Conditions: Acute Myeloid Leukemia Myeloid Dysplastic Syndrome
Keywords: Guadecitabine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
This is a multicenter, open-label extension study for participants who participated in a previous Astex-sponsored guadecitabine clinical study \[including but not limited to SGI-110-01 (NCT01261312), SGI-110-04 (NCT02348489), SGI-110-06 (NCT02920008), and SGI-110-07 (NCT02907359)\].

Detailed description:
Participants who were still receiving treatment with guadecitabine and in the opinion of the investigator were still benefitting from treatment at the time of database close of the original study will be eligible to participate in this extension study. Approximately 250 subjects could be enrolled.

Participants will attend clinic visits on Days 1-5 of each 28-day cycle to receive treatment with guadecitabine. Data collection will be limited to treatment exposure, adverse events, concomitant medications, limited laboratory parameters, and survival status.

Arms:
arm 1: Participants received guadecitabine, subcutaneous (SC) injection on Days 1-5 of each 28-day cycle at the same dose that they were receiving in the last cycle of their prior study or at a different dose as guided by the dose adjustment guidelines in the prior study protocol.

Interventions: intervention 1: Guadecitabine
Intervention descriptions: intervention 1: Guadecitabine

Protocol document:
Prot_000.pdf: 
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.  

SAP_001.pdf: 
Official Title: 
An Open-label, Multicenter, Extension Study for Subjects who Participated
in Prior Guadecitabine Clinical Studies
NCT Number: 
 NCT03603964
Document Date: 
Statistical Analysis Plan Version: 03 November 2021


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STATISTICAL ANALYSIS PLAN 
Protocol Title: 
An Open-Label, Multicenter, Extension Study for Subjects Who 
Participated in Prior Guadecitabine Clinical Studies 
Protocol Number: 
SGI-110-12 
Phase: 
2 
Compound Number: 
Guadecitabine 
Sponsor Name: 
Astex Pharmaceuticals, Inc. 
Legal Registered 
Address: 
4420 Rosewood Drive, Suite 200 
Pleasanton, CA 94588 
Regulatory Agency Identifier Number(s): 
IND Number: 
EudraCT Number: 
102743 
2017-004603-52 
Approval Date: 
03 November 2021 (Version 1.0) 
CONFIDENTIAL 
This document is a confidential communication of Astex Pharmaceuticals, Inc. Acceptance of the document 
constitutes agreement by the recipient that the contents will not be disclosed to any unauthorized personnel without 
the prior written authorization of Astex Pharmaceuticals, Inc. 


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Statistical Analysis Plan – SGI-110-12 
TABLE OF CONTENTS 
VERSION HISTORY .................................................................................................................... 3 
1.0 
INTRODUCTION .............................................................................................................. 4 
1.1 
Objectives and Endpoints ......................................................................................... 4 
1.2 
Study Design ............................................................................................................ 4 
2.0 
STATISTICAL HYPOTHESES ....................................................................................... 5 
3.0 
SAMPLE SIZE DETERMINATION ............................................................................... 5 
4.0 
ANALYSIS SETS ............................................................................................................... 5 
5.0 
STATISTICAL ANALYSES .............................................................................................. 5 
5.1 
General Considerations ............................................................................................ 5 
5.2 
Participant Dispositions ............................................................................................ 6 
5.3 
Primary Endpoint(s) Analysis .................................................................................. 6 
5.4 
Secondary Endpoint Analysis .................................................................................. 6 
5.4.1 
Key/Confirmatory Secondary Endpoint .................................................. 6 
5.4.1.1 
Definition of Endpoint(s) ................................................................. 6 
5.4.1.2 
Main Analytical Approach ............................................................... 6 
5.5 
Safety Analyses ........................................................................................................ 7 
5.5.1 
Extent of Exposure .................................................................................. 7 
5.5.2 
Adverse Events ........................................................................................ 7 
5.5.3 
Additional Safety Assessments (if applicable) ........................................ 8 
5.6 
Interim Analyses ...................................................................................................... 8 
6.0 
SUPPORTING DOCUMENTATION ................................................................................ 9 
6.1 
Appendix 1: List of Abbreviations ........................................................................... 9 
6.2 
Appendix 2: Changes to Protocol-planned Analyses ............................................... 9 
6.3 
Appendix 3: Non-key Analysis Specifications ....................................................... 10 
7.0 
REFERENCES ................................................................................................................. 10 


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VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study SGI-110-12 is based on the protocol dated 
19JAN2018. 
SAP Version 
Approval Date 
Change 
Rationale 
1.0 
03NOV2021 
Not Applicable 
Original version 


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Statistical Analysis Plan – SGI-110-12 
 
1.0 
INTRODUCTION 
 
The purpose of this document is to provide details of the planned analyses for SGI-110-12 study. 
The analyses conducted to support the primary objectives will focus on safety data, in particular 
adverse events. Efficacy data will also be evaluated to obtain long-term survival information. 
 
Descriptions of the planned summaries and analyses of non-key study data such as baseline 
characteristics and demographics, important protocol deviations, and other items not critical for 
regulatory needs, can be found in Appendix 3 (Non-key Analysis Specifications). 
 
Specifications for data tables, listings and figures are detailed in a separate document. 
 
1.1 
Objectives and Endpoints 
 
 
Objectives 
Endpoints 
Primary 
• 
To provide ongoing treatment with 
Guadecitabine for subjects who benefitted 
from guadecitabine treatment in a previous 
Astex-sponsored clinical study and to obtain 
long-term safety information. 
• 
Safety as measured by adverse events 
Secondary 
• 
To obtain long-term survival information on 
subjects who participated in a previous Astex- 
sponsored guadecitabine clinical study. 
• 
Overall Survival 
 
1.2 
Study Design 
 
This is a multicenter, open-label extension study for subjects who participated in a previous Astex- 
sponsored guadecitabine clinical study (including but not limited to SGI-110-01, SGI-110-04, 
SGI-110-05, SGI-110-06, and SGI-110-07). 
 
Subjects who were still receiving treatment with guadecitabine and in the opinion of the 
investigator were still benefitting from treatment at the time of database close of the original study 
will be eligible to participate in this extension study. Approximately 250 subjects could be 
enrolled. 
 
Subjects will attend clinic visits on Days 1-5 of each 28-day cycle to receive treatment with 
guadecitabine. Data collection will be limited to treatment exposure, adverse events, concomitant 
medications, limited laboratory parameters, and survival status. 
 
There is no predetermined schedule of analyses for this study. Analyses could have been performed 
during the course of the study depending on the needs of the clinical development program. The 
analyses described in the SAP are conducted at the conclusion of the study. 


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2.0 
STATISTICAL HYPOTHESES 
 
The primary focus of the study is to offer continued guadecitabine treatment to subjects who are 
benefiting from the treatment and to collect the safety information of guadecitabine. No formal 
statistical hypotheses will be tested in the analysis of the trial data. All analyses will be descriptive 
in nature. 
3.0 
SAMPLE SIZE DETERMINATION 
 
The sample size for this extension study was based on the eligible subjects from prior 
guadecitabine studies. No formal sample size justification was necessary. 
4.0 
ANALYSIS SETS 
 
For purposes of analysis, the following analysis sets are defined: 
 
Analysis Set 
Description 
All Subjects 
All screened subjects, including those who did not meet the study 
entry criteria or did not receive a study treatment. 
Safety 
All subjects who receive any amount of study treatment. 
Efficacy 
All subjects who receive any amount of study treatment. 
 
5.0 
STATISTICAL ANALYSES 
5.1 
General Considerations 
 
No formal statistical hypotheses will be tested. All analyses will be descriptive in nature. 
 
Continuous variables will be summarized with mean, standard deviation, median, minimum, and 
maximum. Categorical variables will be summarized with counts and percentages. The SAS® 
statistical package (version 9.4 or a later version) will be used for the analyses. 
 
Summary tables of efficacy, and safety data will be provided. 
 
Summaries of disposition will be based on the All Subjects analysis set (all screened subjects). 
Demographics and baseline characteristics, as well as efficacy summaries will be based on the 
Efficacy analysis set. Safety summaries will be based on the Safety analysis set. In this study, the 
Safety and Efficacy analysis sets are identically defined. 
 
Unless otherwise specified, the baseline value is defined as the last value collected prior to 
initiation of the study treatment in the SGI-110-12 study. For variables which are collected on 
Day 1 of Cycle 1 (C1D1) without explicit timing, the C1D1 values will be used as the baseline 
values. 


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Month is defined as 30.4375 days for analyses conducted in this study. 
 
Study day of an SGI-110-12 subject is defined in reference to the subject’s C1D1 date in 
SGI-110-12 and calculated following the data programming standards as detailed in 
BDM Manual 02 - Astex Data Programming Standards. 
 
Laboratory values recorded as an interval such as “≥x”, “<x”, or “2+” or recorded as below the 
limit of quantification (BLQ) will be handled, if necessary, for calculation purposes, following the 
data programming standards as detailed in BDM Manual 02 - Astex Data Programming Standards. 
 
Incomplete medication and AE start and stop dates will be imputed conservatively following the 
data programming standards as detailed in BDM Manual 02 - Astex Data Programming Standards. 
5.2 
Participant Dispositions 
 
The number and percentage (n, %) of subjects screened, enrolled (by prior study), treated, 
treatment discontinuation (with reason) and withdrawn from study (with reason) will be 
summarized. All screened subjects will be included in the disposition analysis. 
5.3 
Primary Endpoint(s) Analysis 
 
The primary endpoint is safety as measured by adverse events. Please refer to Section 5.5.2 
Adverse Events for the detail analyses. 
5.4 
Secondary Endpoint Analysis 
5.4.1 
Key/Confirmatory Secondary Endpoint 
 
Long-term overall survival is a secondary endpoint. Survival duration for each subject starting 
from the time of randomization in the prior study will be determined. 
5.4.1.1 
Definition of Endpoint(s) 
 
Overall Survival (OS) 
 
Overall survival is defined as time, in days, from the time of randomization in the prior study to 
the date of death (regardless of cause). Subjects without a documented death date at the time of 
analysis will be censored at the last date known alive. 
 
Survival time in days = (earliest of date of death or censoring – randomization date in the prior 
study) 
5.4.1.2 
Main Analytical Approach 
 
The OS curves will be estimated using the Kaplan-Meier method (Kaplan et al 1958). The median 
(and quartiles) duration of OS and the associated 95% CI (based on the log-log transformation for 
the survival function) will also be generated. 


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In addition, OS curves will also be estimated using the Kaplan-Meier method by the disease types 
(treatment-naive AML, relapse/refractory AML, and relapse/refractory intermediate- or high-risk 
MDS (including CMML). The median (and quartiles) duration of OS and the associated 95% CI 
(based on the log-log transformation for the survival function) will be generated for each group of 
the disease types. 
5.5 
Safety Analyses 
5.5.1 
Extent of Exposure 
 
Exposure to guadecitabine will be summarized by numbers of treatment cycles received, delayed, 
as well as duration of exposure (in months) in the SGI-110-12 study. These measures of exposure 
will be based on dose administrations and dose delays identified by the study site and collected on 
the SGI-110-12 study drug administration CRFs. Duration of exposure, in months, is defined as 
the last treatment date minus the first date of treatment + 1 divided by 30.4375. 
 
Dose intensity, presented as the incidence of subjects receiving <80% of their intended dose, will 
be summarized by cycle. Dose intensity will be calculated as the actual total dose divided by 
planned total dose for each treatment cycle. 
 
Both completed or partially completed dose cycles are counted in these summaries. 
 
5.5.2 
Adverse Events 
 
Adverse event (AE) terms reported by study subjects or observed by investigators will be mapped 
to the appropriate system organ class (SOC) and preferred term (PT) according to the MedDRA 
version 21.0. Severity of AE will be graded by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
 
Treatment-emergent AEs (TEAEs) are defined as events that occur or worsen on or after the date 
of the first study treatment (C1D1) until 30 days after the last dose of study treatment or the start 
of an alternative anti-cancer treatment, whichever occurs first. SAEs that occur more than 30 days 
beyond the last dose of study treatment or the start of an alternative anti-cancer treatment will also 
be considered treatment-emergent if the event is related to the study treatment. 
 
An overall safety summary table containing counts and percentages of subjects with any TEAE, 
any TEAE Grade ≥3, TEAE resulting in permanent treatment discontinuation, TEAE resulting in 
drug interruption, TEAE resulting in dose reduction, any serious AE (SAE), and subcategories of 
SAEs (fatal and non-fatal) will be produced. Related TEAEs will be similarly summarized. Related 
events are those that the investigator considered to be suspected to be related to study treatment as 
described in the study protocol. 
 
The number and percentage of subjects experiencing TEAEs will be summarized by MedDRA 
SOCs (sorted alphabetically) with PTs sorted by decreasing frequency within each SOC. Related 
TEAEs, TEAEs Grade ≥3, related TEAEs Grade ≥3, serious TEAEs, related serious TEAEs, AEs 


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with a fatal outcome, AEs resulting in permanent treatment discontinuation, AEs resulting in drug 
interruption, and TEAEs resulting in dose reduction will be summarized similarly. In addition, 
TEAEs, related TEAEs, and SAEs will be summarized by SOC, PT, and CTCAE grade where 
subjects with multiple occurrences of the same TEAE will be counted once based on the highest 
CTCAE grade. 
 
All AE data collected in the study database will be listed, including those that are not treatment 
emergent. 
5.5.3 
Additional Safety Assessments (if applicable) 
Laboratory Data 
Laboratory values will be graded, if relevant and possible, by CTCAE version 4.03 in conjunction 
with the Harrison (18th edition) lab book normal values (Longo et al 2011). 
 
Shift tables will display (1) shift from baseline grade to the worst grade during the study, and 
(2) shift from baseline grade to the last grade at the end of study. 
 
Summaries will also be provided of the incidence of all new or worsening laboratory abnormalities 
(any CTCAE grade) and new or worsening CTCAE Grade ≥3 laboratory abnormalities by 
parameter. 
 
A listing of potential Hy’s Law cases will be provided. 
 
In addition, for selected laboratory parameters, a figure of mean values by visit will be generated. 
 
5.6 
Interim Analyses 
 
No interim analysis will be performed for this study. Data summaries may be provided during the 
course of the study to meet the needs of the clinical development program. 


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6.0 
SUPPORTING DOCUMENTATION 
6.1 
Appendix 1: List of Abbreviations 
 
Abbreviation 
Definition 
AE 
adverse event 
AML 
acute myeloid leukemia 
BDM 
biostatistics and data management 
CI 
confidence interval 
CTCAE 
Common Terminology Criteria for Adverse Events 
CMML 
chronic myelomonocytic leukemia 
MDS 
myeloid dysplastic syndromes 
MedDRA 
medical dictionary for regulatory activities 
OS 
Overall Survival 
PT 
preferred term 
SAE 
serious adverse event 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 
 
6.2 
Appendix 2: Changes to Protocol-planned Analyses 
 
Overall survival definition is changed from 
 
“Time, in days, from the time of the first dose of Guadecitabine in the prior study to the date of 
death” 
 
to 
 
“Time, in days, from the time of randomization in the prior study to the date of death”. 
 
All subjects enrolled in the SGI-110-12 study were from the prior studies involving randomization. 
These prior studies used the randomization date as the start date for overall survival. The change 
of the SGI-110-12 start time of the overall survival from the first dose of Guadecitabine to the date 
of randomization is to maintain the definition consistence between SGI-110-12 and the prior 
randomized studies. 
 
In addition, overall survival analysis by disease types is added. 


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6.3 
Appendix 3: Non-key Analysis Specifications 
 
Demographics and Other Baseline Characteristics 
 
Subject demographics (age, sex, etc.) and baseline characteristics (total WBC counts, disease 
types, etc.) will be summarized using descriptive statistics. 
 
Concomitant Medications 
 
Medications will be coded by the WHO Drug Dictionary WHO-DDE B2 March 2018. 
 
Concomitant medications are the medications taken with a start date on or after the start of the 
administration of study treatment (C1D1), or those with a start date before the start of the 
administration of study treatment (C1D1) and a stop date on or after the start of the administration 
of study treatment (C1D1). Medications taken beyond 30 days from the last dose of study treatment 
or after the start of an alternative anti-cancer (study disease only) treatment are not considered 
concomitant medications, unless they are used for treating a related SAE. 
 
Concomitant medications will be summarized by WHO Drug’s Therapeutic Subgroup (ATC 
level 2) and Who Drug Name, sorted alphabetically, using counts and percentages. 
 
 
7.0 
REFERENCES 
 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53(282):457–481. 
 
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison's Principles of 
Internal Medicine, 18th edition. New York: McGraw-Hill, 2012.