Randomized, Double-Blind, Placebo-Controlled Study With Open-Label Extension to Evaluate the Efficacy and Safety of Avatrombopag for the Treatment of Chemotherapy-Induced Thrombocytopenia in Subjects With Active Non-Hematological Cancers
Phase: PHASE3
Conditions: Chemotherapy-induced Thrombocytopenia
Sponsor: Sobi, Inc.

C LI NI C A L  ST U D Y P R O T O C O L  
A R a n d o mize d, D o u ble- Bli n d, P l ac e b o-C o ntr olle d St u d y Wi t h a n 
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T hr o m b oc yt o pe ni a i n S u bjects Wit h Acti ve N o n- He m at ol o gic al 
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S Y N O P SI S  
TI T L E:   A  Ra n d o mize d,  D o u ble -Bli n d,  Place b o -C o ntr olle d  St u d y  W it h  a n  O pe n-La bel 
E xte nsi o n  t o  E val uate  t he  Efficac y  a n d  Saf et y  of  A vatr o m b o pa g  f or  t he  Treat me nt  of  
C he m ot hera p y -I n d u ce d T hr o m b oc yt o p e nia i n S u bjects Wit h Acti ve N o n-He mat ol o gi cal Ca ncers  
P R O T O C O L N U M B E R:   A V A -CI T - 3 3 0 
I N V E S TI G A TI O N A L P R O D U C T:  A vatr o m b o pa g t a blets 
P H A S E:   3 
I N DI C A TI O N( S):  Tr eat me nt of c he m ot hera p y-i n d uce d t hr o m b oc yt o pe ni a ( CI T) 
O B J E C TI V E S:  
T he pri mar y o bjecti ve of t his st u d y is t o e val uat e t he efficac y of a v atr o m b o pa g i n i n creasi n g 
platelet c o u nts a n d t heref ore pre v e nti n g t he nee d f or a platelet tra nsf usi o n or c he m ot hera p y d ose 
re d uctio n or del a y i n s u bjects wit h CI T. 
T he sec o n d ar y o bjecti ves of t his st u d y are t he f oll o wi n g:  
•  T o e val uate t he s afet y of a vatr o m b o pa g i n s u bjects wit h CI T, a n d 
•  T o i n vesti gate t h e effect of a vatr o m b o pa g o n bl ee di n g i n s u bjects wit h CI T. 
P O P U L A TI O N:  
I ncl usi o n Criteri a  f or All S u bjects 
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o partici pate i n t he st u d y:  
1.  S u bject is ≥1 8 years of a ge at t he ti me of i nf or me d c o nse nt; 
2.  S u bject wit h a dia g n o sis wit h o vari a n  ca ncer, l u n g ca n cer (s mall cell or n o n-s mall cell), or 
bla d der ca ncer, re q uiri n g s yste mic c h e m ot hera p y; 
3.  S u bject is c urre ntl y r ecei vi n g a c h e m ot hera p y re gi me n gi ve n i n a 2 1 -d a y  or 2 8- da y c ycle ( ot her 
c he m ot hera p y c ycl e le n gt hs are n ot all o w e d), i ncl u di n g 1 or m ore of t he f oll o wi n g a ge nts  or 
class of a ge nts : 
o  N ucle osi de a n al o g, i n cl u di n g ge mcita bi n e a n d fl u or o uracil; 
o  Car b o plati n or cis plati n; 
o  A nt hrac ycli ne;  or  
o  Al k ylati n g a ge nt;  
4.  S u bject  e x perie nce d  se v ere t hr o m b oc yt o pe nia,  d efi ne d  as  2 pl atelet   c o u nts  < 5 0 ×   1 09/ L 
meas ure d at least 2 4 h o urs a part, d uri n g t h e q ualif yi n g c h e m ot hera p y c ycl e ( C ycle X), of t heir 
c urre nt c h e m ot hera p y r e gi me n . Platelet c o u nts o btai ne d per sta n dar d of care d uri n g C ycle X 
pri or t o c o nse nt ma y be use d; 

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5.  S u bject  is  pla n ne d to r ecei ve  t he  sa m e  c h e m ot hera p y re gime n  a n d  t he  sa me  d ose(s)  o n  
C he m ot hera p y Da y ( Da ys 1 -3) of C ycl e X + 1 as was gi v e n i n t he q ualif yi n g c he m ot hera p y 
C ycle X;  
6.  S u bject has a n Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G) perf or ma n ce stat us ≤2; 
7.  S u bject has a life  e x pecta nc y > 1 2 w ee ks at Scree ni n g  a n d is a ble t o recei ve at least 2 a d diti o nal 
c ycles of t he c urr e nt c he m ot hera p y re gi me n ; 
8.  Fe males of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
(e g, t otal a bsti ne nce; a n i ntra uteri ne d e vice; h or m o nal c o ntra ce pti ve gi ve n orall y, b y i nj ecti o n , 
or b y i m pla nt; d o u ble barrier c o ntrace pti o n (i.e., c o n d o m + dia p hra g m) ; or has a vasect o mize d 
part ner wit h c o nfir m e d az o os per mia)  t hr o u g h o ut t he e ntire st u d y p eri o d a n d f or 3 0 da ys after 
i n vesti gati o nal pr o d uct (I P)  disco nti n uati o n. If c urre ntl y a bsti ne nt, t he s u b j ect m ust a gree t o 
use a n effecti ve met h o d as descri b e d a b o ve if s h e bec o mes s e x uall y acti ve d uri n g t he st u d y 
peri o d or f or 3 0 d a ys aft er I P disc o nti n uati o n.   
Male s u bjects m ust be eit he r s ur gicall y sterile or agree t o use a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s per mici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n; 
N ote: All fe male s u bjects  are c o nsi dere d t o be of c hil d beari n g p ote ntial  u nless t he y are  
p ost me n o pa usal ( at least 1 2 m o nt hs c o ns ec uti ve a me n orr h ea a n d wit h o ut a n ot her k n o w n or 
s us pecte d ca us e) or ha ve bee n sterilize d s ur gicall y (ie, bilateral t u bal li gati on, h yst erect o m y, 
or bilateral o o p h or ect o m y) at least 1 m o nt h bef ore d osi n g. 
9.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ects of t he pr ot oc ol; a n d  
1 0.  S u bject m ust pr o vi de writte n i nf or me d c o nse nt. 
E xcl usi o n Criteri a f or All S u bjects  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m partici pati o n i n t he st u d y:  
1.  S u bject has e x perie nce d ≥ Gra de 2 CI T wit h a pl atelet c o u nt < 7 5 ×  1 09/ L ( ot her t ha n d uri n g 
t he c urr e nt c he m ot her a p y treat me nt re gi me n) wit hi n 6 m o nt hs of Scree ni n g; 
2.  S u bject has a  platelet c o u nt > 1 7 5 ×  1 09/ L at Visit 2 (- 1 da y); 
3.  S u bject  wit h  a n y  hist or y  of  h e mat ol o gic  mali g na n cies,  i ncl u di n g  le u ke mia,  m yel o ma,  
m yel o pr olif erati ve diseas e, l y m p h o ma, or m yel o d ys plastic diseas es; 
4.  S u bject w h o r ecei v e d > 2 pre vi o us li nes of c h e m ot hera p y (a dj u va nt/ ne o a dj u va nt t hera p y is 
c o nsi dere d a pr e vi o us li ne; i m m u n ot hera p y al o n e is n ot c o nsi dere d a pre vi o us li ne) or is 
recei vi n g w h ole brai n r a diati o n d uri n g t he st u d y treat me nt peri o d; 
5.  S u bject wit h  a n ala ni ne a mi n otra nsferase  ( A L T) or as partate a mi n otra nsferase  ( A S T) > 5 ×  
u p per li mit of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit of n or mal; 
6.  S u bject has a k n o w n me dical hist or y of h u m a n i m m u n o deficie nc y vir us; 
7.  S u bject has a n y k n o w n cli nicall y si g nifica nt ac ute or acti ve blee di n g (e g, gastr oi ntesti nal or 
ce ntral ner v o us s yste m) wit hi n 7 da ys of Scree ni n g;  

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8.  S u bject has a k n o w n me dical hist or y of ge netic pr ot hr o m b otic s y n dr o mes  (e g, Fact or V 
Lei d e n, pr ot hr o m bi n G 2 0 2 1 0 A, or A TIII defi cie n c y);  
9.  S u bject has a rece nt hist or y ( wit hi n 3 m o nt hs of Scree ni n g) of si g nifica nt car di o vas c ular 
disease ( e g, c o n gesti ve h eart f ail ure e x acer bati o n , arr h yt h mia k n o w n t o i n creas e t he ris k of 
t hr o m b oe m b olic e ve nts [ e g, atri al fi brillati o n], c or o nar y arter y ste nt place me nt, a n gi o plast y, 
or c or o nar y art er y b y pass gr aft);  
1 0.  S u bject has a hist or y of arterial or ve n o us t hr o m b osis wit hi n 3 m o nt hs of Scree ni n g; 
1 1.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of Scree ni n g ( us e of l o w m olec ular 
wei g ht h e pari n , X a i n hi bit ors, or t hr o m bi n i n hi bit ors is all o we d); 
1 2.  S u bject has a hist or y of c hr o nic platelet or bl ee d i n g dis or d ers or t hr o m b o c yt o pe nia d ue t o a n 
eti ol o g y ot her t ha n CI T ( e g, c hr o nic li ver disease or i m m u ne t hr o m b oc yt o p e nia p ur p ura); 
1 3.  S u bject has use d m o derate or str o n g i n d ucers of c yt o c hr o me P 4 5 0 ( C Y P) 2 C or C Y P 3 A 4/ 5 
(see A p p e n di x C ) wit hi n 7 da ys of Scree n i n g; 
1 4.  S u bject has recei ve d a t hr o m b o p oieti n rece pt or a g o nist (e g, eltr o m b o pa g or r o mi pl osti m) or 
rec o m bi na nt h u ma n t hr o m b o p oieti n f or t he treat me nt of CI T wit hi n 3 m o nt hs of Scree ni n g; 
1 5.  S u bject recei v e d a platel et tra nsf usi o n wit hi n 7 2 h o urs of ra n d o mizati o n; 
1 6.  S u bject is u na ble t o ta ke oral me dicati o n ; 
1 7.  S u bject  has  a n y  hist or y  of  a  c o nc o mita nt  m e dical  c o n diti o n  t hat,  i n  t h e  o pi ni o n  of  t h e  
I n v esti gat or, w o ul d c o m pr o mise t he su bject’s a bilit y t o safel y c o m plete t he st u d y, s uc h as 
u nsta ble a n gi na, re n al fail ure re q uiri n g he m o dial ysis, or acti ve i nfecti o n re q uiri n g i ntra ve n o us 
a nti bi otics; 
1 8.  Fe male  s u bjects  w h o  are  lactati n g  or  pre g na nt  at  Scree ni n g  or  t he  Baseli ne  Visit  (as 
d oc u me nte d b y a p ositi ve ser u m or uri n e  beta -h u ma n c h ori o nic g o na d otr o pi n [ β -h C G] test) ; 
1 9.  S u bje ct has h y p erse nsiti vit y t o a vatr o m b o pa g or a n y of its e x ci pie nts; or  
2 0.  S u bject is c urre ntl y e nr olle d i n a n ot her cli nical st u d y wit h a n y i n v esti gati o n al dr u g or de vi ce 
wit hi n 3 0 da ys of Scree ni n g; h o we v er, p artici pati o n i n o bser vati o nal st u dies is per mitte d. 
I ncl usi o n Criteri a f or S u bjects t o C o nti n ue I nt o t he O pti o n al O pe n-L a bel E xte nsi o n Peri o d  
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o c o nti n ue i nt o t he o pti o nal 
O pe n -La b el E xte nsi o n ( O L E ) Peri o d : 
1.  S u bject is c urre ntl y r ecei vi n g t he sa me c h e m ot hera p y a ge nts as w ere gi ve n i n t he q ualif yi n g 
c he m ot hera p y C ycl e X;  
2.  S u bject has a n E C O G  perf or ma nce stat us ≤2; 
3.  Fe males of c hil d beari n g p ote ntial m ust a g ree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
as pre vi o usl y defi ne d. 
Male s u bjects m us t be eit her s ur gicall y sterile or a gree t o use a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s permici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n;  

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N ote:  Al l  fe male s u bjects  are c o nsi dere d t o be of c hil d beari n g p ote ntial  u nless t he y are  
p ost me n o pa usal (at l east 1 2 m o nt hs c o nsec uti ve a me n orr hea i n t he a p pr o priate a ge gr o u p a n d 
wit h o ut a n ot her k n o w n or s us pecte d ca use) or h a ve bee n sterilize d s ur gicall y (ie, bi lateral t u b al 
li gati o n, h yst erect o m y, or bilateral o o p h orect o m y) at least 1 m o nt h bef ore d osi n g. 
4.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ects of t he pr o t oc ol; a n d  
5.  S u bject m ust pr o vi de c o nse nt t o c o nti n ue i nt o t he O L E Peri o d. 
E xcl usi o n  Criteri a f or S u bjects t o C o nti n ue Int o  t he O pti o n al O pe n-L a bel E xte nsi o n Peri o d  
S u bjects w h o meet a n y of t he f oll o wi n g criteria will be e x cl u de d f r o m c o nti n ui n g i nt o t he o pti o nal 
O L E Peri o d:  
1.  S u bject has a pl atelet c o u nt > 1 7 5 ×  1 09/ L o n t he sc he d ule d first d a y of d os i n g of a v atr o m b o pa g 
pri or t o c he m ot her a p y; 
2.  S u bject wit h a n A L T  or A S T > 5 ×  u p per li mit of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit  of  
n or mal; 
3.  S u bject has  a n y k n o w n cli nicall y si g nifica nt ac ute or acti ve blee di n g (e g, gastr oi ntesti nal or 
ce ntral ner v o us s yste m) wit hi n 7 da ys of pre- c he m ot hera p y I P treat me nt i n O L E c ycles ; 
4.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of pre -c he m ot hera p y I P treat me nt i n 
C ycle X + 3 ( use of l o w m olec ular wei g ht h e pari n , Xa i n hi bit ors, or t hr o m bi n i n hi bit ors  is 
all o we d); 
5.  S u bject has use d m o der ate or str o n g i n d ucers of C Y P 2 C or C Y P 3 A 4/ 5 (see  A p p e n di x C ) 
wit hi n 7 da ys of pre- c he m ot hera p y I P treat me nt i n O L E c ycles ; 
6.  S u bject  is u na ble t o ta ke oral me dicati o n ; 
7.  Fe male s u bjects w h o ar e lactati n g or pre g na nt (as d oc u me nte d b y a  p ositi ve uri ne or ser u m  
test) 
S T U D Y D E SI G N A N D D U R A TI O N:  
T his is a P hase 3 ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of t he efficac y a n d safet y of 
oral a vatr o m b o pa g i n s u bjects wit h CI T wit h acti ve n o n -he mat ol o gical ca n cers. T he st u d y c o nsists 
o f 4 peri o ds: a D o u ble -Bli n d Treat me nt Peri o d , a n O bser vati o nal Peri o d, a n opti o nal O L E  Peri o d , 
a n d a L o n g -T er m  F oll o w- U p Peri o d.  
T o be eli gi ble f or t he st u d y, s u bjects m ust ha ve e x perie nce d  t hr o m b oc yt o p e nia d uri n g t heir c urre nt 
c he m ot hera p y r e gi me n as des cri be d i n t he i ncl usi o n criteria. T he q ualif yi n g c h e m ot hera p y c ycle 
is define d as “ C ycl e X” . S u bjects m ust be scree ne d ≤2 8 da ys pri or t o t he Baseli ne Visit , u nless 
Scree ni n g a n d Baseli ne Visits are perf or me d o n t he sa me da y,  a n d be gi n treat me nt d uri n g C ycl e 
X.  
D o u ble -Bli n d Tre at me nt Peri o d  
At  t he  Bas eli ne  Visit,  eli gi ble  s u bjects  will  be  ra n d o mize d  i n  a  2: 1  rati o  t o  recei ve  eit her  
a vatr o m b o pa g  or  place b o  i n  a  d o u ble -bli n d  ma n ner  pri or  t o  a n d  d uri n g  t he  s u bse q ue nt  
c he m ot hera p y  c ycle,  C ycl e  X  +  1.  Ra n d o mizati o n  will  be  stratifie d  b y  t h e  n u m ber of 
c he m ot hera p y  a ge nts  t he  s u bject  is  recei vi n g ( 1  or  ≥2 per missi ble c he m ot hera p y  a ge nts  
[ n ucle osi de  a nal o g,  i n cl u di n g  ge mcita bi ne  a n d  fl u or o uracil;  car b o plati n  or  cis plati n;  

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a nt hrac ycli n e; or al k yl ati n g a ge nt] ). S u bject s will recei ve eit her a vatr o m b o pa g or place b o o nce 
dail y  f or  5  da ys  pri or  t o  C he m ot hera p y  Da y  i n  C ycle  X  +  1.  S u bjects  will  als o recei ve 
a vatr o m b o pa g  or  place b o  o nce  dail y  f or  5  da ys  i m me diatel y  f oll o wi n g  C he m ot hera p y  Da y.  
C he m ot hera p y Da y is defi ne d per p r ot o c ol as Da y 1 t o 3 of t he s u bject’s c he m ot hera p y re gi me n 
(e g, if c he m ot her a p y is gi ve n o n Da y 1 a n d Da y 2, t he sec o n d r o un d of a v atr o m b o pa g or place b o 
will  start  o n  Da y 3).  A vatr o m b o pa g  or  place b o  will  n ot  be  a d mi nistere d  c o nc urre ntl y wit h  
c he m ot hera p y o n  C he m ot hera p y  D a y.  C he m ot hera p y  re gi me ns  re q uiri n g  d osi n g  b e y o n d  
C he m ot hera p y Da y wit hi n t he 2 1 -da y or 2 8 -da y c ycle (e g, g e mcita bi ne o n Da y 8) are all o we d.  
T hese mi d -c ycle c he m ot hera p y d oses, after I P treat me nt, will be part of t he assess me nt of t he 
c o m posite pri mar y e n d p oi nt f or d ose m o dificati o ns or dela ys. 
O bser v ati o n al Peri o d  
C ycle X + 2 will be a n O bser vati o nal Peri o d. T he O bser v ati o nal Peri o d is desi g n e d   t o e na bl e 
assess me nt of  w het her t he s u bject s meet t he c h e m ot hera p y d ose m o difi cati o ns or d ose  de la y 
c o m p o ne nts of t he co m p osite pri mar y e n d p oi nt  o n C he m ot hera p y Da y w hile  re d u ci n g decisi o n-
ma ki n g bias f or c he m ot h era p y d o se m o dificati o ns or dela ys. S u bjects i n t he O bser vati o nal Peri o d 
will n ot recei ve a n y I P pr e - or p ost-C he m ot hera p y Da y i n C ycl e X + 2. 
F or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d, a F oll o w -U p Visit will occ ur pri or t o 
(wit hi n 3 da ys) C he m ot h er a p y Da y i n C ycle X + 3. F or t h ese s u bjects, t heir partici pati o n i n t he 
O bser vati o nal Peri o d  will c o ncl u de after t h e y c o m plete t he F o ll o w-U p Visit a n d at t hat p oi nt t he y 
will e nter t he L o n g - T er m F oll o w- U p Peri o d. 
If C ycle X + 2 is t he s u bject’s last c h e m ot hera p y c ycle, a F oll o w -U p Visit will occ ur at 3 0 d a ys 
(± 3 da ys) after C he m ot h era p y D a y i n C ycl e X + 2.  
O pti o n al O pe n - L a bel E xte nsi o n Peri o d  
S u bjects w h o c o m plete t he D o u ble -Bli n d Treat me nt Peri o d a n d t he O bser vati o nal Peri o d will be 
eli gi ble t o e nter a n o pti o n al O L E  Peri o d at 5 da ys pri or t o C ycle X + 3 , if t he y f ulfill t he i ncl usi o n 
criteria a n d e x cl usi o n crit eria f or t he o pti o nal O L E Peri o d  a n d re mai n o n t h e sa me c he m ot hera p y 
a ge nts as prescri be d i n C ycle X . S u bjects m ust c onti n ue t o f ulfill the i n cl usi o n a n d e x cl usi o n 
criteria pri or t o pre -c he m ot hera p y a v atr o m b o pa g treat me nt i n eac h e nr olle d o pe n -la b el c ycle t o 
c o nti n ue i n t he O L E Per i o d. 
All s u bjects will recei ve a vatr o m b o pa g o nce dail y f or 5 d a ys pri or t o C he m ot hera p y D a y i n 
C ycle  X + 3 . S u bjects will als o recei ve a vatr o m b o p a g o nce dail y f or 5 da ys i m me diatel y f oll o wi n g 
C he m ot hera p y Da y. A vatr o m b o pa g will n ot be a d mi nistere d c o nc urre ntl y wit h c he m ot hera p y o n 
C he m ot hera p y Da y.  
S u bjects ma y re p eat t his treat me nt se q u e nce a n d c o nti n ue i n t he o pti o nal O L E Peri o d u ntil t he e n d 
of t heir c urre nt c h e m ot hera p y re gi me n.  
S u bjects will ha ve a F oll o w -U p Visit at 3 0 da ys ( ± 3 da ys) after t h e last d ose of a v atr o m b o pa g  
treat me nt of t he s u bject’s last c he m ot hera p y c ycle. 
L o n g -Ter m F oll o w -U p  Peri o d  
After t he F oll o w- U p Visit , all s u bjects will be c o ntacte d a p pr o xi matel y e ver y 6 m o nt hs f or u p t o 
5 years b y tele p h o ne d uri n g t he L o n g -Ter m F oll o w -U p Peri o d f or d oc u me ntati o n of vital stat us 
(if deat h occ urr e d, rec or d of date of d eat h) a n d o cc urre nce of sec o n dar y m ali g na n cies.  

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E n d of St u d y  
T he  e n d  of  st u d y ( “st u d y c o m pleti o n”)  is  defi ne d  as  t he  date  of  t he  last  pr ot oc ol-s pecifie d 
visit/assess me nt (i ncl u di n g t e le p h o ne c o ntact) f or t he l ast s u bject i n t he L o n g-T er m F oll o w -U p 
Peri o d . 
D O S A G E F O R M S A N D R O U T E O F A D MI NI S T R A TI O N:  
S u bjects  ra n d o mize d  t o  t he  i n vesti gati o nal  ar m  will  recei ve  6 0  m g  a vatr o m b o pa g  
( 3 ×  2 0 m g  ta blets) f or or al a d mi nistrati o n o nce dail y f or 5 da ys pri o r t o C he m ot hera p y D a y a n d 
f or 5 da ys i m me diatel y f oll o wi n g C he m ot hera p y Da y  d uri n g t he D o u ble -Bli n d Treat me nt Peri o d . 
S u bjects ra n d o mize d t o t he c o ntr ol ar m will recei ve matc hi n g place b o ta blets.  
S u bjects i n t he o pti o nal O L E  Peri o d will recei ve 6 0 m g a vatr o m b o pa g  ( 3 ×  2 0 m g  ta blets) f or oral 
a d mi nistrati o n o nce  dail y  f or  5  da ys  pri or  t o  C he m ot hera p y  D a y  a n d  f or  5  da ys  after  
C he m ot hera p y Da y.  
E F FI C A C Y V A RI A B L E S:  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all  of t h e f ol l o wi n g 
criteria d uri n g  t he  p eri o d after  p ost -c he m ot h era p y I P  treat me nt  i n  C ycle  X + 1  thr o u g h  
C he m ot hera p y Da y  of C ycl e X + 2 : 
•  N ot r e q uiri n g a platel et tra nsf usi o n ; 
•  N ot r e q uiri n g a c h e m ot hera p y d ose re d ucti o n b y ≥1 5 % d ue t o t hr o m b oc yt o pe nia; a n d  
•  N ot r e q uiri n g a c h e m ot hera p y del a y b y ≥4 da ys d ue t o t hr o m b oc yt o p e nia. 
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of se v er e t hr o m b oc yt o p e nia  defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he peri o d 
after p ost -c he m ot her a p y I P treat me nt i n C ycle X + 1 t hr o u g h C he m ot hera p y D a y  of C ycl e X + 2 ; 
•  C ha n ge i n plat elet c o u nt fr o m baseli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( na dir) t o 
C ycle X + 1 ( n a dir);  
•  Pr o p orti o n of s u bjects  w h o d o n ot ha ve  maj or or n o n -maj or cli nicall y rel e va nt blee di n g  d uri n g 
t he peri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 thr o u g h C h e m ot hera p y D a y  of 
C ycle X + 2 ; a n d  
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve platelet tra nsf usi o n  d uri n g t he peri o d after p ost -
c he m ot hera p y I P tr eat me nt i n C ycle X + 1 thr o u g h  C he m ot hera p y Da y  of C ycl e X + 2. 
T he ot her efficac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he peri o d aft er p ost -c he m ot hera p y I P 
treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y D a y of C ycle X + 2 : 
•  Pr o p orti o n of s u bjects w h o d o n ot  ha ve a c he m ot hera p y d ose re d ucti o n t h at is ≥1 5 % d ue  t o 
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n  of  s u bjects  w h o  d o  n ot  ha ve  a  c he m ot hera p y  dela y  t hat  is  ≥4  da ys  d ue  t o  
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n of s u bjects wit h a pre -d efi ne d p ost- bas eli ne na dir platelet c o u nt;  a n d 

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•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost -baseli ne ma xi m u m platelet c o u nt . 
P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C V A RI A B L E S:  
Bl o o d  sa m ples  f or  p h ar mac o ki netic  a n d  p har mac o d y na mics  a n al ysis  will  be  c ollecte d.  
P har mac o ki netic sa m pli n g will occ ur t wice d uri n g t he st u d y wit h 4 sa m ples c ollecte d o n ea c h da y. 
P har mac o d y na mic sa m pl es  (ie, platelet c o u nts) will be c ollecte d t hr o u g h o ut eac h c ycl e of t he 
st u d y i ncl u di n g C ycl e X + 1, C ycl e X + 2, a n d eac h e nr olle d o pe n-l a bel c ycle. 
S A F E T Y V A RI A B L E S:  
Safet y v aria bl es will i ncl u de a d vers e e ve nts, a d v erse e v e nts  of s peci al i nterest ( A E SI), cli nical 
la b orat or y para meters, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns. 
S T A TI S TI C A L A N A L Y S E S:  
A n al ysis  of Effic ac y  
All pri mar y a n d sec o n d ar y efficac y e n d p oi nts  will be a nal yz e d usi n g t he F ull A nal ysis Set ( F A S) . 
T he pr i mar y efficac y a n al ysis will be re peat e d f or t he Per-Pr ot oc ol A n al ysis Set ( P P S) as t he 
s u p p orti ve a nal ysis. 
A n al ysis of t he P ri m a r y E ffic ac y E n d p oi nt   
T he t reat me nt effect o n t he pri mar y effi cac y e n d p oi nt will be teste d bet w ee n a vatr o m b o pa g a n d 
place b o us i n g t he C oc hr a n-Ma ntel -H ae nszel test, a dj usti n g f or n u m ber of c he m ot hera p y a ge nts 
(1, or ≥2  per missi ble  c he m ot hera p y  a ge nts  [ n ucle osi de  a n al o g,  i ncl u di n g  ge mcita bi ne  a n d  
fl u or o uracil;  car b o plati n  or  cis plati n;  a nt hrac ycli ne;  or  al k ylati n g  a ge nt]).  T he  n u m bers  a n d  
perce nt a ges of res p o n d ers i n eac h treat me nt gr o u p, t he ass ociate d 9 5 % c o nfi de nce i nter vals ( CI), 
a n d t he 9 5 % CI f or t he differe n ce bet we e n a v atr o m b o pa g a n d place b o will be calc ulat e d. T he 
pri mar y a n al ysis will be perf or me d bas e d o n t he F A S a n d re p e ate d o n t he P P S. Ot her se nsiti vit y 
a nal ys es of t he pri mar y efficac y e n d p oi nt ma y be perf or me d as a p pr o priate.  
A n al ysis of t he K e y Sec o n d ar y E ffic ac y E n d p oi nts  
If t he test of t he treat me nt effect o n t he pri mar y efficac y e n d p oi nt is statisticall y si g nifica nt, t he 
a nal ysis of t he ke y s ec o n dar y efficac y e n d p oi nts will pr ocee d usi n g ste p-d o w n cl ose d testi n g 
pr oce d ur e i n t he f oll o wi n g or der t o mai ntai n t he fa mil y-wise T y pe I err or rate at si g nifica nce le vel 
al p ha = 0. 0 5 ( 2 -si de d): 
Ste p  1:  Test  t he  treat me nt  eff ec t  at  a  si g nifica nt  le v el  of  0. 0 5  o n  d urati o n  of  se vere  
t hr o m b oc yt o pe ni a  defi ne d  as  a  platelet  c o u nt  < 5 0  ×   1 09/ L d uri n g  t he  peri o d  after  p ost -
c hem o t hera p y I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y D a y  of C ycle X + 2 ; if s uccessf ul, 
pr ocee d t o Ste p 2; ot h er wise st o p at Ste p 1.  
Ste p 2: Test t he tr eat me nt effect at a si g nifica nt le vel of 0. 0 5 o n c h a n ge i n platelet c o u nt fr o m 
baseli ne ( q u alif yi n g c h e m ot hera p y c ycle [ C ycle X]) ( na dir) t o C ycle X + 1 ( na dir); if s u ccessf ul, 
pr ocee d t o Ste p 3; ot her wise st o p at  Ste p 2. 
Ste p 3: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n pr o p orti o n of s u bjects w h o d o n ot 
ha ve maj or or n o n -maj or cli nicall y r ele va nt blee di n g  d uri n g t he peri o d aft er p ost -c he m ot hera p y 

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I P treat me nt i n C ycle X + 1 thr o u g h  C h e m ot hera p y D a y  of C ycle X + 2 ; if s uccessf ul, pr o cee d t o 
Ste p 4; ot her wise st o p at Ste p 3.  
Ste p 4: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n p r o p orti o n of s u bjects w h o d o n ot 
recei v e platelet tr a nsf usi o n d uri n g t he p eri o d after p ost -c he m ot hera p y I P treatme nt i n C ycle X + 1 
thr o u g h C he m ot her a p y D a y  of C ycle X + 2 . 
A n al ysis of O t her E ffic ac y E n d p oi nts:  
T he cate g orical v aria bles (e g, pr o p orti o n) will be s u m marize d a n d a nal yz e d i n t he sa me ma n ner 
as t he pri mar y efficac y e n d p oi nt. T he c o nti n u o us varia bles (e g, c h a n ge fr o m baseli ne i n platelet 
c o u nt) will be a nal yze d usi n g a nal ysis of c o varia n ce m o dels wit h treat me nt a n d t he ra n d o mizati o n 
stratificati o n fact or as mai n effects a n d t he baseli ne meas ure me nt  as a c o variate, a n d Wilc o x o n 
Ra n k S u m tests if t he n or malit y ass u m pti o n is vi olate d. 
T he effi cac y v aria bles c ollecte d  d uri n g t he o pti o nal O L E  Peri o d will be s u m marize d descri pti vel y.  
A n al ysis  of S af et y  
Safet y a n d t olera bilit y will be ass esse d b y e x a mi ni n g t he i n ci de nce of a d verse e ve nts, A E SI , 
cli nical la b orat or y p a r a meters, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns o ver ti me usi n g t h e 
Saf et y A nal ysis Set.  
S A M P L E SI Z E D E T E R MI N A TI O N:  
Ass u mi n g t here is a 4 0 % res p o nse rate i n t he acti ve gr o u p a n d 1 0 % i n t he place b o gr o u p, a n d 
usi n g a 2: 1 ra n d o mizati o n, a 1 0 % pre ma t ure ter mi nati o n rate, a n d 9 0 % p o wer wit h 2-si de d 
al p ha = 0. 0 5, t he sa m ple size is 1 2 0 s u bjects ( 8 0 acti ve s u bjects a n d 4 0 place b o s u bjects).  
SI T E S:   A p pr o xi matel y 7 5 sites gl o ball y  
S P O N S O R:  
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U nite d States  
Tele p h o ne: + 1 9 1 9- 7 4 8- 5 9 7 5 
Fa x: + 1 9 1 9 -7 4 8 -5 9 7 6  

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T A B L E O F C O N T E N T S  
Si g nat ure Pa ge ................................................................................................................................ 2 
I n v esti gat or A gr ee me nt ................................................................................................................... 3 
S y n o psis .......................................................................................................................................... 4 
Ta ble of C o nte nts .......................................................................................................................... 1 2 
List of  Ta bl es  ................................................................................................................................ 1 6 
List of Fi g ures  ............................................................................................................................... 1 6 
List of A b br e viati o ns a n d Defi niti o n of Ter ms ............................................................................. 1 7 
1  I ntr o d u cti o n a n d Bac k gr o u n d I nf or mati o n ............................................................................. 1 8 
1. 1  
T hr o m b oc yt o p e nia ........................................................................................................ 1 8 
1. 2  
C he m ot hera p y -I n d u ce d T hr o m b oc yt o p e nia .................................................................. 1 8 
1. 3  
A vatr o m b o pa g ............................................................................................................... 1 9 
1. 4  
N o ncli nical St u dies  ....................................................................................................... 1 9 
1. 5  
Cli nical St u dies  ............................................................................................................. 1 9 
1. 5. 1  P hase 1 St u dies .................................................................................................. 2 0 
1. 5. 2  P hase 2 St u dies .................................................................................................. 2 0 
1. 5. 3  P hase 3  St u dies .................................................................................................. 2 1 
1. 6  
Rati o nale  ........................................................................................................................ 2 3 
1. 7  
Ris k/ Be nefit  ................................................................................................................... 2 4 
2  St u d y O bjecti ves  ..................................................................................................................... 2 5 
2. 1  
Pri mar y O bj ecti ve  ......................................................................................................... 2 5 
2. 2  
Sec o n dar y O bj ecti ves  .................................................................................................... 2 5 
3  St u d y Descri pti o n .................................................................................................................... 2 6 
3. 1  
S u m mar y of St u d y Desi g n ............................................................................................ 2 6 
3. 1. 1  Scree ni n g/ Q ualif yi n g C h e m ot hera p y Re gi me n ( C ycl e X)  ................................ 2 6 
3. 1. 2  D o u ble- Bli n d Tr eat me nt Peri o d ........................................................................ 2 6 
3. 1. 3  O bser vati o nal Peri o d ......................................................................................... 2 7 
3. 1. 4  O pti o nal O pe n- La b el E xte nsi o n Peri o d  ............................................................ 2 7 
3. 1. 5  L o n g -T er m F ol l o w- U p P eri o d .......................................................................... 2 8 
3. 2  
St u d y D urati o n a n d E n d of St u d y ................................................................................. 2 8 
3. 3  
Data a n d Saf et y M o nit ori n g B oar d ............................................................................... 2 8 

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3. 4  
St u d y I n dicati o n  ............................................................................................................ 2 8 
4  Selecti o n a n d Wit h dra wal of S u bjects .................................................................................... 2 9 
4. 1  
I n cl usi o n Criteria f or All S u bjects  ................................................................................ 2 9 
4. 2  
E x cl usi o n Criteria f or All S u bjects  ............................................................................... 3 0 
4. 3  
I n cl usi o n Criteria f or S u bjects t o C o nti n ue I nt o t h e O pti o nal O pe n-La bel  
E xte nsi o n Peri o d ........................................................................................................... 3 1 
4. 4  
E x cl usi o n Criteria f or S u bjects t o C o nti n ue I nt o t h e O pti o nal O pe n- La bel  
E xte nsi o n Peri o d ........................................................................................................... 3 1 
4. 5  
Wit h dra wal Criteria  ....................................................................................................... 3 2 
4. 5. 1  S u bjects wit h I n vesti gati o nal Pr o d uct I nterr u pti o n or Disc o nti n uati o n ............ 3 2  
5  St u d y Treat me nts  .................................................................................................................... 3 3 
5. 1  
Treat me nt Gr o u ps .......................................................................................................... 3 3 
5. 2  
Rati o nale f or D osi n g ..................................................................................................... 3 3 
5. 3  
Ra n d o mizati o n a n d Bli n di n g ......................................................................................... 3 3 
5. 4  
Brea ki n g t he Bli n d  ........................................................................................................ 3 4 
5. 5  
Dr u g S u p plies ................................................................................................................ 3 4 
5. 5. 1  F or m ulati o n a n d Pac k a gi n g ............................................................................... 3 4 
5. 5. 2  I n v esti gati o nal Pr o d uct Dis pe nsi n g ................................................................... 3 4 
5. 5. 3  I n v esti gati o nal Pr o d uct A d mi nistrati o n ............................................................ 3 4 
5. 5. 4  Treat me nt C o m plia nce  ...................................................................................... 3 5 
5. 5. 5  St ora ge a n d A cc o u nta bilit y ............................................................................... 3 5 
5. 6  
Pri or a n d C o nc o mita nt Me dicati o ns a n d/ or Pr oce d ures ................................................ 3 5 
5. 6. 1  E x cl u de d Me dicati o ns a n d/ or Pr oce d ures ......................................................... 3 5 
5. 6. 2  All o we d Me dicati o ns a n d/ or Pr oce d ures .......................................................... 3 5 
5. 6. 3  D oc u me ntati o n of Pri or a n d C o nc o mita nt Me dicati o n Use .............................. 3 6  
6  St u d y Pr o ce d ur es  .................................................................................................................... 3 7 
6. 1  
I nf or me d C o nse nt .......................................................................................................... 3 7 
6. 2  
C ycle X ( Q ualif yi n g C he m ot hera p y C ycle)  .................................................................. 3 7 
6. 2. 1  Scree ni n g ( Visit 1, Da y - 2 8 t o Da y - 1) ............................................................. 3 7 
6. 2. 2  Baseli ne Visit ( Visit 2, First Da y [ or - 1 Da y] of t he 5-da y I n v esti gati o nal 
Pr o d uct Treat me nt)  ............................................................................................ 3 8 
6. 2. 3  Pre -C he m ot hera p y I n vesti gati o nal Pr o d uct Treat me nt ( Visit 3, Last D a y  
of t he 5- da y I n vesti gati o nal Pr o d uct Treat me nt) ............................................... 3 8 

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6. 3  
D o u ble- Bli n d Tr eat me nt Peri o d ( C ycl e X + 1)  ............................................................. 3 9 
6. 3. 1  C he m ot hera p y Da y ( Visit 4, C ycle X + 1 Da y 1 t o 3)  ...................................... 3 9 
6. 3. 2  P ost- C he m ot hera p y I n vesti gati o nal Pr o d uct Treat me nt ( Visit 5)  ..................... 3 9 
6. 3. 3  C ycle X + 1 D a ys 1 1 ( ± 1 da y), 1 5 ( ± 1 da y), a n d 1 8 ( ± 1 da y)  
( Visits 6, 7, a n d 8) ............................................................................................. 4 0 
6. 4  
O bser vati o nal Peri o d ( C ycle X + 2)  .............................................................................. 4 0 
6. 4. 1  C he m ot hera p y Da y i n C ycl e X + 2 ( Vis it 9) ..................................................... 4 0 
6. 4. 2  C ycle X  + 2 D a ys 1 1 (± 1 da y), 1 5 ( ± 1 da y), a n d 1 8 ( ± 1 da y)  
( Visits 1 0, 1 1, a n d 1 2) ....................................................................................... 4 1 
6. 4. 3  F oll o w- U p Visit ( F or s u bject s n ot c o nti n ui n g i nt o t he o pti o nal  
O pe n - La b el E xte nsi o n Peri o d) .......................................................................... 4 1 
6. 4. 3. 1  Pri or t o C he m ot hera p y D a y i n C ycle X + 3 ( Visit 1 7) ....................... 4 1  
6. 5  
O p ti o nal O pe n- La b el E xte nsi o n Peri o d ( C ycl e X + 3 a n d O n) ..................................... 4 1 
6. 5. 1  Pre - C he m ot hera p y A vatr o m b o pa g Treat me nt ( Visit 1 3) .................................. 4 1 
6. 5. 2  C he m ot hera p y Da y ( Visit 1 4, C ycle  X + 3 Da y 1 t o 3) .................................... 4 2 
6. 5. 3  P ost- C he m ot hera p y A vatr o m b o pa g Treat me nt ( Visit 1 5) ................................ 4 3 
6. 5. 4  C ycle X + 3 D a y 1 5 ( ± 1 da y) ( Visit 1 6)  ............................................................ 4 3 
6. 5. 5  F oll o w- U p Visit  ................................................................................................. 4 3 
6. 5. 5. 1  T hirt y da ys after l ast a vatr o m b o pa g d ose ( Visit 1 7) i n t he O L E 
Peri o d  .................................................................................................. 4 3 
6. 6  
Earl y Ter mi nati o n Visit a n d Wit h dra wal Pr oce d ures  ................................................... 4 4 
6. 7  
L o n g -T er m F oll o w -U p  .................................................................................................. 4 5 
7  Eff icac y Assess me nts.............................................................................................................. 4 6 
8  P har mac o ki netic a n d P har mac o d y na mic Ass ess me nts  ........................................................... 4 7 
8. 1  
P har mac o ki netic Assess me nts  ....................................................................................... 4 7 
8. 2  
P har mac o d y na mic Ass ess me nts  .................................................................................... 4 7 
9  Safet y Assess me nts  ................................................................................................................. 4 8 
9. 1  
A d verse E v e nts  .............................................................................................................. 4 8 
9. 1. 1  Assess me nt of A d vers e E ve nts b y t he I n vesti gat or .......................................... 4 9 
9. 1. 2  A d verse E v e nts of S peci al I nt erest  .................................................................... 5 0 
9. 1. 3  Efficac y E n d p oi nts ............................................................................................ 5 0 
9. 2  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E v e nts ............................. 5 0  
9. 3  
Seri o us A d verse E v e nts  ................................................................................................. 5 1 

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Versi o n 2. 0, 0 4 A pril 2 0 1 9  
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9. 4  
Seri o us A d verse E v e nt Re p orti n g − Pr oce d ures f or I n vesti gat ors ................................ 5 1 
9. 5  
Pre g n a nc y Re p orti n g  ..................................................................................................... 5 2 
9. 6  
Re g ula t or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ................................ 5 2 
9. 7  
Cli nical La b or at or y E val uati o ns .................................................................................... 5 3 
9. 8  
Vital Si g ns ..................................................................................................................... 5 3 
9. 9  
P h ysical E x a mi nati o ns  .................................................................................................. 5 3 
1 0  Statistics  .................................................................................................................................. 5 4 
1 0. 1  A nal ysis P o p ulati o ns ..................................................................................................... 5 4 
1 0. 2  Statistical Met h o ds  ........................................................................................................ 5 4 
1 0. 2. 1  A nal ysis of Efficac y  .......................................................................................... 5 4 
1 0. 2. 1. 1  Pri mar y efficac y a nal ysi s .................................................................... 5 4 
1 0. 2. 1. 2  Ke y sec o n d ar y efficac y a nal ysis  ......................................................... 5 5 
1 0. 2. 1. 3  Ot her efficac y a nal ysis  ........................................................................ 5 5 
1 0. 2. 2  A nal ysis of Safet y  ............................................................................................. 5 6 
1 0. 2. 3  I nteri m A nal ysis ................................................................................................ 5 6 
1 0. 2. 4  Sa m p le Size Deter mi nati o n ............................................................................... 5 6 
1 1  Data Ma na ge me nt a n d R ec or d K ee pi n g  ................................................................................. 5 7 
1 1. 1  Data Ma na ge me nt  ......................................................................................................... 5 7 
1 1. 1. 1  Data Ha n dli n g  ................................................................................................... 5 7 
1 1. 1. 2  C o m p uter S yste ms  ............................................................................................. 5 7 
1 1. 1. 3  Data E ntr y  ......................................................................................................... 5 7 
1 1. 1. 4  Me dical I nf or mati o n C o di n g ............................................................................. 5 7 
1 1. 1. 5  Data Vali dati o n  ................................................................................................. 5 7 
1 1. 2  Rec or d Kee pi n g  ............................................................................................................. 5 8 
1 2  I n v esti gat or Re quire me nts a n d Q ualit y C o ntr ol ..................................................................... 5 9 
1 2. 1  Et hical C o n d uct of t he St u d y ........................................................................................ 5 9 
1 2. 2  I nstit uti o nal Re vie w B oar d/I n d e pe n d e nt Et hics C o m mittee ......................................... 5 9 
1 2. 3  Pr ot oc ol A me n d me nts ................................................................................................... 5 9 
1 2. 4  I nf or me d C o nse nt .......................................................................................................... 5 9 
1 2. 5  St u d y M o nit ori n g Re q uir e me nts  ................................................................................... 6 0 
1 2. 6  Discl os ure of D ata  ......................................................................................................... 6 0 
1 2. 7  Rete nti o n of Rec or ds ..................................................................................................... 6 0 

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1 2. 8  P u blicati o n P olic y  ......................................................................................................... 6 1 
1 2. 9  Fi na ncial Discl os ur e  ...................................................................................................... 6 1 
1 2. 1 0  I ns ura nce a n d I n d e m nit y ............................................................................................... 6 1 
1 3  Refere n ces  ............................................................................................................................... 6 2 
A p pe n di x A:  Sc he d ule of Pr oce d ur es .......................................................................................... 6 4 
A p pe n di x B:  Cli nical La b orat or y A nal ytes ................................................................................. 6 9 
A p pe n di x C:  C yt oc hr o m e P 4 5 0 I n d u cers .................................................................................... 7 0 
A p pe n di x D:  I nter n ati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis Blee di n g Defi niti o ns ....... 7 1  
A p pe n di x E:  Pr ot oc ol A me n d me nts ............................................................................................ 7 2 
 
 
LI S T O F T A B L E S  
Ta ble 1.  
Sc he d ule of Pr oce d ures ( D o u ble- Bli n d Treat me nt Peri o d)  ........................................ 6 4 
Ta ble 2.  
Sc he d ule of Pr oce d ures ( O bser vati o nal Peri o d) ......................................................... 6 6 
Ta ble 3.  
Sc he d ule of Pr oce d ures ( O pti o nal O pe n- La b el E xte nsi o n Peri o d)............................. 6 7  
Ta ble 4  
C yt o c hr o me P 4 5 0 I n d u cers ......................................................................................... 7 0 
Ta ble 5.  
I nter nati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis Blee di n g Defi niti o ns............ 7 1 
 
 
LI S T O F FI G U R E S  
Fi g ure 1.  St u d y Desi g n  ............................................................................................................... 2 6 
Fi g ure 2.  Treat me nt Sc he d ul e f or D o u ble- Bli n d Treat me nt Peri o d  ........................................... 2 7 
Fi g ure 3.  Treat me nt Sc he d ul e f or O pti o nal O pe n- La b el E xte nsi o n Peri o d  ............................... 2 8 
 

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L I S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A b bre viati o n  
Defi n iti o n 
2 1 C F R  
Title 2 1 of t he C o de of Fe deral Re g ul ati o ns  
A E SI  
A d verse e ve nts o f s pecial i nterest 
A L T  
Ala ni ne a mi n otra nsferas e  
A S T  
As partate a mi n otra nsferase  
β -h C G  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
CI  
C o nfi de nce i nter v al  
CI T  
C he m ot hera p y -i n d uce d t hr o m b oc yt o p e nia 
C L D  
C hr o nic li ver disease  
C R A  
Cli nical researc h ass oci ate 
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C Y P  
C yt o c hr o me P 4 5 0  
D S M B  
Data a n d Safet y M o nit ori n g B oar d  
e C R F 
Electr o nic case re p ort f or m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
E D C  
Electr o nic data ca pt ure  
F A S  
F ull A nal ysis Set  
G C P  
G o o d Cli nical Pra ctice  
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I P 
I n v esti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve res p o nse t ec h n ol o g y 
I S T H 
I nter nati o nal S ociet y o n T hr o m b osis a n d Hae m ostasis  
I T P 
I di o pat hic/i m m u ne t hr o m b oc yt o pe ni c p ur p ura 
O L E  
O pe n -la bel e xte nsi o n 
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic (s) 
P P S  
Per -Pr ot oc ol A nal ysis Set  
R DI  
Relati ve d ose i nte nsit y  
S A E  
Seri o us a d verse e ve nt  
S U S A R  
S us pecte d u ne x pecte d seri o us a d ver se reacti o n 
T P O  
T hr o m b o p oieti n  

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1  
IN T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N  
1. 1  
T hr o m b oc yt o pe ni a 
T hr o m b oc yt es or p latel ets are a n i m p orta nt c o m p o ne nt of bl o o d t hat f u ncti o n t o mai ntai n n or mal 
he m ostasis. I n t he cas e of vessel i nj uries, platelets i m me diatel y c o nt r ol blee di n g b y a d h esi o n, 
acti vati o n, a n d a g gre gati o n, t here b y f or mi n g a st a ble cl ot i n c o nj u ncti o n wit h bl o o d c oa g ulati o n 
fact ors.  T hr o m b o p oieti n  ( T P O),  t he  pri n ci pal  p h ysi ol o gic  re g ulat or  of  platelet  pr o d u cti o n,  is  
pr o d uce d c o nstit uti vel y i n t he li ver, circ ulates i n t he bl o o dstrea m, a n d is deli vere d t o t he b o n e 
marr o w,  w her e  it  sti m ulates  t he  earl y  d e vel o p me nt  of  m ulti ple  he mat o p oietic  li nea ges  a n d  
me ga kar y o c yt o p oi esis. B o ne marr o w pr o d ucti o n of platelets is directl y affecte d b y T P O le vels.  
T he cir c ulati n g platelet c o u nt i n bl o o d is deter mi ne d b y t he rates of platelet pr o d ucti o n a n d platel et 
destr ucti o n. I n healt h y i n di vi d uals, t he a v era ge lifes pa n of platel ets is 7 t o 1 0 da ys, aft er w hic h 
t he y are d estr o ye d a n d r e place d wit h ne wl y-ge n erate d platelets. A n or mal bl o o d platelet c o u nt 
ra n ges fr o m 1 5 0 × 1 09/ L t o 4 5 0 × 1 09/ L, a n d p atie nts w h o ha ve less t ha n 1 5 0 × 1 09/ L h a ve t he 
c o n diti o n k n o w n as t hr o m b oc yt o pe ni a. T hr o m b o c yt o p e nia is a p ote ntiall y seri o us c o n diti o n t hat 
is c haracterize d b y a deficie nc y of pl atelets i n t h e circ ul at or y s yste m t hat is ass ociate d wit h a n 
i ncreas e d ris k of bl ee di n g. T hr o m b oc yt o pe nia ca n res ult fr o m decrease d pl atelet pr o d u cti o n i n t he 
b o ne  marr o w,  i ncr eas e d  platelet  destr ucti o n  i n  t he  bl o o d  (s uc h  as  fr o m  a ut o -a nti b o dies), or 
se q uestrati o n of platel ets i n t he s plee n.  
1. 2  
C he m ot her a p y -I n d uce d T hr o m b oc yt o pe ni a 
C he m ot hera p y -i n d uce d  t hr o m b oc yt o p e nia  ( CI T)  is  a  c o m m o n  t o xicit y  of  m yel os u p pressi ve  
c he m ot hera p y.  Occ urre nce  of  t hr o m b oc yt o p e nia  has  t he  p ote ntial  t o  create  si g nifica nt  
c o m plicati o ns . At platelet c o u nts < 1 0, 0 0 0/ µ L, s p o nta ne o us blee di n g ris k is i ncrease d. At platelet 
c o u nts  < 5 0, 0 0 0/ µ L,  pr oc e d ures  are  ofte n  c o m plicate d  b y  blee di n g.  At  platelet  c o u nts  
< 1 0 0, 0 0 0/ µ L,  c h e m ot hera p y  is  a d mi nistere d  wit h  ca uti o n  f or  fear  of  w orse ni n g  t he  
t hr o m b oc yt o pe ni a a n d i n creasi n g t he ris k of blee di n g.1 
Cli nicia ns’ res p o nses t o t hr o m b oc yt o p e nia i n a ca ncer p atie nt var y:  re d ucti o n of t he d ose i nte nsit y 
of c he m ot hera p y is c o m m o n, m ore effecti ve re gi me ns wit h t hr o m b oc yt o pe nic t o xicit y ma y b e 
a v oi de d, a n d tr eat me nt m a y e ve n be pr ecl u de d. Platelet tra nsf usi o ns are oft e n t he o nl y treat m e nt;1 ,2  
h o we ver, platelet tra nsf usi o ns create  t he a d diti o nal ris k of tra nsf usi o n reacti o ns or i nfecti o ns, a n d 
ma y l ea d t o t he d e vel o p me nt of platel et refract ori ness wit h re peat e d plat elet tra nsf usi o ns. T he 
latter i m p orta ntl y eli mi nates platelets as a n o pti o n f or f ut ure e mer ge nt nee ds i n t hese patie nts 
d uri n g t heir c he m ot her a p y r e gi me n or f or ot her e mer ge nt c o n diti o ns t hat ma y d e vel o p. 
T he i nci de nce, se v erit y, a n d d urati o n of t hr o m b oc yt o p e nia var y wit h t he c he m ot hera p y re gi me n. 
K uter,  2 0 1 5  pr o vi des  a n  o ver vie w  of  t he  re p orte d  fre q u e ncies  of  s e v ere  t hr om b oc yt o pe ni a 
( Gra d e 3 = 2 5, 0 0 0 t o < 5 0, 0 0 0/ µ L, Gra d e 4 ≤2 5, 0 0 0/ µ L) ass ociate d wit h vari o us c he m ot hera p y 
re gi me ns.1 

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T he reas o ns t hat s o me patie nts e x perie nce m ore se vere or pr ol o n ge d t hr o m b oc yt o p e nia after 
c he m ot hera p y ar e n ot well u n derst o o d a n d ca n b e diffic ult t o pre dict. T he mec ha nis ms b y w hic h 
c he m ot hera p y re gi me ns r es ult i n t hr o m b oc yt o pe ni a als o differ a n d i ncl u de t he f oll o wi n g: 
•  Al k ylati n g a ge nts s uc h as b us ulfa n affect pl uri p ot e nt ste m cells ; 
•  C ycl o p h os p ha mi d e  s par es  he mat o p oietic  ste m  cells,  b ut  affects  later  me ga kar y oc yte  
pr o ge nit ors; 
•  B ortez o mi b has n o effect o n ste m cells or me ga k ar y o c yt e mat urati o n b ut d oes i n hi bit n uclear 
fact or k a p pa B, a critical re g ulat or of plat elet s he d di n g; a n d 
•  C he m ot hera p y  ma y  e n h a nce  plat elet  cleara n ce  b y  i m m u ne  mec h a nis ms,  as  occ urs  wit h  
fl u dara bi ne. 
T here h as bee n  o ne a p pr o ve d pr o d uct f or t he treat me nt of CI T, o prel ve ki n ( Ne u me ga , Pfizer); 
h o we ver, d ue t o t h e t o xicit y pr ofile ass o ciate d wit h t his pr o d uct (a n a p h yla xis, fl ui d rete nti o n 
i ncl u di n g p ul m o nar y e d e ma, arr h yt h mias), p h ysicia ns c o nti n ue t o rel y o n platelet tra nsf usio ns i n 
t his patie nt p o p ulati o n. As a res ult, CI T re mai ns a c o n diti o n t hat is n ot a de q uatel y treate d wit h 
e xisti n g p har mac ol o gical a ge nts.  
1. 3  
A v atr o m b o p a g 
A vatr o m b o pa g maleate is a n orall y a d mi nistere d T P O rece pt or a g o nist t hat mi mics t he bi ol o gic 
effects of T P O i n vitr o a n d i n vi v o. T hr o m b o p oieti n e x erts its effect o n me ga kar y oc yt o p oie sis a n d 
t hr o m b oc yt o p oiesis t hr o u g h bi n di n g a n d acti vati o n of t he T P O rece pt or, w hic h is e x presse d o n 
he mat o p oietic  ste m  cells,  cells  of  t h e  me ga k ar y o c ytic  li nea ge,  a n d  pl atelets.  A vatr o m b o pa g  
acti vates t he h u ma n T P O rece pt or b y bi n di n g t o a differe nt site o n t he T P O rece pt or, b ut it is still 
ca pa ble of sti m ulati n g si g nal tra ns d u cti o n a n d mi mic ki n g t he bi ol o gic effects of T P O, res ulti n g i n 
a meas ur e d i ncrease i n pl atelet c o u nts.  
1. 4  
N o ncli nic al St u dies  
T he t o xicit y of a v atr o m b o pa g h as bee n e xte nsi vel y e v al uate d i n si n gl e- a n d re peate d -d os e oral 
t o xicit y st u dies i n mice, rats, d o gs, a n d c y n o m ol g us m o n ke ys (f or u p t o 1 3 wee ks i n mice, 
2 6 wee ks i n r ats, 4 wee ks i n d o gs, a n d 5 2 wee ks i n c y n o m ol g us m o n ke ys). T he ge n ot o xicit y of 
a vatr o m b o pa g was e val u ate d i n vitr o a n d i n vi v o. T w o -year carci n o ge nicit y st u dies h a ve bee n 
c o n d ucte d i n mice a n d rats. Re pr o d ucti ve a n d de v el o p me ntal t o xicit y w as e v al uate d b y c o n d ucti n g 
male a n d f e male f ertilit y st u dies i n rats, e m br y o -fetal de vel o p me nt t o xicit y st u dies i n rats a n d 
ra b bits, pre- a n d p ost -nat al de vel o p me nt st u dies i n rats, a n d a j u ve nile d ose ra n ge -fi n di n g st u d y i n 
rats. T he p ote ntial f or der mal a n d e ye irritati o n i n ra b bits, der mal s e nsitizati o n i n g ui n ea pi gs, a n d 
p h ot ot o xicit y  i n  pi g me nte d  rats  was  als o  e val u ate d.  N o ncli nical  st u dies  ha ve  i n dicate d  t hat  
a vatr o m b o pa g w as w ell t olerate d a n d data s u g gest t hat  a vatr o m b o pa g is a pr o misi n g ca n di date f or 
use i n t he treat me nt of t hr o m b oc yt o p e nia of di verse eti ol o gies, i ncl u di n g t he treat me nt of CI T . 
1. 5  
Cli nic al St u dies  
A vatr o m b o pa g has b ee n st u die d i n h u ma ns i n b ot h si n gle - a n d m ulti ple-d ose P hase 1, d ose -risi n g, 
safet y a n d t oler a bilit y st u dies a n d i n P hase 2 a n d P hase 3 efficac y a n d s afet y st u dies. A t otal of 
1 3 6 5 s u bjects ha ve bee n ra n d o mize d acr oss t he 2 4 c o m plete d st u dies i n t he a vatr o m b o pa g cli nical 
de vel o p me nt  pla n.  T he  t otal  safet y  d ata bas e  f or  a vatr o m b o p a g -treate d  s u bjects  i ncl u des 

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1 1 0 7 s u bjects i n t he c o m plete d cli nical st u dies. T his i ncl u des 52 0 healt h y v ol u nteers, 3 9 5  s u bjects 
wit h t hr o m b oc yt o pe nia ass ociate d wit h c hr o nic li ver disease ( C L D) pri or t o sc he d ule d s ur gi cal or 
dia g n ostic pr o ce d ur es, 6 4 s u bjects wi t h c hr o nic he patitis C vir us-relate d t hr o m b oc yt o pe ni a t o 
e na ble i nitiati o n a n d mai nte na nce of a nti viral treat me nt, a n d 1 2 8 s u bjects wit h c hr o nic i m m u ne 
t hr o m b oc yt o pe ni c p ur p ur a (I T P). 
1. 5. 1  
P h ase 1 St u dies  
T he cli nical p h ar mac ol o g y pr o gra m was d esi g n e d t o esta bl is h t he p h ar mac o ki netic ( P K) pr ofile of 
a vatr o m b o pa g,  t he  d eter mi nati o n  of  t he  eli mi nati o n  pat h wa ys,  t he  i n v esti gati o n  of  p ote ntial  
cli nicall y i m p orta nt dr u g -dr u g i nteracti o n s, t he effects of b ot h i ntri nsic a n d e xtri nsic fact ors o n 
P K,  a n d  t he  relati o ns hi p  bet wee n  P K  a n d  p har mac o d y na mic  ( P D)  effects  relate d  t o  cli nical  
efficac y.  I n  1 5  c o m plete d  P hase  1  st u dies  i n v ol vi n g  5 2 0 healt h y  v ol u nteers  e x p ose d  t o  
a vatr o m b o pa g, t he m ost c o m m o n a d verse e ve nt o cc urri n g i n 5 % or m ore of s u bjects treate d wit h 
a vatr o m b o pa g w as hea d ac he.  
A d diti o nal details are a v aila ble i n t he a vatr o m b o p a g I n vesti gat or’s Br o c h ure .3 
1. 5. 2  
P h ase 2 S t u dies 
In 6 4 I T P patie nts w h o were ra n d o mize d i n a d o u ble -bli n d, place b o -c o ntr olle d, P hase 2 efficac y 
a n d saf et y st u d y (St u d y C L -0 0 3), a vatr o m b o p a g de m o nstrate d s u peri or efficac y c o m pare d wit h 
place b o  as  meas ure d  b y  pl atelet  res p o nse  o n  Da y  2 8.  T his  res p o nse  was  d ose -relate d. 
A vatr o m b o pa g c o nti n ue d t o be effecti ve after a n a d diti o nal 6 m o nt hs of treat me nt as meas ure d b y 
d ura ble a n d o ver all platelet res p o nse rates i n 5 3 s u bjects w h o c o nti n ue d i nt o a 6 -m o nt h r oll o ver 
st u dy ( St u d y C L - 0 0 4). D ura ble pl atelet res p o nse was defi ne d as s u bjects w h o ha d at least 7 5 % of 
t heir meas ure d plat elet c o u nt val ues at res p o nse l e vel d uri n g t he last 1 4 wee ks of t he 2 4-wee k 
treat me nt peri o d a n d di d n ot recei ve res c ue t hera p y d uri n g t he st u d y. All s u bjects nee de d t o ha ve 
at least 3 platelet c o u nt assess me nts i n t he last 1 4 wee ks of St u d y C L -0 0 4. O verall res p o nse rate 
was defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve d eit her a d ura ble res p o nse or a tra nsie nt 
res p o nse (tra nsie nt r es p o nse was defi ne d as s u bjects w h ose platelet c o u nts were at a res p o nse le v el 
at 2 or m ore c o nsec uti ve a nal ysis wi n d o ws d uri n g t he 2 4 -wee k treat me nt peri o d o f St u d y C L - 0 0 4, 
wit h o ut ha vi n g ac hie ve d a d ura ble res p o nse). 
I n t he c o m bi ne d C L-0 0 3 a n d C L -0 0 4 st u dies, t he m o st c o m m o n treat me nt-e mer ge nt a d verse 
e ve nts  ( T E A Es),  occ urri n g  i n  5 %  or  m ore  of  s u bjects  treate d  wit h  a vatr o m b o pa g  w ere  ( b y  
decreasi n g  or der  of  fr e q ue nc y)  fati g u e,  hea dac he,  e pista xis,  c o nt usi o n,  art hral gia,  di arr h ea,  
t hr o m b oc yt o pe ni a,  gi n gi val  blee di n g,  bac k  pai n,  e de ma  peri p heral,  pet ec hiae,  platelet  c o u nt  
i ncreas e d,  v o miti n g,  d ys p nea,  n a usea,  u p per  res pirat or y  tract  i nfecti o n,  pai n  i n  e xtre mit y,  
ecc h y m osis,
 c o u g h,
 i ns o m nia,
 dizzi ness,
 p har y n g ol ar y n geal
 pai n,
 h y perli pi de mia,
 
nas o p har y n gitis, a n d platelet c o u nt decrease d. M ost T E A Es were Gra de 1 or Gra de 2, tra nsie nt, 
a n d c o m pletel y res ol v e d.  
A t otal of 1 3 0 s u bjects wit h t hr o m b oc yt o pe nia ass ociate d wit h C L D  w h o were sc h e d ule d t o 
u n der g o  electi ve  s ur gical  or  dia g n ostic  pr oce d ures  were  e nr olle d  i n  a  P hase  2,  ra n d o mize d,  
place b o -c o ntr olle d, d o u ble -bli n d, parallel -gr o u p st u d y ( St u d y 2 0 2). T he s u bjects were s plit i nt o 2 
c o h orts a n d recei ve d eit her a vatr o m b o pa g ( C o h ort A: first ge nerati o n f or m ulati o n; C o h ort B: 
sec o n d ge nerati o n f or m ulati o n) or place b o. T h e pri mar y a nal ysis of t he res p o n der rate i n t he 
o verall c o m bi ne d a vatr o m b o pa g gr o u p w as statisticall y si g nifi ca nt c o m p are d wit h t he o verall 
c o m bi ne d place b o gr o u p . A si milar statistical si g nifica nce was a gai n n ote d w he n t he d ata w ere 

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a dj uste d f or t h e eti ol o g y of li ver disease b y a C oc hra n -Ma ntel -Hae nszel test. Wit hi n C o h ort B, t he 
res p o nse rate i n platelet c o u nts b y D a y 8 i ncreas e d si g nifica ntl y i n s u bjects recei vin g treat me nt 
wit h a vatr o m b o pa g c o m pare d wit h place b o. I n a d diti o n, a statisticall y si g nifica nt re d ucti o n w as 
ac hie ve d  i n  t he  pr o p orti o n  of  s u bjects  recei vi n g  platelet  tra nsf usi o n  bef ore  electi ve  i n vasi ve  
pr oce d ur es i n C o h ort B c o m pare d wit h place b o. T he m ost c o m m o nl y re p orte d T E A Es, occ urri n g 
i n 5 % or m ore of s u bjects treate d wit h a vatr o m b o pa g were ( b y decreasi n g or d er of fre q u e nc y) 
na usea, fati g ue, h ea dac h e, p ortal h y p erte nsi ve gastr o pat h y, di arr h ea, dizzi ness, m uscle s pas ms, 
pr oce d ur al pai n, vari c es es o p h a geal, v o miti n g, a b d o mi nal pai n u p per, a n d e de ma peri p heral. 
St u d y 2 0 3 w as a P hase 2 m ultice nter, m ulti nati o nal, ra n d o mize d, place b o -c o ntr olle d, d o u ble-
bli n d, parallel -gr o u p st u d y t o d e m o nstrate t h e efficac y of  o n ce d ail y d osi n g wit h a vatr o m b o pa g 
c o m pare d t o place b o i n s u bjects  wit h c hr o nic he patitis C vir us -relate d t hr o m b oc yt o p e nia w h o were  
p ote ntial ca n di dates f or a nti viral treat me nt. Pri or t o t he i nitiati o n of a nti viral t hera p y, t h e m ost 
c o m m o nl y re p orte d T E A Es ( ≥5 % of s u bjects) i n t he c o m bi ne d a vatr o m b o p a g gr o u p were na usea 
a n d fati g ue. T he m ost c o m m o nl y re p orte d T E A Es ( ≥5 % of s u bjects) d uri n g t he C ore St u d y a n d 
E xte nsi o n  P hase  i ncl u de d  a ne mia,  ne utr o p e nia,  na usea,  fati g ue,  pr urit us,  le u k o pe nia,  c hills,  
i ns o m nia, hea dac he, r as h, diarr hea, i nfl ue n za-li ke ill ness, c o u g h, p yre xia, ast he nia, v o miti n g, 
irrita bilit y,  a b d o mi nal  pai n,  ascites,  i njecti o n  site  er yt h e ma,  e de ma  peri p heral,  e pista xis,  
a b d o mi nal pai n u p per, de pressi o n, l y m p h o pe ni a, d ys pe psia, he m orr h oi ds, n as o p har y n gitis, u p per 
res pirat or y  tract  i nfecti o n,  h y per urice mia,  dizzi ness,  d ys p nea,  a n d  d ys p nea  e x erti o nal.  T he  
maj orit y of t hese c o m m o nl y re p orte d T E A Es occ urre d after t he i nitiati o n of a nti viral treat me nt, 
a n d are c o nsiste nt wit h w hat is e x pecte d i n p atie nts  recei vi n g a nti viral t hera p y with i nterfer o n, 
ri ba viri n, a n d/ or tela pre vir. 
I n St u d y 2 0 4, a P hase 2, ra n d o mize d, place b o-c o ntr olle d, d o u ble-bli n d, parallel -gr o u p st u d y, a 
t otal of 3 9 J a pa n ese s u bjects wit h t hr o m b oc yt o pe ni a ass oci ate d wit h C L D  w ere ra n d o ml y  assi g n e d 
t o a st u d y gr o u p a n d recei ve d place b o or a vatr o m b o pa g. T h e pri mar y a n al ysis of t he res p o n d er 
rate (res p o n d ers wer e defi ne d as s u bjects wit h a platelet c o u nt ≥5 0 × 1 0 9/ L a n d w h o s h o we d at 
least 2 0 × 1 09/ L i n crease fr o m bas eli ne at Visit 4 [ Da ys 1 0  t o 1 3]) i n t he a v atr o m b o pa g 4 0 m g a n d 
6 0 m g gr o u ps w as statisticall y si g nifica nt c o m pare d wit h t he place b o gr o u p. T he m ost c o m m o nl y 
re p orte d T E A Es (≥5 % of s u bjects) i n t he a vatr o m b o pa g gr o u p were, b y decreasi n g or der o f 
fre q ue n c y, p ost-pr oce d ur al c o m plicati o n, p ost -e m b olisati o n s y n dr o me, diarr hea, bl o o d gl uc ose 
i ncreas e d, he m orr h a ge s u bc uta ne o us, c o nsti pati o n, a n d nas o p har y n gitis. 
1. 5. 3  
P h ase 3 St u dies  
F o ur P hase 3 efficac y a n d safet y st u dies ( St u dies 3 0 2, 3 0 5, 3 1 0, a n d 3 1 1) were c o n d ucte d. 
I n St u d y 3 0 2, a m ultice nter, ra n d o mize d, d o u ble-bli n d , place b o-c o ntr olle d, parallel -gr o u p st u d y 
wit h a n o pe n -la bel e xte nsi o n ( O L E) p has e treati n g t hr o m b oc yt o pe nia i n a d ults wit h c hr o nic I T P, 
s u bjects recei v e d oral a vatr o m b o pa g or matc hi n g place b o, wit h a starti n g d ose of 2 0 m g  o nce dail y 
a vatr o m b o pa g, f oll o w e d wit h d ose titrati o n u p t o a ma xi m u m d ose of 4 0 m g or d o w n t o a mi ni m u m 
d ose  of  5  m g.  T he  O L E  i ncl u de d  o nce  d ail y,  oral  d osi n g  wit h  a  st arti n g  d ose  of  2 0  m g  
a vatr o m b o pa g, f oll o we d wit h d ose titrati o n ( 5, 1 0, 2 0, 3 0, or 4 0 m g d oses). T he pri mar y efficac y 
e n d p oi nt was hi g hl y statisticall y si g nifi ca nt , fa v ori n g a v atr o m b o pa g ( p < 0. 0 0 0 1) c o m pare d wit h 
place b o. T h e me dia n of t he c u m ulati ve n u m ber of wee ks wit h platelet c o u nt ≥5 0 ×  1 09/ L d uri n g 
t he 6-m o nt h treat me nt was 1 2. 4 wee ks f or a v atr o m b o pa g a n d 0 wee ks f or  place b o. T he m ost 
c o m m o nl y re p orte d T E A Es ( ≥5 % of s u bjects) i n t he a vatr o m b o pa g gr o u p i n t he C ore St u d y were 

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hea dac he,  c o nt usi o n,  u p per  res pir at or y  tract  i nfecti o n,  art hral gia,  e pista xis,  fati g ue,  gi n gi val  
blee di n g, p etec hi ae, bac k pai n, i ns o m nia, m o ut h he m orr ha ge, nas o p har y n gitis, na usea, a ne mia, 
bl o o d gastri n i ncreas e d, c o u g h, h y perte nsi o n, i nfl ue nza, t hr o m b oc yt o p e nia, a n d v o miti n g. I n t he 
c o m bi ne d C ore St u d y a n d E xte nsi o n P hase  i n t he a vatr o m b o pa g gr o u p ( n =4 7), t he m ost c o m m o nl y 
re p orte d T E A Es (≥5 % of s u bjects) were c o nt usi o n, hea dac he, u p per res pirat or y tract i nfecti o n, 
t hr o m b oc yt o pe ni a,  e pista xis,  gi n gi val  blee di n g,  fati g ue,  petec hiae,  p h ar y n gitis,  art hral gia,  
h y perte nsi o n, nas o p h ar y n gitis, bac k pai n, i nfl u e n za, m o ut h he m orr ha ge, c o u g h, i ns o m nia, n a use a, 
pai n i n e xtre mit y, a n d uri nar y tract i nfecti o n. 
I n St u d y 3 0 5, a m ultice nter, ra n d o mize d, d o u ble-bli n d, a cti ve-c o ntr olle d, parallel -gr o u p st u d y 
wit h a n O L E p h ase i n a d ults wit h c hr o nic I T P, s u bjects recei ve d oral a v atr o m b o pa g at 5, 1 0, 2 0, 
3 0, or 4 0 m g, wit h a starti n g d ose of a vatr o m b o pa g 2 0 m g, f oll o we d wit h d ose titrati o n d o w n t o 5 
m g or u p t o 4 0 m g. A t otal of 2 3 s u bjects were ra n d o mize d i nt o t he st u d y pri or t o t he pre mat ure 
ter mi nati o n of t he st u d y d ue t o sl o w e nr oll me nt. T he m ost c o m m o nl y re p orte d TE A Es i n t he 
a vatr o m b o pa g gr o u p i n t he C ore St u d y were dizzi ness, hea dac he, i ns o m nia, m usc ul os keletal pai n, 
a n d na usea, ( 3 [ 2 5. 0 %] s u bjects eac h). D uri n g t he c o m bi ne d C ore St u d y a n d E xte nsi o n P hase, t he 
m ost  c o m m o nl y  re p ort e d  T E A Es  were  fati g u e  a n d  hea d ac h e ( 5 [ 2 9. 4 %] s u bjects  eac h)  a n d  
dizzi ness, i ns o m nia, a n d nas o p har y n gitis ( 4 [ 2 3. 5 %] s u bjects eac h). 
T w o ( 1 6. 7 %) s u bjects i n t he a vatr o m b o pa g gr o u p ha d seri o us a d verse e ve nts ( S A Es) d uri n g t he 
C ore St u d y. T he e ve nt of I T P w as n ot c o nsi dere d b y t h e I n v esti gat or t o be rel ate d t o treat me nt. 
T he  e ve nts  of  p ortal  v ei n  t hr o m b osis  a n d  t hr o m b o p hle bitis  se ptic  were  c o nsi dere d  b y  t he  
I n v esti gat or t o be p ossi bl y r elate d t o i n vesti gati o nal pr o d uct (I P). 
St u dies 3 1 0 a n d 3 1 1 e nr olle d a d ults wit h C L D  a n d se vere t hr o m b oc yt o p e nia ( mea n baseli ne 
platelet c o u nt < 5 0 ×  1 09/ L), sc he d ul e d t o u n der g o i n vasi ve pr oce d ures. C o h orts were defi ne d b ase d 
o n baseli ne platelet c o u nt ( C o h ort 1, < 4 0 ×  1 09/ L or C o h ort 2, 4 0 t o < 5 0 ×  1 09/ L), a n d patients 
were ra n d o mize d 2: 1 t o o nce dail y oral a va tr o m b o pa g ( 6 0 m g f or C o h ort 1, 4 0 m g f or C o h ort 2) 
or place b o f or 5 da ys, wit h t he pr oce d ure s c h e d ule d 5 t o 8 da ys after t heir last d ose. 
T he pri mar y efficac y e n d p oi nt was t he pr o p orti o n of patie nts n ot re q uiri n g platelet tra nsf usi o n or 
a n y blee di n g resc u e  pr o ce d ure u p t o 7 da ys p ost -pr oce d ure. Sec o n dar y e n d p oi nts assesse d t h e 
pr o p orti o n of patie nts ac h ie vi n g t he tar get platelet c o u nt (≥5 0 ×  1 09/ L), c h a n ge i n platelet c o u nt 
fr o m baseli ne t o Pr oce d ure Da y, a n d safet y. 
St u d y 3 1 0  ra n d o mize d  2 3 1  patie nts  t o  1  of  2 p ossi ble  c o h orts:  C o h ort  1  ( 9 0  a vatr o m b o pa g  
patie nts / 4 8 place b o patie nts ) or C o h ort 2 ( 5 9 a v atro m b o pa g p atie nts / 3 4 place b o patie nts ). Patie nts 
ha d a me dia n a ge of 5 7 years wit h 6 8 % of patie nts bei n g male a n d a bas eli ne me dia n platel et c o u nt 
of 3 8 ×  1 09/ L. T h e C L D  eti ol o g y of patie nts was 1 4 % alc o h ol, 6 2 % viral h e patitis, a n d 2 3 % ot her. 
St u d y 3 1 1  r a n d o mize d  2 0 4  patie nts  t o  1  of  2  p ossi ble  c o h orts:  C o h ort  1  ( 7 0  a v atr o m b o pa g 
patie nts / 4 3 place b o patie nts ) or C o h ort 2 ( 5 8 a v atr o m b o pa g p atie nts / 3 3 place b o pat ie nts). Patie nts 
ha d a me dia n a ge of 5 9 years wit h 6 2 % of patie nts bei n g male a n d a b aseli ne me dia n  platelet of 
3 9 ×  1 09/ L. T he C L D  eti ol o g y of patie nts w as 1 5 % alc o h ol, 5 3 % viral he patitis, a n d 3 3 % ot her. 
Si g nifica ntl y gr eater  pr o p orti o ns  of  a v atr o m b o pa g -treate d  patie nts  acr oss  all  c o h orts  di d  n ot  
re q uire platelet tra nsf usi o n or blee di n g resc u e pr oce d ures c o m pare d wit h place b o: St u d y 3 1 0: 
C o h ort 1, 6 6 % vers us 2 3 %; C o h ort 2, 8 8 % vers us 3 8 %; eac h p < 0. 0 0 0 1; St u d y 3 1 1: C o h ort 1, 6 9 % 
vers us 3 5 %, p = 0. 0 0 0 6; C o h ort 2, 8 9 % vers us 3 3 %, p < 0. 0 0 0 1. A vatr o m b o p a g was als o s u peri or t o 
place b o f or b ot h sec o n d ar y e n d p oi nts, i ncreasi n g mea n platel et  c o u nts o n Pr oce d ure Da y t o 
6 4 ×  1 09/ L i n C o h ort 1 a n d 8 5 ×   1 09/ L i n C o h ort 2. T he m ost c o m m o n T E A Es were p yre xia, 

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a b d o mi nal pai n, na usea, a n d hea dac he, w hic h w ere si milar f or place b o a n d a vatr o m b o pa g ar ms i n 
b ot h st u dies . M ost T E A Es wer e mil d t o m o derate i n se v erit y;  h o we v er, 1  t hr o m b otic T E A E 
occ urr e d i n C o h ort 2 ( 4 0 m g a vatr o m b o p a g) i n St u d y 3 1 1. T he st u dies c o n cl u de d a vatr o m b o p a g 
gi ve n o v er 5 d a ys si g nifi ca ntl y re d u ce d t he n ee d f or platelet tra nsf usi o ns or resc ue pr oce d ures f or 
blee di n g, a n d it was well t olerate d wit h a safet y pr ofile si milar t o place b o.   
1. 6  
R ati o n ale 
Data i n s u bjects wit h C L D  a n d I T P s u g gest t hat a vatr o m b o pa g is a pr o misi n g ca n di dat e f or use i n 
t he treat me nt of t hr o m b oc yt o p e nia of di verse eti ol o gies. A va tr o m b o pa g is bei n g de vel o pe d t o 
p ote ntiall y a d dress t he u n met me dical nee d of CI T. T he st u d y ai ms t o e val uate t he efficac y of 
a vatr o m b o pa g i n i ncreasi n g platelet c o u nts p ost- c he m ot hera p y t o a v oi d platelet tra nsf usi o ns a n d 
c he m ot hera p y  d ose  del a ys  or  d ose  r e d u cti o ns .  T he  safet y  of  a vatr o m b o pa g  i n  t his  s u bject  
p o p ulati o n will als o be assesse d t hr o u g h m o nit ori n g of a d vers e e ve nts, a d verse e v e nts of s pecial 
i nterest ( A E SI), cli nical la b orat or y p ara met ers, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns.  
T hr o m b o c yt o p e nia occ urs at vari o us gra des of se v erit y i n s u bjects u n der g oi n g c h e m ot hera p y wit h 
m yel os u p pr essi ve a ge nts. Fre q u e ntl y, it is t he maj or d ose -li miti n g he mat ol o gic t o xicit y. T his is 
bec o mi n g  i ncreasi n gl y  i m p orta nt  gi ve n  t h e  rece nt  tre n d  t o w ar d  t he  use  of  d ose -i nte nsi ve 
c o m bi nati o n c he m ot hera p y r e gi me ns facilitate d b y s u p p orti ve he m at o p oietic c ol o n y -sti m ulati n g 
fact ors t o pr e ve nt c h e m ot hera p y-i n d uce d fe brile ne utr o pe nia. T h e sta n dar d treat me nt d uri n g t he 
c ycle of c h e m ot hera p y t o c orr ect platel ets is a t h e ra pe utic platelet tra nsf usi o n, es peciall y i n t he 
setti n g  of  a n  acti ve
 blee di n g  e v e nt.  T he  sta n dar d  pre ve nti ve  meas ure  a gai nst  
c he m ot hera p y-i n d uce d  d e pressi o n  of  platelets  i n  s u bse q ue nt  treat me nt  c ycl es  has  bee n  d ose  
re d ucti o n a n d/ or d ose d el a y.  
W hile plat elet tra nsf usi o ns ofte n resc ue s u bjects wit h ver y l o w platelet le vels, t he y are ass o ciate d 
wit h  t he  ris k  of  viral  a n d  bacterial  i nfecti o ns,  as  well  as  all oi m m u nizat i o n.  Platelet  d o n or  
recr uit me nt ca n als o be diffic ult a n d platelet tra nsf usi o n ca n be ver y ex pe nsi ve de pe n di n g o n t he 
s o urce of platelets. Ca ncer patie nts recei vi n g i nte nsi ve c he m ot hera p y or m yel oa bl ati ve re gi me ns 
ma y re q uir e m ulti ple platelet tra nsf usi o ns . F or t hese patie nts, alter n ate strate gies are n ee d e d s o 
t hat platelet tra nsf usi o ns ca n be si g nifi ca ntl y re d u ce d or eli mi nate d. As a res ult, f or t he p ur p oses 
of t h is st u d y, o ne c o m p o ne nt of t h e pri mar y e n d p oi nt will classif y a res p o n der as a s u bject w h o 
di d N O T re q uir e t he a d mi nistrati o n of a platelet tra nsf usi o n. 
Relati ve d ose i nte nsit y ( R DI) is a ter m t hat refers t o t he a m o u nt of a partic ular c he m ot hera p y gi ve n 
o ver a s pecific ti me i n relati o n t o w hat w as or d ere d ( or is c o nsi dere d st a n dar d). D ose d ela ys a n d 
d ose re d ucti o ns ca n de crease R DI a n d p ote ntiall y i ncrease t he ris k of disease pr o gressi o n   a n d 
m ortalit y. Retr os pecti ve a nal ys es of ra n d o mize d c o ntr olle d cli nical trials h a ve s u g geste d a str o n g 
ass ociati o n bet wee n R DI a n d disease -free a n d o verall s ur vi val, es peciall y f or l y m p h o ma a n d 
ca ncers of t he breast, l u n g, o var y, a n d c ol o n. D ata s h o w i ncreas e d s ur vi val f or s u bjects w h o recei ve 
≥8 5 % R DI a n d, c o n versel y, m ortalit y c ur v es si milar t o u ntreate d p o p ulati o ns w he n t his t hres h ol d 
R DI is n ot a d mi nistere d. As a res ult, f or t he p ur p oses of t h is st u d y, o n e c o m p o ne nt of t he pri mar y 
e n d p oi nt  will  classif y  a  res p o n d er  as  a  s u bject w h o  di d  N O T  h a ve  a  d ose  re d ucti o n  of  
c he m ot hera p y of ≥1 5 % (t o mai ntai n t he R DI > 8 5 %) .5 -9 , 1 1 -2 0 
I n a d diti o n, c h e m ot hera p y d os e del a y ( or t otal d urati o n of c he m ot hera p y) als o c o ntri b utes t o t h e 
o verall o utc o mes of s u bjects recei vi n g c h e m ot hera p y. W hile t here are fe w er st u dies i n vesti gati n g 
t he i m pact of c he m ot her a p y d ose del a y o n o utc o m es, o ne st u d y i n dicate d t h at a n e xte nsi o n of t he 

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ti me t o c o m plete t he e ntire c h e m ot hera p y re gi me n res ulte d i n p o orer o utc o mes .1 0 ,2 1  I n t hat st u d y, 
t he t otal dela y of treat me nt acr oss 5 c ycl es was 9 da ys. W hile a d ela y i n c he m ot hera p y i nitiati on 
of 7  da ys is a c o m m o n d urati o n of dela y d escri b e d i n t he literat ure, mai nl y d ue t o c o n ve nie nce of 
re-sc h e d uli n g  a  c he m ot hera p y  i nf usi o n,  t he  af ore me nti o ne d  st u d y  s u g gests  m ulti ple  s h orter  
d urati o n dela ys ma y res ult i n cli nicall y rele v a nt alterati o ns i n o utc o mes. As a res ult, f or t h e 
p ur p oses of t h is st u d y, on e  c o m p o ne nt of t he pri mar y e n d p oi nt will classif y a res p o n der as a s u bject 
w h o di d N O T h a ve a d os e dela y of c h e m ot hera p y of ≥4 da ys (t o mai ntai n t he o verall d urati o n of 
c he m ot hera p y as s h ort as p ossi ble t o mai ntai n o utc o mes).  
1. 7  
Ris k/ Be nefit  
C urre nt  treat me nt  o pti o ns  f or  patie nts  wit h  CI T  i ncl u de  c he m ot hera p y  d os e  re d u cti o ns,  
c he m ot hera p y d ose d ela ys, a n d platelet tra nsf usi o ns. W hile t he ris ks of si n gl e platelet tra nsf usi o ns 
are  ge n erall y c o nsi dere d  acce pt a ble,  t he y are  o nl y tra nsie ntl y effecti ve  at  i ncreasi n g  platelet  
c o u nts,  a n d  are  ass oci ate d  wit h  i m p orta nt  patie nt  ris ks  t hat  ca n  ha ve  si g nifica nt  healt h  a n d  
ec o n o mic c o nse q u e nces. I n a d diti o n t o t he p ote ntial ris ks of tra nsf usi o n reacti o ns a n d i nfecti o ns, 
w hic h i n rare cases ca n be fatal, t he de vel o p me nt of  a nti-platelet a nti b o dies  a n d t he res ulta nt 
refr act ori ness  t o  s u bse q ue nt  platelet  tra nsf usi o ns  are  of  partic ular  i m p orta nce.  Gi v e n  t hat  
a vatr o m b o pa g sti m ulates t he b o d y’s o w n me ga k ar y o c yt es t o pr o d uce platel ets, t here is n o ris k f or 
i nfecti o n,  a n d  n o  i m m u ne  res p o nse  a n d  t h us  n o  ris k  of  refract ori n ess.  T his  has  i m p orta nt  
i m plicati o ns i n preser vi n g t he utilizati o n of platelets f or e mer ge nt or f ut ure nee ds of t he patie nt, 
w hic h ma y n ot be a v aila ble if t he y b ec o me refract or y.  
A n orall y a d mi nistere d t hr o m b o p oietic a ge nt t hat ca n pre ve n t si g nifica nt t hr o m b oc yt o pe ni a d ue t o 
c he m ot hera p y a n d a v oi d a n y r e d ucti o ns i n d osa ge or dela ys i n c he m ot hera p e utic re gi me ns w o ul d 
pr o vi de a n i m p orta nt p u blic healt h be nefit. 

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S T U D Y O B J E C TI V E S  
2. 1  
Pri m ar y O bjecti ve  
T he pri mar y o bjecti ve  of t his st u d y is t o e v al uate t he efficac y of a vatr o m b o pa g i n i ncreasi n g 
platelet c o u nts a n d t her ef ore pr e ve nti n g t he nee d f or a pl atelet tra nsf usi o n or c he m ot hera p y d os e 
re d ucti o n or del a y i n s u bjects wit h CI T. 
2. 2  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ve s of t his st u d y are t he f oll o wi n g: 
•  T o e val uate t he s afet y of a vatr o m b o pa g i n s u bjects wit h CI T, a n d 
•  T o i n vesti gate t h e effect of a vatr o m b o pa g o n bl ee di n g i n s u bjects wit h CI T. 
 

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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  
4. 1  
I ncl usi o n Criteri a f or All S u bjects 
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o partici pate i n t he st u d y:  
1.  S u bject is ≥1 8 years of a ge at t he ti me of i nf or me d c o nse nt; 
2.  S u bject wit h a dia g n osis  wit h o varia n ca ncer, l u n g ca n cer  (s mall cell or n o n-s mall cell), or 
bla d der ca ncer, re q uiri n g s yste mic c h e m ot hera p y;  
3.  S u bject is c urre ntl y recei vi n g a c h e m ot hera p y re gi me n gi ve n i n a 2 1 -da y or 2 8 -da y c ycl e ( ot her 
c he m ot hera p y c ycl e le n gt hs are n ot all o we d), i n cl u di n g 1 or m ore of t he f oll o wi n g a ge nts or 
class of a ge nts:  
o  N ucle osi de a n al o g, i n cl u di n g ge mcita bi n e a n d fl u or o uracil; 
o  Car b o plati n or cis plati n; 
o  A nt hrac ycli ne; or  
o  Al k ylati n g a ge nt;  
4.  S u bject  e x perie nce d  se v ere  t hr o m b oc yt o pe ni a,  defi ne d  as  2  platelet  c o u nts  < 5 0  ×   1 09/ L 
meas ure d at leas t 2 4 h o urs a part, d uri n g t he q ualif yi n g c he m ot hera p y c ycle ( C ycle X), of t heir 
c urre nt c he m ot her a p y re gi me n. Platelet c o u nts o btai ne d per sta n d ar d of care d uri n g C ycle X 
pri or t o c o nse nt ma y be use d; 
5.  S u bject  is  pla n ne d t o recei ve  t he  sa me  c he m ot hera p y re gime n  a n d  t he  sa me  d ose(s)  o n  
C he m ot hera p y Da y  ( Da ys 1-3) of C ycle X + 1 as wa s gi ve n i n t he q ualif yi n g c h e m ot hera p y 
C ycle X;  
6.  S u bject has a n Easter n C o o perati ve O n c ol o g y Gr o u p ( E C O G) perf or ma n ce stat us ≤2; 
7.  S u bject has a life e x pecta nc y > 1 2 w ee ks at Scree ni n g  an d is a ble t o recei ve at least 2 a d diti o nal 
c ycles of t he c urr e nt c he m ot he ra p y re gi me n; 
8.  Fe males of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
(e g, t otal a bsti ne nce; a n i ntra uteri ne de vice; h or m o nal c o ntrace pti ve gi ve n orall y, b y i njecti o n, 
or b y i m pla nt; d o u ble barrier c o ntr ace pti o n (i.e., c o n d o m + dia p hra g m) ; or has a vasect o mize d 
part ner wit h c o nfir me d az o os per mia) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after 
i n vesti gati o nal pr o d uct (I P) disc o nti n uati o n. If c urre ntl y a bsti ne nt, t he s u bject m ust a gree t o 
use a n eff ecti ve met h o d as descri be d a b o v e if s h e bec o m es se x uall y acti v e d uri n g t he st u d y 
peri o d or f or 3 0 d a ys aft er I P disc o nti n uati o n.   
Male s u bjects m ust be eit her s ur gi call y sterile or a gree t o use  a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s per mici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n; 
N ote:  All  fe mal e  s u bjects  are  c o nsi dere d  t o  be  of  c hil d beari n g p ote nti al  u nless  t he y are  
p ost me n o pa usal (at least 1 2 m o nt hs c o nsec uti ve a me n orr h ea a n d wit h o ut a n ot her k n o w n or 
s us pecte d ca use) or ha v e bee n sterilize d s ur gicall y (i e, bilateral t u bal li gati o n, h ysterect o m y, 
or bilateral o o p h or ect o m y) at least 1 m o nt h bef ore d osi n g. 
9.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ect s of t he pr ot oc ol; a n d  

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1 0.  S u bject m ust pr o vi de writte n i nf or me d c o nse nt. 
4. 2  
E xcl usi o n Criteri a f or All S u bjects  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m partici pati o n i n t he st u d y:  
1.  S u bject has e x perie nce d ≥ Gra de 2 CI T wit h a pl atel et c o u nt < 7 5 ×  1 09/ L ( ot her t ha n d uri n g 
t he c urr e nt c he m ot her a p y treat me nt re gi me n) wit hi n 6 m o nt hs of Scree ni n g; 
2.  S u bject has a platelet c o u nt > 1 7 5 ×  1 09/ L at Visit 2 (- 1 da y); 
3.  S u bject  wit h  a n y  hist or y  of  he mat ol o gic  mali g na n cies,  i ncl u di n g  le u ke mia,  m yel o ma, 
m yel o pr olif erati ve diseas e, l y m p h o ma, or m yel o d ys plastic diseas es; 
4.  S u bject w h o recei ve d > 2 pre vi o us li nes of c he m ot hera p y (a dj u va nt/ ne o a dj u va nt t hera p y is 
c o nsi dere d a pre vi o us li ne; i m m u n ot hera p y al o ne is n ot c o nsi d ere d a pre vi o us li ne) or is 
recei vi ng w h ole brai n r a diati o n d uri n g t he st u d y treat me nt peri o d; 
5.  S u bject wit h a n ala ni ne a mi n otra nsferase  ( A L T) or as partat e a mi n otra nsferase  ( A S T) > 5 ×  
u p per li mit of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit of n or mal; 
6.  S u bject has a k n o w n me dical hist or y of h u m a n i m m u n o deficie nc y vir us; 
7.  S u bject has a n y k n o w n cli nicall y si g nifica nt ac ut e or acti ve blee di n g (e g, gastr oi nte sti nal or 
ce ntral ner v o us s yste m) wit hi n 7 da ys of Scree ni n g; 
8.  S u bject
 has
 a
 k n o w n
 me dical
 hist or y
 of
 ge n etic
 pr ot hr o m b otic
 s y n dr o mes
 
(e g, Fact or V Lei de n, pr ot hr o m bi n G 2 0 2 1 0 A, or A TIII deficie nc y); 
9.  S u bject has a rece nt hist or y ( wit hi n 3 m o nt hs of Scree ni n g ) of si g nifica nt car di o vasc ular 
disease ( e g, c o n gesti ve h eart fail ure e x acer b ati o n , arr h yt h mia k n o w n t o i n creas e t he ris k of 
t hr o m b oe m b olic e ve nts [ e g, atrial fi brillati o n], c or o nar y arter y ste nt place me nt, a n gi o plast y, 
or c or o nar y art er y b y pass gr aft);  
1 0.  S u bject has a hist or y of arterial or ve n o us t hr o m b osis wit hi n 3 m o nt hs of Scree ni n g; 
1 1.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of Scree ni n g ( us e of l o w m olec ular 
wei g ht h e pari n , X a i n hi bit ors, or t hr o m bi n i n hi bit ors is all o we d); 
1 2.  S u bject has a hist or y of c hr o nic platel et or blee di n g dis or d ers or t hr o m b oc yt o pe nia d ue t o a n 
eti ol o g y ot her t ha n CI T ( e g, c hr o nic li ver disease or i m m u ne t hr o m b oc yt o p e nia p ur p ura); 
1 3.  S u bject has use d m o derat e or str o n g i n d ucers of c yt oc hr o me P 4 5 0 ( C Y P) 2 C or C Y P 3 A 4/ 5 (see 
A p p e n di x  C) wit hi n 7 da ys of Scree ni n g; 
1 4.  S u bject has recei ve d a t hr o m b o p oieti n rece pt or a g o nist (e g, eltr o m b o pa g or r o mi pl osti m) or 
rec o m bi na nt h u ma n t hr o m b o p oieti n f or t he treat me nt of CI T wit hi n 3 m o nt hs of Scree ni n g; 
1 5.  S u bject recei v e d a platel et tra nsf usi o n wit hi n 7 2 h o urs of ra n d o mizati o n; 
1 6.  S u bject is u na ble t o ta ke oral me dicati o n ; 
1 7.  S u bject  has  a n y  hist or y  of  a  c o n c o mita nt  me di cal  c o n diti o n  t hat,  i n  t h e  o pi ni o n  of  t he  
I n v esti gat or, w o ul d c o m pr o mise t he s u bject’s a bilit y t o safel y c o m plete t he st u d y, s uc h as 
u nsta ble a n gi na, re n al f ail ure r e q uiri n g he m o dial ysis, or acti ve i nfecti o n re q uiri n g i ntra ve n o us 
a nti bi otics; 

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1 8.  Fe male  s u bj ects  w h o  are  lactati n g  or  pre g n a nt  at  Scree ni n g  or  t he  Baseli ne  Visit  (as 
d oc u me nte d b y a p ositi ve ser u m or uri n e  beta - h u ma n c h ori o nic go na d otr o pi n [ β -h C G] test)  ; 
1 9.  S u bject has h y p erse nsiti vit y t o a vatr o m b o pa g or a n y of its e x ci pie nts; or  
2 0.  S u bject is c urr e ntl y e nr olle d i n a n ot her cli nical st u d y wit h a n y i n vesti gati o nal dr u g or de vice 
wit hi n 3 0 da ys of Scree ni n g; h o we v er, p artici pati o n i n o bs er vati o nal st u dies is per mitte d . 
4. 3  
I ncl usi o n Criteri a f or S u bjects t o C o nti n ue I nt o t he O pti o n al O pe n-L a bel 
E xte nsi o n Peri o d  
S u bjects w h o meet all of t he f oll o wi n g criteria will be eli gi ble t o c o nti n ue i nt o t he o pti o nal O L E 
Peri o d : 
1.  S u bject is c urre ntl y recei vi n g t he sa me c he m ot hera p y a ge nts as w ere gi ve n i n t he q ualif yi n g 
c he m ot hera p y C ycl e X;  
2.  S u bject has a n E C O G  perf or ma nce stat us ≤2; 
3.  Fe males of c hil d beari n g p ote ntial m ust a gree t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n 
as pre vi o usl y d efi ne d.  
Male s u bjects m ust be eit her s ur gi call y sterile or a gree t o use a d o u ble barrier c o ntrace pti o n 
met h o d 
(c o m bi nati o n  of  male  c o n d o m  wit h  eit her  ca p,  dia p hra g m,  or  s p o n ge  wit h  a  
s per mici de) t hr o u g h o ut t he e ntire st u d y peri o d a n d f or 3 0 da ys after I P dis c o nti n uati o n;  
N ote:  All  fe mal e  s u bjects  are  c o nsi dere d  t o  be  of  c hil d beari n g p ote nti al  u nless  t he y are  
p ost me n o pa usal (at least 1 2 m o nt hs c o nsec uti ve a me n orr hea i n t he a p pr o priate a ge gr o u p a n d 
wit h o ut a n ot her k n o w n or s us pecte d ca us e) or h a ve bee n sterilize d s ur gi cal l y (ie, bilateral t u bal 
li gati o n, h yst erect o m y, or bilateral o o p h orect o m y) at least 1 m o nt h bef ore d osi n g. 
4.  S u bject is willi n g a n d a bl e t o c o m pl y wit h all as p ects of t he pr ot oc ol; a n d  
5.  S u bject m ust pr o vi de c o nse nt t o c o nti n ue i nt o t he O L E Peri o d. 
4. 4  
E xcl usi o n Criteri a f or S u bjects t o C o nti n ue I nt o t he O pti o n al O pe n -L a bel 
E xte nsi o n Peri o d  
S u bjects w h o me et a n y of t he f oll o wi n g criteri a will be e x cl u de d fr o m c o nti n ui n g i nt o t he 
o pti o nal O L E Peri o d: 
1.  S u bject has a pl atelet c o u nt > 1 7 5 ×  1 09/ L o n t h e sc he d ule d first d a y of d osi n g of a v atr o m b o pa g 
pri or t o c he m ot her a p y; 
2.  S u bject wit h a n A L T  or A S T > 5 ×  u p p er li mi t of n or mal or t otal bilir u bi n ≥3 ×  u p per li mit of 
n or mal; 
3.  S u bject has a n y k n o w n cli nicall y si g nifica nt ac ut e or acti ve blee di n g (e g , gastr oi ntesti nal or 
ce ntral  ner v o us s yste m) wit hi n 7 da ys of pre-c he m ot hera p y I P treat me nt i n O L E c ycles ; 
4.  S u bject has use d vita mi n K a nta g o nists wit hi n 7 da ys of pre -c he m ot hera p y I P treat me nt i n 
C ycle X + 3 ( use of l o w m olec ular wei g ht h e pari n , Xa i n hi bit ors, or t hr o m bi n i n hi bit ors  is 
all o we d);  

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5.  S u bject has use d m o derate or str o n g i n d ucers of C Y P 2 C or C Y P 3 A 4/ 5 (see  A p pe n di x C ) 
wit hi n 7 da ys of pre- c he m ot hera p y I P treat me nt i n O L E c ycles ; 
6.  S u bjec t is u na ble t o ta ke oral me dicati o n ; 
7.  Fe male s u bjects w h o are l actati n g or pre g n a nt (as d oc u me nte d b y a p ositi ve uri ne or ser u m  
test). 
4. 5  
Wit h dr a w al Criteri a  
Partici pati o n of a s u bject i n t his cli nical st u d y ma y be disc o nti n ue d f or a n y of t he f oll o wi n g 
reas o ns: 
•  T he s u bject wit h dra ws c o nse nt or re q u ests disc o nti n uati o n fr o m t he st u d y f or a n y reas o n; 
•  O cc urre nce of a n y me di cal c o n diti o n or circ u msta nce t hat e x p oses t he s u bject t o s u bsta ntial 
ris k a n d/ or d oes n ot all o w t he s u bject t o a d here t o t he re q uire m e nts of t he pr ot oc ol; 
•  A n y seri o us  a d verse  e v e nt  (S A E ),  cli nicall y  si g nifica nt  a d v erse  e v e nt,  se vere  la b orat or y 
a b n or malit y, i nterc urre nt ill ness, or ot her me dical c o n diti o n w hic h i n dicates t o t he I n vesti gat or 
t hat c o nti n ue d partici pati o n is n ot i n t he best i nterest of t he s u bject; 
•  Pre g n a nc y;  
•  Re q uire me nt of pr o hi bite d c o nc o mita nt me dicati o n;  
•  S u bject fail ur e t o c o m pl y wit h pr ot oc ol re q uire me nts or st u d y- relate d pr o ce d ures; or  
•  Ter mi nati o n of t he st u d y b y t he S p o ns or or t h e re g ulat or y a ut h orit y. 
If a s u bject wit h dra ws pr e mat urel y fr o m t he st u d y d u e t o t he a b o ve criteria or a n y ot her reas o n, 
st u d y staff s h o ul d ma k e e ver y eff ort t o c o m plet e t he f ull pa nel of ass ess me nts sc he d ule d f or 
Visit  1 3 (f or s u bjects n ot i n t he o pti o nal O L E Peri o d) or Visit  1 7 (f or s u bjects partici pati n g i n  t he 
o pti o nal O L E Peri o d) . All s u bjects s h o ul d c o nti n ue i nt o t he L o n g -Ter m F oll o w -U p  Peri o d u nless 
c o nse nt has b ee n wit h dr a w n. T he reas o n f or s u bject wit h dra w al m ust b e d oc u me nte d i n t he 
electr o nic case re p ort f or m (e C R F).  
I n t he case of s u bjects  l ost  t o f oll o w-u p, atte m pts t o c o ntact  t he s u bject  m ust  be ma de a n d 
d oc u me nte d i n t he s u bject ’s me dical rec or ds. 
4. 5. 1  
S u bjects wit h I n vesti g ati o n al Pr o d uct I nterr u pti o n or Disc o nti n u ati o n 
S u bjects w h o disc o nti n ue st u d y dr u g will be f oll o we d f or t he e ntire st u d y d urati o n t hr o u g h t he 
L o n g -t er m F oll o w- U p Peri o d  ( u nless t he s u bject wit h dra ws c o nse nt), a n d all pr oce d ures s h o ul d be 
f oll o we d acc or di n g t o t he pr ot oc ol. 
If a s u bject disc o nti n ues st u d y dr u g d ue t o a n a d verse e ve nt, t he I n vesti gat or will atte m pt t o f oll o w 
t he e ve nt u ntil it has res ol ve d or sta bilize d. 
If a s u bject misses a d ose of st u d y dr u g, te m poraril y i nterr u pts treat me nts ( w het her d ue t o a n 
a d verse e v e nt or ot her reas o n), t he I n vesti gat or s h o ul d c o ntact t he Me dical M o nit or re gar di n g h o w 
t o ha n dle treat me nt r e-i nitiati o n or if per ma ne nt st u d y dr u g disc o nti n uati o n is re q uire d. 

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S T U D Y T R E A T M E N T S  
5. 1  
Tr e at me nt Gr o u ps  
T his is a P hase 3 ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y of t he efficac y a n d safet y of 
oral a vatr o m b o pa g i n s u bjects wit h CI T wit h acti ve n o n -he mat ol o gical ca ncers. T he st u d y c o nsists 
of 4 peri o ds: a D o u ble-Bli n d Treat me nt Peri o d , a n O bser vati o nal Peri o d, a n o pti o nal O L E Peri o d, 
a n d a L o n g- T er m F oll o w - U p Peri o d. 
S u bjects i n t he D o u ble-Bli n d Treat me nt Peri o d will be ra n d o mize d t o o ne of 2 st u d y ar ms: 6 0 m g 
a vatr o m b o pa g ( 3 ×  2 0 m g ta blets) o n ce d ail y  or pl ace b o  ( 3 t a blets).  
S u bject s i n t he O bser vati o nal Peri o d will n ot recei ve a n y I P. 
S u bjects i n t he o pti o nal O L E  Peri o d will recei v e 6 0 m g a vatr o m b o pa g ( 3 ×  2 0 m g  ta blets) o n ce 
dail y.  
S u bjects i n t he L o n g- T er m F oll o w -U p Peri o d will n ot recei ve a n y I P.  
5. 2  
R ati o n ale f or D osi n g 
A P K/ P D m o de l was de vel o pe d t o si m ulate platelet res p o nse t o a vatr o m b o pa g a d mi nistrati o n i n 
or der t o sel ect a d os e r e gi me n f or t his st u d y. Usi n g data fr o m h ealt h y v ol u nt eers a n d s u bjects wit h 
C L D , t h e P K/ P D m o del e val uate d t he relati o ns hi p of a v atr o m b o pa g c o nce ntrati ons t o i ncreases i n 
platelet c o u nts. As a part of t his m o del , t he effect of car b o plati n d ose o n platelet c o u nt o btai ne d 
fr o m p o p ulati o n P K/ P D m o deli n g of eltr o m b o pa g i n s u bjects wit h a d va nce d s oli d t u m ors wit h CI T 
was als o i nc or p orate d.4  Si m ulati o ns were perf or me d ass u mi n g t he bas eli ne platelet c o u nt ra n ge d 
bet wee n 2 5 a n d 1 5 0  ×  1 09/ L wit h a g oal t o i ncrease t he platelet c o u nt t o le vels > 1 0 0 ×  1 09/ L f or 
t he d urati o n of c he m ot hera p y tr eat me nt t o pre ve nt platelet tra nsf usi o n a n d t o all o w t he s u bject t o 
recei v e t he  sa me  d ose  a n d  sc h e d ule of c h e m ot hera p y as  prescri be d  i n  C ycl e X. Si m ulati o ns 
s u g geste d t hat 6 0 m g a v atr o m b o pa g a d mi nistere d o nce dail y f or 5 da ys pri or t o c he m ot hera p y a n d 
o nce dail y f or 5 d a ys f oll o wi n g c h e m ot hera p y w as t he m ost a p pr o priate f or mai ntai ni n g platel et 
c o u nts a b o ve t his t hres h ol d w hile pre ve nti n g platelet c o u nts fr o m ele v ati n g a b o ve t he u p p er li mit 
of n or mal. 
T o e ns ure t he acc ur ac y of t he pre dicti o ns, platelet res p o nse data will be re vie we d b y t he D S M B 
as descri be d i n  Secti o n 3. 3 , a n d if necessar y, d osa ge a dj ust me nts ma y be ma de f oll o wi n g t hese 
data re vie ws.  
5. 3  
R a n d o miz ati o n a n d Bli n di n g  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y. F or t he D o u ble -Bli n d Treat me nt 
Peri o d, s u bjects w h o meet t he i ncl usi o n criteria a n d e x cl usi o n criteria will be ra n d o mize d t o 
recei v e eit her a v atr o m b o pa g 6 0 m g or place b o i n a 2: 1 rati o at t he Baseli ne Visit. Ra n d o mizati o n 
will be stratifie d b y t he n u m ber of c he m ot hera p y a ge nts t he s u bject is recei vi n g  ( 1, ≥2 per missi ble 
c he m ot hera p y a ge nts [ n ucle osi de a n al o g, i ncl u di n g ge mcita bi ne a n d fl u or o uracil; car b o plati n or 
cis plati n; a nt hrac ycli ne; or al k yl ati n g a ge nt] ). Ra n d o mizati o n assi g n me nt will be perf or m e d usi n g 
i nteracti ve  r es p o nse  tec h n ol o g y  (I R T).  F oll o wi n g  ra n d o mizati o n,  I P will  be  dis pe nse d  i n  a  
d o u ble- bli n d ma n ner. T he S p o ns or a n d desi g nate d cli nical site pers o n nel (I n v esti gat or a n d st u d y 
c o or di nat or) will be bli n de d t o t he treat me nt gr o u p f or eac h  s u bject. S ubjects will als o be bli n de d 
t o t he treat me nt t he y recei ve. 

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5. 4  
Bre a ki n g t he Bli n d  
At t he i nitiati o n of t he st u d y, t he I n vesti gat or will be i nstr ucte d o n t he met h o d f or brea ki n g t he 
bli n d. T he  b li n d  is  n ot  t o  be  br o ke n  d uri n g  t he  st u d y  u nless  c o nsi dere d  necessa r y  b y  t h e  
I n v esti gat or f or e mer ge n c y sit uati o ns f or reas o ns of s u bject safet y. U n bli n di n g at t h e cli nical site 
f or a n y ot her reas o ns will be c o nsi der e d a pr ot o c ol de viati o n. T he I n vesti gat or s h o ul d c o ntact t he 
Me dical M o nit or bef or e brea ki n g t he bli n d, if ti me per mits. W he n t he bli n d is br o ke n, t he reas o n 
m ust be f ull y d oc u me nt e d.  
5. 5  
Dr u g S u p plies  
5. 5. 1  
F or m ul ati o n a n d P ac k a gi n g 
A vatr o m b o pa g will be pr o vi de d as fil m -c oat e d ta blets , wit h eac h ta bl et c o ntai ni n g  a v atr o m b o pa g 
maleate (e q ui v ale nt t o  2 0 m g of  a v atr o m b o pa g) a n d t he f oll o wi n g e x ci pie nts: lact ose m o n o h y drate, 
c oll oi dal  silic o n  di o xi de,  cr os p o vi d o ne,  ma g nesi u m  stearate,  micr ocr ystalli ne  cell ul ose,  a n d  
O pa dr y II 8 5 F 4 2 2 4 4.  
Matc hi n g place b o ta bl ets, c o ntai ni n g lact ose m o n o h y drate ( 2 3. 6 m g), will be pr o vi de d. 
I n vesti gati o nal pr o d uct will be pac ka ge d i n bli n de d blister pac ka ges , eac h c o ntai ni n g 1 5 ta blets. 
F or t he o pti o nal O L E Peri o d, a vatr o m b o pa g will be pac ka ge d i n o pe n -la bel blister pac ka ges, eac h 
c o ntai ni n g 1 5 ta bl ets of a vatr o m b o pa g. 
5. 5. 2  
I n vesti g ati o n al Pr o d uct Di s pe nsi n g 
T he I n vesti gat or or desi g nee will pr o vi de s u bjects wit h s ufficie nt I P t o c o m plete eac h 5-d a y c o urse 
of st u d y dr u g d uri n g  t he D o u ble-Bli n d Treat me nt Peri o d  (eac h 5-da y c o urse t o b e dis pe nse d o n 
se parat e  occasi o ns  as  a p pr o priate).  If  s u bj ects  c o nti n ue  i nt o  t he  o pti o nal O L E  Peri o d,  t h e  
I n v esti gat or or desi g n ee will pr o vi de s u bjects wit h a d diti o nal I P t o c o m plete t he o pti o nal O L E 
Peri o d . 
5. 5. 3  
I n vesti g ati o n al Pr o d uct A d mi nistr ati o n  
S u bjects  ra n d o mize d  t o  t he  i n vesti gati o nal  ar m  will  recei ve  6 0  m g  a v atr o m b o pag 
( 3 ×  2 0 m g  ta blets) f or or al a d mi nistrati o n o nce d ail y f or 5 da ys pri or t o C h e m ot hera p y D a y a n d 
f or 5 da ys i m me diatel y f oll o wi n g C he m ot hera p y Da y  d uri n g t he D o u bl e-Bli n d Treat me nt Peri o d . 
S u bjects ra n d o mize d t o t he c o ntr ol ar m w ill recei ve matc hi n g placeb o ta blets.  
S u bjects i n t he o pti o nal O L E  Peri o d will recei ve 6 0 m g a vatr o m b o p a g ( 3 ×  2 0 m g  ta blets) f or oral 
a d mi nistrati o n o nce d ail y f or 5 da ys pri or t o C he m ot hera p y D a y a n d f or 5 d a ys after C he m ot hera p y 
Da y.   
At sc he d ule d st u d y visits, I P ma y b e a d mi nistere d at t he site or t he s u bject ma y self - d ose e x ce pt 
f or Visits 3 a n d 5 w he n s u bjects will be d ose d at t he site a n d serial P K sa m ples will be c ollecte d 
pre - a n d p ost -d os e of I P . S u bjects will self-d ose at all ot her ti mes. S u bjects will be i nstr ucte d t o 
ta ke I P wit h f o o d.  
D uri n g t he st u d y, if t he s u bject has a platelet c o u nt > 4 0 0 ×   1 09/ L, I P d osi n g will be st o p p e d 
te m p oraril y. D osi n g m a y be restart e d f oll o wi n g disc ussi o n wit h t he Me dical M o nit or.  

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T he n u m ber of ta bl ets t o be ta ke n will be t hree 2 0 m g a v atr o m b o pa g t a blets or 3 mat c hi n g place b o 
ta blets o nce dail y . 
Act ual date a n d ti me of c he m ot hera p y d oses will als o be ca pt ure d. 
5. 5. 4  
Tre at me nt C o m pli a nce  
A t sc he d ule d st u d y visits, I P ma y b e a d mi nistere d at t he site or t he s u bject ma y self- d ose e x ce pt 
f or Visits 3 a n d 5 w he n s u bjects will be d ose d at t he site a n d serial P K sa m ples will  be c ollecte d 
pre - a n d p ost -d ose of I P . S u bjects will self-d ose at all ot her ti mes. W he n ta ki n g I P at h o me  f or t he 
d o u ble- bli n d p hase of t he st u d y, s u bjects will be as ke d t o rec or d t he date a n d ti me of eac h I P d ose 
i n t he d osi n g diar y.  
C o m plia nce wit h I P a d mi nistrati o n will be assesse d b y c o u nti n g ret ur n e d I P p ac ka ges a n d a n y 
u n use d I P i n a d diti o n t o re vie wi n g t he d osi n g diar y e ntries of I P i nta k e. A n y discre pa n cies bet wee n 
ret ur ne d I P n u m b er a n d d osi n g i n t he d osi n g diar y will be dis c usse d wit h t he s u bject f or w h o m a 
discre pa n c y was see n a n d rec or d e d i n t he s o urce d oc u me nts. N u m ber of ta blets dis pe nse d a n d 
n u m ber of ta blets r et ur ne d will be rec or d e d o n t he a p pr o priate dr u g acc o u nt a bi lit y e C R F. 
5. 5. 5  
St or a ge a n d Acc o u nt a bilit y 
In v esti gati o nal p r o d uct s h o ul d be st ore d at c o ntr olle d r oo m te m perat ure ( 2 0˚ C t o 2 5˚ C/ 6 8˚ F t o 
7 7˚ F) wit h e x c ursi o ns per mitte d t o 1 5˚ C t o 3 0˚ C ( 5 9˚ F t o 8 6˚ F)  i n a s ec ure l ocati o n a n d i n t h e 
c o ntai ners pr o vi de d.  
Rec or ds  will be mai ntai ne d i n dicati n g t he recei pt a n d dis pe nsa ti o n of all I P s u p plies. At t he 
c o ncl usi o n of t he st u d y, a n y u n use d I P will be ret ur ne d t o t he S p o ns or or t he S p o ns or’s desi g n ee  
or ma y b e d estr o ye d at t he site if a p pr o priate pr o ce d ures are i n place . If n o s u p pl y re m ai ns, t his 
will be i n dicate d i n t he Dr u g Acc o u nta bilit y L o g.  
5. 6  
Pri or a n d C o nc o mit a nt Me dic ati o ns a n d/ or Pr o ce d ures  
5. 6. 1  
E xcl u de d Me dic ati o ns a n d/ or Pr oce d ures  
T he f oll o wi n g m e dicati o ns a n d/ or pr oce d ures are e x cl u de d: 
•  Use of vita mi n K a nta g o nists ; 
•  Use of t hr o m b o p oieti n rece pt or a g o nists or rec o m bi na nt h u ma n t hr o m b o p oieti n; 
•  Use of m o der ate or str o n g i n d ucers of C Y P 2 C or C Y P 3 A 4/ 5 (see A p pe n di x C ); a n d 
•  C urre ntl y e nr olle d i n a n ot her cli nical st u d y wit h a n y i n v esti gati o nal dr u g or d e vice wit hi n 
3 0 da ys o f Scree ni n g; h o we ver, p artici pati o n i n o bser vati o nal st u dies is per mitte d.  
5. 6. 2  
All o w e d Me dic ati o ns a n d/ or Pr oce d ures  
•  U se of pac k e d re d bl o o d cell tra nsf usi o ns, er yt hr o p oieti n, or gra n ul oc yt e -c ol o n y sti m ulati n g 
fact or, as or der e d b y t h e ma na gi n g o nc ol o g y ser vice, is acce pta ble a n d d oes n ot precl u de 
partici pati o n ; a n d  
•  Use of l o w m olec ular wei g ht he pari n, Xa i n hi bit ors, or t hr o m bi n i n hi bit ors is all o we d. 

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5. 6. 3  
D oc u me nt ati o n of Pri o r a n d C o nc o mit a nt Me dic ati o n Use 
A ll c o nc o mita nt me dicati o ns (i ncl u di n g c o n c urre nt t hera pies a n d c o nc urre nt pr oce d ures) will be 
d oc u me nte d fr o m t he ti me of i nf or me d c o nse nt t o t he F oll o w-U p Visit . D ose, i n dicati o n f or 
a d mi nistrati o n, a n d dates of me dicati o n a d mi nistrati o n will als o be ca pt ure d i n s o urce d oc u me nts 
a n d o n t he a p pr o priate e C R F . 

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6  
S T U D Y P R O C E D U R E S  
A sc he d ule of pr o ce d ur es i n ta b ular f or mat is pr o vi de d i n Ta ble 1 , Ta ble 2 , a n d Ta ble 3  i n 
A p pe n di x A .  
L ocal la b or at ories ma y  be use d t o det er mi ne st u d y eli gi bilit y; h o w e ver, f or st u d y a nal ysis a n d 
re p orti n g p ur p oses, o nl y val ues deter mi ne d at a central la b orat or y will be use d wit h t he e x ce pti o n 
of platelet c o u nt. Platelet c o u nt a nal yses will be p erf or me d usi n g l ocal la b orat or y res ults. L o cal 
la b orat ories ma y b e use d if i m me diate res ults are cli nicall y nee d e d (e g,  Bas eli ne  Visit ). 
6. 1  
I nf or me d C o nse nt 
Pri or t o c o n d ucti n g a n y st u d y- r elate d acti vities, writte n i nf or me d c o nse nt m ust be si g ne d a n d 
date d b y t he s u bject. See  Secti o n 1 2. 4  f or a d diti o nal i nf or mati o n o n i nf or m e d c o nse nt. 
6. 2  
C ycle X ( Q u alif yi n g C he m ot her a p y C y cle) 
6. 2. 1  
Scree ni n g ( Visit 1, D a y - 2 8 t o D a y - 1) 
T he Scree ni n g Visit ma y be c o m bi ne d wit h t he  Baseli ne Visit o n t he da y pri or t o I P treat me nt 
( Da y -1) .  
T he f oll o wi n g pr oce d ures will be perf or me d at t he Scree ni n g Visit : 
•  O btai n i nf or me d c o nse nt pri or t o scree ni n g pr oce d ures; 
•  C o ntact I R T t o r e gister t he s u bject i n t he st u d y  
•  C o n d uct eli gi bilit y asses s me nt base d o n i ncl usi o n/e x cl usi o n criteria;  
•  O btai n de m o gr a p hics   (i ncl u di n g race), a n d me dical  hist or y (t o i ncl u de  c he m ot hera p y a n d 
ca ncer hist or y); 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m f ull p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i ncl u des hei g ht, wei g ht, b o d y te m perat ure, bl o o d press ure, a n d p ulse rate) ; 
a n d 
•  Perf or m pre g n a nc y test ( ser u m or uri ne) f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y; 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts (if Scree ni n g Visit occ urs o n the sa me 
da y as t he Baseli ne Visit, o nl y t he Baseli ne l a b orat or y assess me nts s h o ul d be perf or me d): 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts). L ocal plat elet c o u nts ma y be re p eate d as nee de d ; 
a n d 
o  Ser u m c he mistr y  

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6. 2. 2  
B aseli ne Visit ( Visit 2 , First  D a y [or - 1 D a y] of t he 5 - d a y I n vesti g ati o n al Pr o d uct 
Tre at me nt ) 
T he Bas eli ne Visit ma y occ ur o ne da y pri or t o I P treat me nt, a n d ma y be c o m bi ne d wit h t he 
Scree ni n g Visit.  
Eli gi ble s u bjects will recei ve eit h er a v atr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o 
C he m ot hera p y D a y i n C ycl e X + 1. T h e f oll o wi n g pr oce d ures will be perf or me d at t he Bas eli ne 
Visit pri or t o I P d osi n g: 
•  C o n d uct eli gi bilit y assess me nt base d o n i ncl usi o n/e x cl usi o n criteria;  
•  C o ntact I R T t o r a n d o mize t he s u bject; 
•  Perf or m I nter na ti o nal S ociet y o n T hr o m b osis a n d Hae m ostasis (I S T H) bl ee di n g assess me nt 
(see A p p e n d i x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m s y m pt o m -dir ect e d p h ysical e x a mi nati o n (if n ot pre vi o usl y p erf or me d wit hi n 1 wee k 
of Bas eli ne Visit);  
•  Rec or d vital si g ns  (i ncl u des wei g ht, b o d y te m perat ure, bl o o d press ure, a n d p ulse rate). O nl y 
Scree ni n g vital si g ns will be rec or de d if c o m bi ne d wit h t he Scree ni n g Visit ; 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g asses s me nts: 
o  He mat ol o g y (i ncl u di n g platelet c o u nts);  
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test (ser u m or uri ne) f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y; 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  
•  Dis pe nse I P;  
•  Dis pe nse d osi n g di ar y; a n d 
•  A d mi nister or self -d ose I P  wit h f o o d , if t he Baseli ne Visit occ urs  o n t he first da y of t he 5 -da y 
I P treat me nt. 
6. 2. 3  
Pre - C he m ot her a p y I n v esti g ati o n al Pr o d uct Tre at me nt ( Visit 3, L ast D a y of t he 
5- d a y I n vesti g ati o n al Pr o d uct Tre at me nt) 
T he f oll o wi n g pr oce d ures will be p erf or m e d o n t he last da y of t he 5 -da y pre -c h e m ot hera p y I P 
treat me nt at Visit 3: 
•  C o ntact I R T;  
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  

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•  C ollect bl o o d sa m ples f or t he f oll o wi n g a ssess me nts: 
o  He mat ol o g y (i ncl u di n g platelet c o u nts); a nd 
o  P K sa m pli n g at pre - d ose ( wit hi n 3 0 mi n utes of I P d osi n g) a n d 0. 5 t o 2, 2 t o 4, a n d 4 t o 
6 h o urs p ost - d ose. Eac h sa m ple m ust be c ollecte d at least o ne h o ur a part fr o m a djace nt 
sa m ples. 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e; 
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; 
•  A d mi nister I P  i n t he cli ni c wit h f o o d after t he first P K sa m pli n g;  
•  Re vie w d osi n g diar y; a n d 
•  C ollect u n use d I P, if a p plica ble. 
6. 3  
D o u ble -Bli n d Tre at me nt Peri o d  ( C y cle X + 1) 
6. 3. 1  
C he m ot her a p y D a y ( Visit 4, C ycle X + 1 D a y 1 t o 3) 
T he f oll o wi n g pr oce d ures will be perf or me d o n C ycle X + 1 , Da y 1  at Visit 4 pri or t o c he m ot hera p y 
d osi n g: 
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D ); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e  e ve nts;  
•  Perf or m s y m pt o m-dir ect e d p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); a n d  
o  Ser u m c he mistr y;  
•  Assess c he m ot her a p y d ose  m o dificati o ns /sc he d ul e; a n d  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n. 
T he f oll o wi n g pr o ce d ures will be perf or me d p ost- c he m ot hera p y d osi n g (t h ese pr o ce d ures will be 
perf or me d o n t h e last C he m ot hera p y D a y of t he c ycl e): 
•  Dis pe nse I P; a n d  
•  Dis pe nse d osi n g di ar y. 
6. 3. 2  
P ost - C he m ot her a p y In v esti g ati o n al Pr o d uct T re at me nt ( Visit 5) 
S u bjects will als o recei ve a vatr o m b o pa g or pl ace b o o nce dail y f or 5 da ys i m me diatel y f oll o wi n g 
C he m ot hera p y Da y . T h e f oll o wi n g pr o ce d ures will be perf or me d  o n t he last da y of t he 5 -da y 
p ost- c he m ot hera p y I P tr eat me nt at Visit 5:  
•  C o ntact I R T;  

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•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D ); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y (i ncl u di n g platelet c o u nts); a n d  
o  Ser u m C he mistr y;  
o  C oa g ulati o n; a n d  
o  P K sa m pli n g at pre - d ose ( wit hi n 3 0 mi n utes of I P d osi n g) a n d 0. 5 t o 2, 2 t o 4, a n d 4 t o 
6 h o urs p ost - d ose. Eac h sa m ple m ust be c ollecte d at least o ne h o ur a part fr o m a djace nt 
sa m ples. 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; 
•  A d mi nister I P i n t he cli ni c wit h f o o d after t he first P K sa m pli n g;  
•  Re vie w d osi n g diar y; a n d 
•  C ollect u n use d I P, if a p plica ble. 
6. 3. 3  
C ycle X + 1 D a ys 1 1 ( ± 1 d a y), 1 5 ( ± 1 d a y) , a n d 1 8 (± 1 d a y) ( Visits 6, 7, a n d 8 ) 
T he f oll o wi n g pr o ce d ures will be perf or m e d o n C ycl e X + 1 , Da y s 1 1, 1 5, a n d 1 8 at Visit s 6, 7, 
a n d 8: 
•  Rec or d c o n c o mita nt me dicati o ns ; 
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or platelet c o u nts ; 
•  Assess c he m ot her a p y d ose m o dif icati o ns/sc he d ul e; a n d  
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n. 
6. 4  
O bser v ati o n al Peri o d ( C ycle X + 2) 
If C he m ot her a p y D a y i n C ycl e X + 2 is del a ye d, rec or d t h e reas o n f or d ela y i n t he e C R F. If t he 
dela y is d ue t o la b orat or y res ults, rec or d t he rel eva nt res ults i n t he e C R F. 
6. 4. 1  
C he m ot her a p y D a y i n C ycle X + 2 ( Visit 9) 
T he  f oll o wi n g  pr o ce d ur es  will  be  perf or me d  o n C ycl e  X  +  2 , Da y  1  at  Visit 9 pri or  t o  
c he m ot hera p y d osi n g: 
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  Rec or d c o n c o mita nt me dicat i o ns; 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  

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•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts pri or t o c he m ot hera p y d osi n g: 
o  He mat ol o g y (i ncl u di n g plat elet c o u nts);  
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e; a n d  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n. 
6. 4. 2  
C ycle X + 2 D a ys 1 1 ( ± 1 d a y), 1 5 ( ± 1 d a y) , a n d 1 8 (± 1 d a y) ( Visits 1 0, 1 1, a n d 1 2) 
T he f oll o wi n g pr oce d ures will be perf or me d o n C ycl e X + 2 , Da y s 1 1, 1 5, a n d 1 8 at Visits 1 0, 1 1, 
a n d 1 2: 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  Platelet c o u nts ; 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e; a n d  
•  Assess w het her s u bject r e q uire d platelet tra nsf us i o n. 
6. 4. 3  
F oll o w- U p Visit  ( F o r s u bjects n ot c o nti n ui n g i nt o t he o pti o n al O pe n-L a bel 
E xte nsi o n Peri o d)   
6. 4. 3. 1  
Pri or t o C he m ot her a p y D a y i n C ycle X + 3 ( Visit 1 7) 
F or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d, a F oll o w -U p Visit will occ ur pri or t o 
(wit hi n 3 da ys)  C he m ot hera p y  Da y  i n  C ycle  X  +  3.  If  C ycle  X  +  2  is  t he  s u bject’s  last  
c he m ot hera p y c ycl e, a F oll o w -U p Visit will occ ur at 3 0 da ys ( ± 3 da ys) aft er C he m ot hera p y Da y 
i n C ycle X + 2.  S u bjects will c o m plete Visit 1 7 pr oce d ures i n  Secti o n  6. 5. 5 . 
6. 5  
O pti o n al O pe n - L a bel E xte nsi o n Peri o d ( C ycle X + 3 a n d O n) 
6. 5. 1  
Pre - C he m ot her a p y A v atr o m b o p a g Tre at me nt ( Visit 1 3) 
S u bjects  will  recei ve  a vatr o m b o pa g  o nce  d ail y  f or  5  da ys  pri or  t o  C he m ot hera p y  Da y  i n  
C ycle  X + 3 ( Visit 1 3). F or C ycl e X + 4, t his visit will be de n ote d Visit 1 3. 1 a n d f or C ycle X + 5, 
t his visit will be de n ote d Visit 1 3 . 2. T his n u m beri n g sc h e me will c o nti n ue f or s u bse q ue nt e nr olle d 
o pe n- la bel c ycles.  
T he f oll o wi n g pr o ce d ur es will be  perf or me d o n t he first d a y of  pre -c he m ot hera p y a vatr o m b o pa g 
treat me nt at Visit 1 3 pri or t o a vatr o m b o pa g d osi n g: 
•  C o n d uct eli gi bilit y assess me nt base d o n O L E  i ncl usi o n/e x cl usi o n criteria; 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  

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•  C o ntact I R T;  
•  Perf or m I S T H blee di n g as sess me nt (see A p p e n d i x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts pri or t o I P d osi n g: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test ( uri ne  or ser u m ) f or fe mal e s u bjects of c hil d beari n g p ote ntial o nl y; 
•  Assess c he m ot her a p y d ose  m o dificati o ns /sc he d ul e; 
•  Assess w het her s u bject r e q uire d platel et tra nsf usi o n; 
•  Dis pe nse a vatr o m b o pa g;  
•  A d mi nister or self - d ose a vatr o m b o pa g wit h f o o d. 
6. 5. 2  
C he m ot her a p y D a y ( Visit 1 4, C ycle X + 3 D a y 1 t o 3) 
F or C ycle X + 4, t his visit will be de n ote d Visit 1 4 . 1 a n d f or C ycle X + 5, t his visit will be de n ote d 
Visit 1 4. 2. T his n u m beri n g sc h e me will c o nti n ue f or s u bse q ue nt e nr olle d o pe n- la bel c ycles.  
T he  f oll o wi n g  pr oce d ur es  will  be  perf or me d  o n  C ycl e  X  +  3 , Da y 1 at Visit 1 4 pri or  t o  
c he m ot hera p y d osi n g: 
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m s y m pt o m-dir ect e d p h ysical e x a mi nati o n;  
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts) 
•  Assess c he m ot her a p y d ose  m o dificati o ns /sc he d ul e; 
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; a n d 
•  C ollect u n use d a vatr o m b o pa g , if a p plica ble. 
T he f oll o wi n g pr o ce d ures will be perf or me d o n p ost- c he m ot hera p y d osi n g  (t hese pr oce d ures will 
be perf or me d o n t he last C he m ot hera p y Da y of t he c ycle) : 
•  Dis pe nse a vatr o m b o pa g 

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6. 5. 3  
P ost - C he m ot her a p y A v atr o m b o p a g Tre at me nt  ( Visit 1 5) 
F or C ycle X + 4, t his visit will be de n ote d Visit 1 5. 1 a n d f or C ycle X + 5, t his visit will be de n ote d 
Visit 1 5. 2. T his n u m beri n g sc h e me will c o nti n ue f or s u bse q ue nt e nr olle d o pe n- la bel c ycles.  
T he f oll o wi n g pr oce d ur es will be perf or me d o n t he last da y of t he 5-d a y p ost -c he m ot hera p y 
a vatr o m b o pa g tr eat me nt at Visit 1 5: 
•  C o ntact I R T;  
•  Perf or m I S T H blee di n g a ssess me nt (see A p p en di x D) ; 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts: 
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  
•  Assess w het her s u bject r e q uire d platelet tra nsf usi o n; 
•  A d mi nister or self - d ose a vatr o m b o pa g wit h f o o d; a n d 
•  C ollect u n use d a vatr o m b o pa g , if a p plica ble. 
6. 5. 4  
C ycle X + 3  D a y 1 5 (± 1 d a y)  ( Visit 16) 
F or C ycle X + 4, t his visit will be de n ote d Visit 1 6. 1 a n d f or C ycle X + 5, t his visit will be de n ote d 
Visit 1 6. 2. T his n u m beri n g s c he me will c o nti n ue f or s u bse q u e nt e nr olle d o pe n -la bel c ycles. T he 
f oll o wi n g pr o ce d ur es will be perf or m e d o n C ycle X + 3 , Da y 1 5 at Visit 1 6: 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 
•  C ollect bl o o d sa m ple s f or platelet c o u nts; 
•  Assess c he m ot her a p y d ose m o dificati o ns/sc he d ul e;  a n d  
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n. 
6. 5. 5  
F oll o w- U p Visit  
6. 5. 5. 1  
T hi rt y da ys after last a vatr o m b o pa g d ose ( Visit 17) i n t he O L E Peri o d 
T he f oll o wi n g pr oce d ures will be perf or m e d 3 0 d a ys (± 3 d a ys) after last a vatr o m b o pa g d ose at 
Visit 1 7: 
•  C o ntact I R T;  
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D); 

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•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale; 
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m f ull p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate);  
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts:  
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test ( uri ne) f or fe male s u bj ects of c hil d beari n g p ote ntial o nl y; a n d  
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n. 
6. 6  
E arl y Ter mi n ati o n Visit a n d Wit h dr a w al Pr oce d ures  
F or s u bjects w h o are wit h dra w n fr o m t he st u d y pri or t o t he F oll o w -U p Visit , all Visit 1 3 (f or 
s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d) or Visit 1 7 (f or s u bjects c o nti n ui n g i nt o t he 
o pti o nal  O L E  Peri o d)  pr oce d ur es  will  be  perf or me d  at  a n  Earl y  Ter mi nati o n  Visit.  T hese  
pr oce d ur es i ncl u de t he f oll o wi n g: 
•  C o ntact I R T;   
•  Perf or m I S T H blee di n g assess me nt (see A p p e n di x D ); 
•  Assess f u ncti o nal stat us usi n g t he E C O G Perf or m a nce Stat us Scale;  
•  Rec or d c o n c o mita nt me dicati o ns;  
•  Assess a d vers e e ve nts;  
•  Perf or m f ull p h ysical e x a mi nati o n; 
•  Rec or d vital si g ns (i n cl u des bl o o d press ure a n d p ulse rate); 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts:  
o  He mat ol o g y  (i ncl u di n g platelet c o u nts); 
o  C oa g ulati o n; a n d  
o  Ser u m c he mistr y;  
•  Perf or m pre g n a nc y test ( uri ne) f or fe male s u bj ects of c hil d beari n g p ote ntial o nl y; 
•  Assess w het her s u bjec t r e q uire d platelet tra nsf usi o n; a n d 
•  C ollect u n use d I P, if a p p lica ble. 

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6. 7  
L o n g- Ter m F oll o w -U p  
After t he F oll o w -U p Visit, all s u bjects will be c o ntacte d a p pr o xi matel y e ver y 6 m o nt hs f or u p t o 
5 years b y tele p h o n e d uri n g t he L o n g -T er m F oll o w -U p Peri o d f or d o c u me ntati o n of vital stat us (if 
deat h occ urre d, rec or d of date of  deat h) a n d occ urre nce of sec o n d ar y mali g n a ncies.  If a sec o n d ar y 
mali g na n c y h as occ urre d , t he f oll o wi n g i nf or mati o n will be c ollecte d: date of o nset a n d t y pe of 
mali g na n c y, as w ell as a writte n narr ati ve fr o m t he cli nical site s u m marizi n g t he c o urs e of e ve nts 
lea di n g u p t o dia g n osis of t he sec o n d ar y mali g na n c y. 

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7  
E F FI C A C Y A S S E S S M E N T S  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all of t he f oll o wi n g criteria  
d uri n g t he p eri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y D a y  
of C ycl e X + 2 : 
•  N ot re q uiri n g a platel et tra nsf usi o n; 
•  N ot re q uiri n g a c h e m ot hera p y d ose re d ucti o n b y ≥1 5 % d ue t o t hr o m b oc yt o pe nia; a n d 
•  N ot re q uiri n g a c h e m ot hera p y del a y b y ≥4 da ys d ue t o t hr o m b oc yt o p e nia. 
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of s e ver e t hr o m b oc yt o p e nia defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he p eri o d 
after p ost -c he m ot her a p y I P tr eat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y Da y  of C ycl e X + 2 ; 
•  C ha n ge i n platelet c o u nt fr o m baseli ne ( q ualif yi n g c he m ot hera p y c ycle [ C ycl e X]) ( n a dir) t o 
C ycle X + 1 ( n a dir);  
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n- maj or cli nical l y rele v a nt blee di n g d uri n g 
t he peri o d after p ost -c h e m ot hera p y I P treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y Da y  of 
C ycle X + 2 ; a n d  
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve a platelet tra nsf usi o n d uri n g t he peri o d after p ost -
c he m ot hera p y I P tr eat me nt i n C ycle X + 1 thr o u g h  C he m ot hera p y Da y  of C ycl e X + 2 . 
T he ot her efficac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he peri o d after p os t-c he m ot hera p y I P 
treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y D a y of C ycle X + 2 : 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c h e m ot hera p y d ose re d ucti o n t h at is ≥1 5 % d ue t o 
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n  of  s u bjects  w h o  d o  n ot  ha ve  a  c he m ot hera p y  dela y  t hat  is  ≥4 da ys  d ue  t o  
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n of s u bjects wit h a pre -d efi ne d p ost- bas eli ne na dir platelet c o u nt; a n d  
•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost- baseli ne ma xi m u m platelet c o u nt  
Bl o o d  sa m ples  t o  assess  platelet  c o u nt  will be c ollecte d  a s i n dicate d  i n  A p pe n di x  A . L o cal  
la b orat ories ma y  b e use d t o deter mi ne st u d y eli gi bilit y; h o we ver, f or st u d y a nal ysis a n d re p orti n g 
p ur p oses, o nl y v al ues d eter mi ne d at a ce ntral la b orat or y will be use d wit h t h e e x ce pti o n of pl atelet 
c o u nt. L o cal la b or at ories ma y b e use d if i m me diat e res ults are cli nicall y nee de d.   
W het her a s u bject  re q uir es a platelet tra nsf usi o n will be deter mi ne d b y t h e I n v esti gat or or treati n g 
p h ysicia n.  
Blee di n g will be e val uat e d b y t h e I n v esti gat or usi n g t he n o n-s ur gical I S T H blee di n g defi niti o ns 
descri be d i n A p p e n di x D . 

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8  
P H A R M A C O KI N E TI C A N D P H A R M A C O D Y N A MI C A S S E S S M E N T S  
8. 1  
P h ar m a c o ki netic Assess me nts  
Bl o o d sa m ples f or P K a n al ysis will be c ollecte d as i n dicate d i n A p pe n di x A . A d diti o nal ti me p oi nts 
ma y b e c o llecte d as necessar y.  
P har mac o ki netic sa m pli n g will occ ur t wice d uri n g t he st u d y wit h 4 sa m ples c ollecte d o n e ac h da y.  
8. 2  
P h ar m a c o d y n a mi c Ass ess me nts  
Bl o o d s a m ples f or P D a n al ysis will be c ollecte d as i n dicate d i n A p pe n di x A.  
P har mac o d y na mic s a m ples (ie, platele t c o u nts) will be c ollecte d t hr o u g h o ut eac h c ycle of t he 
st u d y i ncl u di n g C ycl e X + 1, C ycl e X + 2, a n d eac h e nr olle d o pe n-l a bel c ycle. 
 

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S A F E T Y A S S E S S M E N T S  
9. 1  
A d verse E ve nts  
A n a d verse e v e nt is defi ne d as a n y u nt o w ar d m e dical occ urre nce i n a s u bject a d mi nister e d a 
p har mace utical pr o d u ct, w hic h d oes n ot n ecess aril y h a ve a ca usal relati o ns hi p wit h t his treat me nt. 
A n a d verse e ve nt ca n t h eref or e be a n y u nfa v ora ble a n d/ or u ni nte n d e d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass o ciate d wit h t he us e of a n i n vesti gati o nal 
me dici nal pr o d uct, w het her or n ot rel ate d t o t he i n vesti gati o nal me dici n al pr o d uct. All a d vers e 
e ve nts, i ncl u di n g o bs er ve d or v ol u nteere d pr o ble ms, c o m plai nts, or s y m pt o ms, are t o be rec or de d 
o n t he a p pr o priat e e C RF. 
A d verse  e v e nts,  w hic h  i ncl u de  cli nical  la b orat or y  test  varia bles,  will  be  m o nit ore d  a n d  
d oc u me nte d fr o m t he ti me of i nf or me d c o ns e nt u ntil t he F oll o w- U p Visit occ urri n g pri or t o (wit hi n 
3 da ys)  C he m ot hera p y Da y i n C ycle X + 3 (f or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E 
Peri o d) a n d t he F oll o w- U p Visit occ urri n g 3 0 da ys aft er last d ose of I P (f or s u bjects c o nti n ui n g 
i nt o t he o pti o nal O L E Peri o d). S u bjects s h o ul d b e i nstr ucte d t o re p ort a n y a d verse e ve nt t h at t he y 
e x perie nce t o t he I n vesti gat or. Be gi n ni n g wit h t he Scree ni n g Visit, In vesti gat ors s h o ul d ma ke a n 
assess me nt f or a d verse e ve nts at e ac h visit a n d rec or d t he e ve nt o n t he a p pr o priate a d verse e ve nt 
e C R F. E ve nts ass o ciate d wit h d isease pr o gressi o n s h o ul d n ot be re p orte d as a d verse e ve nts/S A E s. 
H o we ver, if i n t he I n vesti gat or’s o pi ni o n t he disease pr o gressi o n is ma nifesti n g i n a n u n us ual o r 
u nc haracteristic ma n n er, t he ass ociate d e ve nts s h o ul d be re p orte d as a d verse e v e nts/ S A Es, as 
a p pr o priate. 
W here ver p ossi ble, a s p ecific diseas e or s y n dr o me (ie, dia g n osis) rat her t ha n i n di vi d ual ass ociate d 
si g ns a n d s y m pt o ms s h o ul d be i de ntifie d b y t he In vesti gat or  a n d rec or de d o n t he e C R F.  H o w e ver, 
if a n o bser ve d or re p orte d si g n or s y m pt o m is n ot c o nsi dere d a c o m p o ne nt of a s pecific disease or 
s y n dr o me b y t he I n v esti gat or, it s h o ul d be rec or de d as a s e parate a d vers e e ve nt o n t he e C R F. 
A d diti o nall y, t he c o n diti o n t hat le d t o a me dical or s ur gical pr o ce d ure ( e g, s ur ger y, e n d os c o p y, 
t o ot h e xtracti o n, or tra nsf usi o n) s h o ul d be rec or de d as a n a d verse e v e nt, n ot t he pr oce d ure.  
A n y me dical  c o n diti o n alrea d y pr ese nt at t he S cree ni n g Visit  s h o ul d n ot be re p orte d as a n a d v ers e 
e ve nt u nless t he me dical c o n diti o n or si g ns or s y m pt o ms prese nt at baseli ne c ha n ges i n se verit y, 
fre q ue n c y, or seri o us ness at a n y ti me d uri n g t h e st u d y. I n t his case, it s h o ul d be re p orte d as a n 
a d verse e ve nt.  
Cli nicall y si g nifica nt a b n or mal  la b orat or y or ot her e x a mi nati o n fi n di n gs t hat are det ecte d d uri ng 
t he st u d y or are prese nt at t he Scree ni n g Visit a n d si g nifica ntl y w ors e n d uri n g t he st u d y s h o ul d be 
re p orte d  as  a d v erse  e ve nts.  T he  I n vesti gat or will  e x ercise  his  or  her  me dical  a n d  s cie nti fic 
j u d g me nt i n deci di n g w het her a n a b n or m al la b orat or y fi n di n g or ot her a b n or mal assess me nt is 
cli nicall y  si g nifi ca nt.  Cli nicall y  si g nifica nt  a b n or mal  la b orat or y  val u es  occ urri n g  d uri n g  t he  
cli nical st u d y will be f oll o we d u ntil re peat tests ret ur n t o n or m al, sta bilize, or are n o l o n ger 
cli nicall y si g nifica nt. La b orat or y a b n or malities are n ot c o nsi dere d a d vers e e ve nts u nless t he y are 
ass ociate d wit h cli nical si g ns  or s y m pt o ms, or re q uire me di cal i nter v e nti o n. A n y a b n or mal test 
t hat is deter mi ne d t o be a n err or d o es n ot re q uire re p orti n g as a n a d v erse e v e nt. 
Cli nicall y  si g nifica nt a b n or mal fi n di n gs i n p h ysical e x a mi nati o ns will be re p ort e d as a d v erse 
e ve nts. 

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9. 1. 1  
Assess m e nt of A d verse E ve nts b y t he I n vesti g at or 
T he I n v esti gat or will assess t he s e verit y (i nte nsit y) of eac h a d vers e e ve nt a n d will als o cate g orize 
eac h a d vers e e ve nt as t o its p ote ntial relati o ns hi p t o I P usi n g t he cate g ories of yes or n o. 
Assess me nt of Se veri t y: 
T he se verit y of all a d verse e v e nts s h o ul d be gra de d acc or di n g t o t he C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E v e nts ( C T C A E). F or t h ose a d vers e e ve nts n ot liste d i n t he C T C A E, t he 
f oll o wi n g gr a di n g s yste m s h o ul d be use d: 
•  Mil d ( C T C A E Gra de 1): Tra nsie nt s y m pt o ms, a ware ness of si g n/s y m pt o m, b ut easil y t olerate d 
a n d n o i nterfere nce wit h s u bject’s dail y acti vities.  
•  M o derate  ( C T C A E  Gr a de  2):  Mar k e d  si g ns/s y m pt o ms  t hat  i nterfere  wit h  s u bject’s  us ual  
acti vities, b ut still acce pta ble.  
•  Se vere  ( C T C A E  Gr a de  3):  I nca pacitati n g  si g ns/s y m pt o ms  w hi c h  ca use  c o nsi dera ble  
i nterfer e nce wit h t he s u bject’s dail y acti vities, u nacce pta bl e.  
•  Lif e -t hreate ni n g (C T C A E Gra de 4): Life -t hreate ni n g or disa bli n g a d v erse e ve nt. 
•  Deat h ( C T C A E Gr a de 5):  Deat h -r elate d a d v erse e ve nt. 
Ca usalit y Assess me nt : 
T he relati o ns hi p of a n a d verse e ve nt t o t he a d mi nistrati o n of t he I P is t o be assesse d acc or di n g t o 
t he f oll o wi n g defi niti o ns: 
•  N o ( u nrelate d, n ot relate d, n o relati o n) – T he ti me c o urse bet wee n t he a d mi nistrati o n of I P a n d 
t he occ urr e nce or w orse ni n g of t he a d vers e e ve nt r ules o ut a ca usal relati o nshi p a n d a n ot her 
ca use ( c o nc o mita nt dr u gs, t hera pies, c o m plicati o ns, etc.) is s us pecte d. 
•  Yes (r elate d) – T he ti m e c o urs e bet wee n t he a d mi nistrati o n of I P a n d  t he occ urre n ce or 
w orse ni n g of t he a d vers e e v e nt is c o nsiste nt wit h a ca usal relati o ns hi p a n d n o ot her ca us e 
(c o nc o mita nt dr u gs, t her a pies, c o m plicati o ns, etc.) ca n be i d e ntifie d. 
T he defi niti o n i m plies a reas o na bl e p ossi bilit y of a ca usal relati o ns hi p bet wee n t h e e ve nt a n d t he 
I P. T his mea ns t hat t here are f acts ( e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p. 
T he f oll o wi n g fact ors s h o ul d als o be c o nsi dere d: 
•  T he te m p oral se q u e nce fr o m I P a d mi nistrati o n - 
o  T he e ve nt s h o ul d occ ur after t he I P is gi ve n. T h e le n gt h of ti me fr o m I P e x p os ure t o e ve nt 
s h o ul d be e val uate d i n t h e cli nical c o nte xt of t he e ve nt. 
•  U n derl yi n g, c o nc o mita nt, i nterc urr e nt diseases- 
o  Eac h re p ort s h o ul d be e val uate d i n t he c o nte xt of t he nat ural hist or y a n d c o urse of t he 
disease bei n g treate d a n d a n y ot h er diseas e t he s u bject ma y ha ve.  
•  C o nc o mita nt dr u g- 
o  T he ot her dr u gs t he s u bject is ta ki n g or t he treat me nt t he s u bject recei ves s h o ul d be 
e x a mi ne d t o deter mi ne w het her a n y of t he m mi g ht be rec o g nize d t o ca use t he e ve nt i n 
q uesti o n. 

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•  K n o w n res p o nse p atter n f or t his class of I P- 
o  Cli nical a n d/ or precli nical data ma y i n dicate w het h er a partic ul ar res p o nse is li kel y t o b e a 
class eff ect.  
•  E x p os ure t o p h ysi cal a n d/ or me ntal stresses - 
o  T he e x p os ure t o str ess mi g ht i n d uce a d v erse c ha n ges i n t he reci pie nt a n d pr o vi de a l o gical 
a n d better e x pl a nati o n f or t he e ve nt. 
•  T he p har mac ol o g y a n d P K  of t he I P- 
o  T he k n o w n p h ar mac ol o gi c pr o perties (a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n) 
of t he I P s h o ul d b e c o nsi dere d. 
9. 1. 2  
A d verse E ve nts of S peci al I nterest  
T he I n vesti gat or will m o nit or eac h s u bject  f or cli nical a n d la b orat or y e vi de nce f or pre-d e fi ne d 
A E SI t hr o u g h o ut t heir p artici pati o n i n t his st u d y. T he p ur p ose f or s pecif yi n g t hes e A E SI is t o 
e na ble f urt her c haracteri zati o n of t he cli nical c o urse a n d ma na ge m e nt of t hese e ve nts. A n A E SI 
ma y or m a y n ot be t he c o nse q ue nce of treat me nt wit h a vatr o m b o pa g. 
T he A E SI defi n e d i n t his pr ot oc ol i ncl u de: 
•  T hr o m b oe m b olic e ve nts (a n y t hr o m b otic or e m b olic e ve nt, w het her arterial or ve n o us); a n d  
•  Blee di n g e v e nts (a n y cli nica ll y si g nifica nt bl o o d l oss). 
T hese e ve nts will be rec or de d i n t he a d verse e ve nt e C R F pa ge.  T he I n v esti gat or will assess a n d 
rec or d a n y a d diti o nal i nf or mati o n o n t he A E SI i n detail o n a S A E f or m ( w het her or n ot t he e ve nt 
meets seri o us ness criteria i n Secti o n 9. 3 ), t o be s u b mitte d wit hi n 2 4 h o urs of a ware ness of t he 
e ve nt. D uri n g t he c o urse of t he st u d y, a d diti o nal A E SI ma y b e i de ntifie d b y t he S p o ns or. 
9. 1. 3  
Effic ac y E n d p oi nts 
E fficac y e n d p oi nts, as descri be d i n Secti o n 7 , s h o ul d n ot be re p orte d as a d verse e v e nts u nless i n 
t he  o pi ni o n  of  t he  I n vesti gat or  t he  e ve nt  is  ca usall y  ass o ciate d  wit h  t he  I P.  F or  e x a m ple,  
t hr o m b oc yt o pe ni a, platel et tra nsf usi o ns f or t hr o m b oc yt o p e nia, a n d c he m ot hera p y d ose re d ucti o ns 
or dela ys s h o ul d n ot be re p orte d as a d verse e ve nts; h o we ver, cli nical l y si g nifica nt blee di n g e ve nts 
(a sec o n d ar y e n d p oint) s h o ul d be al wa ys be re p orte d as a n A E SI.  
9. 2  
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts  
A d verse e ve nts will be re p orte d b y t he s u bject ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or 
t he partici pa nt's le gall y a ut h orize d re prese nt ative). Care will be ta ke n n ot t o i ntr o d uce bias w he n 
detecti n g a d v erse e ve nts a n d/ or S A Es. O p e n -e n d e d a n d n o n -lea di n g v er b al q uesti o ni n g of t he 
partici pa nt is t he preferre d met h o d t o i n q uire a b o ut a d verse e ve nt occ urre nces. 

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9. 3  
Seri o us A d verse E ve nt s 
A n a d vers e e v e nt or a d verse reacti o n is c o nsi dere d seri o us if, i n t he vie w of eit her t he I n vesti gat or 
or S p o ns or, it res ults i n a n y of t he f oll o wi n g o ut c o mes: 
•  D eat h, 
•  A life -t hreate ni n g a d vers e e ve nt, 
o  N O T E: A n a d verse e ve nt or a d vers e reacti o n is c o nsi dere d  “life-t hreate ni n g” if, i n vi e w of 
eit her t he I n vesti gat or or S p o ns or, its occ urre n ce places t he s u bject at i m me diate ris k of 
deat h. It d o es n ot i n cl u de a n e ve n t t hat, ha d it o cc urre d i n a m ore s e vere f or m, mi g ht h a ve 
ca use d deat h.  
•  Re q uires h os pitalizati o n  or pr ol o n gati o n of e xisti n g h os pitalizati o n, 
o  N O T E: A n y h os pital a d missi o n e ve n if a d mitte d a n d disc h ar ge d t he s a me da y  will be 
c o nsi dere d  a n  i n patie nt  h os pitalizati o n.  A n  e mer ge nc y  r o o m  visit  wit h o ut  h os pital  
a d missi o n will n ot be r ec or de d as a n S A E  u n d er t his criteri o n, n or will h os pitalizati o n f or 
a  pr o ce d ur e  sc h e d ule d  or  pla n n e d  b ef ore  si g ni n g  of  i nf or m e d  c o nse nt.  H o we v er,  
u ne x pecte d c o m plicati o ns a n d/ or pr ol o n gati o n of h os pitalizati o n t hat occ ur d uri n g electi ve 
s ur ger y s h o ul d be rec or d e d as a d verse e vent s a n d assesse d f or seri o us n ess. A d missi o n t o 
t he h os pital f or s o cial or sit uati o nal reas o ns (i e, n o place t o st a y, li ve t o o far a wa y t o c o me 
f or h os pital visits) will n ot be c o nsi dere d i n p atie nt h os pitalizati o ns.  
•  A  persiste nt  or  si g nifica nt  disa bilit y/i nca p acit y  or  s u bsta ntial  disr u pti o n  of  t he  a bilit y t o  
c o n d uct n or mal life f u n cti o ns, 
•  A c o n ge nital a n o mal y/ birt h defect , 
•  A n i m p orta nt me dical e v e nt, or 
o  N O T E: I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or re q uire 
h os pitalizati o n  ma y  b e  c o nsi dere d  a n  S A E  w he n,  base d  u p o n  a p pr o priate  me dical  
j u d g me nt, t he y ma y j e o p ar dize t he s u bject or ma y re q uire me dical or s ur gi cal i nter v e nti o n 
t o pre ve nt o ne of t he o utc o mes liste d a b o ve. E x a m ples of s uc h me dical e ve nts i ncl u de 
aller gic br o nc h os p as m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me, 
bl o o d d yscr asias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt h os pitalizati o ns, or t he 
de vel o p me nt of dr u g d e p e n de nc y. 
•  A n y s us pecte d tr a ns missi o n via a me dici nal pr o d u ct of a n i nfecti o us a ge nt. 
9. 4  
Seri o us A d verse E ve nt Re p orti n g − Pr oce d ures f or I n vesti g at ors  
I nitial Re p orts: 
All S A Es occ urri n g fr o m  t he ti me of i nf or me d c o nse nt u ntil pri or t o ( wit hi n 3 da ys) C he m ot hera p y 
Da y i n C ycle X + 3 (f or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E Peri o d) a n d 3 0 da ys 
f oll o wi n g t he last a dmi nistrati o n of I P (f or s u bjects c o nti n ui n g i nt o t he o pti o nal O L E Peri o d) m ust 
be re p orte d wit hi n 2 4 h o urs of t he k n o wle d ge of t he occ urre nce (t his refers t o a n y a d v erse e v e nt 
t hat meets a n y of t h e af ore me nti o ne d s eri o us criteria). All S A Es  t hat t he I n vesti gat or b ec o mes 
a war e of a n d c onsi ders r elate d t o I P occ urri n g after t he 3 0 -da y F oll o w- U p Peri o d  m ust be re p orte d 
t o t he S p o ns or. 

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T o re p ort t he S A E, c o m plete t he S A E Re p ort F or m a n d fa x or e m ail as i nstr ucte d o n t he f or m . It 
is ver y i m p orta nt t hat t h e f or m b e fille d o ut as c o m pletel y as p ossi ble at t he ti me of t he i nitial 
re p ort. T his i ncl u des t he I n v esti gat or’s assess me nt of ca usalit y. Preli mi nar y S A E re p orts s h o ul d 
be f oll o we d as s o o n as p ossi ble b y d etaile d des cri pti o ns i ncl u di n g c o pies of h os pital disc ha r ge 
s u m maries, a ut o ps y re p orts, a n d ot her d oc u me nts re q ueste d b y t h e S p o ns or or desi g nee. T he 
I n v esti gat or  m ust  n otif y  his/ her  I nstit uti o nal  Re vie w  B o ar d  (I R B)  or  I n de p e n de nt  Et hics  
C o m mittee  (I E C) of t he occ urr e nce of t he S A E, i n writi n g, if re q uire d b y t heir i nstit uti o n. A c o p y 
of t his c o m m u nicati o n m ust be f or war de d t o t he S p o ns or t o be file d i n t he S p o ns or’s Trial Master 
File.  
F oll o w- U p Re p orts: 
T he I n vesti gat or m ust c o nti n ue t o f oll o w t he s u bject u ntil t he S A E has s u bsi de d or u ntil t he 
c o n diti o n bec o me s c hr o nic i n nat ure, sta bilizes (i n t he case of persiste nt i m pair me nt), t he s u bject 
dies , or t he s u bject is l ost t o f oll o w- u p. 
Wit hi n 2 4 h o urs of recei pt of f oll o w -u p i nf or mati o n, t he I n vesti gat or m ust u p date t he S A E Re p ort 
F or m f or t he st u d y a n d s u b mit a n y s u p p orti n g d o c u me ntati o n ( e g, s u bject disc har ge s u m mar y or 
a ut o ps y r e p orts) via fa x or e- mail.  
9. 5  
Pre g n a nc y Re p orti n g  
If t h e s u bject bec o mes pre g na nt d uri n g t he st u d y or wit hi n 3 0 da ys of disc o nti n ui n g I P, t he 
I n v esti gat or will c o m plete  t he P re g na n c y R e p or t F or m wit hi n 2 4 h o urs of bei n g n otifie d   a n d 
f or war d it t o t he S p o ns or.  
A s u bject bec o mi n g pre g na nt w hile o n I P will i m me diatel y be wit h dra w n fr o m t he st u d y a n d earl y 
ter mi nati o n st u d y pr oce d ures will be perf or me d. 
T he s u bject  s h o ul d be f oll o we d b y t h e I nv esti gat or  u ntil c o m pleti o n of t he pre g n a nc y. If t he 
pre g na nc y e n ds f or a n y r eas o n bef ore t h e a ntici pat e d date, t he I n vesti gat or s h o ul d n otif y Saf et y b y 
c o m pleti n g a n d f or w ar di n g t he Pre g n a nc y Re p ort F or m wit h t he u p date d i nf or mati o n wit hi n 
2 4 h o urs of bei n g n otifie d. At t he c o m pleti o n of t he pre g na n c y, t he I n vesti gat or will d oc u me nt t he 
o utc o me of t he pre g na n c y. If t h e o utc o me of t h e pre g n a nc y m eets t he criteria f or i m me diate 
classificati o n as a n S A E ( ie, p ost part u m c o m plicati o n, s p o nta ne o us a b orti o n, still birt h, ne o natal 
deat h, or c o n ge nital a n o mal y), t h e I n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g a n S A E 
a n d als o u p date t he Pr e g na nc y Re p ort F or m. 
9. 6  
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  
Re g ulat or y re p orti n g r e q uire me nts f or S A Es i ncl u de t he f oll o wi n g: 
•  Pr o m pt n otificati o n b y t he I n vesti gat or t o t he S p o ns or or desi g nee of a n S A E is esse ntial s o 
t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of s u bj ects a n d t he s afet y 
of a st u d y i nter ve nti o n u n der cli nic al i n vesti gati o n are met.  
•  T h e S p o ns or has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ul at or y a ut h orit y a n d ot her 
re g ulat or y a ge n cies a b o ut t he saf et y of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T h e 
S p o ns or or desi g n ee will c o m pl y wit h c o u ntr y- s pecific re g ulat or y re quire me nts relati n g t o 
safet y re p orti n g t o t he re g ulat or y a ut h orit y, I R Bs/I E C, a n d I n vesti gat ors. 

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•  I n v esti gat or safet y r e p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A R) acc or di n g t o l ocal re g ulator y re q uire me nts a n d S p o ns or p olic y a n d f or w ar de d t o 
I n v esti gat ors as necessar y. 
•  A n I n vesti gat or w h o recei ves a n I n vesti gat or s afet y re p ort descri bi n g a S U S A R  or ot her 
s pecific saf et y i nf or m ati o n (e g, s u m mar y or listi n g of SU S A R s) fr o m t he S p o ns or will re vie w 
a n d  t he n  file  it  al o n g  wit h  t he  I n vesti gat or’s  Br oc h ure  a n d  will  n otif y  t he  I R B/I E C,  if  
a p pr o priate acc or di n g t o l ocal re q uire me nts. 
9. 7  
Cli nic al L a b or at or y E v al u ati o ns 
Cli nical safet y la b orat or y assess me nts will i ncl u de ser u m c he mistr y, he mat ol o g y, a n d c o a g ulati o n 
a n d will be o btai ne d as i n dicate d i n  A p pe n di x A . See A p pe n di x B  f or a c o m plete list of a nal ytes. 
9. 8  
Vit al Si g ns  
Vital si g n meas ure me nts will i ncl u de hei g ht (at t h e Scree ni n g Visit o nl y), we i g ht ( Scree ni n g a n d 
Baseli ne Visits o nl y) , b o d y te m perat ure ( Scree ni n g a n d Bas eli ne Visits o nl y), bl o o d press ure, a n d 
p ulse rate , a n d will be meas ure d after resti n g f or 5  mi n utes as i n dicate d i n  A p pe n di x A . 
9. 9  
P h ysic al E x a mi n ati o ns  
P h ysical e x a mi nati o ns will c o nsist of t he f oll o wi n g: ge neral a p peara n ce, hea d a n d nec k, e yes a n d 
ears, n os e a n d t hr oat, c h est, l u n gs, heart, a b d o m e n, e xtre mities a n d j oi nts, l y m p h n o des, s ki n, a n d 
ne ur ol o g y. F ull a n d s y m pt o m -directe d p h ysical e x a mi nati o ns w ill be perf or me d as i n dicate d i n 
A p pe n di x A . 

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S T A TI S TI C S  
1 0. 1  
A n al ysis P o p ul ati o ns 
F ull A nal ysis Set ( F A S): T he F A S will i ncl u de all ra n d o mize d s u bjects.  
Per -Pr ot oc ol A nal ysis Set ( P P S): T he P P S will i ncl u de t he s u bset of s u bjec ts fr o m t he F A S w h o 
d o n ot ha ve  a n y maj or de viati o ns. A f ull list of maj or pr ot oc ol de viati o ns will be fi nalize d pri or t o 
data base l oc k a n d u n bli n di n g.  
Safet y A nal ysis Set: T he Safet y A n al ysis Set will i ncl u de all s u bjects w h o recei v e at least 1 d ose 
of I P.  
1 0. 2  
S t atistic al Met h o ds 
T he st u d y d ata will be cl ea ne d a n d l oc ke d after t h e last s u bject fi nis hes t he O pti o nal O pe n -La bel 
E xte nsi o n Peri o d. T he st u d y will t he n b e u n bli n de d a n d fi nal a n al ysis will be c o n d ucte d. T he d ata 
f or L o n g- Ter m F oll o w-U p Peri o d will b e re p orte d o nce a v aila ble.  
1 0. 2. 1  
A n al ysis of Effic ac y  
A ll pri mar y a n d sec o n d ar y efficac y e n d p oi nts will be a nal yze d usi n g t he F A S. T he pri mar y 
efficac y a n al ysis will be re peat e d f or  t he P P S as t he s u p p orti ve a nal ysis. 
1 0. 2. 1. 1  
Pri mar y efficac y a nal ysis  
T he pri mar y effica c y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all of t he f oll o wi n g criteria  
d uri n g t he p eri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y D a y  
of C ycl e X + 2 : 
•  N ot re q uiri n g a platel et tra nsf usi o n; 
•  N ot re q uiri n g a c h e m ot hera p y  d ose re d ucti o n b y ≥1 5 % d ue t o t hr o m b oc yt o pe nia; a n d 
•  N ot re q uiri n g a c h e m ot hera p y del a y b y ≥4 da ys d ue t o t hr o m b oc yt o p e nia 
S u bjects wit h o ut s ufficie nt data f or t he deter mi nati o n of res p o nse stat us (ie, res p o n der ver s us 
n o n- res p o n der) will be treate d as n o n-res p o n ders i n t he a nal ysis. E ver y eff ort s h o ul d be ma d e 
d uri n g t he c o n d u ct of t he st u d y t o li mit t he e xte nt of missi n g data wit h s u bjects w h o pre mat urel y 
disc o nti n ue I P b ut re mai n i n t he st u d y f or c ollecti o n of data, u nless t he s u bject wit h dra ws c o nse nt.  
T he treat me nt effect o n t he pri mar y efficac y e n d p oi nt will be teste d bet wee n a v atr o m b o pa g a n d 
place b o usi n g t he C oc hra n -Ma ntel -Hae nszel test, a dj usti n g f or n u m ber of c h e m ot hera p y a ge nts ( 1 
or ≥2  per missi ble  c he m ot h era p y  a ge nts  [ n ucle osi de  a nal o g,  i ncl u di n g  ge m cita bi ne  a n d  
fl u or o uracil;  car b o plati n  or  cis plati n;  a nt hrac ycli ne;  or  al k ylati n g  a ge nt]).  T he  n u m bers  a n d  
perce nt a ges of res p o n ders i n eac h treat me nt gr o u p, t he ass ociate d 9 5 % c o nfi de nce i nter vals ( CI), 
a n d t he 9 5 % CI f or t he differe n ce bet wee n a vatr o m b o pa g a n d pl ace b o will be cal c ulate d. T h e 
pri mar y a n al ysis will be perf or me d bas e d o n t h e F A S a n d re p eate d o n t he P P S. Ot her se nsiti vit y 
a nal ys es of t he pri mar y efficac y e n d p oi nt ma y be perf or me d as a p pr o priate. 

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1 0. 2. 1. 2  
K e y sec o n d ar y efficac y a nal ysis  
T he ke y se c o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  D urati o n of s e ver e t hr o m b oc yt o p e nia defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he p eri o d 
after p ost -c he m ot her a p y I P tr eat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y Da y  of C ycl e X + 2 ; 
•  C ha n ge i n platelet c o u n t fr o m baseli ne ( q ualif yi n g c he m ot hera p y c ycle [ C ycl e X]) ( n a dir) t o 
C ycle X + 1 ( n a dir);  
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n- maj o r cli nicall y rele v a nt blee di n g d uri n g 
t he peri o d after p ost -c h e m ot hera p y I P treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y Da y  of 
C ycle X + 2 ; a n d  
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve pl atelet tra nsf usi o n d uri n g t he peri o d after p ost -
c he m ot hera p y I P tr eat me nt i n C ycle X + 1 thr o u g h  C he m ot hera p y Da y  of C ycl e X + 2 .  
If t he test of t he treat me nt effect o n t he pri mar y efficac y e n d p oi nt is statisticall y si g nifica nt, t he 
a nal ysis of t he ke y s ec o n dar y efficac y e n d p oi nts will pr ocee d usi n g ste p-d o w n cl ose d testi n g 
pr oce d ur e i n t he f oll o wi n g or der t o mai ntai n t he fa mil y-wise  T y pe I err or rate at si g nifica nce le vel 
al p ha = 0. 0 5 ( 2-si de d): 
•  Ste p  1:  Test  t he  treat me nt  eff ect  at  a  si g nifica nt  le v el  of  0. 0 5  o n  d urati o n  of  s e vere  
t hr o m b oc yt o pe ni a  defi n e d  as  a  platelet  c o u nt  < 5 0  ×   1 09/ L d uri n g  t h e  peri o d  after  p ost -
c he m ot hera p y I P  treat m e nt  i n  C ycle  X + 1  t hr o u g h C he m ot hera p y  D a y  of  C ycl e  X + 2;  if  
s uccessf ul, pr o cee d t o Ste p 2; ot her wise st o p at Ste p 1.  
•  Ste p 2: Test t he treat me nt eff ect at a si g nifi ca nt le vel of 0. 0 5 o n c ha n ge i n platelet c o u nt fr o m 
baseli ne  ( q ualif yi n g  c he m ot hera p y  c yc le  [ C ycl e  X])  ( na dir)  t o  C ycle  X  +  1  ( na dir);  if  
s uccessf ul, pr o cee d t o Ste p 3; ot her wise st o p at Ste p 2. 
•  Ste p 3: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n pr o p orti o n of s u bjects w h o d o 
n ot  ha ve  maj or  or  n o n -maj or  cli nicall y  rele v a nt  blee di n g d uri n g  t he  peri o d  after  p ost -
c he m ot hera p y I P  treat m e nt  i n  C ycle  X + 1  t hr o u g h C he m ot hera p y  D a y  of  C ycl e  X + 2 ;  if  
s uccessf ul, pr o cee d t o Ste p 4; ot her wise st o p at Ste p 3. 
•  Ste p 4: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n pr o p orti o n of s u bjects w h o d o 
n ot recei v e platelet tr a nsf usi o n d uri n g t he p eri o d after p ost-c he m ot hera p y I P treat me nt i n C ycl e 
X + 1 t hr o u g h C he m ot her a p y Da y  of C ycl e X + 2 . 
1 0. 2. 1. 3  
O t her efficac y a nal ysis  
T he ot her efficac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he peri o d after p os t-c he m ot hera p y I P 
treat me nt i n C ycl e X + 1 thr o u g h C he m ot hera p y D a y of C ycle X + 2 : 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c h e m ot hera p y d ose re d ucti o n t h at is ≥1 5 % d ue t o 
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n  of  s u bjects  w h o  d o  n ot  ha ve  a  c he m ot hera p y  dela y  t hat  is  ≥4  da ys  d ue  t o  
t hr o m b oc yt o pe ni a; 
•  Pr o p orti o n of s u bject s wit h a pre -d efi ne d p ost- bas eli ne na dir platelet c o u nt ; a n d 
•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost- baseli ne ma xi m u m plat elet c o u nt.  

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T he cate g orical varia bl es (e g, pr o p orti o n) will be s u m marize d a n d a nal yze d i n t he sa me m a n ner 
as t he pri mar y e ffi cac y e n d p oi nt. T he c o nti n u o us varia bles (e g, c ha n ge fr o m baseli ne i n platelet 
c o u nt) will be a nal yze d usi n g a nal ysis of c o varia n ce m o dels wit h treat me nt a n d t he ra n d o mizati o n 
stratificati o n fact or as mai n effects a n d t he baseli ne meas ure m e nt as a c o vari ate, a n d Wilc o x o n 
Ra n k S u m tests if t he n or malit y ass u m pti o n is vi olate d.  
T he efficac y vari a bles c ollecte d  d uri n g t he o pti o nal O L E  Peri o d will be s u m marize d descri pti vel y.  
A d diti o nal efficac y a n al ys es will be perf or me d if dee me d necess ar y. T he details of t he a nal yses 
will be descri be d i n t he Statistical A nal ysis Pla n t hat will be fi nalize d pri or t o data base l oc k.   
1 0. 2. 2  
A n al ysi s of S af et y 
S afet y a n d t olera bilit y will be assesse d b y e x a mi ni n g t he i nci de nce of a d verse e v e nts, A E SI , 
cli nical la b or at or y para m eters, p h ysical e x a mi nati o n fi n di n gs, a n d vital si g ns  o ver ti me usi n g t he 
Safet y A nal ysis Set.  
1 0. 2. 3  
I nterim  A n al ysis 
N o f or mal i nteri m a nal ysis is pla n ne d f or t his st u d y. A D S M B will be c o n ve ne d f or t his st u d y, 
pri maril y t o m o nit or safet y  at re g ular i nter vals . A D S M B c harter, detaili n g all as pects of t he 
D S M B’s sc o pe of re vi e w a n d pr oce d ures will be d escri be d i n a s e parate d o c u me nt.  
1 0. 2. 4  
S a m ple Size D eter mi n ati o n  
A ss u mi n g t here is a 4 0 % res p o nse rate i n t he acti ve gr o u p a n d 1 0 % i n t he place b o gr o u p, a n d usi n g 
a 2: 1 ra n d o mizati o n, a 1 0 % pre mat ure ter mi nati o n rate, a n d 9 0 % p o wer wit h 2 -si de d al p ha = 0. 0 5, 
t he sa m ple size is 1 2 0 s u bjects ( 8 0 acti ve s u bjects a n d 4 0 place b o s u bjects). 
T he ass u m pti o ns f or t he res p o nse rat es f or t he n ull a n d alter nati ve h y p ot h eses were base d u p o n 
res ults fr o m a st u d y i n CI T c o m plete d wit h o prel ve ki n ( Ne u me ga, Pfizer). T he st u d y d esi g n f or 
o prel ve ki n was si milar i n t hat s u bjects were ra n d o mize d t o acti ve o r place b o f oll o wi n g occ urre n ce 
of se ver e t hr o m b oc yt o p e nia ( platelet c o u nt ≤2 0 ×   1 09/ L i n a pre vi o us c ycle [C ycl e X ]). T he 
pri mar y e n d p oi nt of t he st u d y assesse d t he a bilit y of o prel v e ki n t o eli mi nate t he nee d f or platelet 
tra nsf usi o ns.  I n  t he  place b o  gr o u p ( n = 3 0),  9 3 %  of  s u bjects  re q uire d  a  platelet  tra nsf usi o n 
( 7 % res p o n d er  r ate)  a n d  7 2 %  of  acti ve  su bj ects  ( n = 2 9)  re q uire d  a  p latelet  tra nsf usi o n  
( 2 8 % res p o n d er rate). T h e res p o n d er rates ass u me d f or t he n ull a n d alter nati ve h y p ot hes es i n t he 
A V A -CI T -3 3 0 st u d y wer e base d u p o n t he res p o n d er rates i n t his si milarl y d esi g ne d st u d y wit h a n 
ass u m pti o n f or a sli g htl y hi g her r es p o nse rate d u e t o t he i ncl usi o n of s u bj ects wit h a platel et c o u nt 
i n C ycle X of < 5 0 ×  1 09/ L, r at her t ha n ≤2 0 ×  1 09/ L. 

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D A T A M A N A G E M E N T A N D R E C O R D K E E PI N G  
1 1. 1  
D at a M a n a ge me nt 
1 1. 1. 1  
D at a H a n dli n g 
D ata will be rec or d e d at t he site o n e C R Fs a n d re vie we d b y t h e cli nical researc h ass oci ate  ( C R A) 
o n a n o n g oi n g basis a n d d uri n g m o nit ori n g visits. T he C R As will verif y data rec or d e d i n t he 
electr o nic data ca pt ure ( E D C ) s yste m wit h s o urce d oc u me nts. All c orrecti o ns or c ha n ges ma de t o 
a n y st u d y d ata m ust be a p p r o priatel y trac ke d i n a n a u dit trail i n t he E D C s yste m. A n e C R F will be 
c o nsi dere d c o m plete w he n all missi n g, i nc orrect, a n d/ or i nc o nsiste nt data has bee n acc o u nte d f or  
a n d rec o n ciliati o n bet wee n ot her data b ases (e g, safet y, I R T) is c o m plete . 
1 1. 1. 2  
C o m p uter S yst e ms  
D ata will b e pr o cesse d usi n g a v ali date d c o m p uter s yste m c o nf or mi n g t o re g ulat or y re q uire me nts.  
1 1. 1. 3  
D at a E ntr y  
D ata m ust be rec or de d usi n g t he E D C s yste m as t he  st u d y is i n pr o gress. All site pers o n nel m ust 
l o g i nt o t he s yste m usi n g t heir sec ur e user na m e a n d pass w or d i n or der t o e nter, re vie w, or c orrect 
st u d y data. T hese pr oce d ures m ust c o m pl y wit h Title 2 1 of t he C o de of Fe d eral Re g ulati o ns 
( 2 1 C F R ) Part 1 1 a nd ot her a p pr o priate i nter nati o nal re g ulati o ns. All pass w or ds will be strictl y 
c o nfi de ntial. 
1 1. 1. 4  
Me di c al I nf or m ati o n C o di n g 
F or me dical i nf or mati o n, t he f oll o wi n g t hes a uri will be use d:  
•  Me dical Dicti o nar y f or R e g ul at or y Acti vities  f or me dical hist or y a n d a d v erse e ve nts, a n d  
•  W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y f or pri or a n d c o n c o mita nt me dicati o ns. 
1 1. 1. 5  
D at a V ali d ati o n 
V ali dati o n  c hec ks  pr o gr a m me d  wit hi n  t he  E D C  s yste m,  as  w ell  as  s u p ple me ntal  vali dati o n  
perf or me d via r e vie w of t he d o w nl oa de d data, will be a p plie d t o t he data i n or der t o e ns ure 
acc ur ate, c o nsiste nt, a n d relia ble data. Data i d e ntifie d as er r o ne o us, or data t hat are missi n g, will 
be ref err e d t o t he i n vesti gati ve site f or res ol uti o n t hr o u g h d ata q ueri es. 
T he e C R Fs m ust be re vi e we d a n d el ectr o nicall y  si g ne d b y t h e I n vesti gat or. 

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1 1. 2  
Rec or d Kee pi n g  
Rec or ds of s u bjects, s o ur ce d oc u m e nts, m o nit ori n g visit l o gs, e C R Fs, i n v e nt or y of st u d y pr o d u ct, 
re g ulat or y d oc u m e nts, a n d ot her S p o ns or c orres p o n de nce p ertai ni n g t o t he st u d y m ust be ke pt i n 
t he a p pr o pri ate st u d y files at t he site. S o urce data are d efi ne d  as all i nf or m ati o n i n ori gi nal rec or ds 
a n d certified c o pies of ori gi nal r ec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a 
cli nical st u d y necessar y f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y. S o urce d ata are 
c o ntai ne d i n  s o urce d oc u me nts ( ori gi nal rec or ds or certifi e d c o pi es). T h ese rec or ds will be retai ne d 
i n a sec ur e file f or t he p eri o d as set f ort h i n t h e Cli nical St u d y A gree me nt. Pri or t o tra nsfer or 
destr ucti o n of t hese rec or ds, t he S p o ns or m ust b e n otifie d i n writi n g a n d be gi v e n t he o p p ort u nit y 
t o f urt her st ore s u c h rec or ds.  

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IN V E S TI G A T O R R E Q UI R E M E N T S A N D Q U A LI T Y C O N T R O L  
1 2. 1  
Et hic al C o n d uct of t he St u d y  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol a n d all re g ul at or y re q uire me nts, i n 
acc or d a nce  wit h  G o o d  Cli nical  Practice  ( G C P),  i ncl u di n g  I nter n ati o nal  C o nfere n ce  o n  
Har m o nisati o n (I C H) g ui deli nes, a n d i n ge n eral c o nf or mit y wit h t he m ost rece nt v ersi o n of t he 
Declar ati o n  of  Helsi n ki.  D o va  P har mace uticals  Q ualit y  Ass ura nce  or  desi g nee  ma y  verif y  
a d here n ce t o t hes e practices a n d pr o ce d ures t hr o u g h a u dit a n d i ns pecti o n. 
1 2. 2  
I nstit uti o n al Re vie w B o ar d/I n de pe n de nt Et hics C o m mittee 
T he I R B/I E C will re vie w all a p pr o priate st u d y d oc u me ntati o n i n or der t o safe g uar d t he ri g hts, 
safet y, a n d w ell-bei n g of s u bjects. T he st ud y will o nl y b e c o n d uct e d at sites w here I R B /I E C 
a p pr o val h as bee n o btai n e d. T he pr ot oc ol, I n v esti gat or’s Br oc h ure, I nf or m e d C o nse nt For m  (I C F), 
a d vertise me nts (if a p plica ble), writte n i nf or mati o n gi ve n t o t he s u bjects, safet y u p dat es, a n n ual 
pr o gress re p orts, a n d a n y r e visi o ns t o t hese d oc u me nts will be pr o vi de d t o t he I R B /I E C b y t he 
I n v esti gat or. 
T he I n vesti gat or is o bli gate d t o kee p t he I R B/I E C i nf or me d of a n y u na ntici pate d pr o ble ms. T his 
ma y i ncl u d e n otificati o n t o t he I R B/I E C of I n v esti gati o nal N e w Dr u g Safet y Re p orts.  
Fe deral  re g ulati o ns  a n d  I C H  r e q uire  t hat  a p pr o val  be  o btai ne d  fr o m  a n  I R B /I E C pri or  t o  
partici pati o n of s u bjects  i n researc h st u dies. Pri or t o st u d y o ns et, t he pr ot oc ol, a n y pr ot oc ol  
a me n d me nts, I C Fs, a d v ertise me nts t o be use d f or s u bject recr uit me nt, a n d a n y ot h er writte n 
i nf or mati o n re gar di n g t his st u d y t o be pr o vi de d t o a s u bject or s u bject’s l e gal g u ar dia n m ust be 
a p pr o ve d b y t he I R B /I E C. 
N o dr u g will be release d t o t he site f or d osi n g u ntil writte n I R B /I E C a ut h orizati o n has bee n 
receiv e d b y t he S p o ns or. 
It is t he r es p o nsi bilit y of t he S p o ns or or t heir desi g nee t o o btai n t he a p pr o val of t he res p o nsi ble 
et hics c o m mittees acc or di n g t o t he nati o nal re g ulati o ns.  
T he st u d y will o nl y start i n t he res pecti ve sites o n ce t he res pecti ve c o m mitte e’s writte n a p pr o v al 
has bee n gi ve n. 
1 2. 3  
Pr ot oc ol A me n d me nts  
A n y a me n d me nts t o t he st u d y pr ot o c ol will be c o m m u nicate d t o t he I n v esti gat ors b y t h e S p o ns or  
or desi g n ee . All pr ot oc ol a me n d me nts will u n der g o t he sa me re vie w a n d a p pr o val pr ocess as t he 
ori gi nal pr ot oc ol. A pr ot oc ol a me n d me nt ma y be i m ple me nte d after it has bee n a p pr o ve d b y t h e 
I R B/I E C,  u nless  i m me diate  i m ple me ntati o n  of  t he  c ha n ge  is  necessar y  f or  s u bject  safet y.  
S u bsta ntial a me n d me nt s m ust be a p pr o ve d as per l ocal re g ulati o ns  pri or t o e nr olli n g s u bjects. I n 
t his case, t he sit uati o n m ust be d oc u me nte d a n d re p orte d t o t he I R B/I E C wit hi n 5 w or ki n g da ys. 
1 2. 4  
I nf or me d C o nse nt 
T he I C F a n d a n y c h a n ges t o t he I C F m a de d uri n g t he c o urs e of t h e st u d y m ust be a gree d t o b y t h e 
S p o ns or or desi g nee a n d t he I R B /I E C pri or t o its use a n d m ust be i n c o m plia nce wit h all I C H G C P, 
l ocal re g ulat or y re q uir e me nts, a n d le gal re q uire me nts.   

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T he I n vesti gat or m ust e ns ure t hat eac h st u d y s u bject is f ull y i nf or me d a b o ut t he nat ure a n d 
o bjecti ves of t he  st u d y a n d p ossi ble ris ks ass ociate d wit h partici pati o n a n d m ust e ns ure t hat t he 
su bject  has  bee n  i nf or m e d  of  his/ her  ri g hts  t o  pri vac y.  T he  I n v esti gat or will  o btai n  writte n  
i nf or me d c o ns e nt fr o m eac h s u bject bef ore a n y st u d y-s pecific acti vit y is perf or me d a n d s h o ul d 
d oc u me nt i n t he s o urce d oc u me ntati o n t hat c o nse nt was o btai ne d pri or t o e nr oll me nt i n t he st u d y. 
T he ori gi nal si g ne d c o p y of t he I C F m ust be m ai ntai ne d b y t he I n vesti gat or a n d is s u bject t o 
i ns pecti o n b y a re prese nt ati ve of t he S p o ns or, t heir re prese ntati ves, a u dit ors, t he I R B/I E C, a n d/ or 
re g ulat or y a ge ncies. A c o p y of t he si g n e d I C F will be gi v e n t o t he s u bject.  
1 2. 5  
St u d y M o nit ori n g Re q uire me nts  
It is t he res p o nsi bilit y of t he I n v esti gat or t o e ns ure t hat t he st u d y is c o n d uct e d i n acc or d a nce wit h 
t he pr ot oc ol, D eclarati o n of Helsi n ki, I C H G C P, Directi ve 2 0 0 1/ 2 0/ E C, a n d a p plica ble  re g ulat or y 
re q uire me nts, a n d t h at vali d data are e ntere d i nt o t he e C R Fs.  
T o ac hie ve t his o bjecti ve, t he C R A ’s d uties are t o ai d t he I n vesti gat or a n d, at t he sa me ti me, t he 
S p o ns or, i n t he mai nte na nce of c o m plete, le gi ble, well or ga nize d, a n d easil y retrie va bl e data. 
Bef ore t he e nr oll me nt of a n y s u bject i n t his st u d y, t he S p o ns or or t heir desi g nee will re vie w wit h 
t he I n vesti gat or a n d site pers o n nel t he f oll o wi n g d oc u me nts: pr ot oc ol, I n vesti gat or’s Br oc h ure, 
e C R Fs a n d pr oce d ures f or t heir c o m pleti o n, i nf or me d c o nse nt pr ocess, a n d t he pr oce d ure f or 
re p orti n g S A Es. 
T he I n v esti gat or will per mit t he S p o ns or or t heir desi g nee t o m o nit or t he st u d y as fre q ue ntl y as 
dee me d necessar y t o  deter mi ne t hat data rec or di n g a n d pr ot oc ol a d here nce are satisfact or y. D uri n g 
t he m o nit ori n g  visits,  i nf or mati o n  rec or de d  o n  t he  e C R Fs  will  be  verifie d  a gai nst  s o urce  
d oc u me nts a n d re q uests f or clarificati o n or c orrecti o n ma y be m a de. After t he e C R F d ata is e ntere d 
b y t he site, t he C R A will re vie w t he data f or safet y i nf or mati o n, c o m pl ete ness, acc urac y, a n d 
l o gical c o nsiste nc y. C o m p uter pr o gr a ms t hat i d e ntif y data i nc o nsiste nci es ma y b e us e d t o h el p 
m o nit or t he cli nical st u d y. If necessar y, re q uests f or cl arificati o n or c orrecti o n will be se nt t o 
In v esti gat ors. T he I n vesti gat or a n d his/ her staff will be e x pecte d t o c o o p erate wit h t he C R A  a n d 
pr o vi de a n y missi n g i nf or mati o n, w he ne ver p ossi ble. 
All m o nit ori n g acti vities will be re p orte d a n d arc hi ve d. I n a d dit i o n, m o nit ori n g visits will be 
d oc u me nte d at t he i n vesti gati o nal site b y si g nat ure a n d date o n t h e st u d y- s pecific m o nit ori n g l o g. 
1 2. 6  
Discl os ure of D at a  
Data  ge nerate d  b y  t his  st u d y  m ust  be  a vaila ble  f or  i ns pecti o n  b y  t he  F o o d  a n d  Dr u g  
A d mi nistrati o n ,  t he  S p o ns or  or  t heir  desi g nee,  a p plica ble  f orei g n  h ealt h  a ut h orities,  a n d  t h e  
I R B/I E C as  ap pr o priate.  S u bjects  or  t h eir  le gal  re prese ntati ves  m a y  re q uest  t heir  me dical  
i nf or mati o n  be  gi ve n  t o  t heir  pers o nal  p h ysicia n  or  ot her  a p pr o priat e  me dical  pers o n nel  
res p o nsible f or t heir welf are.  
S u bject ’s me dical i nf or mati o n o btai ne d d uri n g t he st u d y is c o nfi de ntial a n d discl os ure t o t hir d 
parties ot her t ha n t h ose n ote d a b o ve is pr o hi bite d. 
1 2. 7  
Rete nti o n of Rec or ds  
T o e na ble e val uati o ns a n d/ or a u dits fr o m re g ulat or y a ut h orities or t he S p o ns or, t he In v esti gat or 
will kee p r ec or ds, i ncl u di n g t h e i de ntit y of all partici pati n g s u bjects (s uffici e nt i nf or mati o n t o li n k 
rec or ds, e g, eC R Fs a n d h os pital rec or ds), all ori gi n al si g ne d I C Fs, c o pi es of all eC R Fs, S A E  f or ms, 

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s o urce d oc u me nts, a n d d etaile d rec or ds of treat m e nt dis p ositi o n. T he rec or ds s h o ul d be retai ne d 
b y t h e I n vesti gat or acc or di n g t o s pecificati o ns i n t he I C H g ui deli nes, l ocal re g ulati o ns, or as 
s pecifie d i n t he Cli nical St u d y A gree me nt, w hic he ver is l o n ger. T he I n v esti gat or m ust o btai n 
writte n  per missi o n  fr o m  t he  S p o ns or bef ore  dis p osi n g  of  a n y  rec or ds,  e ve n  if  ret e nti o n  
re q uire me nts ha v e bee n met. 
If t h e I n vesti gat or rel o cat es, retires, or f or a n y reas o n wit h dra ws fr o m t he st u d y, t he S p o ns or s h o ul d 
be pr os pecti vel y n otifie d. T he st u d y rec or ds m ust be tra nsferre d t o a n ac ce pta ble desi g nee, s uc h 
as a n ot her I nv esti gat or , a n ot her i nstit uti o n, or t o t he S p o ns or.   
1 2. 8  
P u blic ati o n P olic y  
F oll o wi n g c o m pleti o n of t he st u d y, t h e data m a y be c o nsi dere d f or p u blicati o n i n a scie ntifi c 
j o ur nal  or  f or  r e p orti n g  at  a  scie ntific  meeti n g.  Eac h I n vesti gat or is  o bli gate d  t o  kee p  data 
pertai ni n g t o t he st u d y c o nfi de ntial. T he I n v esti gat or m ust c o ns ult wit h t he S p o ns or bef ore a n y 
st u d y data ar e s u b mitte d f or p u blicati o n. T he S p o ns or reser ves t he ri g ht t o de n y p u blicati o n ri g hts 
u ntil m ut ual a gree me nt o n t he c o nte nt, f or mat, i nter pretati o n of data i n t he ma n uscri pt, a n d j o ur nal 
selecte d f or p u blicati o n are ac hi e ve d. 
1 2. 9  
Fi n a nci al Discl os ure  
I n v esti gat ors are re q uire d t o pr o vi de fi n a ncial discl os ure i nf or mati o n t o t h e S p o ns or t o per mit t he 
S p o ns or t o f u lfill its o bli gati o ns u n d er 2 1 C F R Pa rt 5 4. I n a d diti o n, In vesti gat ors m ust c o m mit t o 
pr o m ptl y u p dati n g t his i nf or mati o n if a n y rel e va nt c ha n ges o cc ur d uri n g t he st u d y a n d f or a p eri o d 
of 1 year after t he c o m pl eti o n of t he st u d y. 
1 2. 1 0  
I ns ur a nce a n d I n de m nit y 
I n acc or da n ce wit h t he r ele va nt nati o na l re g ulati o ns, t he S p o ns or has ta k e n o ut s u bject lia bilit y 
i ns ura nce f or all s u bjects w h o ha ve gi ve n t heir c o nse nt t o t he cli nical st u d y. T his c o vera ge is 
desi g ne d f or t he e v e nt t hat a fatalit y, p h ysical i nj ur y, or d a ma ge t o healt h occ urs d uri n g t he cli nic al 
st u d y’s e x ec uti o n. 

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1 3  
R E F E R E N C E S  
1.  K uter DJ. Ma na gi n g t hr o m b oc yt o pe ni a ass o ciate d wit h ca ncer c h e m ot hera p y. O nc ol o g y 
( Willist o n Par k). 2 0 1 5 A pr; 2 9( 4): 2 8 2- 9 4. 
2.  Hassa n B A, Y us off Z B, Hassali M A, Bi n Ot h ma n S. Treat me nt patter ns a n d o utc o mes i n 
ma na ge me nt of s ol i d ca n cer p atie nts s ufferi n g fr o m t hr o m b oc yt o p e nia i n P e na n g h os pital. 
Asia n Pac J Ca ncer Pre v. 2 0 1 1; 1 2( 1 1): 2 8 4 1- 5. 
3.  A vatr o m b o pa g maleate Gl o bal I n vesti gat or’s Br o c h ure, v 1 4, J a n uar y 2 0 1 9. 
4.  Ha yes S, M u d d P N Jr, O uellet D,  J o h ns o n B M, Willia ms D, Gi bia ns k y E.  P o p ulati o n 
P K/ P D  m o deli n g  of  eltr o m b o pa g  i n  s u bjects  wit h  a d v a nce d  s oli d  t u m ors  wit h  
c he m ot hera p y-i n d uce d
 t hr o m b oc yt o p e nia.  Ca ncer  C he m ot her  P har mac ol.  2 0 1 3
 
J u n; 7 1( 6): 1 5 0 7- 2 0. 
5.  B o na d o n n a  G,  V ala g ussa  P,  M oliter ni  A,  Za m b etti  M,  Bra m billa  C.   A dj u va nt 
c ycl o ph os p ha mi de,  met h otre x ate,  a n d  fl u or o uracil  i n  n o de -p ositi ve  breast  ca ncer:  t he  
res ults of 2 0 years of f oll o w- u p. N E n gl J Me d. 1 9 9 5 A pr 6; 3 3 2( 1 4): 9 0 1- 6. 
6.  B osl y A, Br o n D, V a n H o of A, De B oc k R, Ber n e m a n  Z, Ferra nt A, Ka uf m a n L, D a u we  M, 
Ver h oef G. Ac hie ve m e nt of o pti mal a vera ge relati ve d ose i nte nsit y a n d c orrelati o n wit h 
s ur vi val i n diff use lar ge B-cell l y m p h o ma patie nts treate d wit h C H O P. A n n He mat ol. 2 0 0 8 
A pr; 8 7( 4): 2 7 7- 8 3. 
7.  C hiri vella I, Ber mej o B, I nsa A, Pérez -Fi dal g o  A, Ma gr o A, R osell o S, García -Garre E, 
Martí n P, B osc h A, Ll u c h A. O pti mal deli ver y of a nt hrac ycli ne -base d c he m ot hera p y i n t he 
a dj u va nt setti n g i m pr o ves o utc o me of breast ca ncer patie nts. Breast Ca ncer R es Treat. 2 0 0 9 
A pr; 1 1 4( 3): 4 7 9- 8 4. 
8.  Ha vriles k y LJ, et al. J Cli n O nc ol. 2 0 1 1: 2 9(s u p pl). A bstract 5 0 8 4. 
9.  We yc k er  D,  Barr o n  R,  E dels ber g  J,  Kartas h o v  A,  L y ma n  G H.  I n ci de n ce  of  re d uce d  
c he m ot hera p y rel ati ve d ose i nte nsit y a m o n g w o me n wit h earl y sta ge breast ca n cer i n U S 
cli nical practice. Breast Ca ncer Res Treat.  2 0 1 2 Ma y; 1 3 3( 1): 3 0 1 - 1 0. 
1 0.  F o ote M. T he  I m p orta nce of Pla n ne d D ose of C he m ot hera p y o n Ti me: D o We Nee d t o 
C ha n ge O ur Cli nical Practice? O nc ol o gist. 1 9 9 8; 3( 5): 3 6 5- 3 6 8. 
1 1.  L y m a n G H. I m p act of c he m ot hera p y d ose i nte nsit y o n ca ncer patie nt o utc o mes. J Natl 
C o m pr Ca nc Net w. 2 0 0 9 J a n; 7( 1): 9 9- 1 0 8. 
1 2.  Hr y ni u k W M. T he i m p orta nce of d ose i nte nsit y i n t he o utc o me of c he m ot hera p y. I m p orta nt 
A d v O nc ol. 1 9 8 8: 1 2 1- 4 1. 
1 3.  Li n k B K, B u d d G T, Sc ott S, Dic k ma n E, Pa ul D, La wless G, Lee M W, Fri d ma n M, F or d 
J,  Carter  W B;  O nc ol o g y Practice  Patter n  St u d y W or ki n g Gr o u p.  D eli veri n g  a dj u va nt  
c he m ot hera p y  t o  w o me n  wit h  earl y-st a ge  breast  carci n o ma:  c urre nt  patter ns  of  care.  
Ca ncer. 2 0 0 1 Se p 1 5; 9 2( 6): 1 3 5 4- 6 7. 
1 4.  L y m a n G H, D ale D C, Cra wf or d J. I nci de n ce a n d pre dict ors of l o w d ose -i nte nsit y i n  
a dj u va nt breast ca n cer c he m ot hera p y: a nati o n w i de st u d y of c o m m u nit y practices. J Cli n 
O nc ol. 2 0 0 3 Dec 1 5; 2 1( 2 4): 4 5 2 4- 3 1. 

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6 3  
1 5.  L y m a n G H, D ale D C, Fri e d ber g J, Cra wf or d J, Fis her RI. I nci de nce a n d pre dict ors of l o w 
c he m ot hera p y d ose-i nte nsit y i n a g gressi ve n o n- H o d g ki n's l y m p h o ma: a nati o n wi de st u d y. 
J Cli n O nc ol. 2 0 0 4 N o v 1; 2 2( 2 1): 4 3 0 2- 1 1. 
1 6.  N ort o n L. T h e oretical c o nce pts a n d t he e m er gi n g r ole of ta x a nes i n a dj u va nt t hera p y. 
O nc ol o gist. 2 0 0 1; 6 S u p pl 3: 3 0- 5. 
1 7.  Pic ozzi VJ, P o hl ma n B L, M orris o n V A, La wless G D, Lee M W, Kerr R O, F or d J M, 
Del ga d o DJ, Fri d ma n M, Carter  W B. Patter ns of c he m ot hera p y a d mi nistrati o n i n patie nts 
wit h  i nter me diate -gra d e  n o n -H o d g ki n's  l y m p h o ma.  O nc ol o g y  ( Willist o n  Par k).  2 0 0 1  
Oct; 1 5( 1 0): 1 2 9 6- 3 0 6; disc ussi o n 1 3 1 0- 1, 1 3 1 4. 
1 8.  Citr o n M L, Berr y D A, Cirri nci o ne C, H u dis C, Wi ner E P, Gra dis h ar WJ, Da vi ds o n N E, 
Marti n o S, Li vi n gst o n R, I n gle J N, Perez E A, Car pe nter J, H ur d D, H olla n d J F, S mit h B L, 
Sart or CI, Le u n g E H, A bra ms J, Sc hils k y R L, M uss H B, N ort o n L. Ra n d o mize d trial of 
d ose- de nse vers us c o n ve nti o nall y s c he d ule d a n d s e q ue ntial vers us c o nc urre nt c o m bi nati o n 
c he m ot hera p y as p ost o perati ve a dj u va nt treat me nt of n o de -p ositi ve pri mar y breast ca ncer: 
first re p ort of I nter gr o u p Trial C 9 7 4 1/ Ca ncer a n d Le u k e mia Gr o u p B Trial 9 7 4 1. J Cli n 
O nc ol. 2 0 0 3 A pr 1 5; 2 1( 8): 1 4 3 1- 9. 
1 9.  K wa k L W, H al per n J, Ols he n  R A, H or ni n g SJ. Pr o g n ostic si g nifi ca nce of act ual d ose 
i nte nsit y i n diff use lar ge-cell l y m p h o ma: res ults of a tree -str uct ure d s ur vi val a nal ysis. 
J Cli n O nc ol. 1 9 9 0 J u n; 8( 6): 9 6 3- 7 7. 
2 0.  B o na d o n n a G, M oliter ni A, Za m betti M, Dai d o ne M G, Pil otti  S, Gia n ni L, Vala g uss a P. 
3 0 years' f oll o w u p of r a n d o mise d st u dies of a dj u va nt C M F i n o pera ble breast ca ncer: 
c o h ort st u d y. B MJ. 2 0 0 5 J a n 2 9; 3 3 0( 7 4 8 5): 2 1 7. 
2 1.  See bac h er V, Rei nt haller A, K o el bl H, C o n ci n N, Ne h o da R, P oltera uer S. T he I m pact of 
t he D urati o n of A dj u v a nt C he m ot hera p y o n S ur vi val i n Patie nts wit h E pit helial O vari a n 
Ca ncer - A Retr os pecti ve St u d y. P L o S O ne. 2 0 1 7 J a n 6; 1 2( 1):e 0 1 6 9 2 7 2. 
 

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A P P E N DI X A:  S C H E D U L E O F P R O C E D U R E S  
T a ble 1. 
Sc he d ule of Pr oce d ures  ( D o u ble-Bli n d Tre at me nt Peri o d)  
Da y  
C he m o t her ap y  C ycle X a 
C he m o t her a p y C ycle X + 1  
Scree ni n g  
D -2 8  t o D -1  
B aseli ne  
Pre -C he m o I P 
Tre at me nt ( 5 D)  
C he m o D a y 
( D 1 u p t o D 3)  
P ost -C he m o  
I P Tre at me nt ( 5 D) 
D 1 1 ( ± 1 D), D 1 5 
(± 1 D), a n d D 1 8 ( ± 1 D)  
Visit  
1 b  
2  
3 c 
4 d  
5 e 
6, 7, 8  
S u bj ect i nf or me d c o nse nt  
X  
 
 
 
 
 
I/E criteria  
X  
X  
 
 
 
 
Ra n d o mizati o n  
 
X f 
 
 
 
 
De m o gra p hics  (i ncl. race) 
X  
 
 
 
 
 
Me dical hist or y
g  
X  
 
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
 
 
C o nc o mita nt me dicati o ns h  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
P h ysical e xa mi nati o n  
X  
X i 
 
X i 
 
 
Vital si g ns j 
X  
X  
 
X  
 
 
P K k 
 
 
X  
 
X  
 
He mat ol o g y (i ncl. platelet c o u nts)  l 
X b  
X  
X  
X  
X  
X  
C oa g ulati o n pa nel  (ce ntral la b) 
 
X  
 
 
X  
 
Ser u m c he mistr y m  
X b  
X  
 
X  
X  
 
Pre g na nc y testi n g n 
X b 
X o 
 
 
 
 
Blee di n g assess me nt (I S T H)  
 
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
p 
 
C o ntact I R T  
X  
X  
X  
 
X  
 
I P d osi n gq 
 
X  
X r 
 
X r 
 
Dis pe nse I P  a n d d osi n g diar y 
 
X  
 
X s 
 
 
C ollect d osi n g diar y a n d I P pac ka ge  
 
 
X  
 
X  
 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E  = i n cl usi o n/e xcl usi o n; i n cl. = i n cl u di n g; I P = i n vesti gati o nal pr o d uct; I R T = I nteracti ve 
Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y  o n T hr o m b osis a n d Hae m ostasis; P K =  p h ar ma c o ki n etic.  
N ote : Pri or t o c o n d u cti n g a n y st u d y -relat e d acti vities, writte n inf or me d c o nse nt m ust b e si g n e d a n d d ate d b y t h e s u bject. T hr o u g h o ut t he d o u ble -bli n d treat me nt peri o d, all s u bjects 
will be assess e d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose re d u cti o ns or d ela ys.  
a. 
T he q ualif yi n g c h e m o c ycle is d efi n e d as C ycle X.  
b.  
Scr ee ni n g Visit ma y o cc ur o n t h e sa me d a y as t h e Baseli n e Visit , if o n e d a y pri or t o I P treat me nt. If t h ese b s o cc ur o n t he sa me da y, o nl y t he Baseli ne ( Visit 2) la b orat or y 
sa mples s h o ul d b e se nt t o t h e ce ntral la b.  L o cal platelet c o u nts ma y b e re p eate d as n e e d e d. 
c. 
Visit 3 will o cc ur o n t h e last d a y of t h e 5 -d a y pre -c h e m o I P treat me nt. 

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d.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 a n d Da y 2, s u bjects will recei ve 
a vatr o m b o p a g or place b o o n Da y 3). A vatr o m b o p a g or place b o will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C he m ot hera p y Da y.  All assess me nts will occ ur 
o n t he first d a y of c h e m ot h era p y  pri or t o c h e m ot h era p y d osi n g.  
e. 
Visit 5 will o cc ur o n t h e last d a y of t h e  5-d a y p ost -c h e m o I P treat me nt.  
f. 
Ra n d o mizati o n m ust o cc ur pri or t o I P d osi n g.  
g.  
Me dical hist or y t o i n cl u d e t u m or t y p e, d ate of ca n cer dia g n osis, a n d pri or c h e m ot h era p e utic re gi me ns ( n u m b e rs of c ycles, dates). 
h.  
C o nc o mita nt me dicati o ns t o i n cl u d e d etails of c h e m ot h era p e utic re gi me n ( d ose s, sc h e d ule) 
i. 
S y m pt o m -directe d p h ysical e xa mi n ati o n; f ull p h ysical e x a mi n ati o n o nl y re q uire d at Scree ni n g.  
j. 
I ncl u des hei g ht (at t h e Scree ni n g Visit o nl y), wei g ht  ( Scree ni n g a n d Baseli n e Visits o nl y), b o d y te m p erat ure ( Scree ni n g a n d Baseli ne Visits o nl y), bl o o d press ure, a n d p ulse 
rate, a n d will b e meas ure d after resti n g f or 5 mi n utes.  O nl y scree ni n g vital si g ns will b e rec or d e d if scree ni n g a n d b aseli ne visits occ ur t he sa me da y.   
k.  
Bl o o d sa m ples f or P K a n al ysis will b e c ollecte d at t h e f oll o wi n g ti me p oi nts: pre -d ose a n d 0. 5 -2, 2 -4, a n d 4 -6 h o urs p ost -d ose. A pre -d ose P K sa m ple will be c ollecte d wit hi n 
3 0 mi n utes of I P d osi n g. Eac h P K sa m ple m ust  b e se p arate d b y at l east o n e  h o ur fr o m a djace nt  sa m ples. P h ar mac o ki netic sa m ples d o n ot nee d t o be collecte d at i de ntical 
ti mes f or pre- a n d p ost -c h e m o visits.  
l. 
He mat ol o g y sa m ples s h o ul d b e se nt t o t h e ce ntral la b i n a d diti o n t o l o cal la b platelet c o u nts at Visits 1, 2, 3, 4, a n d 5. Platelet c o u nts at Baseli ne ( Visit 2) ma y be perf or me d 
pri or ( -1 da y) t o ra n d o mizati o n. O nl y l o cal la b platelet c o u nts will b e assesse d at Visits 6, 7, a n d 8.  
m.   Scree ni n g c h e mistries ca n  b e p erf or me d l o call y t o d eter mi n e eli gi bil it y. C h e mistr y s a m ples will  b e se nt t o t h e ce ntral la b at Visits  1,  2, 4, a n d 5.  
n.  
F or fe males of c hil d b eari n g p ote ntial o nl y. A ser u m  or uri n e  pre g n a n c y test will b e p erf or me d at t h e Scree ni n g Visit. At t he Baseli ne Visit, t he pre g na nc y test will be 
perf or m e d pri or t o I P a d mi nistrati o n.  
o.  
U ri ne or ser u m pre g n a n c y test will b e p erf or me d at t h e Baseli n e Visit . 
p.  
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
q.  
F oll o wi n g ra n d o mizati o n, I P will b e dis p e nse d i n a d o u ble -bli n d ma n n er. S u bjects will recei ve eit h er a vatr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o C he m ot hera p y 
Da y i n C ycle X + 1. S u bjects will als o recei ve a v atr o m b o p a g or place b o o n ce d ail y f or 5 d a ys f oll o wi n g last d a y of c he m ot hera p y treat me nt. T he first d ose o f I P ma y be 
a d mi nistere d at t h e site if t h e Baseli n e visit o cc urs o n t h e first d a y of t h e 5 -d a y I P tr eat me nt, or self-d ose d if t h e Baseli ne visit occ urs t he da y pri or t o t he first da y of I P 
treat me nt. At sc h e d ule d st u d y visits, I P ma y b e a d mi nistere d at t h e site or t h e s u bject ma y self-d ose  e xce pt f or Visits 3 a n d 5  w he n s u bjects will be d ose d at t he site  a n d serial 
P K sa m ples will b e c ollecte d pre - a n d p ost-d ose of I P . S u bjects will self-d ose at all ot h er ti mes. S u bjects will b e i nstr ucte d t o ta ke I P wit h f o o d. T he I n vesti gat or or desi g nee 
will pr o vi de s u bjects wit h s uffi cie nt I P t o c o m plete t h e re gi me n.  
r. 
S u bjects will recei ve t h e last d ose of I P at t h e site.  
s. 
T hese pr oce d ures will b e p erf or me d p ost c h e m ot h era p y d osi n g o n t h e last C h e m ot h era p y Da y of C ycle X  + 1.  
 

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Versi o n 2. 0, 0 4 A pril 2 0 1 9  
6 6  
T a ble 2. 
Sc he d ule of Pr oce d ures ( O bser v ati o n al Peri o d)  
D a y  
C he m o t her ap y  C ycle X + 2 a 
C he m o D a y  
( D 1 u p t o D 3) 
D 1 1  
(± 1 D)  
D 1 5  
(± 1 D)  
D 1 8  
(± 1 D)  
F oll o w -U p  
Pri or t o C he m o D a y (-3 D) 
i n C ycle X + 3 
Visit  
9 b  
1 0  
1 1  
1 2 c 
1 7 / Earl y T er mi n ati o n d  
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
Vital si g ns e 
 
 
 
 
X  
He mat ol o g y (i ncl. platelet c o u nts) f 
X  
X  
X  
X  
X  
C oa g ulati o n  (ce ntral la b) 
X  
 
 
 
X  
Ser u m c he mistr y  (ce ntral la b) 
X  
 
 
 
X  
Pre g na nc y testi n g g 
 
 
 
 
X  
Blee di n g assess me nt (I S T H) h 
X  
 
 
 
X  
C o ntact I R T  
 
 
 
 
X  
C o llect u n use d I P, if a p plica ble 
 
 
 
 
X i 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p;  i n cl. = i n cl u di n g; I P = i n vesti gati o n al 
pr o d uct; I R T = I nteracti ve Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n Thr o m b osis a n d Hae m o stasis; O L E = O pe n-
La bel E xte nsi o n . 
N ote : T hr o u g h o ut t h e o bser vati o nal  p eri o d, all s u bjects will b e assesse d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose 
re d ucti o ns or dela ys. 
a. 
C ycle X + 2 will b e a n O bser vati o n al P eri o d.  
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n . All assess me nts will o cc ur o n t he 
first da y of c h e m ot h era p y pri or t o c h e m ot h era p y d osi n g.  
c. 
O nl y f or s u bjects recei vi n g a 2 8 -da y c ycle w h o are n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d.  
d.  
O nl y f or s u bjects  n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d. F or s u bjects n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, a 
F oll o w- U p Visit will o cc ur pri or t o ( wit hi n 3 d a ys) C h e m ot h era p y Da y i n C ycle X + 3. If C ycle X + 2 is t h e s u bject’s last 
c he m ot hera p y c ycle, a F oll o w-U p Visit will o cc ur at 3 0 d a ys ( ± 3 d a ys) after C h e m ot h era p y Da y i n C ycle X + 2. F or 
s u bjects c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, Visit 13 will o cc ur 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3.  
e. 
I ncl u des bl o o d press ure a n d p ulse rate, a n d will b e meas ure d after r esti n g f or 5  mi n utes.  
f. 
He mat ol o g y sa m ples will  b e se nt t o t h e ce ntral la b i n a d diti o n t o l ocal la b platelet c o u nts at Visits 9 a n d 1 7. O nl y l o cal la b 
platelet c o u nts will b e assesse d at Visits 1 0, 1 1, a n d 1 2.  
g.  
Uri ne pre g n a n c y test ma y  b e p er f or me d f or fe mal es of c hil d b eari n g p ote ntial o nl y. 
h.  
Assess me nt of blee di n g will b e perf or me d if a s u b ject h as a n u nsc h e d ule d st u d y visit. 
i. 
O nl y f or a n E arl y T er mi n ati o n  Visit.  
 

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T a ble 3. 
Sc he d ule of Pr oce d ures ( O pti o n al O pe n -L a bel E xt e nsi o n Peri o d)  
Da y  
 
C he m ot her a p y C ycle X + 3 & O n  
 
Pre -C he m o 
A v atr o m b o p a g 
Tre at me nt ( 5 D)  
C he m o D a y  
( D1  u p t o D 3 ) 
P ost -C he m o 
A v atr o m b o p a g  
Tre at me nt ( 5 D)  
D 1 5 (± 1 D)  
F oll o w -U p  
3 0 D ( ± 3 D)  After L ast 
A v atr o m b o p a g  D ose  
Visit  
1 3 a 
1 4 b  
1 5 c 
1 6 d  
1 7 / Earl y T er mi n ati o n e 
I/ E criteria 
X  
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
S y m pt o m -directe d p h ysical e xa mi nati o n  
 
X  
 
 
 
Vital si g ns f 
X  
X  
 
 
X  
He mat ol o g y  (i ncl. platelet c o u nts)g 
X h 
X  
X  
X  
X  
C oa g ulati o n pa nel  (ce ntral la b) 
X  
 
X  
 
X  
Ser u m c he mistr y  (ce ntral la b) 
X  
 
X  
 
X  
Pre g na nc y testi n g i 
X  
 
 
 
X  
Blee di n g assess me nt (I S T H)  
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
j 
C o ntact I R T  
X  
 
X  
 
X  
A vatr o m b o pa g d osi n g k 
X  
 
X  
 
 
Dis pe nse a vatr o m b o pa g  
X  
X l 
 
 
 
C ollect u n use d a vatr o m b o pa g, if a p plica ble  
 
X  
X  
 
X m  
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E = i n cl usi o n/e xcl usi o n; i n cl.  = i n cl u di n g; I R T = I nteracti ve Res p o nse Tec h n ol o g y; I S T H = 
I nter nati o nal S o ciety o n T hr o m b os is a n d Hae m ostasis. 
N ote : T hr o u g h o ut t h e o p e n -la b el e xte nsi o n p eri o d, all s u bjects will b e assesse d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose re d ucti o ns or dela ys.  
a. 
Visit 1 3 will o cc ur o n t h e first d a y of t h e pre -c h e m ot h era p y a vatr o m b o p ag treat me nt. F or C ycle X + 4, t his visit will be de n ote d Visit 1 3. 1 a n d f or C ycle X + 5, t his visit will 
be de n ote d Visit 1 3. 2. T his n u m b eri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycl es. 
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 an d Da y 2, t he sec o n d r o u n d of 
a vatr o m b o p a g will start o n Da y 3). A vatr o m b o p a g will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C h e m ot hera p y Da y.  All assess me nts will occ ur  o n t he first 
da y of c he m ot h era p y pri or t o c h e m ot h era p y d osi n g. F or C ycle X  + 4, t his visit will b e d e n ote d Visit 1 4. 1 a n d f or C ycle X + 5, t his visit will be de n ote d Visit 1 4. 2. T his 
n u m beri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
c. 
Visit 1 5  will o cc ur o n t h e last d a y of t h e 5 -d a y p ost -c h e m o a v atr o m b o p a g treat me nt. F or C ycle X + 4, t his visit will b e de n ote d Visit 1 5. 1 a n d f or C ycle X + 5, t his visit will 
be de n ote d Visit 1 5. 2. T his n u m b eri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr o lle d o p e n-la b el c ycl es. 
d.  
F or C ycle X + 4, t his visit will b e d e n ote d Visit 1 6. 1 a n d f or C ycle X + 5, t his visit will b e d e n ote d Visit 1 6. 2. T his n u m beri n g sc he me will c o nti n ue f or s u bse q ue nt e nr olle d 
o pe n -la bel c ycl es. 
e. 
S u bjects will h a ve a F oll o w -U p V isit at 3 0 d a ys (± 3 d a ys) after t h e last d ose of a vatr o m b o p a g treat me nt of t h e s u bject’s last c he m ot hera p y c ycle. 
f. 
I ncl u des bl o o d press ure a n d p ulse rate  a n d will b e meas ure d after resti n g f or 5  mi n utes.  
g.  
He mat ol o g y sa m ples will  b e se nt t o t h e ce ntral la b i n a d diti o n t o l ocal la b platelet c o u nts f or Visits 1 3, 1 4, 1 5, a n d 1 7. O nl y l ocal la b platelet c o u nts will be assesse d at Visit 
1 6.  
h.  
Bl o o d sa m ple f or platelet c o u nts will b e c ollecte d pri or t o a vatr o m b o p a g d osi n g.  Platelet c o u nts ma y b e p erf or me d pri or ( -1 da y) t o  a vatr o m b o pa g d osi n g . 

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i. 
F or fe males of c hil d b eari n g p ote ntial o nl y. A ser u m or uri n e pre g n a n c y test ma y  b e p erf or me d at Visit  1 3 . 
j. 
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
k.  
All s u bjects will recei ve a v atr o m b o p a g o n c e d ail y f or 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3. S u bjects will  als o recei ve a vatr o m b o pa g o nce dail y f or 5  da ys 
f oll o wi n g t h e last d a y of c h e m ot h era p y treat me nt. At sc h e d ule d st u d y visits, a v atr o m b o p a g ma y b e a d mi nistere d at t h e site or t he s u bj ect ma y s elf-d ose. S u bjects will 
self-d ose at all ot h er ti mes. S u bjects will b e i nstr u cte d t o ta ke a vatr o m b o p a g  wit h f o o d. T h e I n vesti gat or or d esi g n ee will pr o vi de s u bjects wit h s ufficie nt a vatr o m b o pa g  t o 
c o m plete t h e re gi me n.  
l. 
T hese pr oce d ures will b e p er f or me d p ost-c h e m ot h era p y d osi n g o n t h e last C h e m ot h era p y Da y of t h e c ycle.  
m.  O nl y f or a n E arl y T er mi n ati o n  Visit.  

A P P E N DI X B:  C LI NI C A L L A B O R A T O R Y A N A L Y T E S 
S af et y C he mist r y P a nel  
Ala ni ne a mi n otra nsf eras e  
As partate a mi n otra nsferase  
Al kali ne p h os p hatase  
Dire ct bilir u bi n  
T otal car b o n di o xi de ( Bi car b o nat e ) 
Urea ( Bl o o d urea nitr o ge n ) 
Calci u m  
C hl ori de  
I n or ga nic p h os p h or us 
Creati ni ne  
P otassi u m  
Gl uc ose  
T otal bilir u bi n  
S o di u m  
 
He m at ol o g y  
He mat ocrit  
He m o gl o bi n  
Platelets  
Re d bl o o d cell c o u nt  
W hite bl o o d cell c o u nt a n d differe ntial  
 
 
C o a g ul ati o n  
Pr ot hr o m bi n ti me  
Acti vate d partial t hr o m b o plasti n ti me  
I nter nati o nal n or malize d rati o 
 
 
Pre g n a nc y Test  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
 
 
Cre ati ni ne Cle ar a nce usi n g t he C oc kcr oft -G a ult f or m ul a  

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A P P E N DI X C:  C Y T O C H R O M E P 4 5 0 I N D U C E R S  
T a ble 4 
C yt oc hr o me P 4 5 0 I n d ucers  
 
Str o n g  
M o der ate  
C Y P 2 C 9 i n d ucers  
N A  
A pre pita nt, car ba maze pi ne, 
e nzal uta mi de, f osa pre pita nt, rifa m pi n, 
rit o na vir 
C Y P 3 A 4 i n d ucers  
Car ba maze pi ne, e nzal uta mi de, mit ota ne, 
p he n yt oi n, r ifa m pi n, St.  J o h n’s w ort 
B ose nta n, efa vire nz, etra viri ne, m o dafi nil  
C Y P = c yt oc hr o me P 4 5 0; N A = n ot a p plica ble.  
S o urce:  
htt ps:// w w w.f d a. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr o cess/ De v el o p me nt Res o urces/ Dr u gI nteracti o ns La b eli n g/ u c m 0 9 3 6 6 4. ht m
#i n Vi v o  
 

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A P P E N DI X D:  I N T E R N A TI O N A L S O CI E T Y O N T H R O M B O SI S A N D 
H A E M O S T A SI S B L E E DI N G  D E FI NI TI O N S  
T a ble 5.  I nter n ati o n al S ociet y o n T hr o m b osis a n d H ae m ost asis Blee di n g Defi niti o ns 
Maj or blee di n g  
Defi ne d as o vert blee di n g wit h 1 or m ore of t he f oll o wi n g:  
• 
Ass ociate d wit h a fall i n he m o gl o bi n le vel of 2 0 g/ L ( 1. 2 4 m m ol/ L) or m ore;  
• 
Lea ds t o a tra nsf usi o n of 2 or m ore u nits of pac ke d re d bl o o d cells or w h ole bl o o d;  
• 
Occ urs i n a critical site: i ntracra nial, i ntras pi nal, i ntra oc ular, pericar dial, i ntra -artic ular, 
i ntra m usc ular wit h c o m part me nt s y n dr o me, retr o perit o neal; a n d/ or 
• 
C o ntri b utes t o deat h.  
N o n -maj or 
cli nicall y rele va nt 
blee di n g  
 
Defi ne d as o vert blee di n g n ot meeti n g t he criteria f or maj or blee di n g, b ut ass ociate d wit h 
me dical i nter ve nti o n, u nsc he d ule d c o nt act wit h a p h ysicia n ( visit or tele p h o ne call), 
(te m p orar y) cessati o n of st u d y treat me nt, or ass ociate d wit h a n y ot her disc o mf ort, s uc h as 
pai n or i m pair me nt of dail y acti vities. E xa m ples of s uc h blee di n g i ncl u de:  
• 
A n y blee di n g c o m pr o misi n g he m o d y na mics;  
• 
A n y blee di n g lea di n g t o h os pitalizati o n;  
• 
E pista xis if it lasts f or > 5 mi n utes, if it is re petiti ve (ie, ≥2 e pis o des of tr ue blee di n g [ie, 
n ot s p ots o n a ha n d kerc hief] wit hi n 2 4  h o urs), or if it lea ds t o a n i nter ve nti o n ( pac ki n g, 
electr oc oa g ulati o n, etc.);  
• 
Gi n gi val blee di n g if it occ urs s p o nta ne o usl y (ie, u nrelate d t o t o ot h br us hi n g or eati n g) 
or lasts > 5 mi n ut es;  
• 
He mat uria if it is macr osc o pic a n d eit her s p o nta ne o us or lasts > 2 4 h o urs after 
i nstr u me ntati o n (e g, cat heter place me nt or s ur ger y) of t he ur o ge nital tract; 
• 
Macr osc o pic gastr oi ntesti nal he m orr ha ge (at least 1 e pis o de of mele na/ he mate mesis, if 
cli nicall y a p pare nt, a n d he m oc c ult p ositi ve rectal bl o o d l oss, if m ore t ha n a fe w s p ots o n 
t oilet pa per); 
• 
He m o pt ysis, if m ore t ha n a fe w s pec kles i n t he s p ut u m a n d n ot occ urri n g wit hi n t he 
c o nte xt of a p ul m o nar y e m b olis m;  
• 
I ntra m usc ular he mat o ma;  
• 
S u bc uta ne o us (s ki n) he mat o ma if t he size is > 2 5 c m 2 or > 1 0 0 c m 2 if pr o v o ke d; a n d/ or 
• 
A n y ot her blee di n g t y pe t hat is c o nsi dere d t o ha ve cli nical c o nse q ue nces f or a s u bj ect.  
Mi n or blee di n g  
Defi ne d as all ot her o vert blee di n g e pis o des n ot meeti n g t he criteria f or maj or or cli nicall y 
rele va nt n o n-maj or blee di n g.  
S o urces: Sc h ul ma n S, A n geras D, Ber g q vist B, et al. Defi niti o n of maj or blee di n g i n cli nical i n vesti gati o ns of a nti h e m ostatic 
me dici nal pr o d u cts i n s ur gical p atie nts. J T hr o m b Hae m ost. 2 0 1 0; 8: 2 0 2 -2 0 4 a n d Ta n gel d er M, N wac h u k u C, Jaff M, et al. A 
re vie w of a ntit hr o m b otic t h era p y a n d t h e rati o n ale a n d d esi g n of t he ra n d o mize d e d o xa b a n i n p atie nts wit h p eri p h eral arter y 
di sease (e P A D) trial a d di n g e d o xa b a n or cl o pi d o grel t o as piri n after fe m or o p o pliteal e n d o vasc ular i nter ve nti o n. J E n d o vasc 
T her. 2 0 1 5; 2 2( 2) 2 6 1 -2 6 8.   
 
 
 

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A P P E N DI X E :  Pr ot oc ol A me n d me nts  
A me n d me nt # 1 – 0 4 A pril  2 0 1 9 
 
Rati o nale f or A me n d me nt  
A me n d me nt 1 has bee n i ntr o d uce d t o i ncl u de a n a d diti o nal t u m or t y pe, clarif y t he ti me peri o d f or 
assess me nt  of  t he  efficac y  e n d p oi nts,  a n d  clarif y  certai n  i ncl usi o n  a n d  e x cl usi o n  criteria.  
A d diti o nall y, t he Scree ni n g a n d Baseli ne Visits ma y n o w be c o m bi ne d a n d perf or me d o n  t he sa me 
da y a n d t he wi n d o w f or a se parat e Scree ni n g Visit has bee n i ncreas e d t o 2 8 da ys. 
A d diti o nal T u m or T y pe: D ue t o t he si milarities i n c he m ot hera p y a ge nts us e d i n t he treat me nt of 
s mall cell l u n g ca ncer c o m pare d t o n o n-s mall cell l u n g ca ncer, s u bj ects wit h s mall cell l u n g ca n cer 
are eli gi ble f or e nr oll me nt .  
Ti me  Peri o d  f or  Assess me nt  of  E n d p oi nts:  T he  ti me  peri o d  f or  effi cac y  assess me nts  f or  
c he m ot hera p y d ela ys a n d d ose re d ucti o ns has b ee n clarifie d t o ‘t he peri o d aft er p ost -c h e m ot hera p y 
I P treat me nt i n C ycle X + 1 thr o u g h C he m ot hera p y Da y  of C ycl e X + 2 ’. If a s u bject has decrease d 
or dela ye d d oses of a c he m ot hera pe utic a ge nt d ue t o t hr o m b oc yt o p e nia d uri n g t he mi d dle of C ycl e 
X + 1 ( e g, D a y 1 5 ge mcita bi ne), t his c o ul d affect w het her or n ot t h ere is a nee d f or a dela y or d ose 
re d ucti o n at t he be gi n ni n g of C ycle X + 2 d ue t o t hr o m b oc yt o p e nia.  As a res ult, t his ti me peri o d 
clarificati o n was w arr a nte d t o e ns ur e acc urate dat a c ollecti o n f or t he assess me nt of t he efficac y 
e n d p oi nts. 
I n cl usi o n/ E x cl usi o n Criteria Clarificati o n:  I n cl usi o n  C riteri o n # 5 pre vi o usl y re q uire d t hat  t he 
s u bject w o ul d be a ble t o recei v e t he sa me d os e a n d sc he d ule of c he m ot hera p y i n C ycl e X + 1 as 
t he y recei ve d i n C ycle X. T his criteri o n has n o w bee n clarifie d t o “ S u bject is pla n ne d t o recei ve 
the sa me c he m ot her a p y r e gi me n a n d t h e sa me d os e(s) o n C he m ot he ra p y D a y ( D a ys 1-3) of C ycl e 
X + 1 as was gi ve n i n t he q ualif yi n g c he m ot hera p y C ycle X ” t o ali g n wit h t he clarificati o n i n t he 
ti mi n g of t he efficac y e n d p oi nt clarificati o n descri be d a b o ve.  
E x cl us i o n Criteri o n # 9 has bee n m o difie d t o e x cl u de patie nts wit h a rece nt hist or y ( 3 m o nt hs pri or 
t o Scree ni n g) of si g nifica nt car diac disease. T here is n o e vi de n ce t hat w o ul d precl u d e use of 
a vatr o m b o pa g i n s u bjects wit h sta ble car diac disease.  
D ue t o c o m merc ial a vaila bilit y of r ec o m bi na nt h u ma n T P O i n s o me c o u ntries, E x cl usi o n C riteri o n 
# 1 4 has bee n clarifie d t o e x cl u de rec o m bi na nt h u ma n t hr o m b o p oieti n i n a d diti o n t o t he T P O -
rece pt or a g o nists i n t he 3 m o nt hs pri or t o Scree ni n g.  
C o m bi ne d Scree ni n g a n d Baseli n e: T he Bas eli ne Visit ma y n o w be c o n d u cte d o ne da y pri or t o I P 
treat me nt, a n d ma y be c o m bi ne d wit h t he Scree ni n g Visit. As platelet c o u nts fr o m sta n dar d of care 
la b orat or y  assess me nts  ma y  b e  use d  f or  eli gi bilit y,  t his  c h a n ge  s h o ul d  all o w  f or  l o gistical  
efficie n cies a n d r e d uce t he re q uire d n u m ber of visits f or a p ote ntial s u bject. T he wi n d o w f or a 
se parat e  Scree ni n g  Visit  has  bee n  i ncrease d  t o  2 8  da ys,  fr o m  1 4  da ys,  t o  all o w  f or  earlier  
c o nse nti n g of s u bjects i n or der t o scr ee n f or t hr o m b oc yt o p e nia i n C ycl e X.  
 
 

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S u m mar y of Si g nifica nt C ha n ges i n A m e n d me nt 1 
•  Patie nts wit h s mall cell l u n g ca ncer are eli gi ble t o be e nr olle d  
•  T he ti mefra me f or efficac y assess me nts f or d ose re d ucti o ns a n d dela ys i n c he m ot hera p y 
has bee n clarifie d t o i ncl u de t he peri o d after p ost -c he m ot hera p y I P treat me nt i n C ycle X + 1 
•  E x cl usi o n  C riterio n # 9  h as bee n  clarifie d  t o  e xcl u de  o nl y  t h ose  patie nts  wit h  rece nt  
hist ories of  si g nifica nt  car diac diseas e i n t he 3 m o nt hs pri or t o Scree ni n g; Ex cl usi o n 
C riterio n  # 1 4  n o w e x cl u des rec o m bi na nt h u ma n T P O, i n a d diti o n t o eltr o m b o pa g a n d 
r o mi pl osti m 
•  T he Baseli ne Vi sit ma y b e perf or me d o ne d a y pri or t o I P treat me nt, a n d ma y b e c o m bi ne d 
wit h t he Scree ni n g Visit . T he visit wi n d o w f or t h e Scree ni n g Visit has bee n i ncrease d t o 
2 8 da ys. 
 
T he f oll o wi n g pr ese nts c ha n ges ma d e b y t his a m e n d me nt . Ne w/revise d te xt is prese nte d i n b ol d 
it alics; delete d te xt is i de ntifie d b y stri ket hr o u g h. T y p o gra p hic c orrecti o ns, i ncl u di n g gra m matical 
a n d p u nct uati o n err ors, are n ot s h o w n. 
 
S Y N O P SI S  
3. 1. 1 Scree ni n g/ Q ualif yi n g C he m ot her a p y Re gi me n ( C ycle X)  
T o be eli gi ble f or t he st u d y, s u bjects m ust ha ve e x perie nce d t hr o m b oc yt o pe nia d uri n g t heir c urre nt 
c he m ot hera p y  r e gi me n  as  descri be d  i n  t he  i ncl usi o n  criteria  i n  Secti o n  4. 1.  T he  q ualif yi n g  
c he m ot hera p y c ycle is defi ne d as “ C ycle X”. S u bjects m ust be scree ne d ≤1 4  2 8  da ys pri or t o t he 
Baseli ne Visit, u nless Scree ni n g a n d B aseli ne Visits are perf or m e d o n t he s a m e d ay , a n d be gi n 
treat me nt d uri n g C ycle X. 
3. 1. 2 D o u ble- Bli n d Tr eat me nt Peri o d  
At  t he  Baseli ne  Visit,  eli gi ble  s u bjects  will  be  r a n d o mize d  i n  a  2: 1  ra ti o  t o  recei ve  eit her  
a vatr o m b o pa g  or  pl ace b o  i n  a  d o u ble -bli n d  ma n ner  pri or  t o  a n d  d uri n g  t he  s u bs e q ue nt  
c he m ot hera p y c ycle, C ycle X + 1. Ra n d o mizati o n will be stratifie d b y t he n u m ber of c h e m ot hera p y 
a ge nts t he s u bject is r ecei vi n g ( 1  or  ≥2  per missi ble  c he m ot hera p y a ge nts [ n ucle osi de a nal o g, 
i ncl u di n g  ge mcita bi ne  a n d  fl u or o uracil;  car b o pl ati n  or  cis plati n;  a nt hrac ycli ne;  or  al k ylati n g  
a ge nt]). S u bjects will recei ve eit her a v atr o m b o p a g or place b o o n ce dail y f or 5 da ys pri or t o 
C he m ot he ra p y Da y i n C ycle X + 1. S u bjects will als o recei v e a vatr o m b o pa g or place b o o n ce d ail y 
f or 5 da ys i m me diatel y f oll o wi n g C he m ot hera p y Da y. C he m ot hera p y D a y is defi ne d per pr ot oc ol 
as Da y 1 t o 3 of t h e s u bject’s c h e m ot hera p y re gi me n (e g, if c he m ot hera p y is g i ve n o n D a y 1 a n d 
Da y  2, t he sec o n d r o u n d of a v atr o m b o pa g or place b o will start o n D a y 3). A v atr o m b o pa g or 
place b o  will  n ot  be  a d mi nistere d  c o nc urre ntl y  wit h  c he m ot hera p y  o n  C he m ot hera p y  Da y.  
C he m ot hera p y r e gi me ns re q uiri n g d osi n g be y o n d C he m ot hera p y D a y wit hi n t he 2 1 -da y or 2 8- da y 
c ycle ( e g, ge m cita bi ne o n Da y 8) ar e all o we d. T hese mi d -cycle c he m ot her a py d oses, after I P 
tre at m e nt,  will  be  p art  of  t he  assess m e nt  of  t he  c o m p osite  pri m ary  e n d p oi nt  f or  d os e  
m o dific ati o ns or del ays. 

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3. 1. 3 O bser vati o nal Peri o d  
C ycle X + 2 will be a n  O bser vati o nal Peri o d. T he O bser v ati o nal Peri o d is desi g n e d t o e n a ble 
assess me nt of w h et her t he s u bjects meet t he c h e m ot hera p y d os e m o dificati o ns or d ose dela y 
c o m p o ne nts  of  t he  c o m p osite  pri mar y  e n d p oi nt  o n  t he  C he m ot her a py  D ay  w hile re d uci n g 
decisi o n ma k i n g bias f or c he m ot hera p y d os e m o dificati o ns or dela ys. S u bjects i n t he O bser vati o nal 
Peri o d will n ot recei ve a n y I P pr e- or p ost- C he m ot hera p y Da y i n C ycl e X + 2.  
4. 1 I ncl usi o n Criteri a f or All S u bjects  
2.  S u bject wit h a dia g n osis  wit h o v aria n ca ncer , n o n s mall cell l u n g ca ncer (s m all cell or n o n-
s m all cell), or bla d der ca ncer, r e q uiri n g s yste mic c he m ot hera p y;  
4.  S u bject  e x perie nce d  se v ere  t hr o m b oc yt o pe ni a,  defi ne d  as  2  platelet  c o u nts  < 5 0  ×   1 09/ L 
meas ure d at least 2 4  h o urs a part, d uri n g t he q ualif yi n g c he m ot hera p y c ycle ( C ycle X), of t heir 
c urre nt c he m ot hera p y re gi me n . Pl atel et c o u nts o bt ai ne d per st a n d ar d of c are d uri n g Cycle X 
pri or t o c o nse nt m ay be use d;  
5.  S u bject is a ble pl a n ne d  t o receive t he s a m e c he m ot her a py re gi m e n a n d t he s a m e d ose(s) o n 
C he m ot her a py D ay ( D ays 1 -3) of Cycle X + 1  c o nti n ue t o recei ve t he c urre nt c he m ot hera p y 
re gi me n at t he sa me d ose a n d sc he d ule as w as gi ve n i n t he q ualif yi n g c h e m ot hera p y C ycle X;  
4. 2 E xcl usi o n Criteri a f or All S u bjects  
4.  S u bject w h o recei v e d > 2 pre vi o us lines of c he m ot hera p y ( a dj uv a nt/ ne o a dj uv a nt t her a py is 
c o nsi dere d a previ o us li ne; i m m u n ot her a py al o ne is n ot c o nsi dere d a previ o us li ne)  or is 
recei vi n g w h ole brai n r a diati o n d uri n g t he st u d y treat me nt peri o d; 
6.  S u bject h as a k n o w n me dic al hist ory of  is k n o w n t o be h u ma n i m m u n o deficie nc y vir us 
p ositi ve; 
9.  S u bject has a rece nt  hist or y ( wit hi n 3 m o nt hs of Scree ni n g) of si g nifica nt car di o vas c ular 
disease (e g, c o n gesti ve heart fail ure Ne w Y or k Heart Ass ociati o n Gra d e 3/ 4  e x a cer b ati o n , 
arr h yt h mia  k n o w n  t o  i n creas e  t h e  ris k  of  t hr o m b oe m b olic  e ve nts  [e g,  atrial  fi brillati o n],  
c or o nar y arter y ste nt place me nt, a n gi o plast y, or c or o nar y arter y b y p ass graft);  
1 4.  S u bject  has  pre vi o usl y recei v e d  a  t hr o m b o p oieti n  rece pt or  a g o nist  (e g,  eltr o m b o pa g or 
r o mi pl osti m) or  rec o m bi n a nt  h u m a n  t hr o m b o p oieti n  f or  t he  treat me nt  of  CI T wit hi n  3 
m o nt hs of Scree ni n g ; 
1 5.  S u bject recei v e d a platel et tra nsf usi o n wit hi n 3 da ys 7 2 h o urs  of ra n d o mizati o n; 
1 8.  Fe male  s u bjects  w h o  are  lactati n g  or  pre g n a nt  at  Scree ni n g  or  t he  B aseli ne  Visit  (as 
d oc u me nte d b y a p ositi ve ser u m  or uri ne  beta -h u m a n c h ori o nic g o n a d otr o pi n [ β -h C G] test)  or 
t he Bas eli ne Visit ( uri ne); 
4. 5 Wit h dr a w al Criteri a 
If a s u bject wit h dra ws pr e mat urel y fr o m t he st u d y d u e t o t he a b o ve criteria or a n y ot her reas o n, 
st u d y staff s h o ul d ma k e e ver y eff ort t o c o m plet e t he f ull pa nel of ass ess me nts sc he d ule d f or 
Visit  1 3 (f or s u bjects n ot i n t he o pti o nal O L E Peri o d) or Visit  1 7 (f or s u bjects partici pati n g i n  t he 
o pti o nal O L E Peri o d). All s u bjects s h o ul d c o nti n ue i nt o t he  L o n g -Ter m F oll o w -U p Peri o d u nless 
c o nse nt h as bee n wit h dr a w n.  T he reas o n f or s u bject wit h dra w al m ust b e d oc u me nte d i n t he 
electr o nic case re p ort f or m (e C R F).  

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5. 3 R a n d o miz ati o n a n d Bli n di n g 
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y. F or t he D o u bl e -Bli n d Treat me nt 
Peri o d, s u bjects w h o c o m plete t he Scree ni n g Visit a n d  meet t he i ncl usi o n criteria a n d e x cl usi o n 
criteria will be ra n d o mize d t o recei ve eit her a vatr o m b o pa g 6 0 m g or  place b o i n a 2: 1 rati o at 
t he Bas eli ne Visit. 
5. 6. 1 E x cl u de d Me dicati o ns a n d/ or Pr oce d ures 
T he f oll o wi n g m e dicati o ns a n d/ or pr oce d ures are e x cl u de d: 
•  Use of t hr o m b o p oieti n rece pt or a g o nists or rec o m bi n a nt h u m a n t hr o m b o p oieti n; 
6. 2. 1 Scree ni n g ( Visit 1, Da y  - 1 4 2 8 t o Da y - 1) 
T he Scree ni n g Visit m ay be c o m bi ne d wit h t he B aseli ne Visit o n t he d ay pri or t o I P tre at m e nt 
( D ay -1).  
T he f oll o wi n g pr oce d ures will be perf or me d at t he Scree ni n g Visit:  
•  Perf or m pre g n a nc y test ( ser u m or uri ne ) f or fe male s u bjects of c hil d beari n g p ote ntial o nl y; 
•  C ollect bl o o d sa m ples f or t he f oll o wi n g assess me nts  (if Scree ni n g Visit occ urs o n t he s a me 
d ay as t he B aseli ne Visit, o nly t he B aseli ne l a b or at ory assess m e nts s h o ul d be perf or m e d):  
o  He mat ol o g y (i ncl u di n g platelet c o u nts) . L oc al pl a t elet c o u nts m ay be re pe ate d as nee de d; 
a n d 
6. 2. 2 Bas eli ne Visit ( Visit 2 , First  D a y [ or -1 D ay]  of t he 5-da y I n vesti gati o nal Pr o d uct Treat me nt)  
T he B aseli ne Visit m ay occ ur o ne d ay pri or t o I P tre at m e nt, a n d m ay be c o m bi ne d wit h t he 
Scree ni n g Visit.  
Eli gi ble s u bjects will recei ve eit her a v atr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o 
C he m ot hera p y  D a y i n C ycl e X + 1. T h e f oll o wi n g pr oce d ures will be perf or me d at t he Bas eli ne 
Visit pri or t o I P d osi n g: 
•  Rec or d vital si g ns (i ncl u des wei g ht, b o d y te m perat ure, bl o o d press ure, a n d p ulse rate) . 
O nly Scree ni n g vit al si g ns will be rec or de d if c o m bi ne d wit h t he Scree ni n g Visit ; 
•  Perf or m pre g n a nc y test ( s er u m or uri ne) f or fe m ale s u bjects of c hil d beari n g p ote ntial o nl y;  
•  A d mi nister or self -d ose I P  wit h f o o d , if t he B aseli ne Visit occ urs o n t he first d ay of t he 
5- d ay I P tre at m e nt.  
6. 3. 2  P ost- C he m ot hera p y I n vesti ga ti o nal Pr o d uct Treat me nt ( Visit 5) , Last Da y of t he 5-da y 
I n v esti gati o nal Pr o d uct Treat me nt) 
6. 4 O bser v ati o n al Peri o d ( C ycle X + 2) 
If C he m ot her a py D ay i n Cycle X + 2 is del aye d, r ec or d t he re as o n f or del ay i n t he e C R F. If t he 
del ay is d ue t o l a b or at ory res u lts, rec or d t he relev a nt res ults i n t he e C R F. 
7 E F FI C A C Y A S S E S S M E N T S   

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T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all of t he f oll o wi n g criteria  
d uri n g t he peri o d after p ost -c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py 
D ay of Cycl e X + 2 : 
•  N ot re q uiri n g a platelet tra nsf usi o n  d uri n g C ycl e X + 1 t hr o u g h i m me di atel y pri or t o 
C ycle  X + 2; 
•  N ot  re q uiri n g  a  c he m ot hera p y  d os e  re d ucti o n  b y  ≥1 5 % i n  C ycle  X  +  2 d ue  t o  
t hr o m b oc yt o pe ni a i n C ycle X + 1; a n d  
•  N ot re q uiri n g a c he m ot h er a p y dela y b y ≥4 da ys i n C ycle X + 2 d ue t o t hr o m b oc yt o pe ni a  
i n C ycle X + 1. 
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of se ver e t hr o m b oc yt o pe ni a defi ne d as a platelet c o u nt < 5 0 ×  1 0 9/ L d uri n g t he 
peri o d after p ost -c he m ot her a py I P  tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay 
of Cycle X + 2  C ycle  X + 1 t hr o u g h i m me diatel y pri or t o C ycle X + 2; 
•  C ha n ge i n platel et c o u nt fr o m baseli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( n a dir) 
t o C ycle X + 1 ( na dir); 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n -maj or cli nicall y rel e va nt blee di n g 
d uri n g t he peri o d  after  p ost -c he m ot her a py  I P  tre at m e nt  i n  Cycle  X + 1  t hr o u g h  
C he m ot her a py D ay of Cycle X + 2  C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycle  X + 2; 
a n d 
•  Pr o p orti o n of s u bjects w h o d o n o t recei ve a platelet tra nsf usi o n d uri n g t he peri o d after 
p ost- c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2 
C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycl e X + 2.  
T he ot her effi cac y e n d p oi nts i ncl u de t he f oll o wi n g  d uri n g t he p eri o d after p ost -c he m ot her a py I P 
tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycl e X + 2: 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c h e m ot hera p y d os e re d u cti o n t hat is ≥1 5 % i n 
C ycle  X + 2  d ue t o t hr o m b oc yt o p e nia i n C ycl e X + 1; 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c he m ot hera p y dela y t hat is ≥4 da ys i n C ycl e X 
+ 2 d ue t o t hr o m b oc yt o p e nia i n C ycl e X + 1; 
•  Pr o p orti o n of s u bjects wit h a pre -d efi ne d p ost -bas eli ne na dir platelet c o u nt  d uri n g C ycle 
X +  1 a n d t hr o u g h i m me diatel y pri or t o C ycl e X + 2; a n d 
•  Pr o p orti o n of s u bjects ac hie vi n g a pre -d efi ne d p ost -baseli ne ma xi m u m platelet c o u nt  
d uri n g C ycle X + 1 a n d t hr o u g h i m me diatel y pri or t o C ycle X + 2. 
9. 1 A d verse E ve nts 
A d verse  e v e nts,  w hic h  i ncl u de  cli nical  la b orat or y  test  varia bles,  will  be  m o nit ore d  a n d  
d oc u me nte d fr o m t he ti me of i nf or me d c o ns e nt u ntil t he F oll o w -U p Vi sit occ urri n g pri or t o ( wit hi n 
3 da ys)  C he m ot hera p y Da y i n C ycle X + 3 (f or s u bjects n ot c o nti n ui n g i nt o t he o pti o nal O L E 
Peri o d) a n d t he F oll o w -U p Visit occ urri n g 3 0 da ys aft er last d ose of I P (f or s u bjects c o nti n ui n g 
i nt o t he o pti o nal O L E Peri o d). S u bjects s h o ul d b e i nstr ucte d t o re p ort a n y a d verse e ve nt t h at t he y 
e x perie nce t o t he I n vesti gat or. Be gi n ni n g wit h t he Scree ni n g Visit, I n vesti gat ors s h o ul d ma ke a n 

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assess me nt f or a d verse e ve nts at eac h visit a n d rec or d t he e ve nt o n t he a p pr o priate a d verse e ve nt  
e C R F. E ve nts ass o ciate d wit h disease pr o gressi o n s h o ul d n ot be re p orte d as a d verse e ve nts /S A E s. 
T he e ve nts will be ca pt ure d as a n o utc o me o n a se parate f or m f or deat hs d ue t o disease pr o gress i o n. 
H o we ver, if i n t he I n vesti gat or’s o pi ni o n t he disease pr o gressi o n is ma nifesti n g i n a n u n us ual or 
u nc haracteristic ma n n er, t he ass ociate d e ve nts s h o ul d be re p orte d as a d verse e v e nts/ S A Es, as 
a p pr o priate. 
1 0. 2. 1. 1 Pri mar y efficac y a nal ysis  
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of res p o n ders w h o m eet all o f t he f oll o wi n g criteria 
d uri n g t he peri o d after p ost -c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py 
D ay of Cycl e X + 2 : 
•  N ot re q uiri n g a platelet tra nsf usi o n  d uri n g C ycl e X + 1 t hr o u g h i m me di atel y pri or t o 
C ycle  X + 2; 
•  N ot  re q uiri n g  a  c he m ot hera p y  d os e  re d ucti o n  b y  ≥1 5 % i n  C ycle  X  +  2 d ue  t o  
t hr o m b oc yt o pe ni ai n C ycl e X + 1; a n d  
•  N ot re q uiri n g a c he m ot h era p y dela y b y ≥4 da ys i n C ycle X + 2 d ue t o t hr o m b oc yt o pe ni a  
i n C ycle X + 1. 
1 0. 2. 1. 2 Ke y sec o n d ar y efficac y a nal ysis  
T he ke y sec o n dar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  D urati o n of se ver e t hr o m b oc yt o pe ni a defi ne d as a platelet c o u nt < 5 0 ×  1 0 9/ L d uri n g t he 
peri o d after p ost -c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay 
of Cycle X + 2  C ycle  X + 1 t hr o u g h i m me diatel y pri or t o C ycle X + 2; 
•  C ha n ge i n platel et c o u nt fr o m baseli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( n a dir) 
t o C ycle X + 1 ( na dir); 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve maj or or n o n -maj o r cli nicall y rel e va nt blee di n g 
d uri n g t he  peri o d  after  p ost-c he m ot her a py  I P  tre at m e nt  i n  Cycle  X + 1  t hr o u g h  
C he m ot her a py D ay of Cycle X + 2  C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycle  X + 2; 
a n d 
•  Pr o p orti o n of s u bjects w h o d o n ot recei ve platelet tra nsf usi o n d uri n g t he peri o d after p ost -
c he m ot her a py I P tre at m e nt i n Cycle  X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2  
C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycl e X + 2.   
If t he test of t he treat me nt effect o n t he pri mar y efficac y e n d p oi nt is statisticall y si g nifica nt, t he 
a nal ysis of t he ke y s ec o n dar y efficac y e n d p oi nts will pr ocee d usi n g ste p-d o w n cl ose d testi n g 
pr oce d ur e i n t he f oll o wi n g or der t o mai ntai n t he fa mil y-wise T y pe I err or rate at si g nifica nce le vel 
al p ha = 0. 0 5 ( 2-si de d): 
•  Ste p  1:  Test  t he  treat me nt  effect  at  a si g nifica nt  le vel  of  0. 0 5 o n  d urati o n of se v ere  
t hr o m boc yt o pe ni a defi ne d as a platelet c o u nt < 5 0 ×  1 09/ L d uri n g t he peri o d after p ost -
c he m ot her a py I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2  
d uri n g C ycle X + 1 t hr o u g h i m me diatel y pri or t o  C ycle X + 2 ; if s uccessf ul, pr ocee d t o 
Ste p 2; ot her wise st o p at Ste p 1.  

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•  Ste p 2: Test t he treat me nt effect at a si g nifica nt le vel of 0. 0 5 o n c ha n ge i n platelet c o u nt 
fr o m bas eli ne ( q u alif yi n g c he m ot hera p y c ycle [ C ycle X]) ( na dir) t o C ycle X + 1 ( n a dir); if 
s uccessf ul, pr o cee d t o Ste p 3; ot her wise st o p at Ste p 2. 
•  Ste p 3: Test t he treat me nt effect at a si g nifi ca nt le v el of 0. 0 5 o n pr o p orti o n of s u bjects w h o 
d o n ot ha ve maj or or n o n -maj or cli nicall y rel e va nt blee di n g d uri n g t he peri o d after p ost -
c he m ot her a py  I P tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2 
d uri n g C ycle X + 1 t hr o u g h i m me diatel y pri or t o C ycle X + 2 ; if s uccessf ul, pr ocee d t o 
Ste p 4; ot her wise st o p at Ste p 3. 
•  Ste p 4: Test t he treat me nt effect at a si g nifi ca nt le v el of 0. 0 5 o n pr o p orti o n of s u bjects w h o 
d o  n ot  recei v e  platelet  tra nsf usi o n d uri n g  t he  peri o d  after  p ost -c h e m ot her a py  I P  
tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycle X + 2 d uri n g C ycle X + 1 
t hr o u g h i m me diatel y pri or t o C ycle X + 2. 
1 0. 2. 1. 3 Ot her efficac y a nal ysis  
T he ot her effi cac y e n d p oi nts i ncl u de t he f oll o w i n g d uri n g t he peri o d after p ost -c he m ot her a py I P 
tre at m e nt i n Cycle X + 1 t hr o u g h C he m ot her a py D ay of Cycl e X + 2: 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c he m ot hera p y d ose re d ucti o n t hat is ≥1 5 % i n 
C ycle  X + 2 d ue t o t hr o m b oc yt o p e nia i n C ycl e X + 1; 
•  Pr o p orti o n of s u bjects w h o d o n ot ha ve a c he m ot hera p y del a y t h at is ≥4 da ys i n C ycle X + 
2 d ue t o t hr o m b oc yt o p e nia i n C ycle X + 1; 
•  Pr o p orti o n of s u bjects wit h a pre -defi n e d p ost -bas eli ne na dir pl atelet c o u nt d uri n g C ycl e X 
+ 1 a n d t hr o u g h i m me diatel y pri or t o C ycle X + 2; a n d  
•  Pr o p orti o n  of  s u bjects  ac hie vi n g  a  pre -defi n e d  p ost -baseli ne  ma xi m u m  platelet  c o u nt   
d uri n g C ycle X + 1 a n d t hr o u g h i m me diatel y pri or t o C ycle X + 2. 
 
1 3 R E F E R E N C E S  
3. A vatr o m b o pa g maleate Gl o bal I n vesti gat or’s Br oc h ure, v 1 2 v 1 4, A pril 2 0 1 6 J a n u ary 2 0 1 9 . 

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A P P E N DI X A:  S C H E D U L E O F P R O C E D U R E S  
T a ble 1 
Sc he d ule of Pr oce d ures  ( D o u ble-Bli n d Tre at me nt Peri o d)  
Da y  
C he m o t her a p y C ycle X a 
C he m o t her a p y C ycle X + 1  
Scree ni n g  
D -1 4 2 8  t o D 
-1  
B aseli ne  
Pre -C he m o I P 
Tre at me nt ( 5 D)  
C he m o D a y 
( D 1 u p t o D 3)  
P ost -C he m o  
I P Tre at me nt ( 5 D) 
D 1 1 ( ± 1 D), D 1 5 
(± 1 D), a n d D 1 8 ( ± 1 D)  
Visit  
1 b  
2  
3 c 
4 d  
5 e 
6, 7, 8  
S u bj ect i nf or me d c o nse nt  
X  
 
 
 
 
 
I/ E criteria 
X  
X  
 
 
 
 
Ra n d o mizati o n  
 
X f 
 
 
 
 
De m o gra p hics  (i ncl. race) 
X  
 
 
 
 
 
Me dical hist or y
g  
X  
 
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
 
 
C o nc o mita nt me dicati o ns h  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
P h ysical e xa mi nati o n  
X  
X i 
 
X i 
 
 
Vital si g ns j 
X  
X  
 
X  
 
 
P K k 
 
 
X  
 
X  
 
He mat ol o g y (i ncl. platelet c o u nts)  l 
X b  
X l 
X  
X  
X  
X  
C oa g ulat i o n pa nel (ce ntr al l a b) 
 
X  
 
 
X  
 
Ser u m c he mistr y m  
X b  
X  
 
X  
X  
 
Pre g na nc y testi n g n 
X b  
X o 
 
 
 
 
Blee di n g assess me nt (I S T H)  
 
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
p 
 
C o ntact I R T  
X  
X  
X  
 
X  
 
I P d osi n gq 
 
X  
X r 
 
X r 
 
Dis pe nse I P  a n d d osi n g diar y 
 
X  
 
X s 
 
 
C ollect d osi n g diar y a n d I P pac ka ge  
 
 
X  
 
X  
 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E  = i n cl usi o n/e xcl usi o n; i n cl. = i n cl u di n g; I P = i n vesti gati o nal pr o d uct; I R T = I nteracti ve 
Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n T hr o m b osis a n d Hae m ostasis; P K = p h ar ma c o ki n etic.  
N ote : Pri or t o c o n d u cti n g a n y st u d y-relat e d acti vities, writte n inf or me d c o nse nt m ust b e si g n e d a n d d ate d b y t h e s u bject. T hr o u g h o ut t he d o u ble -bli n d treat me nt peri o d, all s u bjects 
will be assess e d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose re d u cti o ns or d ela ys.  
a. 
T he q ualif yi n g c h e m o c ycle is d efi n e d as C ycle X.  
b.  
Scr ee ni n g Visit will o cc ur at t h e disc o ver y of se vere t hr o m b o c yt o p e nia  m a y o cc ur o n t he s a m e d a y as t he B aseli ne Visit,  if o ne d ay pri or t o I P tre at m e nt. If t hese visits 
occ ur o n t he s a m e d a y, o nly t he B aseli ne ( Visit 2) l a b or at ory s a m ples s h o ul d b e se nt t o t he ce ntr al l a b. L o c al pl atelet c o u nts m ay be re pe ate d as nee de d.  
c. 
Visit 3 will o cc ur o n t h e last d a y of t h e 5 -d a y pre -c h e m o I P treat me nt. 

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d.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 a n d Da y 2, s u bjects will recei ve 
a vatr o m b o p a g or place b o o n Da y 3). A vatr o m b o p a g or place b o will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C he m ot hera p y Da y.  All assess me nts will occ ur 
o n t he first d a y of c h e m ot h era p y pri or t o c h e m ot h era p y d osi n g.  
e. 
Visit 5 will o cc ur o n t h e last d a y of t h e  5-d a y p ost -c h e m o I P treat me nt.  
f. 
Ra n d o mizati o n m ust o cc ur pri or t o I P  d osi n g.  
g.  
Me dical hist or y t o i n cl u d e t u m or t y p e, d ate of ca n cer dia g n osis, a n d pri or c h e m ot h era p e utic re gi me ns ( d oses  n u m b ers of cycles , dates). 
h.  
C o nc o mita nt me dicati o ns t o i n cl u d e d etails of c h e m ot h era p e utic re gi me n ( d oses, sc h e d ule)  
i. 
S y m pt o m -directe d p h ysic al e xa mi n ati o n; f ull p h ysical e x a mi n ati o n o nl y re q uire d at Scree ni n g.  
j. 
I ncl u des hei g ht (at t h e Scree ni n g Visit o nl y), wei g ht ( Scree ni n g a n d Baseli n e Visits o nl y) , b o d y te m p erat ure ( Scree ni n g a n d Baseli ne Visits o nl y), bl o o d press ure, a n d p ulse 
rate, a n d will b e meas ure d after resti n g f or 5 mi n utes.  O nly scree ni n g vit al si g ns will b e rec or d e d if scree ni n g a n d b aseli ne visits occ ur t he s a m e d ay.    
k.  
Bl o o d sa m ples f or P K a n al ysis will b e c ollecte d at t h e f oll o wi n g ti me p oi nts: pre -d ose a n d 0. 5 -2, 2 -4, a n d 4- 6 h o urs p ost -d ose. A pre -d ose P K sa m ple will be c ollecte d wit hi n 
3 0 mi n utes of I P d osi n g. Eac h P K sa m ple m ust  b e se p arate d b y at l east o n e  h o ur f r o m a djace nt  sa m ples. P h ar mac o ki netic sa m ples d o n ot nee d t o be c ollecte d at i de ntical 
ti mes f or pre- a n d p ost-c h e m o visits.  
l. 
He m at ol o g y s a m ples s h o ul d b e se nt t o t he ce ntr al l a b i n a d diti o n t o l o c al l a b pl atelet c o u nts  at Visits 1, 2, 3, 4, a n d 5. Platelet  c o u nts at B aseli ne ( Visit 2)  ma y be 
perf or me d pri or ( -1 d a y) t o ra n d o miz ati o n. O nl y l o c al l a b pl atelet c o u nts will b e assesse d at Visits 6, 7, a n d 8. 
m.  O nl y platelet c o u nts will b e assesse d at Visits 6, 7, a n d 8.  Scree ni n g c he mistries c a n b e p erf or m e d l o c al ly t o d eter mi ne eli gi bility. C he mistry s a m ples will be se nt t o t he 
ce ntr al l a b at Visits 1, 2, 4, a n d 5.  
n.  
F or fe males of c hil d b eari n g p ote ntial o nl y. A ser u m or uri ne  pre g na n c y test will b e p erf or me d at t h e Scree ni n g Visit. At t he Baseli ne Visit, t he pre g na nc y test will be 
perf or me d pri or t o I P a d mi nistrati o n.  
o.  
U ri ne or ser u m  pre g n a n c y test will b e p erf or me d at t h e  Baseli n e Visit . 
p.  
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
q.  
F oll o wi n g ra n d o mizati o n, I P will b e dis p e nse d i n a d o u ble -bli n d ma n n er. S u bjects will recei ve eit h er a vatr o m b o p a g or place b o o nce dail y f or 5 da ys pri or t o C he m ot hera p y 
Da y i n C ycle X + 1. S u bjects will als o recei ve a v atr o m b o p a g or place b o o n ce d ail y f or 5 d a ys f oll o wi n g last d a y of c h e m ot hera p y tre at me nt. T he first d ose of I P m ay be 
a d mi nistere d at t he site if t he B aseli ne visit o cc urs o n t he first d ay of  t he 5-d a y I P tre at m e nt, or self -d ose d if t he B aseli ne visit occ urs t he d ay pri or t o t he first d ay of I P 
tre at m e nt. At sc h e d ule d st u d y visits, I P m a y b e a d mi nistere d at t h e site or t h e s u bject ma y self -d ose  e xce pt f or Visits 3 a n d 5  w he n s u bjects will be d ose d at t he site a n d serial 
P K sa m ples will b e c ollecte d pre - a n d p ost-d ose of I P . S u bjects will self-d ose at all ot h er ti mes. S u bjects will b e i ns tr ucte d t o ta ke I P wit h f o o d. T he I n vesti gat or or desi g nee 
will pr o vi de s u bjects wit h s uffi cie nt I P t o c o m ple te t h e re gi me n.  
r. 
S u bjects will recei ve t h e last d ose of I P at t h e site.  
s. 
T hese pr oce d ures will b e p erf or me d p ost c h e m ot h era p y d osi n g o n t h e last C h e m ot h era p y Da y of C ycle X + 1.  
 

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T a ble 2 
Sc he d ule of Pr oce d ures ( O bser v ati o n al Peri o d)  
D a y  
C he m o t her a p y C ycle X + 2 a 
C he m o D a y  
( D 1 u p t o D 3) 
D 1 1  
(± 1 D)  
D 1 5  
(± 1 D)  
D 1 8  
(± 1 D)  
F oll o w -U p  
Pri or t o C he m o D a y (-3 D) 
i n C ycle X + 3 
Visit  
9 b  
1 0  
1 1  
1 2 c 
1 7 / Earl y T er min ati o n d  
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
Vital si g ns e 
 
 
 
 
X  
He mat ol o g y (i ncl. platelet c o u nts) f 
X  
X f 
X f 
X f 
X  
C oa g ulati o n  (ce ntr al l a b) 
X  
 
 
 
X  
Ser u m c he mistr y  (ce ntr al l a b) 
X  
 
 
 
X  
Pre g na nc y testi n g g 
 
 
 
 
X  
Blee di n g assess me nt (I S T H) h 
X  
 
 
 
X  
C o ntact I R T  
 
 
 
 
X  
C ollect u n use d I P, if a p plica ble  
 
 
 
 
X i 
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p;  i n cl. = i n cl u di n g; I P = i n vesti gati o nal 
pr o d uct; I R T = I nteracti ve Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n T hr o m b osis a n d Hae m ostasis; O L E = O pe n-
La bel E xte nsi o n . 
N ote : T hr o u g h o ut t h e o bser vati o nal  p eri o d, all s u bjects will b e assesse d f or platelet tra nsf usi o ns a n d c h e m ot h era p y d ose 
re d ucti o ns or dela ys. 
a. 
C ycle X + 2 will b e a n O bser vati o n al P eri o d.  
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n . All assess me nts will o cc ur o n t he 
first da y of c h e m ot h era p y pri or t o c h e m ot h era p y d osi n g.  
c. 
O nl y f or s u bjects receivi n g a 2 8-d a y cycle w h o are  n ot c o nti n ui n g i n t o t h e o pti o n al O L E P eri o d. 
d.  
O nl y f or s u bjects n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d. F or s u bjects n ot c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, a 
F oll o w- U p Visit will o cc ur pri or t o ( wit hi n 3 d a ys) C h e m ot h era p y Da y i n C ycle X + 3. If C ycle X + 2 is t h e s u bject’s last 
c he m ot hera p y c ycle, a F oll o w-U p Visit will o cc ur at 3 0 d a ys ( ± 3 d a ys) after C h e m ot h era p y Da y i n C ycle X + 2. F or 
s u bjects c o nti n ui n g i nt o t h e o pti o n al O L E P eri o d, Visit 13 will o cc u r 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3. 
e. 
I ncl u des bl o o d press ure a n d p ulse rate, a n d will b e meas ure d after r esti n g f or 5  mi n utes.  
f. 
He m at ol o g y s a m ples will b e se nt t o t he ce ntr al l a b  i n a d diti o n t o l o c al l a b pl atelet c o u nts at Visits 9 a n d 1 7.  O nl y l oc al 
l a b platelet c o u nts will b e assesse d at Visits 1 0,  1 1, a n d 1 2.  
g.  
Uri ne or ser u m  pre g n a n c y test ma y  b e p erf or me d f or fe males of c hil d b eari n g p ote ntial o nl y.  
h.  
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
i. 
O nl y f o r a n Earl y T er mi n ati o n  Visit.  
 

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T a ble 3 
Sc he d ule of Pr oce d ures ( O pti o n al O pe n -L a bel E xte nsi o n Peri o d)  
Da y  
 
C he m ot her a p y C ycle X + 3 & O n  
 
Pre -C he m o I P 
Av atr o m b o p a g  
Tre at me nt ( 5 D)  
C he m o D a y  
( D1  u p t o D 3 ) 
P ost -C he m o 
Av atr o m b o p a g  
I P Tre at me nt 
( 5D)  
D 1 5 (± 1 D)  
F oll o w -U p  
3 0 D ( ± 3 D)  After L ast 
Av atr o m b o p a g  I P D ose  
Visit  
1 3 a 
1 4 b  
1 5 c 
1 6 d  
1 7 / Earl y T er mi n ati o n e 
I/ E criteria 
X  
 
 
 
 
E C O G perf or ma nce stat us  
X  
 
 
 
X  
C o nc o mita nt me dicati o ns  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
F ull p h ysical e xa mi nati o n  
 
 
 
 
X  
S y m pt o m -directe d p h ysical e xa mi nati o n  
 
X  
 
 
 
Vital si g ns f 
X  
X  
 
 
X  
He mat ol o g y  (i ncl. platelet c o u nts)g 
X g h  
X  
X  
X h 
X  
C oa g ulati o n pa nel  (ce ntr al l a b) 
X  
 
X  
 
X  
Ser u m c he mistr y  (ce ntr al l a b) 
X  
 
X  
 
X  
Pre g na nc y testi n g i 
X  
 
 
 
X  
Blee di n g assess me nt (I S T H)  
←−−−−−−−−−−−− c o nti n u o us  −−−−−−−−−−−−−→
j 
C o ntact I R T  
X  
 
X  
 
X  
A vatr o m b o pa g d osi n g k 
X  
 
X  
 
 
Dis pe nse a vatr o m b o pa g  
X  
X l 
 
 
 
C ollect u n use d a vatr o m b o pa g, if a p plica ble  
 
X  
X  
 
X m  
C he m o = c he m ot h era p y; D = d a y(s); E C O G = Easter n C o o p erati ve O n c ol o g y Gr o u p; I/ E = i n cl usi o n/e xcl usi o n; i n cl.  = i n cl u di n g; I P = i n vesti gati o nal pr o d uct; I R T = I nteracti ve 
Res p o nse Tec h n ol o g y; I S T H = I nter n ati o n al S o ciet y o n T hr o m b osis a n d Hae m ostasis . 
N ote : T hr o u g h o ut t h e o p e n -la b el e xte nsi o n p eri o d, all s u bjects will b e assesse d f or platelet t ra nsf usi o ns a n d c h e m ot h era p y d ose re d ucti o ns or dela ys. 
a. 
Visit 1 3 will o cc ur o n t h e first d a y of t h e pre -c h e m ot h era p y a v atr o m b o p a g  I P treat me nt. F or C ycle X + 4, t his visit will be de n ote d Visit 1 3. 1 a n d f or C ycle X + 5, t his visit 
will be de n ote d Visit 1 3. 2. T his n u m b eri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
b.  
C he m ot hera p y Da y ma y b e 1 t o 3 d a ys d e p e n di n g o n t h e s u bject’s c h e m ot h era p y re gi me n (e g, if c h e m ot h era p y is gi ve n o n Da y 1 a n d Da y 2, t he sec o n d r o u n d of 
a vatr o m b o p a g will st art o n Da y 3). A vatr o m b o p a g will n ot b e a d mi nistere d c o n c urre ntl y wit h c h e m ot h era p y o n C h e m ot hera p y Da y.  All assess me nts will occ ur o n t he first 
da y of c he m ot h era p y pri or t o c h e m ot h era p y d osi n g. F or C ycle X + 4, t his visit will b e d e n ote d Visit 1 4. 1 a n d f o r C ycle X + 5, t his visit will be de n ote d Visit 1 4. 2. T his 
n u m beri n g sc h e me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
c. 
Visit 1 5  will o cc ur o n t h e last d a y of t h e 5 -d a y p ost -c h e m o a v atr o m b o p a g  I P treat me nt. F or C ycle X + 4, t his visit will be de n ote d Visit 1 5. 1 a n d f or C ycle X + 5, t his visit 
will be de n ote d Visit 1 5. 2. T his n u m b eri n g sc he me will c o nti n u e f or s u bse q u e nt e nr olle d o p e n -la b el c ycles. 
d.  
F or C ycle X + 4, t his visit will b e d e n ote d Visit 1 6. 1 a n d f or C ycle X + 5, t his visit will b e d e n ote d Visit 1 6. 2. T his n u m beri n g sc he me will c o nti n ue f or s u bse q ue nt e nr olle d 
o pe n -la bel c ycl es. 
e. 
S u bjects will h a ve a F oll o w -U p V isit at 3 0 d a ys (± 3 d a ys) after t h e last d ose of a v a tr o m b o p a g I P treat me nt of t h e s u bject’s last c he m ot hera p y c ycle. 
f. 
I ncl u des bl o o d press ure a n d p ulse rate  a n d will b e meas ure d after resti n g f or 5  mi n utes.  
g.  
He m at ol o g y s a m ples will b e se nt t o t he ce ntr al l a b i n a d diti o n t o l o c al l a b pl atelet c o u nts  f or Visits 1 3, 1 4, 1 5, a n d 1 7.  O nly l oc al l a b pl atelet c o u nts will be assesse d at 
Visi t 1 6. 

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h.  
Bl o o d sa m ple f or platelet c o u nts will b e c ollecte d pri or t o a v atr o m b o p a g  I P d osi n g.  Platelet c o u nts ma y b e p erf or me d pri or ( -1 da y) t o  av atr o m b o p a g  I P d osi n g . 
i. 
O nl y platelet c o u nts will b e assesse d at Visit 1 6.  
i. 
F or fe males of c hil d b eari n g p ote ntial o n l y. A ser u m or uri n e pre g n a n c y test ma y  b e p erf or me d at Visit  1 3 . 
j. 
Assess me nt of blee di n g will b e perf or me d if a s u bject h as a n u nsc h e d ule d st u d y visit.  
k.  
All s u bjects will recei ve a v atr o m b o p a g o n ce dail y f or 5 d a ys pri or t o C h e m ot h era p y Da y i n C ycle X + 3. S u bjects will als o recei ve a vatr o m b o pa g o nce dail y f or 5  da ys 
f oll o wi n g t h e last d a y of c h e m ot h era p y treat me nt. At sc h e d ule d st u d y visits, a v atr o m b o p a g  I P ma y b e a d mi nistere d at t he  site or t he s u bject ma y self-d ose. S u bjects will 
self-d ose at all ot h er ti mes. S u bjects will b e i nstr u cte d t o ta ke a v atr o m b o p a g  I P wit h f o o d. T h e I n vesti gat or or d esi g n ee will pr o vi de s u bjects wit h s ufficie nt av atr o m b o p a g  I P 
t o c o m plete t h e re gi me n. 
l. 
T hese pr oce d ures will b e p erf or me d p ost -c h e m ot h era p y d osi n g o n t h e last C h e m ot h er a p y Da y of t h e c ycle.  
m.  O nl y f or a n E arl y T er mi n ati o n  Visit.  
 
 
 

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A P P E N DI X C:  C Y T O C H R O M E P 4 5 0 I N D U C E R S  
T a ble 4 
C yt oc hr o me P 4 5 0 I n d ucers  
 
Str o n g  
M o der ate  
C Y P 2 C 9 i n d ucers  
N A  
A pre pita nt, car ba maze pi ne, 
e nzal uta mi de, f os a pre pit a nt, rifa m pi n, 
rit o na vir 
C Y P 3 A 4 i n d ucers  
Car ba maze pi ne, e nzal uta mi de, mit ota ne, 
p he n yt oi n, rifa m pi n, St.  J o h n’s w ort 
B ose nta n, efa vire nz, etra viri ne, m o dafi nil  
C Y P = c yt oc hr o me P 4 5 0; N A = n ot a p plica ble.  
S o urce:  
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