr es cri pti o n, 
o v er-t h e- c o u nt er (  O T  C),  h er b al ,  a n d  ot h er  n utriti o n al  vit a  mi ns  a n d/ or s u p pl e  m e nts t a ke n 
wit hi n  2 8   d a ys  pri or t o    C 1  D 1   will  b e r e c or d e d  o n t h e  e  C  R F. 
T h e  us e  of  a n al g esi cs  a n d t h e  r e gi  m e n us e d  will  b e r e c or d e d  . 
S u bj e cts   w h o  ar e  r e c ei vi n g  c o n c o  mit a nt   w arf ari n s h o ul d  h a v e t h eir  a nti c o a g ul ati o n st at us 
c ar ef ull y   m o nit or e d.   I n  p arti c ul ar, I  N  R s h oul d  b e  o bt ai n e d j ust  pri or t o i niti ati o n  of 
p e xi d arti ni b,   wit hi n  1 t o  2   w e e ks  aft er i niti ati o n,  a n d  p eri o di c all y t h er e aft er,  a n d   w arf ari n 
d os es s h o ul d  b e  a dj ust e d if  a n i n cr e as e i n I  N  R is  n ot e d. 
Si n c e t h e  p ossi bilit y  of  a  dr u g- dr u g i nt er a cti o n  vi a i n hi biti o n  of  c yt o c hr o  m e  P 4 5 0  (  C  Y P) 
is  n ot  e x cl u d e d fr o  m i n  vitr o   C  Y P i n hi biti o n st u di es,  c a uti o n is   w arr a nt e d   w h e n 
a d  mi nist eri n g  p e xi d arti ni b t o s u bj e cts t a ki n g  dr u gs t h at  ar e  hi g hl y  d e p e n d e nt  o n   C  Y P f or 
m et a b olis  m  a n d  h a v e  a  n arr o  w t h er a p e uti c i n d e x.    It is  n ot k n o  w n   w h et h er s yst e  mi c 
e x p os ur e t o t h es e   m e di c ati o ns   will i n cr e as e   w hil e s u bj e cts  ar e r e c ei vi n g  p e xi d arti ni b.  
Of t h e   5   m aj or   C  Y P is of or  ms,  C  Y P  3  A 4   m a y  b e i n v ol v e d i n  P h as e  1   m et a b olis  m  of 
p e xi d arti ni b,   wit h   C  Y P 1  A 2  p ossi bl y  pl a yi n g  a   mi n or r ol e.   (s e e A p p e n d  i x  1 7. 3 f or  a list 
of  c o  m  m o n   C  Y P 3  A 4 i n hi bit ors  a n d i n d u c ers). 
I n  g e n er al, str o n g i n d u c ers  of   C  Y P 3  A 4 s h o ul d  b e  a v oi d e d  u nl ess  cli ni c all y  n e c ess ar y.  
T h es e i n cl u d e  a nti c o n v uls a nts,  c ert ai n   m y ci n  a nti  mi cr o bi als,  a n d  a ntir etr o vir als.   S o  m e 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 4  of  9 0 
c o  m  m o n  e x a  m pl es i n cl u d e i n d u c ers s u c h  as rif a  m pi ci n,  c ar b a  m a z e pi n e,  p h e n yt oi n, 
ef a vir e n z,  a n d  n e vir a pi n e. 
A v oi d  c o n c o  mit a nt  us e  of   p e xi d arti ni b    wit h   m o d er at e  or str o n g   C  Y P 3  A i n hi bit ors  or 
U  G T i n hi bit ors.    If  c o n c o  mit a nt  us e   wit h  a m o d er at e  or str o n g   C  Y P 3  A i n hi bit or  or   U  G T 
i n hi bit or  c a n n ot  b e  a v oi d e d, r e d u c e t h e p e xi d arti ni b  d os e  a c c or di n g t o t h e 
r e c o  m  m e n d ati o ns i n T a bl e   5. 4.  If c o n c o  mit a nt  us e  of  a   m o d er at e  or str o n g   C  Y P 3  A 
i n hi bit or  or   U  G T i n hi bit or is  dis c o nti n u e d, i n cr e as e t h e p e xi d arti ni b  d os e ( aft er  3  pl as  m a 
h alf -li v es  of t h e   m o d er at e  or str o n g   C  Y P 3  A i n hi bit or  or   U  G T i n hi bit or) t o t h e  d os e t h at 
w as  us e d  b ef or e st arti n g t h e i n hi bit o  r. 
 
T a bl e  5. 4:     
R e c o  m  m e n d e d   D os a g e   R e d u cti o ns f o r   P e xi d a rti ni b  wit h     C o n c o  mit a nt 
Us e  of    M o d e r at e  o r  St r o n g   C  Y P 3  A I n hi bit o rs  o r   U  G  T I n hi bit o rs   
C u r r e nt   T ot al   D ail y   D os e       
M o difi e d   T ot al   D ail y   D os e        A d  mi nist r ati o n  of    M o difi e d 
T ot al   D ail y   D os e 
8 0 0   m g  
4 0 0   m g  
2 0 0   m g t  wi c e  d ail y  
6 0 0   m g  
4 0 0   m g  
2 0 0   m g t  wi c e  d ail y  
4 0 0   m g  
2 0 0   m g  
2 0 0   m g  o n c e  d ail y  
5. 9. 1.      
H o r  m o n al   C o nt r a c e pti v es   
P e xi d arti ni b  h as  b e e n i n di c at e d t o  b e  a   m o d er at e   C  Y P 3  A 4 i n d u c er,  as  c o n c urr e nt 
a d  mi nistr ati o n  of  p e xi d arti ni b  d e cr e as e d t h e   A  U  Ci nf  of t h e   C  Y P 3  A 4 s u bstr at e 
mi d a z ol a  m  b y  5 7  %.    As t h e  h or  m o n al  c o ntr a c e pti v e  et hi n yl  estr a di ol is  a   C  Y P 3  A 4 
s u bstr at e, t h er e is  a  p ot e nti al t h at  e x p os ur e  of  et hi n yl  estr a di ol   m a y  d e cr e as e  o n 
c o n c urr e nt  a d  mi nistr ati o n   wit h  p e xi d arti ni b.   As  p e xi d arti ni b   m a y  c a us  e  e  m br y o -f et al 
h ar  m   w h e n  a d  mi nist er e d t o  a  pr e g n a nt   w o  m a n , fe  m al es  of r e pr o d u cti v e  p ot e nti al s h o ul d 
b e  a d vis e d t o  us e  a n  eff e cti v e,  n o n- h or  m o n al   m et h o d  of  c o ntr a c e pti o n  d uri n g tr e at  m e nt 
wit h  p e xi d arti ni b  a n d f or  1   m o nt h  aft er t h e l ast  d os e.    M al es   wit h f e  m  al e  p art n ers  of 
r e pr o d u cti v e  p ot e nti al s h o ul d  b e  a d vis e d t o  us e  a n  eff e cti v e   m et h o d  of  c o ntr a c e pti o n 
d uri n g tr e at  m e nt   wit h  p e xi d arti ni b  a n d f or  1   m o nt h  aft er t h e l ast  d os e.   F e  m al e  p art n ers  of 
m al e  p ati e nts s h o ul d  c o n c urr e ntl y  us e  eff e cti v e  c o ntr a c e pti v e   m  et h o ds ( h or  m o n al  or  n o n-
h or  m o n al). 
5. 9. 2.      
A ci d  - re d u ci n g   A g e nts  
A v oi d t h e  c o n c o  mit a nt  us e  of  pr ot o n  p u  m p i n hi bit ors ( P PIs)   w hil e t a ki n g  p e xi d arti ni b.  
As  a n  alt er n ati v e t o  a  P PI,  a d  mi nist er  p e xi d arti ni b  2  h o urs  b ef or e  or  2  h o urs  aft er t a ki n g  a 
l o c all y-a cti n g  a nt a c i d,  or if  usi n g  a  hist a  mi n e  2 (  H 2)-r e c e pt or  a nt a g o nist,  a d  mi nist er 
p e xi d arti ni b  at l e ast  2  h o urs  b ef or e  or  1 0  h o urs  aft er t a ki n g  a n   H 2- r e c e pt or  a nt a g o nist. 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 5  of  9 0 
T h e f oll o  wi n g   m e di c ati o ns  a n d  pr o d u cts   will  b e  pr o hi bit e d: 
•     Ot h er  a nti c a n c er t h er a p y i n cl u di n g  c yt ot  o xi cs, t ar g et e d  a g e nts, i  m  m u n ot h er a p y,  or 
e n d o cri n e t h er a p y 
•     Ot h er i n v esti g ati o n al  a g e nts   
•     B e c a us e  p e xi d arti ni b is   pri  m aril y   m et a b oli z e d  b y    C  Y P 3  A 4  a n d  gr a p efr uit j ui c e is 
a   C  Y P 3  A 4 i n hi bit or, f o o ds  or  b e v er a g es  c o nt ai ni n g  gr a p efr uit s h o ul d  b e  a v oi d e d 
f or t h e d ur ati o n  of  t h e st u d y. 
5. 1 0.     S u bj e ct  Wit h d r a  w al/  Dis c o nti n u ati o n 
5. 1 0. 1.      R e as o ns f o r    Wit h d r a  w al 
A n y s u bj e ct   w h o  dis c o nti n u es fr o  m t h e st u d y   dr u g  f or  a n y r e as o n   will  h a v e t h eir r e as o n 
f or dis c o nti n u ati o n r e c or d e d. 
S u bj e cts   m a y  b e   wit h dr a  w n fr o  m t h e st u d y  aft er si g ni n g i nf or  m e d  c o ns e nt f or t h e 
f oll o  wi n g r e as o ns: 
•     Dis e as e  pr o gr essi o n   (r a di o gr a p hi c  pr o gr essi o n) 
•     Cli ni c al  pr o gr essi o n ( pr o vi d e  d at e) 
•     A E 
•     L ost t o f oll o  w- u p 
•     D e at h   
•     St u d y t er  mi n at e d  b y  t h e  S p o ns or 
•     Pr ot o c ol  vi ol ati o n (s p e cif y) 
•     Wit h dr a  w al  b y s u bj e ct 
•     Ot h er   ( e g,  dis cr eti o n  of t h e in v esti g at or ) 
5. 1 0. 2.      Wit h d r a  w al    P r o c e d u r es  
If  a s u bj e ct is   wit h dr a  w n fr o  m t h e st u d y, t h e in v esti g at or   will  c o  m pl et e  a n d r e p ort t h e 
o bs er v ati o ns  as t h or o u g hl y  as  p ossi bl e  u p t o t h e  d at e  of   wit h dr a  w al i n cl u di n g t h e  d at e  of 
l ast tr e at  m e nt  a n d t h e r e as o n f or   wit h dr a  w al. 
If t h e s u bj e ct is   wit h dr a  w n  d u e t o  a n A E  , t h e i n v esti g at or will f oll o  w t h e s u bj e ct  u ntil t h e 
A E    h as r es ol v e d  or st a bili z e d. 
All s u bj e cts   w h o  ar e   wit h dr a  w n fr o  m t h e st u d y s h o ul d  c o  m pl et e  pr ot o c ol-  s p e cifi e d 
wit h dr a  w al  pr o c e d ur es.   
5. 1 0. 3.      S u bj e ct   R e pl a c e  m e nt  
S u bj e cts    w h o  ar e   wit h dr a  w n fr o  m t h e st u d y  pri or t o  c o  m pl eti n g   Cy cl e   1 f or  a n y r e as o n 
ot h er t h a n  a   D L T   will  b e r e pl a c e d.   S u bj e ct   n u  m b ers   m ust  n ot  b e r e- us e d. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 6  of  9 0 
S u bj e cts   w h o r e c ei v e  <   7 5  %  of t h e  pl a n n e d  d os e  d uri n g t h e   D L T  e v al u ati o n  p eri o d   will 
n ot  b e  c o nsi d er e d  e v al u a bl e  a n d  n e e d t o  b e r e pl a c e d. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 7  of  9 0 
6.      
S  T  U  D  Y  P  R  O  C  E  D  U  R  E S  
A   S c h e d ul e  of  E v e nts  i n t a b ul ar f or  m at is  pr o vi d e d i n   A p p e n di x  1 7. 1. 
D es cri pti o ns  of t h e s p e cifi c st u d y  pr o c e d ur es  ar e  pr o vi d e d i n t h e f oll o  wi n g s u bs e cti o ns.  
A d diti o n al  d et ails  ar e  pr o vi d e d i n t h e  St u d y   R ef er e n c e   M a n u al  or  L a b or at or y   M a n u al  as 
a p pli c a bl e.  
6. 1.      S c r e e ni n g  
6. 1. 1.      
D a y    – 2 8 t o   D a y  – 1 
T h e f oll o  wi n g  pr o c e d ur es  m ust   b e  p erf or  m e d   wit hi n t h e  2 8- d a y  p eri o d  b ef or e first  d os e 
u nl ess  ot h er  wis e s p e cifi e d,  a n d t h e  r es ults m ust   b e  o bt ai n e d  a n d  e v al u at e d f or  eli gi bilit y 
pri or t o t h e   C 1  D 1  visit: 
•     I nf or  m e d  c o ns e nt 
•     M e di c al  hist or y    c o  m prisi n g  all  pri or  a n d  c urr e nt   m e di c al  hist or y  a n d s  m o ki n g 
hist or y 
•     D e  m o gr a p hi cs,   e g ,  birt h  d at e, s e x, r a c e,  pri  m ar y  c a n c er  hist or y, si g nifi c a nt 
m e di c al  hist or y i nf or  m ati o n  , a n d  pri or tr e at  m e nt  hist or y f or  c a n c er  
•     C o n c o  mit a nt   m e di c ati o ns   
•     H ei g ht  a n d   w ei g ht 
•     E  C  O  G  P S  
•     A E  ass ess  m e nt   
6. 1. 2.      
D a y  – 2 1 t o   D a y  – 1 
T h e f oll o  wi n g  pr o c e d ur es   m ust  b e  p erf or  m e d   wit hi n t h e  2 1- d a y  p eri o d  b ef or e first  d os e: 
•     E  C  H  O  or   m ulti -g a t e d  a c q uisiti o n (  M  U  G  A) s c a n ni n g (  wit hi n  2 1- d a y  p eri o d  b ef or e 
first  d os e) 
•     C o  m p ut e d t o  m o gr a p h y (  C T  )/m a g n eti c r es o n a n c e i  m a gi n g (  M  RI  ) (  M  RI  of t h e 
aff e ct e d j oi nt  f or s u bj e cts   wit h T  G  C T  is   m a n d at or y *) (  wit hi n  2 1- d a y  p eri o d 
b ef or e first  d os e)  
*  F or  T  G  C T s u bj e cts,   M  RI  of t h e  aff e ct e d j oi nt is   m a n d at or y  a n d t h e   C T  or   M  RI s c a ns  of 
t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e  n ot r e q uir e d,  a n d t o  b e  d o n e  u p o n t h e i n v esti g at or’s 
dis cr eti o n. 
6. 1. 3.      
D a y  – 1 4 t o   D a y  – 1 
T h e f oll o  wi n g  pr o c e d ur e   m ust  b e  p erf or  m e d   wit hi n t h e  1 4- d a y  p eri o d  b ef or e first  d os e: 
•     P r e g n a n c y t esti n g ( as  a p pli c a bl e   wit hi n  1 4- d a y  p eri o d  b ef or e first  d os e) 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 8  of  9 0 
6. 1. 4.      
D a y  – 7 t o   D a y  – 1 
T h e f oll o  wi n g  pr o c e d ur es   m ust  b e  p erf or  m e d   wit hi n t h e  7- d a y  p eri o d  b ef or e first  d os e: 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e,   r es pir at or y rat e,  a n d t e  m p er at ur e 
(  wit hi n  7- d a y  p eri o d  b ef or e first  d os e) 
•     C o  m pl et e  p h ysi c al  e x a  mi n ati o n   (  wit hi n  7- d a y  p eri o d  b ef or e first  d os e) 
•     Cli ni c al l a b or at or y t ests   – s er u  m  c h e  mistr y,  h e  m at ol o g y, li v er f u n cti o n,  h or  m o n e 
t esti n g ( as  a p pli c a bl e),  c o a g ul ati o n,  a n d  uri n al ysis (  wit hi n  7- d a y  p eri o d  b ef or e 
first  d os e  e x c e pt f or  c o a g ul ati o n t ests) 
•     1 2- l e a d  E  C  G (  wit hi n  7- d a y  p eri o d  b ef or e first  d os e) 
6. 2.      R a n d o  mi z ati o n 
N ot  a p pli c a bl e.   
6. 3.      T r e at  m e nt   P e ri o d  
6. 3. 1.      
C y cl e    1 
6. 3. 1. 1.      C y cl e  1,   D a y  1 (  C 1  D  1 ;    W e e k  1) 
T o  b e  p erf or  m e d   wit hi n  3  d a ys  b ef or e t h e  first   m or ni n g  d os e  of st u d y dr u g : 
•     Dis p e nsi n g  of st u d y  dr u g  a n d s u bj e ct  di ar y 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     1 2- l e a d  E  C  G 
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  li v er f u n cti o n,  uri n al ysis,  c o a g ul ati o n, 
a n d  h e  m at ol o g y  
•     Bl o o d s a  m pli n g f or  P  D  a n al ysis 
T o  b e  p erf or  m e d  b ef or e t h e first   m or ni n g  d os e  of st u d y  dr u g : 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis 
T o  b e  p erf or  m e d  aft er  t h e first   m or ni n g  d os e  of st u d y  dr u g: 
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis  at t h e f oll o  wi n g ti  m e  p oi nts  :  0. 5,  1,  2,  4,  a n d  8  h 
aft er t h e first   m or ni n g  d os e ( b ef or e  t h e  e v e ni n g  d os e) 
6. 3. 1. 2.      C y cl e    1, D a y    2 (  C 1  D 2;    W e e k  1) 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  4 9  of  9 0 
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis   at  2 4  h  aft er  t h e first   m or ni n g  d os e ( b ef or e t h e 
n e xt  m or ni n g  d os e) 
6. 3. 1. 3.      C y cl e    1,   D a y  8 (  C 1  D 8;    W e e k 2)  ±  2   d a ys 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e,   r es pir at or y r at e, a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     A E  ass ess  m e nt   
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y, li v er f u n cti o n a n d 
uri n al ysis 
•     C o n c o  mit a nt   m e di c ati o ns   
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis  b ef or e t h e   m or ni n g  d os e 
6. 3. 1. 4.      C y cl e    1,   D a y  1 5 (  C 1  D 1 5;    W e e k 3)  ±  2   d a ys 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c a l  e x a  mi n ati o n 
•     A E  ass ess  m e nt   
•     Cli ni c al l a b or at or y t ests   – s er u  m  c h e  mistr y,  h e  m at ol o g y, li v er f u n cti o n  a n d 
uri n al ysis 
•     C o n c o  mit a nt   m e di c ati o ns   
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis  b ef or e t h e   m or ni n g  d os e 
•     Bl o o d s a  m pli n g f or  P  D  a n al ysis  b ef or e t h e   m or ni n g  d os e 
T o  b e  p erf or  m e d  aft er  t h e   m or ni n g  d os e  of st u d y  dr u g: 
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis  at t h e f oll o  wi n g ti  m e  p oi nts:  0. 5,  1,  2,  4,  a n d  8  h 
aft er t h e   m or ni n g  d os e  ( b ef or e t h e  e v e ni n g  d os e) 
6. 3. 1. 5.      C y cl e  1,   D a y  2 2 (  C 1  D 2 2;    W e e k  4)  ±  2  d a ys 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur  e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e  
•     P h ysi c al  e x a  mi n ati o n  
•     A E  ass ess  m e nt   
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n a n d 
uri n al ysis 
•     C o n c o  mit a nt   m e di c ati o ns   
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis  b ef or e t h e   m or ni n g  d os e 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 0  of  9 0 
6. 3. 2.      
C y cl e   2 
6. 3. 2. 1.      C y cl e  2  ,   D a y  1 (  C 2  D 1;    W e e k  5)  ±  2  d a ys 
•     Dis p e nsi n g  of st u d y  dr u g  a n d s u bj e ct  di ar y 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     E  C  O  G  P S  
•     E  C  G  
•     E  C  H  O/  M  U  G  A  
•     A E  ass ess  m e nt   
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y, li v er f u n cti o n,  uri n al ysis, 
a n d   h or  m o n e t esti n g 
•     C o n c o  mit a nt   m e di c ati o ns   
•     Bl o o d s a  m pli n g f or  P  K  a n al ysis  b ef or e t h e   m or ni n g  d os e 
•     Bl o o d s a  m pli n g f or  P  D  a n al ysis  b ef or e t h e   m or ni n g  d os e 
6. 3. 2. 2.      C y cl e  2,   D a y  8   (  C 2  D8 ;    W e e k 6)  ±  2  d a ys 
•     Cli ni c al   l a b or at or y t ests – li v er f u n cti o n 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
6. 3. 2. 3.      C y cl e  2,   D a y  1 5 (  C 2  D 1 5;    W e e k  7)  ±  2  d a ys 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     A E  ass ess  m e nt   
•     Cli ni c al l a b or at or y t e  sts – s er u  m  c h e  mistr y,  h e  m at ol o g y, li v er f u n cti o n,  uri n al ysis 
a n d  h or  m o n e t esti n g 
•     C o n c o  mit a nt   m e di c ati o ns   
6. 3. 2. 4.      C y cl e  2,   D a y  2 2   (  C 2  D2 2 ;    W e e k 8)  ±  2  d a ys 
•     Cli ni c al l a b or at or y t ests   – li v er f u n cti o n 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 1  of  9 0 
6. 3. 3.      
C y cl e  3   
6. 3. 3. 1.      C y cl e  3,   D a y  1 (  C 3  D 1  ;    W e e k  9) ±  2  d a ys 
•     Dis p e nsi n g  of st u d y  dr u g  a n d s u bj e ct  di ar y 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     C T/  M  RI (  M  RI  of t h e  aff e ct e d j oi nt    f or s u bj e cts   wit h T  G  C T  is   m a n d at or y *) 
•     E  C  O  G  P S  
•     E  C  G  
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n, a n d 
uri n al ysis 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
* F or  T  G  C T s u bj e cts,   M  RI  of t h e  aff e ct e d j oi nt is   m a n d at or y  a n d t h e   C T  or   M  RI s c a ns  of 
t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e  n ot r e q uir e d,  a n d t o  b e  d o n e  u p o n t h e i n v esti g at or’s 
dis cr eti o n. 
6. 3. 3. 2.      C y cl e   3,   D a y  8  (  C3  D 8 ;    W e e k 1 0 )  ± 2  d a ys 
•     Cli ni c al l a b or at or y t ests   –li v er f u n cti o n 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
6. 3. 3. 3.      C y cl e   3,   D a y  1 5 (  C3  D 1 5 ;    W e e k 1 1 )  ± 2  d a ys 
•     Cli ni c al l a b or at or y t ests   –li v er f u n cti o n 
•     A  E  ass ess  m e nt  
•     C o n c o  mit a nt   m e di c ati o ns   
6. 3. 4.      
C y cl e  4   
6. 3. 4. 1.      C y cl e   4,   D a y  1 (  C 4 D 1;    W e e k   1 3 ) ±  7  d a ys 
•     Dis p e nsi n g  of st u d y  dr u g  a n d st u d y  di ar y 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     E  C  O  G  P S  
•     E  C  G  
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n, a n d 
uri n al ysis 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 2  of  9 0 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
6. 3. 4. 2.      C y cl e    4,   D a y  1 5 (  C4  D 1 5 ;    W e e k 1 5 )  ± 7  d a ys 
•     Cli ni c al l a b or at or y t ests   –li v er f u n cti o n 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
6. 3. 5.      
C y cl e  5   a n d t h e r e aft e r  ( b ef o r e  e nt e ri n g  e xt e nsi o n  p a rt) 
6. 3. 5. 1.      C y cl e   5,   D a y  1 (  C 5 D 1  + ;    W e e k 1 7 )  a n d t h e r e aft e r ( b ef o r e  e nt e ri n g 
e xt e nsi o n  p a rt )  ±  7  d a ys 
•     Dis p e nsi n g  of st u d y  dr u g  a n d st u d y  di ar y 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     C T/  M  RI (  M  RI  of t h e  aff e ct e d j oi nt    f or s u bj e cts   wit h T  G  C T  is   m a n d at or y *) 
•     E  C  O  G  P S  
•     E  C  G  
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n, a n d 
uri n al ysis 
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
* F or  T  G  C T s u bj e cts,   M  RI  of t h e  aff e ct e d j oi nt is   m a n d at or y  a n d t h e   C T  or   M  RI s c a ns  of 
t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e  n ot r e q uir e d,  a n d t o  b e  d o n e  u p o n t h e i n v esti g at or’s 
dis cr eti o n. 
6. 3. 6.      
T r e at  m e nt   Visits   D u ri n g   E xt e nsi o n  p a rt   
6. 3. 6. 1.      E v e r y  4   w e e ks   ±  7  d a ys 
•     Dis p e nsi n g  of st u d y  dr u g  a n d s u bj e ct  d  i ar y 
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n, a n d 
c o a g ul ati o n 
•     A E  ass ess  m e nt   
6. 3. 6. 2.      E v e r y  1 2   w e e ks    ±  7  d a ys 
•     Dis p e nsi n g  of st u d y  dr u g  a n d s u bj e ct  di ar y 
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e, r es pir at or y r at e,  a n d t e  m p er at  ur e  
•     P h ysi c al  e x a  mi n ati o n  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 3  of  9 0 
•     E  C  G  
•     E  C  H  O/  M  U  G  A  
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n, 
c o a g ul ati o n,  a n d  uri n al ysis 
•     C T/  M  RI (  M  RI  of t h e  aff e ct e d j oi nt    f or s u bj e cts   wit h T  G  C T  is   m a n d at or y *) 
•     S er u  m  pr e g n a n c y t est  
•     A E  ass ess  m e nt   
•     C o n c o  mit a  nt   m e di c ati o ns  
* F or  T  G  C T s u bj e cts,   M  RI  of t h e  aff e ct e d j oi nt is   m a n d at or y  a n d t h e   C T  or   M  RI s c a ns  of 
t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e  n ot r e q uir e d,  a n d t o  b e  d o n e  u p o n t h e i n v esti g at or’s 
dis cr eti o n. 
6. 4.      E n d  of   T r e at  m e nt   
T h e  d at e  of  dis c o nti n u ati o n  of tr e at  m e nt is  d efi n e d  as t h e  d at e  of  d e cisi o n  b y   t h e 
i n v esti g at or.  T h e f oll o  wi n g  ass ess  m e nts   will  b e  p erf or  m e d  at  t h e e n d  of t r e at  m e nt visit 
(  wit hi n  3 d a ys  aft er t h e  d at e  of   dis c o nti n u ati o n).  If t h e ass ess  m e nt s at t h e  e n d  of 
tr e at  m e nt ar e  p erf or  m e d i n t h e tr e at  m e nt  p eri o d, t h e y  c a n  b e  c o nsi d er e d t o  b e t h e  e n d  of 
tr e at  m e nt d at a  a n d t h er e is  n o  n e e d t o r e p e at t h e  m.  
•     A E  ass ess  m e nt   
•     Vit al si g ns, i n cl u di n g  bl o o d  pr ess ur e,  p uls e r at e,   r es pir at or y r at e, a n d t e  m p er at ur e 
•     P h ysi c al  e x a  mi n ati o n  
•     M  U  G  A   
•     Cli ni c al l a b or at or y t ests   –  s er u  m  c h e  mistr y,  h e  m at ol o g y,  li v er f u n cti o n,  uri n al ysis, 
c o a g ul ati o n,  a n d  h or  m o n e t esti n g 
•     1 2- l e a d  E  C  G 
•     C T/  M  RI (  M  RI  of t h e  aff e ct e d j oi nt    f or s u bj e cts   wit h T  G  C T  is   m a n d at or y *) 
•     E  C  O  G  P S  
•     C o n c o  mit a nt   m e di c ati o ns   
•     W ei g ht    
•     Pr e g n a n c y t est  
* F or  T  G  C T s u bj e cts,   M  RI  of t h e  aff e ct e d j oi nt is   m a n d at or y  a n d t h e   C T  or   M  RI s c a ns  of 
t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e  n ot r e q uir e d,  a n d t o  b e  d o n e  u p o n t h e i n v esti g at or’s 
dis cr eti o n. 
6. 5.      F oll o  w- u p  
T h e  f oll o  w- u p  visit is s c h e d ul e d  at  2 8  d a ys ( ± 7  d a ys)  aft er t h e l ast  a d  mi nistr ati o n  of  
p e xi d arti ni b .  If t h e s u bj e ct  b e gi ns  a n ot h er  a nti c a n c er t h er a p y  b ef or e t h e  e n d  of t h e 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 4  of  9 0 
2 8  d a ys ( ±  7  d a ys),  e v er y  eff ort   will  b e   m a d e t o  c o  m pl et e  all t h e  f oll o  w- u p  visit 
ass ess  m e nts  pri or t o  c o  m  m e n ci n g t h e  n e  w t h er a p y.   I n  c as e  of  u nr es ol v e d   A Es, t h e 
i n v esti g at or   will f oll o  w t h e   A Es  u ntil t h e  e v e nt  h as r es ol v e d  or t h e  c o n diti o n  h as 
st a bili z e d  as  p ossi bl e.   If t h e ass ess  m e nts  at  e n d  of t r e at  m e nt or  tr e at  m e nt  p eri o d  ar e 
p erf or  m e d   wit hi n t his  p eri o d, t h e y  c a n  b e  c o nsi d er e d t o  b e t h e f oll o  w- u p  d at a  a n d t h er e is 
n o  n e e d t o r e p e at t h e  m.  
T h e f oll o  wi n g i nf or  m ati o n   will  b e  c oll e ct e d  at  t h e f oll o  w- u p visit:  
•     A E  ass ess  m e nt   
•     C o n c o  mit a nt   m e di c ati o ns   
6. 6.      P h a r  m a c o g e n o  mi c  s a  m pl e  c oll e cti o n  visit  
P arti ci p ati o n i n t his  p art  of t h e st u d y is  o pti o n al f or  all s u bj e cts.  P h ar  m a c o g e n o  mi c  
s a  m pl e   m a y  als o  b e  c oll e ct e d fr o  m  dis c o nti n u e d s u bj e cts   w h o  pr o vi d e  c o ns e nt,  a n d  c o ul d 
b e  c oll e ct e d  a n yti  m e  d uri n g st u d y  c o n d u ct .   F or  o n g oi n g s u bj e cts, t his  visit  c o ul d  b e 
c o  m bi n e d   wit h s u bj e cts’  c urr e nt st u d y  visit s c h e d ul e.  
•     C oll e ct si g n e d i nf or  m e d  c o n  s e nt f or  p h ar  m a c o g e n o  mi cs st u d y  p arti ci p ati o n  
•     C oll e ct  a   si n gl e  bl o o d s a  m pl e ( 1 0   m L)  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 5  of  9 0 
7.      
E F FI  C  A  C  Y   A S S  E S S   M  E  N  T S   
Effi c a c y  ass ess  m e nts   will  b e  b as e d  o n t u  m or  ass ess  m e nts t o  b e  p erf or  m e d  at   t h e 
s cr e e ni n g  p eri o d a n d  at l e ast  e v er y  2  c y cl es  ( ±  7 d a ys) i n t h e first  4  c y cl e s  aft er C 1  D 1    a n d 
t h er e aft er  at l e ast e v er y  3  c y cl es  ( ±  7 d a ys)  if t h e s u bj e ct r e  m ai ns i n t h e st u d y  t h er a p y.  
T h e  cli ni c al  a cti vit y  of  p e xi d arti ni b  will  b e    ass ess e d  b y  e v al u ati n g t u  m or r es p o ns e.  
T u  m or r es p o ns e   will  b e  e v al u at e d  usi n g   R E  CI S T   V ersi o n  1. 1.   T h e  C T  or   M  RI (s pir al   C T 
or   M  RI   wit h  ≤   5   m  m  c uts)  of  br ai n,  c h est,  a b d o  m e n,  a n d  p el vis will    b e  us e d f or t h e t u  m or 
ass ess  m e nt  u nl ess  a n ot h er   m o d alit y  of  dis e as e  ass ess  m e nt is  n e c ess ar y f or t h e l esi o ns  at 
t h e s cr e e ni n g  p eri o d.   E v er y  eff ort s h o ul d  b e   m a d e t o  us e t h e  s a  m e  ass ess  m e nt   m o d alit y 
f or all  ass ess  m e nts f or  e a c h s u bj e ct.     H o  w e v er, if t h er e is  n o br ai n   m et ast asis  at t h e ti  m e 
of s cr e e ni n g,   C T  or   M  RI s h o ul d  b e  p erf or  m e d  o nl y  b e  d o n e   w h e n  s y  m pt o  ms  ass o ci at e d 
wit h  br ai n   m et ast asis  o c c ur  d uri n g   t h e st u d y  p eri o d.   If  n o  cli ni c al s y  m pt o  ms  ar e  o bser v e d, 
br ai n   C T  or   M  RI is  n ot   m a n d at or y  d uri n g  t h e st u d y  p eri o d.  T h e f oll o  wi n g  effi c a c y 
v ari a bl es   will  b e  ass ess e d : 
•     O  R  R   D  C  R    
•     R es p o ns e  d ur ati o n 
•     D ur ati o n  of  S  D 
•     T T  R  
•     P er c e nt a g e  of  c h a n g e i n t ar g et l esi o n (s) 
7. 1.      T u  m o r I  m a gi n g 
T h e s a  m e t u  m or  i  m a gi n g ass ess  m e nt  as  a t t h e ti  m e  of s cr e e ni n g  b y   C T  or   M  RI s c a ns   will 
b e  p erf or  m e d  at l e ast  e v er y  2  c y cl es ( ±  7  d a ys)  i n t h e first 4  c y cl e s  aft er   C 1  D 1, t h er e aft er 
at l e ast  e v er y  3  c y cl es  ( ±  7 d a ys)  if t h e s u bj e ct r e  m ai ns i n t h e st u d y t h er a p y, at  e v er y 
1 2  w e e ks   ( ±  7 d a ys)   d uri n g  e xt e nsi o n p art  of  t h e st u d y,  a n d t h e  e n d  of tr e at  m e nt  visit.  
T h e  ass ess  m e nt   will  b e  c o n d u ct e d  b ef or e   D a y  1  of  e a c h  c y cl e  as  p ossi bl e.   T h e   C T  or 
M  RI s c a ns  of t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e   m a n d at or y.    H o  w e v er, if t h er e is  n o 
br ai n   m et ast asis  at t h e t i  m e  of s cr e e ni n g,   C T  or   M  RI s h o ul d  b e  p erf or  m e d  o nl y   w h e n 
s y  m pt o  ms  ass o ci at e d   wit h  br ai n   m et ast asis  o c c ur.  If  n o  cli ni c al s y  m pt o  ms  ar e  o bs er v e d, 
a  br ai n   C T  or   M  RI is  n ot   m a n d at or y. 
F or s u bj e cts  wit h  T  G  C T  ,  n o n-c o ntr ast   M  RI  of t h e  aff e ct e d j oi nt   will  b e  p er f or  m e d  at t h e 
st u d y  visits i n di c at e d i n t h e  S c h e d ul e  of  E v e nts (  A p p e n di x   1 7. 1) *. 
* F or  T  G  C T s u bj e cts,   M  RI  of t h e  aff e ct e d j oi nt is   m a n d at or y  a n d t h e   C T  or   M  RI s c a ns  of 
t h e  c h est,  a b d o  m e n,  a n d  p el vis  ar e  n ot r e q uir e d,  a n d t o  b e  d o n e  u p o n t h e i n v esti g at or’s 
dis cr eti o n. 
7. 2.      Effi c a c y   E n d p oi nts 
7. 2. 1.      
P ri  m a r y   Effi c a c y  E n d p oi nt  s 
N ot  a p pli c a bl e.   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 6  of  9 0 
7. 2. 2.      
S e c o n d a r y   Effi c a c y  E n d p oi nt  s 
N ot  a p pli c a bl e.   
7. 2. 3.      
E x pl o r at o r y   Effi c a c y   E n d p oi nt  s 
N ot  a p pli c a bl e.   
7. 2. 4.      
A p p r o p ri at e n ess  of  S el e ct e d   Effi c a c y   E n d p oi nts   
N ot   a p pli c a bl e . 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 7  of  9 0 
8.      
P  H  A  R   M  A  C  O  KI  N  E  TI  C/ P  H  A  R   M  A  C  O  D  Y  N  A   MI  C   A S S  E S S   M  E N  T S   
8. 1.      P h a r  m a c o ki n eti c  E n d p oi nt  (s) 
T h e  P  K/ P  D s a  m pli n g   will  b e  p erf or  m e d  at t h e st u d y  visits i n di c at e d i n t h e  S c h e d ul e  of 
E v e nts (  A p p e n di x   1 7. 1).    D et ail e d i nstr u cti o ns  o n  c oll e cti o n,  pr o c essi n g,  h a n dli n g, 
st or a g e,  a n d s a  m pl e s hi p  m e nt  ar e  d es cri b e d  i n t h e s e p ar at e  L a b or at or y   M a n u al. 
Bl o o d s a  m pl es  of  a p pr o xi  m at el y  3   m L f or  P  Ks ( 5     m L f or  P  K  a n d  P  D  o n   C 1  D 1,  a n d 
C 1  D 1 5,   C 2  D 1)  a n al ys es   will  b e  c oll e ct e d  at t h e ti  m e  p  oi nts s p e cifi e d i n  T a bl e   8. 1. 
T h e  e x a ct ti  m e  of  d os e  a d  mi nistr ati o n s h o ul d  b e r e c or d e d  al o n g   wit h t h e  c orr es p o n di n g 
P  K  bl o o d s a  m pli n gs.   T h e  e x a ct ti  m e  of t h e  pr e c e di n g  d os es s h o ul d  als o  b e r e c or d e d. 
T a bl e  8. 1:       P  h a r  m a c o ki n eti cs  S a  m pli n g   Ti  m e  P oi nts  
C y cl e        
D a y       
S a  m pli n g   Ti  m e  P oi nt (  A c c e pt a bl e   R a n g e)   
C y cl e  1        
D a y  1        
Pr e d os e  
0. 5  h  aft er  a d  mi nistr ati o n ( ±  1 0  mi n ut es)    
1  h  aft er  a d  mi nistr ati o n ( ±  1 5   mi n ut e s)   
2  h  aft er  a d  mi nistr ati o n ( ±  1 5   mi n ut e s)   
4  h  aft er  a d  mi nistr ati o n ( ±  2 0   mi n ut e s)   
8  h  aft er  a d  mi nistr ati o n ( ±  2 0   mi n ut e s)   
 
D a y  2        
2 4  h  aft er  a d  mi nistr ati o n ( ±  6 0  mi n ut e s)   
S a  m pl e s h o ul d  b e  c oll e ct e d  b ef or e  t h e m or ni n g  d os e   
 
D a y  8        
Pr e d os e ( ±  2  d a ys)   
 
D a y  1 5       
Pr e d os e  
0. 5  h  aft er  a d  mi nistr ati o n ( ±  1 0  mi n ut es)    
1  h  aft er  a d  mi nistr ati o n ( ±  1 5   mi n ut e s)   
2  h  aft er  a d  mi nistr ati o n ( ±  1 5   mi n ut e s)   
4  h  aft er  a d  mi nistr ati o n ( ±  2 0   mi n ut e s)   
8  h  aft er  a d  mi nistr ati o n ( ±  2 0   mi n ut e s)  
 
D a y  2 2        
Pr e d os e  ( ±  2  d a ys) 
C y cl e  2        
D a y  1        
Pr e d os e ( ±  2  d a ys)  
T h e  pl as  m a  P  K  p ar a  m et ers  of  p e xi d arti ni b  a n d its   m et a b olit e list e d i n  T a bl e   8. 2 f or  e a c h 
s u bj e ct   will  b e  esti  m at e d  usi n g st a n d ar d  n o n- c o  m p art  m e nt al   m et h o ds.   Pri  m ar y  P K 
p ar a  m et ers  ar e t h e  ar e a  u n d er t h e  pl as  m a - c o n c e ntr ati o n-ti  m e  c ur v e fr o  m ti  m e 0 t o  8  h 
(A  U  C 0- 8 h), C  m a x  ,  a n d  Tm a x   f or   D a y  1  a n d   D a y  1 5. 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 8  of  9 0 
T a bl e  8. 2:       P  h a r  m a c o ki n eti cs  P a r a  m et e rs  
D a y   1 
P e a k  dr u g  c o n c e ntr ati o n  (  Cm a x  ) 
Ti  m e  of   m a xi  m u  m  o bs er v e d  c o n c e ntr ati o n  ( Tm a x  ) 
Ar e a   u n d er t h e  pl as  m a  c o n c e ntr ati o n -ti  m e  c ur v e fr o  m ti  m e 0  t o 8  h  (  A  U  C0 -8 h) 
D a y  1 5   
M  a xi  m u  m  pl as  m a  c o n c e ntr ati o n (  C m a x  ) 
Ti  m e  of   m a xi  m u  m  o bs er v e d  c o n c e ntr ati o n  ( Tm a x  ) 
Ar e a  u n d er t h e  pl as  m a  c o n c e ntr ati o n  -ti  m e  c ur v e fr o  m ti  m e 0  t o  8 h (  A  U  C 0 -8 h) 
8. 2.      P h a r  m a c o d y n a  mi c  E n d p oi nts   
Pl as  m a f or  cir c ul ati n g  P  D  bi o  m ar k ers   will  b e  c oll e ct e d  o n c e  p er  d a y  o n t h e s a  m e  d a ys 
w h e n  P  K  bl o o d s a  m pl e(s)  ar e  dr a  w n ( e g,  pr e d os e)  a n d   will  b e  a n al y z e d f or  e x pl or at or y 
bi o  m ar k ers  of   m o n o c yt e  or   m a cr o p h a g e  a cti viti es, i n cl u di n g   C S F- 1  a n d  a di p o n e cti n . 
Bl o o d s a  m pl es f or  P  K/ P  D ( 5   m L f or  P  K  a n d  P  D  o n   C 1  D 1,  a n d   C 1  D 1 5,   C 2  D 1)  a n al ys es 
will  b e  c oll e ct e d  at t h e ti  m e  p oi nts s p e cifi e d i n   A p p e n di x    1 7. 1. 
Bl o o d s a  m pl es  c oll e ct e d  at s p e cifi e d ti  m e  p oi nts   will  b e  a n al y z e d f or  pl as  m a   C S F  - 1  a n d 
a di p o n e cti n  i n di c at e d i n t h e S c h e d ul e  of  E v e nts (  A p p e n di x   1 7. 1).  N o f or  m al st atisti c al 
a n al ysis  of  P  D  v ari a bl es   will  b e  p erf or  m e d.   T h e  P  D   d at a   will  b e list e d  b y  c o h ort  a n d 
s u  m  m ari z e d   wit h  d es cri pti v e st atisti cs  b y  d os e  a n d  visit.  
8. 3.      Bi o  m a r k e r   E n d p oi nt  s 
N ot  a p pli c a bl e.   
8. 4.      I  m  m u n o g e ni cit y  
N ot  a p pli c a bl e.   
8. 5.      P h a r  m a c o g e n o  mi c   A n al ysis 
   A si n gl e  bl o o d s a  m pl e ( 1 0   m L) f or  p h ar  m a c o g e n o  mi cs  a n al ysis   will  b e  c oll e ct e d fr o  m 
e a c h s u bj e ct   w h o  c o ns e nts  t o t his t est.  P h ar  m a c o g e n o  mi c s a  m pl e s m a y  als o  b e  c oll e ct e d 
fr o  m  dis c o nti n u e d s u bj e cts   w h o  pr o vi d e  c o ns e nt.   P arti ci p ati o n i n t his  p art  of t h e st u d y is 
o pti o n al f or  all s u bj e cts. 
P h ar  m a c o g e n o  mi c s a  m pl es  will  b e  a n al y z e d f or   U  G T 1  A 4  g e n ot y p e.   A d diti o n al 
g e n ot y pi n g  m a y  b e   d o n e f or  g e n es i n v ol v e d i n s af et y  of  p e xi d arti ni b.   A d diti o n all y, 
s a  m pl es   m a y  b e  a n al y z e d f or  g e n es i n v ol v e d i n  p e xi d arti ni b-r el at e d si g n ali n g  p at h  w a ys, 
or t o  e x a  mi n e  dis e as es  or  p h ysi ol o gi c  pr o c ess es r el at e d t o  p e xi d arti ni b.  D  N  A s a  m pl es 
will  n ot  b e i  m  m ort ali z e d  or s ol d t o  a n y o n e.   T his i nf or  m ati o n   m a y   b e  us ef ul i n i n cr e asi n g 
t h e  k n o  wl e d g e  of  diff er e n c es  a  m o n g i n di vi d u als i n t h e   w a y t h e y r es p o n d t o t h e st u d y 
dr u g,  as   w ell  as  h el pi n g i n t h e  d e v el o p  m e nt  of  n e  w  dr u gs  or i  m pr o v e  m e nt  of  e xisti n g 
dr u gs.  
S p e ci  m e n s hi p pi n g  a n d  h a n dli n g  d et ails   will  b e i n cl u d e d i n t h e l a b or at or y   m a n u al. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  5 9  of  9 0 
9.      
S  A F  E  T  Y   E  V  A  L  U  A  TI  O  N   A  N  D   R  E P  O  R  TI  N  G  
9. 1.      A d v e rs e   E v e nt   C oll e cti o n  a n d   R e p o rti n g   
All  cli ni c al   A Es (s e e  S e cti o n    9. 4. 1 f or  d efi niti o ns)  o c c urri n g  aft er t h e s u bj e ct si g ns t h e 
IC F    a n d  u p t o t h e F oll o w- u p  v  isit aft er t h e l ast  d os e  of st u d y  dr u g  (i e, t h e F oll o  w- u p 
p eri o d),   w h et h er  o bs er v e d  b y t h e i n v esti g at or  or r e p ort e d  b y t h e s u bj e ct,   will  b e r e c or d e d 
o n t h e  A E    e  C  R F  p a g e.    M e di c al  c o n diti o ns (i n cl u di n g l a b or at or y  v al u es/ vit al si g ns t h at 
ar e  o ut  of r a n g e) t h at   w er e  di a g n os e d  or  k n o  w n t o  e xist  pri or t o i nf or  m e d  c o ns e nt  will  b e 
r e c or de d  as  p art  of  t h e m e di c al  hist or y.   
All   A Es  a n d   S  A Es  ar e t o  b e r e p ort e d  a c c or di n g t o t h e  pr o c e d ur es  i n di c at e d i n  S e cti o n  9. 5. 
All   l a b or at or y r es ults,  vit al si g ns,  a n d  E  C  G fi n di n gs s h o ul d  b e  a p pr ais e d  b y t h e 
i n v esti g at or t o  d et er  mi n e t h eir  cli ni c al si g nifi c a n c e.  All  a b n or  m al l a b or at or y r es ults 
c o nsi d er e d t o  b e  cli ni c all y si g nifi c a nt  b y t h e  in v esti g at or  m ust  b e r e c or d e d  as   A E  s  o n t h e 
e  C  R F,  a n d if s eri o us, r e p ort e d  as  S  A E s f oll o  wi n g t h e  pr o c e d ur es  i n di c at e d i n  S e cti o n  9. 5. 
Dis e as e  pr o gr essi o n   is  a st u d y  e n d p oi nt  a n d  c o ns e q u e ntl y, s h o ul d  n ot  b e r e p ort e d  as  a n 
A E   or  S  A E.    H o  w e v er,   w h e n  a s u bj e c t  di es fr o  m dis e as e  pr o gr essi o n  wit h  o ut  ot h er 
i  m  m e di at e  c a us es,  “d is e as e  pr o gr essi o n” s h o ul d  b e r e p ort e d  as  a  S  A E.   A n y s eri o us, 
u nt o  w ar d  e v e nt t h at  o c c urs s u bs e q u e nt t o t h e r e p orti n g  p eri o d t h at t h e i n v esti g at or 
ass ess es  as r el at e d t o t h e  st u d y  dr u g s h o ul d  als o  b e r e p ort e d  a n d   m a n a g e d  as  a n  S  A E.   At 
e a c h  visit, t h e  i n v esti g at or will  d et er  mi n e   w h et h er  a n y   A Es  h a v e  o c c urr e d  b y  e v al u ati n g 
t h e s u bj e ct.  T h e   A Es  c a n   b e  dir e ctl y  o bs er v e d, r e p ort e d s p o nt a n e o usl y  b y t h e s u bj e ct, or 
b y  q u esti o ni n g t h e s u bj e ct  at  e a c h st u d y  visit.   S u bj e cts s h o ul d  b e  q u esti o n e d i n  a  g e n er al 
w a y   wit h o ut  as ki n g  a b o ut t h e  o c c urr e n c e  of  a n y s p e cifi c s y  m pt o  ms.   T h e i n v esti g at or 
m ust  ass ess  all   A Es t o  d et er  mi n e s eri o us n ess, s e v erit y,  a n d  c a us alit y i n  a c c or d a n c e   wit h 
t h e  d efi niti o ns i n  S e cti o n  9. 4. 3 a n d   9. 4. 4.   T h e in v esti g at or’s  ass ess  m e nt   m ust  b e  cl e arl y 
d o c u  m e nt e d i n t h e  st u d y sit e’s s o ur c e  d o c u  m e nt ati o n   wit h t h e i n v esti g at or’s si g n at ur e.  
Al  w a ys r e p o  rt  di a g n osis  as a n    A E  or  S  A E t er  m.     W h e n  a  di a g n osis is  u n a v ail a bl e, r e p ort 
t h e  pri  m ar y si g n  or s y  m pt o  m  as t h e   A E  or  S  A E t er  m   wit h  a d diti o n al  d et ails i n cl u d e d i n 
t h e  n arr ati v e  u ntil t h e  di a g n osis  b e c o  m es  a v ail a bl e.  If t h e si g ns  a n d s y  m pt o  ms  ar e 
disti n ct  a n d  d o  n ot s u g g est  a  c o  m  m o n  di a g n osis, r e p ort t h e  m  as i n di vi d u al  e ntri es  of   A E 
or  S  A E.  
F or  e v e nts t h at  ar e s eri o us  d u e t o  h os pit ali z ati o n, t h e r e as o n f or  h os pit ali z ati o n   m ust  b e 
r e p ort e d  as a  S  A E ( di a g n osis  or s y  m pt o  m r e q uiri n g  h os pit ali z ati o n).    A  pr o c e d ur e is  n ot 
a n   A E  or  S  A E,  b ut t h e r e as o n f or t h e  pr o c e d ur e   m a y  b e  a n   A E  or  S  A E.   Pr e pl a n n e d ( pri or 
t o si g ni n g t h e IC F  )  pr o c e d ur e  or tr e at  m e nt r e q uiri n g  h os pit ali z ati o n f or  pr e-e xisti n g 
c o n diti o ns  t h at d o  n ot   w ors e n i n s e v erit y s h o ul d  n ot  b e r e p ort e d  as  S  A Es ( s e e 
S e cti o n   9. 4. 2).   F or  d e at hs, t h e  u n d erl yi n g  or i  m  m e di at e  c a us e  of  d e at h s h o ul d  al  w a ys  b e 
r e p ort e d  as  a n  S  A E. 
T h e  i n v esti g at or s h o ul d f oll o  w t h e s u bj e cts   wit h A Es    u ntil t h e  e v e nts  h a v e  b e e n r es ol v e d 
or t h e  c o n diti o n  h as  b e e n  st a bili z e d.  I n  c as e  of  u nr es ol v e d  A Es   i n cl u di n g si g nifi c a nt 
a b n or  m al l a b or at or y  v al u es  at t h e  e n d  of st u d y  ass ess  m e nt, t h es e  e v e nts   will  b e f oll o  w e d 
u p  u ntil r es ol uti o n  or  b e c o  mi n g  n ot  cli ni c all y r el e v a nt.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 0  of  9 0 
9. 2.      S af et y   E n d p oi nt  E v e nt  s 
S af et y  e n d p oi nts i n cl u d e   D L Ts,  S  A Es,  T E  A Es,  p h ysi c al  e x a  mi n ati o n fi n di n gs (i n cl u di n g 
E  C  O  G  P S),  vit al si g n   m e as ur e  m e nts, st a n d ar d  cli ni c al l a b or at or y  p ar a  m et ers,   E  C  G 
p ar a  m et ers,  a n d  E  C  H  O/  M  U  G  A fi n di n gs.   All   T E  A Es   will  b e  gr a d e d  a c c or di n g t o t h e 
N ati o n al   C a n c er I nsti  t ut e   C o  m  m o n  T er  mi n ol o g y   Crit eri a f or   A d v ers e  E v e nt 
(  N  CI-C T  C  A E)     Ver si o n  4. 0. 
9. 3.      E v e nts  of  S p e ci al I nt e r est   
9. 3. 1.      
C o  m bi n e d   El e v ati o ns  of   A  mi n ot r a nsf e r as es  a n d   Bili r u bi n   
C o  m bi n e d  el e v ati o ns  of  a  mi n otr a nsf er as es  a n d  bilir u bi n,  eit h er s eri o us  or  n o ns eri o us  a n d 
w h et h er  or  n ot  c a us all y r el at e d,   m e eti n g t h e l a b or at or y  crit eri a  of  a  p ot e nti al   H y’s  L a  w 
c as e  (A L T  or   A S T  ≥  3   ×  U L  N   wit h si  m ult a n e o us t ot al  bilir u bi n   ≥  2  ×  U L  N  ) s h o ul d 
al  w a ys  b e r e p ort e d t o t h e  S p o ns or  usi n g  a  S eri o us   A d v ers e  E v e nt   R e p ort ( S  A  V E  R)  F or  m 
or  a s p e ci al  c oll e cti o n  of  e  C  R F  al o n g  wit h t h e   i n v esti g at or’s ass ess  m e nt  of s eri o us n ess, 
c a us alit y,  a n d  a  d et ail e d  n arr ati v e.   T h es e  e v e nts s h o ul d  b e r e p ort e d   wit hi n  2 4  h  of  t h e 
i n v esti g at or’s a  w ar e n ess  of t h e  e v e nt s. 
If t h e s u bj e ct  dis c o nti n u es t h e st u d y  dr u g  d u e t o l i v er  e n z y  m e  a b n or  m aliti es, t h e s u bj e ct 
will  h a v e  a d diti o n al  cli ni c al  a n d l a b or at or y  e v al u ati o ns  as  d es cri b e d i n  S e cti o n    5. 1 0 i n 
or d er t o  d et er  mi n e t h e  c a us e  a n d s e v erit y  of t h e  p ot e nti al li v er i nj ur y.  
9. 4.      A d v e rs e   E v e nt   
9. 4. 1.      
D efi niti o n  of   A d v e rs e   E v e nt   
A n   A E   is  an y  u nt o  w ar d   m e di c al  o c c urr e n c e i n  a s u bj e ct  a d  mi nist er e d  a  p h ar  m a c e uti c al 
pr o d u ct  t h at  d o es  n ot  n e c ess aril y  h a v e t o  h a v e  a  c a us al r el ati o ns hi p   wit h t his tr e at  m e nt.  
A n   A E  c a n t h er ef or e  b e  a n y  u nf a v or a bl e  a n d  u ni nt e n d e d si g n (i n cl u di n g  a n  a b n or  m al 
l a b or at or y fi n di n g, f or  e x a  m pl e), s y  m pt o  m,  or  dis e as e t e  m p or all y  ass o ci at e d   wit h t h e  us e 
of  a   m e di ci n al  pr o d u ct,   w h et h er  or  n ot  c o nsi d er e d r el at e d t o t h e   m e di ci n al  pr o d u ct 
(I nt er n ati o n al   C o u n cil f or   H ar  m o nis ati o n [I C  H] E 2  A  G ui d eli n e.    Cli ni c al  S af et y   D at a 
M a n a g e  m e nt:   D efi niti o ns  a n d  St a n d ar ds f or  E x p e dit e d   R e p orti n g,   O ct  1 9 9 4). 
It is t h e r es p o nsi bilit y  of t h e i n v esti g at ors,  b as e d  o n t h eir  k n o  wl e d g e  a n d  e x p eri e n c e, t o 
d et er  mi n e t h os e  cir c u  mst a n c es  or  a b n or  m al l a b or at or y  fi n din gs  t h at s h o ul d  b e  c o nsi d er e d 
A Es  . 
9. 4. 2.      
S e ri o us   A d v e rs e   E v e nt  
S  A E  is  an y  u nt o  w ar d   m e di c al  o c c urr e n c e  at  a n y  d os e:  
•     R es ults i n  d e at h   
•     Is lif e-t hr e at e ni n g 
•     R e q uir es i n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  h os pit ali z ati o n   
•     R es ults i n  p ersist e nt  or si g nifi c a nt  dis a bilit y/i n c a p a cit y   
•     Is  a  c o n g e nit al  a n o  m al y/ birt h  d ef e ct 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 1  of  9 0 
•     Is  a n i  m p ort a nt   m e di c al  e v e nt 
N ot e:  T h e t er  m  “lif e  -t hr e at e ni n g ” i n t h e  d efi niti o n  of  “s eri o us ” r ef ers t o  a n  e v e nt i n   w hi c h 
t h e s u bj e ct   w as  at ris k  of  d e at h  at t h e ti  m e  of t h e  e v e nt; it  do es  n ot r ef er t o  a n  e v e nt  t h at 
h y p ot h eti c all y   mi g ht  h a v e  c a us e d  d e at h if it   w as    m or e s e v er e (I  C  H  E 2  A   G ui d eli n e. 
Cli ni c al  S af et y   D at a   M a n a g e  m e nt:   D efi niti o ns  a n d  St a n d ar ds f or  E x p e dit e d   R e p orti n g, 
O ct    1 9 9 4). 
M e di c al  a n d s ci e ntifi c j u d g  m e nt s h o ul d  b e  e x er cis e d i n     d e ci di n g   w h et h er t h e e x p e dit e d 
r e p orti n g is  a p pr o pri at e i n  ot h er sit u ati o ns, s u c h  as i  m p ort a nt   m e di c al  e v e nts t h at   m a y  n ot 
b e i  m  m e di at el y lif e -t hr e at e ni n g  or r es ult i n  d e at h  or  h os pit ali z ati o n  b ut   m a y j e o p ar di z e 
t h e s u bj e ct  or   m a y r e q uir e i nt er v e nti o n t o pr e v e nt  o n e  of t h e  ot h er  o ut c o  m es list e d i n t h e 
d efi niti o n  a b o v e.   E x a  m pl es i n cl u d e  all er gi c  br o n c h os p as  m,  c o n v ulsi o ns,  a n d  bl o o d 
d ys cr asi as  or  d e v el o p  m e nt  of  dr u g  d e p e n d e n c y  or  dr u g  a b us e. 
N ot e:    Pr o c e d ur es ar e   n ot   A Es or  S  A E s,  b ut t h e r e as o n f or t h e  pr o c e d ur e   m a y  b e  a n   A E  or 
S  A E.    Pr e pl a n n e d ( pri or t o si g ni n g t h e IC F  )  pr o c e d ur es  or tr e at  m e nts r e q uiri n g 
h os pit ali z ati o n f or  pr e- e xisti n g  c o n diti o ns  t h at  d o  n ot   w ors e n i n s e v erit y  ar e  n ot  S  A Es. 
9. 4. 3.      
S e v e rit y   Ass ess  m e nt  
All   A Es   will  b e  gr a d e d ( 1 t o  5; s e e  b el o  w)  a c c o  r di n g t o t h e   N  CI-C T  C  A E     Ver si o n  4. 0: 
•     Gr a d e    1: Mil d  .   A  w ar e n ess  of si g n  or s y  m pt o  m,  b ut  e asil y t ol er at e d, i e,  d o es  n ot 
i nt erf er e   wit h s u bj e ct’s  us u al f u n cti o n 
•     Gr a d e    2:   M o d er at e.   Dis c o  mf ort  e n o u g h t o  c a us e i nt erf er e n c e   wit h  us u al  a cti vit y 
•     Gr a d e    3: S e v er e . I n c ap a cit ati n g   wit h i n a bilit y t o   w or k  or  d o  us u al  a cti vit y, i e, 
i nt erf er es si g nifi c a ntl y   wit h s u bj e ct’s  us u al f u n cti o n 
•     Gr a d e    4: Lif e -t hr e at e ni n g or  dis a bli n g  A E  ;  ur g e nt i nt er v e nti o n i n di c at e d 
•     Gr a d e    5: D e at h r el at e d t o   A E   
S e v erit y  v ers u s  S eri o us n ess:  S e v erit y is  us e d t o  d es cri b e t h e i nt e nsit y  of  a s p e cifi c  e v e nt 
w hil e t h e  e v e nt its elf,  h o  w e v er,   m a y  b e  of r el ati v el y   mi n or   m e di c al si g nifi c a n c e (s u c h  as 
s e v er e  h e a d a c h e).   T his is  n ot t h e s a  m e  as  "s eri o us n ess",    w hi c h is  b as e d  o n s u bj e ct/ e v e nt 
o ut c o  m e  at t h e ti  m e  of  t h e  e v e nt.  F or  e x a  m pl e, t h e   N  CI -C T  C  A E   Gr a d e    4 
(lif e-t hr e at e ni n g c o ns e q u e n c es ,  ur g e nt i nt er v e nti o n i n di c at e d) is  ass ess e d  b as e d  o n  u ni q u e 
cli ni c al   d es cri pti o ns  of s e v erit y f or  e a c h   A E,  a n d t h es e  crit eri a   m a y  b e  diff er e nt fr o  m 
t h os e  us e d f or t h e  ass ess  m e nt of   A E s eri o us n ess.   A n   A E  ass ess e d  as   Gr a d e    4  b as e d  o n 
t h e   N  CI-C T  C  A E    gr a d es   m a y  or   m a y  n ot  b e  ass ess e d  as s eri o us  b as e d  o n t h e s eri o us n ess 
crit eri a.  
9. 4. 4.      
C a us alit y   Ass ess  m e nt   
T h e  i n v esti g at or s h o ul d  ass ess  c a us al r el ati o ns hi p  b et  w e e n  a n A E    a n d t h e st u d y dr u g   o n 
t h e  b asis of  his/ h er  cli ni c al j u d g  m e nt  a n d t h e f oll o  wi n g  d efi niti o ns.   T h e  c a us alit y 
ass ess  m e nt  m ust  b e   m a d e  b as e d  o n t h e  a v ail a bl e i nf or  m ati o n  a n d  c a n  b e  u p d at e d  as  n e  w 
i nf or  m ati o n  b e c o  m es  a v ail a bl e. 
•     R el at e d:   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 2  of  9 0 
−     T h e   A E f oll o  ws  a r e as o n a bl e t e  m p or al s e q u e n c e  fr o  m t h e st u d y  dr u g 
a d  mi nistr ati o n,  a n d  c a n n ot  b e r e as o n a bl y  e x pl ai n e d  b y t h e s u bj e ct’s 
cli ni c al st at e  or  ot h er f a ct ors ( e g,  dis e as e  u n d er st u d y,  c o n c urr e nt  dis e as es, 
a n d  c o n c o  mit a nt   m e di c ati o ns). 
O  R   
−     T h e   A E f oll o  ws  a r e as o n a bl e t e  m p or al s e q u e n c e fr o  m t h e  st u d y  dr u g 
a d  mi nistr ati o n,  a n d is  a  k n o  w n r e a cti o n t o t h e  dr u g  u n d er st u d y  or its 
c h e  mi c al  gr o u p,  or  c a n  b e   pr e di ct e d  b y  k n o  w n  p h ar  m a c ol o g y. 
•     N ot   R el at e d:   
−     T h e   A E  d o es  n ot f oll o  w  a r e as o n a bl e s e q u e n c e fr o  m st u d y  dr u g 
a d  mi nistr ati o n,  or  c a n  b e r e as o n a bl y  e x pl ai n e d  b y t h e s u bj e ct’s  cli ni c al 
st at e  or  ot h er f a ct ors ( e g,  dis e as e  u n d er st u d y,  c o n c urr e nt  dis e as es,  a n d 
c o n c o  mit a nt   m e di c ati o ns).  
9. 4. 5.      
A cti o n  s t o  b e   T a k e n   R e g a r di n g t h e St u d y   D r u g  
T h e f oll o  wi n g  crit eri a s h o ul d  b e  a p pli e d t o  d e ci d e t h e  a cti o n t o  b e t a k e n r e g ar di n g t h e 
st u d y  dr u g: 
•     D os e   N ot   C h a n g e d:   N o  c h a n g e i n   t h e st u d y  dr u g  d os a g e   w as   m a d e. 
•     Dr u g    Wit h dr a  w n:  T h e st u d y  dr u g   w as  p er  m a n e ntl y st o p p e d. 
•     Dr u g I nt err u pt e d:  T h e st u d y  dr u g   w as t e  m p or aril y st o p p e d. 
•     N ot   A p pli c a bl e:   S u bj e ct  di e d,  t h e st u d y dr u g  h a d  b e e n  c o  m p l et e d  pri or t o 
r e a cti o n/ e v e nt,  or r e a cti o n/ e v e nt  o c c urr e d  pri or t o st art  of t h e tr e at  m e nt. 
9. 4. 6.      
Ot h e r   A cti o n  s t o  b e T a k e n f o r   E v e nt   
•     N o n e 
−  N o tr e at  m e nt   w as r e q uir e d   
•     M e di c ati o n r e q uir e d    
−  Pr es cri pti o n  a n d/ or   O T  C   m e di c ati o n   w as r e q uir e d t o tr e at t h e  A E   
•     H os pit ali z ati o  n  or  pr ol o n g ati o n  of  h os pit ali z ati o n r e q uir e d 
−  H os pit ali z ati o n   w as r e q uir e d  or  pr ol o n g e d  d u e t o t h e   A E  ,   w h et h er  or  n ot 
m e di c ati o n   w as r e q uir e d   
•     Ot h er   
9. 4. 7.      
A d v e rs e   E v e nt   O ut c o  m e   
•     R e c o v er e d/  R es ol v e d   
−     T h e s u bj e ct f ull y r e c o v er e d fr o  m t h e  A E     wit h  n o r esi d u al  eff e ct  o bser v e d  
•     R e c o v er e d/  R es ol v e d   wit h  S e q u el a e   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 3  of  9 0 
−     T h e r esi d u al  eff e cts  of t h e  A E   ar e still  pr es e nt  a n d  o bs er v a bl e  
−     I n cl u d e s e q u el a e/r esi d u al  eff e cts 
•     N ot   R e c o v er e d/  N ot   R es ol v e d 
−     T h e  A E   its elf is still  pr es e nt  a n d  o bs er v a bl e 
•     F at al  
−     F at al s h o ul d  b e  us e d   w h e n  d e at h is  a  dir e ct  o ut c o  m e  of t h e  A E   
•     U n k n o  w n 
9. 5.      S e ri o us   A d v e rs e   E v e nts   R e p o rti n g – P r o c e d u r e  F o r I n v esti g at o rs  
All   A Es  a n d  S  A Es   will  b e r e p ort e d i n t h e  e  C  R F. 
T h e f oll o  wi n g t y p es  of  e v e nts s h o ul d  b e r e p ort e d  b y t h e i n v esti g at or  o n t h e  S  A E f or  m  of 
e  C  R F  or  o n  a  S  A  V E  R  F or  m i n  c as e  of  e  C  R F  d o  w n ti  m e  wit hi n   2 4  h  of  a  w ar e n ess:  
•     S  A Es (s e e  S e cti o n   9. 4. 2) 
•     H e p ati c  e v e nts   m e eti n g  c o  m bi n ati o n  a b n or  m aliti es [  A L T  or   A S T   ≥   3  × U L  N   wit h 
si  m ult a n e o us t ot al  bilir u bi n ≥  2  ×   U L  N] ( p ot e nti al   H y’s  L a  w  c as e),  b ot h s eri o us 
a n d  n o ns eri o us (s e e  S e cti o n   9. 3 f or  a d diti o n al  d et ails) 
All  e v e nts (s eri o us  a n d  n o n-s eri o us)   m ust  b e r e p ort e d   al o n g  wit h   t h e i n v esti g at or’s 
ass ess  m e nt  of t h e  e v e nt’s s eri o us n ess, s e v erit y,  a n d  c a us alit y t o t h e st u d y  dr u g.    A 
d et ail e d  n arr ati v e s u  m  m ari zi n g t h e  c o urs e  of t h e  e v e nt, i n cl u di n g its  e v al u ati o n, tr e at  m e nt, 
a n d  o ut c o  m e s h o ul d  b e  pr o vi d e d.   S p e cifi c  or  esti  m at e d  d at es  of  e v e nt  o ns et, tr e at  m e nt, 
a n d r es ol uti o n s h o ul d  b e i n cl u d e d   w h e n  a v ail a bl e.    M e di c al  hist or y,  c o n c o  mit a nt 
m e di c ati o ns,  a n d l a b or at or y  d at a t h at  ar e r el e v a nt t o t h e  e v e nt s h o ul d  als o  b e s u  m  m ari z e d 
i n t h e  n arr ati v e.   F or f at al  e v e nts, t h e  n arr ati v e sh o ul d st at e   w h et h er  a n  a ut o ps y   w as  or 
will  b e  p erf or  m e d,  a n d i n cl u d e t h e r es ults if  a v ail a bl e.   S o ur c e  d o c u  m e nts (i n cl u di n g 
m e di c al r e p orts)   will  b e r et ai n e d  at t h e   st u d y sit e  a n d s h o ul d  n ot  b e s u b  mitt e d t o t h e 
S p o ns or f or  S  A E r e p orti n g  p ur p os e. 
Ur g e nt s af  et y  q u eri es   m ust  b e f oll o  w e d  u p  a n d  a d dr ess e d  pr o  m ptl y.   F oll o  w- u p 
i nf or  m ati o n  a n d r es p o ns e t o  n o n- ur g e nt s af et y  q u eri es s h o ul d  b e  c o  m bi n e d f or r e p orti n g 
t o  pr o vi d e t h e   m ost  c o  m pl et e  d at a  p ossi bl e   wit hi n  e a c h  F oll o  w- u p. 
S e e  A p p e n di x    1 7. 4 f or  c o nt a ct i nf or  m ati o n f or  S  A E r e p orti n g.  Pl e as e  c all t h e l o c al  S  A E 
H otli n e (s e e  St u d y   R ef er e n c e   M a n u al)  or  y o ur   st u d y m o nit or f or  a n y  q u esti o ns  o n  S  A E 
r e p orti n g. 
9. 6.      N otif yi n g   R e g ul at o r y   A ut h o riti es, I n v esti g at o rs,   a n d  Instit uti o n al  R  e vi e  w 
B o a r d 
D aii c hi  S a n k y o  a n d/ or   Q ui ntil esI  M S   will i nf or  m   i n v esti g at ors, I nstit uti o n al   R e vi e  w 
B o ar ds (  I  R  Bs),  a n d r e g ul at or y  a ut h oriti es  of  a n y  S us p e ct e d   U n e x p e ct e d  S eri o us   A d v ers e 
R e a cti o ns ( S  U S  A  Rs)  o c c urri n g i n  ot h er   st u d y sit es  or  ot h er st u di es  of t h e st u d y  dr u g ,  as 
a p pr o pri at e  p er l o c al r e p orti n g r e q uir e  m e nts. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 4  of  9 0 
I n  T ai  w a n,  u p o n r e c ei pt  of t h e  S p o ns or's  n otifi c ati o n  of  S  U S  A  Rs, it is t h e i n v esti g at or's 
r es p o nsi bilit y t o r e p ort  S  U S  A  Rs t o I R  Bs  a c c or di n g t o r e p orti n g  g ui d eli n e  of t h e I R  Bs. 
9. 7.      E x p os u r e I n   Ut e r o   D u  ri n g   Cli ni c al  St u di es  
D aii c hi  S a n k y o    a n d/ or Q ui ntil esI  M S     m ust  b e  n otifi e d  of  a n y s u bj e ct   w h o  b e c o  m es 
pr e g n a nt   w hil e r e c ei vi n g  or   wit hi n  t h e F oll o  w- u p  p eri o d ( 2 8  ±  7  d a ys  aft er t h e l ast  d os e 
of  t h e st u d y dr u g ). 
Alt h o u g h  pr e g n a n c y is  n ot t e c h ni c all y  a n   A E  ,  all  pr e g n a n ci es   m ust  b e f oll o  w e d u ntil 
c o n cl usi o ns  b ei n g r e a c h e d  t o  d et er  mi n e t h eir  o ut c o  m es.   T his i nf or  m ati o n is i  m p ort a nt f or 
b ot h  dr u g s af et y  a n d  p u bli c  h e alt h  c o n c er ns.  It is t h e r es p o nsi bilit y  of t h e i n v esti g at or ,  or 
d esi g n e e, t o r e p ort  a n y  pr e g n a n c y i n  a f e  m al e s u bj e ct  usi n g t h e  E x p os ur e I n   Ut er o ( EI  U) 
R e p ort  i n g  For  m.   Pl e as e  c o nt a ct  y o ur  st u d y m o nit or t o r e c ei v e t h e  EI  U   R e p orti n g  F or  m 
u p o n  l e ar ni n g  of  a  pr e g n a n c y.   T h e i n v esti g at or s h o ul d   m a k e  e v er y  eff ort t o f oll o  w t h e 
s u bj e ct  u ntil  c o  m pl eti o n  of t h e  pr e g n a n c y  a n d  c o  m pl et e t h e  EI  U   R e p orti n g  F or  m   wit h 
c o  m pl et e  pr e g n a n c y  o ut c o  m e i nf or  m ati o n, i n cl u di n g  n or  m al  d eli v er y  a n d i n d u c e d 
a b orti o n.   T h e  a d v ers e  pr e g n a n c y  o ut c o  m e,  eit h er s eri o us  or  n o ns eri o us, s h o ul d  b e 
r e p ort e d i n  a c c or d a n c e   wit h t h e st u d y  pr o c e d ur es.   If t h e  o ut c o  m e  of t h e  pr e g n a n c y   m e ets 
t h e  crit eri a f or i  m  m e di at e  cl assifi c ati o n  as  a  S  A E (i e,  p ost p art u  m  c o  m pli c ati o ns, 
s p o nt a n e o us  or i n d u c e d  a b orti o n, still birt h,  n e o n at al  d e at h,  or  c o n g e nit al  a n o  m al y, 
i n cl u di n g t h at i n  a n  a b ort e d f et us), t h e i nv esti g at or  s h o ul d f oll o  w t h e  pr o c e d ur es f or 
r e p orti n g  S  A Es  o utli n e d i n S e cti o n   9. 5. 
9. 8.      Cli ni c al   L a b o r at o r y   E v al u ati o ns 
Cli ni c al l a b or at or y  e v al u ati o ns   will  b e  p erf or  m e d  at t h e st u d y  visits i n di c at e d i n t h e   
S c h e d ul e  of  E v e nts (  A p p e n di x   1 7. 1).   Eli gi bilit y  d e cisi o ns   will  b e  b as e d  o n l o c al 
l a b or at or y  v al u es.    Cli ni c al l a b or at or y  e v al u ati o ns   will  b e  p erf or  m e d  as  o utli n e d i n 
T a bl e   9. 1. 
Bl o o d s a  m pl es f or  a n al ysis  of t h e f oll o  wi n g  cli ni c al  c h e  mistr y,  h e  m at ol o gi c,  c o a g ul ati o n, 
a n d  h or  m o n e  p ar a  m et ers   will  b e  c oll e ct e d . 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 5  of  9 0 
T a bl e  9. 1:       Cli ni c al   L a b o r at o r y   E v al u ati o ns 
L a b o r at o r y   T ests   
P a r a  m et e rs  
Cli ni c al   c h e  mistr y  
S o di u  m , p ot assi u  m , c hl ori d e , c al ci u  m , p h os p h or us , c ar b o n  di o xi d e , t ot al 
pr ot ei n , al b u  mi n , tri gl y c eri d esa, t ot al  c h ol est er ola, hi g h  d e nsit y 
li p o pr ot ei n-c h ol est er ol a, l o  w  d e nsit y li p o pr ot ei n-c h ol est er ol a, gl u c os e a, 
uri c  a ci d , bl o o d  ur e a  nitr o g e n , l a ct at e  d e h y dr o g e n as e, a n d  cr e ati ni n e  
Li v er  f u n cti o n 
Al k ali n e  p h os p h at as e  , t ot al  bilir u bi n, dir e ct  bilir u bi n , A L T  , A S T  ,  a n d 
G  G T   
H e  m at ol o g y   
R e d  bl o o d  c ell  c o u nt  , h e  m o gl o bi n , w hit e  bl o o d  c ell  c o u nt   wit h   diff er e nti al  
(n e utr o p hils, l y  m p h o c yt es,   m o n o c yt e s,  e osi n o p hils  a n d  b as o p hils), 
h e  m at o crit , a n d  pl at el et  c o u nt  
C o a g ul ati o n   
Pr ot hr o  m bi n ti  m e,  a cti v at e d  p arti al t hr o  m b o pl asti n ti  m e , a n d I  N  R  
H or  m o n e    
W o  m e n   : F S  H , L  H , pr o g est er o n e , a n d  estr a di ol  
M e n  : F S  H , L  H , a n d  t est ost er on e  
Uri n e s a  m pl es   will  b e  o bt ai n e d f or  a n al ysis  of t h e f oll o  wi n g  p ar a  m et ers:   
Uri n al ysis   ( di psti c k  a n d 
mi cr os c o pi c  a n al ysis)   
p  H ,  ket o n es/ a c et o n e , pr ot ei n/ al b u  mi n , h e  m o gl o bi n/ bl o o d , gl u c os e/s u g ar , 
r e d  bl o o d  c ells, w  hit e  bl o o d  c ells,  e pit h eli al  c ells,   ba ct eri a,  c asts,  cr yst als , 
a n d  nitrit e s  
A L T  =  al a ni n e  a  mi n otr a nsf er as e;   A S T  =  as p art at e  a  mi n otr a nsf er as e;   G  G T  =  g a  m  m a  gl ut a  m yl tr a nsf er as e,   F S  H  = 
f olli cl e-sti  m ul ati n g  h or  m o n e; I  N R  = I nt er n ati o n al   N or  m ali z e d   R ati o;  L  H  =  l ut ei ni zi n g h or  m o n e.  
a   F asti n g is r e c o  m  m e n d e d  b ut  n ot r e q uir e d.  
9. 9.      Vit al  Si g ns   
Vit al si g ns, i n cl u di n g s yst oli c/ di ast oli c  bl o o d  pr ess ur e,  p uls e r at e,  a n d   t e  m p er at ur e   will  b e 
m e as ur e d i n  a c c or d a n c e   wit h i nstit uti o n al st a n d ar ds  a n d  g e n er all y s h o ul d  b e  p erf or  m e d 
b ef or e  i n v asi v e  pr o c e d ur es,  e g,  bl o o d  dr aws.    Vit al si g ns  a n d   w ei g ht   will  b e   m e as ur e d  at 
t h e i n di c at e d st u d y  visits  as  i n t h e  S c h e d ul e  of  E v e nts (  A p p e n di x  1 7. 1).  H ei g ht   will  b e 
m e as ur e d  at   scr e e ni n g  p eri o d  o nl y. 
Bl o o d  pr ess ur e  a n d  p uls e r at e   will  b e   m  e as ur e d  aft er t h e s u bj e ct  h as r est e d i n  a r e c u  m b e nt 
p ositi o n f or  5   mi n ut es  or   m or e. 
I nf or  m ati o n   will  b e r e c or d e d i n t h e  e  C  R F, i n cl u di n g   w h et h er  or  n ot b ei n g  m e as ur e d, 
d at e s of   m e as ur e  m e nt,  a n d   m e as ur e  m e nt r es ults f or t h e f oll o  wi n g it e  ms:  
•     S yst oli c  bl o o d  pr e ss ur e 
•     Di ast oli c  bl o o d  pr ess ur e 
•     P uls e r at e  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 6  of  9 0 
•     R es pir at or y r at e   
•     B o d y t e  m p er at ur e   
•     H ei g ht   
•     B o d y   w ei g ht 
9. 1 0.     El e ct r o c a r di o g r a  ms   
A st a n d ar d  1 2-l e a d  E  C  G   will  b e  o bt ai n e d  at t h e st u d y  visits i n di c at e d i n t h e  S c h e d ul e  of 
E v e nts (  A p p e n di x   1 7. 1). 
T h e  E  C  G   will  b e   m e as ur e d  aft er t h e s u bj e ct  h as r est e d i n  a r e c u  m b e nt  p ositi o n f or 
5   mi n ut es  or   m or e.     W h et h er  or  n ot  t h e m e as ur e  m e nt is  p erf or  m e d,  d at e   of   m e as ur e  m e nt , 
r es ults,  a n d fi n di n gs f or t h e f oll o  wi n g  p ar a  m et ers   will  b e r e c or d e d i n t h e  e  C  R F.    At t h e 
visits   w h e n  E  C  Gs  ar e t o  b e  p erf or  m e d, s u bj e cts s h o ul d  b e t ol d  n ot  t o t a k e t h e   m or ni n g 
d os e  of  t h e st u d y dr u g .   T h e  E  C  G s h o ul d  b e  p erf or  m e d  pri or t o  bl o o d s a  m pli n g 
pr o c e d ur es. 
St a n d ar d s u pi n e  1 2- l e a d  E  C  Gs i n tri pli c at e   will  b e  p erf or  m e d  as s p e cifi e d i n t h e  S c h e d ul e 
of  E v e nts (  A p p e n di x   1 7. 1).   T h e  E  C  G r e c or di n gs   m ust  b e  p erf or  m e d  usi n g  a st a n d ar d 
hi g h - q u alit y  a n d  hi g h-fi d elit y  el e ctr o c ar di o gr a p h y   m a c hi n e  e q ui p p e d   wit h  c o  m p ut er-
b as e d i nt er v al  m e as ur e  m e nts.    St a n d ar d  E  C  G  p ar a  m et ers   will  b e   m e as ur e d, i n cl u di n g 
h e art r at e,   R  R,  P  R,   Q T ,   Q T c F i nt er v als,  a n d   Q  R S  d ur ati o n.    All  E  C  Gs   m ust  b e  e v al u at e d 
b y  t h e i n v esti g at or or  d el e g at e d  p h ysi ci a n f or t h e  p ossi bl e  pr es e n c e  of  a b n or  m aliti es . 
9. 1 1.     P h ysi c al   E x a  mi n ati o ns 
P h ysi c al  e x a  mi n ati o n s   will  b e  p erf or  m e d  b y  a  q u alifi e d i n di vi d u al s u c h  as t h e 
i n v esti g at or at t h e st u d y   visits i n di c at e d i n t h e  S c h e d ul e  of  E v e nts (  A p p e n di x  1 7. 1). 
P h ysi c al  e x a  mi n ati o n fi n di n gs i n cl u di n g  E  C  O  G  P S  will   b e  us e d t o  e v al u at e t h e f oll o  wi n g 
b o d y s yst e  ms/ or g a ns:  g e n er al  a p p e ar a n c e , d er  m at ol o gi c al , h e a d  a n d  e y es ,  e ars,  n os e, 
m o ut h,  a n d t hr o at,  p ul  m o n ar y,  c ar di o v as c ul ar,  a b d o  mi n al,  g e nit o uri n ar y ( o pti o n al), 
l y  m p h ati c, m us c ul os k el et al/ e xtr e  miti es  a n d  n e ur ol o gi c al.     W ei g ht  a n d  h ei g ht   will  als o  b e 
r e c or d e d i n  kil o gr a  ms  a n d  c e nti  m et ers, r es p e cti v el y. 
9. 1 2.     Ot h e r   E x a  mi n ati o ns 
9. 1 2. 1.      E c h o c a r di o g r a  m   
A r esti n g  E  C  H  O  or   M  U  G  A s c a n   will  b e  p erf or  m e d  at   t h e st u d y  visits i n di c at e d i n t h e 
S c h e d ul e  of  E v e nts (  A p p e n di x   1 7. 1) t o  e v al u at e t h e s u bj e cts’  c ar di a c f u n cti o n t hr o u g h o ut 
t h eir st u d y  p arti ci p ati o n.   I n t his  pr ot o c ol,  “ E  C  H  O s c a n ”  a n d  “  M  U  G  A s c a n ”   will  b e  us e d 
i nt er c h a n g e a bl y.   T h e  c h oi c e  of   w h et h er t o  p erf or  m  E  C  H  O  or   M  U  G  A s c a n   will  b e  b as ed 
o n t h e  pr ef er e n c e  of t h e  i n v esti g at or,  b ut t h e pl atf or  ms s h o ul d  n ot  b e s  wit c h e d  d uri n g t h e 
c o urs e  of  a s u bj e ct’s st u d y  p arti ci p ati o n.    Cli ni c all y i  m p ort a nt fi n di n gs,  i n cl u di n g t h e l eft 
v e ntri c ul ar  ej e cti o n fr a cti o n,   will  b e r e c or d e d  i n t h e  a p pr o pri at e  e  CR F.   


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 7  of  9 0 
9. 1 2. 2.      P r e g n a n c y   T est  
F or f e  m al e s u bj e cts  of  c hil d b e ari n g  p ot e nti al  o nl y,  a s er u  m  pr e g n a n c y t est ( β - h u  m a n 
c h ori o ni c  g o n a d otr o pi n)   will  b e  p erf or  m e d  at t h e st u d y  visits i n di c at e d i n t h e  S c h e d ul e  of 
E v e nts (  A p p e n di x   1 7. 1). 
F or  p ost  m e n o p a us al s u bj e cts ( n o  c hil d b e ari n g  p ot e nti al,  as i n di c at e d  b y  a n  el a ps e  of  at 
l e ast  1 2   m o nt hs  aft er t h e l ast   m e nstr u ati o n)  or f e  m al e s u bj e cts   w h o  h a v e  n o  p ossi bilit y  of 
pr e g n a n c y  d u e t o st erili z ati o n s ur g er y,  et c.  pr e g n a n c y t est   will  n ot  b e r e q uir e d.  
F e  m al e s u bj e cts   w h o  h a v e  b e e n  a  m e n orr h ei c f or  1 2   m o nt hs  or l o n g er  d u e t o  m e di c al 
r e as o ns  ot h er t h a n st erili z ati o n s ur g er y ( e g,  eff e ct  of   m e di c ati o n)   will  b e r e g ar d e d  as 
w o  m e n  of  c hil d b e ari n g  p ot e nti al  a n d   t h e y  ar e r e q uir e d t o  u n d er g o t h e  pr e g n an c y t est.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 8  of  9 0 
1 0.      
O  T  H  E  R   A S S  E S S   M  E  N  T S   
N o  ot h er  ass ess  m e nts   will  b e  p erf or  m e d. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  6 9  of  9 0 
1 1.      
S  T  A  TI S  TI  C  A  L    M  E  T  H  O  D S   
1 1. 1.     A n al ysis  S ets 
1 1. 1. 1.      E n r oll e d   A n al ysis  S et   
T h e  E nr oll e d   A n al ysis  S et  will i n cl u d e  all s u bj e cts   w h o si g n  e d  t h e I C F a n d   w er e  e nr oll e d 
i n t h e st u d y.  T h e  E nr oll e d   A n al ysis  S et   will  b e  us e d t o s u  m  m ari z e  a n d  d es cri b e t h e 
s u bj e ct  dis p ositi o n  a n d  d e at hs,  u nl ess st at e d  ot h er  wis e. 
1 1. 1. 2.      Effi c a c y   A n al ysis  S et 
T h e  Effi c a c y   A n al ysis  S et   will i n cl u d e  all s u bj e cts   w h o r e c ei v e d  at l e ast   1  d os e  of 
p e xi d arti ni b  a n d  h a d  pr e tr e at  m e nt  a n d  p osttr e at  m e nt effi c a c y  d at a.  
1 1. 1. 3.      D os e  -li  miti n g T o xi cit y   E v al u a bl e  S et 
T h e   D L T -E v al u a bl e  S et  will i n cl u d e  all s u bj e cts   w h o  e x p eri e n c e d  a   D L T  d uri n g   C y cl e  1 
or r e c ei v e d  at l e ast  7 5  %  of t h e  pl a n n e d  d os es  of tr e at  m e nt  d uri n g t h e   D L T  o bs er v ati o n 
p eri o d (  C y cl e  1).  
1 1. 1. 4.      S af et y   A n al ysi s  S et 
T h e  S af et y   A n al ysis  S et  will i n cl u d e  all s u bj e cts   w h o r e c ei v e d  at l e ast   1  d os e  of 
p e xi d arti ni b.   S u bj e cts   will  b e s u  m  m ari z e d  a c c or di n g t o  t h e tr e at  m e nt  a ct u all y r e c ei v e d. 
1 1. 1. 5.      P h a r  m a c o ki n eti c   A n al ysis  S et  
T h e  P  K   A n al ysis  S et  will i n cl u d e  all s u bj e cts i n t  h e  E nr oll e d   A n al ysis  S et   w h o r e c ei v e d 
at l e ast  1  d os e  of  p e xi d arti ni b  a n d  h a d  at l e ast  1  e v al u a bl e  p ost d os e  pl as  m a   c o n c e ntr ati o ns 
of  p e xi d arti ni b  or its   m et a b olit e  wit h o ut   m aj or  pr ot o c ol  d e vi ati o ns  or  e v e nts ( e g,  v o  miti n g 
u ntil  4  h  p ost  d os e, i n c o  m pl et e  d o si n g,  dis all o  w e d  c o n c o  mit a nt   m e di c ati o ns,  et c) 
aff e cti n g  P  K . 
1 1. 1. 6.      P h a r  m a c o d y n a  mi cs   A n al ysis  S et 
T h e  P  D   A n al ysis  S et   will i n cl u d e  all s u bj e cts i n t h e  E nr oll e d   A n al ysis  S et   w h o r e c ei v e d 
at l e ast  1  d os e  of  p e xi d arti ni b  a n d  h a d  a  p ost  d os e  P  D   m e as ur e  m e nt   wit h o ut   m a j or 
pr ot o c ol  d e vi ati o ns  or  e v e nts ( e g,  v o  miti n g, i n c o  m pl et e  d osi n g,  dis all o  w e d  c o n c o  mit a nt 
m e di c ati o ns,  et c)  aff e cti n g  P  D.   
1 1. 2.     G e n e r al  St atisti c al   C o nsi d e r ati o ns 
T h e  d at a  c ut -off f or t h e  pri  m ar y  a n al ysis   will  o c c ur  aft er  all s u bj e cts  h a v e  eit h er 
dis c o nti n u e d t h e st u d y  or  c o  m pl et e d  at l e ast  4  c y cl es.   Aft er t h e  pri  m ar y  a n al ysis, t h e 
m ai n st u d y   will  b e  cl os e d  a n d t h e  d at a   will  b e f oll o  w e d i n t h e  e xt e nsi o n   p art.    D at a 
c oll e ct e d i n t h e  e xt e nsi o n  p art  will  b e r e p ort e d s e p ar at el y fr o  m t h e  cli ni c al st u d y r e p ort  . 
D at a   will  b e list e d  a n d s u  m  m ari z e d  usi n g  St atisti c al   A n al ysis  S yst e  m (  S  A S ® ) V ersi o n    9. 2 
or  hi g h er ( S  A S I nstit ut e, I n c.,   C ar y,   N ort h   C ar oli n a)  a c c or di n g t o t h e  S p o ns or- a gr e e d 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 0  of  9 0 
r e p orti n g st a n d ar ds,   w h er e  a p pli c a bl e.  C o  m pl et e  d et ails   will  b e  d o c u  m e nt e d i n t h e 
St at isti c al   A n al ysis  Pl a n ( S  A P). 
T h e f oll o  wi n g  d es cri pti v e st atisti cs   will  b e  us e d t o s u  m  m ari z e t h e   st u d y d at a  o n t h e  b asis 
of t h eir  n at ur e  u nl ess  ot h er  wis e s p e cifi e d:  
•     C o nti n u o us  v ari a bl es:  n u  m b er  of  n o n  missi n g  o bs er v ati o ns,   m e a n, st a n d ar d 
d e vi ati o n,   m e di a n,   mi ni  m u  m,  a n d   m a xi  m u  m  as   w ell  as  g e o  m etri c   m e a ns  a n d 
g e o  m etri c  c o effi ci e nt  of  v ari ati o n f or   C  m a x  a n d   A  U  C  P  K  p ar a  m et ers  
•     C at e g ori c al  v ari a bl es: fr e q u e n ci es  a n d  p er c e nt a g es   
•     Ti  m e -t o- e v e nt  v ari a bl es:  n u  m b er  of  n o n  missi n g  o bs er v ati o ns (  N),   m e di a n, 
mi ni  m u  m  a n d   m a xi  m u  m.    K a pl a n  -M ei er  e v e nt r at es   m a y  als o  b e  pr o vi d e d if 
a p pli c a bl e f or s p e cifi c ti  m e -t o-e v e nt  v ari a bl es  
Ass ess  m e nts  of  c h a n g e fr o  m  b as eli n e t o  p ost-tr e at  m e nt  or t h e r ati o  of  p ost-  tr e at  m e nt t o 
b as eli n e   will i n cl u d e  o nl y t h os e s u bj e cts   wit h  b ot h  b as eli n e  a n d  p ost- tr e at  m e nt 
m e as ur e  m e nts.   T h e l ast  n o n  missi n g  v al u e  of  a  v ari a bl e t a k e n  b ef or e t h e first  d os e  of 
st u d y  dr u g   will  b e  us e d  as t h e  b as eli n e  v al u e,  u nl ess  ot h er  wis e s p e cifi e d.  I n  g e n er al, 
missi n g  or  dr o p o ut  d at a   will  n ot  b e i  m p ut e d f or t h e  p ur p os e  of  d at a   a n al ysis,  u nl ess 
ot h er  wis e s p e cifi e d.   S a f et y  a n d  effi c a c y  d at a fr o  m t h e  e xt e nsi o n  p art will  b e s u  m  m ari z e d 
usi n g  d es cri pti v e st atisti cs  as t a bl es  a n d listi n gs , if  a p pli c a bl e.   F urt h er  d es cri pti o n  of t h e 
st atisti c al   m et h o ds  a n d  a n al ys es   will  b e  pr o vi d e d i n  t h e  S  A P. 
1 1. 3.     St u d y  P o p ul ati o n   D at a  
S u bj e ct  dis p ositi o n  a n d r e as o ns  of  e n di n g t h e tr e at  m e nt  a n d  dis c o nti n ui n g fr o  m t h e st u d y 
will  b e s u  m  m ari z e d  a n d list e d f or s u bj e cts i n t h e   E nr oll e d   A n al ysis  S et. 
D e  m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs s u c h  as  a g e, s e x, r a c e,  et h ni cit y,  b as eli n e 
E  C  O  G  P S,  hist ol o g y,  c a n c er st a g e,  b est r es p o ns e t o  pri or  c h e  m ot h er a p y, li n es  of  pri or 
r e gi  m e ns,  a n d  pri or tr e at  m e nt t y p e   will  b e s u  m  m ari z e d f or s u bj e cts i n t h e  S af et y   A n al ysis 
S et . 
1 1. 4.     St atisti c al   A n al ys es 
1 1. 4. 1.      Effi c a c y   A n al ys es 
T h e t u  m or r es p o ns e   will  b e  e v al u at e d  usi n g   R E  CI S T   V ersi o n  1. 1.    R es p o ns e   will  b e 
c oll e ct e d i n t h e f or  m  of  4  c at e g ori es:  p r o gr essi v e  dis e as e ( P  D),  S  D (a   mi ni  m u  m  of 
8   w e e ks fr o  m t h e first  d osi n g  d at e),   C  R,  a n d  P  R. 
All  effi c a c y  v ari a bl es   will  b e list e d  a n d s u  m  m ari z e d.    T h e  n u  m b er  a n d  p er c e nt a g e  of 
s u bj e cts i n  e a c h  c at e g or y   will  b e s u  m  m ari z e d.  
O bj e cti v e   R es p o ns e   R at e    a n d   Dis e as e   C o ntr ol   R at e 
T h e  n u  m b er  a n d  pr o p orti o n  of s u bj e cts   w h o  a c hi e v e  o bj e cti v e t u  m or r es p o ns e (  C  R  or  P  R) 
or  S  D   will  b e s u  m  m ari z e d.   T h e  O  R  R  a n d   D  C  R   will   b e  c al c ul at e d  usi n g  p oi nt  esti  m at es 
al o n g   wit h  9 5  %  e x a ct  bi n o  mi al  c o nfi d e n c e i nt er v als (  CIs). 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 1  of  9 0 
D ur ati o n  of   R es p o ns e  or   D ur ati o n  of  St a bl e   Dis e as e 
D ur ati o n  of r es p o ns e f or r es p o n d ers (  C  R  or  P  R) is  d efi n e d  as t h e ti  m e i nt er v al  b et  w e e n 
t h e  d at e  of t h e  e arli est  q u alif yi n g r es p o ns e  a n d t h e  d at e  of pr o gr essi v e  dis e as e  or  d e at h f or 
a n y  c a us e,   w hi c h e v er  o c c urs  e arli er.    F or s u bj e cts   w h o  ar e  ali v e   wit h o ut dis e as e 
pr o gr essi o n f oll o  wi n g t h e  q u alif yi n g r es p o ns e,  d ur ati o n  of r es p o ns e   will  b e  c e ns or e d  o n 
t h e  d at e  of t h e last  e v al u a bl e t u  m or  ass ess  m e nt  or t h e  l ast f oll o  w- u p f or dis e as e 
pr o gr essi o n. 
T h e  T T  R is  d efi n e d  as t h e ti  m e fr o  m t h e  d at e  of t h e first  d os e t o t h e  d at e  at   w hi c h  crit eri a 
ar e first   m et f or   C  R  or  P  R.  
D ur ati o n  of  S  D is  d efi n e d  as t h e ti  m e i nt er v al, i n t h e  a b  s e n c e  of  eit h er   C  R  or  P  R t h at  will 
b e  c al c ul at e d  b et  w e e n t h e  d at e  of  t h e first  a d  mi nistr ati o n  of t h e st u d y  dr u g  a n d t h e  d at e  of 
pr o gr essi v e  dis e as e.   F or s u bj e cts   w h o  ar e  ali v e   wit h o ut  dis e as e  pr o gr essi o n,  d ur ati o n  of 
S  D   will  b e  c e ns or e d  o n t h e  d at e  of t h e l ast  e v al u a bl e t u  m or  ass ess  m e nt.  
D ur ati o n  of r es p o ns e  or  d ur ati o n  of  S  D   will  b e s u  m  m ari z e d. 
1 1. 4. 2.      P h a r  m a c o ki n eti c/ P h a r  m a c o d y n a  mi c   A n al ys es  
1 1. 4. 2. 1.      
P h a r  m a c o ki n eti c   A n al ys es  
T h e  P  K  a n al ys es   will  b e  p erf or  m e d  o n t h e  P  K   A n al ysis  S et .  Pl as  m a  c o n c e ntr ati o n -ti  m e 
d at a f or  p e x i d arti ni b  a n d its   m et a b olit e will  b e list e d,  pl ott e d,  a n d s u  m  m ari z e d  usi n g 
d es cri pti v e st atisti cs  b y  c o h ort  at  e a c h  p oi nt  a n d i n  t h e st u d y  p eri o d. 
T h e  P  K  p ar a  m et ers  of  p e xi d arti ni b  a n d its   m et a b olit e   will  b e list e d  a n d s u  m  m ari z e d  usi n g 
d es cri pti v e st atisti cs.  
Pl as  m a   c o n c e ntr ati o n  d at a   will  b e  us e d t o  p erf or  m  a  p o p ul ati o n  P  K   m o d eli n g.  T h e 
i nfl u e n c es  of i ntri nsi c  or  e xtri nsi c f a ct or   will  b e  ass ess e d i n t h e  p o p ul ati o n  P  K  a n al ysis. 
If  p erf or  m e d, r es ults  of  p o p ul ati o n  P  K  a n al ys es   will  b e r e p ort e d s e p ar at el y (i e,  n ot i n t h e 
Cli ni c al  St u d y   R e p ort).   
1 1. 4. 2. 2.      
P h a r  m a c o d y n a  mi c   A n al ys es 
E x pl or ati v e  a n al ys es f or  bi o  m ar k ers   will  b e list e d  a n d s u  m  m ari z e d  usi n g  d es cri pti v e 
st atisti cs. 
1 1. 4. 2. 3.      
Bi o  m a r k e r   A n al ys es 
N ot  a p pli c a bl e. 
1 1. 4. 3.      S af et y   A n al ys es 
T h e s af et y  pr ofil e   will  b e  b as e d  o n   A Es,  p h ysi c al  e x a  mi n ati o n fi n di n gs,  vit al si g n 
m e as ur e  m e nts,  cli ni c al l a b or at or y   m e as ur e  m e nts,  E  C  G r e c or di n gs,  a n d  E  C  H  O/  M  U  G  A 
fi n di n gs.  T h e  A Es   will  b e  gr a d e d  a c c or di n g t o t h e   N  CI-  C T  C  A E     Versi o n   4. 0.  I n t h e 
d os e- e s c al ati o n  p art, t h e i n ci d e n c e  of   D L Ts   will  als o  b e  e v al u at e d.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 2  of  9 0 
S af et y  a n al ys es i n  g e n er al   will  b e  d es cri pti v e  a n d  b e  pr es e nt e d i n t a b ul ar f or  m at   wit h t h e 
a p pr o pri at e s u  m  m ar y st atisti cs.    T h e  n u  m b er  of   D L Ts i d e ntifi e d  a  m o n g t h e 
D L T  -e v al u a bl e s u bj e cts i n t h e   D L T -E v al u a bl e  S et  will  b e list e d  a n d s u  m  m ari z e d.   
1 1. 4. 3. 1.     A d v e r  s e   E v e nt   A n al ys es 
A  T E  A E is  d efi n e d  as  a n   A E t h at  e  m er g es  d uri n g t h e tr e at  m e nt  p eri o d (fr o  m first  d os e 
d at e  u ntil  F oll o  w- u p  v isit  aft er t h e l ast  d os e  of st u d y dr u g ),  h a vi n g  b e e n  a bs e nt  at 
pr etr e at  m e nt;  or r e e  m er g es  d uri n g tr e at  m e nt,  h a vi n g  b e e n  pr es e nt  at  b as eli n e  b ut st o p p e d 
pri or t o tr e at  m e nt;  or   w ors e ns i n s e v erit y  aft er st arti n g tr e at  m e nt r el ati v e t o t h e 
pr etr e at  m e nt st at e,   w h e n t h e   A E is  c o nti n u o us. 
T h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts r e p orti n g  T E  A Es   will  b e t a b ul at e d  b y t h e   w orst 
N  CI  -  C T  C  A E  gr a d e,  S yst e  m   Or g a n   Cl ass ( S  O  C),  a n d  Pr ef err e d T er  m.  
Si  mil arl y, t h e  n u  m b er  a n d  p er c e nt a g e  of s u bj e cts r e p orti n g tr e at  m e nt- e  m er g e nt  S  A Es   will 
b e t a b ul at e d,  as   w ell  as t h e  T E  A Es/ S  A Es  c o nsi d er e d r el at e d t o  p e xi d arti ni b.   A  b y  -s u bj e ct 
A E (i n cl u di n g  T E  A E)  d at a listi n g   w  ill  b e  pr o vi d e d i n cl u di n g,  b ut  n ot li  mit e d t o,  v er b ati  m 
t er  m, Pr ef err e d  T er  m ,  S  O  C,   N  CI-C T  C  A E  gr a d e,   a n d r el ati o ns hi p t o st u d y  dr u g. 
D e at hs,  ot h er  S  A Es,  a n d  ot h er si g nifi c a nt   A Es, i n cl u di n g t h os e l e a di n g t o  p er  m a n e nt 
dis c o nti n u ati o n fr o  m  p e xi d arti ni b,   will  b e list e d.  
1 1. 4. 3. 2.     Cli ni c al   L a b o r at o r y   E v al u ati o n   A n al ys es 
D es cri pti v e st atisti cs   will  b e  pr o vi d e d f or s el e ct e d  cli ni c al l a b or at or y t est r es ults 
( h e  m at ol o g y  a n d  c h e  mistr y)  a n d  c h a n g es fr o  m  b as eli n e  b y s c h e d ul e d ti  m e  of  e v al u ati o n, 
i n cl u di n g t h e  e n d  of st u d y  visit, m a xi  m u  m  p ost  -tr e at  m e nt  v al u e,  a n d   mi ni  m u  m 
p ost- tr e at  m e nt  v al u e. 
A b n or  m al l a b or at or y r es ults   will  b e  gr a d e d  a c c or di n g t o t h e   N  CI-  C T  C  A E   V  ersi o n   4. 0, if 
a p pli c a bl e.    A s hift t a bl e,  pr es e nti n g t h e  2 -  w a y fr e q u e n c y t a b ul ati o n f or  b as eli n e  a n d t h e 
w orst  p ost-  tr eat  m e nt  v al u e  a c c or di n g t o t h e   N  CI -  C T  C  A E  gr a d e,   will  b e  pr o vi d e d f or 
s el e ct e d  cli ni c al l a b or at or y t ests.    A b n or  m al  cli ni c al l a b or at or y t est r es ults t h at  ar e 
d e e  m e d  as  cli ni c al l y si g nifi c a nt or  e v al u at e d  as   Gr a d e  3  or  4   will  b e list e d . 
1 1. 4. 3. 3.     Vit al  Si g n   A n al ys es 
D e  s cri pti v e st atisti cs   will  b e  pr o vi d e d f or t h e  vit al si g ns   m e as ur e  m e nts  a n d  c h a n g es fr o  m 
b as eli n e  b y s c h e d ul e d ti  m e  of  e v al u ati o n, i n cl u di n g t h e  e n d  of st u d y  v isit  a n d t h e 
m a xi  m u  m  a n d   mi ni  m u  m  p ost  -tr e at  m e nt  v al u es. 
1 1. 4. 3. 4.     El e ct r o c a r di o g r a  m   A n al ys es   
All  E  C  G  p ar a  m et  ers, i n cl u di n g t h e   Q T c,   will  b e list e d f or  e a c h s u bj e ct  a n d s u  m  m ari z e d 
b y  d os e l e v el  a n d s c h e d ul e d ti  m e  of e v al u ati o n .    C h a n g e fr o  m  b as eli n e   will  als o  b e 
s u  m  m ari z e d.  R el ati o ns hi p  b et  w e e n  d os e l e v el  a n d   Q T c  c h a n g es   will  b e  e x pl or e d  b y 
gr a p hs.   T h e  Q T c   will   b e  c al c ul at e d  usi n g  Fri d eri ci a’s f or  m ul a . 
1 1. 4. 3. 5.     P h ysi c al   E x a  mi n ati o n   A n al ys es 
P h ysi c al  e x a  mi n ati o n  fi n di n gs i n cl u di n g  E  C  O  G  P S   will  b e list e d. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 3  of  9 0 
1 1. 4. 3. 6.     E x pl o r at o r y  S af et y   A n al ys es 
T h e  E  C  H  O/  M  U  G  A fi n di n gs   will  b e list e d.  
1 1. 4. 4.      Ot h e r   A n al ysis 
R es ults f or  p h ar  m a c o g e n o  mi cs   a n al ys is will  b e list e d  . 
1 1. 5.     I nt e ri  m   A n al ys es  
N ot  a p pli c a bl e.   
1 1. 6.     S a  m pl e  Si z e   D et e r  mi n ati o n  
T h e st u d y  c o nsists  of  2  d os e l e v els  wit h  at l e ast  3   D L T  -e v al u a bl e s u bj e cts  p er  d os e l e v el.   
At l e ast  9   D L T  -e v al u a bl e s u bj e cts  ar e  n e e d e d t o r e a c h  a n  a c c ur at e  esti  m at e  of t h e 
M T  D/  R P 2  D.    T h e s a  m pl e si z e f or  e xt e nsi o n  p art    will  d e p e n d  o n  h o  w   m a n y s u bj e cts  ar e 
b e n efiti n g fr o  m tr e at  m e nt  d uri n g t h e st u d y. 
T h e s a  m pl e si z es  h a v e  b e e n  d et er  mi n e d  b y  pr a cti c al  c o nsi d er ati o ns f or t h e st u d y.    N o 
f or  m al st atisti c al  ass ess  m e nt  h as  b e e n  p erf or  m e d. 
1 1. 7.     St atisti c al   A n al ysis  P r o c ess  
T h e  cli ni c al st u d y   will  b e  a n al y z e d  b y  Q ui ntil esI  M S  . 
T h e st atisti c al   m et h o d ol o g y s e cti o n   m ust r efl e ct t h e  pl a n n e d  a n al ys es.   
T h e  S  A P   will  pr o vi d e t h e st atisti c al   m et h o ds  a n d  d efi niti o ns f or  a n al y zi n g  t h e  effi c a c y 
a n d s af et y  d at a ,  as   w ell  as  d es cri b e t h e  a p pr o a c h es t o  b e t a k e n f or s u  m  m ari zi n g  ot h er 
cli ni c al st u d y i nf or  m ati o n s u c h  as s u bj e ct  dis p ositi o n,  d e  m o gr a p hi c  a n d  b as eli n e 
c h ar a ct eristi cs, st u d y  dr u g  e x p os ur e,  a n d  pri or  a n d  c o n c o  mit a nt   m e di c ati o ns.   T h e  S  A P 
will  als o i n cl u d e   a  d es cri pti o n  of  h o  w   missi n g,  u n us e d,  a n d s p uri o us  d at a   will  b e 
a d dr ess e d.  
T o  pr es er v e t h e i nt e grit y  of t h e st atisti c al  a n al ysis  a n d  cli ni c al st u d y  c o n cl usi o ns, t h e  S  A P 
will  b e fi n ali z e d  pri or t o  d at a b as e l o c k. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 4  of  9 0 
1 2.      
D  A  T  A I  N  T  E  G  RI  T  Y   A  N  D   Q  U  A  LI  T  Y   A S S  U  R  A  N  C  E   
T h e  i n v esti g at or/i n v esti g ati o n al st u d y sit e  will  p er  mit st u d y  -r el at e d   m o nit ori n g,  a u dits, 
I  R  B r e vi e  w,  a n d r e g ul at or y i ns p e cti o ns  b y  pr o vi di n g  dir e ct  a c c ess t o s o ur c e 
d at a/ d o c u  m e nts.   Dir e ct  a c c ess i n cl u d es  p er  missi o n t o  e x a  mi n e,  a n al y z e,  v erif y,  a n d 
r e pr o d u c e  a n y r e c or ds  a n d r e p orts t h at  ar e i  m p ort a nt t o t h e  e v al u ati o n  of  a  cli ni c al st u d y. 
1 2. 1.     M o nit o ri n g  a n d I ns p e cti o ns    
T h e  S p o ns or  or  Q ui ntil esI  M S  ’ st u d y m o nit or  a n d r e g ul at or y  a ut h orit y i ns p e ct ors  ar e 
r es p o nsi bl e f or  c o nt a cti n g  a n d  visiti n g t h e i n v esti g at or f or t h e  p ur p os e  of i ns p e cti n g t h e 
f a ciliti es  a n d,  u p o n r e q u est, i ns p e cti n g t h e  v ari o us r e c or ds  of t h e st u d y ( e g,  eC  R Fs, 
s o ur c e  d at a,  a n d  ot h er  p erti n e nt  d o c u  m e nts). 
T h e  v erifi c ati o n  of  a d h er e n c e t o t h e  pr ot o c ol;  c o  m pl et e n ess,  a c c ur a c y,  a n d  c o nsist e n c y  of 
t h e  d at a;  a dh er e n c e t o I  C  H   G  C P  a n d l o c al r e g ul ati o ns  o n t h e  c o n d u ct  of  cli ni c al r es e ar c h 
will  b e  a c c o  m plis h e d t hr o u g h  a  c o  m bi n ati o n  of  o nsit e  visits  b y t h e s  t u d y m o nit or  a n d 
r e vi e  w  of st u d y  d at a r e  m ot el y.   T h e fr e q u e n c y  of t h e   m o nit ori n g  visit   will  v ar y  b as e d  o n 
t h e  a cti vit y  at  e a c h st u d y sit e.   T h e st u d y m o nit or is r es p o nsi bl e f or i ns p e cti n g t h e  e  C  R Fs 
a n d  e ns uri n g  c o  m pl et e n ess  of t h e st u d y  ess e nti al  d o c u  m e nts.   T h e s t u d y m o nit or s h o ul d 
h a v e  a c c ess t o s u bj e ct   m e di c al r e c or ds  a n d  ot h er st u d y -r el at e d r e c or ds  n e e d e d t o  v erif y 
t h e  e ntri es  o n t h e  eC  R Fs.      D et ail e d i nf or  m ati o n is  pr o vi d e d i n t h e   m o nit ori n g  pl a n. 
T h e  st u d y m o nit or   will  c o  m  m u ni c at e  d e vi ati o ns fr o  m t h e  pr ot o c ol,  S  O Ps,   G  C P,  a n d 
a p pli c a bl e r e g ul ati o ns t o t h e i n v esti g at or  a n d   will  e ns ur e t h at  a p pr o pri at e  a cti o n (s) 
d esi g n e d t o  pr e v e nt r e c urr e n c e  of t h e  d et e ct e d  d e vi ati o ns is t a k e n  a n d  d o c u  m e nt e d.  
T h e  i n v esti g at or a gr e es t o  c o o p er at e   wit h t h e  st u d y   m o nit or t o  e ns ur e t h at  a n y  pr o bl e  ms 
d et e ct e d i n t h e  c o urs e  of t h es e   m o nit ori n g  visits  ar e  a d dr ess e d  t o t h e s atisf a cti o n  of t h e 
S p o ns or  a n d  d o c u  m e nt e d. 
I n  a c c or d a n c e   wit h I  C  H   G  C P  a n d t h e  S p o ns or’s  a u dit  pl a ns, t his st u d y   m a y  b e s el e ct e d 
f or  a u dit  b y r e pr es e nt ati v es fr o  m t h e S p o ns or.  I ns p e cti o n  of  st u d y sit e f a ciliti es ( e g, 
p h ar  m a c y,  dr u g st or a g e  ar e as, l a b or at ori es,  et c .)  a n d r e vi e  w  of st u d y-r el at e d r e c or ds   will 
o c c ur i n  or d er t o  e v al u at e t h e st u d y  c o n d u ct  a n d  c o  m pli a n c e   wit h t h e  pr ot o c ol, I C  H  G  C P, 
a n d  a p pli c a bl e r e g ul at or y r e q uir e  m e nts. 
1 2. 2.     D at a   C oll e cti o n 
T h e  i n v esti g at or or st u d y st aff   will  e nt er  t h e  d at a i n t h e e  C  R F i n  a c c or d a n c e   wit h t h e 
e  C R F   C o  m pl eti o n   G ui d eli n es t h at  ar e  pr o vi d e d  b y t h e  S p o ns or. 
T h e  e  C  R F  c o  m pl eti o n s h o ul d  b e  k e pt  c urr e nt t o  e n a bl e t h e s t u d y m o nit or t o r e vi e  w t h e 
s u bj e ct’s st at us t hr o u g h o ut t h e  c o urs e  of t h e st u d y.   T h e  e  C  R F   will  b e  c o  m pl et e d, 
r e vi e  w e d,  a n d si g n e d  off  or  e-si g n e d  b y t h e i n v esti g at or aft er  all  q u eri es  h a v e  b e e n 
s atisf a ct oril y r es ol v e d . 
T h e  i n v esti g at or  e-si g ns  a c c or di n g t o t h e st u d y  d at a fl o  w. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 5  of  9 0 
A n y  cli ni c al  d at a  e nt er e d i n t h e   e C  R F   will  b e s u bj e ct e d t o t h e  d at a   m a n a g e  m e nt 
pr o c e d ur es  a n d   will  b e i n cl u d e d i n t h e fi n al st u d y  d at as ets  a c c or di n g t o  Cli ni c al   D at a 
I nt er c h a n g e  St a n d ar ds   C o ns orti u  m (  C  DI S  C) st a n d ar ds. 
1 2. 3.     D at a    M a n a g e  m e nt 
T h e  e  C  R Fs    will  b e  pr o d u c e d  b y Q ui ntil esI  M S  .   El e ctr o ni c   D at a   C a pt ur e ( E  D  C)   will  b e 
us e d f or t his st u d y,   m e a ni n g t h at  all  e  C  R F  d at a   will  b e  e nt er e d i n  el e ctr o ni c f or  ms  at t h e 
st u d y sit e.    D at a  c oll e ctio n   will  b e  c o  m pl et e d  b y  a ut h ori z e d  st u d y sit e st aff  d esi g n at e d  b y 
t h e i n v esti g at or.    A p pr o pri at e tr ai ni n g  a n d s e c urit y   m e as ur es   will  b e  c o  m pl et e d   wit h th e 
i n v esti g at or a n d  all  a ut h ori z e d  st u d y sit e st aff  pri or t o t h e st u d y  b ei n g i niti at e d  a n d  a n y 
d at a  b ei n g  e nt er e d i nt o t h e s yst e  m f or  a n y st u d y s u bj e cts.  
All  d at a   m ust  b e  e nt er e d i n  E n glis h.   T h e  e  C  R Fs s h o ul d  al  w a ys r efl e ct t h e l at est 
o bs er v ati o ns  f or t h e s u bj e cts  p arti ci p ati n g i n t he st u d y.   T h er ef or e, t h e  e  C  R Fs  ar e t o  b e 
c o  m pl et e d  as s o o n  as  p ossi bl e  d uri n g  or  aft er t h e s u bj e ct’s  visit.   T o  a v oi d i nt er o bs er v er 
v ari a bilit y,  e v er y  eff ort s h o ul d  b e   m a d e t o  e ns ur e t h at t h e s a  m e i n di vi d u al   w h o   m a d e t h e 
i niti al  b as eli n e  d et er  mi n ati o ns  c o  mpl et es  all s af et y  e v al u ati o ns.   T h e  i n v esti g at or m ust 
v erif y t h at  all  d at a  e ntri es i n t h e  e  C  R Fs  ar e  a c c ur at e.  If s o  m e  ass ess  m e nts  ar e  n ot  d o n e, 
or if  c ert ai n i nf or  m ati o n is  n ot  a v ail a bl e  or  n ot  a p pli c a bl e  or  u n k n o  w n, t h e i n v esti g at or 
s h o ul d i n di c at e t his i n t h e  e  C  R F.   T h e in v esti g at or   will  b e r e q uir e d t o  el e ctr o ni c all y  si g n 
off  o n t h e  cli ni c al  d at a.  
T h e  st u d y m o nit or   will r e vi e  w t h e  e  C  R Fs  a n d  e v al u at e t h e  m f or  c o  m pl et e n ess  a n d 
c o nsist e n c y.   T h e  e  C  R F   will  b e  c o  m p ar e d   wit h t h e s o ur c e  d o c u  m e nts t o  e ns ur e t h at  t h er e 
ar e  n o  dis cr e p a n ci es  b et  w e e n  criti c al  d at a.    All  e ntri es,  c orr e cti o ns  a n d  alt er ati o ns  ar e t o 
b e   m a d e  b y t h e r es p o nsi bl e i n v esti g at or  or  his/ h er  d esi g n e e.   T h e s t u d y m o nit or  c a n n ot 
e nt er  d at a i n t h e  e  C  R Fs.    O n c e  cli ni c al  d at a  of t h e  e  C  R F  h a v e  b e e n s u b  mitt e d t o t h e 
c e ntr al s er v er,  c orr e cti o ns t o t h e  d at a fi el ds   will  b e  a u dit tr ail e d,   m e a ni n g t h at t h e r e as o n 
f or  c h a n g e, t h e  n a  m e  of t h e  p ers o n   w h o  p erf or  m e d t h e  c h a n g e, t o g et h er   wit h ti  m e  a n d 
d at e   will  b e l o g g e d.    R ol es  a n d ri g hts  of t h e  st u d y sit e st aff r es p o nsi bl e f or  e nt eri n g t h e 
cli ni c al  d at a i nt o t h e  e  C  R F   will  b e  d et er  mi n e d i n  a d v a n c e.  If  a d diti o n al  c orr e cti o ns  ar e 
n e e d e d, t h e r es p o nsi bl e s t u d y m o nit or  or  d  at a  m  a n a g er   will r ais e  a  q u er y i n t h e  E  D  C 
a p pli c ati o n.   T h e  a p pr o pri at e  st u d y sit e st aff   will  ans  w er t h e  q u eri es s e nt t o t h e 
i n v esti g at or.   T his   will  b e  a u dit tr ail e d  b y t h e  E  D  C  a p pli c ati o n, m e a ni n g t h at t h e  n a  m e  of 
st u d y sit e st aff, ti  m e, a n d  d at e st a  m p  ar e  c a pt ur e d.  
T h e  e  C  R F is  ess e nti all y  c o nsi d er e d  a  d at a  e ntr y f or  m  a n d s h o ul d  n ot  c o nstit ut e t h e 
ori gi n al ( or s o ur c e)   m e di c al r e c or ds  u nl ess  ot h er  wis e s p e cifi e d.   S o ur c e  d o c u  m e nts  ar e  all 
d o c u  m e nts  us e d  b y t h e i n v esti g at or  or  h os pit al t h at r el at e t o t h e s u bj e ct’s   m e di c al  hist or y, 
v erif y t h e  e xist e n c e  of t h e s u bj e ct, t h e i n cl usi o n  a n d  e x cl usi o n  crit er i a, a n d  all r e c or ds 
c o v eri n g t h e s u bj e ct’s  p arti ci p ati o n i n t h e st u d y.   T h e y i n cl u d e l a b or at or y  n ot es,  E  C  G 
r es ults,   m e  m or a n d a,  p h ar  m a c y  dis p e nsi n g r e c or ds, s u bj e ct fil es,  et c. 
T h e  i n v esti g at or is r es p o nsi bl e f or   m ai nt ai ni n g s o ur c e  d o c u  m e nts.   T h es e   will  b e m a d e 
a v ail a bl e f or i ns p e cti o n  b y t h e  st u d y m o nit or  at  e a c h   m o nit ori n g  visit.   T h e i n v esti g at or 
m ust s u b  mit  a  c o  m pl et e d  e  C  R F f or  e a c h s u bj e ct   w h o r e c ei v es st u d y   dr u g , r e g ar dl ess  of 
d ur ati o n.    All s u p p orti v e  d o c u  m e nt ati o n s u b  mitt e d   wit h t h e  e  C  R F, s u c h  as l a b or at or y  or 
h os pit al r e c or ds, s h o ul d  b e  cl e arl y i d e ntifi e d   wit h t h e st u d y  a n d s u bj e ct  n u  m b er.    A n y 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 6  of  9 0 
p ers o n al i nf or  m ati o n, i n cl u di n g s u bj e ct  n a  m e, s h o ul d  b e r e  m o v e d  or r e n d er e d ill e gi bl e t o 
pr es er v e i n di vi d u al  c o nfi d e nti alit y. 
El e ctr o ni c  c as e r e p ort f or  m r e c or ds   will  b e  a ut o  m ati c all y  a p p e n d e d   wit h t h e i d e ntifi c ati o n 
of t h e  cr e at or,  b y   m e a ns  of t h eir  u ni q u e   Us erI  D.   S p e cifi e d r e c or ds   will  b e  el e ctr o ni c all y 
si g n e d  b y t h e in v esti g at or  t o  d o c u  m e nt  his/ h er r e vi e  w  of t h e  d at a  a n d  a c k n o  wl e d g e  m e nt 
t h at t h e  d at a  ar e  ac c ur at e.   T his   will  b e f a cilit at e d  b y   m e a ns  of t h e  i n v esti g at or’s  u ni q u e 
Us erI  D  a n d  p ass  w or d;  d at e  a n d ti  m e st a  m ps   will  b e  a d d e d  a ut o  m ati c all y  at   t h e ti  m e  of 
el e ctr o ni c si g n at ur e.  If  a n  e ntr y  o n  a n  e  C  R F r e q uir es  c h a n g e, t h e  c orr e cti o n s h o ul d  b e 
m a d e i n  a c c or d a n c e   wit h t h e r el e v a nt s oft  w ar e  pr o c e d ur es.    All  c h a n g es   will  b e f ull y 
r e c or d e d i n  a  pr ot e ct e d  a u dit tr ail,  a n d  a r e as o n f or t h e  c h a n g e   will  b e r e q uir e d. 
All   A Es     will  b e  c o d e d  usi n g t h e  c urr e nt  v ersi o n  of t h e   M e di c al   Di cti o n ar y f or   R e g ul at or y 
A cti viti e  s.    C o n c o  mit a nt   m e di c ati o ns  pl us  pri or  c a n c er t h er a p y   will  b e  c o d e d  usi n g t h e 
W orl d   H e alt h   Or g a ni z ati o n   Dr u g   Di cti o n ar y   . 
R ef er t o   A p p e n di x    1 7. 2 f or  d et ails  of t h e  E  D  C s yst e  m  us e d f or  c o  m pl eti n g  e  C  R F. 
1 2. 4.     St u d y   D o c u  m e nt ati o n  a n d  St o r a g e 
S o ur c e  d o c u  m e nts  ar e  ori gi n al  d o c u  m e nts,  d at a,  a n d r e c or ds fr o  m   w hi c h t h e s u bj e ct’s 
e  C  R F  d at a  ar e  o bt ai n e d.   T h es e i n cl u d e,  b ut  ar e  n ot li  mit e d t o , h os pit al r e c or ds,  cli ni c al 
a n d  offi c e  c h arts, l a b or at or y  a n d  p h ar  m a c y r e c or ds,  di ari es,  mi cr ofi c h es,   X  -r a ys,  a n d 
c orr es p o n d e n c e.  
R e c or ds  of s u bj e cts, s o ur c e  d o c u  m e nts,   m o nit ori n g  visit l o gs,  d at a  c orr e cti o n f or  ms, 
e  C  R Fs, i n v e nt or y  of st u d y  dr u g, r e g ul at or y  d o c u  m e nts ( e g,  pr ot o c ol  a n d  a  m e n d  m e nts, 
I  R  B  c orr es p o n d e n c e  a n d  a p pr o v als,  a p pr o v e d  a n d si g n e d I  C Fs, i n v esti g at or’s   A gr e e  m e nt, 
cli ni c al s u p pli es r e c ei pts,  distri b uti o n  a n d r et ur n r e c or ds),  a n d  ot h er  S p o ns or 
c orr es p o n d e n c e  p ert ai ni n g t o t h e st u d y   m ust  b e  k e pt i n  a p pr o pri at e st u d y fil es  at t h e  st u d y 
sit e ( Tri al   M ast er  Fil e).   S o ur c e  d o c u  m e nts i n cl u d e  all r e c or di n gs  a n d  o bs er v ati o ns  or 
n ot ati o ns  of  cli ni c al  a cti viti es  a n d  all r e p orts  a n d r e c or ds  n e c ess ar y f or t h e  e v al u ati o n  a n d 
r e c o nstr u cti o n  of t h e  cli ni c al st u d y.   T h es e r e c or ds   will  b e r et ai n e d i n  a s e c ur e fil e f or t h e 
p eri o d r e q uir e d  b y t h e i nstit uti o n  or st u d y sit e   p oli c y.   Pri or t o tr a nsf er  or  d estr u cti o n  of 
t h es e r e c or ds, t h e  S p o ns or   m ust  b e  n otifi e d i n   writi n g  a n d  b e  gi v e n t h e  o p p ort u nit y t o 
f urt h er st or e s u c h r e c or ds. 
1 2. 5.     R e c o r d   K e e pi n g   
T h e  i n v esti g at or  a n d st u d y sit e st aff  ar e r es p o nsi bl e f o r   m ai nt ai ni n g  a  c o  m pr e h e nsi v e  a n d 
c e ntr ali z e d fili n g s yst e  m ( Tri al   M ast er  Fil e)  of  all st u d y -r el at e d ( ess e nti al)  d o c u  m e nt ati o n, 
s uit a bl e f or i ns p e cti o n  at  a n y ti  m e  b y r e pr es e nt ati v es fr o  m t h e  S p o ns or  a n d/ or  a p pli c a bl e 
r e g ul at or y  a ut h oriti es.   Ess e nti al  d o c u  m e nts i n cl u d e: 
•     S u bj e ct fil es  c o nt ai ni n g  c o  m pl et e d  e C  R Fs,   I C Fs,  a n d s u p p orti n g  c o pi es  of s o ur c e 
d o c u  m e nt ati o n (if  k e pt) 
•     St u d y fil es  c o nt ai ni n g t h e  pr ot o c ol   wit h  all  a  m e n d  m e nts, I B,  c o pi es  of r el e v a nt 
ess e nti al  d o c u  m e nts r e q uir e d  pri or t o  c o  m  m e n ci n g  a  cli ni c al st u d y,  a n d  all 
c orr es p o n d e n c e t o  a n d fr o  m t h e I R  B  a n d t h e  S p o ns or 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 7  of  9 0 
•     R e c or ds r el at e d t o t h e st u d y  dr u g(s) i n cl u di n g  a c k n o  wl e d g  m e nt  of r e c ei pt  at   st u d y 
sit e,  a c c o u nt a bilit y r e c or ds,  a n d fi n al r e c o n cili ati o n  a n d  a p pli c a bl e 
c orr es p o n d e n c e 
I n  a d diti o n,  all  ori gi n al s o ur c e  d o c u  m e nts s u p p orti n g  e ntri es i n t h e  e  C  R Fs   m ust  b e 
m ai nt ai n e d  a n d  b e r e a dil y  a v ail a bl e.   
S u bj e ct's   m e di c al fil es s h o ul d  b e r et ai n e d i n  a c c or d a n c e   wit h  a p pli c a bl e l e gisl ati o n  a n d i n 
a c c or d a n c e   wit h t h e   m a xi  m u  m  p eri o d  of ti  m e  p er  mitt e d  b y t h e  h os pit al, i nstit uti o n , or 
pri v at e  pr a cti c e.  
N o st u d y  d o c u  m e nt s h o ul d  b e  d estr o y e d   wit h o ut  pri or   writt e n  a gr e e  m e nt  b et  w e e n   t h e 
S p o ns or  a n d t h e i n v esti g at or.   S h o ul d t h e i n v esti g at or   wis h t o  assi g n t h e st u d y r e c or ds t o 
a n ot h er  p art y  or   m o v e t h e  m t o  a n ot h er l o c ati o n,  h e/s h e   m ust  n otif y  S p o ns or i n   writi n g  of 
t h e  n e  w r es p o nsi bl e  p ers o n  a n d/ or t h e  n e  w l o c ati o n. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 8  of  9 0 
1 3.      
FI  N  A  N  CI  N  G   A  N  D I  N S  U  R  A  N  C  E  
1 3. 1.     Fi n a n c es  
Pri or t o st arti n g t h e st u d y, t h e i n v esti g at or  a n d/ or i nstit uti o n   will si g n  a  cli ni c al st u d y 
a gr e e  m e nt   wit h   D aii c hi  S a n k y o  or  Q ui ntil esI  M S.   T his  a gr e e  m e nt   will i n cl u d e t h e 
fi n a n ci al i nf or  m ati o n  a gr e e d  u p o n  b y t h e  p arti es. 
1 3. 2.     R ei  m b u rs e  m e nt, I n d e  m nit y,  a n d I ns u r a n c e   
T h e  S p o ns or  pr o vi d es i ns ur a n c e f or st u d y s u bj e cts t o   m a k e  a v ail a bl e  c o  m p e ns ati o n i n 
c as e  of st u d y -r el at e d i nj ur y. 
R ei  m  b urs e  m e nt, i n d e  m nit y,  a n d i ns ur a n c e s h all  b e  a d dr ess e d i n  a s e p ar at e  a gr e e  m e nt  o n 
t er  ms  a gr e e d  u p o n  b y t h e  p arti es. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  7 9  of  9 0 
1 4.      
P  U  B  LI  C  A  TI  O  N  P  O  LI  C  Y  
A   st u d y sit e   m a y  n ot  p u blis h r es ults  of  a st u d y  u ntil  aft er  a  c o or di n at e d   m ulti c e nt er 
p u bli c ati o n  h as  b e e n s u b  mitt e d f or  p u bli c ati o n  or  u ntil  1  y e ar  aft er t h e st u d y  h as  e n d e d, 
w hi c h e v er  o c c urs first.   T h er ef or e, t h e   st u d y sit e   will  h a v e t h e  o p p ort u nit y t o  p u blis h t h e 
r es ults  of t h e st u d y,  pr o vi d e d t h at   D aii c hi  S a n k y o  h as  h a d t h e  o p p ort u nit y t o r e vi e  w  a n d 
c o  m  m e nt  o n t h e st u d y  sit e’s pr o p os e d  p u bli c ati o n  pri or t o t h e s u b  missi o n f or  p u bli c ati o n 
wit h t h e  pri or  a d vi c e  of   D  aii c hi  S a n k y o  L e g al   Aff airs (i nt ell e ct u al  pr o p ert y  c o u n cil)  a n d 
wit h  pr o p er r e g ar d t o t h e  pr ot e cti o n  of s u bj e cts’ i d e ntiti es. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 0  of  9 0 
1 5.      
E  T  HI  C S   A  N  D   S  T  U  D  Y   A  D   MI  NI S  T  R  A  TI  V  E  I  N FO  R   M  A  TI  O  N   
1 5. 1.     C o  m pli a n c e  St at e  m e nt,   Et hi cs  a n d   R e g ul at o r y   C o  m pli a n c e   
T his st u d y   will  b e  c o n d u ct e d i n  c o  m pli a n c e   wit h t h e  pr ot o c ol, t h e  et hi c al  pri n ci pl es t h at 
h a v e t h eir  ori gi n i n t h e   D e cl ar ati o n  of   H elsi n ki, t h e I C  H  c o ns oli d at e d   G ui d eli n e  E 6 f or 
G  C P (  C P  M P/I C  H/  1 3 5/ 9 5),  a n d  a p pli c a bl e  l o c al r e g ul at or y r e q uir e  m e nts. 
1 5. 2.     S u bj e ct   C o nfi d e nti alit y  
T h e  i n v esti g at ors  a n d t h e  S p o ns or   will  pr es er v e t h e  c o nfi d e nti alit y  of  all s u bj e cts 
p arti ci p ati n g  i n t h e st u d y, i n  a c c or d a n c e   wit h   G  C P  a n d l o c al r e g ul ati o ns. 
T h e  i n v esti g at or m ust  e ns ur e t h at t h e s u bj e ct’s  a n o n y  mit y is   m ai nt ai n e d.    O n t h e   e C  R Fs 
or  ot h er  d o c u  m e nts s u b  mitt e d t o t h e  S p o ns or  or  Q ui ntil esI  M S  , s u bj e cts s h o ul d  b e 
i d e ntifi e d  b y  a  u ni q u e s u bj e ct i d e ntifi er  as  d esi g n at e d  b y t h e  S p o ns or.    D o c u  m e nts t h at 
ar e  n ot f or s u b  missi o n t o t h e  S p o ns or  or  Q ui ntil esI  M S   ( e g, si g n e d I C F) s h o ul d  b e  k e pt i n 
stri ct  c o nfi d e n c e  b y t h e i n v esti g at or. 
I n  c o  m pli a n c e   wit h I  C  H   G  C P   G ui d eli n es, it is r e q uir e d t h at t h e i n v esti g at or  a n d t h e 
i nstit uti o n  a ut h ori z e d r e pr es e nt ati v es  of t h e  c o  m p a n y, t h e r e g ul at or y  a g e n c y(s),  a n d t h e 
I  R  B h a v e  dir e ct  a c c ess t o r e vi e  w t h e s u bj e ct’s  ori gi n al   m e di c al r e c or ds f or  v erifi c ati o n  of 
st u d y-r el at e d  pr o c e d ur es  a n d  d at a.   T h e i n v esti g at or is  o bli g at e d t o i nf or  m t h e s u bj e ct t h at 
his/ h er st u d y- r el at e d r e c or ds   will  b e r e vi e  w e d b y t h e  a b o v e  n a  m e d r e pr es e nt ati v es 
wit h o ut  vi ol ati n g t h e  c o nfi d e nti alit y  of t h e s u bj e ct.   
1 5. 3.     I nf o r  m e d   C o ns e nt  
B ef or e  a s u bj e ct’s  p arti ci p ati o n i n t h e st u d y, it is t h e   in v esti g at or’s  r es p o nsi bilit y t o 
o bt ai n fr e el y  gi v e n  c o ns e nt, i n   writi n g, fr o  m t h e s u bj e ct  a ft er  a d e q u at e  e x pl a n ati o n  of t h e 
ai  ms,   m et h o ds,  a nti ci p at e d  b e n efits,  a n d  p ot e nti al  h a z ar ds  of t h e st u d y,  b ef or e  a n y 
pr ot o c ol-s p e cifi c  pr o c e d ur es  or  a n y st u d y  dr u gs  ar e  a d  mi nist er e d.   S u bj e cts s h o ul d  b e 
gi v e n t h e  o p p ort u nit y t o  as k  q u esti o ns  t o r e c ei v e s atisf a ct or y  a ns  w ers t o t h eir i n q uiri es, 
a n d s h o ul d  h a v e  a d e q u at e ti  m e t o  d e ci d e   w h et h er  or  n ot t o  p arti ci p at e i n t h e st u d y.   T h e 
writt e n I C F s h o ul d  b e  pr e p ar e d i n t h e l o c al l a n g u a g e(s)  of t h e  p ot e nti al s u bj e ct  p o p ul ati o n. 
I n  o bt ai ni n g  a n d  d o c u  m e nti n g i nf or  m e d  c o ns e nt, t h e in v esti g at or  s h o ul d  c o  m pl y   wit h t h e 
a p pli c a bl e r e g ul at or y r e q uir e  m e nts,  a d h er e t o   G  C P  a n d t o t h e  et hi c al  pri n ci pl es t h at  h a v e 
t h eir  ori gi n i n t h e   D e cl ar ati o n  of   H elsi n ki.   T h e  c o ns e nt f or  m  a n d  a n y r e visi o n(s) s h o ul d 
b e  a p pr o v e d  b y t h e I  R  B  pri or t o  b ei n g  pr o vi d e d t o  p ot e nti al s u bj e cts. 
T h e s u bj e ct’s   writt e n i nf or  m e d  c o ns e nt s h o ul d  b e  d o c u  m e nt e d i n t h e s u bj e ct’s   m e di c al 
r e c or ds.   T h e I  C F s h o ul d  b e si g n e d  a n d  p ers o n all y  d at e d  b y t h e s u bj e ct  a n d  b y t h e  p ers o n 
w h o  c o n d u ct e d t h e i nf or  m e d  c o ns e nt  dis c ussi o n ( n ot  n e c ess aril y t h e i n v esti g at or).   T h e 
ori gi n al si g n e d I  C F s h o ul d  b e r et ai n e d i n  a c c or d a n c e   wit h i nstit uti o n al  p oli c y,  a n d  a  c o p y 
of t h e si g n e d  c o ns e nt f or  m s h o ul d  b e  pr o vi d e d t o t h e s u bj e ct.   T h e  d at e  a n d ti  m e (if 
a p pli c a bl e) t h at i nf or  m e d  c o ns e nt   w as  gi v e n s h o ul d  b e r e c or d e d i n  t h e e C  R F.   
If t h e s u bj e ct  c a n n ot r e a d, t h e n  a c c or di n g t o I C  H   G  C P   G ui d eli n es,  S e cti o n  4. 8. 9,  a n 
i  m p arti al   wit n ess s h o ul d  b e  pr es e nt  d uri n g t h e  e ntir e i nf or  m e d  c o ns e nt  dis c ussi o n.   T his 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 1  of  9 0 
wit n ess s h o ul d si g n t h e I  C F  aft er t h e s u bj e ct  h as  c o ns e nt e d t o t h e s u bj e ct’s  p arti ci p ati o n 
a n d, if  p ossi bl e, si g n e d t h e I C F.    B y si g ni n g t h e I C F, t h e   wit n ess  att ests t h at t h e 
i nf or  m ati o n i n t h e I C F  a n d  a n y  ot h er   writt e n i nf or  m ati o n   w as  a d e q u at el y  e x pl ai n e d t o  a n d 
a p p ar e ntl y  u n d erst o o d  b y t h e s u bj e ct  a n d t h at i nf or  m e d  c o ns e nt   w as fr e el y  gi v e n  b y t h e 
s u bj e ct. 
S u g g est e d   m o d el t e xt f or t h e I C F f or t h e st u d y  a n d  a n y  a p pli c a bl e s u b p arts ( g e n o  mi c,  P  K, 
et c .)  ar e  pr o vi d e d i n t h e  S p o ns or’s I C F t e  m pl at e f or t h e i n v esti g at or t o  pr e p ar e t h e 
d o c u  m e nts t o  b e  us e d  at  his  or  h er  st u d y sit e.    U p d at es t o  a p pli c a bl e f or  ms   will  b e 
c o  m  m u ni c at e d  vi a l ett er fr o  m t h e  S p o ns or. 
1 5. 4.     R e g ul at o r y   C o  m pli a n c e 
T h e st u d y  pr ot o c ol, s u bj e ct  I C F, t h e I  B,  a n y s u bj e ct   writt e n i nstr u cti o ns t o  b e  gi v e n t o t h e 
s u bj e ct,  a v ail a bl e s af et y i nf o r  m ati o n, s u bj e ct r e cr uit  m e nt  pr o c e d ur es ( e g,  a d v ertis e  m e nts), 
i nf or  m ati o n  a b o ut  p a y  m e nts  a n d  c o  m p e ns ati o n  a v ail a bl e t o t h e s u bj e cts, a n d 
d o c u  m e nt ati o n  e vi d e n ci n g t h e i n v esti g at or’s  q u alifi c ati o ns s h o ul d  b e s u b  mitt e d t o t h e 
I  R  B f or  et hi c al r e vi e  w  a n d  a p pr o val  a c c or di n g t o l o c al r e g ul ati o ns  pri or t o t h e st u d y st art.  
T h e   writt e n  a p pr o v al s h o ul d i d e ntif y  all  d o c u  m e nts r e vi e  w e d  b y  n a  m e  a n d  v ersi o n. 
C h a n g es i n t h e  c o n d u ct  of t h e st u d y  or  pl a n n e d  a n al ysis   will  b e  d o c u  m e nt e d i n  a  pr ot o c ol 
a  m e n d  m e nt  a n d/ or t h e  S  A P. 
T h e  i n v esti g at or  a n d/ or  S p o ns or   m ust s u b  mit  a n d,   w h er e  n e c ess ar y,  o bt ai n  a p pr o v al fr o  m 
t h e I R  B f or  all s u bs e q u e nt  pr ot o c ol  a  m e n d  m e nts  a n d  c h a n g es t o t h e I  C F.   T h e 
i n v esti g at or s h o ul d  n otif y t h e I  R  B  of  d e vi ati o ns fr o  m t h e  pr ot o c ol  or  S  A Es  o c c urri n g  at 
t h e st u d y sit e  a n d  ot h er   A E r e p orts r e c ei v e d fr o  m t h e  S p o ns or  or Q ui ntil esI  M S  , i n 
a c c or d a n c e   wit h l o c al  pr o c e d ur es.  
As r e q uir e d  b y l o c al r e g ul ati o ns, t h e  S p o ns or’s l o c al   R e g ul at or y   Aff airs  gr o u p  or 
r e pr es e nt ati v e t o   w h o  m t his r es p o nsi bilit y  h as  b e e n  d el e g at e d will  e ns ur e  all l e g al  as p e cts 
ar e  c o v er e d,  a n d  a p pr o v al  fr o  m t h e  a p pr o pri at e r e g ul at or y  b o di es  o bt ai n e d,  pri or t o st u d y 
i niti ati o n,  a n d t h at i  m pl e  m e nt ati o n  of  c h a n g es t o t h e i niti al  pr ot o c ol  a n d  ot h er r el e v a nt 
st u d y  d o c u  m e nts  h a p p e n  o nl y  aft er  t h e a p pr o v al  b y t h e r el e v a nt r e g ul at or y  b o di es.  
I n t h e  e v e nt  of  a n y  pr o hi biti o n  or r estri cti o n i  m p os e d (e g ,  cli ni c al  h ol d)  b y  a n  a p pli c a bl e 
R e g ul at or y     A ut h oriti es i n  a n y  ar e a  of t h e w orl d,  or if t h e i n v esti g at or   is  a  w ar e  of  a n y  n e  w 
i nf or  m ati o n t h at   mi g ht i nfl u e n c e t h e  e v al u ati o n  of t h e  b e n efits  a n d ris ks  of t h e st u d y dr u g , 
t h e S p o ns or s h o ul d  b e i nf or  m e d i  m  m e di at el y. 
I n  a d diti o n, t h e i n v esti g at or will i nf or  m   t h e S p o ns or  i  m  m e di at el y  of  a n y  ur g e nt s af et y 
m e as ur es   t a k e n  b y t h e in v esti g at or  t o  pr ot e ct t h e st u d y s u bj e cts  a g ai nst  a n y i  m  m e di at e 
h a z ar d,  a n d  of  a n y  s us p e ct e d/ a ct u al s eri o us  G  C P    n o n c o  m pli a n c e t h at t h e i n v esti g at or 
b e c o  m es  a  w ar e  of.  
1 5. 5.     P r ot o c ol   D e vi ati o ns 
T h e  i n v esti g at or s h o ul d  c o n d u ct t h e st u d y i n  c o  m pli a n c e   wit h t h e  pr ot o c ol  a gr e e d t o  b y 
t h e S p o ns or  a n d, if r e q uir e d,  b y t h e r e g ul at or y  a ut h orit y  (i es), t o   w hi c h t h e 
a p pr o v al/f a v or a bl e  o pi ni o n  b y t h e I R  Bs  w as  gi v e n  . 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 2  of  9 0 
A  d e vi ati o n t o  a n y  pr ot o c ol  pr o c e d ur e  or   w ai v er t o  a n y st at e d  crit eri a   will  n ot  b e  all o  w e d 
i n t his st u d y  e x c e pt f or  eli  mi n ati n g i  m  m e di at e  h a z ar d(s) t o t h e su bj e ct.   T h e  S p o ns or   m ust 
b e  n otifi e d  of  all i nt e n d e d  or  u ni nt e n d e d  d e vi ati o ns t o t h e  pr ot o c ol ( e g, 
i n cl usi o n/ e x cl usi o n  crit eri a,  d osi n g,   miss e d st u d y  visits)  o n  a n  e x p e dit e d  b asis. 
T h e  i n v esti g at or,  or  p ers o n  d esi g n at e d  b y t h e i n v esti g at or, s h o ul d  d o c u  m e nt  a n d  e x pl ai n 
a n y  d e vi ati o n fr o  m t h e  a p pr o v e d  pr ot o c ol. 
If  a s u bj e ct   w as i n eli gi bl e  or r e c ei v e d  a n i n c orr e ct  d os e  or st u d y dr u g ,  a n d  h a d  at l e ast 
1  a d  mi nistr ati o n  of  st u d y  dr u g,  d at a s h o ul d  b e  c oll e ct e d f or s af et y  p ur p os es. 
If  a p pli c a bl e, t h e i n v esti g at or s h o ul d  n otif y t h e I R  B  of  d e vi ati o ns fr o  m t h e  pr ot o c ol i n 
a c c or d a n c e   wit h l o c al  pr o c e d ur es.  
1 5. 6.     S u p pl y  of  N e  w   I nf o r  m ati o n   Aff e cti n g t h e   C o n d u ct  of t h e  St u d y 
W h e n  n e  w i nf or  m ati o n  b e c o  m es  a v ail a bl e t h at   m a y  a d v ers el y  aff e ct t h e s af et y  of s u bj e cts 
or t h e  c o n d u ct  o f t h e st u d y, t h e  S p o ns or   will i nf or  m  all i n v esti g at ors i n v ol v e d i n t h e 
cli ni c al st u d y, I  R  Bs,  a n d r e g ul at or y  a ut h oriti es  of s u c h i nf or  m ati o n,  a n d   w h e n  n e e d e d, 
will  a  m e n d t h e  pr ot o c ol  a n d/ or s u bj e ct i nf or  m ati o n. 
T h e  i n v esti g at or s h o ul d i  m  m e di at el y i nf or  m t h e  s u bj e ct   w h e n e v er  n e  w i nf or  m ati o n 
b e c o  m es  a v ail a bl e t h at   m a y  b e r el e v a nt t o t h e s u bj e ct’s  c o ns e nt  or i nfl u e n c e t h e s u bj e ct’s 
willi n g n ess t o  c o nti n u e  p arti ci p ati o n i n t h e st u d y.   T h e  c o  m  m u ni c ati o n s h o ul d  b e 
d o c u  m e nt e d  o n   m e di c al r e c or ds, f or  e x a  m pl e,  a n d it s h o ul d  b e  c o nfir  m e d   w h et h er t h e 
s u bj e ct is   willi n g t o r e  m ai n i n t h e st u d y.  
If t h e s u bj e ct i nf or  m ati o n is r e vis e d, it   m ust  b e r e- a p pr o v e d  b y t h e I R  B.   T h e in v esti g at or 
s h o ul d  o bt ai n   writt e n i nf or  m e d  c o ns e nt t o  c o nti n u e  p arti ci p ati o n   wit h t h e r e vis e d   writt e n 
i nf or  m ati o n  e v e n if t h e s u bj e cts   w er e  alr e a d y i nf or  m e d  of t h e r el e v a nt i nf or  m ati o n.   T h e 
i n v esti g at or  or  ot h er r es p o nsi bl e  p ers o n n el   w h o  pr o vi d e d  e x pl a n ati o ns  a n d t h e s u bj e ct 
s h o ul d si g n  a n d  d at e t h e r e vis e d I  C F. 
1 5. 7.     P r ot o c ol  A  m e n d  m e nts   
A n y  a  m e n d  m e nts t o t h e st u d y  pr ot o c ol t h at s e e  m t o  b e  a p pr o pri at e  as t h e st u d y 
pr o gr ess es   will  b e  c o  m  m u ni c at e d t o t h e i n v esti g at or  b y   D aii c hi  S a n k y o  or  Q ui ntil esI  M S  .  
Als o, t h e  S p o ns or   will   e ns ur e  t h e ti  m el y s u b  missi o n  of  a  m e n d  m e nts t o r e g ul at or y 
a ut h oriti es.  
A  gl o b al  pr ot o c ol   a  m e n d  m e nt   will  aff e ct st u d y  c o n d u ct  at st u d y sit e .   S u c h  a  m e n d  m e nts 
will  b e i n c or p or at e d i nt o  a r e vis e d  pr ot o c ol  d o c u  m e nt.    C h a n g es   m a d e  b y s u c h 
a  m e n d  m e nts   will  b e  d o c u  m e nt e d i n  a  S u  m  m ar y  of   C h a n g es  d o c u  m e nt.   T h es e  pr ot o c ol 
a  m e n d  m e nts   will  u n d er g o t h e s a  m e r e vi e  w  a n d  a p pr o v al  pr o c ess  as t h e  ori gi n al  pr ot o c ol. 
A   l o c al  pr ot o c ol  a  m e n d  m e nt   will  aff e ct st u d y  c o n d u ct  at  p arti c ul ar st u d y sit e(s)  a n d/ or i n 
a  p arti c ul ar r e gi o n/ c o u ntr y.   S p o ns or  a p pr o v al  of l o c al  a  m e n d  m e nts   will  b e  cl e arl y 
d o c u  m e nt e d. 
A  pr ot o c ol  a  m e n d  m e nt   m a y  b e i  m pl e  m e nt e d  aft er it  h as  b e e n  a p pr o v e d  b y t h  e I R  B  a n d  b y 
r e g ul at or y  a ut h oriti es   w h er e  a p pr o pri at e, u nl ess i  m  m e di at e i  m pl e  m e nt ati o n  of t h e  c h a n g e 
is  n e c ess ar y f or s u bj e ct s af et y. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 3  of  9 0 
1 5. 8.     St u d y   T e r  mi n ati o n  
T h e st u d y   m a y  b e t er  mi n at e d  at  a n y ti  m e  b y t h e I  R  B, t h e  S p o ns or,  or r e g ul at or y  a g e n ci es 
as  p art  of t h eir   d uti es is t o  e ns ur e t h at t h e r es e ar c h s u bj e cts  ar e  pr ot e ct e d. 
T h e  S p o ns or r es er v es t h e ri g ht t o t e  m p or aril y s us p e n d  or  pr e  m at ur el y  dis c o nti n u e t his 
st u d y  at st u d y sit e at  a n y ti  m e f or r e as o ns i n cl u di n g,  b ut  n ot li  mit e d t o, s af et y  or  et hi c al 
iss u es  or s e v er e  n o n c o  m pli a n c e.  If t h e  S p o ns or  d et er  mi n es s u c h  a cti o n is  n e e d e d, t h e 
S p o ns or   will  dis c uss t his   wit h t h e i n v esti g at or (i n cl u di n g t h e r e as o ns f or t a ki n g s u c h 
a cti o n)  at t h at ti  m e.     W h e n f e asi bl e, t h e  S p o ns or   will  pr o vi d e  pri or  n otifi c ati o n t o t h e 
i n v esti gat or  of t h e i  m p e n di n g  a cti o n  pri or t o its t a ki n g  eff e ct.  
T h e  S p o ns or   will  pr o  m ptl y i nf or  m  all  ot h er i n v esti g at ors  a n d/ or  st u d y sit es  c o n d u cti n g 
t h e st u d y if t h e st u d y is s us p e n d e d  or t er  mi n at e d f or s af et y r e as o ns,  a n d   will  als o i nf or  m 
t h e r e g ul at or y  a ut h oriti es  of t h e s us p e nsi o n  or t er  mi n ati o n  of t h e st u d y  a n d t h e r e as o ns f or 
t h e  a cti o n.  If r e q uir e d  b y  a p pli c a bl e r e g ul ati o ns, t h e in v esti g at or   m ust i nf or  m t h e I R  B  
pr o  m ptl y  a n d  pr o vi d e t h e r e as o ns f or t h e s us p e nsi o n  or t er  mi n ati o n. 
If t h e st u d y is  pr e  m at ur el y  dis c o nti n u e d,  all st u d y  d at a   m ust  b e r et ur n e d t o t h e  S p o ns or.  
I n  a d diti o n,  arr a n g e  m e nts   will  b e   m a d e f or r et ur n  of  all  u n us e d st u d y  dr u g  i n  a c c or d a n c e 
wit h t h e  S p o ns or’s  a p pli c a bl e  pr o c e d ur es f or t h e st u d y. 
Fi n a n ci al  c o  m p e ns ati o n t o t h e i n v esti g at ors  a n d / or i nstit uti o ns   will  b e i n  a c c or d a n c e   wit h 
t h e  a gr e e  m e nt  est a blis h e d  b et  w e e n t h e in v esti g at or  a n d t h e  S p o ns or. 
1 5. 9.     S af et y     M o nit o ri n g   C o  m  mitt e e 
A n  S  M  C   will  b e  est a blis h e d f or t h e  p ur p os e  of  ass essi n g s af et y  a n d t ol er a bilit y  of t h e 
s u bj e cts.  T h e  S  M  C   m e eti n gs   w ill  b e  h el d  b et  w e e n  c o h orts  aft er  c ert ai n  n u  m b er  of t h e 
e nr oll e d s u bj e cts i n  1  c o h ort  h a v e  c o  m pl et e d t h e first  c y cl e  of tr e at  m e nt.     A d  h o c 
m e eti n gs   will  b e  h el d t o  dis c uss s u bj e ct s af et y  a  n d   D L T  d et er  mi n ati o n  as  n e e d e d.  
T h e  S  M  C   will  e v al u at e  pr o gr ess  of t h e st u d y,  ass ess s af et y  a n d  ot h er r el e v a nt i nf or  m ati o n  , 
a n d t h e n   m a k e  d e cisi o ns  o n  c o h ort  es c al ati o ns  or  d e- es c al ati o n  as   w ell  as st u d y 
c o nti n u ati o n  or  dis c o nti n u ati o n.   T h e  S  M  C   m e  m b er s m a y i n cl u d e   m e di c al  e x p erts  of 
D aii c hi  S a n k y o, s  t u d y m o nit or  of t his st u d y,  a n d i n v esti g at or   of t h e  st u d y sit e.  D et ail e d 
pr o c e d ur es  of  t h e S  M  C   will  b e s p e cifi e d i n t h e  S  M  C   C h art er.  
1 5. 1 0.   A d d r ess   List   
Pl e as e r ef er t o  A p p e n di x    1 7. 4 f or t h e  a d dr ess list  of  v ari o us st a k e h ol d ers i n v ol v e d i n t his 
st u d y.  


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 4  of  9 0 
1 6.      
R  E F  E  R  E  N  C  E S   
1.    Fl et c h er J  A,   R u bi n   B P.   KI T   m ut ati o ns i n   GI S T.   C urr   O pi n   G e n et   D e v.  2 0 0 7; 1 7: 3  7. 
2.    T a  m    W F,   Gillil a n d   D  G.   C a n  Flt 3 i n hi bit ors  o v er c o  m e r esist a n c e i n   A  M L ?   B est  Pr a ct 
R es   Cli n   H a e  m at ol.  2 0 0 8; 2 1: 1 3  2 0. 
3.    P oll ar d J   W.   M a cr o p h a g es  d efi n e t h e i n v asi v e   mi cr o e n vir o n  m e nt i n  br e ast  c a n c er. J 
L e u k o c   Bi ol.  2 0 0 8; 8 4: 6 2 3  3 0. 
4.    Y a n g  F  C, I n gr a  m   D  A,   C h e n  S,  Z h u   Y,   Y u a n J,  Li   X,   Y a n g   X,   K n o  wl es  S,   H or n    W,  Li 
Y,  et  al.   Nf 1  - d e p e n d e nt t u  m ors r e q uir e  a   mi cr o e n vir o n  m e nt  c o nt ai ni n g   Nf 1 +/--  a n d 
c- kit- d e p e n d e nt  b o n e   m arr o  w.   C ell.  2 0 0 8; 1 3 5:  4 3 7  4 8. 
5.    C off elt  S  B,   H u g h es   R,  L e  wis   C E.  T u  m or-  ass o ci at e d   m a cr o p h a g es:  Eff e ct ors  of 
a n gi o g e n esis  a n d t u  m or  pr o gr essi o n.   Bi o c h e  m   Bi o p h ys   A ct a.  2 0 0 9; 1 7 9 6( 1): 1 1  1 8. 
6.    St ei dl   C,  L e e  T,  S h a h  S P,  F ari n h a  P,   H a n   G,   N a y ar  T,  et  al.  T u  m or- ass o ci at e d 
m a cr o p h a g es  a n d s ur vi v al i n  cl assi c   H o d g ki n’s l y  m p h o  m a.   N  E n gl J   M e d. 
2 0 1 0; 3 6 2: 8 7 5  8 5. 
7.    L a  m pr e c ht   B,    W alt er   K,   Kr e h er  S,   K u  m ar   R,   H u  m  m el   M,  L e n z e   D,  et  al. 
D er e pr essi o n  of  a n  e n d o g e n o us l o n g t er  mi n al r e p e at  a cti v at es t h e   C S F 1  R  pr ot o  -
o n c o g e n e i n  h u  m a n l y  m p h o  m a.   N at   M e d.  2 0 1 0; 1 6: 5 7 1  7 9. 
8.    T a n a k a  S.  Si g n ali n g  a xis i n  ost e o cl ast  bi ol o g y  a n d t h er a p e uti c t ar g eti n g i n t h e 
R  A  N  K L/  R  A  N  K/  O P  G s yst e  m.   A  m J   N e p hr ol.  2 0 0 7; 2 7: 4 6 6  7 8. 
9.    Li pt o n   A, J u n  S.   R  A  N  K L i n hi biti o n i n t h e tr e at  m e nt  of  b o n e   m et ast as es.   C urr   O pi n 
S u p p ort  P alli at   C ar e.  2 0 0 8; 2: 1 9 7  2 0 3. 
1 0.  D e  N ar d o   D  G,   Br e n n a n   DJ,   R e x h e p aj  E,   R uff ell   B,  S hi a o  S L,   M a d d e n  S F,  et  al. 
L e u k o c yt e  c o  m pl e xit y  pr e di cts  br e ast  c a n c er s ur vi v al  a n d f u n cti o n all y r e g ul at es 
r es p o ns e t o  c h e  m ot h er a p y.   C a n c er   Dis c o v er y.  2 0 1 1; 1: 5 4 – 6 7. 
1 1.  Mit c h e  m J  B,   Br e n n a n   DJ,   K n ol h off   B L,   B elt   B  A,  Z h u   Y,  S a nf or d   D E,  et  al. 
T ar g eti n g t u  m or -i nfiltr ati n g   m a cr o p h a g es  d e cr e as es t u  m or-i niti ati n g  c ells, r eli e v es 
i  m  m u n os u p pr essi o n,  a n d i  m pr o v es  c h e  m ot h er a p e uti c r es p o ns es.   C a n c er   R es. 
2 0 1 3; 7 3: 1 1 2 8 – 1 1 4 1. 
1 2.  X u J,  Es c a  mill a J,   M o k  S,   D a vi d J,  Pri c e  m a n  S,    W est   B,  et  al.   C S F 1  R si g n ali n g 
bl o c k a d e st a n c h es t u  m or- i nfiltr ati n g   m y el oi d  c ells  a n d i  m pr o v es t h e  effi c a c y  of 
r a di ot h er a p y i n  pr ost at e  c a n c er.   C a n c er   R es.  2 0 1 3; 7 3: 2 7 8 2 – 2 7 9 4. 
1 3.  K o h n o   N.  Tr e at  m e nt  of  br e ast  c a n c er   wit h  b o n e   m et ast asis:  bis p h os p h o n at e t  r e at  m e nt 
–  c urr e nt  a n d f ut ur e. I nt J   Cli n   O n c ol.  2 0 0 8; 1 3: 1 8 – 2 3. 
 
 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 5  of  9 0 
1 7.      
A P P  E  N  DI  C  E S   
1 7. 1.     S c h e d ul e  of   E v e nts  
P r o c e d u r e  
S c r e e ni n g  C 1   
D 1   
C 1   
D 2   
C 1   
D 8   
C 1   
D 1 5   
C 1   
D 2 2   
C 2   
D 1   
C 2   
D 8 
C 2   
D 1 5   
C 2   
D  2 2  
C 3   
D 1   
C 3 
D 8   
C 3 
D 1 5 
C 4 
D 1 
C 4 
D 1 5   
C 5 + 
D 1 m  
T r e at  m e nt  visit 
d u ri n g t h e  
e xt e nsi o n  p a rt  
E n d  of 
T r e at  -
m e nt   
F oll o  w -
u p  
P  G x o  
≤  2 8   d  
t o -  1 
W  K 
1 
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 3 
W  K    
1 5 
W  K 
1 7 + 
E  v e r y  4    
w e e ks   ± 
7  d  
E  v e r y  1 2 
w e e ks   ±  7 
d 
D  C    
+  3  d  
2 8  ±  7  d 
aft e r l ast 
d os e  
P e xi d arti ni b 
a d  mi nistr ati o n  
 
BI  D (  m o r ni n g  a n d  e v e ni n g)   
 
I nf or  m e d 
c o ns e nt  
X      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
      
      
      
      
 
 
Dis p e nsi n g  of 
st u d y  dr u g 
       
X            
      
      
       
X            
      
       
X            
       
X             
X 
X  
X  
      
 
 
Dis p e nsi n g  of 
s u bj e ct  di ar y 
       
X            
      
      
       
X            
      
       
X            
       
X             
X 
X  
X  
      
 
 
D e  m o gr a p h y 
a n d   m e di c al 
hist or y  
X      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
      
      
      
      
 
 
H ei g ht a, 
w ei g ht   
X      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
      
      
       
X      
 
 
E  C  O  G  P S      
X       
     
     
     
     
     
X       
     
     
     
X       
     
     
X       
     
X  
     
     
X   
 
 
P uls e,   B P,   R  R, 
t e  m p er at ur eb 
≤  7  d        
X             
X       X       X       X             
X             
X            
       
X             
X 
 
X  
X 
 
 
P h ysi c al 
e x a  mi n ati o n b  
≤  7  d        
X             
X       X       X       X             
X             
X            
       
X             
X 
 
X  
X 
 
 
E  C G c  
≤  7  d      
X       
 
     
 
     
X       
     
     
     
X       
     
     
X       
     
X  
 
X  
X   
 
 
E  C  H  O/  M  U  G  A      ≤  2 1  d      
     
     
 
 
     
X       
     
     
     
     
     
     
     
 
     
 
X  
X       
     
 
C h e  mistr y, 
h e  m at ol o g y d  
≤  7  d        
X             
X       X       X       X             
X             
X            
       
X             
X 
X  
X  
X 
 
 
Li v er f u n cti o n 
tests d, e 
≤  7  d        
X             
X       X       X       X       X       X       X       X       X       X       X       X       X       
X 
X  
X      
 
 
Uri n al ysis d      
≤  7  d      
X       
     
X       X       X       X       
     
X       
     
X       
     
     
X       
     
X  
 
X  
X   
 
 
C o a g ul ati o n 
t ests d  
≤  7  d  
X            
      
      
      
      
      
      
      
      
      
      
      
 
 
X  
X  
X 
 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 6  of  9 0 
P r o c e d u r e  
S c r e e ni n g  C 1   
D 1   
C 1   
D 2   
C 1   
D 8   
C 1   
D 1 5   
C 1   
D 2 2   
C 2   
D 1   
C 2   
D 8 
C 2   
D 1 5   
C 2   
D  2 2  
C 3   
D 1   
C 3 
D 8   
C 3 
D 1 5 
C 4 
D 1 
C 4 
D 1 5   
C 5 + 
D 1 m  
T r e at  m e nt  visit 
d u ri n g t h e  
e xt e nsi o n  p a rt  
E n d  of 
T r e at  -
m e nt   
F oll o  w -
u p  
P  G x o  
≤  2 8   d  
t o -  1 
W  K 
1 
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 3 
W  K    
1 5 
W  K 
1 7 + 
E  v e r y  4    
w e e ks   ± 
7  d  
E  v e r y  1 2 
w e e ks   ±  7 
d 
D  C    
+  3  d  
2 8  ±  7  d 
aft e r l ast 
d os e  
P e xi d arti ni b 
a d  mi nistr ati o n  
 
BI  D (  m o r ni n g  a n d  e v e ni n g)   
 
H or  m o n e 
t esti ng f 
≤  7  d       
      
      
      
      
       
X             
X            
      
      
      
      
 
      
      
       
X      
 
 
C T/  M  RI   of 
t u  m or g  
≤  2 1  d       
      
      
      
      
      
      
      
      
       
X            
      
      
 
X ( at 
l e ast 
e v er y 
3 
c y cl es) 
 
X  
X 
 
 
S er u  m 
pr e g n a n c y 
t est h  
≤  1 4   d      
      
      
      
      
      
      
      
      
      
      
      
      
      
 
      
 
X  
X      
 
 
P  K,  bl o o d 
s a  m pli ng i 
       
X 
X 
X       X       X       X            
      
      
      
      
      
      
 
      
      
      
      
 
 
P  D , bl o o d 
s a  m pli ng j 
 
X       
 
X             
X            
      
      
      
      
      
      
 
      
      
      
      
 
 
C  o n c o  mit a nt 
m e di c ati o ns k 
X       
X       X       X       X       X       X       X       X       X       X       X       X 
X  
X  
X  
 
X  
X       
X 
 
A d v er s e 
e v e nts l 
X       
X       X       X       X       X       X       X       X       X       X       X       X 
X  
X  
X  
X 
X  
X       
X 
 
P  G x  i nf or  m e d 
c o ns e nt  
      
      
      
      
      
      
      
      
      
      
      
      
 
      
      
 
 
 
      
       
X 
P  G x  bl o o d 
s a  m pli n gn 
      
      
      
      
      
      
      
      
      
      
      
      
 
      
      
 
 
 
      
 
X 
BI  D  = t  wi c e  d ail y;   B P  =  bl o o d  pr ess ur e;   C  =  c y cl e;   C T  =  c o  m p ut e d t o  m o gr a p h y;   D( d)  =  d a y;   D  C:   D at e  of  dis c o  n ti n u ati o n ( T h e  d at e  of  dis c o ntin u ati o n  of tr e at  m e nt is 
d efi n e d  as t h e  d at e  of  d e cisi o n  b y t h e  in v esti g at or ); E  C  G  =  el e ctr o c ar di o gr a  m;  E  C  H  O  =  e c h o c ar di o gr a  m;  E  C  O  G  P S   = E ast er n   C o o p er ati v e   O n c ol o g y   Gr o u p  S c al e  of 
P erf or  m a n c e  St at us;  M  RI  =   m a g n eti c r es o n a n c e i  m a gi n g;   M  U  G  A  =   m ulti  -g at e d  a c q uisiti o n;  P  D   = p h ar  m a c o d y n a  mi c;  P  K   = p h ar  m a c o ki n eti c ; R  R  = r es pir at or y r at e  ;    WK 
=   w e e k ,  P  G x  = p h ar  m a c o g e n o  mi cs . 
a     H ei g ht ( o nl y  at s cr e e ni n g)   will  b e r e c or d e d.   
b     P h ysi c al  e x a  mi n ati o n i n cl u di n g  vit al si g ns (s yst oli c  a n d  di ast oli c  bl o o d  pr ess ur e,  p uls e r at e,  r es pir at or y r at e,  a n d  b o d y t e  m p er at ur e)   will  b e  d o ne  o n  visit  d a ys 
i n di c at e d  b y a n  X.   
c     1 2 -L e a d  E  C  G   will  b e  p erf or  m e d i n tri pli c at e.   R e a di n gs   will  b e  p erf or  m e d  pr e d os e  o n   D a y   1  of  e a c h  c y cl e  a n d  at t h e  e n d  of t r e at  m e nt. 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 7  of  9 0 
d     S af et y l a b or at or y s a  m pl es f or   D a y   1 pr e d os e ( c o  m pl et e  bl o o d  c o u nt   wit h  diff er e nti al  a n d r eti c ul o c yt e  c o u nts, s er u  m  c h e  mistr y,  uri n al ysis,  a n d  c o a g ul ati o n  pr ofil e ) 
c a n  b e  c oll e ct e d   wit hi n  7 2  h  b ef or e t h e first  d os e.   
e 
Al k ali n e  p h os p h at as e, t ot al  a n d  dir e ct  bilir u bi n,   A L T,   A S T,  a n d   G  G T s h o  ul d  b e  ass ess e d  at s cr e e ni n g,   w e e kl y  f or  1 0   w e e ks (  C 1  D 1 t hr o u g h   C 3  D 1 5),  a n d t h e n bi  w e e kl y  till   C 5  D 1 (  C 4  D 1, 
C 4  D 1 5,  a n d   C 5  D 1)   a n d  o n   D a y  1  of  e v er y  c y cl e t h er e aft er.  
f     W o  m e n    w h o  ar e  n ot  usi n g  h or  m o n al  c o ntr a c e pti o n   will  b e t est e d f or l e v els  of  F S  H,  L  H,  pr o g e  st er o n e,  a n d  estr a di ol.  H or  m o n e t esti n g   will  n ot  b e r e q uir e d f or 
w o  m e n   w h o  h a v e  eit h er  h a d  a n  o o p h  o r e ct o  m y  or  ar e  p ost  m e n o p a us al.  M e n   will  b e t est e d f or l e v els  of  L  H,  F S  H,  a n d t est ost er o n e.     M al e   s u bj e cts w h os e t est ost er o n e 
l e v el is  b el o  w  b as eli n e  at t h e l ast  ass ess  m e nt s h o ul d  b e f oll o  w e d  u ntil t h e l e v el  h as b e e n  st a bili z e d  or r et ur n e d t o  b as eli n e. 
g     T u  m or  ass ess  m e nt  b y  p h ysi c al  e x a  mi n ati o n  a n d   R E  CI S T  v 1. 1   will  b e  p erf or  m e d   at t h e s cr e e ni n g  p eri o d  a n d  at  l e ast  e v er y 2  c y cl es  ( ±  7 d a ys) i n t h e first  4  c y cl e s 
aft er   C 1  D 1  a n d t h er e aft er  at  l e ast e v er y  3  c y cl es  ( ±  7 d a ys)  if t h e s u bj e ct r e  m ai ns i n t h e st u d y t h er a p y,  a n d t h e  e n d  of tr e at  m e nt. 
h     W o  m e n  of  c hil d b e ari n g  p ot e nti al   m ust  h a v e  a s er u  m  pr e g n a n c y t est   wit hi n  1 4  d a ys  of r a n d o  mi z ati o n ( or,   w h er e  diff er e nt r   e g ul ati o ns  a p pl y,   wit hi n  7 2  h  of 
r a n d o  mi z ati on).   W o  m e n   w h o  h a v e  d o c u  m e nt ati o n  of  at l e ast  1 2    m o nt hs  of s p o nt a n e o us  a  m e  n orr h e a  a n d  h a v e  a n  F S  H l e v el  >  4 0  mI  U/  m L   will  b e  c o nsi d er e d 
p ost  m e n o p a us al  a n d  n e e d  n ot  u n d er g o  pr e g n a n c y t esti n g.  
i     O n   C 1  D  1  a n d   C 1  D 1 5 , bl o o d   will  b e  o bt ai n e d  at  pr e d os e  a n d  0. 5,  1,  2,  4  a n d  8  h o urs  aft er   m or ni n g  d os e .  I n  a d diti o n,  bl o o d   will  b e  c oll e ct e d  at  pr e d os e  o n C 1  D 2, 
C 1  D 8  ,   C 1  D 2 2, a n d  C 2  D 1  . 
j     T h e  P  D s a  m pl e (f or  pl as  m a   C S F - 1 a n d  a di p o n e cti n )   will  b e  o bt ai n e d  at  pr e d os e,  a n d  pr e d os e o n   C 1  D 1,   C 1  D 1 5,  a n d   C 2  D 1 . 
k     S u bj e cts r e c ei vi n g  c o n c o  mit a nt   w arf ari n s h o ul d  h a v e t h eir  a nti c o a g ul ati o n st at us  c ar ef ull y   m o nit or e d f or  a n y  n e c ess ar y  d os e  a dj ust  m e nts . 
l     S  A Es  ar e   m o nit or e d  u p o n  o c c urr e n c e  d uri n g  e xt e nsi o n  p art .  A Es   will  b e   r e p ort e d  at tr e at  me nt  visits.  
m     S u bj e cts   will  c o nti n u e st u d y  visit i n  d os e  es c al ati o n  p art  till t h e  c ut-off  d at e ( T h e  c ut -off  is  d efi n e d  as t h e  d at e  aft er  all s u bj e cts  h a v e  eit h er  dis c o nti n u e d t h e st u d y  or 
c o  m pl et e d  at l e ast  4  c y cl es.   S u bj e cts   w h o  ar e still  o n g oi n g i n t h e  st u d y  aft er t h e  c ut-off  d at e  a n d  w h o  ar e   r es p o n di n g  or st a bl e  aft er  p e xi d arti ni b  d uri n g t h e d os e 
es c al ati o n  p art  will   e nt er  e xt e nsi o n  p art  t o r e c ei v e  e xt e n d e d tr e at  m e nt of  p e xi d arti ni b.  
n       T h e  p h ar  m a c o g e n o  mi c  bl o o d s a  m pl e is  o pti o n al. If t a k e n, it s h o ul d  o nl y  b e t a k e n  o n c e  as s o o n  as r e as o n a bl y  p ossi bl e  aft er t h e s u bj e ct  h as si g n e d t h e  c o ns e nt f or  m.  
o     T h e  p h ar  m a c o g e n o  mi c s a  m pl e  vi sit .  T h e  p h ar  m a c o g e n o  mi c  bl o o d s a  m pl e  c o ul d  b e  c oll e ct e d  a n yti  m e  d uri n g st u d y  c o n d u cti o n . 
 
 
 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 8  of  9 0 
1 7. 2.     El e ct r o ni c   D at a   C a pt u r e  S yst e  m   
T h e  E  D  C s yst e  m  us e d f or  c o  m pl eti n g  e  C  R F i n t his st u d y is s h o  w n  b el o  w. 
N a  m e  of  E  D  C s yst e  m   us e d f or 
c o  m pl eti n g t h e  e  C  R F  
M e di d at a   R a v e
®  
E  D  C s yst e  m  d e v el o p er  
M e di d at a  S ol uti o ns I n c.    
E ntr y   m et h o d  
W e b   -b as e d  d at a  e ntr y  
I n p ut t er  mi n al 
D es kt o p/l a pt o p  c o  m p ut er   at t h e  st u d y sit e  
A b br e vi ati o ns:   e  C  R F  =  el e ctr o ni c  c as e r e p ort f or  m;  E  D  C   = el e ctr o ni c  d at a  c a pt ur e.  
              


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  8 9  of  9 0 
1 7. 3.     C  Y P 3  A 4   In hi bit o rs  a n d I n d u c e rs  
St r o n g I n hi bit o rs  
St r o n g I n d u c e r s  
Pr ot e as e i n hi bit ors   
•      Rit o n a vir   
•      I n di n a vir 
•      N elfi n a vir   
 
M a cr oli d e  a nti bi oti cs    
•      Er yt hr o  m y ci n  
•      T elit hr o  m y ci n  
•      Cl arit hr o  m y ci n   
 
A z ol e  a ntif u n g als   
•      Fl u c o n a z ol e  
•      K et o c o n a z ol e   
•      Itr a c o n a z ol e 
 
C hl or a  m p h e ni c ol ( a nti bi oti c)   
N ef a z o d o n e ( a nti d e pr ess a nt)   
B er g a  m otti n ( c o nstit u e nt  of  gr a p e fr uit j ui c e)   
A pr e pit a nt ( a nti e  m eti c)   
V er a p a  mil ( c al ci u  m  c h a n n el   bl o c k er)  
A nti c o n v uls a nts,   m o o d st a bi  li z ers 
•      P h e n yt oi n  
•      C ar b a  m a z e pi n e   
•      O x c ar b a z e pi n e   
 
N o n  -n u cl e osi d e r e v ers e tr a ns cri pt as e i n hi bit ors  
•      Ef a vir e n z  
•      N e vir a pi n e   
•      Etr a viri n e  
 
P h e n o b ar bit al ( b ar bit ur at e)  
Rif a  m pi ci n ( b a ct eri ci d al)   
M o d afi nil (sti  m ul a nt)    
H y p erf ori n ( c o nst  it u e nt  of  St. J o h n’s w  ort)  
C y pr ot er o n e ( a nti a n dr o g e n,  pr o g esti n)   
 
S o ur c e:  Fl o c k h art,   D  A.   Dr u g I nt er a cti o ns:   C yt o c hr o  m e  P 4 5 0   Dr u g I nt er a cti o n  T a bl e. I n di a n a   U ni v ersit y  S c h o ol  of 
M e di ci n e [ 2 0 0 9].   A v ail a bl e fr o  m:  htt p://  m e di ci n e.i u p ui. e d u/ cli n p h ar  m/ d dis/  m ai n   -t a bl e/.   A c c ess e d   O ct o b er  2 2,  2 0 1 4. 
 


Pr ot o c ol  P L 3 3 9 7-  A- A 1 0 3   
V ersi o n  5. 0,  2 5 F E  B 2 0 2 0 
C o nfi d e nti al 
P a g e  9 0  of  9 0 
1 7. 4.     A d d r ess   List   
R ef er t o  pr ot o c ol s u p pl e  m e nt   V ersi o n  3. 0   d at e d  1 0  A P  R    2 0 1 8.