An Open-Label, Multicenter, Extension Study for Subjects Who Participated in Prior Guadecitabine Clinical Studies
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Myeloid Dysplastic Syndrome
Sponsor: Astex Pharmaceuticals, Inc.

Offici al Titl e:      
A n  O p e n-l a b el, M ultic e nt er , E xt e nsi o n St u d y f or S u bj ects w h o P artici p at e d
i n Pri or G u a d e cit a bi n e Cli nic al St u di es
N C T N u m b er: 
 N C T 0 3 6 0 3 9 6 4
D oc u m e nt D at e: 
Pr ot oc ol V ersi o n Ori gi n al : 1 9  Ja n u ary  2 0 1 8

Ast e x  P h a r  m a c e uti c als, I n c. 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 
1 9  J a n u a r y  2 0 1 8  
Cli ni c al  St u d y  P r ot o c ol    —  S  GI- 1 1 0- 1 2 
A n   O p e n-  L a b el,    M ulti c e nt e r,   E xt  e nsi o n  St u d y f o r  S u bj e cts    W h o  P a rti ci p at e d i n  P ri o r 
G u a d e cit a bi n e   Cli ni c al  S  t u di es 
P  R  O  T  O  C  O  L   TI  T  L  E  P  A  G  E 
S p o ns o r:    
Ast e x  P h ar  m a c e uti c als, I n c. 
4 4 2 0   R os e  w o o d   Dri v e,  S uit e  2 0 0 
Pl e as a nt o n,   C  A   9 4 5 8 8 
Ast e x  P h a r  m a c e uti c als   
,   M  D,  P h  D 
M e di c al    M o nit o r:    
 (  m o bil e)
 (t el)
 (f a x)
Ast e x  P h a r  m a c e uti c als         
L o c al  F a x: 
 
D r u g  S af et y: 
T oll  Fr e e  F a x: 
 
E-  m ail: 
I  N  D   N u  m b e r: 
1 0 2 7 4 3
E u d r a  C  T   N u  m b e r:   
2 0 1 7- 0 0 4 6 0 3- 5 2
St u d y   Cli ni c al  P h as e:  
P h as e  2
V e rsi o n   D at e:   
Ori gi n al ( 1 9 J a n u ar y  2 0 1 8)

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
5 
1 9  J a n u a r y  2 0 1 8  
P  R  O  T  O  C  O  L  S  Y  N  O P SI S 
St u d y   N u  m b e r  a n d   Titl e: 
S  GI- 1 1 0- 1 2 : A n   O p e n- L a b el,   M ulti c e nt er,  E xt e nsi o n  St u d y f or  S u bj e cts    W h o  P a  rti ci p at e d i n  Pri or   G u a d e cit a bi n e 
Cli ni c al  St u di es  
I n v esti g ati o n al   D r u g:    G u a d e cit a bi n e ( S  GI- 1 1 0) f or s u b c ut a n e o us ( S  C) i nj e cti o n 
Cli ni c al  P h as e:   2  
St u d y   C e nt e rs  Pl a n n e d/  C o u nt r y :   M ulti c e nt er  gl o b al st u d y ( a p pr o xi  m at el y  1 5 0  c e nt ers i n  a p pr o xi  m at el y 
2 0  c o u ntri es)  
St u d y   O bj e cti v e(s):   
P ri  m a r y   O bj e cti v e 
•      T o  pr o vi d e  o n g oi n g tr e at  m e nt   wit h  g u a d e cit a bi n e f or s u bj e cts   w h o  b e n efitt e d fr o  m  g u a d e cit a bi n e tr e at  m e nt i n 
a  pr e vi o us   Ast e x-s p o ns or e d  cli ni c al st u d y  a n d t o  o bt ai n l o n g-t e r  m s af et y i nf or  m ati o n. 
S e c o n d a r y   O bj e cti v e(s) 
•      T o  o bt ai n l o n g-t er  m s ur vi v al i nf or  m ati o n  o n s u bj e cts   w h o  p arti c  i p at e d i n  a  pr e vi o us   Ast e x-s p o ns or e d 
g u a d e cit a bi n e  cli ni c al st u d y. 
St u d y   D esi g n  a n d I n v esti g ati o n al  Pl a n:   
T his is  a   m ulti c e nt er,  o p e n-l a b e l  e xt e nsi o n st u d y f or s u bj e cts   w h o  p arti ci p at e d i n  a  pr e vi o us   Ast e x-s p o ns or e d 
g u a d e cit a bi n e  cli ni c al st u d y (i n cl u di n g  b ut  n ot li  mit e d t o  S  GI- 1 1 0- 0 1,  S  GI- 1 1 0- 0 4,  S  GI- 1 1 0- 0 5,  S  GI- 1 1 0- 0 6,  a n d 
S  GI- 1 1 0- 0 7). 
S u bj e cts   w h o   w er e still r e c ei vi n g t r e at  m e nt   wit h  g u a d e cit a bi n e a n d i n t h e  o pi ni o n  of t h e i n v esti g at or   w er e still 
b e n efitti n g fr o  m tr e at  m e nt  at t h e ti  m e  of  d at a b as e  cl os e  of t h e  ori gi n al st u d y   will  b e  eli gi bl e t o  p arti ci p at e i n t his 
e xt e nsi o n st u d y.   A p pr o xi  m at el y  2 5 0 s u bj e cts  c o ul d  b e  e nr oll e d. 
S u bj e cts   will  att e n d  cli ni c  visits   o n   D a ys  1- 5  of  e a c h  2 8- d a y  cy cl e t o r e c ei v e tr e at  m e nt   w it h  g u a d e cit a bi n e.   D at a 
c oll e cti o n   will  b e li  mit e d t o tr e at  m e nt  e x p os ur e,  a d v ers e  e v e nts,  c o n c o  mit a nt   m e di c ati o ns, li  mit e d l a b or at or y 
p ar a  m et ers,  a n d s ur vi v al st at us.  
St u d y  P o p ul ati o n : 
I n cl usi o n   C rit e ri a 
S u bj e cts   m ust f ulfill  all  of t h e f oll o  wi n g i n cl usi o n  crit eri a: 
1.     Pr e vi o us   p arti ci p ati o n  i n   a n    Ast e x-s p o ns or e d   g u a d e cit a bi n e   cli n i c al  tri al  (i n cl u di n g   b ut   n ot  li  mit e d  t o 
S  GI- 1 1 0- 0 1,  S  GI- 1 1 0- 0 4,  S  GI- 1 1 0- 0 5,  S  GI- 1 1 0- 0 6,  a n d  S  GI- 1 1 0- 0 7) , i n   w hi c h t h e  s u bj e ct   w as tr e at e d   wit h 
g u a d e cit a bi n e  a n d   w as  still  o n  a cti v e tr e at  m e nt   wit h  g u a d e cit a b i n e  at t h e ti  m e  of  d at a b as e  cl os e f or t h e  pri or 
st u d y. 
2.     S u bj e ct is  c o nsi d er e d t o  b e  b e n efitti n g fr o  m  g u a d e cit a bi n e tr e a t  m e nt i n t h e  o pi ni o n  of t h e tr e ati n g i n v esti g at or. 
3.     S u bj e ct is  a bl e t o  u n d erst a n d  a n d  c o  m pl y   wit h t h e st u d y  pr o c e d u r es,  u n d erst a n d t h e ris ks i n v ol v e d i n t h e st u d y, 
a n d  pr o vi d e   writt e n i nf or  m e d  c o ns e nt  b ef or e  a n y st u d y-s p e cifi c  pr o c e d ur e. 
4.     W o  m e n  of  c hil d b e ari n g  p ot e nti a   l  ( a c c or di n g  t o  r e c o  m  m e n d ati o ns  of  t h e    Cli ni c al   Tri al  F a cilit ati o n    Gr o u p 
[  C T F  G];  s e e  pr ot o c ol S e cti o n  5. 2  f or  d et ails)   m ust  n ot  b e  pr e g n a nt  or  br e astf e e di n g  a n d   m ust  h av e  a  n e g ati v e 
pr e g n a n c y t est  at  s cr e e ni n g.    W o  m e n  of  c hil d b e ari n g  p ot e nti al  a n d   m e n   wit h  f e  m al e  p art n ers  of  c hil d b e ari n g 
p ot e nti al    m ust  a gr e e  t o  pr a cti c e  2  hi g hl y  eff e cti v e  c o ntr a c e pti v e   m e as ur es  of  birt h  c o ntr ol  ( as  d es cri b e d  i n 
S e cti o n  5. 2 )  a n d   m ust  a gr e e  n ot t o  b e c o  m e  pr e g n a nt  or f at h er  a  c hil d   w hil e r e c ei vi n g  g u a d e cit a bi n e  a n d f or  at 
l e ast  3   m o nt hs  aft er  c o  m pl eti n g  g u a d e cit a bi n e tr e at  m e nt. 
E x cl usi o n   C rit e ri a 
S u bj e cts   m e eti n g  a n y  of t h e f oll o  wi n g  e x cl usi o n  crit eri a   will  b e  e x cl u d e d fr o  m t h e st u d y: 
1.     A n y  s u bj e ct   w h o, i n t h e  o pi ni o n  of t h e i n v esti g at or,   m a y  h a v e  ot h er  c o n diti o ns,  or g a n  d ysf u n cti o n,  or  h a v e 
s af et y  d at a  fr o  m  t h eir  pri or  st u d y  p arti ci p ati o n  t h at  s u g g est  t h at  t h e  ris ks  of  c o nti n ui n g  tr e at  m e nt    wit h 
g u a d e cit a bi n e   m a y  o ut  w ei g h t h e  b e n efits. 
 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
6 
1 9  J a n u a r y  2 0 1 8  
St u d y   T r e at  m e nt: 
S u bj e cts   will r e c ei v e  g u a d e cit a bi n e tr e at  m e nt  at t h e s a  m e  d os e  t h at t h e y   w er e r e c ei vi n g i n th e l ast  c y cl e  of t h eir 
pri or st u d y  or  at  a  diff er e nt  d os e  as  g ui d e d  b y t h e  d os e  a dj ust m e nt  g ui d eli n es i n t h e  pri or st u d y  pr ot o c ol. 
S u bs e q u e nt tr e at  m e nt  d el a ys  a n d/ or  d os e r e d u cti o n  ar e  at t h e  dis cr eti o n  of t h e i n v esti g at or  as  g ui d e d  b y t h e  d os e 
a dj ust  m e nt  g ui d eli n es  of t h e  pri or st u d y  pr ot o c ol.  Tr e at  m e nt   m a y  c o nti n u e  as l o n g  as t h e s u bj e ct  c o nti n u es t o 
b e n efit  b as e d  o n i n v esti g at or j u d g  m e nt. 
T h er e is  n o r estri cti o n  o n t h e  us e  of  b est s u p p orti v e  c ar e  or  h  y dr o x y ur e a.  S u bj e ct s   w h o  n e e d t o r e c ei v e  ot h er 
a nti c a n c er t h er a pi es  or  ot h er i n v esti g ati o n al tr e at  m e nts   will  b e   wit h dr a  w n fr o  m t his st u d y. 
St u d y   E n d p oi nts: 
P ri  m a r y   E n d p oi nt 
•      S af et y  as   m e as ur e d  b y  a d v ers e  e v e nts. 
S e c o n d a r y   E n d p oi nt 
•      S ur vi v al st at us. 
St u d y   Ass ess  m e nts  a n d  P r o c e d u r es: 
I nf or  m e d  c o ns e nt  a n d  eli gi bilit y  ass ess  m e nt ( p h ysi c al  e x a  mi n atio n  a n d  h e  m at ol o g y/l a b or at or y  ass ess  m e nts t o 
j u d g e  c o nti n u e d f a v or a bl e  b e n efit/ris k  ass ess  m e nt)   will  b e  p erfor  m e d  at s cr e e ni n g.  
S u bj e cts   will  att e n d t h e  cli ni c f or tr e at  m e nt   wit h  g u a d e cit a bi n e  o n   D a ys  1- 5  of  e a c h  2 8- d a y  c y cl e.    W h e n tr e at  m e nt 
is  p er  m a n e ntl y  dis c o nti n u e d, foll o  w- u p   will st o p   wit h t h e s af et y f oll o  w- u p  visit  o c c urri n g  3 0   ±  7  d a ys  aft er t h e l ast 
g u a d e cit a bi n e tr e at  m e nt  or   w h e n   a n  alt er n ati v e  a nti c a n c er tr e atm e nt is  a d  mi nist er e d,   w hi c h e v er  o c c urs first. 
A d v ers e  e v e nts  a n d  c o n c o  mit a nt   m  e di c ati o ns   will  b e  c oll e ct e d t h r o u g h o ut t h e st u d y.  S a  m pl es f or li  mit e d 
h e  m at ol o g y  a n d s er u  m  c h e  mistr y  ass ess  m e nts   will  b e  c oll e ct e d  at  s cr e e ni n g,   D a y  1  of  e a c h  c y cl e,  a n d  at t h e s af et y 
f oll o  w- u p  visit.  F or   w o  m e n  of  c hil d b e ari n g  p ot e nti al,  a  pr e g n a nc y t est   will  b e  p erf or  m e d  at s cr e e ni n g  a n d  o n 
D a y  1  of  e a c h  c y cl e  pri or t o t  r e at  m e nt.  S ur vi v al st at us   will  b e r e c or d e d   w h e n t h e s u bj e ct is   wit h dr a  w n fr o  m t h e 
st u d y.   Ot h er  cli ni c al  ass ess  m e nts    m a y  b e  p erf or  m e d  as  p art  of st a n d ar d  of  c ar e  b ut t h e  perf or  m a n c e  a n d r es ults  of 
t h es e  ass ess  m e nts   will  n ot  b e  c oll e ct e d f or t his st u d y. 
S a  m pl e  Si z e  a n d  St at isti c al   A n al ys es: 
T h er e is  n o s a  m pl e si z e r e q uir e  m e nt f or t his  e xt e nsi o n st u d y.  S u  m  m ari es  of tr e at  m e nt  e x p os ur e  a n d  a d v ers e  e v e nts 
m a y  b e  pr o vi d e d.  T h e ti  mi n g  of s  u c h  a n al ys es   will  d e p e n d  o n t h e   n e e ds  of t h e  cli ni c al  d e v el o p  m e nt  pr o gr a  m.  
St u d y   D u r ati o n  a n d   T e r  mi n ati o n: 
T h e st u d y is  e x p e ct e d t o st art  i n   Q 2  2 0 1 8.  T h e st u d y   m a y  c o nti nu e  as l o n g  as s u bj e cts  ar e  r e c ei vi n g tr e at  m e nt   wit h 
g u a d e cit a bi n e,  or  u ntil  g u a d e cit a bi n e  b e c o  m es  c o  m  m er ci all y  a v ai l a bl e ( a nti ci p at e d f or   Q 4  of  2 0 1 9).  
C o  m pli a n c e  St at e  m e nt: 
T h e st u d y   will  b e  c o n d u ct e d i n  a c c or d a n c e   wit h t h e I nt er n ati o n a l   C o u n cil f or   H ar  m o nis ati o n (I  C  H)   G o o d   Cli ni c al 
Pr a cti c e (  G  C P)  g ui d eli n es,  pri n ci pl es  e n u n ci at e d i n t h e   D e cl ar a ti o n  of   H elsi n ki;  a n d  all h u  m a n  cli ni c al r es e ar c h 
r e g ul ati o ns i n  c o u ntri es   w her e t h e st u d y is  c o n d u ct e d. 
 
 
 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
7 
1 9  J a n u a r y  2 0 1 8  
T  A  B  L  E   O F   C  O  N  T  E  N  T S 
P  R  O  T  O  C  O  L   A P P  R  O  V  A  L  P  A  G  E ............................................................................................... 3  
A  B  B  R  E  VI  A  TI  O  N S   A  N  D   D  E FI  NI  TI  O  N S .................................  ................................................ 1 0 
1. 0  
I  N  T  R  O  D  U  C  TI  O  N   A  N  D   B  A  C  K  G  R  O  U  N  D .................................................................... 1 1 
1. 1  
G u a d e cit a bi n e   M e c h a nis  m  of   A cti o n .............................  ........................................ 1 1 
1. 2  
N o n cli ni c al   D at a  o n   G u a d e cit a bi n e ....................................................................... 1 2  
1. 3  
Cli ni c al   D at a  a n d   H u  m a n  P h ar  m a c o ki n eti cs ......................  ................................... 1 2 
1. 4  
P ot e nti al   Ris ks  a n d   B e n efits t o   H u  m a n  S u bj e cts ................ ................................... 1 3 
2. 0  
R  A  TI  O  N  A  L  E ................................................................................................................... 1 3  
2. 1  
R ati o n al e f or t h e  St u d y .......................................................................................... 1 3  
2. 2  
R ati o n al e f or   G u a d e cit a bi  n e   D os e  a n d   R e gi  m e n .................. ................................. 1 4 
3. 0  
S  T  U  D  Y   O  B J  E  C  TI  V  E S .................................................................................................... 1 4  
3. 1  
Pri  m ar y   O bj e cti v e .................................................................................................. 1 4  
3. 2  
S e c o n d ar y   O bj e cti v e(s) .......................................................................................... 1 4  
4. 0  
I  N  V  E S  TI  G  A  TI  O  N  A  L  P  L  A  N ......................................................................................... 1 4  
4. 1  
O v er all  St u d y   D esi g n ..........................................  ................................................... 1 4 
4. 2  
Dis c ussi o n  of  St u d y   D esi g n ....................................  ............................................... 1 5 
4. 3  
St u d y  E n d p oi nts ............................................... ...................................................... 1 5 
4. 3. 1  
Pri  m ar y  E n d p oi nt .............................................. .................................... 1 5 
4. 3. 2  
S e c o n d ar y  E n d p oi nt ............................................ .................................. 1 5 
5. 0  
S  E  L  E  C  TI  O  N   A  N  D    WI  T  H  D  R  A   W A  L   O F  S  U  B J  E  C  T S ................................................ 1 5  
5. 1  
N u  m b er  of  S u bj e cts  a n d   C e nt ers ............................................................................ 1 5  
5. 2  
I n cl usi o n   Crit eri a ................................................................................................... 1 6 
5. 3  
E x cl usi o n   Crit eri a .................................................................................................. 1 6  
5. 4  
Tr e at  m e nt   Dis c o nti n u ati o n  a n d    Wit h dr a  w al  of  S u bj e cts .......... ............................. 1 7 
5. 4. 1  
Dis c o nti n u ati o n fr o  m  St u d y  Tr e at  m e nt ..........................  ....................... 1 7 
5. 4. 2  
Wit h dr a  w al fr o  m t h e  St u d y .....................................   .............................. 1 7 
6. 0  
E  N  R  O  L  L   M  E  N  T  P  R  O  C  E  D  U  R  E S .................................................................................. 1 7  
7. 0  
S  T  U  D  Y   T  R  E  A  T   M  E  N  T S ................................................................................................. 1 7  
7. 1  
I n v esti g ati o n al   M e di ci n al  Pro d u ct (I  M P):   G u a d e cit a bi n e ........ ............................. 1 7 
7. 1. 1  
I  M P I nf or  m ati o n ................................................................................... 1 8 
7. 1. 2  
I  M P   R e gi  m e ns  a n d   A d  mi nistr ati o n ....................................................... 1 8 
7. 2  
G ui d eli n es f or   A dj usti n g  or    Wit h h ol di n g  St u d y  Tr e at  m e nt .......  ........................... 1 9 
7. 3  
C o n c o  mit a nt  Tr e at  m e nt .........................................  ................................................ 1 9 
7. 3. 1  
S u p p orti v e,  Pr o p h yl a cti c,  or   Ot h er  Tr e at  m e nts ................. ................... 1 9 
7. 3. 2  
Pr o hi bit e d   M e di c ati o ns ......................................................................... 1 9  

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
8 
1 9  J a n u a r y  2 0 1 8  
7. 4  
O v er d os e I nstr u cti o ns ............................................................................................ 1 9  
8. 0  
RI S  K S/ P  R  E  C  A  U  TI  O  N S ................................................................................................. 2 0  
8. 1  
D os e  Li  miti n g  T o xi citi es ......................................  ................................................. 2 0 
8. 2  
M y el os u p pr essi o n (  N e utr o p e ni a,  F e b   ril e   N e utr o p e ni a,  T hr o  m b o c yt op e ni a,  a n d  
A n e  mi a)  a n d its   C o ns e q u e n c es (I n  f e cti o ns  a n d/ or   H e  m orr h a g e) .......................... 2 0 
8. 3  
F ertilit y ..................................................... .............................................................. 21  
8. 4  
I nj e cti o n  Sit e   R e a cti o ns ......................................................................................... 2 1 
8. 5  
A d v ers e  E v e nts ...................................................................................................... 2 1  
9. 0  
S  T  U  D  Y   A S S  E S S   M  E  N  T S   A  N  D  P  R  O  C  E  D  U  R  E S .............................. ............................ 2 2 
9. 1  
Effi c a c y   Ass ess  m e nts .......................................... ................................................... 2 2 
9. 2  
S af et y   Ass ess  m e nts ............................................ .................................................... 2 2 
9. 3  
St u d y  Pr o c e d ur es ................................................................................................... 2 2  
9. 3. 1  
S c h e d ul e  of  E v e nts ............................................ .................................... 2 2 
9. 3. 2  
S cr e e ni n g  Pr o c e d ur es .......................................... .................................. 2 3 
9. 3. 3  
Tr e at  m e nt  Pr o c e d ur es........................................... ................................. 2 4 
9. 3. 4  
Tr e at  m e nt   Dis c o nti n u ati o n  a n d  S af et y  F oll o  w- u p   Visit ....................... 2 5  
1 0. 0  
E  V  A  L  U  A  TI  O  N,   R  E  C  O  R  DI  N  G,   A  N  D   R  E P  O  R  TI  N  G   O F   A  D  V  E  R S  E   E  V  E  N  T S ...... 2 5  
1 0. 1  
D efi niti o ns....................................................  .......................................................... 2 5 
1 0. 1. 1  
A d v ers e  E v e nt (  A E) .............................................................................. 2 5  
1 0. 1. 2  
S eri o us   A d v ers e  E v e nts ( S  A Es) ............................................................ 2 6  
1 0. 2  
A d v ers e  E v e nt   R e p orti n g  a n d   D es cri pti o ns ........................................................... 2 6  
1 0. 2. 1  
S e v erit y ................................................................................................. 2 7  
1 0. 2. 2  
R el ati o ns hi p t o  St u d y  Tr e at  m e nt (  S us p e ct e d   A d v ers e   R e a cti o ns) . ....... 2 7 
1 0. 2. 3  
Pr e g n a n c y  a n d   A b orti o n ........................................ ................................ 2 8 
1 0. 3  
R e p orti n g   R e q uir e  m e nts f or  S eri  o us   A d v ers e  E v e nts ( S  A Es) ...... ......................... 2 8 
1 0. 4  
F oll o  w- u p f or   A d v ers e  E v e nts ............................................................................... 2 9  
1 1. 0  
S  T  A  TI S  TI  C S .................................................... ................................................................ 3 0 
1 1. 1  
S a  m pl e  Si z e ................................................... ......................................................... 3 0 
1 1. 2  
A n al ysis  S ets .................................................  ......................................................... 3 0 
1 1. 3  
S c h e d ul e  of   A n al ys es .......................................... ................................................... 3 0 
1 1. 4  
Dis p ositi o n ...................................................  .......................................................... 3 0 
1 1. 5  
A n al ysis  of   D e  m o gr a p hi c  a n d   B as eli n e   D at a ........................................................ 3 0  
1 1. 6  
Effi c a c y   A n al ys es .................................................................................................. 3 1  
1 1. 7  
S af et y   A n al ys es ............................................... ....................................................... 3 1 
1 1. 8  
I nt eri  m   A n al ysis ..................................................................................................... 3 1 
1 1. 9  
Pr o c e d ur es f or   H a n dli n g   Mi ssi n g,   U n us e d,  a n d  S p uri o us   D at a............................. 3 1  

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
9 
1 9  J a n u a r y  2 0 1 8  
1 2. 0  
S  T  U  D  Y   D  U  R  A  TI  O  N   A  N  D   T  E  R   MI  N  A  TI  O  N ................................ ............................... 3 1 
1 3. 0  
S  T  U  D  Y   C  O   M P  LI  A  N  C  E   A  N  D   E  T  HI  C  A  L   C  O  N SI  D  E  R  A  TI  O  N S ............................... 3 2  
1 3. 1  
C o  m pli a n c e  St at e  m e nt ..........................................  ................................................. 3 2 
1 3. 2  
I nf or  m e d   C o ns e nt................................................................................................... 3 2 
1 3. 3  
I nstit uti o n al   R e vi e  w   B o ar d  or In d e p e n d e nt  Et hi cs   C o  m  mitt e e (I  R  B /I E  C) ........... 3 2 
1 4. 0  
A  D   MI  NI S  T  R  A  TI  V  E  P  R  O  C  E  D  U  R  E S .....................................  ...................................... 3 2 
1 4. 1  
S p o ns or   R es p o nsi biliti es ........................................................................................ 3 2  
1 4. 1. 1  
St u d y  S u p pli es ....................................................................................... 3 3  
1 4. 1. 2  
I n v esti g at or  Tr ai ni n g ............................................................................. 3 3 
1 4. 1. 3  
O n g oi n g   C o  m  m u ni c ati o n  of  S af et y I  nf or  m ati o n   D uri n g t h e  St u d y .. .... 3 3 
1 4. 1. 4  
St u d y   M o nit ori n g .................................................................................. 3 3  
1 4. 1. 5  
St u d y   A u diti n g  a n d I ns p e cti n g ................................. ............................. 3 4 
1 4. 2  
I n v esti g at or   R es p o nsi biliti es .................................................................................. 3 4 
1 4. 2. 1  
S u bj e ct  S cr e e ni n g  L o g ......................................... ................................. 3 4 
1 4. 2. 2  
G u a d e cit a bi n e   A c c o u nt a bilit y ............................................................... 3 4  
1 4. 2. 3  
R e p orti n g  a n d   R e c or di n g  of  St u d y   D at a ............................................... 3 5  
1 4. 2. 4  
S o ur c e   D o c u  m e nt ati o n .......................................... ................................ 3 5 
1 4. 2. 5  
R e c or ds   R et e nti o n .............................................  .................................... 3 6 
1 4. 3  
Cli ni c al  Tri al I ns ur a n c e .......................................................................................... 3 6  
1 4. 4  
St u d y   A d  mi nistr ati v e  L ett ers  a n d  Pr ot o c ol   A  m e n d  m e nts .......... ........................... 3 6 
1 5. 0  
P  O  LI  C  Y  F  O  R  P  U  B  LI  C  A  TI  O  N   A  N  D  P  R  E S  E  N  T  A  TI  O  N   O F   D  A  T  A ........................ 3 7  
1 6. 0  
R  E F  E  R  E  N  C  E S ................................................................................................................. 3 8  
  
LI S  T   O F   T  A  B  L  E S 
T a bl e  1:  
S c h e d ul e  of  E v e nts ............................................ ......................................... 2 3 
T a bl e  2:  
Cli ni c al  L a b or at or y  T ests .....................................  ...................................... 2 4 
  

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 0 
1 9  J a n u a r y  2 0 1 8  
A  B  B  R  E  VI  A  TI  O  N S   A  N  D   D  E FI  NI  TI  O  N S 
A  D L      
a cti viti es  of  d ail y li vi n g 
A  D  M E      
a bs or pti o n,  distri b uti o n,   m et a b olis  m,  e x cr eti o n 
A E      
a d v ers e  e v e nt 
A L T      
al a ni n e tr a ns a  mi n as e (s er u  m    gl ut a  mi c  p yr u vi c tr a ns a  mi n as e [S  G P T]) 
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 tr a ns a  mi n as e (s er u  m  gl ut a  mi c  o x al o a c eti c tr a ns a  mi  n as e [ S  G  O T]) 
B S  A      
b o d y s urf a c e  ar e a 
C F  R       
C o d e  of  F e d er al   R e g ul ati o ns 
C  M  M L      
c hr o ni c   m y el o  m o n o c yti c l e u k e  mi a 
C p  G      
c yt osi n e- p h os p h at e- g u a ni n e 
C  R F/ e  C  R F      c as e r e p ort f or  m/ el e ctr o ni c  c as e r e p ort f or  m 
C T  C  A 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 
C T F  G       
Cli ni c al  Tri al  F a cilit ati o n   Gr o u p 
D  N  M T       
D  N  A   m et h yl tr a nsf er as e 
F  D  A      
F o o d  a n d   Dr u g   A d  mi nistr ati o n 
G  C P       
G o o d   Cli ni c al  Pr a cti c e 
G L P       
G o o d  L a b or at or y  Pr a cti c e 
H  C  C      
h e p at o c ell ul ar  c ar ci n o  m a 
H  M  A      
h y p o  m et h yl ati n g  a g e nt 
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  M P      
i n v esti g ati o n al   m e di ci n al pr o d u ct (t h e s p e cifi c   Ast e x  dr u g  pr o d u ct  u n d er st u d y) 
I E  C      
I n d e p e n d e nt  Et hi cs   C o  m  mitt e e  
I  R  B      
I nstit uti o n al   R e vi e  w   B o ar d 
LI  N E- 1      
l o n g i nt ers p ers e d  n u cl e ar  el e  m e nt- 1 
M  D S       
m y el oi d  d ys pl asti c s y n dr o  m es 
M e d  D  R  A       
M e di c al   Di cti o n ar y f or   R e g ul at or y   A cti viti es 
M S  D S       
M at eri al  S af et y   D at a  S h e et 
O  H S  A       
O c c u p ati o n al   H e alt h  a n d  S af et y 
P  K 
p h ar  m a c o ki n eti c(s) 
P T 
Pr ef err e d  T er  m 
R  B  C      
r e d  bl o o d  c ell 
r/r 
r el a ps e d/r efr a ct or y 
S  A E      
s eri o us  a d v ers e  e v e nt 
S  C 
s u b c ut a n e o us 
S  O  C      
S yst e  m   Or g a n   Cl ass 
S  U S  A  R      
s eri o us  u n e x p e ct e d s us p e ct e d  a d v ers e r e a cti o n 
T  C 
tr e at  m e nt  c h oi c e 
T  K      
t o xi c o ki n eti cs 
T  N      
tr e at  m e nt  n aï v e 
W  B  C       
w hit e  bl o o d  c ell 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 1 
1 9  J a n u a r y  2 0 1 8  
T h e st u d y   will  b e c o n d u ct e d i n a c c or d a n c e   wit h t h e I nt er n ati o n a l  C o u n cil f or   H ar  m o nis ati o n (I  C  H) 
G o o d  Cli ni c al  Pr a cti c e (  G  C P)  g ui d e  li n es,  pri n ci pl es  e n u n ci at e d i n t h e   D e cl ar ati o n  of   H elsi n ki,  a n d 
all   h u  m a n   cli ni c al   r es e ar c h   r e g ul ati o ns   i n   c o u ntri es     w h er e   t h e   st u d y   is   c o n d u ct e d   (s e e 
S e cti o n  1 3. 0 ). 
1. 0      I  N  T  R  O  D  U  C  TI  O  N   A  N  D   B  A  C  K  G  R  O  U  N  D 
G u a d e cit a bi n e ( S  GI- 1 1 0) is  a  n e x  t- g e n er ati o n  h y p o  m et h yl ati n g  a ge nt (  H  M  A)  b ei n g  e v al u at e d i n 
s u bj e cts     wit h    h e  m at ol o gi c al      m ali g n a n ci es    i n cl u di n g    a c ut e      m y el oi d    l e u k e  mi a    (  A  M L), 
m y el o d ys pl asti c  s y n dr o  m es  (  M  D S),  a n d  c hr o ni c   m y el o  m o n o c yti c l e u k e  mi a  (  C  M  M L),  a n d  s oli d 
t u  m ors i n cl u di n g  o v ari a n  c a n c er  a n d  h e p at o c ell ul ar  c ar ci n o  m a (  H  C  C).  T his is  a n  e xt e nsi o n  st u d y 
t o  all o  w  o n g oi n g tr e at  m e nt   wit h  g u a d e cit a bi n e  f or  s u bj e cts   w h o  h a v e  b e n efitt e d  fr o  m tr e at  m e nt 
wit h  g u a d e cit a bi n e  i n  pri or  g u a d e  cit a bi n e  cli ni c al  st u di es.   D es cri pti o ns  of  t h e  diff er e nt  dis e as e 
c o n diti o ns  u n d er  st u d y  a n d tr e at  m e nt  o pti o ns f or  e a c h  ar e  pr o vi d e d i n t h e r es p e cti v e  pri or  st u d y 
pr ot o c ols. 
1. 1      G u a d e cit a bi n e    M e c h a nis  m  of   A cti o n 
G u a d e cit a bi n e  is  a  p ot e nt  i n hi b  it or  of    D  N  A    m et h yl ati o n.    G u a d e cit a bi n e  is  a  di n u cl e oti d e  of 
d e cit a bi n e  a n d  d e o x y g u a n osi n e  li n k e d    wit h  a  p h os p h o di est er  b o n d .    D e cit a bi n e  is  t h e  a cti v e 
m et a b olit e.   G u a d e cit a bi n e is  a  n e  w  c h e  mi c al  e ntit y t h at   w as  d es  i g n e d t o  e n h a n c e  p h ar  m a c o ki n eti c 
pr o p erti es  c o  m p ar e d    wit h   d e cit a bi n e,    wit h   p ot e nti al  t o  i  m pr o v e   p h ar  m a c o d y n a  mi cs,  cli ni c al 
effi c a c y,  a n d  s af et y.    U nli k e  d e ci t a bi n e,  g u a d e cit a bi n e  is  r esist a nt  t o  d e a  mi n ati o n  b y  c yti di n e 
d e a  mi n as es.    G u a d e cit a bi n e  is   cl e a v e d   b y  i ntr a-   a n d   e xtr a c ell ul a r   p h os p h or yl as es   a n d   ot h er 
e n z y  m es, r el e asi n g  d e cit a bi n e.   T his  cl e a v a g e r es ults i n  gr a d u al  r el e as e  of  d e cit a bi n e  b ot h  e xtr a- 
a n d i ntr a c ell ul arl y, t h us  pr ol o n gi n g t h e  e x p os ur e  of t u  m or  c ell s t o its  a cti v e   m et a b olit e  d e cit a bi n e 
c o  m p ar e d t o  p ar e nt al  d e cit a bi n e. 
G u a d e cit a bi n e  ( a n d   d e cit a bi n e)  r e v ers es    D  N  A   h y p er  m et h yl ati o n   b y    i n hi biti n g    D  N  A    m et h yl 
tr a nsf er as e  (  D  N  M T)   e n z y  m es.    H y p er  m et h yl ati o n   of   c yt osi n e- p h os p hat e- g u a ni n e  (  C p  G)  ri c h 
r e gi o ns (  C p  G isl a n ds) is  a  p h ysi ol o gi c   m e c h a nis  m  of  p er  m a n e nt  ge n e i n a cti v ati o n t h at is  us ur p e d 
b y l e u k e  mi c  c ells,   w hi c h  us e it t o sil e n c e t u m or s u p pr ess or  g e n  es  a n d r el at e d  pr ot ei ns ( G or e  2 0 0 9
).   D e cit a bi n e is  a  c yti di n e  a n al o g t h at i n hi bits   D  N  A   m et h yl ati on i n  vitr o, r es ulti n g i n r e- e x pr essi o n 
of  pr e vi o usl y  sil e n c e d  g e n es  ( St e e ns  m a  2 0 0 9 ).    D e cit a bi n e  a p p e ars  t o  h a v e  a  d u al  a cti o n  o n 
n e o pl asti c  c ells.  B y i n c or p or ati o n i nt o   D  N  A  a n d  c o v al e nt  b o n d f or  m ati o n   wit h   D  N  M T,  d e cit a bi n e 
eff e cti v el y  d e pl et es t h e  c ells  of   m et h yl ati n g  e n z y  m es ( St e e ns  m a  2 0 0 9).   T his  e n z y  m e  d efi ci e n c y 
r e n d ers  t h e  c ell  u n a bl e  t o    m ai nt ai n    D  N  A    m et h yl ati o n  aft er  c ell ul ar  r e pli c ati o n,  r es ulti n g  i n 
eff e cti v e  h y p o  m et h yl ati o n.   H o  w e v e r, t h e r e q uir e  m e nt f or c ell  divisi o n t o a c hi e v e  h y p o  m et h yl ati o n 
a n d t h e  s h ort  h alf-lif e  of  d e cit a bi n e  s u g g est t h at  pr ol o n g e d  e x p os ur e is  pr ef er a bl e f or  a c hi e vi n g  a 
diff er e nti ati o n  eff e ct ( St e e ns  m a  2 0 0 9).   At  hi g h  c o n c e ntr ati o ns,   c o v al e ntl y tr a p p e d   D  N  M T  a cts  as 
a  b ul k y   D  N  A  a d d u ct  a n d r es ults i n  c yt ot o xi cit y r at h er t h a n  h y p o m et h yl ati o n. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 2 
1 9  J a n u a r y  2 0 1 8  
1. 2      N o n cli ni c al   D at a  o n   G u a d e cit a bi n e 
G u a d e cit a bi n e  h as  b e e n st u di e d f or its  p h ar  m a c o d y n a  mi c  eff e cts   o n  gl o b al   D  N  A   m et h yl ati o n  a n d 
o n t h e r e- e x pr essi o n  of s p e cifi c  g e n es t h at ar e sil e n c e d i n c a n c er c ells  d u e t o a n alt er e d   m et h yl ati o n 
st at us  of t h eir   D  N  A s e q u e n c e.   Gl o b al   D  N  A   m et h yl ati o n is  e v al u at e d t hr o u g h t h e  p yr os e q u e n ci n g 
of l o n g i nt ers p ers e d  n u cl e ar  el e  m e nt- 1  ( LI  N E- 1) i n   D  N  A  e xtr a ct e d  fr o  m  bl o o d  or t u  m or tiss u e. 
G u a d e cit a bi n e  h as  b e e n  e v al u at e d   i n s e v er al  diff er e nt i n  vitr o a n d i n  vi v o   m o d els  of  v ari o us t y p es 
of  c a n c er  a n d i n s af et y  p h ar  m a c ol o g y st u di es. 
T h e  p h ar  m a c o ki n eti c  pr ofil e  a n d t h e  a bs or pti o n,  d istri b uti o n,   met a b olis  m  a n d  e x cr eti o n (  A  D  M E) 
of  g u a d e cit a bi n e  ar e   w ell  c h ar a ct eri z e d i n  n o n cli ni c al  s p e ci es  as   w ell  as  h u  m a ns.  T h e  si n gl e-  a n d 
r e p e at- d os e  n o n cli ni c al  p h ar  m a c o ki n eti cs ( P  K)  a n d t o xi c o ki n eti c ( T  K)  pr ofil es  of  g u a d e cit a bi n e 
a n d its  a cti v e   m et a b olit e  d e cit a bi n e  h a v e  b e e n  e x a  mi n e d i n  s e v er al  st u di es i n   mi c e, r ats, r a b bits, 
a n d   m o n k e ys. 
A  c o  m pr e h e nsi v e   pr o gr a  m   of  i n   vitr o  a n d  i n   vi v o   n o n cli ni c al  t o x  i c ol o g y  st u di es   h as   b e e n 
c o n d u ct e d   wit h  g u a d e cit a bi n e i n c l u di n g   G o o d  L a b or at or y  Pr a cti c e (  G L P)- c o  m pli a nt s u b c ut a n e o us 
( S  C) t o xi cit y st u di es i n r ats, r a b bits,  a n d   m o n k e ys,  a n d i n  vitr o  g e n eti c t o xi cit y t ests. 
D et ails  o n  n o n cli ni c al  st u di es  c o n  d u ct e d    wit h  g u a d e cit a bi n e  ar e    pr o vi d e d  i n  t h e   pri or  st u d y 
pr ot o c ol  a n d i n t h e I n v es ti g at or’s   Br o c h ur e (I  B). 
1. 3      Cli ni c al   D at a  a n d   H u  m a n  P h a r  m a c o ki n eti cs 
G u a d e cit a bi n e is  b ei n g  e v al u at e d i n  p ati e nts   wit h  h e  m at ol o gi c al     m ali g n a n ci es (  A  M L,    M  D S,  a n d 
C  M  M L) a n d i n  p ati e nts   wit h s oli d t u  m ors ( o v ari a n c a n c er a n d   H  C  C  ).  LI  N E- 1  d e  m et h yl ati o n,  g e n e-
s p e cifi c  d e  m et h yl ati o n,  a n d  cli ni c al r es p o ns es  h a v e  b e e n  o bs er v e d i n  p ati e nts   wit h   A  M L  a n d   M  D S 
( St u d y  S  GI- 1 1 0- 0 1; Iss a  et  al  2 0 1 5; K a nt arji a n  et  al  2 0 1 7  ; R o b o z  et  al  2 0 1 8  ),  as   w ell  as i n  p ati e nts 
wit h  o v ari a n  c a n c er  a n d   H  C  C ( S  t u di es  S  GI- 1 1 0- 0 2  a n d  S  GI- 1 1 0- 0 3).  
T h e  cli ni c al  d e v el o p  m e nt  pr o gr a  m  f or  g u a d e cit a bi n e i n cl u d es  8  cli ni c al st u di es,  as f oll o  ws: 
•     S  GI- 1 1 0- 0 1   –    P h as e   1/ 2   st u d y   of    g u a d e cit a bi n e     m o n ot h er a p y   i n   4 0 1 s u bj e cts     wit h 
A  M L/  M  D S/  C  M  M L. I n cl u d e d  a  P h as e  1  d os e  es c al ati o n  a n d  a  P h as e  2   d os e  e x p a nsi o n. 
•     S  GI- 1 1 0- 0 2  –  P h as e  2 st u d y  of  g u a d e cit a bi n e i n  c o  m bi n ati o n   wit h   c ar b o pl ati n i n  1 2 0 s u bj e cts 
wit h  pl ati n u  m-r esist a n  t  o v ari a n  c a n c er. 
•     S  GI- 1 1 0- 0 3  –  P h as e  2 st u d y  of  g u a d e cit a bi n e   m o n ot h er a p y i n  5 0 s u bj e cts   wit h  h e p at o c ell ul ar 
c ar ci n o  m a. 
•     3 4 3- 1 4- 0 0 1  –  P h as e  1  d os e es c al ati o n st u d y  of  g u a d e cit a bi n e   m o n ot h er a p y i n  1 4   A  M L s u bj e cts 
c o n d u ct e d i n J a p a n. 
•     S  GI- 1 1 0- 0 4  –  P h as e  3  st u d y  of  g u a d e cit a bi n e  vs  tr e at  m e nt  c h oi c e   ( T  C)  i n  a p pr o xi  m at el y 
8 0 0 s u bj e cts   wit h tr e at  m e nt-  n aï v e ( T  N)   A  M L. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 3 
1 9  J a n u a r y  2 0 1 8  
•     S  GI- 1 1 0- 0 5  –  P h as e  1   A  D  M E  st u d y i n  a p pr o xi  m at el y  6  s u bj e cts   wit h   A  M L,    M  D S,  or  s oli d 
t u  m ors. 
•     S  GI- 1 1 0- 0 6   –   P h as e   3  st u d y   of   g u a d e cit a bi n e   vs    T  C  i n  a p pr o xi  m at el y   4 0 0  a d ults    wit h 
pr e vi o usl y tr e at e d   A  M L. 
•     S  GI- 1 1 0- 0 7  –  P h as e  3 st u d y  of  g u a d e cit a bi n e  vs  T  C i n  a p pr o xi  m at el y  4 0 0  a d ults   wit h   M  D S  or 
C  M  M L  pr e vi o usl y tr e at e d   w  it h  h y p o  m et h yl ati n g  a g e nts.  
A d diti o n al  g u a d e cit a bi n e  st u di es   m a y  b e i niti at e d i n t h e  f ut ur e  .   A  s u  m  m ar y  of  a v ail a bl e  r es ults 
fr o  m  cli ni c al st u di es is  pr o vi d ed i n t h e  pri or st u d y  pr ot o c ol  a n d t h e   m ost r e c e nt I  B. 
1. 4      P ot e nti al   Ris ks  a n d   B e n efits t o   H u  m a n  S u bj e cts 
I n t h e s etti n g  of   A  M L/  M  D S, it is  diffi c ult t o s e p ar at e t h e ris ks  ass o ci at e d   wit h  g u a d e cit a bi n e fr o  m 
t h os e  of t h e  dis e as e, as  p a n c yt o p e ni a is a  h all  m ar k  of  b ot h.  R e p ort e d s eri o us a d v ers e e v e nts ( S  A Es) 
ass o ci at e d    wit h  g u a d e cit a bi n e  i n cl u d e    m y el os u p pr essi o n-i n d u c e d   p a n c yt o p e ni a  a n d  its  t y pi c al 
s e q u el a e, s u c h  as i nf e cti o n  pr o gr essi n g t o s e psis  or  p n e u  m o ni a,    m ulti or g a n  d ysf u n cti o n s e c o n d ar y 
t o  h y p ot e nsi o n  a n d  h y p o xi a,   m u c os al i nfl a  m  m ati o n,  a n d  bl e e di n g. I n r ar e  c as es, t h e  s u bj e ct   m a y 
e x p eri e n c e  dr u g-r el at e d  h y p ers e nsi ti vit y,  d es cri b e d  as  f a ci al  ed e  m a  or  c ell ulitis.  S u bj e cts    wit h 
s oli d t u  m ors  als o  e x p eri e n c e d  a d v ers e  e v e nts r el at e d t o   m y el os u p pr essi o n.  T h es e  a n d  ot h er ris ks 
of  g u a d e cit a bi n e i n  h u  m a ns  ar e  d es cri b e d  f urt h er i n  S e cti o n  8. 0 .  F or   m or e  d et ail e d i nf or  m ati o n, 
pl e as e r ef er t o t h e I  B f or  g u a d e cit a bi n e.  
Pr eli  mi n ar y  d at a i n di c at e  cli ni c al  a cti vit y  of  g u a d e cit a bi n e i n    A  M L  a n d    M  D S,   wit h t h e  p ot e nti al 
b e n efits  of s y  m pt o  m i  m pr o v e  m e nt, i  m pr o v e  m e nt i n  bl o o d  c o u nts,  d e cr e as e d  n e e d f or tr a nsf usi o ns, 
d el a y e d   dis e as e   pr o gr essi o n  i n cl u di n g   pr o gr essi o n  t o    A  M L,   d el a y e d   n e e d   f or   s u bs e q u e nt 
a nti c a n c er t h er a p y,  a n d  pr ol o n g ati o n  of  s ur vi v al.   H e n c e,  b e n efi ts  of  r es p o ns e t o tr e at  m e nt   m a y 
o ut  w ei g h  i n cr e  m e nt al  ris ks  of  g u a d e cit a bi n e  t h er a p y.  F or  p ati e n ts   wit h  s oli d  t u  m ors  r e c ei vi n g 
g u a d e cit a bi n e  as  a  si n gl e  a g e nt  or i n  c o  m bi n ati o n, t h er e  ar e  d a t a  s u g g esti v e  of  cli ni c al  a cti vit y; 
h o  w e v er, t h e ris k/ b e n efit r ati o  i n  s oli d t u  m ors  d o es  n ot  s u p p ort  us e  of  g u a d e cit a bi n e  o utsi d e  of  a 
cli ni c al tri al. 
Ris k- b e n efit  c o nsi d er ati o ns f a v or  p erf or  m a n c e  of t his tri al.  E n  r oll  m e nt i n t his  st u d y is li  mit e d t o 
s u bj e cts   w h o  h a v e  b e e n r e c ei vi n g  g u a d e cit a bi n e i n  a  pri or  cli ni c al tri al  a n d  ar e  b e n efitti n g fr o  m 
g u a d e cit a bi n e tr e at  m e nt  b as e d  o n t h e I n v esti g at or’s  ass ess  m e nt.  
2. 0      R  A  TI  O  N  A  L  E 
2. 1      R ati o n al e f o r t h e  St u d y 
W hil e   m ort alit y  is  t h e   m ost  c o  m  m o n  o ut c o  m e  f or  p ati e nts   wit h  t h   e  c o n diti o ns  b ei n g  tr e at e d i n 
g u a d e cit a bi n e  cli ni c al  st u di es,  a  s  m all  pr o p orti o n  of  s u bj e cts  s ur vi v e t o t h e  e n d  of t h e  st u d y  a n d 
c o nti n u e t o r e c ei v e tr e at  m e nt   wit h  g u a d e cit a bi n e  at t h e ti  m e  of   d at a b as e  cl os e.   Of t h e  4 0 1 s u bj e cts 
tr e at e d  i n  t h e  first  g u a d e cit a bi n e  cli ni c al  st u d y  ( S  GI- 1 1 0- 0 1),  8 s u bj e cts  c o nti n u e  t o  r e c ei v e 
g u a d e cit a bi n e  tr e at  m e nt,    wit h  a  tr e at  m e nt  d ur ati o n  ( as  of    N o v e  m b er  2 0 1 7)  of  2. 8 t o  5. 6  y e ars 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 4 
1 9  J a n u a r y  2 0 1 8  
( 3 4- 6 8  c y cl es).  P h as e  3  St u d y  S  GI- 1 1 0- 0 4   will  cl os e i n  2 0 1 8  a n d it is  e x p e ct e d t h at t h er e   will  b e 
s u bj e cts  still  b e n efitti n g  fr o  m  g u a d e cit a bi n e tr e at  m e nt  at t h e  ti  m e t h at  st u d y  cl os es.   R at h er t h a n 
h a v e  e a c h  cli ni c al  st u d y r e  m ai n  o p e n t o  all o  w  c o nti n u e d  g u a d e cit a bi n e tr e at  m e nt, t his  e xt e nsi o n 
st u d y   will  pr o vi d e  o n e  pr ot o c ol  u n d er   w hi c h  s u bj e cts   w h o  h a v e  b e n efitt e d  fr o  m  g u a d e cit a bi n e 
tr e at  m e nt   m a y  c o nti n u e t o re c ei v e  g u a d e cit a bi n e.  
2. 2      R ati o n al e f o r   G u a d e cit a bi n e   D os e  a n d   R e gi  m e n 
T h e  g u a d e cit a bi n e  d os e  a n d  r e gi  m e n  a d  mi nist er e d  i n  cli ni c al  st u di es   h as   b e e n   diff er e nt  f or 
diff er e nt  i n di c ati o ns.  S u bj e cts  i n  t his  st u d y   will  c o nti n u e  r e cei vi n g  t h e  g u a d e cit a bi n e  d os e  a n d 
r e gi  m e n t h at t h e y   w er e r e c ei vi n g i n t h e l ast  c y cl e  of t h eir  prior  st u d y.   T h e r ati o n al e f or t h e  d os e 
a n d r e gi  m e n is  pr o vi d e d i n t h e  p ri or st u d y  pr ot o c ols fr o  m   w hi c h s u bj e cts   will  b e  e nr oll e d i nt o t his 
e xt e nsi o n st u d y  pr ot o c ol. 
3. 0      S  T  U  D  Y   O  B J  E  C  TI  V  E S 
3. 1      P ri  m a r y   O bj e cti v e 
•     T o   pr o vi d e   o n g oi n g   tr e at  m e nt     wit h   g u a d e cit a bi n e   f or   s u bj e cts     w h  o   b e n efitt e d   fr o  m 
g u a d e cit a bi n e  tr e at  m e nt  i n  a  pr e vi o us   Ast e x-s p o ns or e d  cli ni c al   st u d y  a n d  o bt ai n  l o n g-t er  m 
s af et y i nf or  m ati o n. 
3. 2      S e c o n d a r y   O bj e cti v e(s) 
•     T o  o bt ai n l o n g-t er  m  s ur vi v al i nf o r  m ati o n  o n  s u bje cts   w h o  p arti c i p at e d i n  a  pr e vi o us   Ast e x-
s p o ns or e d  g u a d e cit a bi n e  cli ni c al st u d y. 
4. 0      I  N  V  E S  TI  G  A  TI  O  N  A  L  P  L  A  N 
4. 1      O v e r all  St u d y   D esi g n 
T his is a   m ulti c e nt er,  o p e n-l a b e l  e xt e nsi o n st u d y f or s u bj e cts w h o  p arti ci p at e d i n  a  pr e vi o us   Ast e x-
s p o ns or e d  g u a d e cit a bi n e  cli ni c al   st u d y  (i n cl u di n g  b ut  n ot  li  mite d  t o  S  GI- 1 1 0- 0 1,  S  GI- 1 1 0- 0 4, 
S  GI- 1 1 0- 0 5,  S  GI- 1 1 0- 0 6,  a n d  S  GI- 1 1 0- 0 7).  
S u bj e cts    w h o    w er e  still  r e c ei vi n g  tr e at  m e nt    wit h   g u a d e cit a bi n e   a n d  i n  t h e   o pi ni o n   of  t h e 
i n v esti g at or   w er e still  b e n efitti n g fr o  m tr e at  m e nt  at t h e ti  m e of  d at a b as e  cl os e  of t h e  ori gi n al st u d y 
will  b e eli gi bl e t o  p arti ci p at e i n t his e xt e nsi o n st u d y.   A p pr o x  i  m at el y  2 5 0 s u bj e cts c o ul d  b e e nr oll e d 
at  a p pr o xi  m at el y  1 5 0  c e nt ers i n  a p pr o xi  m at el y  2 0  c o u ntri es   w orl d  wi d e. 
S u bj e cts    will  att e n d  cli ni c  visits  o n    D a ys  1- 5  of  e a c h  2 8- d a y  c y cl e  t o  r e c ei v e  tr e at  m e nt    wit h 
g u a d e cit a bi n e.  S u bj e cts    will  r e c ei v e  t h e  s a  m e  g u a d e cit a bi n e  d os e  a n d  r e gi  m e n  t h at  t h e y    w er e 
r e c ei vi n g  i n  t h e  l ast  c y cl e  of  t h e  pri or  st u d y.    D os e  a dj ust  m e nt   is  p er  mitt e d  u n d er  t h e  s a  m e 
g ui d eli n es  pr o vi d e d  i n  t h e  pri or   st u d y  pr ot o c ol.    D at a  c oll e cti on    will  b e  li  mit e d  t o  tr e at  m e nt 
e x p os ur e,  a d v ers e  e v e nts,  c o n c o  mit a nt   m e di c ati o ns, li  mit e d l a b o r at or y  p ar a  m et ers,  a n d  s ur vi v al 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 5 
1 9  J a n u a r y  2 0 1 8  
st at us.   Ot h er cli ni c al ass ess  m e nts   m a y  b e  p erf or  m e d as  p art  of st a n d ar d  of c ar e  b ut t h e  p erf or  m a n c e 
a n d r es ults  of t h es e  ass ess  m e nts   will  n ot  b e  c oll e ct e d f or t his  st u d y. 
Tr e at  m e nt   m a y c o nti n u e as l o n g as t h e s u bj e ct c o nti n u es t o  b e n efit  b as e d  o n i n v esti g at or j u d g  m e nt. 
S u bj e cts   w h o  n e e d t o r e c ei v e  ot h er  a nti c a n c er t h er a pi es  or  ot h e r i n v esti g ati o n al tr e at  m e nts   will  b e 
dis c o nti n u e d  fr o  m  t his  st u d y.  S u bj e cts    w h o  ar e    wit h dr a  w n  fr o  m  t r e at  m e nt    will  h a v e  a  s af et y 
f oll o  w- u p  visit  at  3 0  ± 7  d a ys  aft er t h e l ast  g u a d e cit a bi n e  d os e  or  pri or t o  b e gi n ni n g  alt er n ati v e 
a nti c a n c er t h er a p y,   w hi c h e v er  c o  m es first,  a n d t h e n   will  b e   wit h dr a  w n fr o  m t h e st u d y. 
T h e  pri  m ar y  e n d p oi nt  is  s af et y  as    m e as ur e d  b y  a d v ers e  e v e nts.  S  ur vi v al  st at us  is  a  s e c o n d ar y 
e n d p oi nt. 
4. 2      Dis c ussi o n  of  St u d y   D esi g n 
T his  st u d y  is  d esi g n e d  t o  all o  w  o n g oi n g  tr e at  m e nt    wit h  g u a d e cit  a bi n e  t o  s u bj e cts    w h o  h a v e 
b e n efitt e d fr o  m  g u a d e cit a bi n e tr e at  m e nt i n  pri or   Ast e x-s p o ns or e d st u di es.  T o   mi ni  mi z e t h e  b ur d e n 
o n st u d y  c e nt ers  a n d s u bj e cts,  ass ess  m e nts  h a v e  b e e n li  mit e d t o  t h os e r e q uir e d t o  ass ess l o n g-t er  m 
s af et y. 
T h e s a  m pl e si z e  of  a p pr o xi  m at el y  2 5 0 s u bj e cts is  a n  esti  m at e.   M ost  of t h e s u bj e cts  e nr oll e d i n t his 
st u d y    will  h a v e  p arti ci p at e d  i n  1  of  3  o n g oi n g   P h as e  3  st u di es   t h at   ar e  t o   e nr oll   a  t ot al   of 
a p pr o xi  m at el y  1 6 0 0 s u bj e cts  ( St u di es  S  GI- 1 1 0- 0 4,  S  GI- 1 1 0- 0 6,  a n d  S  GI- 1 1 0- 0 7).   B as e d  o n t h e 
n u  m b er  of  d e at h  e v e nts  n e e d e d f or t h e  pri  m ar y  a n al ysis f or  e a c h   of t h os e  st u di es, t h e  n u  m b er  of 
g u a d e cit a bi n e   s u bj e cts   r e c ei vi n g   tr e at  m e nt   at   t h e   e n d   of   t h e   st u di es   c o ul d   r a n g e   fr o  m 
1 8 0 ( ass u  mi n g  n o tr e at  m e nt  diff er e n c e  a n d  n o   wit h dr a  w als) t o  3 2 6 ( ass u  mi n g  all  s ur vi v ors   w er e 
g u a d e cit a bi n e s u bj e cts  a n d  n o   w it h dr a  w als).   As   m or e  g u a d e cit a bin e  cli ni c al st u di es  ar e c o n d u ct e d, 
t h e  n u  m b er  of s u bj e cts  e nr oll ed i n t his  e xt e nsi o n st u d y  c o ul d i n cr e as e. 
4. 3      St u d y   E n d p oi nts 
4. 3. 1      
P ri  m a r y   E n d p oi nt 
•     S af et y  as   m e as ur e d  b y  a d v ers e  e v e nts 
4. 3. 2      
S e c o n d a r y   E n d p oi nt 
•     S ur vi v al st at us 
5. 0      S  E  L  E  C  TI  O  N   A  N  D    WI  T  H  D  R  A   W  A  L   O F  S  U  B J  E  C  T S 
5. 1      N u  m b e r  of  S u bj e cts  a n d   C e nt e rs 
A p pr o xi  m at el y  2 5 0 s u bj e cts   will  b e    e nr oll e d i n t his st u d y  at  a ppr o xi  m at el y  1 5 0 st u d y  c e nt ers. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 6 
1 9  J a n u a r y  2 0 1 8  
5. 2      I n cl usi o n   C rit e ri a 
T o  b e  eli gi bl e f or t h e st u d y, s u bj e cts   m ust f ulfill  all  of t h e  f oll o  wi n g i n cl usi o n  crit eri a: 
1.    Pr e vi o us  p arti ci p ati o n  i n  a n   Ast e x-s p o ns or e d  g u a d e cit a bi n e  cli n i c al  tri al  (i n cl u di n g  b ut  n ot 
li  mit e d t o  S  GI- 1 1 0- 0 1,  S  GI- 1 1 0- 0 4,  S  GI- 1 1 0- 0 5,  S  GI- 1 1 0- 0 6,  a n d  S  GI- 1 1 0- 0 7), i n   w hi c h t h e 
s u bj e ct   w as tr e at e d   wit h  g u a d e cit a bi n e  a n d   w as still  o n  a cti v e tr e at  m e nt   wit h  g u a d e cit a bi n e  at 
t h e ti  m e  of  d at a b as e  cl ose f or t h e  pri or st u d y. 
2.    S u bj e ct  is  c o nsi d er e d  t o  b e  b e n efitti n g  fr o  m  g u a d e cit a bi n e  tr e a t  m e nt  i n  t h e  o pi ni o n  of  t h e 
tr e ati n g i n v esti g at or. 
3.    A bl e t o  u n d erst a n d  a n d  c o  m pl y   wit h t h e st u d y  pr o c e d ur es,  u n d ers  t a n d t h e ris ks i n v ol v e d i n t h e 
st u d y,  a n d  pr o vi d e   writt e n i nf or  m e d  c o ns e nt  b ef or e  a n y st u d y-s p e cifi c  pr o c e d ur e. 
4.    W o  m e n   of   c hil d- b e ari n g   p ot e nti al  ( a c c or di n g  t o  r e c o  m  m e n d ati o ns     of  t h e    Cli ni c al   Tri al 
F a cilit ati o n   Gr o u p [  C T F  G]; s e e  b el o  w *  f or  d et ails)   m ust  n ot  b e  pr eg n a nt  or  br e astf e e di n g  a n d 
m ust  h a v e  a  n e g ati v e  pr e g n a n c y t e  st  at  s cr e e ni n g.    W o  m e n  of  c hil d- b e ari n g  p ot e nti al  a n d   m e n 
wit h  f e  m al e  p art n ers  of  c hil d- b e ari n g  p ot e nti al    m ust  a gr e e  t o  p  r a cti c e  2  hi g hl y  eff e cti v e 
c o ntr a c e pti v e   m e as ur es   w hil e r e c ei vi n g tr e at  m e nt   wit h  g u a d e cit a bi n e  a n d f or  at l e ast  3   m o nt hs 
aft er  c o  m pl eti n g  tr e at  m e nt  a n d    m ust  a gr e e  n ot  t o  b e c o  m e  pr e g n a n t  or  f at h er  a  c hil d   w hil e 
r e c ei vi n g  st u d y tr e at  m e nt  a n d f or  at l e ast  3   m o nt hs  aft er  c o  m pleti n g  g u a d e cit a bi n e tr e at  m e nt. 
C o ntr a c e pti v e    m e as ur es    w hi c h    m a y   b e   c o nsi d er e d   hi g hl y   eff e cti v e     c o  m pris e   c o  m bi n e d 
h or  m o n al   c o ntr a c e pti o n   ( or al,   v a gi n al,   or   tr a ns d er  m al)   or   pr o g est o g e n- o nl y   h or  m o n al 
c o ntr a c e pti o n   ( or al,   i nj e ct a bl e,   i  m pl a nt a bl e)   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,  intr a ut eri n e  h or  m o n e-r e l e asi n g  s yst e  m,  bilat er al  t u b al  o c cl usi o n,  s e x u al 
a bsti n e n c e,   a n d  s ur gi c all y  s u c c essf ul   v as e ct o  m y.    A bsti n e n c e  is   a c c e pt a bl e   o nl y  if  it  is 
c o nsist e nt    wit h  t h e  pr ef err e d  a n d  us u al  lif est yl e  of  t h e  s u bj e c t.   P eri o di c  a bsti n e n c e  ( e g, 
c al e n d ar,   o v ul ati o n,   s y  m pt ot h er  m al,   or   p ost o v ul ati o n    m et h o ds)   a n d    wit h dr a  w al   ar e   n ot 
a c c e pt a bl e   m et h o ds  of  birt h  c o ntr ol. 
5. 3      E x cl usi o n   C rit e ri a 
S u bj e cts   m e eti n g  a n y  of t h e f oll o  wi n g  e x cl usi o n  crit eri a   will  b e  e x cl u d e d fr o  m t h e st u d y: 
1.      
A n y  s u bj e ct   w h o,  i n  t h e  o pi ni o n  of  t h e  i n v esti g at or,    m a y  h a v e  o  t h er  c o n diti o ns,  or g a n 
d ysf u n cti o n,  or  h a v e  s af et y  d at a  fr o  m t h eir  pri or  st u d y  p arti cip ati o n t h at  s u g g est t h at t h e 
ris ks  of  c o nti n ui n g tr e at  m e nt   wit h  g u a d e cit a bi n e   m a y  o ut  w ei g h th e  b e n efits. 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
*  A c c or di n g t o  r e c o  m  m e n d ati o ns  of t h e   C T F  G  (  C T F  G  2 0 1 4  ),  a   w o  m a n is  c o nsi d er e d  of  c hil d b e ari n g 
p ot e nti al  (i e,  f ertil e)  f oll o  wi n g    m e n ar c h e  a n d  u ntil  b e c o  mi n g  p ost  m e n o p a us al,  u nl ess  p er  m a n e ntl y 
st eril e.  P er  m a n e nt  st erili z ati o n    m et h o ds  i n cl u d e  h yst er e ct o  m y,  bil at er al  s al pi n g e ct o  m y  a n d  bil at er al 
o o p h or e ct o  m y.    A    m a n  is   c o nsi d er e d  f ertil e   aft er   p u b ert y   u nl ess   p er  m a n e nt   st eril e   b y   bil at er al 
or c hi d e ct o  m y. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 7 
1 9  J a n u a r y  2 0 1 8  
5. 4      T r e at  m e nt   Dis c o nti n u ati o n    a n d    Wit h d r a  w al  of  S u bj e cts 
5. 4. 1      
Dis c o nti n u ati o n f r o  m  St u d y   T r e at  m e nt 
S u bj e cts    w h o  p er  m a n e ntl y  dis c o nti n u e  st u d y  tr e at  m e nt    will  att e n d  a  s af et y  f oll o  w- u p  visit  at 
3 0  ±  7  d a ys  aft er  t h e  l ast  d os e  of  g u a d e cit a bi n e  or  pri or  t o  t h e  st art  of  alt er n ati v e  a nti c a n c er 
t h er a p y,   w hi c h e v er c o  m es first. R e as o ns f or tr e at  m e nt  dis c o nti n  u ati o n c o ul d i n cl u d e t h e f oll o  wi n g: 
•     I n v esti g at ors  c a n  dis c o nti n u e  s u bj e cts fr o  m  st u d y tr e at  m e nt i n  c as e  of  u n a c c e pt a bl e t o xi cit y, 
n o n c o  m pli a n c e,   dis e as e   pr o gr essi o n   r e q uiri n g   alt er n ati v e  t h er a py,   or  if  t h e  i n v esti g at or 
d et er  mi n es it is i n t h e  s u bj e ct's  b est i nt er est. 
•     Ast e x  P h ar  m a c e uti c als   m a y  r e q uir e  t h at  a  s u bj e ct is  dis c o nti n u e  d  fr o  m  tr e at  m e nt  f or  s af et y 
r e as o ns  or f or  n o n c o  m pli a n c e. 
I n  all  c as es, t h e r e aso n(s) f or  dis c o nti n u a ti o n fr o  m st u d y tr e at  m e nt   m ust  b e r e c or d e d i n t h e s o ur c e 
d o c u  m e nt  a n d  o n t h e r el e v a nt  p a g e  of t h e s u bj e ct's  c as e r e p ort  f or  m  or  el e ctr o ni c  c as e r e p ort f or  m 
(  C  R F/ e  C  R F). 
5. 4. 2      
Wit h d r a  w al f r o  m t h e  St u d y 
S u bj e cts   m a y   wit h dr a  w  c o ns e nt f or t h e  st u d y  at  a n y ti  m e,  or  s u b j e cts   m a y  b e l ost t o f oll o  w- u p. It 
is  i  m p ort a nt  t o  o bt ai n  f oll o  w- u p  i nf or  m ati o n,  a c c or di n g  t o  st a nd ar d    m e di c al  pr a cti c e,  o n  a n y 
s u bj e ct   wit h dr a  w n  pr e  m at ur el y  fr o  m t h e  st u d y.   E v er y  eff ort   m ust   b e   m a d e t o  u n d ert a k e  at l e ast 
st a n d ar d  ass ess  m e nts t h at  ar e  criti c al f or s af et y  e v al u ati o n, s u c h  as  a d v ers e  e v e nts. 
Ast e x  P h ar  m a c e uti c als   m a y  st o p t h e  st u d y  at  a n y ti  m e. I n t his  e  v e nt,   Ast e x   will   m a k e r e as o n a bl e 
eff orts t o  e ns ur e s u bj e cts  ar e tr a nsiti o n e d  off st u d y i n  a n  or d erl y   m a n n er. 
6. 0      E  N  R  O  L  L   M  E  N  T  P  R  O  C  E  D  U  R  E S 
S u bj e cts   will  b e  s cr e e n e d  at  e a c h  st u d y  c e nt er  f or  ass ess  m e nt  of  eli gi bilit y  f or  t h e  st u d y.   T his 
s cr e e ni n g   m a y st art  o n c e t h e  d at e   of  d at a  c ut- off f or t h e  pri or st u d y  h as  b e e n  d et er  mi n e d. 
All s cr e e n e d s u bj e cts   will  b e  a  ssi g n e d  a  u ni q u e i d e ntifi er t h at   will i n cl u d e t h e st u d y  n u  m b er fr o  m 
t h eir  pri or st u d y. 
7. 0      S  T  U  D  Y   T  R  E  A  T   M  E  N  T S 
G u a d e cit a bi n e is t h e I n v esti g a  ti o n al   M e di ci n al  Pr o d u ct (I  M P). 
7. 1      I n v esti g ati o n al    M e di ci n al  P r o d u ct (I   M P):   G u a d e cit a bi n e 
G u a d e cit a bi n e ( 2'- d e o x y- 5- a z a c y  ti d yl yl-( 3'   → 5')- 2'- d e o x y g u a n osi ne  s o di u  m  s alt is  a  di n u cl e oti d e 
i n c or p or ati n g  d e cit a bi n e   wit h  d eo x y g u a n osi n e  vi a  a  3’   → 5’  p h os p h o di est er  b o n d. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 8 
1 9  J a n u a r y  2 0 1 8  
7. 1. 1      
I   M P I nf o r  m ati o n 
G u a d e cit a bi n e ( S  GI- 1 1 0)   will  b e s u p pli e d i n  a t  w o- vi al  c o nfi g ur  ati o n. 
S  GI- 1 1 0 f or I nj e cti o n,  1 0 0   m g is  a  gl ass  vi al  c o nt ai ni n g l y o p hi li z e d  g u a d e cit a bi n e  dr u g  p o  w d er 
f or r e c o nstit uti o n  a n d  S  C i nj e cti o n  usi n g t h e  c ust o  m  dil u e nt  s up pli e d i n  a  s e p ar at e  vi al.  E a c h  vi al 
is st o p p er e d  a n d s e al e d   wit h  a fli p- off  c a p. 
S  GI- 1 1 0   Dil u e nt f or   R e c o nstit uti o n, is  a  gl ass  vi al  of  c ust o  m  d il u e nt.   E a c h  vi al is  st o p p er e d  a n d 
s e al e d   wit h  a fli p- off  c a p.  T h e  di l u e nt  c o  m pris es  3  c o  m  m o nl y  use d  e x ci pi e nts,  pr o p yl e n e  gl y c ol, 
gl y c eri n,  a n d  et h a n ol,   w hi c h  ar e   g e n er all y r e c o g ni z e d  as s af e. 
T h e  s p o ns or  r e c o  m  m e n ds  f oll o  wi n g    O c c u p ati o n al  S af et y  a n d    H e alt h      A d  mi nistr ati o n  (  O S  H  A) 
G ui d eli n es  f or  h a n dli n g  c yt ot o xi c  dr u gs  o utli n e d  i n    Y o d ai k e n  a n d    B e n n ett  ( 1 9 8 6)    or  si  mil ar 
i nstit uti o n al  or  c o u ntr y-s p e cifi c  g ui d eli n es.  Pr e p ar ati o n  s h o uld  o c c ur  a c c or di n g  t o  i nstit uti o n al 
pr a cti c e.  F or s ki n  c o nt a ct  or s p ill a g e, r ef er t o t h e   m at eri al saf et y  d at a s h e et (  M S D S) f or tr e at  m e nt 
o pti o ns. 
R e c o nstit ut e d  dr u g  pr o d u ct is i nt  e n d e d f or  S  C  a d  mi nistr ati o n  at   a r e c o  m  m e n d e d  c o n c e ntr ati o n  of 
1 0 0   m g/  m L. 
R e c or ds  of  t h e  r e c ei pt  a n d  dis p  e nsi n g  of  dr u g  s u p pli es    will  b e  k e pt  at  t h e  st u d y  c e nt ers  a n d 
r e c o n cil e d  at t h e  e n d  of t h e st u d y t o  pr o vi d e  a  c o  m pl et e  a c c o u nti n g  of  all  us e d  a n d  u n us e d I  M P. 
Pl e as e  r ef er  t o  t h e   S  GI- 1 1 0- 1 2   P h ar  m a c y    M a n u al  f or  f urt h er  i nf o r  m ati o n   o n   g u a d e cit a bi n e 
i n cl u di n g st or a g e  c o n diti o ns. 
7. 1. 2      
I   M P   R e gi  m e ns  a n d A d  mi nist r ati o n 
S u bj e cts   will r e c ei v e  g u a d e cit a bi n e tr e at  m e nt  at t h e s a  m e  d os e  t h at t h e y   w er e r e c ei vi n g i n t h e l ast 
c y cl e  of t h eir  pri or st u d y  or  at   a  diff er e nt  d os e  as  g ui d e d  b y t h e  d os e  a dj ust  m e nt  g ui d eli n es i n t h e 
pri or st u d y  pr ot o c ol.  S u bs e q u e nt tr e at  m e nt  d el a ys  a n d/ or  d os e r e d u cti o n  ar e  at t h e  dis cr eti o n  of t h e 
i n v esti g at or  as  g ui d e d  b y t h e  d os e  a dj ust  m e nt  g ui d eli n es  of t h e  pri or  st u d y  pr ot o c ol.   Tr e at  m e nt 
m a y  c o nti n u e  as l o n g  as t h e s u bj  e ct  c o nti n u es t o  b e n efit  b as e d  o n i n v esti g at or j u d g  m e nt. 
A d  mi nist er  g u a d e cit a bi n e  b y  S  C i  nj e cti o n,  pr ef er a bl y i n t h e  a b d o  mi n al  ar e a,  u p p er t hi g h,  or  ar  m. 
T h e t ot al  a  m o u nt (i n   m g)  of  g u a d e cit a bi n e t o  b e  a d  mi nist er e d is   d et er  mi n e d  b y  b o d y  s urf a c e  ar e a 
(  B S  A). I n  c al c ul ati n g   B S  A,  us e  a ctu al  h ei g hts  a n d   w ei g hts.   D o  n ot  a dj ust t o  "i d e al "  b o d y   w ei g ht. 
T h e i nstit uti o n al st a n d ar d f or   c al c ul ati n g   B S  A is  a c c e pt a bl e.  
T a k e  c ar e t o  a v oi d i ntr a d er  m al i n j e cti o n,  as t his   m a y r es ult i n i nj e cti o n sit e  p ai n (s e e S e cti o n  8. 4 ).  
A d diti o n al  g ui d eli n es r e g ar di n g  S  C i nj e cti o n   will  b e  d et ail e d i  n t h e  S  GI- 1 1 0- 1 2  P h ar  m a c y   M a n u al. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
1 9 
1 9  J a n u a r y  2 0 1 8  
I n v esti g at ors  ar e  pr o hi bit e d fr om s u p pl yi n g  g u a d e cit a bi n e t o  a n  y s u bj e ct  n ot  e nr oll e d i n t his st u d y 
or t o  a n y  p h ysi ci a ns  or  s ci e ntists  e x c e pt t h os e  d esi g n at e d  as  s u b-i n v esti g at ors.   T h e i n v esti g at or 
m ust  e ns ur e  t h at  s u bj e cts  r e c ei v e  g u a d e cit a bi n e  o nl y  fr o  m  p ers o  n n el   w h o  f ull y  u n d erst a n d  t h e 
pr o c e d ur es f or  a d  mi nist eri n g t h e st u d y tr e at  m e nt. 
T h er e is  n o  r estri cti o n  o n t h e  us e  of  b est  s u p p orti v e  c ar e  or  h y dr o x y ur e a.  S u bj e cts   w h o  n e e d t o 
r e c ei v e  ot h er  a nti c a n c er t h er a pi es  or  ot h er i n v esti g ati o n al tr eat  m e nts   will  b e   wit h dr a  w n fr o  m t his 
st u d y. 
7. 2      G ui d eli n es f o r   A dj usti n g  o r      Wit h h ol di n g  St u d y   T r e at  m e nt 
Tr e at  m e nt  d el a ys  a n d/ or  d os e r e d u cti o n  ar e  at t h e  dis cr eti o n  of  t h e i n v esti g at or  as  g ui d e d  b y t h e 
d os e  a dj ust  m e nt  g ui d eli n es  of  t h e  pri or st u d y  pr ot o c ol. 
7. 3      C o n c o  mit a nt   T r e at  m e nt 
O n t h e  c o n c o  mit a nt   m e di c ati o n  e  C  R F,  d o c u  m e nt  all   m e di c ati o ns  a   s u bj e ct t a k es, st arti n g fr o  m t h e 
first  d a y  of tr e at  m e nt i n t his  st u d y  a n d  e n di n g  3 0  d a ys  aft er th e l ast  d os e  of  st u d y tr e at  m e nt  or 
w h e n t h e s u bj e ct  b e gi ns  alt er n  ati v e  a nti c a n c er t h er a p y,   w hi c h e v er  c o  m es first. I n cl u d e s u p p orti v e 
or   p alli ati v e   tr e at  m e nt   (s e e    S e cti o n  7. 3. 1 )     w h et h er   pr es cri pti o n   or   n o n pr es cri pti o n,   a n d 
m e di c ati o ns  t a k e n  f or   pr o c e d ur es  ( e g,   bi o ps y).  I n cl u d e  st art  a n  d  st o p   d at es  a n d  i n di c ati o n. 
Pr e v e nti v e   m e as ur es   m a y  b e  pr es cri b e d  a c c or di n g t o i nstit uti o n a l  a n d st a n d ar d  pr a cti c e.  
7. 3. 1      
S u p p o rti v e,  P r o p h yl a cti c,  o r   Ot h e r   T r e at  m e nts 
T h er e is  n o r estri cti o n  o n t h e   us e  of  b est s u p p orti v e c ar e  or  hy dr o x y ur e a.   Gi v e s u p p orti v e tr e at  m e nt 
a c c or di n g t o t h e i nstit uti o n al st a n d ar d  pr a cti c e  or  ot h er  est a b lis h e d st a n d ar d  of  c ar e  g ui d eli n es. 
7. 3. 2      
P r o hi bit e d    M e di c ati o ns 
Ot h er  a nti c a n c er  t h er a pi es  ( e x c e pt  t h os e  s p e cifi e d  i n    S e cti o n  7. 3. 1   a b o v e)  ar e  n ot  t o  b e  us e d. 
C yt ot o xi c  c h e  m ot h er a p y  a n d  i n v e  sti g ati o n al  tr e at m e nts  ar e  pr o hi  bit e d  f or  as  l o n g  as  s u bj e cts 
r e  m ai n  o n st u d y tr e at  m e nt. 
V a c ci n ati o n   wit h li v e  v a c ci n es is    pr o hi bit e d   w hil e s u bj e cts r e  mai n  o n st u d y tr e at  m e nt. 
S u bj e cts   w h o  n e e d t o r e c ei v e  ot h er  a nti c a n c er t h er a pi es  or  ot h e r i n v esti g ati o n al tr e at  m e nts   will  b e 
wit h dr a  w n fr o  m t his st u d y. 
7. 4      O v e r d os e I nst r u cti o ns 
R e c or d  t h e  a ct u al  d os e  of  st u d y   dr u g  a d  mi nist er e d  i n  t h e  s o ur c e   d o c u  m e nt  a n d  o n  t h e   D osi n g 
C  R F/ e  C  R F.   R e c or d  a n y  a d v ers e  cli n  i c al si g ns  a n d s y  m pt o  ms  ass o ciat e d   wit h  a  p ot e nti al  o v er d os e 
o n t h e  a d v ers e  e v e nt  (  A E)   C  R F/ e  C  R F.   R e p ort  si g ns  a n d  s y  m pt o  ms  o f  a  p ot e nti al  o v er d os e t h at 
m e et  S  A E  crit eri a  ( d efi n e d  i n    S e cti o n  1 0. 1. 2 )  t o   Ast e x  o n  t h e  S  A E  f or  m   wit hi n  2 4  h o urs  (s e e 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 0 
1 9  J a n u a r y  2 0 1 8  
S e cti o n  1 0. 3 ).   Tr e at  a n y   A E  (i n cl u di n g  S  A E)  b as e d  o n  st a n d ar d  c ar e  f or  t h e  s p e cifi c  si g ns  a n d 
s y  m pt o  ms.  
8. 0      RI S  K S/ P  R  E  C  A  U  TI  O  N S 
R ef er t o t h e   G u a d e cit a bi n e I  B f or t h e   m ost  c urr e nt ris ks  a n d  pr  e c a uti o ns,  as   w ell  as  a  c o  m pl et e list 
of   A Es  c o nsi d er e d  e x p e ct e d   w it h  g u a d e cit a bi n e t h er a p y. 
Si n c e  g u a d e cit a bi n e is  a n i n v es ti g ati o n al  dr u g,  u n e x p e ct e d  a n d p ot e nti all y  cli ni c all y  si g nifi c a nt 
A Es  or  S  A Es   m a y  o c c ur   wit h its  us e.   All  s u bj e cts tr e at e d   wit h  g  u a d e cit a bi n e  s h o ul d  b e  cl os el y 
m o nit or e d.    T h e  a cti v e    m et a b olit e  of  g u a d e cit a bi n e  is  d e cit a bi n e    s o  all  e v e nts  e x p e ct e d    wit h 
d e cit a bi n e  ( as  d es cri b e d  i n   D a c o g e n  p a c k a g e  i ns ert  [  U S]    a n d  D a c o g e n  s u  m  m ar y  of  pr o d u ct   
c h ar a ct eristi cs [ E  U] )   w o ul d  als o  b e  c o nsi d er e d  e x p e ct e d f or  g u a d e cit a bi n e. 
G u a d e cit a bi n e  s h o ul d  n ot  b e  gi v e n  t o    w o  m e n    w h o  ar e  pr e g n a nt  or    t o  s u bj e cts    wit h  k n o  w n 
s e nsiti vit y t o  d e cit a bi n e. 
8. 1      D os e   Li  miti n g   T o xi citi es 
D os e  li  miti n g  t o xi citi es  r el at e d    t o    m y el os u p pr essi o n  o c c urr e d  in  2 s u bj e cts    wit h    M  D S  i n  t h e 
P h as e  1   D os e   Es c al ati o n  ( S  GI- 1 1 0- 0 1)  f or  t h e  5- d a y  r e gi  m e n  at  a   d os e  of  1 2 5   m g/  m2   S  C  a n d 
i n cl u d e d t hr o  m b o c yt o p e ni a (  Gr a d e  4),  n e utr o p e ni a (  Gr a d e  4),  a n d s e psis (  Gr a d e  5). 
8. 2      M y el os u p p r essi o n (  N e ut r o p e ni a,  F e   b ril e   N e ut r o p e ni a,   T h r o  m b o c yt o p e ni a,  a n d 
A n e  mi a)  a n d its   C o ns e q u e n c es (I nf e cti o ns  a n d/ o r   H e  m o r r h a g e) 
M y el os u p pr essi o n   a n d   its   c o ns e q u e n c es   ( p n e u  m o ni a,   s e psis,   a n d   o   t h er   i nf e cti o ns   a n d/ or 
h e  m orr h a g e fr o  m t hr o  m b o c yt o p e ni a)  ar e t h e  pri  m ar y t o xi citi es  as s o ci at e d   wit h  a d  mi nistr ati o n  of 
g u a d e cit a bi n e  a n d  its  eff e cts  aft e r  5  c o ns e c uti v e  d a ys  of  a d  mi nistr ati o n  ar e    m a xi  m al  b et  w e e n 
D a ys  1 5  a n d  2 2 i n  a  c y cl e   wit h r e c o v er y i n  1 t o  3   w e e ks.  P a n c yt  o p e ni a is  a  h all  m ar k  of   A  M L  a n d 
M  D S  a n d   m a y  a g gr a v at e  or  o bs c ur e    t h e  eff e cts  of  g u a d e cit a bi n e. H o  w e v er, if  a  cli ni c al r es p o ns e 
o c c urs   a n d    n or  m al    h e  m at o p oi eti c   c ells   r e p o p ul at e   t h e    b o n e     m arr o w,    n e utr o p e ni a   a n d 
t hr o  m b o c yt o p e ni a   m a y  a b at e. 
C o  m pl et e  bl o o d  a n d  pl at el et  c o u nts  s h o ul d  b e  p erf or  m e d  as  n e e d e  d  t o    m o nit or  c o u nts.  Si n c e 
m y el os u p pr essi o n  a n d i nf e cti o n  e v e  nts  ar e  als o   m a nif est ati o ns  o f t h e  u n d erl yi n g  dis e as e  of   A  M L, 
M  D S,  a n d   C  M  M L,  c ar ef ul i n v esti g at  or j u d g  m e nt r e g ar di n g r el ati o n s hi p t o tr e at  m e nt is i  m p ort a nt 
t o   g ui d e  t h e   d e cisi o n    w h et h er  t o   d os e   d el a y,   d os e  r e d u c e,   or   b ot h.    T h e   c y cli c   n at ur e   of 
m y el os u p pr essi o n (r e d u cti o n  of  c o u nts  b et  w e e n   D a y  8- 1 5  a n d tr e n d t o r e c o v er  b y   D a y  2 2- 2 8  or 
l at er)  c o ul d  b e   m or e i n di c ati v e  of  a  dr u g  eff e ct,   w hil e  p ersiste nt l o  w  c o u nts r e g ar dl ess  of tr e at  m e nt 
is  pr o b a bl y    m or e  i n di c ati v e  of  a  dis e as e  eff e ct  t h at  n e e ds  t o  be  tr e at e d    wit h o ut  d os e  d el a y. 
I n v esti g at ors   s h o ul d   us e  t h eir   cli ni c al  j u d g  m e nt   g ui d e d   b y  t h e   r e c o  m  m e n d ati o ns  f or   d os e 
a dj ust  m e nt f or  g u a d e cit a bi n e  i n t h e  pri or st u d y  pr ot o c ol. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 1 
1 9  J a n u a r y  2 0 1 8  
8. 3      F e rtilit y 
D e cit a bi n e, t h e  a cti v e   m et a b olit e  of  g u a d e cit a bi n e,  alt ers f ert  ilit y  a n d is   m ut a g e ni c.  B e c a us e  of t h e 
p ossi bilit y  of i nf ertilit y,   m e n s h o ul d  h a v e s o u g ht  a d vi c e  o n  cr y o pr es er v ati o n  of s p er  m,  a n d   w o  m e n 
of  c hil d b e ari n g  p ot e nti al  s h o ul d   h a v e  s o u g ht  c o ns ult ati o n  r e g ar di n g  o o c yt e  cr y o pr es er v ati o n 
b ef or e  st u d y tr e at  m e nt   w as  st art e d i n t h e  pri or  st u d y.    W o  m e n  of   c hil d- b e ari n g  p ot e nti al   m ust  n ot 
b e  pr e g n a nt  or  br e astf e e di n g  a n d  m ust  h a v e  a  n e g ati v e  pr e g n a n c y    t est  at  s cr e e ni n g.    W o  m e n  of 
c hil d- b e ari n g  p ot e nti al  a n d    m e n    wit h  f e  m al e  p art n ers  of  c hil d- b e ari n g  p ot e nti al    m ust  a gr e e  t o 
pr a cti c e  2  hi g hl y  eff e cti v e  c o ntr a c e pti v e   m e as ur es  of  birt h  c o n tr ol  a n d   m ust  a gr e e  n ot t o  b e c o  m e 
pr e g n a nt  or f at h er  a  c hil d   w hil e r e c ei vi n g tr e at  m e nt   wit h  g u a d e cit a bi n e  a n d f or  at l e ast  3   m o nt hs 
aft er  c o  m pl eti n g tr e at  m e nt. 
8. 4      I nj e cti o n  Sit e   R e a cti o ns 
I nj e cti o n  sit e  r e a cti o ns,  s u c h  as  p ai n, irrit ati o n, i nfl a  m  m ati on,  er yt h e  m a,  a n d  b ur ni n g  h a v e  b e e n 
r e p ort e d i n t h e   A  M L/  M  D S  p o p ul ati o n  a n d i n  s u bj e cts   wit h  s oli d tu  m ors. I nj e cti o n  sit e r e a cti o ns 
ar e r el at e d t o  g u a d e cit a bi n e  S  C  a d  mi nistr ati o n  a n d  ar e   m ostl y   G r a d e  1  or  2. 
C ar e   m ust  b e t a k e n t o  a v oi d i ntr a d er  m al i nj e cti o n.  If i nj e cti o n    sit e  p ai n is  r e p ort e d, it  c o ul d  b e 
a v oi d e d  or  di  mi nis h e d  b y  sl o  w  S  C i nj e cti o n  a n d t h e  a p pli c ati o n  of i c e  p a c ks t o t h e i nj e cti o n  sit e 
b ot h  b ef or e  a n d  aft er  i nj e cti o n.  I f  i nj e cti o n  sit e  p ai n  is  still  cli ni c all y  si g nifi c a nt  at  s u bs e q u e nt 
i nj e cti o ns  d es pit e  sl o  w  i nj e cti o n  a n d  us e  of  i c e  p a c ks,  pr etr e at  m e nt    wit h  t o pi c al  or  s yst e  mi c 
a n al g esi cs  c a n  b e  c o nsi d er e d. I n  c as e  of i nj e cti o n  sit e  p ai n   w h e n i nj e cti o n  v ol u  m e is  gr e at er t h a n 
1   m L,  c o nsi d er s plitti n g t h e  d os e i nt o  2 i nj e cti o ns. 
8. 5      A d v e rs e   E v e nts 
M ost   A Es  o bs er v e d  i n  t h e   P h as e  1- 2  cli ni c al  tri al  ar e  c o  m  m o n  i n     t h e   A  M L/  M  D S  p o p ul ati o n. 
C o  m  m o n   A Es, r e g ar dl ess  of r el ati o ns hi p t o  g u a d e cit a bi n e,  o bs er v  e d i n t h e   A  M L/  M  D S  p o p ul ati o ns 
(r el a ps e d/r efr a ct or y [r/r]   A  M L,  TN   A  M L,  T  N   M  D S, r/r   M  D S,   N = 3 0 8 [ P h as e  2   D os e  E x p a nsi o n]) 
tr e at e d   wit h  g u a d e cit a bi n e  ( 6 0- 9 0   m g/  m2  5- d a y  r e gi  m e n  or  6 0   m g/  m2  1 0- d a y  r e gi  m e n  i n   A  M L 
o nl y) i n cl u d e d i nj e cti o n sit e   A Es, f e bril e  n e utr o p e ni a, t hr o  m b o c yt o p e ni a,  di arr h e a, f ati g u e,  n a us e a, 
a n e  mi a,  a n d  c o nsti p ati o n.   T h e    m ost  c o  m  m o n  S  A Es    w er e  f e bril e  n e u tr o p e ni a,  p n e u  m o ni a,  a n d 
s e psis. 
M  D S  a n d   A  M L  s u bj e cts  c o  m  m o nl y  h a v e  s e v er el y  c o  m pr o  mis e d  b o n e   m arr o  w  a n d  bl o o d  c o u nts. 
S e v er e  or  pr ol o n g e d   m y el os u p pr essi o n  h a v e  b e e n r e p ort e d  as r el at e d t o  g u a d e cit a bi n e,  p arti c ul arl y 
at  hi g h  d os es   w h e n t h e  dr u g   m a y  e x ert  c yt ot o xi c  eff e cts. 
C o  m  m o n   A Es,  r e g ar dl ess  of  r el ati o  ns hi p  t o  g u a d e cit a bi n e,  o bs er v e d  i n  s u bj e cts   wit h  a d v a n c e d 
H  C  C    w h o  f ail e d  pri or  tr e at  m e nt    wit h  s or af e ni b  ( St u d y   S  GI- 1 1 0- 0 3  )    w h o    w er e  tr e at e d    wit h 
g u a d e cit a bi n e   ( 4 5- 6 0   m g/  m 2    5- d a y)   i n cl u d e d    n e utr o p e ni a,   i nj e cti o n   sit e   e v e nts,   f ati g u e, 
t hr o  m b o c yt o p e ni a,   a n d  l e u k o p e ni a.    T h e    m ost   c o  m  m o n   S  A E  i n  t h es e   s u bj e cts    w as   f e bril e 
n e utr o p e ni a. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 2 
1 9  J a n u a r y  2 0 1 8  
C o  m  m o n   A Es,  r e g ar dl ess  of  r el ati o  ns hi p t o  g u a d e cit a bi n e,  o bs er v e d i n  s u bj e cts   wit h  pl ati n u  m-
r esist a nt  r e c urr e nt  o v ari a n  c a n c er  ( St u d y  S  GI- 1 1 0- 0 2)   w h o   w er e  tr e at e d   wit h  g u a d e cit a bi n e  i n 
c o  m bi n ati o n    wit h  c ar b o pl ati n  i n cl u d e d   n e utr o p e ni a,   n a us e a,  f ati g u e,   v o  miti n g,  i nj e cti o n  sit e 
e v e nts,   c o nsti p ati o n,   a b d o  mi n al   p ai n,   di arr h e a,  l e u k o p e ni a,   a n e mi a,  t hr o  m b o c yt o p e ni a,   a n d 
h y p o  m a g n es a e  mi a.   T h e   m ost  c o  m  m o n   S  A Es i n  s u bj e cts i n t h es e  s u bj e cts   w er e  s  m all i nt esti n al 
o bstr u cti o n,   v o  miti n g,   a b d o  mi n al   p ai n,  f e bril e   n e utr o p e ni a,   n e u tr o p e ni a,   a n d   n a us e a.    T hr e e 
s u bj e cts  h a d  dr u g-r el at e d  S  A Es (s e psis,  pl e ur al  eff usi o n,  a n d f e bril e  n e utr o p e ni a)   wit h  a n  o ut c o  m e 
of  d e at h. 
9. 0      S  T  U  D  Y   A S S  E S S   M  E  N  T S   A  N  D  P  R  O  C  E  D  U  R  E S 
9. 1      Effi c a c y   Ass ess  m e nts 
T h er e   ar e   n o   effi c a c y   ass ess  m e nts  i n  t his  st u d y,   e x c e pt  f or  s ur  vi v al  st at us    w hi c h    will   b e 
d o c u  m e nt e d  at t h e ti  m e  of   w it h dr a  w al fr o  m t h e st u d y. 
9. 2      S af et y   Ass ess  m e nts 
S af et y  ass ess  m e nts   will  b e  b as e d  o n   A Es,  c o n c o  mit a nt   m e di c ati o n s,  a n d li  mit e d  cli ni c al l a b or at or y 
p ar a  m et ers ( h e  m at ol o g y  a n d  c h e  mistr y). 
9. 3      St u d y  P r o c e d u r es 
9. 3. 1      
S c h e d ul e  of   E v e nts 
T a bl e  1  pr es e nts t h e  c o  m pl et e s c h e d ul e   of  e v e nts   wit h  d et ails f oll o  wi n g i n t e xt. 
A d diti o n al  pr o c e d ur es    m a y  b e  p erf or  m e d  as  p art  of  st a n d ar d  of  c  ar e  b ut  t h e  p erf or  m a n c e  a n d 
o ut c o  m e  of t h es e  ass ess  m e nts   w ill  n ot  b e  c oll e ct e d  as  p art  of this st u d y. 
N ot e  a n y  d e vi ati o n  fr o  m  pr ot o c ol  pr o c e d ur es.  I n v esti g at ors  ar e  r es p o nsi bl e  f or  i  m pl e  m e nti n g 
a p pr o pri at e   m e as ur es t o  pr e v e nt t h e r e c urr e n c e  of  vi ol ati o ns  a n d  d e vi ati o ns  a n d t o r e p ort t o t h eir 
I nstit uti o n al   R e vi e  w   B o ar d / In d e p e n d e nt  Et hi cs   C o  m  mitt e e (I  R  B/ I E  C)  a c c or di n g t o  p oli c y. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 4 
1 9  J a n u a r y  2 0 1 8  
•     C o  m pl et e  p h ysi c al  e x a  m  i n cl u di n g   h ei g ht  a n d    w ei g ht,  a n d  e x a  mi n ati o n  of  b o d y  s yst e  ms 
a c c or di n g t o i nstit uti o n al st a n d ar ds. 
•     S er u  m  or  uri n e  pr e g n a n c y t est: f or   w o  m e n  of c hil d- b e ari n g  p ot e n ti al  o nl y.   M ust  b e  d o n e   wit hi n 
7  d a ys  of   C y cl e  1   D a y  1.   R es ults   m ust  b e  n e g ati v e f or t h e s u bj e ct t o  b e  eli gi bl e f or  e nr oll  m e nt 
i nt o t h e st u d y. 
•     S a  m pl e  c oll e cti o n  f or  cli ni c al  l a b or at or y  t ests  ( h e  m at ol o g y  a n d   s er u  m  c h e  mistr y; T a bl e  2 ). 
C oll e cti o n,  a n al ysis,  a n d r e p or  ti n g i nf or  m ati o n  ar e  d es cri b e d in t h e  St u d y  L a b   M a n u al. 
•     B S  A  c al c ul ati o n. 
•     I n v esti g at or's  c o nfir  m ati o n  of  eli gi bilit y  a n d f a v or a bl e  b e n efit/ris k  ass ess  m e nt f or t h e s u bj e ct. 
P erf or  m  all  n e c ess ar y  pr o c e d ur es  a n d  e v al u ati o ns  t o  d o c u  m e nt  t h at  t h e  s u bj e ct    m e ets  e a c h 
eli gi bilit y  crit eri o n. 
T a bl e  2: 
Cli ni c al   L a b o r at o r y   T ests 
H e  m at ol o g y 
S e r u  m   C h e  mist r y 
U ri n al ysis 
S e r ol o g y 
-    C o  m pl et e  bl o o d  c o u nt (  C  B  C) 
   -   H e  m o gl o bi n 
   -   R  B  C  c o u nts 
   -    W  B  C  c o u nts 
   -  Pl at el ets 
   -   A bs ol ut e  n e utr o p hil  c o u nt 
 
-    W  B  C  diff er e nti al 
-    Al b u  mi n 
-    Al k ali n e  p h os p h at as e 
-    A L T 
-    A S T 
-    Cr e ati ni n e 
-   T ot al  bilir u bi n 
-    Dir e ct  bilir u bi n ( o nl y if t ot al 
bilir u bi n is  el e v at e d) 
-  Pr e g n a n c y t est  
(if  a p pli c a bl e) 
-  Pr e g n a n c y t est (if 
a p pli c a bl e) 
 
9. 3. 3      
T r e at  m e nt  P r o c e d u r es 
Visits    will   o c c ur   o n  e v er y  tr e at  m e nt   d a y  (  D a ys   1- 5   of  e a c h   2 8- d  a y  c y cl e).    T h e  f oll o  wi n g 
pr o c e d ur es   will  b e  p erf or  m e d:  
•     S a  m pl e  c oll e cti o n f or  cli ni c al l a b or at or y t ests (  D a y  1  o nl y) ( T a bl e  2 ), i n cl u di n g  h e  m at ol o g y, 
s er u  m  c h e  mistr y,  a n d  pr e g n a n c y t est  f or   w o  m e n  of  c hil d- b e ari n g  p ot e nti al  ( c oll e ct  s a  m pl es 
pri or t o  g u a d e cit a bi n e tr e at  m e nt).  F or   C y cl e  1,   D a y  1  h e  m at ol o g y  a n d  s er u  m  c h e  mistr y  d o es 
n ot  n e e d t o  b e r e p e at e d if  s cr e e ni n g is  d o n e   wit hi n  1   w e e k  of   C y cl e  1   D a y  1.  Pr e g n a n c y t est 
d o es  n ot  n e e d t o  b e r e p e at e d  o n   C y cl e  1   D a y  1 if  d o n e  at  s cr e e n i n g.   C oll e cti o n,  a n al ysis,  a n d 
r e p orti n g i nf or  m ati o n  ar e  d es crib e d i n t h e  St u d y  L a b   M a n u al.  
•     W ei g ht (  D a y  1  o nl y). If   w ei g ht  h   as  c h a n g e d  ± 1 0  % fr o  m t h e l ast   m e as ur e  m e nt,   B S  A s h o ul d  b e 
r e c al c ul at e d. 
•     G u a d e cit a bi n e  a d  mi nistr ati o n (  D a ys  1- 5). 
•     A d v ers e  e v e nts  a n d  c o n c o  mit a nt   m e di c ati o ns. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 5 
1 9  J a n u a r y  2 0 1 8  
9. 3. 4      
T r e at  m e nt   Dis c o nti n u ati o n  a n d  S af et y  F oll o  w- u p   Visit 
E a c h  s u bj e ct  s h o ul d  b e  f oll o  w e d  u p,  t o  d o c u  m e nt  t h e  o c c urr e n c e  of  a n y  n e  w   A Es,  f or  at  l e ast 
3 0 ( + 7)  d a ys aft er  his  or  h er l ast  d os e  of st u d y tr e at  m e nt,  or  u ntil a n y   A E  or  S  A E ass ess e d as r el at e d 
t o  st u d y tr e at  m e nt  or  pr o c e d ur es  h as r es ol v e d t o  a  cli ni c all y  ac c e pt a bl e  or  st a bl e r es ol uti o n (s e e 
S e cti o n  1 0. 4 ).  S u bj e cts   w h o   wit h dr a  w  c o ns e nt s h o ul d still  b e  e n c o ur a g e d t o c o  m pl et e t his  visit. If 
t h e  s u bj e ct is  u n a bl e t o  att e n d t h e  cli ni c, t h e  visit   m a y  b e  c on d u ct e d  b y t el e p h o n e t o  c oll e ct   A Es 
a n d  s ur vi v al  st at us.  If  t h e  s u bj e ct  dis c o nti n u e d  g u a d e cit a bi n e   tr e at  m e nt  t o  r e c ei v e  alt er n ati v e 
t h er a p y,  t his  visit  s h o ul d  b e  c o n d u ct e d  pri or  t o  t h e  st art  of  alt er n ati v e  t h er a p y.   T h e  f oll o  wi n g 
e v al u ati o ns  ar e t o  b e  p erf or  m e d: 
•     S a  m pl e   c oll e cti o n   f or   cli ni c al  l a b or at or y  t ests   ( T a bl e  2 ),  i n cl u di n g   h e  m at ol o g y,   s er u  m 
c h e  mistr y,  a n d  pr e g n a n c y t est f or   w o  m e n  of  c hil d- b e ari n g  p ot e nt i al.   C oll e cti o n,  a n al ysis,  a n d 
r e p orti n g i nf or  m ati o n  ar e  d es crib e d i n t h e  St u d y  L a b   M a n u al. 
•     A d v ers e  e v e nts  a n d  c o n c o  mit a nt   m e di c ati o ns. 
•     S ur vi v al st at us. 
1 0. 0      E  V  A  L  U  A  TI  O  N,   R  E  C  O  R  DI  N  G,   A  N  D   R  E P  O  R  TI  N  G   O F   A  D  V  E  R S  E   E  V  E  N  T S 
1 0. 1      D efi niti o ns 
1 0. 1. 1      A d v e rs e   E v e nt (  A  E) 
A d v ers e   E v e nt  (  A E):    A n y  u nt o  w ar d    m e di c al  o c c urr e n c e  ass o ci at e d    wit h  t h e  us e  of  a  dr u g  i n 
h u  m a ns,   w h et h er  or  n ot  c o nsi d er e d   dr u g  r el at e d.   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  cli n i c all y  si g nifi c a nt  a b n or  m al  fin di n g i n l a b or at or y t ests  or  ot h er 
di a g n osti c  pr o c e d ur es), 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  dr u g,   wit h o ut 
a n y j u d g  m e nt  a b o ut  c a us alit y.   A n   A E  c a n  aris e fr o  m  a n y  us e  of t h e  dr u g  a n d fr o  m  a n y r o ut e  of 
a d  mi nistr ati o n, f or  m ul ati o n,  or   d os e, i n cl u di n g  a n  o v er d os e. 
Dis e as e  pr o gr essi o n is  n ot  c o nsi d er e d t o  b e  a n   A E  or  s eri o us  a d  v ers e  e v e nt  ( S  A E).  If t h er e  ar e 
s p e cifi c   A Es t h at  ar e  al  w a ys  p a rt  of  dis e as e  pr o gr essi o n, t h es e  d o  n ot  n e e d t o  b e r e p ort e d  as   A Es 
or  S  A Es.  Pr e- e xisti n g    m e di c al  c o n diti o ns  ( ot h er  t h a n  n at ur al  pr o gr essi o n  of  t h e  dis e as e  b ei n g 
st u di e d) j u d g e d  b y t h e i n v esti g at or  or s u bj e ct t o  h a v e   w ors e n e d  i n s e v erit y  or fr e q u e n c y  or c h a n g e d 
i n  c h ar a ct er  d uri n g t h e  pr ot o c ol-s p e cifi e d   A E r e p orti n g  p eri o d will  b e r e p ort e d  as   A Es  or  S  A Es  as 
a p pr o pri at e. 
A n   A E  or  S  A E  c a n  als o  b e  a  c o  m pli c ati o n t h at  o c c urs  as  a r es ult    of  pr ot o c ol   m a n d at e d  pr o c e d ur es 
( e g, i n v asi v e  pr o c e d ur es s u c h  as  bi o psi es). 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 6 
1 9  J a n u a r y  2 0 1 8  
1 0. 1. 2      S e ri o us   A d v e rs e   E v e nts ( S  A  Es) 
A n   A E is  c o nsi d er e d  s eri o us, if i n t h e  vi e  w  of  eit h er t h e i n v es  ti g at or  or  s p o ns or, it r es ults i n  a n y 
of t h e f oll o  wi n g  o ut c o  m es: 
•     D e at h. 
•     A lif e-t hr e at e ni n g   A E. 
A n   A E is  c o nsi d er e d  "lif e-t hr e at e ni n g " if i n t h e  vi e  w  of  eit h er   t h e i n v esti g at or,  or  s p o ns or, its 
o c c urr e n c e  pl a c es t h e s u bj e ct  at i  m  m e di at e ris k  of  d e at h. It  d o es  n ot i n cl u d e  a n   A E t h at,  h a d it 
o c c urr e d i n  a   m or e s e v er e f or  m,   mi g ht  h a v e  c a us e d  d e at h. 
•     I n p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  a n  e xisti n g  h os pitali z ati o n.  
•     A  p ersist e nt  or si g nifi c a nt i n c a  p a cit y  or s u bst a nti al  disr u pti o n  of t h e  a bilit y  t o  c o n d u ct  n or  m al 
lif e f u n cti o ns. 
•     A  c o n g e nit al  a n o  m al y  or  birt h  d ef e ct. 
I  m p ort a nt   m e di c al  e v e nts t h at   m a y  n ot r es ult i n  d e at h,  b e lif e-t hr e at e ni n g  or r e q uir e  h os pit ali z ati o n 
m a y  b e  c o nsi d er e d s eri o us   w h e n,   b as e d  o n t h e  a p pr o pri at e   m e di c al j u d g  m e nt, t h e y   m a y j e o p ar di z e 
t h e s u bj e ct  a n d   m a y r e q uir e   m e dic al  or s ur gi c al i nt er v e nti o n t o   pr e v e nt  o n e  of t he  o ut c o  m es list e d 
i n t h e  d efi niti o n  of  S  A E.  E x a  m pl es  of s u c h   m e di c al e v e nts ar e i nt e nsi v e tr e at  m e nt i n a n e  m er g e n c y 
r o o  m  or  at  h o  m e;  bl o o d  d ys cr asi as  or  c o n v ulsi o ns t h at  d o  n ot r es ult i n i n p ati e nt  h os pit ali z ati o n;  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. 
1 0. 2      A d v e rs e   E v e nt   R e p o rti n g  a n d   D es c ri pti o ns 
R e c or d  n e  w    A Es  fr o  m  t h e  st art  of  st u d y  tr e at  m e nt  u ntil  3 0  d a ys   aft er  t h e  l ast  d os e  of  st u d y 
tr e at  m e nt  or  u ntil  t h e  s u bj e ct  st arts  n e  w  a nti c a n c er  tr e at  m e nt,  i n cl u di n g  n e  w  i n v esti g ati o n al 
tr e at  m e nt,   w hi c h e v er  o c c urs  e arli er. 
R e c or d  all   A Es  eit h er  o bs er v e d  b y t h e i n v esti g at or  or  o n e  of  hi  s  or  h er   m e di c al  c oll a b or at ors,  or 
r e p ort e d  b y  t h e  s u bj e ct  s p o nt a n e o usl y,  or  i n  r es p o ns e  t o  t h e  dir e ct  q u esti o n  b el o  w,  i n  t h e   A Es 
s e cti o n  of t h e  s u bj e ct's   C  R F/ e  C  R F, i n t h e  s o ur c e  d o c u  m e nt,  a n d  if  a p pli c a bl e, r e c or d  o n t h e  S  A E 
f or  m.    W h e n e v er  p ossi bl e, t h e in v esti g at or s h o ul d  gr o u p si g ns  a n d s y  m pt o  ms (i n cl u di n g l a b or at or y 
t ests  or  ot h er  r es ults  of  di a g n osti c  pr o c e d ur es) i nt o  a  si n gl e  di a g n osis  u n d er  a  si n gl e  t er  m.  F or 
e x a  m pl e,  c o u g h,  r hi nitis,  a n d  s n e e zi n g    mi g ht  b e  r e p ort e d  as  " u p p er  r es pir at or y  i nf e cti o n "  or  a 
p ul  m o n ar y i nfiltr at e,  p ositi v e s p ut u  m  c ult ur e  a n d f e v er   mi g ht  b e r e p ort e d  as  " p n e u  m o ni a. " 
T o  o pti  mi z e  c o nsist e n c y  of   A E  r e p orti n g  a cr oss  c e nt ers,  as k t h e  s u bj e ct  a  st a n d ar d,  g e n er al,  n o n-
l e a di n g  q u esti o n t o  eli cit  a n y   A Es (s u c h  as  "  H a v e  y o u  h a d  a n y  ne  w  s y  m pt o  ms, i nj uri es, ill n ess es 
si n c e  y o ur l ast  visit ? "). 
D e at h is a n  o ut c o  m e  of  a n  S  A E  a n d  us u all y  n ot its elf  a n  S  A E,  u n  l ess it is  d e at h   wit h  n o i d e ntifi a bl e 
c a us e  or  e v e nt. I n  all  ot h er  c as es, r e c or d t h e  c a us e  of  d e at h  a s t h e  S  A E. I n v esti g at ors   will  ass ess 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 7 
1 9  J a n u a r y  2 0 1 8  
t h e  st at us  of  pr e vi o usl y r e p ort e d,  a n d  o c c urr e n c e  of  n e  w   A Es  a nd  S  A Es  at  all  s u bj e ct  e v al u ati o n 
ti  m e  p oi nts  d uri n g t h e st u d y. 
1 0. 2. 1      S e v e rit y 
Us e t h e  d efi niti o ns f o u n d i n t h e   C  o  m  m o n   T o xi cit y   Crit eri a f or   A d v ers e   E v e nts (  C T  C  A E)  v 4. 0 3 
f or  gr a di n g t h e  s e v erit y (i nt ensit y)  of   A Es.   T h e   C T  C  A E  v 4. 0 3  di s pl a ys   Gr a d es  1 t hr o u g h  5   wit h 
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 r ef er e n c e d   A E  a n d  pr o vi d es  g ui d a n c e  n ot list e d. 
S h o ul d  a  s u bj e ct  e x p eri e n c e  a n y   A E   n ot list e d i n t h e   C T  C  A E  v 4. 03,  us e t h e  f oll o  wi n g  gr a di n g 
s yst e  m t o  ass ess s e v erit y: 
•     Gr a d e  1  –    Mil d;  as y  m pt o  m ati c  or   mil d  s y  m pt o  ms;  cli ni c al  or  di a g  n osti c  o bs er v ati o ns  o nl y; 
i nt er v e nti o n  n ot i n di c at e d. 
•     Gr a d e  2  –    M o d er at e;    mi ni  m al,  l o  c al  or  n o ni n v asi v e  i nt er v e nti o n   i n di c at e d;  li  miti n g  a g e-
a p pr o pri at e i nstr u  m e nt al  a cti viti es  of  d ail y li vi n g (  A  D L),  s u c h   as  pr e p ari n g   m e als,  s h o p pi n g 
f or  gr o c eri es  or  cl ot h es,  usi n g t h e t el e p h o n e,   m a n a gi n g   m o n e y, et c. 
•     Gr a d e  3  –  S e v er e  or   m e di c all y si g nifi c a nt  b ut  n ot i  m  m e di at el y l  if e-t hr e at e ni n g;  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 i n di c at e d;  dis a bli n g; li  miti n g s elf- c ar e   A  D L, s u c h as  b at hi n g, 
dr essi n g  a n d  u n dr essi n g, f e e di n g s elf,  usi n g t h e t oil et, t a ki n g   m e di c ati o ns,  a n d  n ot  b e dri d d e n. 
•     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. 
•     Gr a d e  5  –   D e at h r el at e d t o   A E. 
1 0. 2. 2      R el ati o ns hi p t o  St u d y   T r e at  m e nt (  S us p e ct e d   A d v e rs e   R e a cti o ns) 
Ass ess  all   A Es/ S  A Es f or r el ati  o ns hi p t o st u d y tr e at  m e nt  or if  a p pli c a bl e, t o st u d y  pr o c e d ur e. 
T o  e ns ur e  c o nsist e n c y  of    A E  a n d  S  A E  c a us alit y  ass ess  m e nts,  i n v e  sti g at ors  s h o ul d  a p pl y  t h e 
g e n er al  g ui d eli n e  s h o  w n  b el o  w.    M ulti- dr u g r e gi  m e ns  s h o ul d  h a v e  a  c a us alit y  ass ess  m e nt  of  e a c h 
c o  m p o n e nt t o  ai d i n  a n al ysis. 
R el at e d  
( S us p e ct e d   A d v ers e 
R e a cti o n) 
A  s us p e ct e d  a d v ers e  r e a cti o n    m e a ns  a n y   A E  f or   w hi c h  t h er e  is  a 
r e as o n a bl e   p ossi bilit y  t h at  t h e   dr u g  c a us e d  t h e    A E.    R e as o n a bl e 
p ossi bilit y   m e a ns t h er e is  e vi d e n c e t o  s u g g est  a  c a us al r el ati o ns hi p 
b et  w e e n   t h e   dr u g   a n d   t h e     A E   s u c h   as   a   pl a usi bl e   t e  m p or al 
r el ati o ns hi p  b et  w e e n t h e  o ns et  of t h e   A E  a n d  a d  mi nistr ati o n  of  t h e 
dr u g;  a n d/ or t h e   A E f oll o  ws  a  k n o  w n  p att er n  of r es p o ns e t o t h e  dr u g; 
a n d/ or t h e   A E  a b at es  or r es ol v es   u p o n  dis c o nti n u ati o n  of t h e  dru g  or 
d os e   r e d u cti o n   a n d,  if   a p pli c a b l e,   r e a p p e ars   u p o n   r e c h all e n g e. 
F urt h er  e x a  m pl es  of  t y p e  of  e vi d e n c e  t h at   w o ul d  s u g g est  a  c a us a l 
r el ati o ns hi p  b et  w e e n t h e  dr u g  a n d t h e   A E: 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 8 
1 9  J a n u a r y  2 0 1 8  
•     A si n gl e  o c c urr e n c e  of    a n  e v e nt t h at is  u n c o  m  m o n  a n d  k n o  w n t o 
b e  str o n gl y  ass o ci at e d    wit h   dr u g  e x p os ur e  ( e g,  a n gi o e d e  m a, 
h e p ati c i nj ur y,  St e v e ns-J o h ns o n  S y n dr o  m e), 
•     O n e  or    m or e  o c c urr e n c es  of  a n  e v e nt  t h at  is  n ot  c o  m  m o nl y 
ass o ci at e d   wit h  dr u g e x p os ur e,  b ut is  ot h er  wis e  u n c o  m  m o n i n t h e  
p o p ul ati o n  e x p os e d t o t h e  dr u g ( e g,  a c ut e   m y o c ar di al i nf ar cti o n  
i n  a  y o u n g   w o  m a n), 
•     A n  a g gr e g at e  a n al ysis  of  s p e cifi c  e v e nts  o bs er v e d i n  a  cli ni c al   
st u d y (s u c h  as  k n o  w n  c o ns e q u e n c es  of t h e  u n d e rl yi n g  dis e as e  or 
c o n diti o n  u n d er  i n v esti g ati o n  or   ot h er  e v e nts  t h at  c o  m  m o nl y 
o c c ur i n t h e  st u d y  p o p ul ati o n i n d e p e n d e nt  of  dr u g t h er a p y) t h at  
i n di c at es   t h os e   e v e nts   o c c ur     m or e   fr e q u e ntl y   i n   t h e   dr u g 
tr e at  m e nt  gr o u p t h at i n  a  c o n c urr ent  or  hist ori c al  c o ntr ol  gr o u p. 
N ot   R el at e d  
(  N ot  S us p e ct e d) 
A d v ers e  e v e nts t h at  d o  n ot   m e et t h e  d efi niti o n  a b o v e. 
 
1 0. 2. 3      P r e g n a n c y  a n d   A b o rti o n  
R e p ort  a n y  pr e g n a n c y t h at  o c c urs i n  a  s u bj e ct  or   m al e  s u bj e ct's    f e  m al e  p art n er  d uri n g t h e ti  m e 
b et  w e e n t h e first  d os e  of st u d y tr e at  m e nt  a n d  6 0  d a ys  aft er t h e  l ast  d os e  of st u d y tr e at  m e nt.  R e c or d 
a n y  o c c urr e n c e  of  pr e g n a n c y  o n  t h e  Pr e g n a n c y   E x p os ur e   R e p ort  F o r  m  P art  I  a n d  f a x  t o   Ast e x 
P h ar  m a c e uti c als   Dr u g  S af et y   wit h i n  2 4  h o urs  of l e ar ni n g  of t h e  e v e nt.   Aft er t h e  birt h  of t h e  b a b y, 
c oll e ct a d diti o n al i nf or  m ati o n  o n t h e  b a b y  u ntil t h e  b a b y is  1  y e ar  ol d  b y c o  m pl eti n g t h e  Pr e g n a n c y 
E x p os ur e   R e p ort  F or  m  P art II. 
A  s u bj e ct   m ust  i  m  m e di at el y i nf or  m    t h e  i n v esti g at or  if  t h e  s u bj ect  or  s u bj e ct's  p art n er  b e c o  m es 
pr e g n a nt  d uri n g t h e ti  m e  b et  w e e n  t h e first  d os e  of  st u d y tr e at  me nt  a n d  6 0  d a ys  aft er t h e l ast  d os e 
of  st u d y  tr e at  m e nt.   A n y  f e  m al e  s u bj e cts  r e c ei vi n g  st u d y  tr e at  m e nt   w h o  b e c o  m e  pr e g n a nt    m ust 
i  m  m e di at el y  dis c o nti n u e  st u d y tre at  m e nt.  T h e i n v esti g at or  s h o ul d  c o u ns el t h e  s u bj e ct,  dis c ussi n g 
a n y ris ks  of  c o nti n ui n g t h e  pr e g n a n c y  a n d  a n y  p ossi bl e  eff e cts  o n t h e f et us. 
R e p ort  a n y  a b orti o n  a n d t h e r e as o n f or it,   w h et h er t h er a p e uti c,  el e cti v e,  or  s p o nt a n e o us, t o   Ast e x 
P h ar  m a c e uti c als   Dr u g  S af et y   wit hi n  2 4  h o urs, t hr o u g h t h e  S  A E r e p orti n g  pr o c ess ( S e cti o n  1 0. 3 ). 
1 0. 3      R e p o rti n g   R e q ui r e  m e nts f o r  S e ri o us   A d v e rs e   E v e nts ( S  A  Es) 
All   S  A Es  r e g ar dl ess  of  c a us alit y   will  b e  r e p ort e d  b y t h e i n v est  i g at or t o   Ast e x   P h ar  m a c e uti c als 
t hr o u g h t h e  3 0- d a y  p eri o d  aft er th e l ast  d os e  of st u d y tr e at  m e n t.   D e at hs  a n d  S  A Es  o c c urri n g  aft er 
t h e  3 0- d a y s af et y f oll o  w- u p  p eri o d   A  N  D  c o nsi d er e d r el at e d t o stu d y tr e at  m e nt  or st u d y  pr o c e d ur es 
m ust  als o  b e r e p ort e d. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
2 9 
1 9  J a n u a r y  2 0 1 8  
R e p ort  all  S  A Es (i niti al  a n d f oll o  w- u p i nf or  m ati o n)  o n  a n  S  A E f or  m  a n d  s e n d t h e f or  m t o   Ast e x 
P h ar  m a c e uti c als    Dr u g  S af et y,  or  d esi g n e e,    wit hi n  2 4  h o urs  of  t h e  dis c o v er y  of  t h e  e v e nt  or 
i nf or  m ati o n  (s e e  b el o  w).    Ast e x  P h ar  m a c e uti c als    m a y  r e q u est  f ollo  w- u p  a n d  ot h er  a d diti o n al 
i nf or  m ati o n fr o  m t h e i n v esti gat or ( e g,  h os pit al  a d  missi o n  or  di s c h ar g e  n ot es, l a b or at or y r es ults). 
Ast e x  P h a r  m a c e uti c als   D r u g  S a  f et y   C o nt a ct I nf o r  m ati o n 
T el e p h o n e   N u  m b e rs 
L o c al   N u  m b er: 
 
N ort h   A  m eri c a  T oll  Fr e e 
 
F a x   N u  m b e rs 
L o c al  F a x: 
 
T oll  Fr e e  F a x 
 
E  m ail 
Dr u g  S af et y I n b o x 
 
Ot h er  c o u ntri es:   R ef er t o t h e   Ast e x  F a x   C o v er  S h e et f or t h e   Dr u  g 
S af et y   D e p art  m e nt.   All s af et y f a x  n u  m b ers  ar e list e d t h er e. 
 
R e p ort  all  d e at hs   wit h t h e  pri  m ar y  c a us e  of  d e at h  as t h e  S  A E t e  r  m,  as  d e at h is t h e  o ut c o  m e  of t h e 
e v e nt,  n ot t h e  e v e nt its elf. If  a n  a ut o ps y   w as  p erf or  m e d, r e p or t t h e  pri  m ar y  c a us e  of  d e at h  o n t h e 
a ut o ps y   r e p ort   as   t h e    S  A E   t er  m.    F or  w ar d   a ut o ps y   a n d   p ost  m ort e  m    r e p orts   t o     Ast e x 
P h ar  m a c e uti c als   Dr u g  S af et y,  or  d esi g n e e,  as  o utli n e d  a b o v e. 
If  st u d y tr e at  m e nt is  dis c o nti n u e d, t e  m p or aril y  s us p e n d e d,  or  dos e  r e d u c e d  b e c a us e  of  a n  S  A E, 
i n cl u d e t his i nf or  m ati o n i n t h e  S  A E r e p ort. 
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)  ar e  S  A E s t h at  q u alif y f or   m a n d at or y 
e x p e dit e d r e p orti n g t o r e g ul at or y  a ut h oriti es   w h er e t h e  S  A E is  s us p e ct e d t o  b e  c a us e d  b y t h e st u d y 
tr e at  m e nt  a n d is  c o nsi d er e d  u n e x p e ct e d (i e,  n ot  d efi n e d  as  e x p ect e d i n t h e  c urr e nt I  B  cli ni c al st u d y 
pr ot o c ol,  or  a p pr o v e d  l a b eli n g  f or    m ar k et e d  dr u gs).  I n  t his  c as e,    Ast e x  P h ar  m a c e uti c als    Dr u g 
S af et y   or   d esi g n e e    will  r e p ort  t o  t h e  r el e v a nt  r e g ul at or y   a ut h o riti es   a n d  f or  w ar d   a  f or  m al 
n otifi c ati o n  d es cri bi n g t h e  S  U S  A R t o i n v esti g at ors,  a c c or di n g t  o  r e g ul at or y  r e q uir e  m e nts.   E a c h 
i n v esti g at or   m ust t h e n  n otif y  his  or  h er  I  R  B/I E  C  of t h e  S  U S  A  R  as  r e q uir e d  b y l o c al  r e g ul at or y 
a ut h oriti es  a n d i n  a c c or d a n c e   wit h I  R  B/I E  C  p oli c y. 
1 0. 4      F oll o  w- u p f o r   A d v e rs e   E v e nts 
F oll o  w  all   A Es  a n d  S  A Es t h at  ar e  e n c o u nt er e d  d uri n g t h e  pr ot o c o l-s p e cifi e d   A E r e p orti n g  p eri o d 
u ntil  ( 1)  t h e y  ar e  r es ol v e d,  or  ( 2) t h e  i n v esti g at or  ass ess es  t h e  s u bj e ct  as  st a bl e  a n d  t h e  e v e nt 
f oll o  ws  a  cli ni c all y  e x p e ct e d  o utc o  m e,  or  ( 3)  u ntil t h e  s u bj e ct  is l ost t o  f oll o  w- u p  or   wit h dr a  ws 
c o ns e nt  or is   wit h dr a  w n fr o  m t h e st u d y. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 0 
1 9  J a n u a r y  2 0 1 8  
1 1. 0      S  T  A  TI S  TI  C S 
St atisti c al  a n al ys es   will  b e  p e rf or  m e d  b y   Ast e x  P h ar  m a c e uti c als  or its  d esi g n e e. 
D at a  s u  m  m ari es  a n d listi n gs   will   b e  g e n er at e d  usi n g  S  A S  v ersi o n   9. 4  or  a   m or e  r e c e nt  v ersi o n 
( S  A S I nstit ut e I n c.,   C ar y,   N  C,   U S  A). 
T h e  st atisti c al  a n al ysis  pl a n  a n d / or t h e  cli ni c al  st u d y r e p ort will  pr o vi d e  a d diti o n al  d et ails  of t h e 
a n al ysis.  T h e  cli ni c al st u d y r e p ort   will  d es cri b e  d e vi ati o ns fr o  m t h e st atisti c al  a n al ysis  pl a n, if  a n y. 
1 1. 1      S a  m pl e  Si z e 
T h er e is  n o  s a  m pl e  si z e  r e q uir e  m e nt  f or t his  e xt e nsi o n  st u d y.  I  t is  e x p e ct e d t h at  a p pr o xi  m at el y 
2 5 0 s u bj e cts  c o ul d  b e  e nr oll e d.   As   m or e  g u a d e cit a bi n e  cli ni c al  st u di es  ar e  c o n d u ct e d, t h e  n u  m b er 
of s u bj e cts  e nr oll e d i n t his  e x t e nsi o n st u d y  c o ul d i n cr e as e. 
1 1. 2      A n al ysis  S ets 
All s u bj e cts   w h o r e c ei v e d  a n y tr  e at  m e nt  d uri n g t his st u d y   will  b e i n cl u d e d i n t h e  a n al ysis f or t his 
st u d y. 
1 1. 3      S c h e d ul e  of   A n al ys es 
T h er e is  n o  pr e d et er  mi n e d s c h e d ul e  of  a n al ys es f or t his st u d y.   A n al ys es   m a y  b e  p erf or  m e d  d uri n g 
t h e c o urs e  of t h e st u d y  d e p e n di n g  o n t h e  n e e ds  of t h e cli ni c al d e v el o p  m e nt  pr o gr a  m.   A n al ys es   m a y 
als o  b e  p erf or  m e d  aft er t h e l ast  s u bj e ct  h as  dis c o nti n u e d tr e at  m e nt  a n d  b e e n   wit h dr a  w n fr o  m t h e 
st u d y. 
1 1. 4      Dis p ositi o n 
If  r e q uir e d,  t h e   n u  m b er  a n d   p er c e nt a g e  ( n,    %)   of  s u bj e cts  s cr e en e d,  e nr oll e d,  tr e at e d,  a n d 
wit h dr a  w n  (  wit h  r e as o n)    will  b e    s u  m  m ari z e d.    All  s cr e e n e d  s u bj e cts    will  b e  i n cl u d e d  i n  t h e 
dis p ositi o n  a n al ysis. 
1 1. 5      A n al ysis  of   D e  m o g r a p hi c  a n d   B as eli n e   D at a 
D e  m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs  ar e  n ot  c oll e ct e d  as  p  art  of t his  st u d y. If  s u  m  m ari es  of 
d e  m o gr a p hi c  a n d  b as eli n e  c h ar a ct eristi cs  ar e r e q uir e d f or t his st u d y, t h e r el e v a nt i nf or  m ati o n   will 
b e  o bt ai n e d  fr o  m t h e  d at a b as e  of t h e  pri or  st u d y.  If  r e q uir e d,  s u bj e ct  d e  m o gr a p hi c  a n d  b as eli n e 
c h ar a ct eristi cs   will  b e s u  m  m ari z e d  b y   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 
f or  c o nti n u o us  v ari a bl es;  a n d  b y c o u nts  a n d  p er c e nt a g es f or  c at e g ori c al  v ari a bl es,  or  as a p pr o pri at e 
d e p e n di n g  o n t h e  p ur p os e  of t h e  a n al ysis. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 1 
1 9  J a n u a r y  2 0 1 8  
1 1. 6      Effi c a c y   A n al ys es 
S ur vi v al  st at us is t h e  o nl y  effi c a c y  o ut c o  m e  c oll e ct e d  as  p art  of t his  st u d y.  S ur vi v al  d ur ati o n f or 
e a c h  s u bj e ct  st arti n g  fr o  m  t h e  ti  m e  of  first  g u a d e cit a bi n e  tr e a t  m e nt  i n  t h e  pri or  st u d y    m a y  b e 
d et er  mi n e d. 
1 1. 7      S af et y   A n al ys es 
S af et y    will   b e   ass ess e d   b y   s u bj e ct   r e p ort e d   a n d  i n v esti g at or   o b s er v e d    A Es,   c o n c o  mit a nt 
m e di c ati o ns,  a n d  cli ni c al  l a b or  at or y  t ests  ( h e  m at ol o g y,  s er u  m  c h e  mistr y).  If  r e q uir e d,  s af et y 
v ari a bl es   will  b e t a b ul at e d a n d  pr es e nt e d f or all s u bj e cts   w h o r e c ei v e a n y a  m o u nt  of  g u a d e cit a bi n e. 
All  s af et y  d at a  c oll e ct e d  d uri n g  t h e  st u d y    will  b e  i n cl u d e d  i n   t h e  st u d y  d at a b as e.  I n  a d diti o n, 
s u  m  m ari es  of  e x p os ur e t o  g u a d e ci t a bi n e  a n d r e as o ns f or  dis c o ntin u ati o n   m a y  b e  pr o vi d e d.  
A Es    will  b e    m a p p e d  t o  t h e  a p pr o pri at 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  ( P T) 
a c c or di n g t o 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 es ( M e d  D  R  A)  S e v erit y  of   A Es   will  b e 
gr a d e d  usi n g   C T  C  A E  v ersi o n  4. 0 3. 
Tr e at  m e nt- e  m er g e nt    A Es    will  b e  d efi n e d  as  t h os e  o c c urri n g  or    w o rs e ni n g  aft er  st arti n g  st u d y 
tr e at  m e nt  u n d er t his  st u d y  pr ot o c ol.  S u  m  m ari es   m a y  b e  pr o vi d e d f or  all tr e at  m e nt- e  m er g e nt   A Es 
a n d  S  A Es,  a n d  tr e at  m e nt- e  m er g e nt    A Es  a n d  S  A Es  c o nsi d er e d  r el at e d  t o  st u d y  tr e at  m e nt,  as 
f oll o  ws: 
•     B y   m a xi  m u  m s e v erit y.  
•     I n ci d e n c e  b y  S  O  C ( b y s e verit y  gr a d e  a n d  o v er all). 
•     I n ci d e n c e r at e  b y  P T ( b y s e v erit y  gr a d e  a n d  o v er all)   wit hi n  e a ch  S  O  C. 
L a b or at or y  v al u es r e p ort e d  b y  diff er e nt l o c al l a bs   will  b e list e d.  S u  m  m ari es  of l a b or at or y  d at a   m a y 
b e  pr o vi d e d if  d e e  m e d  n e c ess ar y.  
1 1. 8      I nt e ri  m   A n al ysis 
N o i nt eri  m  a n al ysis   will  b e  p er  f or  m e d f or t his st u d y.   D at a s u  m  mari es   m a y  b e  pr o vi d e d  d uri n g t h e 
c o urs e  of t h e st u d y t o   m e et t h e  n e e ds  of t h e  cli ni c al  d e v el o p  m e nt  pr o gr a  m.  
1 1. 9      P r o c e d u r es f o r   H a n dli n g    Missi n g,   U n us e d,  a n d  S p u ri o us   D at a 
N o i  m p ut ati o n  of  v al u es f or   missi n g  d at a   will  b e  p erf or  m e d.   D at  a fr o  m  s u bj e cts l ost t o f oll o  w- u p 
will  b e i n cl u d e d i n st atisti c al  a  n al ys es t o t h e  p oi nt  of t h eir  l ast  e v al u ati o n. 
1 2. 0      S  T  U  D  Y   D  U  R  A  TI  O  N   A  N  D   T  E  R   MI  N  A  TI  O  N 
T h e st u d y is  e x p e ct e d t o st art i n   Q 2  2 0 1 8.  T h e st u d y   m a y  c o nti n u e  as l o n g  as s u bj e cts  ar e r e c ei vi n g 
tr e at  m e nt   wit h  g u a d e cit a bi n e,  or  u ntil  g u a d e cit a bi n e  b e c o  m es  c o  m  m er ci all y  a v ail a bl e ( a nti ci p at e d 
f or   Q 4  of  2 0 1 9  at t h e  e arli est).  

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 2 
1 9  J a n u a r y  2 0 1 8  
1 3. 0      S  T  U  D  Y   C  O   M P  LI  A  N  C  E   A  N  D   E  T  HI  C  A  L   C  O  N SI  D  E  R  A  TI  O  N S 
1 3. 1      C o  m pli a n c e  St at e  m e nt 
T h e st u d y   will  b e  c o n d u ct e d i n  a c c or d a n c e   wit h t h e I  C  H   G  C P  g ui d eli n es,  pri n ci pl es  e n u n ci at e d i n 
t h e   D e cl ar ati o n  of   H elsi n ki,  a n d  all  h u  m a n  cli ni c al  r es e ar c h  r eg ul ati o ns  i n  c o u ntri es   w h er e  t h e 
st u d y is  c o n d u ct e d. 
1 3. 2      I nf o r  m e d   C o ns e nt 
T h e I  C Fs  us e d f or t h e st u d y   m ust   c o  m pl y   wit h t h e   D e cl ar ati o n  of   H elsi n ki, f e d er al r e g ul ati o ns   U S 
2 1   C F  R  P art  5 0,  a n d I  C  H   G  C P  g ui d eli n es  a n d  a n y  ot h er l o c al r e g u l ati o ns.  T h e i n v esti g at or,  or  a 
p ers o n  d el e g at e d  b y t h e i n v esti g at or,   m ust  e x pl ai n t h e   m e di c al  as p e cts  of t h e  st u d y, i n cl u di n g t h e 
n at ur e  of t h e  st u d y  a n d t h e tr e at  m e nt,  or all y  a n d i n   writi n g, i n  s u c h  a   m a n n er t h at t h e  s u bj e ct is 
a  w ar e  of  p ot e nti al  b e n efits  a n d  ris ks.  S u bj e cts   m ust  b e i nf or  m ed t h at  p arti ci p ati o n is  v ol u nt ar y  a n d 
t h at t h e y   m a y   wit h dr a  w fr o  m t h e st u d y  at  a n y ti  m e,   wit h o ut  pr eju di c e.  S u bj e cts,  or  a l e g al  g u ar di a n 
if t h e s u bj e ct is  u n a bl e t o,   m ust  gi v e i nf or  m e d  c o ns e nt i n   writi n g. 
T h e i nf or  m e d  c o ns e nt  pr o c ess   m ust  b e  c o n d u ct e d,  d o c u  m e nt e d i n t  h e s o ur c e  d o c u  m e nt (i n cl u di n g 
t h e  d at e), a n d t h e f or  m   m ust  b e si g n e d,  b ef or e t h e s u bj e ct  u n d er g o es a n y st u d y-s p e cifi c  pr o c e d ur es. 
1 3. 3      I nstit uti o n al   R e vi e  w   B o a r d  o r I n d e p e n d e nt   Et hi cs   C o  m  mitt e e (I  R  B /I  E  C) 
T h e i n v esti g at or   m ust  s u b  mit t h e   pr ot o c ol,  pr ot o c ol  a  m e n d  m e nts,   a n d t h e  I  C F  f or t h e  pr o p os e d 
st u d y,  al o n g    wit h  a n y  ot h er  d o c u  m e nts  r e q uir e d  b y  t h e  c e nt er's  I  R  B/I E  C  t o  t h e  c e nt er's  d ul y 
c o nstit ut e d I  R  B/I E  C f or r e vi e  w   a n d  a p pr o v al.  T h e i n v esti g at or   must  als o  e ns ur e t h at t h e I  R  B/I E  C 
r e vi e  ws t h e  pr o gr ess  of t h e  st u d y  o n  a r e g ul ar  b asis  a n d, if  n ec ess ar y, r e n e  ws its  a p pr o v al  of t h e 
st u d y  o n a n a n n u al  b asis.   A c o p y  of e a c h I  R  B/I E  C a p pr o v al l ett er   m ust  b e f or  w ar d e d t o t h e s p o ns or 
b ef or e t h e st u d y is i  m pl e  m e nt e d.   D o c u  m e nt ati o n  of s u bs e q u e nt r e vi e  ws  of t h e st u d y   m ust  als o  b e 
f or  w ar d e d t o t h e s p o ns or. 
1 4. 0      A  D   MI  NI S  T  R  A  TI  V  E  P  R  O  C  E  D  U  R  E S 
1 4. 1      S p o ns o r   R es p o nsi biliti es 
Ast e x  P h ar  m a c e uti c als  r es er v es t h e  ri g ht t o t er  mi n at e t h e  st u d y    a n d  r e  m o v e  all  st u d y   m at eri als 
fr o  m  a  st u d y  c e nt er  at  a n y  ti  m e.    Ast e x  P h ar  m a c e uti c als  a n d  t h e  i n v esti g at ors    will  ass ur e  t h at 
a d e q u at e  c o nsi d er ati o n is  gi v e n  t o t h e  pr ot e cti o n  of t h e s u bj e cts' i nt er ests.  S p e cifi c  cir c u  mst a n c es 
t h at   m a y  pr e ci pit at e s u c h t er  mi n ati o n  ar e: 
•     R e q u est  b y   H e alt h   A ut h orit y   t o t er  mi n at e t h e st u d y 
•     U ns atisf a ct or y s u bj e ct  e nr oll  m e n  t   wit h r e g ar d t o  q u alit y  or  q u antit y 
•     Si g nifi c a nt  or  n u  m er o us  d e vi ati o ns   fr o  m  st u d y  pr ot o c ol  r e q uir e  me nts,  s u c h  as  f ail ur es  t o 
p erf or  m  r e q uir e d  e v al u ati o ns  o n   s u bj e cts,    m ai nt ai n  a d e q u at e  st u d y  r e c or ds  or  i n a c c ur at e, 
i n c o  m pl et e  or l at e  d at a r e c or di n g  o n  a r e c urr e nt  b asis 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 3 
1 9  J a n u a r y  2 0 1 8  
•     T h e i n ci d e n c e  or  s e v erit y  of   A Es i n t his  or  ot h er  st u di es i n di c ati n g  a  p ot e nti al  h e alt h  h a z ar d 
c a us e d  b y t h e st u d y tr e at  m e nt 
1 4. 1. 1      St u d y  S u p pli es 
T h e s p o ns or   will s u p pl y s uffi ci e nt  q u a ntiti es  of t h e f oll o  wi n g   m at eri als t o  e a c h  cli ni c al  c e nt er: 
•     G u a d e cit a bi n e  as  d es cri b e d i n   S e cti o n  7. 0 . 
•     I  B f or  g u a d e cit a bi n e. 
•     C as e r e p ort f or  ms  or  d a  t a  c oll e cti o n t o ols. 
1 4. 1. 2      I n v esti g at o r   T r ai ni n g 
As  p art  of t h e  pri or st u d y  pr ot o c ols,  all st u d y  c e nt ers  h a d  a  c  e nt er-s p e cifi c st u d y  i niti ati o n   m e eti n g 
t o  e ns ur e t h e  c e nt er st aff  u n d erst o o d t h e  pr ot o c ol, st u d y r e q uir e  m e nts,  a n d  d at a  c a pt ur e  pr o c ess es. 
T his  pr ot o c ol c o nt ai ns  n o  n e  w  pr o c ess es  or i nf or  m ati o n  b e y o n d t h os e i n t h e  pri or st u d y.  E a c h st u d y 
c e nt er   will  b e  pr o vi d e d   wit h i nf or  m ati o n r e g ar di n g   G  C P  a n d r e g u l ati o ns s p e cifi c t o t h e  c o n d u ct  of 
cli ni c al  st u di es.   E a c h  c e nt er is   r es p o nsi bl e  f or  e ns uri n g t h at  n e  w t e a  m   m e  m b ers  ar e  a d e q u at el y 
tr ai n e d  a n d t h e tr ai ni n g is  d o c u  m e nt e d. 
1 4. 1. 3      O n g oi n g   C o  m  m u ni c ati o n  of  S af et y   I nf o r  m ati o n   D u ri n g t h e  St u d y 
T h e s p o ns or   will  pr o vi d e t h e i n v esti g at or   wit h  d o c u  m e nt ati o n  of   S  A Es, fr o  m t his st u d y  a n d  ot h er 
st u di es,  t h at  ar e  r el at e d  t o  t h e  I  M P  a n d  u n e x p e ct e d  (s e e   S e cti o n  1 0. 3 ),  as  a p pr o pri at e.    T h e 
i n v esti g at or   m ust f or  w ar d t his  d o c u  m e nt ati o n t o t h e I  R  B/I E  C,  as  d es cri b e d i n  S e cti o n  1 0. 3. 
T h e s p o ns or   will  als o  n otif y t h e i n v esti g at or  a b o ut  a n y  ot h er si g nifi c a nt s af et y fi n di n gs t h at  c o ul d 
alt er t h e  s af et y  pr ofil e  of t h e I  M P fr o  m   w h at is  d es cri b e d i n t h e  pr ot o c ol  a n d  si g nifi c a ntl y  aff e ct 
t h e  s af et y  of  s u bj e cts,  aff e ct  t h e  c o n d u ct  of  t h e  st u d y,  or  alter  t h e  I  R  B/I E  C's  o pi ni o n  a b o ut 
c o nti n u ati o n  of t h e st u d y.  
1 4. 1. 4      St u d y    M o nit o ri n g 
R e pr es e nt ati v es  of   Ast e x  P h ar  m  a c e uti c als   will   m o nit or t h e  st u d y .   R o uti n e   m o nit ori n g  visits   will 
b e  c o n d u ct e d t o: 
•     Ass ur e  c o  m pli a n c e   wit h t h e st  u d y  pr ot o c ol  a n d  a p pr o pri at e r e g ul ati o ns. 
•     V erif y  t h at   ( 1)  t h e  i nf or  m e d   c o ns  e nt   pr o c ess    w as   c o n d u ct e d   b ef o r e  i niti ati o n   of   a n y 
st u d y-s p e cifi c  pr o c e d ur es (i e,  p erf or  m e d  s ol el y f or t h e  p ur p os e   of  d et er  mi ni n g  eli gi bilit y f or 
t h e  st u d y)   a n d   b ef or e   pr o visi o n   of  st u d y  tr e at  m e nt,   a n d  ( 2)  t his   pr o c ess  is   a d e q u at el y 
d o c u  m e nt e d. 
•     V erif y  t h at  t h e  pr ot o c ol,  pr ot o c  ol  a  m e n d  m e nts,  a n d  s af et y i nf or m ati o n  ar e  s u b  mitt e d  t o t h e 
I  R  B/I E  Cs  a n d  a p pr o v e d  b y t h e I  R  B/I E  Cs i n  a ti  m el y   m a n n er. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 4 
1 9  J a n u a r y  2 0 1 8  
•     R e vi e  w t h e  C  R F/ e  C  R Fs  a n d s o ur c e  d o c u  m e nts t o  e ns ur e t h at r e p ort  e d st u d y  d at a  ar e  a c c ur at e, 
c o  m pl et e,  a n d  v erifi a bl e fr o  m s o ur c e  d o c u  m e nts. 
•     V erif y t h at st u d y tr e at  m e nts  ar e   st or e d  pr o p erly  a n d  u n d er t h e  pr o p er  c o n diti o ns, t h at t h e y  ar e 
i n  s uffi ci e nt  s u p pl y,  a n d t h at re c ei pt,  us e,  a n d r et ur n  of  g u a d e cit a bi n e  at t h e  st u d y  c e nt ers is 
c o ntr oll e d  a n d  d o c u  m e nt e d  a d e q u at el y. 
•     V erif y t h at t h e i n v esti g at or  a  n d st u d y  c e nt er  p ers o n n el r e  m ai n  a d e q u at el y  q u alifi e d t hr o u g h o ut 
t h e st u d y. 
•     V erif y  t h at  t h e  r es e ar c h  f a ciliti es,  i n cl u di n g  l a b or at ori es  a n d    e q ui p  m e nt,  ar e    m ai nt ai n e d 
a d e q u at el y t o s af el y  a n d  pr o p erl y  c o n d u ct t h e st u d y. 
1 4. 1. 5      St u d y   A u diti n g  a n d I ns p e cti n g 
T h e  s p o ns or   m a y  a u dit t h e  st u d y  c o n d u ct,  c o  m pli a n c e   wit h t h e  pr ot o c ol  a n d  a c c ur a c y  of t h e  d at a 
i n  o n e  or   m or e  c e nt ers. 
T h e i n v esti g at or(s)/i nstit uti o n(s)   will  p er  mit  st u d y-r el at e d   m o nit ori n g,  a u dits,  a n d i ns p e cti o ns  b y 
t h e   s p o ns or,   I  R  B/I E  C,   g o v er n  m e nt   r e g ul at or y   b o di es   a n d     Ast e x   P har  m a c e uti c als     Q u alit y 
Ass ur a n c e  p ers o n n el  or its  d esi  g n e es  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  aft er 
a p pr o pri at e  n otifi c ati o n fr o  m s p o ns or. 
1 4. 2      I n v esti g at o r   R es p o nsi biliti es 
1 4. 2. 1      S u bj e ct  S c r e e ni n g   L o g 
T h e i n v esti g at or   m ust  k e e p  a r e c or d t h at lists  all s u bj e cts   w h o  si g n e d  a n i nf or  m e d  c o ns e nt  a n d t h e 
r e as o n f or  n o n-i n cl usi o n if t h ey   w er e  n ot  ulti  m at el y tr e at e d. 
1 4. 2. 2      G u a d e cit a bi n e   A c c o u nt a bilit y 
A n i niti al  s u p pl y  of  g u a d e cit a bi n e   will  b e  s hi p p e d t o  e a c h  st u d  y  c e nt er's  p h ar  m a c y   w h e n  all t h e 
i niti ati o n   d o c u  m e nts,  i n cl u di n g   I  R  B/I E  C   a p pr o v als,   I  R  B/I E  C   a p pro v e d   I  C F,   a n d   b usi n ess 
a gr e e  m e nts,  h a v e  b e e n  r e c ei v e d  a n d  r e vi e  w e d  b y   Ast e x  P h ar  m a c e ut i c als  a n d  u p o n  a cti v ati o n  of 
t h e st u d y  c e nt er  b y   Ast e x  P h ar  m a c e uti c als.  T h er e aft er, s u p pli es   will  b e  a ut or efill e d. 
K e e p  g u a d e cit a bi n e i n a l o c k e d, li  mit e d- a c c ess r o o  m.  T h e st u d y   tr e at  m e nt   m ust  n ot  b e  us e d  o utsi d e 
t h e  c o nt e xt  of t h e  pr ot o c ol.   U n d er  n o  cir c u  mst a n c es  s h o ul d t h e i n v esti g at or  or  ot h er  st u d y  c e nt er 
p ers o n n el  s u p pl y  g u a d e cit a bi n e t o  ot h er i n v esti g at ors,  s u bj e cts ,  or  cli ni cs  or  all o  w  s u p pli es t o  b e 
us e d   ot h er   t h a n   as   dir e ct e d   b y   t his   pr ot o c ol     wit h o ut   pri or   a ut h ori z ati o n   fr o  m     Ast e x 
P h ar  m a c e uti c als. 
T h e     m o nit or     will   r e g ul arl y   r e vi e  w   a n d   v erif y   all   g u a d e cit a bi n e    s u p pli es   a n d   ass o ci at e d 
d o c u  m e nt ati o n. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 5 
1 9  J a n u a r y  2 0 1 8  
M ai nt ai n  a n  a c c ur at e  a c c o u nti n g   of  t h e   g u a d e cit a bi n e.    T h es e  r e c   or ds    m ust  s h o  w   d at es,  l ot 
n u  m b ers,  q u a ntiti es r e c ei v e d,  di s p e ns e d,  a n d r et ur n e d  a n d   m ust b e  a v ail a bl e f or   m o nit ori n g  b y t h e 
s p o ns or.   T h e  i n v esti g at or   will  e n s ur e  t h at  a n y  us e d  a n d  u n us e d  g u a d e cit a bi n e  a n d  ot h er  st u d y 
m at eri al is  d estr o y e d  or r et ur  n e d t o t h e s p o ns or  o n  c o  m pl eti o n  of t h e st u d y. If t h e  g u a d e cit a bi n e is 
d estr o y e d  at t h e st u d y  c e nt er,  t h er e s h o ul d  b e  d o c u  m e nt ati o n  of  d estr u cti o n at t h e st u d y c e nt er.  T h e 
s p o ns or   a n d/ or   t h eir   r e pr es e nt ati v es     will   v erif y   fi n al   dr u g   a c c o u nt a bilit y.     G u a d e cit a bi n e 
a c c o u nt a bilit y r e c or ds   m ust  b e   m ai nt ai n e d  a n d r e a dil y  a v ail a bl e  f or i ns p e cti o n  b y r e pr es e nt ati v es 
of   Ast e x  P h ar  m a c e uti c als  a n d  ar e  o p e n t o i ns p e cti o ns  b y r e g ul at or y  a ut h oriti es  at  a n y ti  m e. 
1 4. 2. 3      R e p o rti n g  a n d   R e c o r di n g  of  St u d y   D at a 
D at a    will   b e   c a pt ur e d   a n d   c o  m pil e d   usi n g   pr o c e d ur es   d e v el o p e d   b  y  t h e   s p o ns or   or  t h eir 
r e pr es e nt ati v es.   Cl e arl y r e c or d  all r e q u est e d  st u d y  d at a  o n t h e   C  R F/ e  C  R F  a n d  ot h er  st u d y f or  ms 
as r e q uir e d.    W h e n e v er  p ossi bl e, r e c or d t h e r e as o n f or   missi n g  d at a i n t h e  s o ur c e  d o c u  m e nt.   O nl y 
i n di vi d u als   w h o  ar e  i d e ntifi e d o n  t h e  st u d y  p ers o n n el  r es p o nsi b ilit y/si g n at ur e  l o g   m a y  e nt er  or 
c orr e ct  d at a i n t h e   C  R F/ e  C  R F. I n c o  m pl et e  or i n c o nsist e nt  d at a  o n t h e   C  R F/ e  C  R Fs   will r es ult i n 
d at a  q u eri es t h at r e q uir e r es ol uti o n  b y t h e i n v esti g at or  or  d es i g n e e. 
T h e  i n v esti g at or    m ust  ass ur e  s u bj e ct  a n o n y  mit y  a n d  pr ot e cti o n  o f  i d e ntiti es  fr o  m  u n a ut h ori z e d 
p arti es.   O n  C  R F/ e  C  R Fs  or  ot h er  d o c u  m e nts  or s u bj e ct r e c or ds  pr o vi d e d t o   Ast e x  P h ar  m a c e uti c als, 
i d e ntif y  s u bj e cts  b y  c o d e  (s u bj e ct  n u  m b er)  a n d  n ot  b y  n a  m es.   T h e  pri n ci p al i n v esti g at or  s h o ul d 
m ai nt ai n  d o c u  m e nts  n ot f or  s u b  missi o n t o   Ast e x  P h ar  m a c e uti c als   ( e g,  s u bj e cts'  si g n e d i nf or  m e d 
c o ns e nt), i n stri ct  c o nfi d e n c e. 
1 4. 2. 4      S o u r c e   D o c u  m e nt ati o n 
T h e i n v esti g at or   m ust   m ai nt ai n  a d e q u at e  a n d  a c c ur at e s o ur c e  d o c u  m e nts  u p o n   w hi c h   C  R F/ e  C  R Fs 
f or  e a c h s u bj e ct  ar e  b as e d.  T h e y  ar e t o  b e s e p ar at e  a n d  disti n ct fr o  m  C  R F/ e  C  R Fs,  e x c e pt f or  c as es 
i n   w hi c h t h e  s p o ns or  h as  pr e d et er  mi n e d t h at  dir e ct  d at a  e ntr y int o  s p e cifi e d  p a g es  of t h e  s u bj e ct's 
C  R F/ e  C  R F is  a p pr o pri at e.  T h es e r  e c or ds s h o ul d i n cl u d e  d et ail e d  n ot es  o n: 
•     T h e  or al  a n d   writt e n  c o  m  m u ni c ati o n   wit h t h e s u bj e ct r e g ar di n g t h e st u d y tr e at  m e nt (i n cl u di n g 
t h e  ris ks  a n d  b e n efits  of  t h e  stu d y).    R e c or d  t h e  d at e  of  i nf or  m e d  c o ns e nt  i n  t h e  s o ur c e 
d o c u  m e nt ati o n. 
•     T h e  s u bj e ct's  b asi c  i d e ntif yi n g  i nf or  m ati o n,  s u c h  as  d e  m o gr a p hi cs,  t h at  li n ks  t h e  s u bj e ct's 
s o ur c e  d o c u  m e nts   wit h t h e   C  R F/ e  C  R Fs. 
•     T h e r es ults  of  all  di a g n osti c t ests  p erf or  m e d,  di a g n os es   m a d e,   t h er a p y  pr o vi d e d,  a n d  a n y  ot h er 
d at a  o n t h e  c o n diti o n  of t h e s u bj e ct. 
•     T h e s u bj e ct's  e x p os ur e t o st u d y tr e at  m e nt. 
•     All   A Es. 
•     T h e  s u bj e ct's  e x p os ur e  t o  a n y  c o n c o  mit a nt  t h er a p y  (i n cl u di n g  st  art  a n d  st o p  d at es,  r o ut e  of 
a d  mi nistr ati o n,  a n d  d os a g e). 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 6 
1 9  J a n u a r y  2 0 1 8  
•     All r el e v a nt  o bs er v ati o ns  a n d  d at a  o n t h e  c o n diti o n  of t h e s u bj  e ct t hr o u g h o ut t h e st u d y. 
1 4. 2. 5      R e c o r ds   R et e nti o n 
T h e  i n v esti g at or    m ust  e ns ur e  t h at  cli ni c al  st u d y  r e c or ds  ar e  r e  t ai n e d  a c c or di n g  t o   n ati o n al 
r e g ul ati o ns,  as  d o c u  m e nt e d  i n  th e  cli ni c al  tri al  a gr e e  m e nt  e nt e r e d  i nt o    wit h  t h e  s p o ns or  i n 
c o n n e cti o n   wit h t his st u d y.  T h e  i n v esti g at or   will   m ai nt ai n  all r e c or ds  a n d  d o c u  m e nts  p ert ai ni n g t o 
t h e st u d y i n cl u di n g,  b ut  n ot li  mit e d t o, t h os e  o utli n e d  a b o v e (s e e S e cti o n  1 4. 2. 4 ) f or  a  p eri o d  of:  at 
l e ast  2  y e ars  aft er  F  D  A  a p pr o v al of t h e  dr u g  or  at l e ast  2  y e ar s  aft er   wit h dr a  w al  of t h e I  N  D  u n d er 
w hi c h t his st u d y   w as  c o n d u ct e d,   w hi c h e v er is l o n g er. I n  c o u ntri  es  o utsi d e t h e   U S, r e c or ds   m ust  b e 
k e pt f or t h e  p eri o d  of ti  m e r e q uir e d  b y t h e   U S  F  D  A  as  a   mi ni  m u  m ,  a n d r e c or d r et e nti o n  s h o ul d 
als o  c o  m pl y   wit h t h e l o c al  c o u ntr y r e g ul at or y r e q uir e  m e nts, if l o n g er r et e nti o n ti  m es  ar e r e q uir e d 
t h a n i n t h e   U S.    M a n d at or y  d o c u  m e nt ati o n i n cl u d es  c o pi es  of  st u dy  pr ot o c ols  a n d  a  m e n d  m e nts, 
fi n a n ci al   dis cl os ur es,   e a c h   F  D  A   F or  m   1 5 7 2,  I  R  B/I E  C   a p pr o v al  l ett ers,   si g n e d  I  C Fs,   dr u g 
a c c o u nt a bilit y  r e c or ds,  S  A E  f or  ms  tr a ns  mitt e d  t o    Ast e x  P h ar  m a c e uti c als,  s u bj e ct  fil es  (s o ur c e 
d o c u  m e nt ati o n)  t h at  s u bst a nti at e  e ntri es  i n   C  R F/ e  C  R Fs,  all  r el e v a nt  c orr es p o n d e n c e,  a n d  ot h er 
d o c u  m e nts  p ert ai ni n g t o t h e  c o n d u ct  of t h e  st u d y.   T h es e  r e c or ds    m ust  r e  m ai n i n  e a c h  s u bj e ct's 
st u d y fil e  a n d  b e  a v ail a bl e f or   v erifi c ati o n  b y st u d y   m o nit ors at  a n y ti  m e. 
T h e  i n v esti g at or    m ust  i nf or  m  t h e  s p o ns or  i  m  m e di at el y  if  a n y  d o c  u  m e nts  ar e  t o  b e  d estr o y e d, 
tr a nsf err e d t o  a  diff er e nt f a cilit y,  or tr a nsf err e d t o  a  diff ere nt  o  w n er.  T h e s p o ns or s h o ul d  b e  gi v e n 
t h e  o pti o n  of  c oll e cti n g t h e  d o cu  m e nts  b ef or e  d estr u cti o n. 
1 4. 3      Cli ni c al   T ri al I ns u r a n c e 
Cli ni c al tri al i ns ur a n c e  h as  b e e n  u n d ert a k e n  a c c or di n g t o t h e l  a  ws  of t h e  c o u ntri es   w h er e t h e st u d y 
will  b e c o n d u ct e d.   A n i ns ur a n c e c ertifi c at e   will  b e   m a d e a v ail a  bl e t o t h e  p arti ci p ati n g st u d y c e nt ers 
u p o n r e q u est. 
1 4. 4      St u d y   A d  mi nist r ati v e   L ett e rs   a n d  P r ot o c ol   A  m e n d  m e nts 
Ast e x  P h ar  m a c e uti c als   m a y iss u e  St u d y   A d  mi nistr ati v e  L ett ers ( 1  ) t o  cl arif y  c ert ai n st at e  m e nts  or 
c orr e ct  o b vi o us  err ors /t y p os/i n c o nsist e n ci es i n t h e  st u d y  pr ot oc ol, ( 2) t o  c h a n g e t h e l o gisti c al  or 
a d  mi nistr ati v e  as p e cts  of  t h e  st u d y,  s u c h  as  st u d y  p ers o n n el  or  c o nt a ct  i nf or  m ati o n,  or  ( 3)  t o 
i nstr u ct   i n v esti g at ors   of     D at a   S af et y    R e vi e  w    C o  m  mitt e e   s af et y   de cisi o ns   f or   i  m  m e di at e 
i  m pl e  m e nt ati o n f or s af et y r e as o ns. 
F or  all  ot h er  c h a n g es,   Ast e x  P h ar  m a c e uti c als   will i niti at e  a n y  c h a n g e t o t h e  pr ot o c ol i n  a  pr ot o c ol 
a  m e n d  m e nt  d o c u  m e nt.  T h e st u d y  c e nt er   will s u b  mit t h e  a  m e n d  m e nt  t o t h e I  R  B/I E  C t o g et h er   wit h, 
if  a p pli c a bl e,  a  r e vis e d    m o d el  I  C F.  If  t h e  c h a n g e  i n  a n y   w a y  i ncr e as es  t h e  ris k  t o  t h e  s u bj e ct, 
i nf or  m ati o n  o n t h e i n cr e as e d ris k   m ust  b e  pr o vi d e d t o s u bj e cts alr e a d y  a cti v el y  p arti ci p ati n g i n t h e 
st u d y,  a n d t h e y   m ust r e a d,  u n d ers t a n d  a n d si g n  a n y r e vis e d I  C F c o nfir  mi n g   willi n g n ess t o r e  m ai n 
i n t h e st u d y. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 7 
1 9  J a n u a r y  2 0 1 8  
T h e   i n v esti g at or     m ust   o bt ai n   I R  B/I E  C   a p pr o v al   b ef or e   a n y   pr ot o c  ol   a  m e n d  m e nt   c a n   b e 
i  m pl e  m e nt e d,  e x c e pt f or  a d  mi nistr ati v e  c h a n g es  or  c h a n g es  n e c ess ar y t o  eli  mi n at e  a n i  m  m e di at e 
ris k t o st u d y s u bj e cts,  as  o utli n e d  a b o v e. 
1 5. 0      P  O  LI  C  Y  F  O  R  P  U  B  LI  C  A  TI  O  N   A N  D  P  R  E S  E  N  T  A  TI  O  N   O F   D  A  T  A 
T h e s p o ns or  e n c o ur a g es t h e s ci e n tifi c  p u bli c ati o n  of  d at a fr o  m cli ni c al r es e ar c h st u di es.   H o  w e v er, 
i n v esti g at ors    m a y  n ot  pr es e nt  or  p u blis h  p arti al  or  c o  m pl et e  st u d y  r es ults  i n di vi d u all y   wit h o ut 
r e vi e  w  b y  t h e  s p o ns or.   T h e  pri n cip al  i n v esti g at ors  a n d  t h e  s p o n s or    m a y  pr o p os e  a p pr o pri at e 
s ci e ntifi c   m a n us cri pts  or  a bstr a cts fr o  m t h e st u d y  d at a.  T h e s p o ns or   m ust r e vi e  w  a n d  c o  m  m e nt  o n 
all  pr o p os e d  p u bli c ati o ns  b ef or e  s u b  missi o n f or  p u bli c ati o n.  T h e  d et ail e d  pr o c e d ur es f or t h e r e vi e  w 
of  p u bli c ati o ns ar e s et  o ut i n t h e cli ni c al tri al a gr e e  m e nt e nt er e d i nt o   wit h t h e s p o ns or i n c o n n e cti o n 
wit h t his st u d y.  T h es e  pr o c e d ur es  ar e i n  pl a c e t o  e ns ur e  c o or di  n ati o n  of st u d y  d at a  p u bli c ati o n  a n d 
a d e q u at e r e vi e  w  of  d at a f or  p u bl i c ati o n  a g ai nst t h e  v ali d at e d  st u d y  d at a b as e f or  a c c ur a c y.   N a  m es 
of  all i n v esti g at ors  a n d  s p o ns or  r e pr es e nt ati v es r es p o nsi bl e f or  d esi g ni n g t h e  st u d y  a n d  a n al y zi n g 
t h e r es ults   will  b e i n cl u d e d i n t h e  p u bli c ati o n(s). 
Q u alifi c ati o n  of a ut h ors hi p   will f oll o  w t h e r e q uir e  m e nts  of t h e   I nt er n ati o n al  C o  m  mitt e e  of   M e di c al 
J o ur n al  E dit ors (  w  w  w.i c  mj e. or g). I n   m ost  c as es, t h e  pri n ci p al i n v esti g at ors  at t h e   c e nt ers   wit h t h e 
hi g h est  p arti ci p ati o n i n t h e st u d y s h all  b e list e d  as l e a d  a ut h ors  o n   m a n us cri pts  a n d r e p orts  of st u d y 
r es ults.  I n  a d diti o n,  ot h er  t h a n  cli ni c al  p h ar  m a c ol o g y  st u di es  i n  h e alt h y  v ol u nt e ers  or  P h as e  1 
st u di es,  all  cli ni c al st u di es   m ust  b e r e gist er e d   wit h   Cli ni c al T ri als. g o v. 

Ast e x  P h a r  m a c e uti c als, I n c. 
 
G u a d e cit a bi n e 
Cli ni c al  P r ot o c ol  S  GI- 1 1 0- 1 2  
C o nfi d e nti al I nf o r  m ati o n 
3 8 
1 9  J a n u a r y  2 0 1 8  
1 6. 0      R  E F  E  R  E  N  C  E S 
Cli ni c al    Tri al   F a cilit ati o n    Gr o u p  (  C T F  G).    R e c o  m  m e n d ati o ns    R el at  e d  t o    C o ntr a c e pti o n   a n d 
Pr e g n a n c y       T esti n g     i n       Cli ni c al       Tri als.      2 0 1 4.      htt p://  w  w  w. h  m a. e u/f il e a d  mi n/ d at ei e n/ 
H u  m a n _  M e di ci n es/ 0 1-  A b o ut _  H  M  A  /   W or ki n g _  Gr o u ps/  C T F  G/ 2 0 1 4 _ 0 9 _  H  M  A _  C TF  G _ 
C o ntr a c e pti o n. p df 
D a c o g e n ®  [ p a c k a g e i ns ert].  2 0 1 4.  R o c k vill e,   M  D:   Ots u k a   A  m eri c a  P h ar  m a c euti c al, I n c.   A v ail a bl e 
at  htt p://  w  w  w. d a c o g e n. c o  m/. 
D a c o g e n ®  [s u  m  m ar y  of  pr o d u ct  c h ar a ct eristi cs].  2 0 1 5.   B el gi u  m:  J a nss e n-  Cil a g I nt er n ati o n al   N  V. 
A v ail a bl e  at:  htt p://  w  w  w. e  m a. e ur o p a. e u/ e  m a/. 
G or e   S  D.  I n  vitr o  b asis  f or  tr e at  m e nt    wit h  h y p o  m et h yl ati n g  a g e n  ts  a n d  hist o n e  d e a c et yl as e 
i n hi bit ors:  c a n  e pi g e n eti c  c h a n g es  b e  us e d t o   m o nit or tr e at  m e nt ?  L e u k  R es.  2 0 0 9;  3 3( S u p pl  2): S 2-
S 6. 
Iss a  J- P,   R o b o z   G,   Ri z zi eri   D,  Ja b b o ur  E,  St o c k    W,   O’  C o n n ell   C,   et  al.  S af et y  a n d t ol er a bilit y  of 
g u a d e cit a bi n e ( S  GI- 1 1 0) i n  p ati e nts   wit h   m y el o d ys pl asti c s y n dr o m e a n d a c ut e   m y el oi d l e u k a e  mi a: 
a   m ulti c e ntr e, r a n d o  mis e d,  d os e- es c al ati o n  p h as e  1 st u d y.  L a n c e t   O n c ol.  2 0 1 5; 1 6( 9): 1 0 9 9 – 1 1 1 0. 
K a nt arji a n   H  M,   R o b o z   GJ,   Kr o pf  P L,   Y e e   K   W L,   O’  C o n n ell   C L,   Ti b es     R,  et  al.   G u a d e cit a bi n e 
( S  GI- 1 1 0)  i n  tr e at  m e nt- n ai v e  p ati e nts    wit h  a c ut e    m y el oi d  l e u k a emi a:   p h as e   2  r es ults  fr o  m  a 
m ulti c e ntr e, r a n d o  mis e d,  p h as e  1/  2 tri al.  L a n c et   O n c ol.  2 0 1 7; 1 8: 1 3 1 7- 1 3 2 6. 
R o b o z   GJ,   K a nt arji a n   H,   Y e e   K   W L,   Kr o pf  P L,   O’  C o n n ell  C L,   Griffi  t hs  E  A,  et  al.   D os e, s c h e d ul e, 
s af et y,  a n d  effi c a c y  of  g u a d e cit a bi n e  i n  r el a ps e d  or  r efr a ct or y   a c ut e   m y el oi d  l e u k e  mi a.   C a n c er 
2 0 1 8; 1 2 4: 3 2 5 – 3 3 4. 
St e e ns  m a   D P.   D e cit a bi n e tr e at  m e nt   of  p ati e nts   wit h  hi g h er-ris k m y el o d ys pl asti c s y n dr o  m es.  L e u k 
R es.  2 0 0 9; 3 3( S u p pl  2): S 1 2- S 1 7. 
Y o d ai k e n   R E,   B e n n ett   D.   O S  H  A   w or k- pr a cti c e  g ui d eli n es  f or  p ers o  n n el  d e ali n g   wit h  c yt ot o xi c 
( a nti n e o pl asti c)   dr u gs.    O c c u p atio n al   S af et y  a n d    H e alt h    A d  mi nist r ati o n.    A  m  J    H os p   P h ar  m. 
1 9 8 6; 4 3( 5): 1 1 9 3- 1 2 0 4.