An Open Label Phase 1b/2 Study of Orally Administered PLX3397 in Combination With Radiation Therapy and Temozolomide in Patients With Newly Diagnosed Glioblastoma
Phase: PHASE1
Conditions: Patients With Newly Diagnosed Glioblastoma
Sponsor: Daiichi Sankyo



P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 
Ple x xi k o n I nc.  
3. 0  
T A B L E O F C O N T E N T S  
1. 0  
S P O N S O R SI G N A T U R E  .................................................................................................. 2 
2. 0  
I N V E S TI G A T O R SI G N A T U R E ...................................................................................... 2 
3. 0  
T A B L E O F C O N T E N T S  .................................................................................................. 3 
LI S T O F T A B L E S  ......................................................................................................................... 7 
LI S T O F FI G U R E S  ....................................................................................................................... 7 
4. 0  
C O N T A C T S  ....................................................................................................................... 8 
4. 1  
E mer ge nc y C o ntacts – Me dical M o nit or:  ................................................................ 8 
4. 2  
A d diti o nal C o nta cts ................................................................................................. 8 
4. 3  
S A E Re p orti n g C o ntact............................................................................................ 8  
5. 0  
LI S T O F A B B R E VI A TI O N S ........................................................................................... 9  
6. 0  
S T U D Y S Y N O P SI S  ......................................................................................................... 1 2 
7. 0  
I N T R O D U C TI O N............................................................................................................ 2 1 
7. 1  
Bac k gr o u n d ............................................................................................................ 2 1  
7. 2  
P h ar mac o d y na mics  ................................................................................................ 2 2 
7. 2. 1  
I n Vitr o P har mac o d y na mics .................................................................. 2 2 
7. 2. 2  
I n Vi v o P har mac o d y na mics .................................................................. 2 3 
7. 3  
N o ncli nical Meta b olis m a n d P har mac o ki netics  ..................................................... 2 4 
7. 4  
S u m mar y of N o ncli nical T o xic ol o g y, Ge n ot o xicit y, a n d Safet y P har mac ol o g y ... 2 6  
7. 4. 1  
Re peat -d ose T o xicit y i n Rats  ................................................................ 2 7 
7. 4. 2  
Re peat -d ose T o xicit y i n D o gs  ............................................................... 2 8 
7. 5  
Pre vi o us H u ma n E x perie nce .................................................................................. 3 0  
7. 6  
Precli nical E vi de nce f or S y ner g y of P L X 3 3 9 7 wit h Ra diati o n ............................. 3 2  
8. 0  
R A TI O N A L E  ................................................................................................................... 3 5 
8. 1  
R o ute a n d Re gi me n ................................................................................................ 3 5  
8. 2  
Treat me nt Peri o d  .................................................................................................... 3 5 
9. 0  
O B J E C TI V E S  .................................................................................................................. 3 6 
1 0. 0  
D E SI G N  ............................................................................................................................ 3 6 
1 0. 1  
Descri pti o n  ............................................................................................................. 3 6 
1 0. 2  
N u m ber of Patie nts  ................................................................................................ 3 6 
1 0. 3  
N u m ber of St u d y Ce nters ....................................................................................... 3 6  
1 0. 4  
D urati o n of Patie nt Partici pati o n  ........................................................................... 3 7 
1 0. 5  
D urati o n of St u d y ................................................................................................... 3 7  
1 1. 0  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  ................................................................... 3 7 
1 1. 1  
I ncl usi o n Criteria ................................................................................................... 3 7 
1 1. 2  
E xcl usi o n Criteria  .................................................................................................. 3 8 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 
Ple x xi k o n I nc.  
1 1. 3  
Scree n Fail ures  ....................................................................................................... 3 9 
1 2. 0  
C O N C O MI T A N T T R E A T M E N T ................................................................................. 3 9  
1 3. 0  
P R O C E D U R E S  ................................................................................................................ 4 0 
1 3. 1  
Scree ni n g E val uati o n ............................................................................................. 4 0  
1 3. 2  
C ycle 1 Da y 1 (- 2 Da ys), [ 4 wee k c ycle]  .............................................................. 4 0 
1 3. 3  
C ycle 1 Da y 8 ( ± 2 Da ys), [ 4 wee k c ycle] ............................................................. 4 1  
1 3. 4  
C ycle 1 Da y 1 5 ( ± 2 Da ys), [ 4 wee k c ycle] ........................................................... 4 1  
1 3. 5  
C ycle 2 Da y 1 ( ± 2 Da ys), [ 3 wee k c ycle] ............................................................. 4 2  
1 3. 6  
C ycle 2 Da y 2 2 ( ± 2 Da ys), [ 3 wee k c ycle] ........................................................... 4 2  
1 3. 7  
Da y  1 of C ycle 3 ( ± 7 Da ys), [ 4 wee k c ycle]  ......................................................... 4 3 
1 3. 8  
Da y 2 2 of C ycle 3 ( ± 2 Da ys), [ 4 wee k c ycle] ....................................................... 4 3  
1 3. 9  
Da y 2 2 of C ycle 4 + ( ± 7 Da ys), [ 4 wee k c ycle]  .................................................... 4 4 
1 3. 1 0  Assess me nts After 0 1 Oct o ber 2 0 1 7 t o Be Perf or me d A p pr o xi matel y E ver y 
1 2 Wee ks  ................................................................................................................ 4 4 
1 3. 1 1  E n d of Trea t me nt ................................................................................................... 4 4 
1 3. 1 2  C o nti n ue d D osi n g  .................................................................................................. 4 5 
1 3. 1 3  D ose Le vels f or t he P hase 1 b P orti o n .................................................................... 4 5  
1 3. 1 3. 1  
D ose Escalati o n  ..................................................................................... 4 5 
1 3. 1 3. 2  
D ose -Li miti n g T o xicities  ...................................................................... 4 6 
1 3. 1 3. 3  
Li ver E nz y me A b n or malities ................................................................ 4 7  
1 3. 1 4  D ose M o dificati o n  ................................................................................................. 4 8 
1 3. 1 4. 1  
P hase 1  .................................................................................................. 4 8 
1 3. 1 4. 2  
P hase 2  .................................................................................................. 4 9 
1 3. 1 5  Disc o nti n uati o n of Treat me nt, Patie nt Wit h dra wal, a n d Re place me nt .................. 5 3  
1 3. 1 6  St o p pi n g R ules ....................................................................................................... 5 4  
1 4. 0  
S T U D Y D R U G  ................................................................................................................. 5 4 
1 4. 1  
St u d y Dr u g A d mi nistrati o n .................................................................................... 5 4  
1 4. 2  
Pac ka gi n g a n d La beli n g ......................................................................................... 5 5  
1 4. 3  
St ora ge a n d Sta bilit y  .............................................................................................. 5 5 
1 4. 4  
St u d y dr u g Acc o u nta bilit y, Rec o nciliati o n, a n d Ret ur n ........................................ 5 5  
1 4. 5  
St u d y Dr u g C o m plia nce ......................................................................................... 5 5  
1 5. 0  
R A DI A TI O N T H E R A P Y  ................................................................................................ 5 5 
1 5. 1  
D ose S pecificati o ns a n d Sc he d ule  ......................................................................... 5 5 
1 5. 2  
Tec h nical Fact ors  ................................................................................................... 5 6 
1 5. 3  
L ocalizati o n, Si m ulati o n, a n d I m m o bilizati o n ....................................................... 5 6  
1 5. 4  
T reat me nt Pla n ni n g/ Tar get V ol u mes ..................................................................... 5 6 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 
Ple x xi k o n I nc.  
1 5. 4. 1  
I nitial Tar get V ol u me ............................................................................ 5 6 
1 5. 4. 2  
B o ost Tar get V ol u me ............................................................................ 5 7  
1 5. 4. 3  
D ose G ui deli nes .................................................................................... 5 7  
1 5. 4. 4  
D ose Li mitati o ns a n d Critical Str uct ures  .............................................. 5 8 
1 5. 5  
C o m plia nce C riteria ............................................................................................... 5 8 
1 5. 6  
Ra diati o n T hera p y A d verse E ve nts ....................................................................... 5 9  
1 5. 6. 1  
Ac ute  ..................................................................................................... 5 9 
1 5. 6. 2  
Earl y Dela ye d  ........................................................................................ 5 9 
1 5. 6. 3  
Late Dela ye d  ......................................................................................... 5 9 
1 6. 0  
T E M O Z O L O MI D E T H E R A P Y  .................................................................................... 5 9 
1 6. 1  
Te m oz ol o mi de D uri n g C o nc o mita nt Ra diati o n T hera p y ...................................... 5 9  
1 6. 2  
P ost - Ra diati o n Te m oz ol o mi de............................................................................... 6 0 
1 6. 3  
Te m oz ol o mi de Prescri bi n g I nf or mati o n ................................................................ 6 1  
1 6. 3. 1  
St ora ge a n d Sta bilit y  ............................................................................. 6 1 
1 6. 3. 2  
P har mac o ki netics .................................................................................. 6 2  
1 6. 3. 3  
Meta b olis m a n d Eli mi nati o n  ................................................................. 6 2 
1 6. 3. 4  
S pecial P o p ulati o ns ............................................................................... 6 2  
1 6. 3. 5  
Dr u g -Dr u g I nteracti o ns  ......................................................................... 6 3 
1 6. 3. 6  
A d verse E ve nts ..................................................................................... 6 3  
1 6. 3. 7  
S pecial Ha n dli n g a n d Preca uti o ns ......................................................... 6 3  
1 6. 3. 8  
C o ntrai n dicati o ns  .................................................................................. 6 3 
1 6. 3. 9  
Pre g na nc y Cate g or y D  .......................................................................... 6 3 
1 6. 3. 1 0  
S u p pl y ................................................................................................... 6 4  
1 7. 0  
M E A S U R E S T O MI NI MI Z E/ A V OI D BI A S  ................................................................ 6 4 
1 8. 0  
S A F E T Y E V A L U A TI O N  ................................................................................................ 6 4 
1 8. 1  
P h ysical E xa mi nati o n ............................................................................................. 6 4 
1 8. 2  
Vital Si g ns  .............................................................................................................. 6 4 
1 8. 3  
Electr ocar di o gra ms  ................................................................................................ 6 5 
1 8. 4  
Safet y La b orat or y Deter mi nati o ns ......................................................................... 6 5  
1 9. 0  
BI O M A R K E R S A M P L E S  .............................................................................................. 6 5 
2 0. 0  
P H A R M A C O KI N E TI C E V A L U A TI O N  ...................................................................... 6 5 
2 0. 1  
Bl o o d C ollecti o n .................................................................................................... 6 5  
2 0. 2  
Bi oa nal ytical Met h o d ol o g y .................................................................................... 6 5  
2 1. 0  
S T A TI S TI C A L A N A L Y SI S  ........................................................................................... 6 6 
2 1. 1  
Ge neral Statistical C o nsi derati o ns  ......................................................................... 6 6 
2 1. 1. 1  
P hase 1 b P orti o n .................................................................................... 6 6  

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 
Ple x xi k o n I nc.  
2 1. 1. 2  
P hase 2 P orti o n ...................................................................................... 6 6  
2 1. 2  
Sa m ple Size a n d P o wer .......................................................................................... 6 6  
2 1. 3  
A nal ysis P o p ulati o ns .............................................................................................. 6 6  
2 1. 4  
Efficac y A nal ysis  ................................................................................................... 6 7 
2 1. 5  
Safet y A nal ysis  ...................................................................................................... 6 7 
2 1. 6  
P har mac o ki netic A nal ysis ...................................................................................... 6 8  
2 1. 7  
P har mac o d y na mic A nal ysis  ................................................................................... 6 8 
2 1. 7. 1  
Ce ntral hist o pat h ol o gic re vie w a n d tiss ue re q uire me nts ....................... 6 8  
2 1. 7. 2  
Tiss ue E val uati o n  .................................................................................. 6 8 
2 1. 7. 3  
Ser u m bi o mar ker a nal ysis  ..................................................................... 6 9 
2 2. 0  
P R E C A U TI O N S  .............................................................................................................. 6 9 
2 3. 0  
A D V E R S E E V E N T S  ....................................................................................................... 6 9 
2 3. 1  
Defi niti o ns .............................................................................................................. 6 9 
2 3. 2  
Rec or di n g a n d Re p orti n g ....................................................................................... 7 2  
2 3. 3  
Seri o us A d verse E ve nt Re p orti n g .......................................................................... 7 2  
2 4. 0  
S T U D Y S U S P E N SI O N, T E R MI N A TI O N, A N D C O M P L E TI O N  ............................. 7 3 
2 5. 0  
I N F O R M E D C O N S E N T ................................................................................................. 7 3 
2 6. 0  
P R O T O C O L A M E N D M E N T S  ...................................................................................... 7 3 
2 7. 0  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E ................................................................. 7 4 
2 8. 0  
DI R E C T A C C E S S, D A T A H A N D LI N G, A N D R E C O R D  K E E PI N G  ...................... 7 4 
2 8. 1  
I n vesti gat or ............................................................................................................ 7 4 
2 8. 2  
S p o ns or .................................................................................................................. 7 4  
2 9. 0  
P R E -S T U D Y D O C U M E N T A TI O N  ............................................................................... 7 5 
3 0. 0  
R E C O R D S R E T E N TI O N  ............................................................................................... 7 5 
3 1. 0  
R E F E R E N C E S  ................................................................................................................. 7 7 
A T T A C H M E N T 1:  L A B O R A T O R Y T E S T S  .......................................................................... 7 9 
A T T A C H M E N T 2:  S T R O N G C Y P 3 A 4 I N HI BI T O R S A N D I N D U C E R S  .......................... 8 0 
A T T A C H M E N T 3:  R A N O R E S P O N S E C RI T E RI A  ............................................................. 8 1 
A T T A C H M E N T 4:  T E M O Z O L O MI D E P R E S C RI BI N G I N F O R M A TI O N  ...................... 8 3 
 
 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 
Ple x xi k o n I nc.  
LI S T O F T A B L E S  
T RI A L F L O W C H A R T – P hase 1 b D ose Escalati o n P hase  ......................................................... 1 7 
T RI A L F L O W C H A R T – P hase 2  ................................................................................................ 1 9 
Ta ble 1:  
I C5 0 Val ue s of P L X 3 3 9 7 A ga nst Selecte d Ki nases ................................... 2 2 
Ta ble  2: 
P L X 3 3 9 7 D osi n g C o h orts .......................................................................... 4 5  
Ta ble  3: 
P L X 3 3 9 7 D ose M o dificati o n G ui deli nes f or Treat me nt -Relate d 
T o xicities, E xcl u di n g Li ver F u ncti o n ........................................................ 5 0  
Ta ble  4: 
D ose M o dificati o n G ui deli nes f or Li ver F u ncti o n A b n or malities ............. 5 2  
Ta b le 5: 
A d diti o nal Li ver E val uati o n  ...................................................................... 5 3 
Ta ble  6: 
Ma xi m u m D oses Per missi ble f or Critical Str uct ures ................................. 5 8 
Ta ble  7: 
Te m oz ol o mi de D ose Le vels f or Mai nte na nce Treat me nt  .......................... 6 1 
Ta ble  8: 
Te m oz ol o mi de D ose Re d ucti o n or Disc o nti n uati o n D uri n g 
Mai nte na nce Treat me nt  ............................................................................. 6 1 
 
LI S T O F FI G U R E S  
Fi g ure 1:  
P L X 3 3 9 7-i n d uce d Re d ucti o n of Circ ulati n g T u m or Cells i n P y M T 
M o use M o del of Breast Ca ncer  ................................................................. 2 4 
Fi g ure 2:  
P L X 3 3 9 7 I n hi bits I ntracra nial T u m or Gr o wt h i n t he 9 L Fis her 
Gli o blast o ma Rat M o del ............................................................................ 3 2  
Fi g ure 3:  
P L X 3 3 9 7 I n hi bits Micr o glia/ Macr o p ha ge Recr uit me nt t o G L 2 6 1 
T u m ors i n Vi v o .......................................................................................... 3 3  
Fi g ure 4:  
P L X 3 3 9 7 I n hi bits R M- 1 T u m or Re gr o wt h After Irra diati o n i n Vi v o  ....... 3 4 
Fi g ure 5:  
P L X 3 3 9 7 S y ner gizes wit h Irra diati o n i n t he U 2 5 1 Gli o blast o ma M o del .. 3 5  
 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
9 
Ple x xi k o n I nc.  
5. 0  
 LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n or Ter m a 
Defi niti o n/ E x pl a n ati o n  
A E  
A d verse e ve nt  
A L T  
Ala ni ne a mi n otra nsferase  
A N C O V A  
A nal ysis of c o varia nce  
A N O V A  
A nal ysis of varia nce  
A P T T  
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate a mi n otra nsferase  
A U C 0- ∞ 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o e xtra p olate d t o i nfi nite ti me 
A U C 0- 6 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 6 hrs p ost d osi n g 
A V  
Atri o ve ntric ular  
β -H C G  
Beta -h u ma n c h ori o nic g o na d otr o pi n  
BI D  
T wice dail y  
B L Q  
Bel o w li mit of q ua ntificati o n  
B MI  
B o d y mass i n de x  
B P  
Bl o o d press ure  
B U N  
Bl o o d urea nitr o ge n  
Ca + +  
Calci u m  
C B C  
C o m plete bl o o d c o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
C H F  
C o n gesti ve heart fail ure  
CI  
C o nfi de nce i nter val  
Cl - 
C hl ori de  
C Lcr  
Creati ni ne cleara nce  
C ma x  
Ma xi m u m o bser ve d c o nce ntrati o n  
C mi n  
Tr o u g h o bser ve d c o nce ntrati o n  
C N S  
Ce ntral ner v o us s yste m  
C R  
C o m plete res p o nse  
C R F  
Case re p ort f or m  
C S F -1  
C ol o n y sti m ulati n g fact or -1 [als o k n o w n as macr o p ha ge sti m ulati n g fact or ( M -C S F)]  
C S F -1 R  
C ol o n y sti m ulati n g fact or rece pt or (als o k n o w n as F ms)  
C T A  
Cli nical Trial A gree me nt  
C T  
C o m p ute d t o m o gra p h y  
C T Cs  
Circ ulati n g T u m or Cells  
C T C A E  
C o m m o n T o xicit y Criteria f or A d verse E ve nts  
C V  
C oeffic ie nt of variati o n 
C Y P  
C yt oc hr o me P 4 5 0  
D/ C  
Disc o nti n ue  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
D L T  
D ose Li miti n g T o xicit y  
E C G  
Electr ocar di o gra m  

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 0  
Ple x xi k o n I nc.  
A b bre vi ati o n or Ter m a 
Defi niti o n/ E x pl a n ati o n  
E D 5 0 
Effecti ve d ose  
E g  
E xe m pli gratia (f or e xa m ple)  
E S R  
Er yt hr oc yte se d i me ntati o n rate 
F  
Bi oa vaila bilit y  
F A C S  
Fl u oresce nce Acti vate d Cell S orti n g  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C  
Gas c hr o mat o gra p h y  
F D G -P E T  
Fl u or o de o x y gl uc ose ( F D G) -p ositr o n e missi o n t o m o gra p h y ( P E T)  
G C P  
G o o d Cli nical Practice  
G F R  
Gl o mer ular filtrati o n rate  
G G T  
Ga m ma gl uta m yl tra nsferase  
G L P  
G o o d la b orat or y practice  
G V H D  
Graft vs. h ost disease  
H Bs A g  
He patitis B s urface a nti ge n  
H B V  
He patitis B vir us  
H C O 3 - 
Bicar b o nate  
H C V  
He patitis C vir us  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H N S T D  
Hi g hest n o n -se verel y t o xic d ose  
H P F  
Hi g h -p o wer fiel d  
H P L C  
Hi g h -perf or ma nce li q ui d c hr o mat o gra p h y  
H R  
Heart rate  
hr  
H o ur or h o urs  
I C5 0 
Half ma xi mal i n hi bit or y c o nce ntrati o n  
i.e. 
I d est (t hat is) 
I E C 
I n de pe n de nt et hics c o m mittee 
I L-1 β  
I nterle u ki n-1 β  
I L-6  
I nterle u ki n-6  
I L-3 4  
I nterle u ki n-3 4  
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal re vie w b oar d 
I U 
I nter nati o nal u nit 
I V 
I ntra ve n o us, i ntra ve n o usl y 
L D 5 0 
Me dia n let hal d ose  
L D H  
Lactate de h y dr o ge nase  
L C  
Li q ui d c hr o mat o gra p h y  
L L Q  
L o wer li mit of q ua ntitati o n  
L n  
Nat ural l o garit h m  
Me d R A  
Me dical Dicti o nar y f or Dr u g Re g ulat or y Acti vities  
MI C  
Mi ni m u m i n hi bit or y c o nce ntrati o n  
M M P -3  
Matri x metall o pe pti dase -3  
M RI  
Ma g netic res o na nce i ma gi n g  

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 1  
Ple x xi k o n I nc.  
A b bre vi ati o n or Ter m a 
Defi niti o n/ E x pl a n ati o n  
M R S D  
Ma xi m u m rec o m me n de d starti n g  d ose  
M R T  
Mea n resi de nce ti me  
M S  
Mass s pectr o metr y  
M T D  
Ma xi m u m t olerate d d ose  
N O A E L  
N o -o bser ve d -a d verse-effect le vel  
N O E L  
N o -o bser ve d -effect-le vel 
P D  
P har mac o d y na mic(s)  
P F S  
Pr o gressi o n Free S ur vi val  
P K  
P har mac o ki netic(s)  
P O  
Per os (a d mi nistere d b y m o ut h)  
P R  
Partial res p o nse  
P T  
Pr ot hr o m bi n ti me  
P T T  
Partial t hr o m b o plasti n ti me  
Q C  
Q ualit y c o ntr ol  
R B C  
Re d bl o o d cell  
R T  
Ra diati o n t hera p y  
Q D  
O nce dail y  
Q Tc  
Q T i nter val c orrecte d  
Q Tc F  
Q T i nter val c orrecte d usi n g Fre dericia e q uati o n  
S A E  
Seri o us a d verse e ve nt  
S D  
Sta n dar d de viati o n or sta ble disease  
S T D  
Se verel y t o xic d ose  
S T D 1 0 
Se verl y t o xic d ose i n 1 0 % of a ni mals  
T 1/ 2 
Ter mi nal eli mi nati o n half -life 
T 3  
Trii o d ot h yr o ni ne  
T 4  
T h yr o xi ne  
T ma x  
Ti me of ma xi m u m o bser ve d c o nce ntrati o n  
T A Ms  
T u m or -associate d macr o p ha ges  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
TI D  
T hree ti mes dail y  
T M Z  
Te m oz ol o mi de  
T S H  
T h yr oi d -sti m ulati n g h or m o ne 
U L N  
U p per li mit of n or mal  
U L Q  
U p per li mit of q ua ntitati o n  
U V  
Ultra vi olet  
Vz  
V ol u me of distri b uti o n d uri n g t he ter mi nal p hase  
Vz/ F  
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase  
Vss  
V ol u me of distri b uti o n at stea d y state  
W B C  
W hite bl o o d cell  
W O C B P  
W o me n of c hil d beari n g p ote ntial  
W O N C B P  
W o me n of n o nc hil d beari n g p ote ntial  
a 
All of t hese a b bre viati o ns ma y or m a y n ot be use d i n pr ot oc ol.  

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 2  
Ple x xi k o n I nc.  
6. 0  
S T U D Y S Y N O P SI S  
Title  
A n O pe n La bel P hase 1 b/ 2 St u d y of Orall y A d mi nistere d P L X 3 3 9 7 i n C o m bi nati o n wit h 
Ra diati o n T hera p y a n d Te m oz ol o mi de i n Patie nts Wit h Ne wl y Dia g n ose d Gli o blast o ma  
St u d y 
O bjecti ve(s)  
T he st u d y o bjecti ves a re t o assess t he p ote ntial f or P L X 3 3 9 7 t o i m pr o ve t he efficac y of 
sta n dar d of care ra diati o n t hera p y ( R T) + te m oz ol o mi de ( T M Z) i n patie nts wit h ne wl y 
dia g n ose d gli o blast o ma ( G B M). F or P hase 1 b d ose escalati o n, t he pri mar y o bjecti ve is 
i de ntificati o n of t he rec o m me n de d P hase 2 d ose ( R P 2 D). F or P hase 2, t he pri mar y o bjecti ve is 
t he c o m paris o n of me dia n Pr o gressi o n Free S ur vi val ( P F S) t o a hist orical c o ntr ol. Sec o n dar y 
o bjecti ves i ncl u de t he e val uati o n of o verall s ur vi val ( O S), p har mac o ki netics ( P K), c orrelati ve 
i ma gi n g st u dies, safet y, a n d e x pl orat or y e n d p oi nts of p har mac o d y na mic ( P D) effects of 
P L X 3 3 9 7.  
St u d y Desi g n  
T his will be a n o pe n la bel, u nc o ntr olle d P hase 1 b/ 2 trial i n patie nts wit h ne wl y dia g n ose d 
G B M w h o ha ve rec o vere d fr o m c o m plete or partial s ur g ical resecti o n. All patie nts will be 
treate d wit h P L X 3 3 9 7 i n a d diti o n t o sta n dar d-of -care c o m bi nati o n ra diati o n t hera p y ( R T) pl us 
te m oz ol o mi de ( T M Z) f oll o we d b y a dj u va nt T M Z. D uri n g P hase 1 b d ose escalati o n, t w o 
P L X 3 3 9 7 a d mi nistrati o n sc he d ules, 7 da ys/ wee k vs. 5 da ys/ wee k ( M -F) will be e x pl ore d. 
D uri n g P hase 2, patie nts will be treate d wit h t he R P 2 D.  
T here are 4 se q ue ntial peri o ds:  1 -wee k P L X 3 3 9 7 m o n ot hera p y; 6 -wee k P L X 3 3 9 7/ R T/ T M Z 
c o m bi nati o n t hera p y; 4 -wee k rec o ver y; a n d, P L X 3 3 9 7/ T M Z a dj u va nt t hera p y. P L X 3 3 9 7 will 
be a d mi nistere d t wice dail y eit her 7 da ys/ wee k or 5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) 
starti n g 1 wee k pri or t o t he i nitiati o n of R T a n d will c o nti n ue t wice dail y eit her 7 da ys/ wee k or 
5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) d uri n g t he 6 -wee k c o urse of R T.  
P hase 1 b P L X 3 3 9 7 d ose a n d sc he d ule c o h orts are:  
C o h ort  
C o m bi n ati o n P L X 3 3 9 7/ R T/ T M Z  
A dj u v a nt P L X 3 3 9 7/ T M Z  
P L X 3 3 9 7 
D ose 
P L X 3 3 9 7  
Sc he d ule  
P L X 3 3 9 7  
D ose 
P L X 3 3 9 7  
Sc he d ule  
-2  
6 0 0 m g/ da y  
5 da ys/ wee k  
( M-F) b 
8 0 0 m g/ da y b 
7 da ys/ wee k  
-1  
6 0 0 m g/ da y  
7 da ys/ wee k a 
6 0 0 m g/ da y a 
8 0 0 m g/ da y b 
7 da ys/ wee k  
1  
8 0 0 m g/ da y  
7 da ys/ wee k a 
5 da ys/ wee k ( M -F) b 
1 0 0 0 m g/ da y b 
7 da ys/ wee k  
2  
1 0 0 0 m g/ da y  
5 da ys/ wee k ( M -F) b 
1 2 0 0 m g/ da y b 
7 da ys/ wee k  
a 
A me n d me nt 1.  
b 
A me n d me nt 2.  
F or c o m bi nati o n P L X 3 3 9 7/ R T/ T M Z P L X 3 3 9 7 treat me nt, d ose escalati o n t o t he ne xt hi g hest 
c o h ort ma y occ ur after all patie nts ha ve c o m plete d t he 1 1 -wee k D L T -o bser vati o n peri o d (i.e., 
1- wee k P L X 3 3 9 7 m o n ot hera p y; 6 -wee k P L X 3 3 9 7/ R T/ T M Z c o m bi nati o n t hera p y; 4 -wee k 
rec o ver y). F or a dj u va nt P L X 3 3 9 7/ T M Z P L X 3 3 9 7 treat me nt, d ose escalati o n t o t he ne xt 
hi g hest c o h ort ma y occ ur after all patie nts ha ve c o m plete d a n 8 -wee k D L T -o bser vati o n peri o d 
(i.e., 2 c ycles of a dj u va nt treat me nt). F or patie nts partici pati n g i n P hase 1 b, i ntra a n d i nter 
patie nt d ose escalati o n t o a hi g her d os e le vel/sc he d ule will be per mitte d after t hat d ose 
le vel/sc he d ule has bee n esta blis he d t o be safe. 
T he R T sc he d ule will be o nce 5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) f or 6 wee ks (t otal 
ra diati o n d ose of 6 0 G y usi n g eit her c o nf or mal or I M R T pla n ni n g). Oral tem oz ol o mi de will be 
a d mi nistere d o nce dail y ( 7 da ys per wee k) f or t he d urati o n of R T. F o ur wee ks after t he 
c o m pleti o n of t he c o urse of R T, patie nts will be starte d o n o nce -dail y a dj u va nt te m oz ol o mi de 
( Da y 1-5 of a 2 8 da y c ycle) f or u p t o 1 2 c ycles as l o n g as t here is n o disease pr o gressi o n or 
u nacce pta ble t o xicit y a n d P L X 3 3 9 7 t wice dail y ( 2 8 da ys of a 2 8 da y c ycle) f or as l o n g as t here 
is n o disease pr o gressi o n or u nacce pta ble t o xicit y. After disc o nti n uati o n of st u d y dr u g, patie nts 
will c o nti n ue t o be f oll o w e d f or O S e ver y 6 m o nt hs.  

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 3  
Ple x xi k o n I nc.  
N u m ber of 
P atie nts/ Sites  
F or P hase 1 b, 5 c o h orts ( 2 c o h orts fr o m A me n d me nt 1 a n d 3 fr o m A me n d me nt 2) are pla n ne d 
t o be e nr olle d at a p pr o xi matel y 7 t o 1 0 sites. Eac h c o h ort will c o nsist of a p pr o xi matel y 
7 patie nts. T heref ore, a p pr o xi matel y 3 5 patie nts will be e nr olle d i n P hase 1 b. A d diti o nal 
patie nts ma y be re q uire d f or re place me nt patie nts. P hase 2 will e nr oll a p pr o xi matel y 
4 4  patie nts.  
St u d y 
Pr oce d ures  
After pr o vi di n g i nf or me d c o nse nt, patie nts will u n der g o scree ni n g f or eli gi bilit y t o partici pate 
i n t he st u d y. Scree ni n g will start wit hi n 3 wee ks pri or t o P L X 3 3 9 7 d osi n g. F oll o wi n g rec o ver y 
fr o m s ur gical resecti o n, patie nts w h o meet i ncl usi o n/e xcl usi o n criteria will start st u d y dr u g o n 
t he m or ni n g of a n y M o n da y t hr o u g h Fri da y ( C ycle 1 Da y 1; C 1 D 1). T his visit s h o ul d occ ur 
bet wee n 3 wee ks a n d 5  wee ks after s ur ger y. Patie nts will c o nti n ue t o d ose st u d y dr u g t wice 
dail y eit her 7 da ys/ wee k or 5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) a n d ret ur n t o t he cli nic f or 
e val uati o n o n C 1 D 8, t he da y t he y  i nitiate ra diati o n t hera p y pl us te m oz ol o mi de. 
F or t he P hase 1 b p orti o n of t he st u d y, a bl o o d sa m ple will be o btai ne d pre -d ose o n C 1 D 1f or 
t he baseli ne P K. O n C 1 D 8 a n d o n C 1 D 1 5, bl o o d sa m ples will be o btai ne d pre-d ose a n d 1, 2, 4, 
a n d 6 h o urs p ost -d ose t o e sti mate P L X 3 3 9 7 P K. Patie nts will ret ur n t o t he cli nic o n C ycle 2 
Da y 1 ( C 2 D 1) f or e val uati o n. If P L X 3 3 9 7 has bee n well t olerate d a n d t here has bee n n o 
cli nical e vi de nce of disease pr o gressi o n, c o nti n ue d d osi n g will be per mitte d. Patie nts will be 
m o nit ore d  f or res p o nse a n d disease pr o gressi o n wit h M RI brai n sca ns e ver y 2 c ycles, wit h t he 
brai n sca n o btai ne d a p pr o xi matel y 3 -4 wee ks after t he c o m pleti o n of R T ser vi n g as t he 
baseli ne sca n f or deter mi nati o n of pr o gressi o n.  
F or P hase 1 b P L X 3 3 9 7 d ose a n d sc he d ule  c o h orts a n d escalati o n, see St u d y Desi g n  (a b o ve.) 
F or t he P hase 2 p orti o n of t he st u d y, patie nts will be treate d wit h P L X 3 3 9 7 at t he R P 2 D le vel.  
F or b ot h p hases, patie nts will be m o nit ore d t hr o u g h o ut t he st u d y f or a d verse reacti o ns t o t he 
st u d y dr u g a n d/ or st u d y pr oce d ures. 
He mat ol o g y assess me nts (i.e., C B C, differe ntial c o u nt, a n d platelet c o u nt) will be perf or me d 
wee kl y starti n g wit h C 1 D 1 a n d c o nti n ui n g t hr o u g h t he first wee k of t he Rec o ver y Peri o d 
( R P D 8). Ser u m c he mistr y assess me nts will be perf or me d at Scree ni n g, C 1 D 1, C 1 D 1 5, C 2 D 1, 
a n d C 2 D 2 2 (c o m pleti o n of R T). F or t he a dj u va nt treat me nt peri o d, assess me nts will be ma de 
o n t he da y of treat me nt i nitiati o n ( C 3 D 1), C 3 D 2 2, a n d D 2 2 of eac h s u bse q ue nt c ycle, a n d at 
st u d y c o m pleti o n or u p o n earl y wit h dra wal. A ser u m pre g na nc y test will be c o m plete d at 
Scree ni n g f or a p plica ble patie nts.  
Bl o o d press ure, res pirat or y rate, p ulse rate a n d te m perat ure will be meas ure d at eac h st u d y 
visit. A sta n dar d 1 2 -lea d electr ocar di o gra m ( E C G) will be perf or me d f or eac h patie nt at 
Scree ni n g, C 1 D 1, C 2 D 1, a n d st u d y c o m pleti o n.  
A c o m plete p h ysical e xa mi nati o n will be perf or me d f or eac h patie nt at Scree ni n g. A 
ne ur ol o gical e xa m a n d a s y m pt o m -directe d p h ysical e xa m will be c o m plete d o n eac h 
s u bse q ue nt visit w hile c o nti n ui n g st u d y t herap y, a n d at st u d y c o m pleti o n or u p o n earl y 
wit h dra wal. Patie nts will als o c o m plete t he M D A n ders o n S y m pt o m I n ve nt or y -Brai n T u m or 
M o d ule at t he ti me p oi nts n ote d i n t he Trial Fl o w C hart, a n d Kar n ofs k y perf or ma nce stat us 
will be rec or de d as n ote d.  
A s ur gical paraffi n t u m or bl oc k ( or at least 2 0 u nstai ne d sli des)  will be i de ntifie d d uri n g 
Scree ni n g f or s u bse q ue nt s hi p me nt t o t he ce ntral pat h ol o gist. Bl o o d sa m ples f or circ ulati n g 
C S F -1, bi o mar kers of ki nase i n hi biti o n a n d m yel oi d cell recr uit me nt will be o btai ne d pre -d ose 
o n C 1 D 1, C 1 D 8, C 2 D 1, a n d C 3 D 1. C D 1 4/ 1 6 m o n o n uclear cell c o u nts will be o btai ne d pre -
d ose o n C 1 D 1 a n d C 1 D 8.  
C o m me nci n g o n 0 1 Oct o ber 2 0 1 7, p atie nt visits, cli nic al l a b or at or y testi n g, a n d M RI 
br ai n sc a ns will be perf or me d a p pr o xi m atel y e ver y 1 2 wee ks ( ple ase refer t o t he 
T RI A L  F L O W C H A R T – P h ase 2  f or det ails). 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 4  
Ple x xi k o n I nc.  
Ke y P atie nt 
Selecti o n 
Criteri a  
I ncl usi o n 
1.  Male or fe male patie nts ≥1 8 years ol d.  
2.  Hist ol o gicall y c o nfir me d defi niti ve G B M or gli osarc o ma b y partial or c o m plete 
s ur gical resecti o n (i.e. n ot b y bi o ps y o nl y) wit hi n 5 wee ks pri or t o P L X 3 3 9 7 
a d mi nistrati o n ( C 1 D 1). T u m or m ust ha ve a s u prate nt orial c o m p o n e nt. F or all patie nts, 
a vaila bilit y of a s ur gical paraffi n t u m or bl oc k s ufficie nt t o ge nerate at least 2 0 u nstai ne d 
sli des; or, if a paraffi n t u m or bl oc k is u na vaila ble, at least 2 0 u nstai ne d sli des. 
3.  T he patie nt m ust ha ve rec o vere d fr o m t he effects of s ur g er y, p ost-o perati ve i nfecti o n, 
a n d ot her c o m plicati o ns bef ore st u d y re gistrati o n.  
4.  A dia g n ostic c o ntrast -e n ha nce d M RI or C T sca n of t he brai n m ust be perf or me d 
pre o perati vel y a n d p ost o perati vel y pri or t o t he i nitiati o n of ra di ot hera p y, wit hi n 2 8 da ys 
( prefera bl y 1 4 da ys) pri or t o C 1 D 1. 
5.  Patie nts u na ble t o u n der g o M R i ma gi n g beca use of n o n -c o m pati ble de vices ca n be 
e nr olle d, pr o vi de d pre - a n d p ost-o perati ve c o ntrast -e n ha nce d C T sca ns are o btai ne d a n d 
are of s ufficie nt q ualit y.  
6.  Patie nts m ust recei ve R T at t he p artici pati n g i nstit uti o n.  
7.  W o me n of c hil d -beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test wit hi n 1 4 da ys 
of i nitiati o n of d osi n g a n d m ust a gree t o use a n acce pta ble met h o d of birt h c o ntr ol 
w hile o n st u d y dr u g a n d f or 3 m o nt hs after t he last d ose. W o me n of n o n -c hil d beari n g 
p ote ntial ma y be i ncl u de d if t he y are eit her s ur gicall y sterile or ha ve bee n 
p ost me n o pa usal f or ≥1 year. Me n of c hil d -beari n g p ote ntial m ust als o a gree t o use a n 
acce pta ble met h o d of birt h c o ntr ol w hile o n st u d y dr u g, a n d f or 3 m o nt hs  after t he 
last d ose. 
8.  Kar n ofs k y perf or ma nce stat us of ≥7 0.  
9.  A de q uate he mat ol o gic, he patic, a n d re nal f u ncti o n (a bs ol ute ne utr o p hil c o u nt 
≥1. 5 x  1 0 9/ L, H g b > 1 0 g/ d L, platelet c o u nt ≥1 0 0 x 1 09/ L, A S T/ A L T ≤2. 5 x U L N, 
creati ni ne ≤1. 5 x U L N).  
1 0.  Willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt pri or t o a n y st u d y relate d 
pr oce d ures a n d t o c o m pl y wit h all st u d y re q uire me nts.  
E xcl usi o n  
1.  E vi de nce of rec urre nt G B M or metastases detecte d o utsi de of t he cra nial va ult.  
2.  I n vesti gati o nal dr u g use wit hi n 2 8 da ys of t he first d ose of P L X 3 3 9 7 or c o nc urre ntl y. 
3.  Pri or use of Gli a del wafers or a n y ot her i ntrat u m oral or i ntraca vitar y treat me nt.  
4.  Pri or ra diati o n or c he m ot hera p y f or gli o blast o ma or gli o ma.  
5.  Pri or c he m ot hera p y or ra di ose nsitizers f or ca ncer of t he hea d a n d nec k (e xce pt f or T 1 
gl ottic ca ncer) t hat w o ul d res ult i n a n o verla p of ra diati o n fiel ds.  
6.  Pri or aller gic reacti o n t o te m oz ol o mi de.  
7.  Hist or y of Gra de 2 ( C T C A E v 4) or greater ac ute i ntracra nial he m orr ha ge.  
8.  Acti ve ca ncer (eit her c o nc urre nt or wit hi n t he last 3 years) t hat re q ui res n o n-s ur gical 
t hera p y (e. g. c he m ot hera p y or ra diati o n t hera p y), wit h t he e xce pti o n of s ur gicall y 
treate d basal or s q ua m o us cell carci n o ma of t he s ki n, mela n o ma i n-sit u, or carci n o ma 
i n-sit u of t he cer vi x. 
9.  C hr o nic acti ve he patitis B or C.  
1 0.  Refract or y na us ea a n d v o miti n g, mala bs or pti o n, biliar y s h u nt, or si g nifica nt b o wel 
resecti o n t hat w o ul d precl u de a de q uate a bs or pti o n of st u d y dr u g. 
1 1.  Patie nts wit h seri o us ill nesses, u nc o ntr olle d i nfecti o n, me dical c o n diti o ns, or ot her 
me dical hist or y i ncl u di n g a b n or mal la b orat or y res ults, w hic h i n t he i n vesti gat or’s 
o pi ni o n w o ul d be li kel y t o i nterfere wit h a patie nt’s partici pati o n i n t he st u d y, or wit h 
t he i nter pretati o n of t he res ults. 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 5  
Ple x xi k o n I nc.  
1 2.  W o me n of c hil d -beari n g p ote ntial w h o are pre g na nt or breast fee di n g.  
1 3.  At Scree ni n g Q Tc F ≥4 5 0 msec f or males a n d ≥4 7 0 msec f or fe males.  
D os a ge a n d 
Re gi me n  
St u d y dr u g will be a d mi nistere d orall y usi n g a ca ps ule f or m ulati o n ( 2 0 0 m g per ca ps ule). T he 
t otal dail y d ose of P L X 3 3 9 7 will be di vi de d a n d a d mi nistere d BI D. F or a n u ne ve n n u m ber of 
ca psules, t he lar ger d ose will be a d mi nistere d i n t he m or ni n g.  
F or P hase 1 b P L X 3 3 9 7 d ose a n d sc he d ule c o h orts a n d escalati o n, see St u d y Desi g n  (a b o ve). 
T he P hase 2 p orti o n of t he st u d y will use t he R P 2 D selecte d fr o m t he P hase 1 b  p orti o n of t he 
st u d y. 
As a part of sta n dar d of care, patie nts will recei ve t he f oll o wi n g:  
•  
6 0 G y of ra diati o n t hera p y M o n da y -Fri da y f or a t otal of 3 0 ra diati o n treat me nts o ver 
a p pr o xi matel y 6 wee ks.  
•  
Te m oz ol o mi de 7 5 m g/ m 2 P O o nce dail y f or a p pr o xi matel y 6 wee ks be gi n ni n g t he 
first da y of R T u ntil R T e n d, f oll o we d b y a dj u va nt treat me nt at a d ose of 1 5 0 m g/ m2 
o nce dail y o n Da ys 1 -5 of t he first 2 8 da y c ycle after c o m pleti o n of ra diati o n t hera p y 
(start of C ycle 3). T he d ose ca n be escalate d t o 2 0 0 m g/ m2 if t he n o n -he mat ol o gic 
t o xicit y is Gra de ≤2 (e xce pt f or al o pecia, na usea, a n d v o miti n g), a bs ol ute ne utr o p hil 
c o u nt ( A N C) is ≥1. 5 x 1 0 9/ L, a n d t he platelet c o u nt is ≥1 0 0 x 1 09/ L. 
•  
D uri n g t he 4 -wee k brea k after t he c o m pleti o n of R T, neit her te m oz ola mi de n or st u d y 
dr u g will be a d mi nistere d.  
S afet y a n d 
T oler a bilit y 
Assess me nts 
P h ysical e xa mi nati o ns, vital si g ns, 1 2 -lea d E C Gs, a d verse e ve nts, he mat ol o g y, a n d ser u m 
c he mistr y will be use d t o assess safet y a n d t olera bilit y.  
As t his is a n o pe n la bel st u d y, o n g oi n g safet y will be c o nti n u o usl y a n d ri g or o usl y m o nit ore d 
b y t he S p o ns or. A d diti o nall y, bi wee kl y telec o nfere nces are pla n ne d t o re vie w i n detail t he 
safet y acr oss all st u d y sites. Pri or t o d ose escalati o n i n t he P hase 1 b p orti o n, safet y data will be 
c ollate d a n d re vie w e d b y t he S p o ns or a n d st u d y sites b y telec o nfere nce.  
D ose Li miti n g 
T o xicities  
( P h ase 1 b) 
Usi n g C T C A E v 4 gra di n g criteria:  
He mat ol o gic D L Ts  
•  
Gra de ≥3 fe brile ne utr o pe nia  
•  
Gra de 4 ne utr o pe nia lasti n g f or > 7 da ys ( gr o wt h fact ors all o we d)  
•  
Gra de 3 t hr o m b oc yt o pe ni a ( platelets ≤5 0. 0/ µ L) lasti n g f or > 7 da ys  
Gra de 3 -4 l y m p h o pe nia is N O T c o nsi dere d a D L T.  
N o n -he mat ol o gic D L Ts  
•  
A n y Gra de ≥3 n o n -he mat ol o gic t o xicit y, pr o ba bl y relate d t o st u d y dr u g, E X C E P T f or t he 
f oll o wi n g: 
•  
Gra de ≥3 ne ur ol o gic deficits c o nsi dere d t o be d u e t o t he effects of t u m or, resecti o n, 
or e x pecte d p ost -s ur gical m or bi dities 
•  
Seiz ures of a n y gra de, as t his is c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n  
•  
Gra de ≥3 t hr o m b oe m b olic e ve nt, as t his is c o m m o nl y o bser ve d i n t his patie nt 
p o p ulati o n  
•  
Gra de 3 na usea , v o miti n g, or diarr hea t hat res ol ves t o Gra de ≤2 wit hi n 3 da ys of 
o nset  
•  
Gra de 3 hea dac he, i ns o m nia, or a m nesia t hat res ol ves t o Gra de ≤2 wit hi n 1 4  da ys of 
o nset  
•  
Gra de 3 fati g ue t hat res ol ves t o ≤Gra de 2 wit hi n 2 1 da ys of o nset  
•  
Gra de 3 A S T or A L T t hat res o l ves t o ≤Gra de 2 wit hi n 2 1 da ys of o nset 
•  
Gra de ≥3 C P K, G G T, A L P, h y p o ma g nese mia, or h y p o p h os p hate mia t hat is felt b y 
t he i n vesti gat or t o be cli nicall y i nsi g nifica nt 

P L X 3 3 9 7  
 
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 6  
Ple x xi k o n I nc.  
•  
Al o pecia of a n y Gra de  
St o p pi n g R ules  
F or P hase 1 d ose escalati o n, a d ose le vel will be c o n si dere d u nacce pta ble if 2 or m ore patie nts 
of t he 6 eli gi ble patie nts e x perie nce a D L T (see bel o w). S h o ul d all 7 patie nts i n t he C o h ort be 
a nal yza ble f or a d verse e ve nts, o nl y t he first 6 will be c o nsi dere d i n t he deter mi nati o n of D L Ts. 
A patie nt w h o misses  m ore t ha n 7 da ys of P L X 3 3 9 7 a d mi nistrati o n d uri n g t he 7 -wee k d osi n g 
peri o d of C ycle 1 ( 4 wee ks) a n d C ycle 2 ( 3 wee ks) f or reas o ns ot her t ha n ha vi n g ha d a D L T 
will be re place d. If 2 or m ore patie nts i n a C o h ort e x perie nce a D L T, n o patie nts i n t he C o h ort 
w ill be re place d. If > 2 of t he first 6 patie nts i n D ose Le vel -2 ( 4 0 0 m g/ da y of P L X 3 3 9 7) 
e x perie nce a pr ot oc ol -defi ne d D L T, t he c o m bi nati o n will be c o nsi dere d t o o t o xic a n d t he st u d y 
will be disc o nti n ue d.  
After a p pr o xi matel y 5 0 % of t he pla n ne d P hase 2 patie nts ha ve c o m plete d t heir c o nc urre nt 
ra diati o n t hera p y, a n o verall i nteri m safet y s u m mar y will be re vie we d b y t he Me dical M o nit or 
a n d pri nci pal i n vesti gat ors t o e ns ure t hat t he p ote ntial cli nical be nefit o ut wei g hs t he o bser ve d 
cli nical ris k t o date. If t he safet y o bser vati o ns d o n ot warra nt c o nti n ue d e nr ol me nt, t he st u d y 
will be disc o nti n ue d.  
P K 
P ar a meters  
F or t he P hase 1 b p orti o n of t he st u d y, a partial A U C ( A U C 0- 6) will be calc ulate d usi n g sa m ples 
c ollecte d fr o m C 1 D 8 ( pre -te m oz ol o mi de) a n d C 1 D 1 5 (c o nc urre nt te m oz ol o mi de). Val ues f or 
C ma x  a n d T ma x  will be deter mi ne d fr o m t he c o nce ntrati o n -ti me pr ofile. 
P D P ar a meters  
C D 1 4/ 1 6 m o n o n uclear cell c o u nts, C S F -1, a n d bi o mar kers of ki nase i n hi biti o n a n d m yel oi d 
cell recr uit me nt. S ur gical tiss ue will be e val uate d f or M G M T met h ylati o n, C S F -1, C S F 1 R, 
t u m or-ass ociate d macr o p ha ges, a n d ot her pr o g n ostic bi o mar kers i n or der t o c orrelate wit h 
treat me nt res p o nse a n d i nf or m e nric h me nt strate gies f or s u bse q ue nt st u dies i n t his patie nt 
p o p ulati o n. If t he M G M T met h ylati o n stat us  of t he st u d y p o p ulati o n differs fr o m t hat o bser ve d 
i n t he R T O G 0 5 2 5 st u d y, t he be nc h mar k m P F S of 5. 5 m o nt hs will be a dj uste d a p pr o priatel y. 
E n d p oi nts  
Pri mar y:  Me dia n P F S b y R A N O criteria  
Sec o n dar y:  Safet y, O S, P K, c orrelati ve i ma gi n g  
E x pl orat or y:  P D b i o mar kers 
St atistic al 
C o nsi der ati o ns  
F or t he pri mar y e n d p oi nt of me dia n P F S, base d o n a o ne -si de d l o g ra n k test wit h a 
si g nifica nce le vel of 0. 1 a n d p o wer of 8 0 %, 2 2 e ve nts ( deat h or pr o gressi o n) i n a p pr o xi matel y 
3 1 patie nts w o ul d be re q uire d t o detect a 5 0 % relati ve hazar d re d ucti o n i n pr o gressi o n -free 
s ur vi val d ue t o t he a d diti o n of P L X 3 3 9 7 c o m pare d t o t he rece nt hist orical c o ntr ol me dia n P F S 
of 5. 5 m o nt hs ( R T O G 0 5 2 5). Ass u mi n g a ~ 3 0 % rate of n o n -e val ua bilit y, a p pr o xi matel y 
3 7  patie nts are pla n ne d t o be  e nr olle d i n t he P hase 2 p orti o n of t he st u d y, w hic h w he n 
c o m bi ne d wit h t he 7 patie nts treate d at t hat d ose le vel i n t he P hase 1 p orti o n of t he st u d y will 
yiel d a p pr o xi matel y 4 4 patie nts.  
 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
1 8  
Ple x xi k o n I nc.  
E X P L A N A TI O N O F S U P E R S C RI P T S:  
1.  T he c ycle le n gt h f or C ycle 2 is 3 wee ks, t o c o m plete t he 6 wee ks t otal of ra diati o n t hera p y.  
2.  C 3 D 1 is t he first d ose of t he a dj u va nt retreat me nt  wit h te m oz ol o mi de a n d st u d y dr u g, be gi n ni n g a p pr o xi matel y 4 wee ks after t he c o m pleti o n of R T.  
3.  If well t olerate d a n d n o t u m or pr o gressi o n; cli nic visits, la b orat ories e ver y 4 wee ks wit h ra di o gra p hic assess me nt perf or me d e ver y 8 wee ks (e ver y 2 c ycles).  
4.  C o m p lete p h ysical e xa m (i ncl u di n g ne ur ol o gical e xa m) at Scree ni n g, a n d ne ur ol o gical e xa m pl us s y m pt o m-directe d p h ysical e xa m s u bse q ue ntl y.  
5.  He mat ol o g y:  C B C, differe ntial c o u nt, platelet c o u nt.  
6.  O n C 1 D 1, o btai ne d pre -d ose. O n C 1 D 8 a n d C 1 D 1 5, o btai ne d pre -d ose, 1 , 2, 4, a n d 6 h o urs p ost-d ose.  
7.  Bl o o d sa m ples f or circ ulati n g C S F -1 a n d bi o mar kers of ki nase i n hi biti o n a n d m yel oi d cell recr uit me nt will be o btai ne d pre -d ose o n C 1 D 1, C 1 D 8, C 2 D 1, a n d C 3 D 1. 
C D 1 4/ 1 6 m o n o n uclear cell c o u nts will be o btai ne d pre -d ose o n C 1 D 1 a n d C 1 D 8. Sa m ples will be c ollecte d a n d pr ocesse d b y La b C or p acc or di n g t o t he st u d y -s pecific 
la b orat or y ma n ual. La b C or p will perf or m t he M G M T a nal yses. 
8.  F or w o me n of c hil d -beari n g p ote ntial. At scree ni n g, o btai ne d wit hi n 1 4 da ys of t he first d ose of st u d y dr u g.  
9.  A dia g n ostic c o ntrast -e n ha nce d M RI or C T sca n of t he brai n m ust be perf or me d pre o perati vel y a n d p ost o perati vel y pri or t o t he i nitiati o n of ra di ot hera p y, i.e. wit hi n 2 8 da ys 
( 1 4 da ys preferre d) pri or t o st u d y dr u g a d mi nistrati o n ( C 1 D 1). Patie nts u na ble t o u n der g o M R i ma gi n g beca use of n o n-c o m pati ble de vices ca n be e nr olle d, pr o vi de d pre - a n d 
p ost -o perati ve c o ntrast -e n ha nce d C T sca ns are o btai ne d a n d are of s ufficie nt q ualit y.  
1 0.  T w o P L X 3 3 9 7 BI D a d mi nistrati o n sc he d ules, 7 da ys/ wee k vs. 5 da ys/ wee k ( M -F) wil l be e x pl ore d f or C ycle 1 a n d 2. P L X 3 3 9 7 will be a d mi nistere d BI D 7 da ys/ wee k 
f or C ycle 3 a n d s u bse q ue bt c ycles u ntil diasease pr o gressi o n disease or u nacce pta ble t o xicit y. 
1 1.  Te m oz ol o mi de is ta ke n orall y o nce dail y f or 5 da ys f oll o we d b y 2 3 da ys wit h o ut trea t me nt f or eac h c ycle be gi n ni n g wit h C 3 D 1 f or u p t o 1 2 c ycles. 
1 2.  M o nit ore d t hr o u g h o ut t he st u d y via sa fet y assess me nts, o bser vati o n, a n d partici pa nt re p orti n g. 
1 3.  Sta n dar d 1 2 -lea d E C G wit h Q Tc F calc ulati o n. Fri dericia’s f or m ula is re q uire d. Q Tc F = ( Q T)/3√( R R)  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 0  
Ple x xi k o n I nc.  
E X P L A N A TI O N O F S U P E R S C RI P T S:  
1.  T he c ycle le n gt h f or C ycle 2 is 3 wee ks, t o c o m plete t he 6 wee ks t otal of ra diati o n t hera p y.  
2.  C 3 D 1 is t he first d ose of t he a dj u va nt retreat me nt wit h te m oz ol o mi de a n d st u d y dr u g, be gi n ni n g 4 wee ks after t he c o m pleti o n o f R T. 
3.  If well t olerate d a n d n o t u m or pr o gressi o n; cli nic visits, la b orat ories e ver y 4 wee ks wit h ra di o gra p hic assess me nt perf orme d e ver y 8 wee ks (e ver y 2 c ycles)  
4.  C o m plete p h ysical e xa m (i ncl u di n g ne ur ol o gical e xa m) at Scree ni n g a n d ne ur ol o gical e xa m pl us s y m pt o m -directe d p h ysical e xa m s u bse q ue ntl y.  
5.  Bl o o d sa m ples f or circ ulati n g C S F -1 a n d bi o mar kers of ki nase i n hi biti o n a n d m yel oi d  cell recr uit me nt will be o btai ne d pre -d ose o n C 1 D 1, C 1 D 8, C 2 D 1, a n d C 3 D 1. 
C D 1 4/ 1 6 m o n o n uclear cell c o u nts will be o btai ne d pre -d ose o n C 1 D 1 a n d C 1 D 8. Sa m ples will be c ollecte d a n d pr ocesse d b y La b C or p acc or di n g t o t he st u d y -s pecific 
la b orat or y ma n ual. La bC or p will perf or m t he M G M T a nal yses.  
6.  F or w o me n of c hil d -= beari n g p ote ntial. At scree ni n g, o btai ne d wit hi n 1 4 da ys of t he first d ose of st u d y dr u g.  
7.  A dia g n ostic c o ntrast -e n ha nce d M RI or C T sca n of t he brai n m ust be perf or me d pre o perati vel y a n d p ost o perati vel y pri or t o t he i nitiati o n of ra di ot hera p y, i.e., wit hi n 2 8 da ys 
( 1 4 da ys preferre d) pri or t o st u d y dr u g a d mi nistrati o n ( C 1 D 1). Patie nts u na ble t o u n der g o M R i ma gi n g beca use of n o n -c o m pati ble de vices ca n be e nr olle d, pr o vi de d pre - a n d 
p ost -o perati ve c o ntra st-e n ha nce d C T sca ns are o btai ne d a n d are of s ufficie nt q ualit y  
8.  T w o P L X 3 3 9 7 BI D a d mi nistrati o n sc he d ules, 7 da ys/ wee k vs. 5 da ys/ wee k ( M -F) will be e x pl ore d f or C ycle 1 a n d 2. P L X 3 3 9 7 will be a d mi nistere d BI D 7  da ys/ wee k 
f or C ycle 3 a n d s u bse q ue bt c ycles until diasease pr o gressi o n disease or u nacce pta ble t o xicit y.  
9.  Te m oz ol o mi de is ta ke n orall y o nce dail y f or 5 da ys f oll o we d b y 2 3 da ys wit h o ut treat me nt f or eac h c ycle be gi n ni n g wit h C 3 D 1  f or u p t o 1 2 c ycles. 
1 0.  M o nit ore d t hr o u g h o ut t he st u d y via safet y assess me n ts, o bser vati o n, a n d partici pa nt re p orti n g. 
1 1.  Sta n dar d 1 2 -lea d E C G wit h Q Tc F calc ulati o n. Fri dericia’s f or m ula is re q uire d. Q Tc F = ( Q T)/3√( R R)  
1 2.  C o m me nci n g o n 0 1 Oct o ber 2 0 1 7, patie nt visits, cli nical la b orat or y testi n g, a n d M RI brai n sca ns will be perf or me d a p pr o xi mate l y e ver y 1 2 wee ks. 
 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 1  
Ple x xi k o n I nc.  
7. 0  
I N T R O D U C TI O N 
7. 1  
B ac k gr o u n d 
Ki nases pla y a u bi q uit o us r ole i n t he si g nali n g pat h wa ys f or pr oliferati o n, meta stasis, a n d 
s ur vi val of m ost t u m or t y pes. P L X 3 3 9 7 is a p ote nt a n d selecti ve i n hi bit or of F ms (t he rece pt or 
f or c ol o n y sti m ulati n g fact or 1, C S F 1, als o k n o w n as macr o p ha ge-c ol o n y sti m ulati n g fact or, 
M- C S F), Kit (t he rece pt or f or ste m cell fact or, S C F) a n d o nc o ge nic Flt 3 (t he rece pt or f or Flt 3 
li ga n d). F ms a n d Kit are re g ulat ors of ke y c o m p o ne nts of t he t u m or micr oe n vir o n me nt, na mel y 
micr o glia, macr o p ha ges, oste oclasts, a n d mast cells.  
P L X 3 3 9 7 is a n o vel, orall y acti ve, s mall m olec ule i n hi bit or t hat tar gets F ms, Kit a n d o nc o ge nic 
Flt 3, b ut re mai ns hi g hl y selecti ve vers us ot her ki nases. T he p ote nt i n hi biti o n of t hese t hree 
ki nases ca n be e x pl oite d t o attac k t u m ors via differe nt mec ha nis ms:  1) directl y i n hi biti n g 
o nc o ge nic dri vers s uc h as o nc o ge nic Kit a n d Flt 3 m uta nt pr otei ns, 2) i n hi biti n g paracri ne l o o ps 
bet wee n str o mal cells a n d t u m ors, 3) bl oc ki n g mi grati o n a n d a n gi o ge nesis, a n d 4) disr u pti n g 
oste ol ytic metastases. T he i n hi biti o n of t hese acti vities b y P L X 3 3 9 7 has bee n c haracterize d i n 
cell ular a n d i n vi v o assa ys. T he p har mac ol o gic efficac y de m o nstrate d t o date a n d t he t hera pe utic 
pr o mise s u p p ort f urt her de vel o p me nt of P L X 3 3 9 7 as a n a nti- ca ncer t hera pe utic.  
Gli o blast o ma ( G B M) is t he m ost fre q ue nt brai n t u m or, acc o u nti n g f or a p pr o xi matel y 1 2 % t o 
1 5 % of all brai n t u m ors. T he pea k i nci de nce occ urs bet wee n t he a ges of 4 5 a n d 7 0 years. F or 
patie nts wit h gli o blast o ma ( W orl d Healt h Or ga nizati o n gra de I V), t here is n o c ure, a n d sta n dar d 
l ocal treat me nt of s ur ger y pl us ra di ot hera p y ± c he m ot hera p y is ass ociate d wit h o nl y a m o dest 
i m pr o ve me nt i n o utc o me para meters. Acc or di n g t o t he Nati o nal Ca ncer I nstit ute, patie nts wit h 
brai n t u m ors t hat are eit her i nfre q ue ntl y c ura ble or u nresecta ble s h o ul d be c o nsi dere d ca n di dates 
f or cli nical trials t hat e val uate ne w dr u gs a n d bi ol o gical res p o nse m o difiers f oll o wi n g ra diati o n 
t hera p y. 
T he rati o nale f or testi n g t he F ms/ Kit i n hi bit or P L X 3 3 9 7 i n G B M is pr o vi de d b y t he f oll o wi n g 
scie ntific e vi de nce: 
1.  I nfiltrati n g micr o glia are ass ociate d wit h a mar ke dl y re d uce d s ur vi val (K o m o hara 2 0 0 8 ) 
2.  A mese nc h y mal si g nat ure als o pre dicts re d uce d s ur vi val i n G B M ( P hilli ps 2 0 0 6 ). T his 
si g nat ure i ncl u des well- descri be d micr o glial mar kers s uc h as C D 6 8, P T P R C, T N F, a n d 
N F 1 m utati o ns ( Ver haa k 2 0 1 0 ) 
3.  A micr o glial - wea ke ni n g p ol y m or p his m ( V 2 4 9I) is ass ociate d wit h i ncrease d s ur vi val 
(R o der o 2 0 0 8 ) 
4.  Ma n y gli o ma cell li nes esta blis he d fr o m patie nt sa m ples e x press hi g h c o nce ntrati o ns of 
li ga n ds f or F ms ( C S F- 1 a n d I L- 3 4) or Kit ( S C F). T his secreti o n i n t ur n attracts a n d 
acti vates s urr o u n di n g micr o glia, w hic h facilitate t u m or i n vasi o n via ela b orati o n of 
pr oteases s uc h as M T 1 -M M P a n d M M P 2.  
5.  De pleti o n of micr o glia i n ort h ot o pic G B M m o dels re d uces t u m or b ur de n a n d s prea d. 
6.  Macr o p ha ges a n d micr o glial cells are recr uite d b y t u m or cells as a resista nce mec ha nis m 
i n res p o nse t o ra di ot hera p y (A h n 2 0 1 0 ). 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 2  
Ple x xi k o n I nc.  
I n p har mac ol o g y st u dies, P L X 3 3 9 7 ( 1 µ M) has bee n s h o w n t o mar ke dl y re d uce t he i n vasi o n of 
G L 2 6 1 gli o blast o ma cells w he n c o- c ult ure d wit h micr o glia i n a matri gel i n vasi o n assa y. 
F urt her m ore, P L X 3 3 9 7 a d mi nistere d b y c h o w f or 1 0 da ys res ulte d i n a si g nifica nt re d ucti o n 
( p = 0. 0 2 9) i n t u m or gr o wt h i n t he 9 L Fis her rat gli o ma m o del. Als o, P L X 3 3 9 7 a vi dl y cr osses i nt o 
t he C N S of r ats (si milar t o t he p ositi ve brai n pe netrati o n c o ntr ol c o m p o u n d, a nti p yri ne) a n d is 
n ot a s u bstrate f or acti ve tra ns p ort, s u g gesti n g t hat P L X 3 3 9 7 will reac h G B M t u m ors a n d 
s urr o u n di n g str o mal tiss ue wit hi n t he C N S e ve n wit h a n i ntact bl o o d brai n barrier. Fi nall y, 
P L X 3 3 9 7 has s h o w n a s y ner gistic effect w he n c o m bi ne d wit h ra diati o n t hera p y i n p har mac ol o g y 
m o dels of pr ostate ca ncer a n d G B M.  
7. 2  
P h ar m ac o d y n a mics 
I n brief, bi oc he mical data s u p p ort F ms, Kit a n d o nc o ge nic Flt 3 as ke y tar gets of P L X 3 3 9 7. 
C o nse q ue ntl y, pr oliferati o n of cell li nes t hat alter nati vel y de pe n d o n C S F- 1 or S C F li ga n ds, or 
are dri ve n b y Flt 3 t hat is o nc o ge nicall y acti vate d b y i nter nal ta n de m d u plicati o ns ( Flt 3- I T D), is 
i n hi bite d b y P L X 3 3 9 7 at I C5 0 val ues bel o w 1 µ M. F urt her m ore, C S F - 1-i n d uce d 
a ut o p h os p h or ylati o n of F ms a n d S C F- i n d uce d a ut o p h os p h or ylati o n of Kit are p ote ntl y i n hi bite d 
b y P L X 3 3 9 7. B y c o ntrast, b ot h a ut o p h os p h or ylati o n a n d pr oliferati o n of cells i n d uce d b y 
a d diti o n of Flt 3 li ga n d are o nl y wea kl y i n hi bite d b y P L X 3 3 9 7, s u g gesti n g prefere ntial i n hi biti o n 
of t he o nc o ge nicall y-acti vate d Flt 3 ki nase. Fi nall y, t he R A N K- L a n d C S F - 1- de pe n de nt 
differe ntiati o n of oste oclast prec urs ors is als o p ote ntl y i n hi bite d b y P L X 3 3 9 7. T hese i n vitr o 
effects tra nslat e d t o effects i n a variet y of i n vi v o m o dels desi g ne d t o test t he effects of P L X 3 3 9 7 
o n F ms- de pe n de nt pr oliferati o n, F ms- de pe n de nt oste oclast differe ntiati o n, a n d Flt 3- I T D 
de pe n de nt t u m or gr o wt h.  
7. 2. 1  
I n Vitr o P h ar m ac o d y n a mics 
P L X 3 3 9 7 s h o ws si g nifica nt selecti vit y vers us a pa nel of o ver 2 0 0 ki nases. F ms, Kit, a n d m uta nt 
Flt 3 -I T D a p pear t o be t he m ost se nsiti ve tar get ki nases, wit h I C5 0 val ues of 1 7, 1 2, a n d 9 n M, 
res pecti vel y (see Ta ble 1 ). 
T a ble 1: 
I C5 0 V al ues of P L X 3 3 9 7 A g a nst Selecte d Ki n ases  
Ki n ase  
F ms  
Kit  
Flt 3 -I T D 
K dr  
Lc k  
Flt 1  
Tr k C  
P L X 3 3 9 7  
1 7 n M  
1 2 n M  
9 n M  
2 1 3 n M  
8 6 0 n M  
8 8 0 n M  
8 9 0 n M  
K dr ki nase acti vit y is o nl y m o destl y affecte d, a n d ot her ki nases teste d are e ve n less se nsiti ve t o 
P L X 3 3 9 7. W hile p h ysi ol o gic effects d ue t o t he i n hi biti o n of F ms a n d Kit are e x pecte d, t he 
selecti vit y of P L X 3 3 9 7 s u g gests t hat mi ni mal off-tar get effects s h o ul d be o bser ve d. W he n 
scree ne d a gai nst a br oa d pa nel of a d diti o nal ki nases, I C 5 0 val ues were > 1 µ M f or all, w it h t he 
maj orit y > 1 0 µ M.  
P L X 3 3 9 7 als o de m o nstrate d ne gli gi ble acti vit y i n a sta n dar d N o vascree n pa nel. T his is a scree n 
f or off-tar get acti vit y a gai nst a br oa d arra y of 7 1 tar gets i n 8 fa milies ( Ne ur otra ns mitter-relate d, 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 3  
Ple x xi k o n I nc.  
Ster oi ds, I o n C ha n nels, Nitric O xi d e, Pr osta gla n di ns, Gr o wt h Fact ors, Brai n/ G ut Pe pti des, a n d 
E nz y mes). At a ser u m -free c o nce ntrati o n of 1 0 µ M of P L X 3 3 9 7, all res ults were wit hi n 4 0 % of 
Baseli ne, i n dicati n g n o rele va nt off- tar get acti vit y. 
M- N F S -6 0 cells a n d B A C 1. 2 F 5 cells are m o use cell li nes t hat re q uire C S F - 1 t o pr oliferate, a n d 
M o 7 E cells are h u ma n cells t hat re q uire S C F t o pr oliferate. T he li ga n d de pe n de nt pr oliferati o n of 
t hese cells is i n hi bite d b y P L X 3 3 9 7 wit h I C5 0 val ues of 0. 3 3, 0. 2 3 a n d 0. 3 1 μ M, res pecti vel y. I n 
T H P -1 cells, F ms a ut o p h os p h or ylati o n i n d uce d b y C S F- 1 ca n be i n hi bite d b y 7 n M 
c o nce ntrati o ns of P L X 3 3 9 7. B y c o ntrast, i n R S 4; 1 1 cells, Flt 3 a ut o p h os p h or ylati o n ca n be 
i n d uce d b y Flt 3 li ga n d a n d t his a ut o p h os p h or ylati o n re q uires hi g h le vels of P L X 3 3 9 7 ( 1 5 0 0 n M) 
f or i n hi biti o n, s u g gesti n g t hat P L X 3 3 9 7 bi n ds o nl y wea kl y t o u nacti vate d Flt 3. O n t he ot her 
ha n d, pr oliferati o n of M V 4- 1 1 cells (t hat e x press Flt 3 -I T D) is p ote ntl y i n hi bite d b y P L X 3 3 9 7 
wit h a n I C 5 0 val ue of 2 6 n M. Fi nall y, h u ma n oste oclast prec urs or cells ca n be i n d uce d t o 
differe ntiate i nt o mat ure oste oclasts b y t he c o m bi nati o n of R A N K- L a n d C S F - 1. P L X 3 3 9 7 
i n hi bits t his oste oclast differe ntiati o n wit h a n I C5 0 val ue of 3 3 n M. 
7. 2. 2  
I n Vi v o P h ar m ac o d y n a mics 
M o dels of F ms- de pe n de nt pr oliferati o n a n d F ms- de pe n de nt oste oclast ac ti vit y ca n be i n hi bite d 
b y 5- 1 0 m g/ k g d oses of P L X 3 3 9 7 i n vi v o. T his was de m o nstrate d i n a F ms- de pe n de nt 
s ple n o me gal y m o del, a metastatic breast ca ncer m o del, a n d a m uri ne c olla ge n-i n d uce d art hritis 
m o del. 
Ba F 3 cells are m o use pre - B cells t hat de pe n d o n i nterle u ki n-3 (I L - 3) f or s ur vi val. B y e n gi neeri n g 
Ba F 3 cells t o e x press B C R -acti vate d F ms ki nase acti vit y, t he de pe n de nce o n I L- 3 ca n be 
re place d. C o nse q ue ntl y, t hese B C R-F ms e x pressi n g Ba F 3 cells are de pe n de nt o n F ms ki nase 
acti vit y f or s ur vi val. I n vitr o, pr oliferati o n of t hese cells ca n be p ote ntl y i n hi bite d b y P L X 3 3 9 7, 
wit h a n I C 5 0 val ue of 7 n M. A c orres p o n di n g Ba F 3 cell li ne e x pressi n g B C R-Kit is als o q uite 
se nsiti ve t o P L X 3 3 9 7, wit h a n I C 5 0 val ue of 1 3 0 n M. 
I njecti o n of t he B C R-F ms -e x pressi n g Ba F 3 cell s i nt o t he tail vei n of n u de mice res ults i n h o mi n g 
of t hese cells t o t he s plee n a n d s u bse q ue nt cell ular pr oliferati o n t hat res ults i n dra matic 
s ple n o me gal y o ver t he c o urse of 1 4- 1 8 da ys. Oral d osi n g of P L X 3 3 9 7 f or t he fi nal 8 da ys of t his 
m o del res ults i n  d ose- de pe n de nt i n hi biti o n of t he s ple n o me gal y. T he E D5 0 of t his effect is 
bet wee n 2 a n d 5 m g/ k g. T heref ore, we belie ve t hat a 5 m g/ k g oral d ose of P L X 3 3 9 7 i n mice 
c orres p o n ds t o a n efficaci o us d ose. P har mac o ki netic a nal ysis re veals t hat t his 5 m g/ k g d ose 
ac hie ves a n A U C 0 – 2 4 of 9 9. 8 μ M• h, a n d a C ma x  of 1 3. 4 μ M. We will use t hese val ues t o defi ne a n 
efficaci o us e x p os ure, a n d t his will be use d as t he de n o mi nat or i n calc ulati o ns of t hera pe utic 
m ulti ples.  
I n a se parate m o del, mice e x pressi n g t he p ol y o ma mi d dle T a nti ge n ( P y M T) behi n d a ma m mar y 
pr o m oter de vel o p breast ca ncer t hat metastasizes after se veral m o nt hs. D uri n g t he metastatic 
pr ocess, circ ulati n g t u m or cells t hat e x press P y M T ca n be meas ure d a m o n g circ ulati n g bl o o d 
cells. Si nce F ms acti vit y is a critical c o m p o ne nt of e xtr a vasati o n i nt o t he bl o o d strea m, re d ucti o n 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 4  
Ple x xi k o n I nc.  
i n t he n u m ber of t hese circ ulati n g t u m or cells ca n be a meas ure of a nti-F ms acti vit y. Wit hi n 
2 4 h o urs of a si n gle oral d ose of 4 0 m g/ k g P L X 3 3 9 7, a 1 0- f ol d decrease i n t hese circ ulati n g 
t u m or cells ca n be deter mi ne d (see Fi g ure 1 ). 
Fi g ure 1:  
P L X 3 3 9 7- i n d uce d Re d ucti o n of Circ ul ati n g T u m or Cells i n P y M T 
M o use M o del of Bre ast C a ncer  
 
I n or der t o deter mi ne effects of P L X 3 3 9 7 o n oste oclastic acti vit y i n vi v o, a m uri ne c olla ge n-
i n d uce d art hritis m o del was i m ple me nte d. I n t his m o del, d o u ble i m m u nizati o n of t he mice wit h 
c olla ge n lea ds t o pr o gressi ve cli nical s y m pt o ms rese m bli n g r he u mat oi d art hritis. Hist ol o g y ca n 
be use d t o meas ure oste oclasts t hat c o ntri b u te b o ne- destr ucti ve pat h ol o g y i n t his m o del. 
Oste oclasts are meas ure d usi n g a n oste oclast -s pecific mar ker, na mel y tartrate-resista nt aci d 
p h os p hatase 5 B ( T R A P 5 B). Treat me nt of t hese mice wit h 5 0 m g/ k g P L X 3 3 9 7 o ver t he c o urse 
of 2 4 da ys res ults i n si g nific a nt sta bilizati o n of disease, a n d t his is acc o m pa nie d b y dra matic 
re d ucti o ns i n macr o p ha ges i nfiltrati n g t he j oi nts. I m p orta ntl y, j oi nt-i nfiltrati n g oste oclasts are 
als o re d uce d b y 1 0- f ol d, ill ustrati n g t he p ote nt a nti- oste oclastic effects of P L X 3 3 9 7. 
Si nc e P L X 3 3 9 7 per meates t he bl o o d- brai n barrier a n d F ms - de pe n de nt micr o glia are li kel y 
me diat ors of pai n tra ns missi o n, P L X 3 3 9 7 was teste d i n a f or mali n- pai n m o del. T his f or mali n 
m o del meas ures b ot h ac ute n ocice pti ve a n d ac ute i nfla m mat or y pai n res p o nses. P L X 3 3 9 7 
s h o we d re d ucti o n i n b ot h p hases of t he f or mali n pai n res p o nse, s u g gesti n g t hat effects o n b ot h 
ac ute a n d i nfla m mat or y pai n ma y be e x pecte d i n f urt her st u dies.  
Please refer t o t he I n vesti gat or’s Br oc h ure f or u p date d i nf or mati o n a n d detaile d descri pti o n of 
t he n o ncli nical p har mac ol o g y data. 
7. 3  
N o ncli nic al Met a b olis m a n d P h ar m ac o ki netics  
Please refer t o t he I n vesti gat or’s Br oc h ure f or u p date d i nf or mati o n a n d detaile d descri pti o n of 
t he n o ncli nical meta b olis m a n d P K. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 5  
Ple x xi k o n I nc.  
P L X 3 3 9 7 has l o w a q ue o us s ol u bilit y a n d m o dest per mea bilit y. It is n ot a s u bstrate or i n hi bit or of 
P g p. Se veral st u dies i n f o ur s pecies ( m o use, rat, d o g a n d m o n ke y) e val uate d f or m ulati o ns t o 
o pti mize a bs or pti o n a n d s yste mic e x p os ure f oll o wi n g oral a d mi nistrati o n. P L X 3 3 9 7 was 
a bs or be d wit hi n t w o t o t hree h o urs f oll o wi n g oral a d mi nistrati o n. I n se veral st u dies, plas ma 
e x p os ure ( base d o n A U C val ues) was greater i n fe males ( u p t o 3 4 % i n rats). Eli mi nati o n half 
li ves ra n ge d fr o m 2 t o 5 h o urs i n t hese f o ur s pecies. A st u d y c o n d ucte d i n c y n o m ol g us m o n ke ys 
s h o we d t hat f o o d d oes n ot i n hi bit or dela y a bs or pti o n of P L X 3 3 9 7 f oll o wi n g oral ( ga va ge) 
a d mi nistrati o n. 
T he e xte nt t o w hic h P L X 3 3 9 7 bi n ds t o t he plas ma pr otei ns was e val uate d i n vitr o usi n g a Ra pi d 
E q uili bri u m Dial ysis i n verte d met h o d. P L X 3 3 9 7 is str o n gl y pr otei n b o u n d i n plas ma f or all f o ur 
s pecies teste d ( m o use, rat, d o g, a n d h u ma n). Wit h re gar ds t o p ote ntial s pecies differe nces, t he 
bi n di n g i n m o use, d o g a n d h u ma n plas ma at 7 5 µ M was a p pr o xi matel y e q ual ( 9 9. 8 %, 9 9. 7 %, 
a n d 9 9. 8 % res pecti vel y) w hile rat pr otei n bi n di n g was mar gi nall y l o wer ( 9 8. 3 %). 
T w o e x peri me nts e val uate d t he partiti o ni n g of P L X 3 3 9 7 bet wee n bl o o d a n d brai n, base d o n 
meas ure me nts of test article i n brai n tiss ue, cere br os pi nal fl ui d  a n d plas ma. I n o ne st u d y, 
a p precia ble a m o u nts of P L X 3 3 9 7 were rec o vere d i n w h ole bl o o d ( vs. plas ma), s u g gesti n g t hat 
P L X 3 3 9 7 ass ociates wit h cell ular ele me nts of bl o o d. I n e x peri me nts t hat q ua ntifie d P L X 3 3 9 7 
c o nce ntrati o n i n brai n tiss ue a n d cere br os pi nal fl ui d 4 a n d 6 h o urs f oll o wi n g oral a d mi nistrati o n 
i n rats, t he brai n: plas ma rati o a vera ge d 0. 4 1 a n d 0. 3 6, res pecti vel y – val ues cl ose t o t hat of 
a nti p yre ne, a p ositi ve c o ntr ol ( 0. 5 0 a n d 0. 5 4). T he rati os of C S F: plas ma at t hese ti me p oi nts f or 
P L X 3 3 9 7, h o we ver, were l o wer ( 0. 0 2 6 a n d 0. 0 1 4) t ha n t h ose f or a nti p yre ne ( 1. 0 6 a n d 0. 9 2). 
A series of i n vitr o st u dies e xa mi ne d t he meta b olic sta bilit y of P L X 3 3 9 7 usi n g eit her li ver S 9 
fracti o n or i ntact he pat oc ytes fr o m se veral s pecies, i ncl u di n g rats a n d d o gs, t he t w o s pecies use d 
i n t o xic ol o g y st u dies, as well as h u ma ns. St u dies wit h i ntact he pat oc ytes re veale d t hat P L X 3 3 9 7 
was ver y sl o wl y meta b olize d i n all t hree s pecies, es peciall y h u ma n li ver cells. Alt h o u g h t he 
e xact m olec ular s pecies were n ot i de ntifie d, i n t he prese nce of h u ma n he pat oc ytes, se veral 
m olec ular s pecies c orres p o n di n g t o gl uc ur o ni de c o nj u gates were detecte d, wit h mi ni mal 
e vi de nce of brea k d o w n. T hese data, al o n g wit h t he hi g h pr otei n bi n di n g, s u g gests t hat t he 
cleara nce of P L X 3 3 9 7 fr o m h u ma n plas ma ma y be sl o w. A n ot her st u d y was c o n d ucte d t o 
e val uate t he C Y P 4 5 0 p he n ot y pes of P L X 3 3 9 7 meta b olis m i n vitr o. Of t he fi ve maj or C Y P 
is of or ms, 3 A 4 ( B F C) ma y be i n v ol ve d i n P hase I meta b olis m of P L X 3 3 9 7, wit h p ossi bl y 
C Y P 1 A 2 pl a yi n g a mi n or r ole. 
P L X 3 3 9 7 d oes n ot a p pear t o i n hi bit C Y P dr u g - meta b olizi n g e nz y mes t o a n i m p orta nt e xte nt. 
St u dies usi n g h u ma n li ver micr os o mes yiel de d e nz y me i n hi bit or y c o nsta nt ( Ki) val ues e xcee di n g 
3 0 µ M f or C Y P 1 A 2 a n d 3 A 4 (test oster o ne s u bstrate), > 1 2 µ M f or 3 A 4 ( mi daz ola m s u bstrate), 
2 D 6 a n d 2 C 9. A Ki val ue < 1 0 µ M was o btai ne d f or o nl y o ne C Y P is oz y me:  2 C 1 9 
( Ki = 8. 4 µ M). It is w ort h n oti n g t hat t he latter e x peri me nt was c o n d ucte d i n t he a bse nce of 
h u ma n ser u m al b u mi n ( H S A). W he n P L X 3 3 9 7 was e val uate d f or its a bilit y t o i n hi bit t he maj o r 
h u ma n C Y P is oz y mes i n t he prese nce of 1 0 µ M H S A, I C 5 0 val ues greater t ha n 3 0 µ M were 
u nif or ml y o btai ne d. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 6  
Ple x xi k o n I nc.  
I n a n ot her series of e x peri me nts, P L X 3 3 9 7 was de m o nstrate d n ot t o i n d uce t he e x pressi o n of 
ge nes t hat e nc o de C Y P e nz y mes a n d se veral ot her pr otei ns i n v ol ve d i n meta b olis m a n d 
tra ns p ort. 
I n a g gre gate, a n e xte nsi ve series of n o n-cli nical st u dies e val uati n g P L X 3 3 9 7 re veal a 
meta b olicall y sta ble dr u g t hat dis pla ys e xte nsi ve pr otei n bi n di n g. Cli nicall y rele va nt dr u g- dr u g 
i nteracti o ns are n ot a ntici pate d base d u p o n e x peri me ntal e vi de nce of ne gli gi ble C Y P i n hi biti o n 
or i n d ucti o n i n vitr o. 
7. 4  
S u m m ar y of N o ncli nic al T o xic ol o g y, Ge n ot o xicit y, a n d S afet y P h ar m ac ol o g y 
A t otal of 1 2 t o xic ol o g y st u dies were c o m plete d i n rats a n d d o gs wit h fi ve a n d t hree st u dies i n 
eac h of t hese t w o s pecies, res pecti vel y, perf or me d u n der G L P c o n diti o ns. T he i nitial t w o G L P 
t o xic ol o g y st u dies i n v ol ve d dail y ( BI D i n d o gs a n d Q D i n rats) oral ( ga va ge) a d mi nistrati o n of 
P L X 3 3 9 7 f or f o ur wee ks, wit h 1 4- da y ( d o g) or 1 6- da y (rat) rec o veries. Nei t her a n o-effect-le vel 
( N O E L) n or a n o-a d verse -effect -le vel ( N O A E L) of P L X 3 3 9 7 c o ul d be deter mi ne d i n eit her 
s pecies i n t hese st u dies. T he si g nifica nt a d verse, test article-relate d o bser vati o ns see n i n t hese 
t w o hi g h-d ose G L P st u dies a p pear t o be relate d t o t he mec ha nis m of P L X 3 3 9 7- me diate d 
i n hi biti o n of F ms a n d Kit ki nase. All a d verse fi n di n gs were partiall y or f ull y re versi ble. T w o 
a d diti o nal G L P t o xic ol o g y st u dies at l o wer d ose le vels i n v ol ve d dail y ( Q D i n rats a n d d o gs) oral 
( ga va ge) a d mi nistrati o n of PL X 3 3 9 7 f or f o ur wee ks, wit h 8- wee k rec o veries at d oses of 1, 6, a n d 
3 0 m g/ k g/ da y i n d o gs a n d 0. 5, 2 a n d 1 0 m g/ k g/ da y i n rats. N O A E Ls of P L X 3 3 9 7 were 
deter mi ne d t o be 6 m g/ k g/ da y i n d o gs a n d 1 0 m g/ k g/ da y i n rats i n t hese a d diti o nal st u dies. 
T w o  1 3-wee k G L P t o xic ol o g y st u dies i n v ol ve d dail y ( Q D i n rats a n d d o gs) oral ( ga va ge) 
a d mi nistrati o n of P L X 3 3 9 7 f or 1 3 wee ks, wit h 8- wee k rec o veries at d oses of 1, 6, a n d 
3 0 m g/ k g/ da y i n d o gs a n d 0. 5, 4 a n d 2 0 m g/ k g/ da y i n rats. N O A E Ls of P L X 3 3 9 7 were 
deter mi ne d t o be 6 m g/ k g/ da y i n d o gs a n d 4 m g/ k g/ da y i n rats i n t hese a d diti o nal st u dies. 
T hree ge n ot o xicit y st u dies were perf or me d, i ncl u di n g t he A mes assa y, c hr o m os o mal a berrati o ns 
i n h u ma n peri p heral bl o o d l y m p h oc ytes, a n d m o use b o ne marr o w micr o n ucle us assa y, u n der 
G L P -c o m plia nt c o n diti o ns. A n a d diti o nal s p ot test m uta ge nicit y assa y i n S al m o nell a  a n d E. c oli  
was n ot perf or me d u n der G L P-c o m plia nt c o n diti o ns. O n t he basis of t hese st u dies, P L X 3 3 9 7 was 
c o ncl u de d n ot t o e xert a n y m uta ge nic, clast o ge nic effects. 
I n G L P-c o m plia nt res pirat or y a n d ce ntral ner v o us s yste m safet y st u dies, t he N O E L f or P L X 3 3 9 7 
was 2 0 0 m g/ k g i n rats. A d diti o nall y, t hree G L P-c o m plia nt safet y p har mac ol o g y st u dies 
a d dresse d t he p ote ntial a d verse car di o vasc ular or car diac electr o p h ysi ol o gical effects of 
P L X 3 3 9 7. W he n e val uate d i n a ser u m free h E R G st u d y, P L X 3 3 9 7 was s h o w n t o bi n d t o t he 
c ha n nel (I C 5 0 0. 7 µ M). H o we ver, i n a f oll o w - u p car diac P ur ki nje fi ber st u d y, n o test article-
relate d effects o n re p olarizati o n, A P a m plit u de or s pee d of car diac de p olarizati on were o bser ve d. 
F urt her m ore, i n a d o g i n vi v o G L P car di o vasc ular safet y st u d y, all electr ocar di o gra p hic 
para meters were q ualitati vel y a n d q ua ntitati vel y wit hi n n or mal li mits, de m o nstrati n g t hat 
P L X 3 3 9 7 d oes n ot pr ol o n g car diac re p olarizati o n u p t o t he hi g hest d ose teste d ( 1 0 0 0 m g/ k g). 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 7  
Ple x xi k o n I nc.  
7. 4. 1  
Re pe at - d ose T o xicit y i n R ats 
7. 4. 1. 1  
4- wee k R at St u dies  
I n t he i nitial G L P 2 8- da y st u d y wit h a 1 4- da y rec o ver y peri o d, S pra g ue-Da wle y rats were d ose d 
at 2 0, 6 0, a n d 2 0 0 m g/ k g/ da y. N o n-a d verse l o wer b o d y wei g hts a n d f o o d c o ns u m pti o n w ere 
n ote d f or t he 2 0 0 m g/ k g/ da y gr o u p fe males. B o d y a n d f o o d c o ns u m pti o n effects res ol ve d d uri n g 
t he rec o ver y peri o d. 
C ha n ges i n he mat ol o g y para meters c o nsiste d of d ose-relate d l o wer W B C, R B C, P T, a P T T, a n d 
l o wer retic ul oc yte c o u nts i n all test article-treate d gr o u ps. At st u d y da y 4 3 rec o ver y e val uati o n, 
t he W B C c o u nts ha d re b o u n de d, t he R B C mass partiall y rec o vere d, retic ul oc yte c o u nts were 
hi g her t ha n t he c o ntr ol gr o u p, a n d fi bri n o ge n, P T, a n d A P T T ha d res ol ve d i n t he 2 0 0 m g/ k g/ da y 
gr o u ps. Micr osc o pic alt erati o ns i ncl u de d d ose-relate d mi ni mal t o m o derate s u b p h yseal 
h y per ost osis i n t he fe m ur, mi ni mal t o m o derate p h yseal h y pertr o p h y i n t he fe m ur, a n d d ose-
relate d re d ucti o n i n t he de nsit y of he mat o p oietic cells of all li nea ges wit hi n t he b o ne marr o w 
(ster n u m a n d fe m ur). D ose-relate d he pat ocell ular ce ntril o b ular h y pertr o p h y was n ote d f or t he 
2 0 0 m g/ k g/ da y gr o u ps, a n d c orrelate d wit h hi g her li ver e nz y me le vels a n d hi g her li ver wei g hts, 
a n d a hi g her i nci de nce a n d/ or se verit y of c hr o nic pr o gressi ve ne p hr o pat h y was n ote d f or t he 
2 0 0 m g/ k g/ da y gr o u ps. T his fi n di n g is a n or mal s p o nta ne o us c ha n ge i n S pra g ue- Da wle y rats a n d 
was als o n ote d i n t he ve hicle c o ntr ol gr o u ps. Micr osc o pic fi n di n gs i n t he s ki n a n d l y m p h oi d 
tiss ues i ncl u de d a d ose-relate d hi g her i nci de nce of mi ni mal t o mil d m y x o mat o us c ha n ge i n t he 
s ki n/s u bc utis a n d l y m p h oi d de pleti o n of t he t h y mic c orte x. Micr osc o pic fi n di n gs i n e n d ocri ne 
a n d re pr o d ucti ve tiss ues i ncl u de d d ose -relate d hi g her i nci de nce a n d se verit y of he m orr ha gic 
c or p ora l uteal c ysts i n t he o varie s a n d hi g her i nci de nce a n d/ or se verit y of t h yr oi d f ollic ular cell 
h y pertr o p h y i n t he 2 0 0 m g/ k g/ da y gr o u ps. Mi ni mal t o m o derate de pleti o n of s per mat o ge nic 
e pit heli u m was n ote d i n t he 6 0 a n d 2 0 0 m g/ k g/ da y gr o u p males, a n d t he 2 0 0 m g/ k g/ da y gr o u p 
males were o fte n c o m pl etel y de v oi d of s per mat o g o nia a n d pac h yte ne s per mat oc ytes. At st u d y 
Da y 4 3, t here was a n i ncrease i n t he s per mat o g o nial p o p ulati o n. Alterati o ns i n testes a n d o varies 
are li kel y relate d t o t he mec ha nis m of P L X 3 3 9 7 - me diate d i n hi biti o n of F ms a n d Kit ki nase. 
T he maj orit y of alterati o ns i n m or p h ol o gic pat h ol o g y para meters, e xce pt f or l uteal c ysts a n d 
c hr o nic pr o gressi ve ne p hr o pat h y, partiall y or c o m pletel y res ol ve d f oll o wi n g t he rec o ver y peri o d. 
A N O A E L was n ot deter mi ne d. T his st u d y als o di d n ot esta blis h a let hal d ose i n 5 0 % of rats 
L D 5 0 or se verel y t o xic d ose i n 1 0 % of rats ( S T D1 0). 
A f oll o w- u p st u d y e val uate d t he p ote ntial t o xicit y at d oses of 0. 5, 2 a n d 1 0 m g/ k g/ da y t o 
S pra g ue- Da wle y rats f or 2 8 c o nsec uti ve da ys, wit h a rec o ver y peri o d of 8 wee ks t o assess t he 
re versi bilit y, persiste nce, or dela ye d occ urre nce of p ote ntial test article-relate d effects. T here 
were n o test article -relate d effects o n cli nical or macr osc o pic o bser vati o ns. B o d y wei g hts, f o o d 
c o ns u m pti o n, a n d uri nal ysis para meters were u n affecte d b y test article a d mi nistrati o n.  
N o n -a d verse he mat ol o g y alterati o ns were n ote d, i ncl u di n g hi g her R D W, l o wer a bs ol ute 
ne utr o p hil c o u nts, hi g her fi bri n o ge n, a n d l o wer R B C c o u nt. S mall a n d n o n- a d verse ser u m 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 8  
Ple x xi k o n I nc.  
c he mistr y alterati o ns i ncl u de d hi g her ser u m al b u mi n, t otal pr otei n, a n d A L T le vels. T he mea n 
val ues f or all affecte d para meters were wit hi n t he hist orical c o ntr ol ra n ge ra n d rec o vere d b y 
Wee k 1 2. Decreases i n s ple nic e xtra me d ullar y he mat o p oiesis were o bser ve d f or t he 
1 0 m g/ k g/ da y gr o u p males a n d fe m al es at t he pri mar y necr o ps y. T hese effects o n t he s plee n were 
re versi ble a n d n ot n ote d at t he Wee k 1 2 rec o ver y necr o ps y, a n d were t heref ore c o nsi dere d n o n-
a d verse. All s yste mic effects of P L X 3 3 9 7 i n t his st u d y were re versi ble a n d n ot c o nsi dere d b y t he 
st ud y direct or t o be a d verse. T heref ore, t he N O A E L f or oral ( ga va ge) a d mi nistrati o n of 
P L X 3 3 9 7 was 1 0 m g/ k g/ da y ( A U C last of 2 4 5 1 5 n g• h/ m L a n d C ma x  of 3 3 9 0 n g/ m L f or males a n d 
fe males c o m bi ne d). 
7. 4. 1. 2  
1 3- wee k R at St u d y  
A 1 3 - wee k st u d y e val uate d t he p ote ntial t o xicit y a n d t o xic o ki netic pr ofile of P L X 3 3 9 7 H Cl, 
w he n a d mi nistere d orall y ( ga va ge) at d oses of 0. 5, 4 a n d 2 0 m g/ k g/ da y t o S pra g ue- Da wle y rats 
f or 1 3 c o nsec uti ve wee ks, wit h a rec o ver y peri o d of 8 wee ks. S yste mic e x p os ure t o P L X 3 3 9 7 
ge nerall y i ncrease d pr o p orti o nall y as d osa ge i ncrease d o ver t he 0. 5 t o 2 0 m g/ k g/ da y ra n ge. 
E x p os ure t o P L X 3 3 9 7 was c o nsiste ntl y sli g htl y hi g her f or fe males t ha n f or males ( u p t o 1. 8-f ol d 
f or A U Cl ast). T here were n o test article-relate d cli nical o bser vati o ns or effects o n b o d y wei g hts, 
f o o d c o ns u m pti o n, o p ht hal mic e xa mi nati o ns, uri nal ysis, or macr osc o pic e xa mi nati o ns. 
At 2 0 m g/ k g/ da y, P L X 3 3 9 7 was ass ociate d wit h cli nical pat h ol o g y c ha n ges s u g gesti ve of a ne mia 
(er yt hr o n c ha n ges) ge neralize d stress (l y m p h o pe nia a n d e osi n o pe nia), de h y drati o n ( hi g her 
al b u mi n, gl o b uli n, a n d t otal pr otei n), hi g her A S T a n d A L T, hi g her fi bri n o ge n, calci u m, a n d 
c h olester ol i n males, a n d l o wer p otassi u m i n fe males. A d diti o nall y, l o wer a bs ol ute a n d relati ve 
s plee n a n d t h y m us wei g hts were n ote d f or b ot h se xes. Micr osc o picall y, males were o bser ve d 
wit h mi ni mal t o mil d acc u m ulati o n of pi g me nt rese m bli n g he m osi deri n i n t he pr o xi mal t u b ules 
of t he ki d ne y w hic h was c o nsiste nt wit h t he o bser ve d a ne mia, mi ni mal or m o derate 
he pat ocell ular vac u olati o n, a n d mil d t h y mic atr o p h y. A ni mals fr o m b ot h se xes were n ote d wit h 
mil d t o m o derate ge neralize d b o ne marr o w de pleti o n a n d mi ni mal t o m o derate he m osi deri n i n 
t he s plee n. F oll o wi n g a n 8 wee k rec o ver y peri o d, persiste nt effects c o nsiste d of mil d 
he pat ocell ular vac u olati o n i n 1 of 6 males a n d mil d he m osi deri n de p ositi o n i n t he s plee n of 5 of 
6 fe males. Ta ke n t o get her, t he o bser ve d a ne mia a n d b o ne marr o w de pleti o n are s u g gesti ve of a n 
a d verse effect o n t he he mat o p oietic s yste m, w hic h was re versi ble f oll o wi n g a n 8 - wee k rec o ver y 
peri o d. H e pat ocell ular vac u olati o n o bser ve d i n males was ass ociate d wit h hi g her A S T, A L T, a n d 
c h olester ol val ues at t he pri mar y necr o ps y, persiste d t o t he e n d of t he rec o ver y peri o d, a n d was 
c o nsi dere d a d verse. T here were n o hist ol o gic a b n or malities n ote d i n t he e pi di d y mi des or testes. 
T he N O A E L was c o nsi dere d t o be 4 m g/ k g/ da y. T his d osa ge le vel c orres p o n de d t o A U C last a n d 
C ma x  val ues of 1 1 4 4 0 n g• hr/ m L a n d 1 2 7 1 n g/ m L, res pecti vel y.  
7. 4. 2  
Re pe at - d ose T o xicit y i n D o gs 
7. 4. 2. 1  
4- wee k D o g St u dies  
I n t he i nitial G L P t o xicit y st u d y, gr o u ps of Bea gle d o gs were a d mi nistere d P L X 3 3 9 7 f or 2 8 da ys 
at d oses of 1 0 0, 3 0 0, a n d 1 0 0 0 m g/ k g/ da y w hic h was t he n re d uce d t o 5 0, 1 0 0, a n d 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
2 9  
Ple x xi k o n I nc.  
3 0 0 m g/ k g/ da y after t he first wee k d ue t o let har g y, wei g ht l oss, a n d lac k of f o o d c o ns u m pti o n i n 
se veral hi g h d ose a ni mals. Mea n e x p os ure ge nerall y i ncrease d as d osa ge i ncrease d. T here were 
n o test- article-relate d o p ht hal mic or macr osc o pic fi n di n gs or effects o n uri nal ysis, E C G or or ga n 
wei g ht para meters.  
T hree d o gs i n t he hi g h d ose gr o u p were e ut ha nize d i n e xtre mis o n st u d y da ys 8, 1 5, a n d 1 7 d ue 
t o pr ostrati o n, tre m ors, i m paire d c o or di nati o n, a n d tac h y p nea. E mesis a n d m o dest b o d y wei g ht 
decli nes were n ote d i n all gr o u ps wit h a n i ncrease d i nci de nce i n t he mi d a n d hi g h d ose gr o u ps. 
T hese c ha n ges c orrelate d wit h decrease d f o o d c o ns u m pti o n a n d were re versi ble d uri n g t he 
rec o ver y peri o d. 
C ha n ges i n he mat ol o g y para meters c o nsiste d of ti me- a n d d ose- relate d decli nes i n R B C mass 
a n d retic ul oc yte c o u nts. T he a ne mia i ncrease d i n se verit y at st u d y Wee k 4, des pite a re b o u n d i n 
a bs olute n u m bers of retic ul oc ytes. T hese effects were c o nsi dere d a d verse t h o u g h re versi ble, 
base d o n partial rec o ver y n ote d at st u d y Wee k 6. Hi g her fi bri n o ge n le vels were als o n ote d i n all 
d ose gr o u ps. . 
P L X 3 3 9 7 ca use d si g nifica nt, partiall y re versi ble testic ular atr o p h y at all t hree d oses. P L X 3 3 9 7-
relate d alterati o ns were less pr o mi ne nt i n t he o var y, p ossi bl y beca use m ost o varies were 
i m mat ure. Alterati o ns i n testes a n d o varies are li kel y relate d t o t he mec ha nis m of P L X 3 3 9 7-
me diate d i n hi biti o n of F ms a n d Kit ki nase. B o ne marr o w e x hi bite d a d ose- relate d mi ni mal t o 
mil d h y p ocell ularit y wit h rec o ver y. I n t he s plee ns, mi ni mal t o mil d i ncrease d e xtra me d ullar y 
he mat o p oiesis was n ote d i n all d ose gr o u ps. I n t he fe m ur, mi ni mal t o m o derate s u b p h yseal 
h y per ost osis was e vi de nt, c o nsi dere d a re versi ble c o nse q ue nce of p har mac ol o gic effect o n 
oste oclasts. L y m p h oi d de pleti o n was e vi de nt i n t he t h y m us, l y m p h n o des, Pe yer’s patc hes, a n d 
s plee n m ore fre q ue ntl y, c o m pare d t o ve hicle c o ntr ols. T hese effects were c o nsi dere d t o be 
sec on dar y t o P L X 3 3 9 7 -relate d n o ns pecific stress fact ors. 
D ue t o t he a d verse cli nical o bser vati o ns of e mesis -relate d fi n di n gs, b o d y wei g ht l osses wit h 
ass ociate d l o w f o o d c o ns u m pti o n, a n d micr osc o pic fi n di n gs of t he testes, b o ne marr o w, ki d ne ys, 
s plee n, a n d l y mp h oi d de pleti o n i n t he t h y m us, a N O A E L was n ot deter mi ne d. T his st u d y als o di d 
n ot esta blis h a let hal d ose i n 5 0 % of d o gs L D 5 0. 
A f oll o w- u p st u d y was c o m plete d at d oses of 1, 6 a n d 3 0 m g/ k g/ da y f or 2 8 c o nsec uti ve da ys, 
f oll o we d b y a rec o ver y peri o d of 8 wee ks. Mea n s yste mic e x p os ure i ncrease d as d osa ge 
i ncrease d o ver t he 1 t o 3 0 m g/ k g/ da y ra n ge. B o d y wei g hts, f o o d c o ns u m pti o n, cli nical pat h ol o g y 
para meters, a n d or ga n wei g hts were u naffecte d b y test article a d mi nistrati o n. T here were n o test 
article-relate d macr osc o pic fi n di n gs. I n t he 3 0 m g/ k g/ da y gr o u p, t here was a n i ncrease d 
i nci de nce of e mesis 4 h o urs p ost- d osi n g. Test article-relate d, c o m pletel y re versi ble, a d verse 
s per mat o g o nial/s per mat oc ytic de pleti o n a n d mi ni mal de pleti o n of r o u n d s per mati ds were n ote d 
i n t he 3 0 m g/ k g/ da y gr o u p males. Base d o n t he fi n di n gs of e mesis a n d re versi ble s per mat o g o nial 
de pleti o n, t he N O E L a n d N O A E L was 6  m g/ k g/ da y, c orres p o n di n g t o ge n der-c o m bi ne d A U Clast 
of 3 9 6 0 n g• h/ m L a n d C ma x  of 7 8 0 n g/ m L.  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 0  
Ple x xi k o n I nc.  
7. 4. 2. 2  
1 3- wee k St u d y  
I n t his G L P st u d y, d oses of 1, 6 a n d 3 0 m g/ k g/ da y were a d mi nistere d f or 1 3 c o nsec uti ve wee ks 
wit h a n 8- wee k rec o ver y peri o d. S yste mic e x p os ure t o P L X 3 3 9 7 ge nerall y i ncrease d 
pr o p orti o nall y as d osa ge i ncrease d. T here were n o test article -relate d macr osc o pic fi n di n gs. 
B o d y wei g hts, f o o d c o ns u m pti o n, o p ht hal mic, a n d electr ocar di o gra p h y para meters were 
u naffecte d b y test article a d mi nistrati o n. T here was a hi g h i nci de nce of e mesis f or t he 
3 0 m g/ k g/ da y gr o u p w hic h was n ot c o nsi dere d a d verse d ue t o t he a bse nce of effects o n b o d y 
wei g ht or f o o d c o ns u m pti o n. 
A d verse test article -relate d micr osc o pic fi n di n gs c o nsiste d of m o derate t o se vere de pleti o n of t he 
s per mat o g o nia, s per mat oc ytes, r o u n d s per mati ds, a n d/ or el o n gate s per mati ds i n t he testes, 
m o derate h y p os per mat o ge nesis, a n d m o derate or se vere h y p os per mia i n t he e pi di d y mi des of all 
3 0 m g/ k g/ da y gr o u p males at t he st u d y wee k 1 3 pri mar y necr o ps y. Q ualitati vel y, 
s per mat o ge nesis was n or mal i n all ot her males, base d u p o n e val uati o ns of P A S H-stai ne d tiss ue 
secti o ns. T hese alterati o ns were re versi ble wit hi n a n 8-wee k rec o ver y i nter val. T he N O A E L was 
6 m g/ k g/ da y f or males, c orres p o n di n g t o a n A U C last of 3 0 3 9 n g• h/ m L a n d C ma x  of 5 7 5 n g/ m L, 
a n d 3 0 m g/ k g/ da y f or fe males, c orres p o n di n g t o a n A U C last of 1 7 9 4 0 n g• h/ m L a n d C ma x  of 
1 9 4 8 n g/ m L. 
7. 5  
Pre vi o us H u m a n E x perie nce  
T he o n g oi n g P hase 1 d ose escalati o n st u d y P L X 1 0 8- 0 1 i n patie nts wit h s oli d t u m ors is desi g ne d 
t o e val uate t he safet y a n d P K of P L X 3 3 9 7. As of J u ne 2 0 1 2, a t otal of 6 2 patie nts ha ve bee n 
treate d wit h P L X 3 3 9 7, i ncl u di n g 4 1 patie nts i n t h e d ose escalati o n c o h orts a n d 2 1 patie nts i n t he 
E xte nsi o n c o h orts. T he rec o m me n de d P hase 2 d ose has bee n esta blis he d at 1 0 0 0 m g/ da y. Plas ma 
c o nce ntrati o ns of P L X 3 3 9 7 de m o nstrate a T ma x  of a p pr o xi matel y 2 h o urs, a mea n eli mi nati o n 
half-life of a p pr o xi matel y 2 0 h o urs, a n d a mea n acc u m ulati o n rati o c o m pare d t o Da y 1 val ues of 
a p pr o xi matel y 2-f ol d. I n ge neral, t here is i ncreasi n g e x p os ure wit h i ncreasi n g d ose. Ot her si n gle 
a ge nt st u dies o n g oi n g or c o m plete d i ncl u de refract or y H o d g ki n l y m p h o ma, Flt 3- I T D + A M L, 
castrate-resista nt pr ostate ca ncer, a n d rec urre nt G B M. C o m bi nati o n st u dies wit h paclita xel a n d 
Eri b uli n are als o o n g oi n g. 
I n t he rec urre nt G B M st u d y, as of 1 3-Dec - 2 0 1 2, a t otal of 3 4 patie nts ha ve bee n e nr olle d. Of 
t hese, 2 3 patie nts ha ve disc o nti n ue d st u d y dr u g d ue t o pr o gressi ve disease ( n = 2 1) or S A Es 
( n = 2). A t otal of 1 1 patie nts are o n g oi n g, wit h 6 patie nts t o be recr uite d. I n ge neral, t he 
t olera bilit y of st u d y dr u g i n t his patie nt p o p ulati o n has bee n si milar t o ot her patie nts wit h s oli d 
t u m ors, wit h fe w patie nts re q uiri n g dr u g h oli da ys or d ose re d ucti o ns. I m p orta ntl y, t he 
c o nce ntrati o n of P L X 3 3 9 7 meas ure d i n t he t u m or tiss ue of t he 1 2 patie nts treate d wit h 7 da ys of 
ne oa dj u va nt t hera p y was si milar t o plas ma c o nce ntrati o ns, c o nfir mi n g t he r o b ust pe netrati o n of 
P L X 3 9 9 7 acr oss t he bl o o d brai n barrier i n h u ma ns wit h G B M. 
As of J u ne 2 0 1 2, a t otal of 1 0 7 patie nts ha ve bee n treate d t o date. T here ha ve bee n n o safet y 
si g nals i n vital si g ns, p h ysical e xa mi nati o ns, or E C Gs (i ncl u di n g caref ul e val uati o n of p ote ntial 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 1  
Ple x xi k o n I nc.  
Q T pr ol o n gati o n). At d ose le vels of ≥6 0 0 m g/ da y, tra nsie nt i ncreases i n A S T a n d/ or A L T ha ve 
bee n o bser ve d i n a p pr o xi matel y half t he patie nts. A m o n g t he 9 2 patie nts wit h s oli d t u m ors 
treate d t o date, t he m ost c o m m o n A Es of all gra des ha ve bee n fati g ue, decrease d a p petite, 
na usea, v o miti n g, a ne mia, hair c ol or c ha n ge ( de pi g me ntati o n), a n d diarr hea. Wit h t he e xce pti o n 
of v o miti n g a n d diarr hea, m ost of t hese A Es ha ve bee n c o nsi dere d p ossi bl y or pr o ba bl y 
treat me nt-relate d. I n t he A M L st u d y ( P L X 1 0 8- 0 5; n = 1 5), t he m ost c o m m o n A Es t o date ha ve 
bee n fati g ue, fe brile ne utr o pe nia, decrease d a p petite, na usea, diarr hea, a n d v o miti n g. I n all 
st u dies, dr u g-relate d Gra de 3 a d verse e ve nts ha ve bee n ver y u nc o m m o n. F or m ore details 
c o ncer ni n g safet y, please c o ns ult t he I n vesti gat or’s Br oc h ure. 
A n u m ber of res p o nse bi o mar kers are bei n g assa ye d t o pr ofile t he i n hi bit or y acti vit y of P L X 3 3 9 7 
o n F ms a n d Kit acti vit y as a f u ncti o n of d ose a n d e x p os ure. T hese bi o mar kers i ncl u de circ ulati n g 
t u m or cell ( C T C) a n d C D 1 4 +/ C D 1 6 + pr oi nfla m mat or y macr o p ha ge cell n u m bers; ser u m I L- 6, 
I L- 1 beta a n d M M P 3 c o nce ntrati o ns; a n d mar kers of oste oclast acti vit y. M ost of t he s ol u ble 
mar kers are n ot ele vate d at Baseli ne i n t he o nc ol o g y patie nts treate d t o date, s o n o decrease wit h 
treat me nt ca n be a ntici pate d. H o we ver, i n 5 patie nts t o date, C T C c o u nts were ele vate d at 
Baseli ne. I n 3 of t h ose 5 patie nts, C T C val ues decrease d after treat me nt wit h P L X 3 3 9 7.  
Re d ucti o ns i n t he C D 1 4 +/ C D 1 6 + cell p o p ulati o ns ha ve als o bee n o bser ve d i n all patie nts treate d 
t o date. Ser u m C S F - 1 le vels ha ve i ncrease d i n all patie nts after i nitiati o n of P L X 3 3 9 7 d osi n g, as 
w o ul d be a ntici pate d fr o m F ms i n hi biti o n, res ulti n g i n re d uce d cleara nce of t he li ga n d. 
I m p orta ntl y, hi g her plas ma P L X 3 3 9 7 c o nce ntrati o ns are ass ociate d wit h hi g her ele vati o ns of 
C S F - 1, s u p p orti n g a c o nce ntrati o n- de pe n de nt pat h wa y i n hi biti o n. Uri nar y N T X c o nce ntrati o ns 
s h o we d a c o nce ntrati o n-de pe n de nt decrease fr o m Baseli ne, c o nsiste nt wit h oste oclast i n hi biti o n. 
Cli nicall y rele va nt i ncreases i n a di p o necti n were al s o o bser ve d, wit h 2- 3 f ol d i ncreases fr o m 
Baseli ne ge nerall y o bser ve d i n patie nts treate d at d ose le vels of 9 0 0 m g/ da y a n d hi g her. 
A p pr o xi matel y half of patie nts treate d at d oses of ≥6 0 0  m g/ da y ha ve ha d a m o dest ele vati o n of 
A S T a n d A L T. D uri n g t he first 4 wee ks, t he tra nsa mi nases te n d t o i ncrease t o a p pr o xi matel y 
1. 5 x U L N wit h o ut s y m pt o ms or i ncreases i n A L P or bilir u bi n. T he n t he tra ns mi nases te n d t o 
decrease a gai n a n d ret ur n t o Baseli ne or re mai n sli g htl y ele vate d wit hi n t he n or mal ra n ge. We 
belie ve t his patter n of mil d i ncrease, o bser ve d i n t he hi g h d ose t o xic ol o g y st u dies as well, is d ue 
t o tar get i n hi biti o n of C S F 1 R i n t he K u pffer cells t hat are res p o nsi ble f or cleari n g tra ns mi nases 
t hat lea k fr o m he pat oc ytes a n d ot her tiss ues i n t he b o d y. O ver ti me, t here a p pears t o be a n 
a da pti ve res p o nse f or t he m ost part. N o net heless, s o me patie nts ca n s h o w G 3 ele vati o ns t hat 
re q uire a dr u g h oli da y a n d p ossi ble d ose re d ucti o n. 
O ne i m p orta nt P D bi o mar ker is hair de pi g me ntati o n t hat has bee n o bser ve d i n virt uall y all 
patie nts w h o ha ve dar k hair at Baseli ne a n d recei ve d d oses of 6 0 0  m g/ da y or hi g her. T his is 
belie ve d d ue t o Kit i n hi biti o n, d ue t o its r ole i n mela n o ge nesis. T here is n o l oss of hair, a n d t he 
de pi g me ntati o n a p pears t o be c o m pletel y re versi ble wit h dr u g disc o nti n uati o n. Beca use 
P L X 3 3 9 7 is e q ui p ote nt o n C S F 1 R a n d Kit, t his c ha n ge ca n be c o nsi dere d a relia ble bi o mar ker of 
tar get i n hi bitio n. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 3  
Ple x xi k o n I nc.  
Fi g ure  3:  
P L X 3 3 9 7 I n hi bits Micr o gli a/ M acr o p h a ge Recr uit me nt t o G L 2 6 1 
T u m ors i n Vi v o  
 
N ote:  Scale bar = 1 0 0 μ m; * p < 0. 0 0 1 c o m pare d wit h c o ntr ol)  
Gr o wi n g e vi de nce i n t he literat ure s u g gests t hat macr o p ha ges a n d micr o glial cells are recr uite d 
b y t u m or cells as a resista nce mec ha nis m i n res p o nse t o ra di ot hera p y ( A h n  2 0 1 0). Acc or di n gl y, 
i n s u bc uta ne o usl y i m pla nte d R M-1 s y n ge neic pr ostate ca ncer t u m or cells, t here is e n ha nce d 
recr uit me nt of b ot h t u m or ass ociate d macr o p ha ges ( T A Ms) a n d m yel oi d deri ve d s u p press or cells 
( M D S Cs) after 5 da ys of irra diati o n. I n t his m o del, irra diati o n has a m o dest effect o n t u m or 
gr o wt h, a n d P L X 3 3 9 7 treat me nt has esse ntiall y n o si n gle a ge nt effect. H o we ver, t he c o m bi nati o n 
pr o vi des hi g hl y s y ner gistic t u m or c o ntr ol as s h o w n i n Fi g ure 4  ( pa nel A). T he relati ve resista nce 
t o irra diati o n a p pears t o c orrelate wit h hi g her le vels of T A Ms ( pa nels B, D) a n d M D S Cs ( pa nels 
C, E) i n b ot h t u m or a n d s plee n. P L X 3 3 9 7 s u bsta ntiall y re d uces le vels of T A Ms a n d M D S Cs, a n d 
bl oc ka de of t hese cells li kel y lea ds t o ra di ose n sitizati o n. T hese res ults al o n g wit h o n g oi n g 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 4  
Ple x xi k o n I nc.  
st u dies c o m bi ni n g irra diati o n wit h P L X 3 3 9 7 i n gli o blast o ma a ni mal m o dels str o n gl y s u p p ort t he 
cli nical e val uati o n of P L X 3 3 9 7 as a ra di ose nsitizi n g a nti-t u m or a ge nt. 
Fi g ure  4:  
P L X 3 3 9 7 I n hi bits R M- 1 T u m or Re gr o wt h After Irr a di ati o n i n Vi v o 
 
I n a preli mi nar y st u d y, t he ra di ose nsitizi n g acti vit y of P L X 3 3 9 7 has bee n e x pl ore d directl y i n a 
m o use m o del of gli o blast o ma. I n t his m o del, U 2 5 1 gli o blast o ma cells are i m pla nte d 
ort h ot o picall y wit hi n t he cra ni u m or n u de mice. T his st u d y i ncl u de d 4 gr o u ps:  ( 1) C o ntr ol, ( 2) 
P L X 3 3 9 7 al o ne dail y f or 6 wee ks, ( 3) W h ole brai n Irra diati o n wit h 1 2 G y, a n d ( 4) W h ole brai n 
Irra diati o n wit h 1 2 G y wit h P L X 3 3 9 7 gi ve n dail y f or 6 wee ks starti n g t he da y of irra diati o n. As 
s h o w n i n Fi g ure 5 , t he c o m bi nati o n of P L X 3 3 9 7 wit h irra diati o n is clearl y s y ner gistic. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 5  
Ple x xi k o n I nc.  
Fi g ure 5:  
P L X 3 3 9 7 S y ner gizes wit h Irr a di ati o n i n t he U 2 5 1 Gli o bl ast o m a 
M o del  
 
8. 0  
R A TI O N A L E  
As desc ri be d a b o ve, t here is a str o n g rati o nale f or t he use of a selecti ve F ms i n hi bit or t o decrease 
t he r ole of acti vate d micr o glia i n G B M a n d t o i ncrease t he efficac y of ra diati o n a n d c o nc urre nt 
te m oz ol o mi de. T his st u d y will pr o vi de a n assess me nt of t he safet y a n d efficac y of P L X 3 3 9 7 
a d de d t o sta n dar d ra diati o n a n d te m oz ol o mi de i n patie nts wit h ne wl y dia g n ose d G B M, c o m pare d 
t o hist orical c o ntr ol data. 
8. 1  
R o ute a n d Re gi me n  
P L X 3 3 9 7 will be a d mi nistere d orall y t wice dail y i n ca ps ule f or m at t he d ose descri be d i n 
Secti o n  1 3. 1 3. 
8. 2  
Tre at me nt Peri o d  
T here are 4 se q ue ntial peri o ds:  1 - wee k P L X 3 3 9 7 m o n ot hera p y; 6-wee k P L X 3 3 9 7/ R T/ T M Z 
c o m bi nati o n t hera p y; 4- wee k rec o ver y; a n d, P L X 3 3 9 7/ T M Z a dj u va nt t hera p y. P L X 3 3 9 7st u d y 
dr u g will be a d mi nistere d t wice dail y eit her 7 da ys/ wee k or 5 da ys/ wee k ( M o n da y t hr o u g h 
Fri da y) starti n g 1 wee k pri or t o t he i nitiati o n of R T a n d will c o nti n ue t wice dail y eit her 
7 da ys/ wee k or 5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) d uri n g t he 6- wee k c o urse of R T. F o ur 
wee ks after t he c o m pleti o n of t he c o urse of R T, patie nts will be starte d o n o nce- dail y a dj u va nt 
te m oz ol o mi de ( Da y 1- 5 of a 2 8 da y c ycle) f or u p t o 1 2 c ycles as l o n g as t here is n o disease 
pr o gressi o n or u nacce pta ble t o xicit y a n d P L X 3 3 9 7 t wice dail y ( 2 8 da ys of a 2 8 da y c ycle) f or as 
l o n g as t here is n o disease pr o gressi o n or u nacce pta ble t o xicit y. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 6  
Ple x xi k o n I nc.  
9. 0  
O B J E C TI V E S  
T he st u d y o bjecti ves are t o assess t he p ote ntial f or P L X 3 3 9 7 t o i m pr o ve t he efficac y of sta n dar d 
of care ra diati o n t hera p y ( R T) + te m oz ol o mi de i n patie nts wit h ne wl y dia g n ose d gli o blast o ma 
( G B M). F or P hase 1 b d ose escalati o n, t he pri mar y o bjecti ve is i de ntificati o n of t he 
rec o m me n de d P hase 2 d ose ( R P 2 D). F or P hase 2, t he pri mar y o bjecti ve is t he c o m paris o n of 
me dia n Pr o gressi o n Free S ur vi val ( P F S) t o hist orical c o ntr ol. Sec o n dar y o bjecti ves i ncl u de t he 
e val uati o n of o verall s ur vi val ( O S), p har mac o ki netics ( P K), c orrelati ve i ma gi n g st u dies, safet y, 
a n d t he e x pl orat or y e n d p oi nt of p har mac o d y na mic ( P D) effects of P L X 3 3 9 7. 
1 0. 0  
D E SI G N  
1 0. 1  
Descri pti o n  
T his will be a n o pe n la bel, u nc o ntr olle d P hase 1 b/ 2 trial i n patie nts wit h ne wl y dia g n ose d G B M 
w h o ha ve rec o vere d fr o m fr o m c o m plete or partial s ur gical resecti o n. All patie nts will be treate d 
wit h P L X 3 3 9 7 i n a d diti o n t o sta n dar d- of-care c o m bi nati o n ra diati o n t hera p y ( R T) pl us 
te m oz ol o mi de ( T M Z) f oll o we d b y a dj u va nt T M Z. D uri n g P hase 1 b d ose escalati o n, t w o 
P L X 3 3 9 7 a d mi nistrati o n sc he d ules, 7 da ys/ wee k vs. 5 da ys/ wee k ( M- F) will be e x pl ore d. D uri n g 
P hase 2, patie nts will be treate d wit h t he R P 2 D. 
T here are 4 se q ue ntial peri o ds:  1 -wee k P L X 3 3 9 7 m o n ot hera p y; 6- wee k P L X 3 3 9 7/ R T/ T M Z 
c o m bi nati o n t hera p y; 4- wee k rec o ver y; a n d, P L X 3 3 9 7/ T M Z a dj u va nt t hera p y. P L X 3 3 9 7 will be 
a d mi nistere d t wice dail y eit her 7 da ys/ wee k or 5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) starti n g 
1 wee k pri or t o t he i nitiati o n o f R T a n d will c o nti n ue t wice dail y eit her 7 da ys/ wee k or 
5 da ys/ wee k ( M o n da y t hr o u g h Fri da y) d uri n g t he 6- wee k c o urse of R T.  
P hase 1 b P L X 3 3 9 7 d ose a n d sc he d ule c o h orts are s h o w n i n Ta ble  2. 
A detaile d Trial Fl o w C hart is a vaila ble i n  Secti o n 6. 0 , a n d pr oce d ures b y st u d y da y are pr o vi de d 
i n Secti o n 1 3. 0 . 
1 0. 2  
N u m ber of P atie nts  
F or t he P hase 1 b p orti o n of t he st u d y, 5 c o h orts ( 2 c o h orts fr o m A me n d me nt 1 a n d 3 fr o m 
A me n d me nt 2) are pla n ne d t o be e nr olle d. Eac h c o h ort will c o nsist of a p pr o xi matel y 7 patie nts. 
T heref ore, a p pr o xi matel y 3 5 patie nts will be e nr olle d i n P hase 1 b. A d diti o nal patie nts ma y be 
re q uire d f or re place me nt patie nts, or if l o wer d ose c o h orts ( 6 0 0 m g or 4 0 0 m g) are re q uire d. 
P hase 2 will e nr oll a p pr o xi matel y 4 4 patie nts. 
1 0. 3  
N u m ber of St u d y Ce nters  
T he st u d y will be perf or me d at a p pr o xi matel y 7- 1 0 sites.  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 7  
Ple x xi k o n I nc.  
1 0. 4  
D ur ati o n of P atie nt P artici p ati o n  
Eac h patie nt will be offere d c o nti n ue d d osi n g wit h P L X 3 3 9 7 a n d sta n dar d te m oz ol o mi de u p t o 
1 2 c ycles of a dj u va nt treat me nt after ra diati o n if t his is well t olerate d a n d t here is n o disease 
pr o gressi o n. 
1 0. 5  
D ur ati o n of St u d y  
T he d urati o n of t he P hase 1 b p orti o n of t he st u d y will de pe n d o n t he n u m ber of c o h orts re q uire d 
a n d t he nee d f or re place me nt patie nts. F or t he P hase 2 p orti o n of t he st u d y, a recr uit me nt rate of 
1 patie nt per site per m o nt h is a ntici pate d. T he t otal d urati o n of e nr oll me nt is e x pecte d t o be 
a p pr o xi matel y 1 8 m o nt hs. T he d urati o n of f oll o w- u p will de p e n d o n t he pr ol o n gati o n of t he 
me dia n P F S; t he st u d y is p o were d t o detect a me dia n P F S of a p pr o xi matel y 8 m o nt hs. 
1 1. 0  
S E L E C TI O N O F S T U D Y P O P U L A TI O N  
All patie nts m ust partici pate i n t he c o nse nt pr ocess. D uri n g t he c o nse nt pr ocess, t he pers o n 
o btai ni n g c o nse nt m ust i nf or m t he patie nt of all ele me nts of i nf or me d c o nse nt. N o pr ot oc ol-
s pecific pr oce d ures, i ncl u di n g scree ni n g pr oce d ures, are t o be perf or me d u ntil t he patie nt has 
si g ne d a n d date d a n i nstit uti o nal re vie w b oar d (I R B)/i n de pe n de nt et hics c o m mittee (I E C)-
a p pr o ve d i nf or me d c o nse nt f or m. T he st u d y be gi ns wit h t he si g ni n g a n d dati n g of t he i nf or me d 
c o nse nt f or m. Patie nts m ust als o meet t he i ncl usi o n a n d e xcl usi o n criteria t o be e nr olle d i n t he 
st u d y. 
1 1. 1  
I ncl usi o n Criteri a 
1.  
Male or fe male patie nts ≥1 8 years ol d.  
2.  
Hi st ol o gicall y c o nfir me d defi niti ve G B M or gli osarc o ma b y partial or c o m plete s ur gical 
resecti o n (i.e. n ot b y bi o ps y o nl y) wit hi n 5 wee ks pri or t o P L X 3 3 9 7 a d mi nistrati o n 
( C 1 D 1). T u m or m ust ha ve a s u prate nt orial c o m p o ne nt. F or all patie nts, a vaila bilit y of a n  
arc hi val paraffi n t u m or bl oc k s ufficie nt t o ge nerate at least 2 0 u nstai ne d sli des; or, if a 
paraffi n t u m or bl oc k is u na vaila ble, at least 2 0 u nstai ne d sli des . 
3.  
T he patie nt m ust ha ve rec o vere d fr o m t he effects of s ur ger y, p ost -o perati ve i nfecti o n, a n d 
ot her  c o m plicati o ns bef ore st u d y re gistrati o n.  
a. A dia g n ostic c o ntrast -e n ha nce d M RI or C T sca n of t he brai n m ust be perf or me d 
pre o perati vel y a n d p ost o perati vel y pri or t o t he i nitiati o n of ra di ot hera p y, i.e., wit hi n 
2 8  da ys ( 1 4 da ys preferre d) pri or t o st u d y dr u g a d mi nistrati o n ( C 1 D 1).  
b.  Patie nts u na ble t o u n der g o M R i ma gi n g beca use of n o n -c o m pati ble de vices ca n be 
e nr olle d, pr o vi de d pre - a n d p ost-o perati ve c o ntrast -e n ha nce d C T sca ns are o btai ne d a n d 
are of s ufficie nt q ualit y.  
2.  Patie nts m ust recei ve R T at t he partici p ati n g i nstit uti o n. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 8  
Ple x xi k o n I nc.  
3.  W o me n of c hil d- beari n g p ote ntial m ust ha ve a ne gati ve pre g na nc y test wit hi n 1 4 da ys of 
i nitiati o n of d osi n g a n d m ust a gree t o use a n acce pta ble met h o d of birt h c o ntr ol w hile o n 
st u d y dr u g a n d f or 3 m o nt hs after t he last d ose. W o me n of n o n-c hil d beari n g p ote ntial ma y be 
i ncl u de d if t he y are eit her s ur gicall y sterile or ha ve bee n p ost me n o pa usal f or ≥1 year. Me n of 
c hil d- beari n g p ote ntial m ust als o a gree t o use a n acce pta ble met h o d of birt h c o ntr ol w hile o n 
st u d y dr u g, a n d f or 3 m o nt hs after t he last d ose. 
4.  Kar n ofs k y perf or ma nce stat us of ≥7 0.  
5.  A de q uate he mat ol o gic, he patic, a n d re nal f u ncti o n (a bs ol ute ne utr o p hil c o u nt ≥1. 5 x 1 0 9/ L, 
H g b > 1 0 g/ d L, platelet c o u nt ≥1 0 0 x 1 0 9/ L, A S T/ A L T ≤2. 5 x U L N, creati ni ne ≤1. 5 x U L N). 
6.  Willi n g a n d a ble t o pr o vi de writte n i nf or me d c o nse nt pri or t o a n y st u d y relate d pr oce d ures 
a n d t o c o m pl y wit h all st u d y re q uire me nts.  
1 1. 2  
E xcl usi o n Criteri a  
1.  E vi de nce of rec urre nt G B M or metastases detecte d o utsi de of t he cra nial va ult.  
2.  I n vesti gati o nal dr u g use wit hi n 2 8 da ys of t he first d ose of P L X 3 3 9 7 or c o nc urre ntl y. 
3.  Pri or use of Gli a del wafers or a n y ot her i ntrat u m oral or i ntraca vitar y treat me nt.  
4.  Pri or ra diati o n or c he m ot hera p y f or gli o blast o ma or gli o ma. 
5.  Pri or c he m ot hera p y or ra di ose nsitizers f or ca ncer of t he hea d a n d nec k (e xce pt f o r T 1 gl ottic 
ca ncer) t hat w o ul d res ult i n a n o verla p of ra diati o n fiel ds. 
6.  Pri or aller gic reacti o n t o te m oz ol o mi de.  
7.  Hist or y of Gra de 2 ( C T C A E v 4) or greater ac ute i ntracra nial he m orr ha ge. 
8.  Acti ve ca ncer (eit her c o nc urre nt or wit hi n t he last 3 years) t hat re q uires n o n -s ur gical t hera p y 
(e. g. c he m ot hera p y or ra diati o n t hera p y), wit h t he e xce pti o n of s ur gicall y treate d basal or 
s q ua m o us cell carci n o ma of t he s ki n, mela n o ma i n-sit u, or carci n o ma i n-sit u of t he cer vi x. 
9.  C hr o nic acti ve he patitis B or C. 
1 0.  Refract or y na usea a n d v o miti n g, mala bs or pti o n, biliar y s h u nt, or si g nifica nt b o wel resecti o n 
t hat w o ul d precl u de a de q uate a bs or pti o n of st u d y dr u g. 
1 1.  Patie nts wit h seri o us ill nesses, u nc o ntr olle d i nfecti o n, me dical c o n diti o ns, or ot her me dical 
hist or y i ncl u di n g a b n or mal la b orat or y res ults, w hic h i n t he i n vesti gat or’s o pi ni o n w o ul d be 
li kel y t o i nterfere wit h a patie nt’s partici pati o n i n t he st u d y, or wit h t he i nter pretati o n of t he 
res ults. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
3 9  
Ple x xi k o n I nc.  
1 2.  W o me n of c hil d- beari n g p ote ntial w h o are pre g na nt or breast fee di n g. 
1 3.  At Scree ni n g Q Tc F ≥4 5 0 msec f or males a n d ≥4 7 0 msec f or fe males. 
1 1. 3  
Scree n F ail ures  
Patie nts w h o si g n a n i nf or me d c o nse nt f or m, are n ot assi g ne d t o a treat me nt, a n d d o n ot recei ve 
st u d y dr u g are defi ne d as scree n fail ures. F or all scree n fail ures, t he i n vesti gat or is t o mai ntai n a 
scree ni n g l o g t hat d oc u me nts t he scree ni n g n u m ber, patie nt i nitials, a n d reas o n(s) f or scree n 
fail ure. T his i nf or mati o n will be trac ke d i n t he E D C s yste m a n d retai ne d i n t he i n vesti gat or's 
st u d y files. 
1 2. 0  
C O N C O MI T A N T T R E A T M E N T  
C o nc o mita nt treat me nt is per mitte d if t he me dicati o n is n ot e x pecte d t o i nterfere wit h t he 
e val uati o n of safet y or efficac y of t he st u d y dr u g. D uri n g t he st u d y, if t he use of a n y c o nc o mita nt 
treat me nt bec o mes necessar y (e. g., f or treat me nt of a n a d verse e ve nt), t he treat me nt m ust be 
rec or de d o n t he e C R F, i ncl u di n g t he reas o n f or treat me nt, ge neric na me of t he dr u g, d osa ge, 
r o ute, a n d date of a d mi nistrati o n. 
Patie nts e nr olli n g i n st u dies wit h P L X 3 3 9 7 w h o are als o recei vi n g c o nc o mita nt warfari n s h o ul d 
ha ve t heir a nti-c oa g ulati o n stat us caref ull y m o nit ore d, es peciall y s h ortl y after i nitiati o n of 
P L X 3 3 9 7, f or t he p ote ntial nee d t o ma ke a dj ust me nts i n warfari n d osi n g. I n partic ular, I N R 
s h o ul d be o btai ne d j ust pri or t o i nitiati o n of P L X 3 3 9 7, wit hi n 1- 2 wee ks after i nitiati o n, a n d 
peri o dicall y t hereafter. D ose a dj ust me nts of warfari n s h o ul d be ma de as me dicall y i n dicate d.  
Alt h o u g h P L X 3 3 9 7 d oes n ot a p pear t o i n hi bit C Y P dr u g- meta b olizi n g e nz y mes t o a n i m p orta nt 
e xte nt, ca uti o n is warra nte d w he n a d mi nisteri n g P L X 3 3 9 7 t o s u bjects ta ki n g dr u gs t hat are 
hi g hl y de pe n de nt o n C Y P 3 A 4 f or meta b olis m a n d ha ve a narr o w t hera pe utic i n de x. It is n ot 
k n o w n w het her s yste mic e x p os ure t o t hese me dicati o ns will de m o nstrate a n i ncrease w hile 
patie nts are recei vi n g P L X 3 3 9 7. 
Of t he fi ve maj or C Y P is of or ms, 3 A 4 ( B F C) ma y be i n v ol ve d i n P hase I meta b olis m of 
P L X 3 3 9 7, wit h p ossi bl y C Y P 1 A 2 pl a yi n g a mi n or r ole. U ntil i nf or mati o n re gar di n g e x p os ure-
t o xicit y a n d e x p os ure-res p o nse relati o ns hi ps are a vaila ble wit h P L X 3 3 9 7, c o nc o mita nt C Y P 3 A 4 
i n hi bit ors a n d i n d ucers s h oul d be a d mi nistere d wit h ca uti o n, i n t he e ve nt t he y alter t he s yste mic 
e x p os ure t o P L X 3 3 9 7 (see Attac h me nt 2  f or a list of str o n g C Y P 3 A 4 i n hi bit ors a n d i n d ucers). I n 
ge neral, str o n g i n hi bit ors or i n d ucers of C Y P 3 A 4 s h o ul d be a v oi de d u nless a bs ol utel y necessar y. 
T hese i ncl u de a ntic o n v ulsa nts ( p he n yt oi n, car ba maze pi ne, p he n o bar bital), m yci n a nti micr o bials, 
a n d a ntiretr o virals. Str o n g C Y P 3 A 4 i n d ucers or i n hi bit ors s h o ul d be disc o nti n ue d at least 
1 4 da ys pri or t o t he i nitiati o n of d osi n g wit h P L X 3 3 9 7. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 0  
Ple x xi k o n I nc.  
1 3. 0  
P R O C E D U R E S  
1 3. 1  
Scree ni n g E v al u ati o n  
Wit hi n 2 1 da ys bef ore st u d y dr u g a d mi nistrati o n o n C 1 D 1 t o ra diati o n t hera p y, all patie nts will 
ha ve a Scree ni n g e val uati o n t hat i ncl u des t he f oll o wi n g: 
[ N ote:  Safet y assess me nts o btai ne d as Sta n dar d of Care ma y be use d f or scree ni n g p ur p oses.] 
1.  Si g n a n d date a n I R B/I E C-a p pr o ve d i nf or me d c o nse nt f or m bef ore a n y st u d y- s pecific 
scree ni n g pr oce d ures are perf or me d. 
2.  Me dical hist or y. 
3.  Hei g ht, wei g ht, vital si g ns (sitti n g bl o o d press ure, p ulse rate, res pirat or y rate, a n d 
te m perat ure), a n d p h ysical e xa mi nati o n. 
4.  Sta n dar d 1 2- lea d E C G. 
5.  Cli nical la b orat or y e val uati o n [ he mat ol o g y, c he mistr y, ser u m pre g na nc y test ( w o me n of 
c hil d-beari n g p ote ntial); see Attac h me nt 1 ]. Safet y assess me nts o btai ne d as Sta n dar d of 
Care ma y be use d f or scree ni n g p ur p oses.  
6.  A vaila bilit y of arc hi val paraffi n t u m or bl oc k s ufficie nt t o ge nerate at least 2 0 u nstai ne d 
sli des ( or at least 2 0 u nstai ne d sli des ). 
7.  Kar n ofs k y perf or ma nce stat us assess me nt.  
8.  M RI brai n sca n wi t hi n 2 8 da ys ( 1 4 da ys preferre d) of C 1 D 1. 
9.  Rec or di n g of c o nc o mita nt me dicati o ns. 
If scree ni n g tests a n d pr oce d ures are perf or me d wit hi n 2 da ys pri or t o C 1 D 1 P L X 3 3 9 7 
a d mi nistrati o n a n d t heir res ults are a vaila ble f or t he i n vesti gat or t o re vie w wit hi n t he 2 - da y 
peri o d pri or t o C 1 D 1 P L X 3 3 9 7 a d mi nistrati o n, t he scree ni n g tests a n d pr oce d ures t hat w o ul d be 
re peate d at C 1 D 1 d o n ot nee d t o be re peate d bef ore C 1 D 1 P L X 3 3 9 7 a d mi nistrati o n. 
Patie nts w h o d o n ot meet all i ncl usi o n a n d e xcl usi o n criteria will be n ote d as scree n fail ures i n 
t he E D C s yste m. 
1 3. 2  
C ycle 1 D a y 1 (- 2 D a ys), [ 4 wee k c ycle] 
T he C 1 D 1 visit m ust occ ur a n y M o n da y t hr o u g h Fri da y ≥3 wee ks a n d ≤5 wee ks si nce s ur ger y. 
At t his visit, all patie nts will ret ur n t o t he cli nic a n d u n der g o t he f oll o wi n g pr oce d ures:  
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 1  
Ple x xi k o n I nc.  
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c he mistr y).  
3.  F or P hase 1 b d ose escalati o n patie nts o nl y :  Pre- d ose bl o o d sa m ple c ollecti o n f or P K. 
4.  Pre - d ose bl o o d sa m ple c ollecti o n f or P D res p o nse bi o mar kers a n d C D 1 4/ 1 6 m o n o n uclear 
cell c o u nts. 
5.  Kar n ofs k y perf or ma nce stat us assess me nt.  
6.  M D A S y m pt o m I n ve nt or y. 
7.  Rec or di n g of c o nc o mita nt me dicati o ns. 
8.  I nitiati o n of d osi n g wit h st u d y dr u g eit her 7 da ys/ wee k or 5 da ys/ wee k ( M o n da y t hr o u g h 
Fri da y).  
9.  A E M o nit ori n g, be gi n ni n g after first d ose of st u d y dr u g. 
1 3. 3  
C ycle 1 D a y 8 ( ± 2 D a ys), [ 4 wee k c ycle] 
O n C 1 D 8, all patie nts will ret ur n t o t he cli nic a n d u n der g o t he f oll o wi n g pr oce d ures: 
1.  Vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n. 
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c h e mistr y). 
3.  F or P hase 1 b d ose escalati o n patie nts o nl y :  Pre- d ose a n d 1, 2, 4, a n d 6 h o urs p ost-d ose 
bl o o d sa m ple c ollecti o n f or P K. 
4.  Pre - d ose bl o o d sa m ple c ollecti o n f or P D res p o nse bi o mar kers a n d C D 1 4/ 1 6 m o n o n uclear 
cell c o u nts. 
5.  St u d y dr u g c o m plia nce. 
6.  Rec or di n g of c o nc o mita nt me dicati o ns. 
7.  A E m o nit ori n g.  
8.  I nitiati o n of ra diati o n t hera p y a n d te m oz ol o mi de. 
1 3. 4  
C ycle 1 D a y 1 5 ( ± 2 D a ys), [ 4 wee k c ycle] 
O n C 1 D 1 5, all patie nts will ret ur n t o t he cli nic a n d u n der g o t he f oll o wi n g pr oce d ures: 
1.  F or P hase 1 b d ose escalati o n patie nts o nl y:  Vital si g ns, ne ur ol o gical e xa m pl us 
s y m pt o m- directe d p h ysical e xa mi nati o n. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 2  
Ple x xi k o n I nc.  
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c he mistr y).  
3.  F or P hase 1 b d ose escalati o n patie nts o nl y :  Pre- d ose a n d 1, 2, 4, a n d 6 h o urs p ost-d ose 
bl o o d sa m ple c ollecti o n f or P K. 
4.  St u d y dr u g c o m plia nce. 
5.  Rec or di n g of c o nc o mita nt me dicati o ns. 
6.  A E m o nit ori n g.  
7.  I nstr uct patie nt t o o btai n C 1 D 2 2 ( ± 2 da ys) he mat ol o g y e val uati o n ( C B C, differe ntial 
c o u nt, platelet c o u nt) eit her at st u d y site or l ocal la b orat or y. 
1 3. 5  
C ycle 2 D a y 1 ( ± 2 D a ys), [ 3 wee k c ycle] 
O n C 2 D 1, all patie nts will ret ur n t o t he cli nic a n d u n der g o t he f oll o wi n g pr oce d ures: 
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n.  
2.  Sta n dar d 1 2- lea d E C G. 
3.  Cli nical la b orat or y e val uati o n ( h e mat ol o g y a n d ser u m c he mistr y). 
4.  Pre - d ose bl o o d sa m ple c ollecti o n f or P D res p o nse bi o mar kers. 
5.  Kar n ofs k y perf or ma nce stat us assess me nt.  
6.  St u d y dr u g c o m plia nce. 
7.  Rec or di n g of c o nc o mita nt me dicati o ns. 
8.  A E m o nit ori n g.  
9.  I nstr uct patie nt t o o btai n C 2 D 8 ( ± 2 da ys) a n d C 2 D 1 5 ( ± 2 da ys) he mat ol o g y e val uati o n 
( C B C, differe ntial c o u nt, platelet c o u nt) eit her at st u d y site or l ocal la b orat or y. 
1 3. 6  
C ycle 2 D a y 2 2 ( ± 2 D a ys), [ 3 wee k c ycle] 
O n C 2 D 2 2, all patie nts will ret ur n t o t he cli nic a n d u n der g o t he f oll o wi n g pr oce d ures: 
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n.  
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c he mistr y).  
3.  Kar n ofs k y perf or ma nce stat us assess me nt.  
4.  M D A S y m pt o m I n ve nt or y. 
5.  St u d y dr u g c o m plia nce. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 3  
Ple x xi k o n I nc.  
6.  Rec or di n g of c o nc o mita nt me dicati o ns.  
7.  A E m o nit ori n g.  
8.  I nstr uct patie nt t o o btai n R P D 8 ( ± 2 da ys) he mat ol o g y e val uati o n ( C B C, differe ntial 
c o u nt, platelet c o u nt) eit her at st u d y site or l ocal la b orat or y. 
1 3. 7  
D a y 1 of C ycle 3 ( ± 7 D a ys), [ 4 wee k c ycle] 
F oll o wi n g a 4 wee k rec o ver y peri o d, all patie nts will ret ur n t o t he cli nic o n C 3 D 1 a n d u n der g o 
t he f oll o wi n g pr oce d ures: 
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n.  
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c he mistr y).  
3.  Pre - d ose bl o o d sa m ple c ollecti o n f or P D res p o nse bi o mar kers. 
4.  Kar n ofs k y perf or ma nce stat us assess me nt.  
5.  M D A S y m pt o m I n ve nt or y. 
6.  M RI brai n sca n t o be o btai ne d at t he e n d of eac h e ve n - n u m bere d c ycle. 
7.  Re -i nitiati o n of st u d y dr u g d osi n g 7 da ys/ wee k. 
8.  I nitati o n of te mez ol o mi de a dj u va nt t hera p y. Te m oz ol o mi de is ta ke n orall y o nce dail y f or 
5 da ys f oll o we d b y 2 3 da ys wit h o ut treat me nt f or eac h c ycle be gi n ni n g wit h C 3 D 1. 
9.  Rec or di n g of c o nc o mita nt me dicati o ns. 
1 0.  A E m o nit ori n g.  
1 3. 8  
D a y 2 2 of C ycle 3 ( ± 2 D a ys), [ 4 wee k c ycle] 
O n C 3 D 2 2, all patie nts will ret ur n t o t he cli nic a n d u n der g o t he f oll o wi n g pr oce d ures: 
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n.  
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c he mistr y).  
3.  Kar n ofs k y perf or ma nce stat us assess me nt.  
4.  M D A  S y m pt o m I n ve nt or y. 
5.  St u d y dr u g c o m plia nce. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 4  
Ple x xi k o n I nc.  
6.  Rec or di n g of c o nc o mita nt me dicati o ns. 
7.  A E m o nit ori n g.  
1 3. 9  
D a y 2 2 of C ycle 4 + ( ± 7 D a ys), [ 4 wee k c ycle] 
O n Da y 2 2 of C ycle 4 a n d all s u bse q ue nt c ycles, all patie nts will ret ur n t o t he cli nic a n d u n der g o 
t he f oll o wi n g pr oce d ures: 
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n.  
2.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d ser u m c he mistr y).  
3.  Kar n ofs k y perf or ma nce stat us assess me nt.  
4.  M D A S y m pt o m I n ve nt or y. 
5.  M RI brai n sca n t o be o btai ne d at t he e n d of eac h e ve n- n u m bere d c ycle. 
6.  St u d y dr u g c o m plia nce. 
7.  Rec or di n g of c o nc o mita nt me dicati o ns. 
8.  A E m o nit ori n g.  
1 3. 1 0  Assess me nts After 0 1 Oct o ber 2 0 1 7 t o Be Perf or me d A p pr o xi m atel y E ver y 
1 2 Wee ks  
C o m me nci n g o n 0 1 Oct o ber 2 0 1 7, p atie nt visits, cli nic al l a b or at o r y testi n g, a n d M RI br ai n 
sc a ns will be perf or me d a p pr o xi m atel y e ver y 1 2 wee ks ( ple ase refer t o t he 
T RI A L  F L O W  C H A R T – P h ase 2  f or det ails). 
1 3. 1 1  E n d of Tre at me nt  
All patie nts w h o per ma ne ntl y disc o nti n ue P L X 3 3 9 7 are e x pecte d t o ret ur n t o t he cli nic wit hi n 
3 0 da ys a n d u n der g o t he f oll o wi n g pr oce d ures: 
1.  Wei g ht, vital si g ns, ne ur ol o gical e xa m pl us s y m pt o m- directe d p h ysical e xa mi nati o n.  
2.  Sta n dar d 1 2- lea d E C G. 
3.  Cli nical la b orat or y e val uati o n [ he mat ol o g y, ser u m c he mistr y, ser u m pre g n a nc y test 
( w o me n of c hil d-beari n g p ote ntial)].  
4.  Kar n ofs k y perf or ma nce stat us assess me nt.  
5.  M D A S y m pt o m I n ve nt or y. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 5  
Ple x xi k o n I nc.  
6.  St u d y dr u g c o m plia nce. 
7.  Rec or di n g of c o nc o mita nt me dicati o ns. 
8.  A E m o nit ori n g.  
1 3. 1 2  C o nti n ue d D osi n g  
Patie nts ma y c o nti n ue o nce- dail y a dj u va nt te m oz ol o mi de ( Da y 1- 5 of a 2 8- da y c ycle) f or u p t o 
1 2 c ycles as l o n g as t here is n o disease pr o gressi o n or u nacce pta ble t o xicit y a n d P L X 3 3 9 7 t wice 
dail y ( 2 8 da ys of a 2 8- da y c ycle) f or as l o n g as t here is n o disease pr o gressi o n or u nacce pta ble 
t o xicit y. After disc o nti n uati o n of st u d y dr u g, patie nts will c o nti n ue t o be f oll o we d f or O S e ver y 
6 m o nt hs. St u d y visits will occ ur at a p pr o xi matel y 4- wee k i nter vals. Brai n M RI sca ns s h o ul d be 
o btai ne d a p pr o xi matel y e ver y 8 wee ks. T he sa me met h o d use d at Scree ni n g s h o ul d be use d f or 
all serial meas ure me nts.  
1 3. 1 3  D ose Le vels f or t he P h ase 1 b P orti o n  
1 3. 1 3. 1  
D ose Esc al ati o n 
A t otal of a p pr o xi matel y 7 patie nts will be e nr olle d i n eac h d ose le vel (see Ta ble  2). T he starti n g 
d ose le vel of P L X 3 3 9 7 will be 8 0 0 m g/ da y a d mi nistere d 7 da ys/ wee k ( C o h ort 1). 
T a ble  2: 
P L X 3 3 9 7 D osi n g C o h orts 
C o h ort  
C o m bi n ati o n P L X 3 3 9 7/ R T/ T M Z  
A dj u v a nt P L X 3 3 9 7/ T M Z  
P L X 3 3 9 7 D ose  
P L X 3 3 9 7 Sc he d ule  
P L X 3 3 9 7 D ose  
P L X 3 3 9 7 Sc he d ule  
-2  
6 0 0 m g/ da y  
5 da ys/ wee k ( M -F) b 
8 0 0 m g/ da y b 
7 da ys/ wee k  
-1  
6 0 0 m g/ da y  
7 da ys/ wee k a 
6 0 0 m g/ da y a 
8 0 0 m g/ da y b 
7 da ys/ wee k  
1  
8 0 0 m g/ da y  
7 da ys/ wee k a 
5 da ys/ wee k ( M -F) b 
1 0 0 0 m g/ da y b 
7 da ys/ wee k  
2  
1 0 0 0 m g/ da y  
5 da ys/ wee k ( M -F) b 
1 2 0 0 m g/ da y b 
7 da ys/ wee k  
a 
A me n d me nt 1.  
b 
A me n d me nt 2.  
 
St u d y dr u g will be a d mi nistere d orall y usi n g a ca ps ule f or m ulati o n ( 2 0 0 m g per ca ps ule). T he 
t otal dail y d ose of P L X 3 3 9 7 will be di vi de d a n d a d mi nistere d BI D. F or a n u ne ve n n u m ber of 
ca ps ules, t he lar ger d ose will be a d mi nistere d i n t he m or ni n g. 
F or c o m bi nati o n P L X 3 3 9 7/ R T/ T M Z P L X 3 3 9 7 treat me nt, d ose escalati o n t o t he ne xt hi g hest 
c o h ort ma y occ ur after all patie nts ha ve c o m plete d t he 1 1- wee k D L T - o bser vati o n peri o d (i.e., 
1- wee k P L X 3 3 9 7 m o n ot hera p y; 6- wee k P L X 3 3 9 7/ R T/ T M Z c o m bi nati o n t hera p y; 4- wee k 
rec o ver y). F or a dj u va nt P L X 3 3 9 7/ T M Z P L X 3 3 9 7 treat me nt, d ose escalati o n t o t he ne xt hi g hest 
c o h ort ma y occ ur after all patie nts ha ve c o m plete d a n 8- wee k D L T - o bser vati o n peri o d (i.e., 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 6  
Ple x xi k o n I nc.  
2 c ycles of a dj u va nt treat me nt). F or patie nts partici pati n g i n P hase 1 b, i ntra a n d i nter p atie nt d ose 
escalati o n t o a hi g her d ose le vel/sc he d ule will be per mitte d after t hat d ose le vel/sc he d ule has 
bee n esta blis he d t o be safe.  
Pri or t o d ose escalati o n, safet y data will be c ollate d a n d re vie we d b y t he S p o ns or a n d st u d y sites 
b y telec o nfere nce. A d ose le vel will be c o nsi dere d u nacce pta ble if 2 or m ore patie nts of t he 
6 eli gi ble patie nts e x perie nce a D L T (see bel o w). S h o ul d all 7 patie nts i n t he C o h ort be 
a nal yza ble f or a d verse e ve nts, o nl y t he first 6 will be c o nsi dere d i n t he deter mi nati o n of D L T s. A 
patie nt w h o misses m ore t ha n 7 da ys of P L X 3 3 9 7 a d mi nistrati o n d uri n g t he 7- wee k d osi n g 
peri o d of C ycle 1 ( 4 wee ks) a n d C ycle 2 ( 3 wee ks) f or reas o ns ot her t ha n ha vi n g ha d a D L T will 
be re place d. If 2 or m ore patie nts i n a C o h ort e x perie nce a D L T, n o p atie nts i n t he C o h ort will be 
re place d. 
If 2 or m ore of t he first 6 patie nts i n C o h ort - 2 ( 6 0 0 m g/ da y of P L X 3 3 9 7; 5 da ys/ wee k [ M -F] ) 
e x perie nce a pr ot oc ol- defi ne d D L T, t he c o m bi nati o n will be c o nsi dere d t o o t o xic a n d t he st u d y 
will be disc o nti n ue d.  
1 3. 1 3. 2  
D ose -Li miti n g T o xicities  
D ose -li miti n g t o xicities will be assesse d usi n g C T C A E v 4 gra di n g criteria. D uri n g t he P hase 1 b 
p orti o n of t he st u d y, t he D L T wi n d o w will c o nsist of 1 1 wee ks ( 1 wee k P L X 3 3 9 7 r u n-i n, 
6 wee ks of P L X 3 3 9 7 i n c o m bi nati o n wit h R T/te m oz ol o mi de, a n d 4 wee ks of p ost- R T rec o ver y). 
T he f oll o wi n g will be c o nsi dere d D L Ts: 
He mat ol o gic D L Ts 
•  Gra de ≥3 fe brile ne utr o pe nia  
•  Gra de 4 ne utr o pe nia lasti n g f or > 7 da ys ( gr o wt h fact or s u p p ort all o we d) 
•  Gra de 3 t hr o m b oc yt o pe nia ( platelets ≤5 0. 0/ µ L) lasti n g f or > 7 da ys  
Gra de 3 - 4 l y m p h o pe nia is N O T c o nsi dere d a D L T. 
N o n - he mat ol o gic D L Ts 
•  A n y Gra de ≥3 n o n -he ma t ol o gic t o xicit y, pr o b a bl y rel ate d t o st u d y dr u g,  E X C E P T f or t he 
f oll o wi n g relate d A E’s: 
•  Gra de ≥3 ne ur ol o gic deficits c o nsi dere d t o be d ue t o t he effects of t u m or, resecti o n, or 
e x pecte d p ost -s ur gical m or bi dities 
•  Seiz ures of a n y gra de, as t his is c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n 
•  Gra de ≥3 t hr o m b oe m b olic e ve nt, as t his is c o m m o nl y o bser ve d i n t his patie nt p o p ulati o n  
•  Gra de 3 na usea, v o miti n g, or diarr hea t hat res ol ves t o Gra de ≤2 wit hi n 3 da ys of o nset  
•  Gra de 3 hea dac he, i ns o m nia, or a m nesia t hat re s ol ves t o Gra de ≤2 wit hi n 1 4 da ys of 
o nset 
•  Gra de 3 fati g ue t hat res ol ves t o ≤Gra de 2 wit hi n 2 1 da ys of o nset  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 7  
Ple x xi k o n I nc.  
•  Gra de 3 A S T or A L T t hat res ol ves t o ≤Gra de 2 wit hi n 2 1 da ys of o nset  
•  Gra de ≥3 C P K, G G T, A L P, h y p o ma g nese mia, or h y p o p h os p hate mia t hat is felt b y t h e 
i n vesti gat or t o be cli nicall y i nsi g nifica nt 
•  Al o pecia of a n y Gra de. 
 
1 3. 1 3. 3  
Li ver E nz y me A b n or m alities  
P L X 3 3 9 7 ca n ca use a b n or malities i n li ver f u ncti o n t hat i n s o me cases ha ve bee n c o nsi dere d 
se vere. Ta ki n g P L X 3 3 9 7 t o get her wit h ot her me dicati o ns t hat ca n ca use li ver f u ncti o n 
a b n or malities ma y f urt her i ncrease t he ris k of se vere li ver i nj ur y. Li ver la b orat or y a b n or malities 
s h o ul d be ma na ge d wit h d ose re d ucti o n, treat me nt i nterr u pti o n, or treat me nt disc o nti n uati o n. 
Disc o nti n uati o n of treat me nt s h o ul d be c o nsi dere d if a n y of t he f oll o wi n g occ urs: 
•  A L T or A S T > 8 x U L N  
•  A L T or A S T > 5 x U L N f or m ore t ha n 2 wee ks 
•  A L T or A S T > 3 x U L N a n d T otal bilir u bi n ( T bili) > 2 x U L N or I N R > 1. 5 
•  A L T or A S T > 3 x U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
Ple x xi k o n s h o ul d be i nf or me d as s o o n as p ossi ble w he n a n y of t he a b o ve occ urs. 
I n t he e ve nt t hat st u d y me dicati o n is disc o nti n ue d f or a n y of t he reas o ns a b o ve, a n d if e nz y me 
ele vati o ns persist f or m ore t ha n 2 wee ks a n d n o clear alter nati ve ca use of t he a b n or malities are 
f o u n d, c o nsi derati o n s h o ul d be gi ve n t o war ds o btai ni n g a li ver bi o ps y, if t here are n o 
c o ntrai n dicati o ns (e. g., blee di n g diat hesis). 
Ge nerall y, rec halle n ge of patie nts wit h si g nifica nt A S T/ A L T ele vati o ns ( > 5 x U L N, Gra de 3) 
s h o ul d n ot be atte m pte d. Rec halle n ge ca n be c o nsi dere d if t he patie nt has s h o w n i m p orta nt 
be nefit fr o m t he dr u g a n d ot her o pti o ns are n ot a vaila ble b ut m ust be disc usse d wit h t he me dical 
m o nit or pri or t o re -starti ng. T he patie nt s h o ul d be ma de a ware of t he p ote ntial ris k, a n d c o nse nt 
t o t he rec halle n ge, a n d t he i nstit uti o nal re vie w b oar d c o ns ulte d. 
If t here is Gra de 2 or hi g her A L T or A S T ele vati o n (i.e. > 3 x u p per li mit of n or mal) at a n y ti me 
d uri n g treat me nt, t he patie nt s h o ul d be f oll o we d cl osel y, w hic h i ncl u des t he f oll o wi n g: 
•  Re peati n g li ver e nz y me a n d ser u m bilir u bi n tests t w o or t hree ti mes wee kl y. Fre q ue nc y 
of retesti n g ca n decrease t o o nce a wee k or less if a b n or malities sta bilize or t he trial dr u g 
has bee n disc o nti n ue d a n d t he patie nt is as y m pt o matic. 
•  O btai ni n g a m ore detaile d hist or y of s y m pt o ms a n d pri or or c o nc urre nt diseases. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 8  
Ple x xi k o n I nc.  
•  O btai ni n g a hist or y of c o nc o mita nt dr u g use (i ncl u di n g n o n prescri pti o n me dicati o ns a n d 
her bal a n d dietar y s u p ple me nt pre parati o ns), alc o h ol use, recreati o nal dr u g use, a n d 
s pecial diets. 
•  R uli n g o ut ac ute viral he patitis t y pes A, B, C, D, a n d E; a ut oi m m u ne or alc o h olic 
he patitis; N A S H; h y p o xic/isc he mic he pat o pat h y; a n d biliar y tract disease.  
•  O btai ni n g a hist or y of e x p os ure t o e n vir o n me n tal c he mical a ge nts. 
•  O btai ni n g a d diti o nal tests t o e val uate li ver f u ncti o n, as a p pr o priate (e. g., I N R, direct 
bilir u bi n).  
•  C o nsi deri n g gastr oe nter ol o g y or he pat ol o g y c o ns ultati o ns. 
 
1 3. 1 4  D ose M o dific ati o n 
1 3. 1 4. 1  
P h ase 1  
P L X 3 3 9 7 or te m oz ol o mi de d ose re d ucti o ns a n d i nter r u pti o ns will be per mitte d d uri n g t he 
1 1- wee k D L T wi n d o w ( C ycle 1 t hr o u g h C ycle 2, i.e., 1 wee k P L X 3 3 9 7 r u n-i n, 6 wee ks of 
P L X 3 3 9 7 + R T + te m oz ol o mi de, a n d 4 wee ks of p ost- R T rec o ver y) o nl y if a patie nt e x perie nces 
a D L T (see Secti o n 1 3. 1 3. 2  D ose -Li miti n g T o xicities).  P L X 3 3 9 7 i nterr u pti o ns d uri n g t he 
1 1- wee k  D L T wi n d o w are als o per mitte d f or Gra de 3 v o miti n g t hat persists des pite o pti mal 
s u p p orti ve care. 
If a patie nt e x perie nces a D L T d uri n g t he 1 1-wee k D L T wi n d o w, treat me nt c o nti n uati o n at a 
l o wer d ose ma y be per mitte d at t he discreti o n of t he I n vesti gat or a n d i n c o ns ultati o n wit h t he 
Me dical M o nit or. P L X 3 3 9 7 d ose re d ucti o ns s h o ul d occ ur i n i ncre me nts of 2 0 0 m g/ da y, 
de pe n di n g o n t he t o xicit y gra de, as n ote d i n Ta ble  3, P L X 3 3 9 7 D ose M o dificati o ns. F or d ose 
re d ucti o ns see Secti o n 1 3. 1 3. 1  D ose Escalati o n.  
If d ose i nterr u pti o n c o nti n ues after t he patie nt’s sc he d ule d C 3 D 1 P L X 3 3 9 7 d ose a d mi nistrati o n, 
t he patie nt s h o ul d disc o nti n ue st u d y treat me nt a n d ha ve t he pr oce d ures o utli ne d i n Secti o n 1 3. 1 1  
E n d of Treat me nt. 
D uri n g t he a dj u va nt treat me nt peri o d, P L X 3 3 9 7 or te m oz ol o mi de d ose re d ucti o ns a n d 
i nterr u pti ons will be per mitte d i n c o ns ultati o n wit h t he Me dical M o nit or. P L X 3 3 9 7 d ose 
re d ucti o ns s h o ul d occ ur i n i ncre me nts of 2 0 0 m g/ da y, de pe n di n g o n t he t o xicit y gra de, as n ote d 
i n Ta ble  3 P L X 3 3 9 7 D ose M o dificati o ns. F or d ose re d ucti o ns see Secti o n 1 3. 1 3. 1  D ose 
Escalati o n.  
If a patie nt e x perie nces a D L T, te m oz ol o mi de d ose re d ucti o n s h o ul d be ma de acc or di n g t o t he 
prescri bi n g i nf or mati o n n ote d i n Attac h me n t 4 a n d als o s u m marize d i n Secti o n 1 6 . 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
4 9  
Ple x xi k o n I nc.  
1 3. 1 4. 2  
P h ase 2  
P hase 2 will n ot i ncl u de a se parate d ose escalati o n desi g n, as t here has bee n n o dela ye d t o xicit y 
o bser ve d f or P L X 3 3 9 7 i n e xte nsi ve n o ncli nical a n d cli nical e val uati o ns t o date, a n d 
te m oz ol o mi de is gi ve n at a l o wer i nte nsit y sc he d ule c o m pare d t o t he dail y sc he d ule d uri n g 
c o nc o mita nt ra diati o n t hera p y. D uri n g P hase 2, re d ucti o n/i nterr u pti o n of d osi n g f or a d verse 
e ve nts ma y ta ke place at a n y ti me d uri n g t he st u d y acc or di n g t o t he g ui deli nes i n Ta ble 3. 1, 
Ta ble 3. 2, a n d Ta ble 3. 3. 
D ose re d ucti o n/i nterr u pti o n g ui deli nes f or he mat ol o gic a n d n o n he mat ol o gic treat me nt- relate d 
T E A Es are base d o n se verit y. D ose i nterr u pti o ns ca n be i m ple me nte d at t he discreti o n of t he 
treati n g I n vesti gat or t o ma na ge i nt olera ble or cli nicall y si g nifica nt t o xicit y. If a d ose i nterr u pti o n 
is re q uire d, st u d y assess me nts s h o ul d be perf or me d as sc he d ule d, irres pecti ve of t he st u d y dr u g 
dela y, wit h t he e xce pti o n of P K assess me nts, w hic h s h o ul d be deferre d u ntil treat me nt is 
res u me d. I nterr u pti o ns d ue t o t o xicit y lasti n g > 1 4 da ys re q uire treat me nt disc o nti n uati o n u nless 
t he me dical m o nit or a p pr o ves c o nti n uati o n. 
D ose re d ucti o ns of te m oz ol o mi de s h o ul d be ma de acc or di n g t o t he prescri bi n g i nf or mati o n n ote d 
i n Attac h me nt 4  a n d als o s u m marize d i n Secti o n 1 6 . 
Bel o w are g ui deli nes f or d osa ge m o dificati o n f or P L X 3 3 9 7- relate d t o xicities as well as 
g ui deli nes f or t heir ma na ge me nt. D ose re d ucti o ns s h o ul d occ ur i n i ncre me nts of 2 0 0 m g/ da y, 
de pe n di n g o n t he t o xicit y gra de, as n ote d i n Ta ble  3, Ta ble  4, a n d Ta ble  5. As t he ca ps ules are 
pr o vi de d i n 2 0 0 m g stre n gt hs, d ose re d ucti o n s h o ul d occ ur b y a re d ucti o n of o ne ca ps ule fr o m 
eit her t he m or ni n g or e ve ni n g d ose. 
U p t o 5 da ys of treat me nt i nterr u pti o n are per mitte d f or a n y reas o n. I nterr u pti o ns of 6 t o 
7 treat me nt da ys will be co nsi dere d a n acce pta ble pr ot oc ol de viati o n. F or i nterr u pti o ns of 8 da ys 
or greater, c o nti n uati o n of patie nts i n t he st u d y s h o ul d be disc usse d wit h t he me dical m o nit or. 
Te m oz ol o mi de d ose re d ucti o n s h o ul d be ma de acc or di n g t o t he prescri bi n g i nf or mati o n n ote d i n 
Attac h me nt 4  a n d als o s u m marize d i n Secti o n 1 6 . 
T hese para meters are o nl y a g ui de a n d are n ot i nte n de d t o s u perse de t he cli nical j u d g me nt of t he 
treati n g p h ysicia n. All a dj ust me nts s h o ul d be ma de i n c o ns ultati o n wit h t he Me dical M o nit or. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 0  
Ple x xi k o n I nc.  
T a ble  3: 
P L X 3 3 9 7 D ose M o dific ati o n G ui deli nes f or Tre at me nt -Rel ate d 
T o xicities, E xcl u di n g Li ver F u ncti o n 
All Dr u g -Rel ate d 
T o xicities  
Fre q ue nc y  
W he n t o H ol d or St o p  
W he n t o Rest art a n d Rest art D ose  
( See T a ble 2 f or d ose le vels.) 
Gr a de 3 or 4 
ne utr o pe ni a  
1st A p peara nce  
I nterr u pt u ntil A N C 
rec o vers t o ≥1 x 1 0 9/ L; 
gr o wt h fact or s u p p ort 
per mitte d  
If rec o vere d t o A N C ≥1 x  1 0 9/ L i n 
≤7  da ys, res u me at sa me d ose.  
If n ot rec o vered t o A N C ≥1  x  1 0 9/ L after 
7 da ys, re d uce d ose b y 1 d ose le vel.  
2 n d A p peara nce  
I nterr u pt u ntil A N C 
rec o vers t o ≥1 x 1 0 9/ L; 
gr o wt h fact or s u p p ort 
per mitte d  
If rec o vere d t o A N C ≥1 x  1 0 9/ L i n 
≤7  da ys, re d uce d ose b y 1 d ose le vel.  
If n ot rec o vere d t o A N C ≥1  x  1 0 9/ L after 
7 da ys, re d uce d ose b y 2 d ose le vels.  
3r d A p peara nce  
I nterr u pt u ntil A N C 
rec o vers t o ≥1 x 1 0 9/ L; 
gr o wt h fact or s u p p ort 
per mitte d  
If rec o vere d t o A N C ≥1 x  1 0 9/ L i n 
≤7  da ys, re d uce d ose b y 1 d ose le vel.  
If n ot rec o vere d t o A N C ≥1 x  1 0 9/ L after 
7 da ys, disc o nti n ue per ma ne ntl y.  
4t h A p peara nce  
Disc o nti n ue per ma ne ntl y; 
gr o wt h fact or s u p p ort 
per mitte d  
N/ A  
Gr a de 3 or 4 
fe brile 
ne utr o pe ni a  
1st A p peara nce  
I nterr u pt u ntil A N C a n d 
fe ver rec o ver; pr o vi de 
gr o wt h fact or s u p p ort  
If rec o vere d t o AN C ≥1 x 1 0 9/ L a n d 
T ≤3 8° C i n ≤7 da ys, re d uce d ose b y 
1 d ose le vel.  
If n ot rec o vere d t o A N C ≥1 x  1 0 9/ L after 
7 da ys, disc o nti n ue per ma ne ntl y.  
2 n d A p peara nce  
I nterr u pt u ntil A N C a n d 
fe ver rec o ver; pr o vi de 
gr o wt h fact or s u p p ort  
If rec o vere d t o A N C ≥1 x 1 09/ L a n d 
T ≤3 8° C, re d uce d ose b y a n a d diti o nal 
1 d ose le vel.  
If n ot rec o vere d t o A N C ≥1 x  1 0 9/ L after 
7 da ys, disc o nti n ue per ma ne ntl y.  
3r d A p peara nce  
Disc o nti n ue per ma ne ntl y; 
pr o vi de gr o wt h fact or 
s u p p ort 
N/ A  
Gr a de 4 
t hr o m b o-
c yt o pe ni a 
1st A p peara nce  
I nterr u pt u ntil P L T 
≥7 5  x 1 0 9/ L  
If rec o vere d t o P L T ≥7 5 x  1 0 9/ L ≤7 da ys, 
res u me at sa me d ose. 
If n ot rec o vere d t o P L T ≥7 5 x  1 0 9/ L after 
7 da ys, re d uce d ose b y 1 d ose le vel.  
2 n d A p peara nce  
I nterr u pt u ntil P L T 
≥7 5  x 1 0 9/ L 
If rec o vere d t o P L T ≥7 5 x  1 0 9/ L i n 
≤7  da ys, re d uce d ose b y 1 d ose le vel.  
If n ot rec o vere d t o P L T ≥7 5 x  1 0 9/ L after 
7 da ys, re d uce d ose b y 2 d ose le vels.  
3r d A p peara nce  
I nterr u pt u ntil P L T 
≥7 5  x 1 0 9/ L 
If rec o vere d t o P L T ≥7 5 x  1 0 9/ L i n 
≤7  da ys, re d uce d ose b y 1 d ose le vel.  
If not rec o vere d t o P L T ≥7 5  x  1 0 9/ L after 
7 da ys, disc o nti n ue per ma ne ntl y.  
4t h A p peara nce  
Disc o nti n ue per ma ne ntl y  
N/ A  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 1  
Ple x xi k o n I nc.  
All Dr u g -Rel ate d 
T o xicities  
Fre q ue nc y  
W he n t o H ol d or St o p  
W he n t o Rest art a n d Rest art D ose  
( See T a ble 2 f or d ose le vels.) 
N o n -
He m at ol o gic 
Gr a de 3 
(e xcl u di n g tr a ns-
a mi n ase 
i ncre ases) 
1st A p peara nce a 
I nterr u pt u ntil res ol ve d 
( Gra de 0 -1); start 
s y m pt o matic treat me nt if 
p ossi ble  
If rec o vere d < 5 da ys, res u me at sa me 
d ose.  
If s y m pt o ms persist f or > 5 da ys des pite 
s u p p orti ve ma na ge me nt, re d uce b y 
1 d ose le vel. b 
2 n d A p peara nce  
I nterr u pt u ntil res ol ve d 
( Gra de 0-1); start 
s y m pt o matic treat me nt if 
p ossi ble  
If rec o vere d < 5 da ys, re d uce d ose b y 
1 d ose le vel.  
If s y m pt o ms persist f or > 5 da ys des pite 
s u p p orti ve ma na ge me nt, disc o nti n ue 
per ma ne ntl y.  
3r d A p peara nce  
Disc o nti n ue per ma ne ntl y; 
start s y m pt o matic 
treat me nt if p ossi ble 
N/ A  
N o n -
He m at ol o gic 
Gr a de 4 
(e xcl u di n g tr a ns-
a mi n ase 
i ncre ases) 
1st A p peara nce  
I nterr u pt u ntil res ol ve d 
( Gra de 0-1); start 
s y m pt o matic treat me nt if 
p ossi ble  
If rec o vere d < 5 da ys, re d uce b y 1 d ose 
le vel. 
If s y m pt o ms persist f or ≥5 da ys des pite 
s u p p orti ve ma na ge me nt, disc o nti n ue 
per ma ne ntl y.  
2 n d A p peara nce  
Disc o nti n ue per ma ne ntl y; 
start s y m pt o matic 
treat me nt if p ossi ble 
N/ A  
A N C = a bs ol ute ne utr o p hil c o u nt; I N R = i nter nati o nal n or malize d rati o; N/ A = n ot a p plica ble; P L T = platelet;  
T = te m perat ure; U L N = u p per li mit of n or mal  
a  
E xce pt f or c ases of Gra de 3 e mesis.  
b 
E xce pt i n cases of Gra de 3 s y m pt o matic ras h.  
 
D ose i nterr u pti o ns f or Gra de 2 n o n- he mat ol o gic t o xicit y f or u p t o 1 wee k ca n be i m ple me nte d at 
t he discreti o n of t he treati n g p h ysicia n t o ma na ge i nt olera ble or cli nicall y si g nifica nt t o xicit y. N o 
d ose re d ucti o n is re q uire d w he n res u mi n g treat me nt. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 2  
Ple x xi k o n I nc.  
T a ble  4: 
D ose M o dific ati o n G ui deli nes f or Li ver F u ncti o n A b n or m alities  
T o xicit y Gr a de  
C T C A E v 4. 0  
I niti al Acti o n 
O utc o me  
Acti o n  
A L T or A S T 
Gra de 2 ( > 3 -5 ×  
U L N); N o 
i ncrease i n 
bilir u bi n a 
Re -c hec k A L T a n d A S T 
i m me diatel y 
H ol d st u d y dr u g  
M o nit or wee kl y
b 
C hec k f or c ha n ges t o 
me dicati o ns a n d f or 
s y m pt o ms 
Res ol uti o n t o Gra de  0 – 1 
or baseli ne ( n o bilir u bi n 
i ncrease) 
Restart o n res ol uti o n Gra de 0 – 1 or 
baseli ne at 1  d ose l o wer ( re d uce b y 
o ne 2 0 0 m g ca ps ule)  
Gra de 3 A L T or 
A S T i ncrease 
( > 5-2 0 ×  U L N); 
N o i ncrease i n 
bilir u bi n a 
Re -c hec k A L T a n d A S T 
i m me diatel y 
H ol d st u d y dr u g  
M o nit or 2 x/ wee k
b 
C hec k f or c ha n ges t o 
me dicati o ns a n d f or 
s y m pt o ms 
Res ol uti o n t o Gra de  0 – 1 
or baseli ne ( n o bilir u bi n 
i ncrease) wit hi n 1 4 da ys 
Restart o n res ol uti o n t o Gra de 0 – 1 
or baseli ne at 1 d ose l o wer (re d uce 
b y o ne 2 0 0 m g ca ps ule)  
A L T a n d A S T n ot 
decreasi n g wit hi n 
1 4  da ys of h ol di n g st u d y 
dr u g  
Pr ocee d t o li ver e val uati o n as 
o utli ne d i n Ta ble  5. Restart o nl y o n 
res ol uti o n t o Gra de 0-1/ baseli ne at 1 
d ose l o wer (re d uce b y o ne 2 0 0  m g 
ca ps ule); F or ma x A S T or A L T > 8 ×  
U L N, c o ns ult wit h me dical m o nit or 
pri or t o re -start 
Gra de 4 A L T or 
A S T  
( > 2 0 ×  U L N)  
Disc o nti n ue trea t me nt 
M o nit or 2 x/ wee k u ntil 
res ol uti o n t o Gra de 2 
F oll o w -u p u ntil res ol uti o n 
Gra de 0 – 1 or baseli ne  
C hec k f or c ha n ges t o 
me dicati o ns a n d f or 
s y m pt o ms 
All o utc o mes  
Disc o nti n ue treat me nt; Pr ocee d t o 
li ver e val uati o n as o utli ne d i n 
Ta ble  5. If clear c o nfir me d alter nate 
ca use, restart o n res ol uti o n t o Gra de 
0 – 1 or baseli ne at 1 d ose l o wer 
(re d uce b y o ne 2 0 0 m g ca ps ule)  
A n y gra de A L T or 
A S T i ncrease a 
wit h a n y bilir u bi n 
i ncrease or si g ns 
of h y perse nsiti vit y  
Disc o nti n ue tr eat me nt  
M o nit or 2 x/ wee k u ntil 
res ol uti o n t o Gra de 2 
F oll o w -u p u ntil res ol uti o n 
Gra de  0-1 or baseli ne  
C hec k f or c ha n ges t o 
me dicati o ns a n d f or 
s y m pt o ms 
All o utc o mes  
Disc o nti n ue treat me nt; Pr ocee d t o 
li ver e val uati o n as o utli ne d i n 
Ta ble  5. If clear c o nfir me d alter nate 
ca use, restart o n res ol uti o n t o Gra de 
0 – 1 or baseli ne at 1 d ose l o wer 
(re d uce b y o ne 2 0 0 m g ca ps ule)  
A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase;  
C T C A E  = C o m m o n Ter mi n ol o g y Criter ia f or A d verse E ve nts; U L N = u p per li mit of n or mal 
a 
A n i ncrease i n bilir u bi n is defi ne d as all of t he f oll o wi n g: t otal bilir u bi n > U L N, t otal bilir u bi n > 2 0 % a b o ve 
baseli ne, a n d direct bilir u bi n is > U L N. If all of t hese c o n diti o ns are met, t he n bilir u bi n is  c o nsi dere d i ncrease d 
a n d s h o ul d be i m me diatel y re -c hec ke d. Pe xi darti ni b treat me nt s h o ul d be i m me diatel y disc o nti n ue d f or 
i ncrease d bilir u bi n u nless a n d u ntil t here is a clear, c o nfir me d alter nate ca use.  
b 
If A L T, A S T, or bilir u bi n w orse ns d uri n g t he m o nit ori n g peri o d, f oll o w t he a p plica ble g ui da nce f or t he w orst 
t o xicit y gra de.  
 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 3  
Ple x xi k o n I nc.  
T a ble  5: 
A d diti o n al Li ver E v al u ati o n  
E v al u ati o n  
C o m me nts  
I ncrease fre q ue nc y of testi n g li ver c he mistries t o t wice 
per wee k, i ncl u di n g I N R, a n d c o nti n ue u ntil li ver 
c he mistries ha ve sta bilize d, a n d t he n re d uce t o wee kl y 
u ntil li ver c he mistries ret ur n t o n or mal or baseli ne . 
I n vesti gati o nal treat me nt ma y be starte d after li ver 
f u ncti o n tests rec o ver t o Gra de 0 t o 1 or baseli ne le vel, 
a n d i n c o ns ultati o n wit h  Me dical M o nit or.  
Detaile d hist or y f oc usi n g o n me dicati o ns a n d s u bsta nces 
use d: alc o h ol, c ha n ge i n me dicati o n d osa ges, ne w 
me dicati o ns a d de d, atte nti o n t o use of aceta mi n o p he n, 
O T C me dicati o n use, a n d recreati o nal dr u g use. C hec k 
f or c ha n ge i n diet or use of dietar y s u p ple me nts, wit h 
partic ular atte nti o n t o d ose a n d d urati o n of a n y her bal 
pr o d uct.  
S us pect me dicati o ns will be disc o nti n ue d or s u bstit ute d 
f or if p ossi ble. 
Detaile d me dical hist or y a n d p h ysical e xa mi nati o n 
see ki n g ne w a b n or malities. 
E val uate a b n or malities f o u n d.  
F ull ser ol o gical e val uati o n f or he patitis  A, B, C, a n d E 
(I g G a n d I g M). C hec k f or a ut oi m m u ne he patitis wit h 
ser ol o gical la b orat or y st u dies. 
If viral he patitis or a ut oi m m u ne he patitis s u g geste d, 
ha ve patie nt e val uate d b y he pat ol o gist.  
Li ver ultras o u n d perf or me d t o e val uate li ver a n d biliar y 
tree. 
E val uate a n y a b n or malities f o u n d.  
C hec k hist or y f or e x p os ure t o c he mical a ge nts.  
Re m o ve c he mical e x p os ure a n d ha ve patie nt see n b y 
he pat ol o gist.  
O btai n he pat ol o g y c o ns ult if li ver f u ncti o n c o nti n ues t o 
rise be y o n d 1 4 da ys.  
C o ntact Me dical M o nit or.  
We re q uest t h at c ases be disc usse d wit h t he Me dic al M o nit or as defi ne d i n t he pr ot oc ol w he ne ver 
i n vesti g ati o n al pr o d uct is bei n g hel d f or li ver f u ncti o n test a b n or m alit y. 
I g =  I m m u n o gl o b uli n; I N R =  i nter nati o nal n or malize d rati o; O T C =  o ver -t he-c o u nter 
 
F or s us pecte d cases of c h olestatic li ver i nj ur y (e g, a mi n otra nsferase i ncrease c o nc urre nt wit h 
h y per bilir u bi ne mia, or li ver bi o ps y s u g gesti n g c h olestasis a n d/ or d uct o pe nia), patie nts will be 
f oll o wed t o assess l o n g -ter m o utc o me. A d diti o nal dia g n ostic a n d f oll o w- u p pr oce d ures mi g ht be 
i m ple me nte d as a p pr o priate t o f ull y assess t he e ve nt. 
1 3. 1 5  Disc o nti n u ati o n of Tre at me nt, P atie nt Wit h dr a w al, a n d Re pl ace me nt  
T he reas o ns a patie nt ma y disc o nti n ue or be wit h d ra w n fr o m t he st u d y i ncl u de, b ut are n ot 
li mite d t o, a d verse e ve nt, disease pr o gressi o n, patie nt re q uest, i n vesti gat or decisi o n, pr ot oc ol 
vi olati o n, patie nt n o nc o m plia nce, a n d st u d y ter mi nati o n b y t he S p o ns or. W he n a patie nt 
disc o nti n ues or is wit h dra w n, t he i n vesti gat or will n otif y t he S p o ns or a n d s h o ul d perf or m t he 
pr oce d ures i n dicate d i n t he E n d of R x c ol u m n i n t he trial fl o w c hart wit hi n 3 0 da ys after 
disc o nti n uati o n of st u d y dr u g a n d pri or t o i nitiati o n of a n y t hera p y. After disc o nti n uati o n of 
st u d y dr u g, patie nts a n d/ or t heir fa milies will c o nti n ue t o be m o nit ore d b y tele p h o ne e ver y 
6 m o nt hs f or O S. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 4  
Ple x xi k o n I nc.  
Patie nts wit h dra w n fr o m t he st u d y f or reas o ns ot her t ha n t o xicit y or disease pr o gressi o n (e. g. 
pr ot oc ol vi olati o n or n o nc o m plia nce) ma y be re place d at t he discreti o n of t he me dical m o nit or 
a n d t he i n vesti gat or. St u d y dr u g a d mi nistrati o n ma y be disc o nti n ue d f or a n a d verse e ve nt or at 
t he discreti o n of t he i n vesti gat or. 
1 3. 1 6  St o p pi n g R ules  
T he Ple x xi k o n Me dical M o nit or will m o nit or safet y data t hr o u g h o ut t he c o urse of t he st u d y. T he 
Me dical M o nit or will re vie w S A Es wit hi n ti mefra mes ma n date d b y c o m pa n y pr oce d ures a n d 
will re vie w tre n ds, la b orat or y a nal ytes, a n d a d verse e ve nts at peri o dic i nter vals a n d pr o vi de f or 
i nteri m safet y a nal yses if a p pr o priate. Safet y data acr oss all st u d y patie nts will be re vie we d at 
pla n ne d bi m o nt hl y telec o nfere nces wit h all partici pati n g sites. 
F or P hase 1 d ose escalati o n, a d ose le vel will be c o nsi dere d u nacce pta ble if 2 or m ore patie nts of 
t he 6 eli gi ble patie nts e x perie nce a D L T (see bel o w). S h o ul d all 7 patie nts i n t he C o h ort be 
a nal yza ble f or a d verse e ve nts, o nl y t he first 6 will be c o nsi dere d i n t he deter mi nati o n of D L Ts. A 
patie nt w h o misses m ore t ha n 7 da ys of P L X 3 3 9 7 a d mi nistrati o n d uri n g t he 7- wee k d osi n g 
peri o d of C ycle 1 ( 4 wee ks) a n d C ycle 2 ( 3 wee ks) f or reas o ns ot her t ha n ha vi n g ha d a D L T will 
be re place d. If 2 or m ore patie nts i n a C o h ort e x perie nce a D L T, n o patie nts i n t he C o h ort will be 
re place d. 
If 2 or m ore of t he first 6 patie nts i n C o h ort - 2 ( 4 0 0 m g/ da y of P L X 3 3 9 7) e x perie nce a pr ot oc ol -
defi ne d D L T, t he c o m bi nati o n will be c o nsi dere d t o o t o xic a n d t he st u d y will be disc o nti n ue d. 
After a p pr o xi matel y 5 0 % of t he pla n ne d P hase 2 patie nts ha ve bee n c o m plete d t heir c o nc urre nt 
ra diati o n t hera p y, a n o verall i nteri m safet y s u m mar y will be re vie we d b y t he Me dical M o nit or 
a n d pri nci pal i n vesti gat ors t o e ns ure t hat t he p ote ntial cli nical be nefit o ut wei g hs t he o bser ve d 
cli nical ris k t o date. If t he safet y o bser vati o ns d o n ot warra nt c o nti n ue d e nr oll me nt, t he st u d y 
will be disc o nti n ue d. 
1 4. 0  
S T U D Y D R U G  
1 4. 1  
St u d y Dr u g A d mi nistr ati o n  
P L X 3 3 9 7 will be d ose d orall y usi n g a ca ps ule f or m ulati o n ( 2 0 0 m g per ca ps ule), t wice dail y i n 
t he fasti n g state wit h 2 4 0 m L ( 8 oz) of r o o m-te m perat ure water. T he P L X 3 3 9 7 dail y d ose s h o ul d 
be di vi de d a n d a d mi nistere d t wice dail y a p pr o xi matel y 1 2 h o urs a part. W he n t he d ose ca n n ot be 
e ve nl y di vi de d, t he hi g her of t he t w o d oses s h o ul d be a d mi nistere d i n t he m or ni n g. F or e xa m ple, 
t he P L X 3 3 9 7 1 0 0 0 m g dail y d ose s h o ul d be di vi de d 6 0 0/ 4 0 0 A M/ P M. F or eac h d ose, t he patie nt 
s h oul d fast at least 1 h o ur bef ore a n d 1 h o ur after a d mi nistrati o n. Patie nts will be per mitte d t o eat 
a l o w-fat s nac k (e. g., crac kers, t oast, tea) d uri n g t he fasti n g peri o d if nee de d. 
Te m oz ol o mi de will be a d mi nistere d o nce dail y, eit her i n t he m or ni n g or e ve ni n g, als o i n t he 
fasti n g, as n ote d i n Secti o n 1 6, eit her bef ore or after P L X 3 3 9 7. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 5  
Ple x xi k o n I nc.  
St u d y dr u g s h o ul d be ta ke n at a p pr o xi matel y t he sa me ti mes of da y, a p pr o xi matel y 1 2 h o urs 
a part. O n P K c ollecti o n da ys, t he m or ni n g d ose of P L X 3 3 9 7 will be gi ve n at t he cli ni cal site; 
patie nts s h o ul d be i nstr ucte d N O T t o ta ke t he st u d y dr u g at h o me t he m or ni n g of t he cli nic visit. 
T he ti me of d osi n g will be rec or de d; patie nts will t he n ta ke t he e ve ni n g d ose at h o me. Bet wee n 
cli nic visits, patie nts will ta ke t he st u d y dr u g at h o me a n d rec or d d osi n g i nf or mati o n o n t he 
d osi n g diar y. Misse d d oses ( ge nerall y o utsi de of a + 2 h o ur d osi n g wi n d o w) s h o ul d be s ki p pe d 
a n d n ot a d mi nistere d as a d o u ble d ose at t he ne xt a d mi nistrati o n. Patie nts w h o v o mit t heir d ose 
s h o ul d be i nstr ucte d t o N O T t o ma ke u p t hat d ose. 
1 4. 2  
P ac k a gi n g a n d L a beli n g  
P L X 3 3 9 7- H Cl ca ps ules ( 2 0 0 m g stre n gt h of t he acti ve free base of P L X 3 3 9 7) are ma n ufact ure d, 
pac ka ge d, a n d la bele d acc or di n g t o G M P a n d G C P at t he f oll o wi n g a d dress: 
Catale nt P har ma S ol uti o ns  
1 0 2 4 5 Hic k ma n Mill s Dri ve 
Ka nsas Cit y, M O 6 4 1 3 7 
1 4. 3  
St or a ge a n d St a bilit y  
P L X 3 3 9 7- H Cl ca ps ules will be st ore d at t he cli nical site, as i n dicate d o n t he st u d y dr u g la bel, 
i.e., r o o m te m perat ure ( 1 5- 3 0°C).  
Patie nts will be re q ueste d t o st ore t he st u d y dr u g at t he rec o m me n de d st or a ge c o n diti o ns n ote d 
o n t he la bel, o ut of t he reac h of c hil dre n or ot her c o ha bita nts. 
1 4. 4  
St u d y dr u g Acc o u nt a bilit y, Rec o ncili ati o n, a n d Ret ur n  
T he i n vesti gat or is acc o u nta ble f or all st u d y dr u g s u p plie d b y t he S p o ns or. T he desi g nate d c o pies 
of t he c o m pl ete d dis pe nsi n g a n d i n ve nt or y rec or d will be ret ur ne d t o t he S p o ns or after t he 
S p o ns or has perf or me d acc o u nta bilit y pr oce d ures. Ret ur ne d a n d u n use d st u d y dr u g s h o ul d be 
destr o ye d a n d d oc u me nt e d at t he i n vesti gati ve site i n acc or da nce wit h G C P, after t he st u d y 
m o nit or has perf or me d dr u g acc o u nta bilit y. 
1 4. 5  
St u d y Dr u g C o m pli a nce  
At eac h cli nic visit, patie nts will be q uesti o ne d a b o ut t heir c o m plia nce wit h st u d y dr u g 
a d mi nistrati o n, a n d t heir d osi n g diar y s h o ul d be re vie we d. 
1 5. 0  
R A DI A TI O N T H E R A P Y  
1 5. 1  
D ose S pecific ati o ns a n d Sc h e d ule 
I nte nsit y M o d ulate d R T (I M R T) is all o we d, b ut t he m o dalit y c h ose n at re gistrati o n m ust be use d 
f or t he e ntire c o urse of treat me nt. Pr ot o n bea m t hera p y is n ot all o we d. F or b ot h I M R T a n d 3 D-
C R T pla ns, o ne treat me nt of 2 G y will be gi ve n dail y 5 da ys per wee k f or a t otal of 6 0 G y o ver 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 6  
Ple x xi k o n I nc.  
a p pr o xi matel y 6 wee ks. All p ortals s hall be treate d d uri n g eac h treat me nt sessi o n, f or eac h 
c o urse/s u b -c o urse of t hera p y, i.e. f or t he i nitial a n d b o ost p hases. D oses are s pecifie d s uc h t hat at 
least 9 5 % of t he Pla n ni n g Tar get V ol u me ( P T V) s hall recei ve 1 0 0 % of t he prescri be d d ose; D ose 
V ol u me Hist o gra ms ( D V Hs) are necessar y t o ma ke t his selecti o n.  
1 5. 2  
Tec h nic al F act ors  
Treat me nt s hall be deli vere d wit h me ga v olta ge mac hi nes wit h a mi ni m u m e ner g y of 6 M V 
p h ot o ns. Selecti o n of t he a p pr o priate p h ot o n e ner g y/e ner gies s h o ul d be base d o n o pti mizi n g t he 
ra diati o n d ose distri b uti o n wit hi n t he tar get v ol u me a n d mi ni mizi n g d ose t o n o n-tar get n or mal 
tiss ue. S o urce s ki n dista nce f or S S D tec h ni q ues or s o urce a xis dista nce f or S A D tec h ni q ues must 
be at least 8 0 c m. Treat me nt wit h electr o ns or brac h yt hera p y is n ot per missi ble.  
1 5. 3  
L oc aliz ati o n, Si m ul ati o n, a n d I m m o biliz ati o n  
T he patie nt s hall be treate d i n t he s u pi ne or ot her a p pr o priate p ositi o n f or t he l ocati o n of t he 
lesi o n. A hea d- h ol di n g de vice t o e ns ure a de q uate i m m o bilizati o n d uri n g t hera p y a n d e ns ure 
re pr o d uci bilit y is str o n gl y rec o m me n de d. Si m ulati o n ma y i ncl u de a de dicate d ra di ot hera p y 
si m ulat or or a virt ual si m ulati o n usi n g a treat me nt pla n ni n g C T. F usi o n wit h M R i ma ges is 
str o n gl y rec o m men de d, w he ne ver feasi ble. 
F or patie nts accr ue d t o t he pr ot oc ol, treat me nt verificati o n a n d d oc u me ntati o n s h o ul d be carrie d 
o ut, at least f or t he first treat me nt fracti o n, a n d m ore fre q ue ntl y, base d o n i nstit uti o nal p olic y; 
wee kl y verificati o n is c o m m o n. We s u g gest ort h o g o nal i ma ges f or d oc u me nti n g is oce nter set u p 
acc urac y f or t he first fracti o n. T hese ort h o g o nal i ma ges ca n be o btai ne d wit h fil m or E PI D. 
Ot her i ma gi n g tec h ni q ues are p ossi ble, f or e xa m ple, t he Brai n La b E xac Trac s yste m t hat uses t w o 
ort h o g o nal i ma gi n g pa nels irra diate d wit h K V x-ra ys. A n ot her e xa m ple is t he v ol u me i ma ges 
o btai ne d wit h c o ne- bea m C T, or helical t o m ot hera p y or a n y ot her C T ca pa bilit y t hat is i nte grate d 
wit h t he treat me nt u nit. F or u nits wit h b uilt -i n or “ o n-rail” M R ca pa bilities, if t he wee kl y 
i ma gi n g is perf or me d wit h M R i ma ges, t hese m ust be f use d wit h t he baseli ne pla n ni n g C T f or 
p ur p oses of verificati o n. 
1 5. 4  
Tre at me nt Pl a n ni n g/ T ar get V ol u mes  
Treat me nt pla ns ma y i ncl u de o p p ose d lateral fiel ds, a we d ge pair of fiel ds, r otati o n, or m ul ti ple 
fiel d tec h ni q ues. I nte nsit y- m o d ulate d i n verse- pla n ne d a p pr oac hes are per mitte d. A n y of t he 
met h o ds of I M R T (i ncl u di n g t o m ot hera p y a n d v ol u metric arc- m o d ulate d tec h ni q ues) ma y be 
use d, s u bject t o pr ot oc ol l ocalizati o n a n d d osi metr y c o nstrai nts. C T- base d treat me nt pla n ni n g is 
necessar y t o ass ure acc urac y i n t he selecti o n of fiel d arra n ge me nts. M RI -f usi o n f or acc urate 
tar get deli neati o n is str o n gl y rec o m me n de d. 
1 5. 4. 1  
I niti al T ar get V ol u me 
Tar get v ol u mes will be base d u p o n p ost o perati ve- e n ha nce d M RI. Pre o perati ve i ma gi n g ma y be 
use d f or c orrelati o n a n d i m pr o ve d i de ntificati o n as cli nicall y necessar y a n d rele va nt. T w o 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 7  
Ple x xi k o n I nc.  
pla n ni n g tar get v ol u mes ( P T V) will be defi ne d, as o utli ne d bel o w. T he i nitial gr oss t u m or 
v ol u me ( G T V 1) will be defi ne d b y eit her t he T 2 or t he F L AI R a b n or malit y o n t he p ost- o perati ve 
M RI sca n I n a d diti o n t o t he T 2 a n d F L AI R v ol u me, G T V 1 m ust als o i ncl u de all p ost o perati ve 
M RI e n ha nce me nt, a n d t he s ur gical ca vit y. T he i nitial cli nical tar get v ol u me ( C T V 1) will be t he 
G T V pl us a mar gi n of 2 c m. If n o s urr o u n di n g e de ma is prese nt, or t he G T V 1 v ol u me is i de ntical 
t o t he G T V 2 v ol u me, t he i nitial pla n ni n g tar get v ol u me ( P T V 1) s h o ul d i ncl u de t he c o ntrast-
e n ha nci n g lesi o n (a n d s h o ul d i ncl u de t he s ur gical resecti o n ca vit y) pl us a 2. 5-c m mar gi n. T he 
C T V 1 mar gi n ma y be re d uce d t o as little as 0. 5 c m ar o u n d nat ural barriers t o t u m or gr o wt h s uc h 
as t he s k ull, ve ntricles, fal x, etc, a n d als o t o all o w s pari n g of t he o ptic ner ve/c hias m, or ot her 
critical str uct ures, if necessar y. T he i nitial pla n ni n g tar get v ol u me ( P T V 1) is a n a d diti o nal 
mar gi n of 3 t o 5 m m, de pe n di n g u p o n l ocalizati o n met h o d a n d re pr o d uci bilit y, at eac h ce nter. 
P T V mar gi ns acc o u nt f or variati o ns i n set - u p a n d re pr o d uci bilit y. Re d uci n g P T V mar gi ns t o 
m o dif y or ga n at ris k ( O A R) d ose(s) is n ot ge nerall y  per missi ble. H o we ver, O A R m ust be 
defi ne d, al o n g wit h a pla n ni n g ris k v ol u me ( P R V) f or eac h O A R. Eac h P R V will be its O A R 
pl us 3 m m. I n t he e ve nt t hat a n O A R is i n i m me diate pr o xi mit y t o a P T V s uc h t hat d ose t o t he 
O A R ca n n ot be c o nstrai ne d wit hi n pr ot oc o l li mits, a sec o n d P T V ( P T V o verla p), defi ne d as t he 
o verla p bet wee n t he P T V 1 a n d t he partic ular P R V of c o ncer n, ma y be create d. D ose t o t he 
P T V o verla p m ust be as cl ose as per missi ble t o 4 6 G y w hile n ot e xcee di n g t he O A R d ose li mit.  
1 5. 4. 2  
B o ost T ar get V ol u me 
T he b o ost gr oss t u m or v ol u me ( G T V 2) will be defi ne d b y t he c o ntrast-e n ha nce d T 1 a b n or malit y 
o n t he p ost- o perati ve M RI sca n. T his m ust als o i ncl u de t he s ur gical ca vit y. T he b o ost cli nical 
tar get v ol u me ( C T V 2) will be t he G T V pl us a mar gi n of 2 c m. T he C T V 2 mar gi n ma y be 
re d uce d t o as little as 0. 5 c m ar o u n d nat ural barriers t o t u m or gr o wt h s uc h as t he s k ull, ve ntricles, 
fal x, etc, a n d als o t o all o w s pari n g of t he o ptic ner ve/c hias m, or ot her critical str uct ures, if 
necessar y. T he b o ost pla n ni n g tar get v ol u me ( P T V 2) is a n a d diti o nal mar gi n of 3 t o 5 m m, 
de pe n di n g u p o n l ocalizati o n met h o d a n d re pr o d uci bilit y, at eac h ce nter. P T V mar gi ns acc o u nt 
f or variati o ns i n set- u p a n d re pr o d uci bilit y. Re d uci n g P T V mar gi ns t o m o dif y or ga n at ris k 
( O A R) d ose(s) is n ot ge nerall y per missi ble. H o we ver, O A R m ust be defi ne d, al o n g wit h a 
pla n ni n g ris k v ol u me ( P R V) f or eac h O A R. Eac h P R V will be its O A R pl us 3 m m. I n t he e ve nt 
t hat a n O A R is i n i m me diate pr o xi mit y t o a P T V s uc h t hat d ose t o t he O A R ca n n ot be 
c o nstrai ne d wit hi n pr ot oc ol  li mits, a sec o n d P T V ( P T V o verla p), defi ne d as t he o verla p bet wee n 
t he P T V 2 a n d t he partic ular P R V of c o ncer n, ma y be create d (t he o verla p is t he i ntersecti o n 
bet wee n t he P T V 1 a n d t he P R V). D ose t o t he P T V o verla p m ust be as cl ose as per missi ble t o 
1 4 G y w h ile n ot e xcee di n g t he O A R d ose li mit. 
1 5. 4. 3  
D ose G ui deli nes  
T he i nitial tar get v ol u me will be treate d t o 4 6 G y i n 2 3 fracti o ns. After 4 6 G y, t he c o ne d o w n or 
b o ost v ol u me will be treate d t o a t otal of 6 0 G y, wit h se ve n a d diti o nal fracti o ns of 2 G y eac h 
( 1 4 G y b o ost d ose). 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 8  
Ple x xi k o n I nc.  
Is o d ose distri b uti o ns f or t he i nitial tar get v ol u me ( P T V 1) a n d t he c o ne d o w n tar get v ol u me 
( P T V 2) are re q uire d o n all patie nts. A c o m p osite pla n is re q uire d s h o wi n g t he res pecti ve tar get 
v ol u mes. T he i n h o m o ge neit y wit hi n t he tar get v ol u me s hall be ke pt t o ± 1 0 % of t he prescri be d 
d ose. 
T he mi ni m u m d ose t o t he tar get v ol u me s h o ul d be ke pt wit hi n 1 0 % of t he prescri be d. D oses are 
s pecifie d s uc h t hat at least 9 5 % of t he P T V s hall recei ve 1 0 0 % of t he prescri be d d ose; D V Hs are 
necessar y t o ma ke t his selec ti o n. 
1 5. 4. 4  
D ose Li mit ati o ns a n d Critic al Str uct ures  
I n a d diti o n t o t he a b o ve defi ne d G T Vs, C T Vs a n d P T Vs t he le nses of b ot h e yes, b ot h reti nae, 
b ot h o ptic ner ves, t he o ptic c hias m, a n d t he brai nste m m ust be defi ne d. T he ma xi m u m p oi nt 
( defi ne d as a v ol u me greater t ha n 0. 0 3 cc) d oses per missi ble t o t he str uct ures are liste d i n t he 
ta ble bel o w. 
T a ble  6: 
M a xi m u m D oses Per missi ble f or Critic al Str uct ures  
Critic al Str uct ure  
M a xi m u m D ose  
Le nses  
8 G y  
Reti nae  
5 0 G y  
O ptic Ner ves  
5 6 G y  
O ptic C hi as m 
5 6 G y  
Brai nste m  
6 1 G y  
1 5. 5  
C o m pli a nce Criteri a  
F or all patie nts, as me nti o ne d a b o ve, t w o P T V prescri pti o ns, P T V 1 a n d P T V 2 will be use d a n d 
t he prescri pti o n is o d ose ( 4 6 G y f or P T V 1 a n d 1 4 G y f or P T V 2) m ust c o ver > 9 5 % of t he P T V 
v ol u me; t heref ore, t he t otal d ose i n t he P T V 2 v ol u me will be 6 0 G y. T he mi ni m u m acce pta ble 
d ose wit hi n P T V 1 will be 4 1. 4 G y ( 9 0 % of 4 6 G y), a n d i n t he P T V 2 v ol u me, it will be 5 4 G y 
( 9 0 % of 6 0 G y). T his mi ni m u m d ose m ust c o ver 1 0 0 % of t he P T V. If t he mi ni m u m d ose falls 
bel o w t hese par a meters, a n u nacce pta ble de viati o n will be assi g ne d. T he ma xi m u m d ose f or t he 
P T V 2 s h o ul d n ot e xcee d 6 6 G y ( 1 1 0 % of 4 6 G y). If t he ma xi m u m d oses e xcee d t hese 
para meters, a n u nacce pta ble de viati o n will be assi g ne d.  
U p t o 5 da ys of treat me nt i nterr u pti o n are per mitte d f or a n y reas o n. I nterr u pti o ns of 6 t o 
7 treat me nt da ys will be c o nsi dere d a n acce pta ble pr ot oc ol de viati o n. F or i nterr u pti o ns of 8 da ys 
or greater, c o nti n uati o n of patie nts i n t he st u d y s h o ul d be disc usse d wit h t he me dical m o nit or. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
5 9  
Ple x xi k o n I nc.  
1 5. 6  
R a di ati o n T he r a p y A d verse E ve nts  
1 5. 6. 1  
Ac ute  
E x pecte d ac ute ra diati o n -i n d uce d t o xicities i ncl u de hair l oss, fati g ue, a n d er yt he ma or s ore ness 
of t he scal p. P ote ntial ac ute t o xicities i ncl u de na usea a n d v o miti n g as well as te m p orar y 
a g gra vati o n of brai n t u m or s y m pt o ms s uc h as hea dac hes, seiz ures, a n d wea k ness. Reacti o ns i n 
t he ear ca nals a n d o n t he ear s h o ul d be o bser ve d a n d treate d s y m pt o maticall y; t hese reacti o ns 
c o ul d res ult i n s h ort- ter m heari n g i m pair me nt. Dr y m o ut h or altere d taste ha ve bee n occasi o nall y 
re p orte d. 
1 5. 6. 2  
E arl y Del a ye d  
P ossi ble earl y dela ye d ra diati o n effects i ncl u de let har g y a n d tra nsie nt w orse ni n g of e xisti n g 
ne ur ol o gical deficits occ urri n g 1 -3 m o nt hs after ra di ot hera p y treat me nt.  
1 5. 6. 3  
L ate Del a ye d 
P ossi ble late dela ye d effects of ra di ot hera p y i ncl u de ra diati o n necr osis, e n d ocri ne d ysf u ncti o n, 
a n d ra diati o n-i n d uce d ne o plas ms. I n a d diti o n, ne ur oc o g niti ve deficits, w hic h c o ul d lea d t o 
me ntal sl o wi n g a n d be ha vi oral c ha n ge, are p ossi ble. Per ma ne nt heari n g i m pair me nt a n d vis ual 
da ma ge are rare. Cataracts ca n be e nc o u ntere d. 
1 6. 0  
T E M O Z O L O MI D E T H E R A P Y  
1 6. 1  
Te m oz ol o mi de D uri n g C o nc o mit a nt R a di ati o n T her a p y  
Te m oz ol o mi de will be a d mi nistere d c o nti n u o usl y fr o m da y 1 of ra di ot hera p y t o t he last da y of 
ra di ot hera p y at a dail y oral d ose of 7 5 m g/ m2 f or a ma xi m u m of 4 9 da ys. T he dr u g will be 
a d mi nistere d orall y 1 h o ur bef ore eac h sessi o n of ra di ot hera p y d uri n g wee k da ys ( M o n da y 
t hr o u g h Fri da y). D uri n g wee ke n ds wit h o ut ra di ot hera p y ( Sat ur da y a n d S u n da y), t he dr u g will be 
ta ke n i n t he m or ni n g. 
T he d ose will be deter mi ne d usi n g act ual b o d y s urface area ( B S A) as calc ulate d i n s q uare meters 
at t he be gi n ni n g of t he c o nc o mita nt treat me nt. T he B S A will be calc ulate d fr o m t he hei g ht 
o btai ne d at t he pretreat me nt visit a n d t he wei g ht o btai ne d at t he visit i m me diatel y bef ore t he first 
da y of treat me nt. Ca ps ules of te m oz ol o mi de are a vaila ble i n 5, 2 0, 1 0 0, 1 4 0, 1 8 0, a n d 2 5 0 m g. 
T he dail y d ose will be r o u n de d t o t he nearest 5 m g. If t he i n vesti gat or d oes n ot wa nt t o prescri be 
t he te m oz ol o mi de 5 m g u nit stre n gt h, he/s he s h o ul d r o u n d off t he d ose t o t he cl osest 1 0 m g. F or 
e xa m ple, f or a 1. 7 m 2 s u bject, t he 7 5 m g/ m2 d ose w o ul d be 1 2 7. 5 m g a n d t he d ose w o ul d be 
r o u n de d off t o 1 2 0 m g. F or t he sa me s u bject, t he 1 5 0 m g/ m2 d ose w o ul d be 2 5 5 m g a n d t he d ose 
w o ul d be r o u n de d off t o 2 6 0 m g. T he e xact d ose a d mi nistere d s h o ul d be rec or de d i n t he C R F. 
Eac h dail y d ose s h o ul d be gi ve n wit h t he least n u m ber of ca ps ules.  
Patie nts will be i nstr ucte d t o s wall o w t he ca ps ules w h ole, i n ra pi d s uccessi o n, wit h o ut c he wi n g 
t he m. If v o miti n g occ urs d uri n g t he c o urse of treat me nt, n o re- d osi n g of t he patie nt is all o we d 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 0  
Ple x xi k o n I nc.  
bef ore t he ne xt sc he d ule d d ose. T he ca ps ules s h o ul d be ta ke n o n a n e m pt y st o mac h, t heref ore a 
mi ni m u m of 2 h o urs after eati n g a n d wit h n o f o o d c o ns u m pti o n f or at least 1 h o ur after 
te m oz ol o mi de a d mi nistrati o n. Alt h o u g h, ni g htl y a d mi nistrati o n j ust bef ore be dti me has bee n 
re p orte d t o i m pr o ve t olera nce, t he l o w dail y d ose a d mi nistere d d uri n g ra diati o n is ver y well 
t olerate d a n d a d mi nistrati o n i n t he m or ni n g bef ore ra diati o n d osi n g is re q uire d f or t his pr ot oc ol. 
A d mi nistrati o n of  t he hi g her d osi n g re gi me n d uri n g t he a dj u va nt p hase of t he pr ot oc ol s h o ul d be 
perf or me d usi n g t he ni g htl y a d mi nistrati o n.  
A ntie metic pr o p h yla xis is us uall y n ot re q uire d f or t he c o nti n u o us dail y d osi n g sc he d ule ( d uri n g 
ra diati o n). H o we ver, pr o p h yla xis wit h a 5- H T 3 a nta g o nist is rec o m me n de d pri or t o 
a d mi nistrati o n of t he first fe w te m oz ol o mi de d oses a n d s h o ul d be a d mi nistere d orall y 3 0 t o 
6 0 mi n utes bef ore te m oz ol o mi de treat me nt. M ost patie nts re p ort o pti mal na usea c o ntr ol wit h t he 
use of a 5 - H T 3 a nta g o nist. R o uti ne use of a ntie metics is rec o m me n de d d uri n g t he a dj u va nt p hase 
of treat me nt. A d diti o nall y, p ne u m oc ystis cari nii pr o p h yla xis is at t he discreti o n of t he 
I n vesti gat or d uri n g t he ra diati o n p hase. 
D uri n g t he 4- wee k brea k after c o m pleti o n of ra di ot hera p y, neit her te m oz ol o mi de n or st u d y dr u g 
will be a d mi nistere d.  
1 6. 2  
P ost -R a di ati o n Te m oz ol o mi de  
Patie nts will recei ve u p t o 1 2 c ycles of a dj u va nt te m oz ol o mi de at a d ose of 1 5 0- 2 0 0 m g/ m 2 
Da ys  1- 5 of a 2 8- da y c ycle a n d al o n g wit h P L X 3 3 9 7. Te m oz ol o mi de will be a d mi nistere d orall y 
o nce per da y f or 5 c o nsec uti ve da ys ( Da ys 1 - 5) of a 2 8- da y c ycle. T he starti n g d ose f or t he first 
c ycle will be 1 5 0 m g/ m 2/ da y, wit h a si n gle d ose escalati o n t o 2 0 0 m g/ m2/ da y i n s u bse q ue nt 
c ycles if n o treat me nt -relate d a d verse e ve nts > Gra de 2 are n ote d. 
T he start of t he first c ycle will be sc he d ule d 2 8 da ys ± 7 da ys after t he last da y of ra di ot hera p y. 
T he start of all s u bse q ue nt c ycles ( 2 - 1 2) will be sc he d ule d e ver y 4 wee ks ( 2 8 da ys ± 7 da ys) after 
t he first dail y d ose of te m oz ol o mi de of t he prece di n g c ycle. 
T he d ose will be deter mi ne d usi n g t he B S A calc ulate d at t he be gi n ni n g of eac h treat me nt c ycle. 
T he B S A will be calc ulate d fr o m t he hei g ht o btai ne d at t he pretreat me nt visit a n d fr o m t he 
wei g ht o btai ne d at t he visit i m me diatel y bef ore eac h c ycle. Ca ps ules of te m oz ol o mi de are 
a vaila ble i n 5, 2 0, 1 0 0, 1 4 0, 1 8 0, a n d 2 5 0 m g. T he dail y d ose will be r o u n de d t o t he nearest 
5 m g. If t he i n vesti gat or d oes n ot wa nt t o prescri be t he te m oz ol o mi de 5 m g u nit stre n gt h, he/s he 
s h o ul d r o u n d off t he d ose t o t he cl osest 1 0 m g. F or e xa m ple f or a 1. 7 m 2 s u bject, t he 7 5 m g/ m2 
d ose w o ul d be 1 2 7. 5 m g a n d t he d ose w o ul d be r o u n de d off t o 1 2 0 m g. F or t he sa me s u bject, t he 
1 5 0 m g/ m 2 d ose w o ul d be 2 5 5 m g a n d t he d ose w o ul d be r o u n de d off t o 2 6 0 m g. T he e xact d ose 
a d mi nistere d s h o ul d be rec or de d i n t he C R F. Eac h dail y d ose s h o ul d be gi ve n wit h t he least 
n u m ber of ca ps ules.  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 1  
Ple x xi k o n I nc.  
Patie nts will be i nstr ucte d t o fast at least 2 h o urs bef ore a n d 1 h o ur after te m oz ol o mi de 
a d mi nistrati o n. Water is all o we d d uri n g t he fast peri o d. Patie n ts will be i nstr ucte d t o s wall o w t he 
ca ps ules w h ole, i n ra pi d s uccessi o n, wit h o ut c he wi n g t he m. Treat me nt s h o ul d be gi ve n at ni g ht. 
If v o miti n g occ urs d uri n g t he c o urse of treat me nt, n o re- d osi n g of t he patie nt is all o we d bef ore 
t he ne xt sc he d ule d d ose. 
A n tie metic pr o p h yla xis wit h a 5- H T 3 a nta g o nist is str o n gl y rec o m me n de d a n d s h o ul d be 
a d mi nistere d 3 0 t o 6 0 mi n utes bef ore te m oz ol o mi de a d mi nistrati o n. 
D ose re d ucti o ns of te m oz ol o mi de d uri n g t he a dj u va nt peri o d s h o ul d be ma de acc or di n g t o t he 
prescri bi n g i nf o r mati o n, as s u m marize d bel o w. 
T a ble  7: 
Te m oz ol o mi de D ose Le vels f or M ai nte n a nce Tre at me nt  
D ose Le vel  
D ose ( m g/ m 2/ d a y) 
Re m ar ks  
-1  
1 0 0  
Re d ucti o n f or pri or t o xicit y  
0  
1 5 0  
D ose d uri n g C ycle 1  
1  
2 0 0  
D ose d uri n g C ycles 2 -6 i n a bse nce o f t o xicit y 
T a ble  8: 
Te m oz ol o mi de D ose Re d ucti o n or Disc o nti n u ati o n D uri n g 
M ai nte n a nce Tre at me nt  
T o xicit y  
Re d uce T M Z b y 1 D ose Le vel a 
Disc o nti n ue T M Z  
A bs ol ute Ne utr o p hil C o u nt  
< 1. 0 x 1 0 9/ L 
See f o ot n ote b 
Platelet C o u nt  
< 5 0 x 1 0 9/ L 
See f o ot n ote b 
C T C N o n -he mat ol o gical T o xicit y (e xce pt f or 
al o pecia, na usea, v o miti n g)  
C T C Gra de 3  
C T C Gra de 4 b 
T M Z = te m oz ol o mi de; C T C = C o m m o n T o xicit y Criteria  
a 
T M Z d ose le vels are liste d i n Ta ble  7. 
b 
T M Z is t o be disc o nti n ue d if d ose re d ucti o n t o < 3 0 0 m g/ m 2 is re q uire d or if t he sa me Gra de 3 
n o n he mat ol o gical t o xicit y (e xce pt f or al o pecia, na usea, v o miti n g) rec urs after d ose re d ucti o n.  
 
1 6. 3  
Te m oz ol o mi de Prescri bi n g I nf or m ati o n  
F ull te m oz ol o mi de prescri bi n g i nf or ma ti o n is l ocate d i n Attac h me nt 4 . Ke y feat ures are 
hi g hli g hte d bel o w.  
1 6. 3. 1  
St or a ge a n d St a bilit y  
T he ca ps ules are pac ka ge d i n a m ber glass b ottles a n d s h o ul d be st ore d at 2 5° C. Te m perat ure 
e xc ursi o ns bet wee n 1 5 a n d 3 0° C are per miss i ble. Refer t o t he c o m merciall y la bele d b ottles f or 
e x pirati o n dati n g. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 2  
Ple x xi k o n I nc.  
1 6. 3. 2  
P h ar m ac o ki netics  
Te m oz ol o mi de is ra pi dl y a n d c o m pletel y a bs or be d after oral a d mi nistrati o n; pea k plas ma 
c o nce ntrati o ns occ ur i n 1 h o ur. F o o d re d uces t he rate a n d e xte nt of te m oz ol o mi de a bs or pti o n. 
Mea n pea k plas ma c o nce ntrati o n a n d A U C decrease d b y 3 2 % a n d 9 %, res pecti vel y, a n d T
ma x  
i ncrease d 2-f ol d (fr o m 1. 1 t o 2. 2 5 h o urs) w he n te m oz ol o mi de was a d mi nistere d after a m o difie d 
hi g h- fat brea kfast. 
Te m oz ol o mi de is ra pi dl y eli mi nate d wit h a m ea n eli mi nati o n half -life of 1. 8 h o urs a n d e x hi bits 
li near ki netics o ver t he t hera pe utic d osi n g ra n ge. Te m oz ol o mi de has a mea n a p pare nt v ol u me of 
distri b uti o n of 0. 4 L/ k g ( % C V = 1 3 %). It is wea kl y b o u n d t o h u ma n plas ma pr otei ns; t he mea n 
perce nt b o u n d of dr u g- relate d t otal ra di oacti vit y is 1 5 %. 
1 6. 3. 3  
Met a b olis m a n d Eli mi n ati o n  
Te m oz ol o mi de is s p o nta ne o usl y h y dr ol yze d at p h ysi ol o gic p H t o t he acti ve s pecies, 3- met h yl-
(triaze n- 1-yl)i mi daz ole - 4-car b o xa mi de ( M TI C) a n d t o te m oz ol o mi de aci d meta b olite. M TI C is 
f urt her h y dr ol yze d t o 5-a mi n o-i mi daz ole- 4-car b o xa mi de ( AI C), w hic h is k n o w n t o be a n 
i nter me diate i n p uri ne a n d n ucleic aci d bi os y nt hesis a n d t o met h yl h y drazi ne, w hic h is belie ve d t o 
be t he acti ve al k ylati n g s pecies. C yt oc hr o me P 4 5 0 e nz y mes pla y o nl y a mi n or r ole i n t he 
meta b olis m of te m oz ol o mi de a n d M TI C. 
1 6. 3. 4  
S peci al P o p ul ati o ns  
Cre ati ni ne Cle ar a nce  
Ca uti o n s h o ul d be e xercise d w he n te m oz ol o mi de is a d mi nistere d t o patie nts wit h se vere re nal 
i m pair me nt. Te m oz ol o mi de has n ot bee n st u die d i n patie nts o n dial ysis. 
He p atic all y I m p aire d P atie nts  
I n a p har mac o ki netic st u d y, t he p har mac o ki netics of te m oz ol o mi de i n patie nts wit h mil d t o 
m o derate he patic i m pair me nt ( C hil d’s - P u g h Class I-II) were si milar t o t h ose o bser ve d i n patie nts 
wit h n or mal he patic f u ncti o n. Ca uti o n s h o ul d be e xercise d w he n te m oz ol o mi de is a d mi nistere d 
t o patie nts wit h se vere he patic i m pair me nt. 
Ge n der  
P o p ulati o n p har mac o ki netic a nal ysis i n dicates t hat w o me n ha ve a n a p pr o xi matel y 5 % l o wer 
cleara nce (a dj uste d f or b o d y s urface area) f or te m oz ol o mi de t ha n me n. W o me n ha ve hi g her 
i nci de nces of Gra de 4 ne utr o pe nia a n d t hr o m b oc yt o pe nia i n t he first c ycle of t hera p y t ha n me n. 
A ge  
P o p ulati o n p har mac o ki netic a nal ysis i n dicates t hat a ge (ra n ge 1 9- 7 8 years) has n o i nfl ue nce o n 
t he p har mac o ki netics of te m oz ol o mi de. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 3  
Ple x xi k o n I nc.  
1 6. 3. 5  
Dr u g -Dr u g I nter acti o ns 
I n a m ulti ple d ose st u d y, a d mi nistrati o n of te m oz ol o mi de wit h ra niti di ne di d n ot c ha n ge t he Cma x  
or A U C val ues f or te m oz ol o mi de or M TI C. P o p ulati o n a nal ysis i n dicates t hat a d mi nistrati o n of 
val pr oic aci d decreases t he cleara nce of te m oz ol o mi de  b y a b o ut 5 %. T he cli nical i m plicati o n of 
t his effect is n ot k n o w n. P o p ulati o n a nal ysis faile d t o de m o nstrate a n y i nfl ue nce of 
c o-a d mi nistere d de xa met has o ne, pr oc hl or perazi ne, p he n yt oi n, car ba maze pi ne, o n da nsetr o n, 
H 2-rece pt or a nta g o nists, or p he n o bar bital o n t he cleara nce of orall y a d mi nistere d te m oz ol o mi de. 
1 6. 3. 6  
A d verse E ve nts  
•  He mat ol o gic:  T hr o m b oc yt o pe nia, le u k o pe nia, m yel o d ys plastic s y n dr o me  
•  Gastr oi ntesti nal:  Na usea, v o miti n g, a n ore xia  
•  He patic:  Ele vate d li ver e nz y mes (re versi ble). A d diti o nal i nf or mati o n r e gar di n g he patic 
t o xicit y ca n be f o u n d i n Attac h me nt 4 . 
•  S ki n:  Ras h 
•  Ne ur ol o gic:  C o n v ulsi o ns, wea k ness o n o ne si de of t he b o d y, a b n or mal c o or di nati o n, 
paral ysis  
•  Ot her:  C o nsti pati o n, diarr hea, st o matitis, fati g ue, decrease d perf or ma nce stat us, hea dac he  
 
1 6. 3. 7  
S peci al H a n dli n g a n d Prec a uti o ns  
Ca ps ules s h o ul d n ot be o pe ne d or da ma ge d. Ri g or o us preca uti o ns s h o ul d be ta ke n t o a v oi d 
ca ps ule c o nte nts ha vi n g c o ntact wit h s ki n or m uc o us me m bra nes. Ca ps ule c o nte nts ma y be 
irritati n g t o s ki n a n d e yes. M uta ge nic a n d pr ol o n ge d e x p os ure ma y ca use seri o us healt h effects 
( o utsi de of prescri be d d osa ge i n t his trial). 
Te m oz ol o mi de is p ote ntiall y m uta ge nic a n d s h o ul d be ha n dle d wit h a p pr o priate preca uti o ns b y 
b ot h staff a n d patie nts. Ca ps ules s h o ul d n ot be o pe ne d. If ca ps ules are acci de ntall y o pe ne d or 
da ma ge d, ri g or o us preca uti o ns s h o ul d be ta ke n wit h t he ca ps ule c o nte nts t o a v oi d i n halati o n or 
c o ntact wit h t he s ki n or m uc o us me m bra nes. Pr oce d ures f or pr o per ha n dli n g a n d dis p osal of 
a ntica ncer dr u gs s h o ul d be c o nsi dere d. 
1 6. 3. 8  
C o ntr ai n dic ati o ns  
Te m oz ol o mi de is c o ntrai n dicate d i n patie nts w h o ha ve a hist or y of a h y perse nsiti vit y reacti o n t o 
a n y of its c o m p o ne nts or t o D TI C. 
1 6. 3. 9  
Pre g n a nc y C ate g or y D 
Te m oz ol o mi de ma y ca use fetal har m w he n a d mi nistere d t o a pre g na n t w o ma n. T here are n o 
a de q uate a n d well -c o ntr olle d st u dies i n pre g na nt w o me n. If t his dr u g is use d d uri n g pre g na nc y, 
or if t he patie nt bec o mes pre g na nt w hile ta ki n g t his dr u g, t he patie nt s h o ul d be a p prise d of t he 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 4  
Ple x xi k o n I nc.  
p ote ntial hazar d t o t he fet us. W o me n of c h il d be ari n g p ote nti al s h o ul d be a d vise d t o a v oi d 
bec o mi n g pre g n a nt d uri n g t her a p y wit h te m oz ol o mi de.  
Treat me nt of a ma n wit h te m oz ol o mi de ma y i ncrease t he ris k of birt h defects if he ca uses a 
w o ma n t o bec o me pre g na nt w hile he is ta ki n g te m oz ol o mi de. Me n treate d wit h te m oz ol o mi de 
ma y ha ve diffic ult y ca usi n g a w o ma n t o bec o me pre g na nt after t heir treat me nt is c o m plete d. 
Me n recei vi n g te m oz ol o mi de s h o ul d be directe d t o use effecti ve c o ntrace pti o n w hile t he y are 
bei n g treate d. T here is i ns ufficie nt data t o k n o w w hat t he ris k of s u bse q ue nt pr o ble ms wit h 
fertilit y will be. Si milarl y, w o me n w h o are treate d wit h te m oz ol o mi de ma y ha ve diffic ult y 
bec o mi n g pre g na nt i n t he f ut ure a n d ma y at be at i ncrease d ris k of ha vi n g c hil dre n wit h birt h 
defects. T here is i ns ufficie nt  e vi de nce t o deter mi ne w hat t he ris k of t hese c o m plicati o ns will be.  
1 6. 3. 1 0  
S u p pl y  
C o m merciall y a vaila ble.  
1 7. 0  
M E A S U R E S T O MI NI MI Z E/ A V OI D BI A S  
Eac h patie nt will be assi g ne d a u ni q ue n u m ber a n d will kee p t his n u m ber f or t he d urati o n of t he 
st u d y. Patie nt n u m bers will n ot be reassi g ne d or re use d f or a n y reas o n. Patie nts s h o ul d be 
i de ntifie d t o t he S p o ns or o nl y b y t heir assi g ne d n u m ber, i nitials, date of birt h, a n d se x. T he 
i n vesti gat or m ust mai ntai n a patie nt master l o g. 
1 8. 0  
S A F E T Y E V A L U A TI O N  
R o uti ne safet y a n d t olera bilit y  will be e val uate d fr o m t he res ults of re p orte d si g ns a n d 
s y m pt o ms, sc he d ule d p h ysical e xa mi nati o ns, vital si g n meas ure me nts, 1 2-lea d E C Gs (i ncl u di n g 
Q Tc F i nter vals), a n d cli nical la b orat or y test res ults.  
M ore fre q ue nt safet y e val uati o ns ma y be perf or me d i f cli nicall y i n dicate d or at t he discreti o n of 
t he i n vesti gat or. All A Es will be rec or de d fr o m t he ti me t he patie nt recei ves t he first d ose of 
st u d y dr u g u p t o 2 8 da ys after t he last d ose. 
As t his is a n o pe n la bel st u d y, o n g oi n g safet y will be c o nti n u o usl y a n d ri g or o usl y m o nit ore d b y 
t he S p o ns or. A d diti o nall y, bi wee kl y telec o nfere nces are pla n ne d t o re vie w i n detail t he safet y 
acr oss all st u d y sites.  
1 8. 1  
P h ysic al E x a mi n ati o n  
C o m plete a n d s y m pt o m- directe d p h ysical e xa mi nati o ns (i ncl u di n g ne ur ol o gical e xa m) will be 
perf or me d b y a lice nse d p h ysicia n ( or p h ysicia n’s assista nt or n urse practiti o ner). 
1 8. 2  
Vit al Si g ns  
Vital si g ns ( bl o o d press ure, res pirat or y rate, p ulse rate a n d te m perat ure) will be o btai ne d i n t he 
sitti n g p ositi o n. Patie nts s h o ul d be sitti n g f or 3-5 mi n ut es pri or t o o btai ni n g vital si g ns.  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 5  
Ple x xi k o n I nc.  
1 8. 3  
Electr oc ar di o gr a ms  
Patie nts s h o ul d rest i n t he s u pi ne p ositi o n f or at least 5 mi n utes bef ore eac h 1 2- lea d E C G 
rec or di n g is starte d. T he E C Gs s h o ul d be re vie we d, si g ne d, a n d date d b y a q ualifie d p h ysicia n 
( or q ualifie d p h ysicia n’s assista nt or n urse practiti o ner) a n d a n y cli nicall y i m p orta nt fi n di n g 
rec or de d o n t he a p pr o priate e C R F. T he i n vesti gat or is res p o nsi ble f or pr o vi di n g t he 
i nter pretati o n of all E C Gs. T he res ults will i ncl u de heart rate, res pirat or y rate ( R R), P R i nter val, 
Q R S i nter val, Q T i nter val, a n d Q Tc F i nter val. Fri dericia’s f or m ula is re q uire d.:   
Q Tc F = ( Q T)/ 3√( R R)  
1 8. 4  
S afet y L a b or at or y Deter mi n ati o ns 
La b orat or y e val uati o ns will be perf or me d as n ote d i n t he fl o w c hart. Please see At tac h me nt 1 f or 
t he s pecific la b orat or y tests t o be perf or me d. 
1 9. 0  
BI O M A R K E R S A M P L E S  
Bl o o d sa m pl es f or P D bi o mar kers will be o btai ne d as n ote d i n t he fl o w c hart. Sa m ples will be 
c ollecte d a n d pr ocesse d b y La b C or p acc or di n g t o t he st u d y- s pecific la b orat or y ma n ual. La b C or p 
will perf or m t he M G M T a nal yses. F or all patie nts, arc hi val t u m or sa m ples will be o btai ne d. 
Please see Attac h me nt 1  f or t he s pecific la b orat or y tests t o be perf or me d o n b ot h plas ma a n d 
tiss ue sa m ples. 
2 0. 0  
P H A R M A C O KI N E TI C E V A L U A TI O N  
2 0. 1  
Bl o o d C ollecti o n  
F or eac h P K sa m ple, bl o o d s h o ul d be c ollecte d as n ote d i n t he fl o w c hart. Sa m ples will be 
c ollecte d, pr ocesse d, st ore d, a n d s hi p pe d acc or di n g t o t he st u d y- s pecific la b orat or y ma n ual. 
Bl o o d sa m pl es f or P K a nal ysis s h o ul d be c ollecte d at t he re q ueste d ti me b ut wit hi n a ± 1 5 mi n ute 
wi n d o w. T he e xact act ual ti me of c ollecti o n s h o ul d be n ote d i n t he s o urce d oc u me nts a n d 
e C R Fs.  
T he t otal a m o u nt of bl o o d t o be c ollecte d fr o m eac h patie nt is < 3 0 m L d uri n g scree ni n g, < 6 0 m L 
d uri n g C ycle 1, a n d < 3 0 m L f or s u bse q ue nt c ycles. 
2 0. 2  
Bi o a n al ytic al Met h o d ol o g y 
T he plas ma a n d tiss ue sa m ples will be a nal yze d f or P L X 3 3 9 7 b y usi n g a vali date d met h o d ( hi g h 
perf or ma nce li q ui d c hr o mat o gra p h y ( H P L C) wit h ta n de m q ua dr u p ole mass s pectr o metric 
detecti o n) of a p pr o priate s pecificit y a n d se nsiti vit y. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 6  
Ple x xi k o n I nc.  
2 1. 0  
S T A TI S TI C A L A N A L Y SI S  
2 1. 1  
Ge ner al St atistic al C o nsi der ati o ns  
2 1. 1. 1  
P h ase 1 b P orti o n  
T he o bjecti ve of t he P hase 1 b p orti o n of t his st u d y is t o deter mi ne t he rec o m me n de d P hase 2 
d ose ( R P 2 D) of P L X 3 3 9 7 w he n c o m bi ne d wit h c o nc urre nt ra diati o n t hera p y a n d te m oz ol o mi de. 
T w o e x pecte d d ose le vels are s pecifie d f or testi n g, wit h o ne or m ore l o wer d oses t o be e val uate d 
if t he starti n g d ose of 8 0 0 m g/ da y is a b o ve t he M T D. F or eac h d ose le vel, 7 patie nts will be 
accr ue d t o ass ure t hat t here  will be 6 patie nts eli gi ble f or e val uati o n of t o xicit y. A patie nt 
re gistere d t o t he st u d y w h o is f o u n d retr os pecti vel y n ot t o meet t he st u d y eli gi bilit y criteria, w h o 
d oes n ot recei ve a n y P L X 3 3 9 7, or w h o is c o nsi dere d n o n-e val ua ble d uri n g t he t o xicit y 
e val uati o n peri o d f or reas o ns n ot relate d t o st u d y dr u g will be e xcl u de d fr o m e val uati o n of D L T 
a n d re place d.  
Patie nt accr ual will be s us pe n de d after eac h d ose c o h ort is e nr olle d u ntil t here is s ufficie nt 
i nf or mati o n c ollecte d t o ma ke a decisi o n relati ve t o dose escalati o n. A d ose le vel f or P L X 3 3 9 7 
will be c o nsi dere d acce pta ble if n o m ore t ha n 2 patie nts of t he 6 eli gi ble patie nts e x perie nce a 
D L T. S h o ul d all 7 patie nts be a nal yza ble f or a d verse e ve nts, o nl y t he first 6 will be c o nsi dere d i n 
t he deter mi nati o n of D L Ts. If t he c urre nt le vel is c o nsi dere d acce pta ble, t he n d ose escalati o n will 
occ ur a n d t he pr ot oc ol will be re o pe ne d. Ot her wise, t he prece di n g acce pta ble d ose le vel will be 
declare d t he M T D. T he S p o ns or, t o get her wit h t he st u d y i n vesti gat ors, will e va l uate t he safet y of 
eac h c o h ort pri or t o d ose escalati o n. 
2 1. 1. 2  
P h ase 2 P orti o n 
F or Part 2 ( P hase 2 p orti o n), t he pri mar y o bjecti ve is t he c o m paris o n of me dia n Pr o gressi o n Free 
S ur vi val ( P F S) t o hist orical c o ntr ol. Sec o n dar y o bjecti ves i ncl u de t he e val uati o n of o verall 
s ur vi val ( O S), p har mac o ki netics ( P K), c orrelati ve i ma gi n g st u dies, safet y, a n d t he e x pl orat or y 
e n d p oi nt of p har mac o d y na mic ( P D) effects of P L X 3 3 9 7. 
2 1. 2  
S a m ple Size a n d P o wer  
F or t he pri mar y e n d p oi nt of me dia n P F S, base d o n a o ne- si de d l o g ra n k test with a si g nifica nce 
le vel of 0. 1 a n d p o wer of 8 0 %, 2 2 e ve nts ( deat h or pr o gressi o n) i n a p pr o xi matel y 3 1 patie nts 
w o ul d be re q uire d t o detect a 5 0 % relati ve hazar d re d ucti o n i n pr o gressi o n-free s ur vi val d ue t o 
t he a d diti o n of P L X 3 3 9 7 c o m pare d t o t he rece nt hist orical c o ntr ol me dia n P F S of 5. 5 m o nt hs 
( R T O G 0 5 2 5). Ass u mi n g a ~ 3 0 % rate of n o n-e val ua bilit y, a p pr o xi matel y 3 7 patie nts are pla n ne d 
t o be e nr olle d i n t he P hase 2 p orti o n of t he st u d y, w hic h w he n c o m bi ne d wit h t he 7 patie nts 
treate d at t hat d ose le vel i n t he P hase 1 p orti o n of t he st u d y will yiel d a p pr o xi matel y 4 4 patie nts. 
2 1. 3  
A n al ysis P o p ul ati o ns  
T he pri mar y p o p ulati o n f or efficac y a n d safet y will c o nsist of t he m o difie d I T T p o p ulati o n, i.e., 
patie nts w h o recei ve at least o ne d ose of st u d y dr u g a n d ha ve a n y f oll o w- u p data. A per pr ot oc ol 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 7  
Ple x xi k o n I nc.  
efficac y p o p ulati o n will c o nsist of all patie nts w h o f ulfill t he i ncl usi o n/e xcl usi o n criteria a n d 
recei ve at least 4 wee ks of treat me nt wit h st u d y dr u g as well as at least 9 0 % of t he pla n ne d 
ra diati o n t hera p y. 
2 1. 4  
Effic ac y A n al ys is 
Res p o nse t o treat me nt will e val uate d usi n g t he Res p o nse Assess me nt i n Ne ur o - O nc ol o g y 
( R A N O) criteria (We n 2 0 1 0 ). T he res p o nse criteria are s u m marize d i n Attac h me nt 3 . All patie nts 
w h o are eli gi ble f or efficac y a nal yses will be e val ua ble f or P F S, calc ulate d f or eac h s u bject as 
t he n u m ber of da ys fr o m t he first da y of treat me nt ( C 1 D 1) t o t he date of t he first d oc u me nte d 
disease pr o gressi o n or date of deat h, w hic he ver occ urs first. T he Ka pla n -Meier  met h o d will be 
use d t o esti mate t he me dia n P F S.  
Statistical m o deli n g will be use d t o matc h t he e x peri me ntal gr o u p t o t he R T O G 0 5 2 5 hist orical 
gr o u p f or e x pecte d pr o g n osis base d o n b ot h cli nical a n d m olec ular fact ors, i m p orta ntl y t he le vel 
of M G M T met h ylat i o n i n t he t u m or tiss ue. 
F or eac h s u bject wit h a res p o nse t o t hera p y, d urati o n of res p o nse will be calc ulate d. T he d urati o n 
of res p o nse is defi ne d as n u m ber of da ys fr o m t he date of i nitial res p o nse t o t he date of first 
d oc u me nte d disease pr o gressi o n or deat h, w hic he ver occ urs first. T he Ka pla n -Meier met h o d will 
be use d t o esti mate me dia n d urati o n of res p o nse. I n t he e ve nt n o disease pr o gressi o n or deat h is 
d oc u me nte d pri or t o st u d y ter mi nati o n, a nal ysis c ut off, or t he start of c o nf o u n di n g a ntica ncer 
t hera py, P F S a n d d urati o n of res p o nse will be ce ns ore d at t he date of last e val ua ble t u m or 
assess me nts. T he me dia n d urati o n will be c o m pare d t o t he hist orical c o ntr ol P F S of 5. 5 m o nt hs. 
T he sec o n dar y e n d p oi nt of O S will be a nal yze d i n a si milar fas hi o n. 
A d diti o n al sec o n dar y a nal ysis of efficac y will i ncl u de patie nt -s pecific bi o mat he matical m o deli n g 
of t u m or gr o wt h ( Bal d oc k 2 0 1 3 ) t o all o w q ua ntificati o n of t he de gree of deflecti o n of t he t u m or 
off of its gr o wt h c ur ve relate d t o t he t hera p y (Neal 2 0 1 3a ; Neal 2 0 1 3 b ; A dair 2 0 1 4 ). T he patie nt-
s pecific m o del will be t u ne d t o t he pre-treat me nt M RIs. T he de gree of deflecti o n of t he t u m or off 
of its gr o wt h c ur ve will be meas ure d as Da ys Gai ne d a n d as Ra dial Treat me nt Res p o nse as i n 
(Neal 2 0 1 3a ; Neal 2 0 1 3 b ; A dair 2 0 1 4 ). Briefl y, patie nt-s pecific si m ulati o ns of pre dicte d t u m or 
gr o wt h will be c o m pare d wit h f oll o w u p M RIs i n ter ms of a te m p oral dela y of i ma gea ble t u m or 
gr o wt h ( Da ys Gai ne d) or as a dela y of t u m or gr o wt h i n ter ms of size ( Ra dial Treat me nt 
Res p o nse). T hese metrics will be c orrelate d wit h P F S a n d O S t hr o u g h c orrelati ve a n d Ka pla n -
Meier a nal yses t o c o n nect treat me nt res p o nse wit h o utc o mes. I n a d diti o n, relati o ns hi ps bet wee n 
treat me nt res p o nse, P F S, P D bi o mar kers, a n d tiss ue pr o g n ostic mar kers will be e x pl ore d. 
2 1. 5  
S afet y A n al ysis 
Safet y varia bles t o be a nal yze d are  A Es, la b orat or y test res ults ( he mat ol o g y a n d cli nical 
c he mistr y), E C G, wei g ht, a n d vital si g ns. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 8  
Ple x xi k o n I nc.  
A d verse e ve nt ter ms rec or de d o n t he e C R Fs will be ma p pe d t o preferre d ter ms usi n g t he Me dical 
Dicti o nar y f or Dr u g Re g ulat or y Acti vities ( Me d D R A ® ) versi o n 1 0. 1 or later. All A Es will be 
s u m marize d acc or di n g t o t he s yste m or ga n class a n d preferre d ter m wit hi n t he or ga n class. 
A d verse e ve nts will be tallie d f or o verall fre q ue nc y ( n u m ber a n d perce nta ge of s u bjects), w orst 
re p orte d se verit y, a n d relati o ns hi p t o st u d y dr u g f or eac h preferre d ter m per s u bject. Seri o us 
a d verse e ve nts will be si milarl y s u m marize d. Listi n gs of deat hs, S A Es, a n d A Es lea di n g t o earl y 
ter mi nati o n of st u d y treat me nt or pre mat ure wit h dra wal fr o m st u d y will als o be pr o vi de d. 
La b orat or y varia bles  will be e xa mi ne d usi n g mea n c ha n ge i n val ue fr o m baseli ne t o sc he d ule d 
ti me p oi nts. La b orat or y val ues will als o be cate g orize d acc or di n g t o t heir C T C A E ( versi o n 4) 
t o xicit y gra de a n d ta b ulate d b y w orst o n-st u d y t o xicit y gra de. T he baseli ne val ue of a varia ble is 
defi ne d as t he last val ue o btai ne d o n or bef ore t he date a n d ti me of t he first P L X 3 3 9 7 d ose. 
E C G, wei g ht, a n d vital si g ns will als o be s u m marize d b y c ha n ges fr o m baseli ne t o sc he d ule d 
ti me p oi nts usi n g descri pti ve statistics. 
2 1. 6  
P h ar m ac o ki netic A n al ys is 
F or t he P hase 1 b p orti o n of t he st u d y, a partial A U C ( A U C 0- 6) will be calc ulate d usi n g sa m ples 
c ollecte d fr o m C 1 D 8 ( pr e-te m oz ol o mi de) a n d C 1 D 1 5 (c o nc urre nt te m oz ol o mi de). Val ues f or 
C ma x  a n d Tma x  will be deter mi ne d fr o m t he c o nce ntrati o n -ti me pr ofile. 
A f or mal P K statistical a nal ysis pla n will be create d f or t his pr ot oc ol, a n d a se parate f or mal P K 
re p ort will be writte n f or i ncl usi o n i n t he fi nal st u d y re p ort. 
2 1. 7  
P h ar m ac o d y n a mic A n al ysis 
2 1. 7. 1  
Ce ntr al hist o p at h ol o gic re vie w a n d tiss ue re q uire me nts  
At least 2 0 u ns tai ne d F F P E sli des fr o m a re prese ntati ve bl oc k of t u m or tiss ue ( 0. 5 c m dia meter) 
s h o ul d be s u b mitte d o n all partici pa nts i n t he st u d y. O ne sli de will be H & E stai ne d at t he ce ntral 
site t o c o nfir m dia g n osis a n d deter mi ne eli gi bilit y f or f urt her st u d y. T he re mai ni n g sli des will be 
utilize d f or M G M T met h ylati o n assess me nt, bi o mar ker a nal ysis, a n d c orrelati o n of treat me nt 
effect wit h ge n ot y pe a n d p he n ot y pe. 
2 1. 7. 2  
Tiss ue E v al u ati o n 
T he rati o nale f or e val uati o n of t u m or tiss ue is t w o-f ol d:  1) t o a nal yze pr o g n ostic m ol ec ular 
fact ors t o be a ble t o c o m pare t he data vs. hist orical c o ntr ol data, a n d 2) t o c o n d uct e x pl orat or y 
e val uati o n of bi o mar kers of F ms i n hi biti o n, as well as c orrelati o n of cli nical o utc o mes wit h 
res p o nse a n d t u m or para meters. Beca use of t he i m p orta nce of t his t u m or tiss ue e val uati o n, 
s ur gical sa m ples are re q uire d, a n d bi o ps y- o nl y sa m ples are n ot all o we d. 
Pla n ne d bi o mar kers are liste d i n Attac h me nt 1 . T he stai ni n g patter ns will be se mi- q ua ntitati vel y 
a n d ma n uall y sc ore d a n d c orrelate d wit h ot her meas ures f or n u m ber of T A Ms a n d t heir 
m or p h ol o g y a n d l ocati o n wit hi n t he t u m or. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
6 9  
Ple x xi k o n I nc.  
N o f or mal statistical a nal ysis of P D e n d p oi nts will be perf or me d. P D data fr o m eac h assa y will 
be liste d, a n d p ossi ble relati o ns hi ps bet wee n cli nical res p o nse a n d P D varia bles will be e x pl ore d. 
A n y bi ol o gical acti vit y will be descri be d. 
2 1. 7. 3  
Ser u m bi o m ar ker a n al ysis  
Ser u m bi o mar kers will als o be assa ye d at a ce ntral la b orat or y. Please c o ns ult t he la b orat or y 
ma n ual f or s hi p pi n g a n d ha n dli n g i nstr ucti o ns. 
2 2. 0  
P R E C A U TI O N S  
Alt h o u g h maj or a d verse e ve nts are n ot a ntici pate d, t he i n vesti gat or m ust pr ocee d wit h ut m ost 
ca uti o n. E q ui p me nt, s u p plies, a n d pr o perl y s kille d me dical pers o n nel m ust be i m me diatel y 
a vaila ble f or e mer ge nc y use i n t he e ve nt of a n u ne x pecte d reacti o n. Patie nts m ust be caref ull y 
selecte d a n d cl osel y m o nit ore d. 
F or a c o m plete descri pti o n of precli nical a n d cli nical st u dies of P L X 3 3 9 7, please refer t o t he 
P L X 3 3 9 7 I n vesti gat or’s Br oc h ure.  
2 3. 0  
A D V E R S E E V E N T S  
F or safet y i nf or mati o n o n P L X 3 3 9 7, refer t o t he m ost rece nt versi o n of t he I n vesti gat or’s 
Br oc h ure. 
2 3. 1  
Defi niti o ns  
A n a d verse e ve nt  ( A E) is a n y u nt o war d, u n desire d, or u n pla n ne d e ve nt i n t he f or m of si g ns, 
s y m pt o ms, disease, or la b orat or y or p h ysi ol o gic o bser vati o ns occ urri n g i n a pers o n gi ve n a st u d y 
dr u g i n a cli nical st u d y. T he e ve nt d oes n ot nee d t o be ca usall y relate d t o t he st u d y dr u g. A n A E 
i ncl u des, b ut is n ot li mite d t o, t he f oll o wi n g: 
•  A n y cli nicall y si g nifica nt w orse ni n g of a pree xisti n g c o n diti o n. 
•  A n A E occ urri n g fr o m o ver d ose (i.e., a d ose hi g her t ha n t hat i n dicate d i n t he pr ot oc ol) of a 
st u d y dr u g, w het her acci de ntal or i nte nti o nal. 
•  A n A E occ urri n g fr o m a b use (e. g., use f or n o ncli nical reas o ns) of a st u d y dr u g. 
•  A n A E t hat has bee n ass ociate d wit h t he disc o nti n uati o n of t he use of a st u d y dr u g. 
A n y trea t me nt-e mer ge nt a b n or mal la b orat or y res ult w hic h is cli nicall y si g nifica nt, i.e., meeti n g 
o ne or m ore of t he f oll o wi n g c o n diti o ns, s h o ul d be rec or de d as a si n gle dia g n osis o n t he a d verse 
e ve nt pa ge i n t he e C R F: 
•  Acc o m pa nie d b y cli nical s y m pt o ms  
•  Lea di n g t o a c ha n ge i n st u d y me dicati o n (e. g., d ose m o dificati o n, i nterr u pti o n or per ma ne nt 
disc o nti n uati o n) 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 0  
Ple x xi k o n I nc.  
•  Re q uiri n g a c ha n ge i n c o nc o mita nt t hera p y (e. g., a d diti o n of, i nterr u pti o n of, disc o nti n uati o n 
of, or a n y ot her c ha n ge i n a c o nc o mita nt me dicati o n, t hera p y or t reat me nt) 
A seri o us a d verse e ve nt is a n A E t hat: 
•  Res ults i n deat h ( N O T E:  deat h is a n o utc o me, n ot a n e ve nt)  
•  Is life-t hreate ni n g. 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of a n e xisti n g h os pitalizati o n. 
•  Res ults i n a persiste nt or si g nifica nt disa bilit y or i nca pacit y.  
•  Res ults i n a c o n ge nital a n o mal y or birt h defect. 
•  A d diti o nall y, 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 be c o nsi dere d S A Es w he n, base d o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he patie nt a n d ma y re q uire me dical or s ur gical i nter ve nti o n 
t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h e ve nts i ncl u de 
aller gic br o nc h os pas 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 yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g 
de pe n de nc y or dr u g a b use. 
Cle ar pr o gressi o n of ne o pl asi a s h o ul d n ot be re p orte d as a n a d verse e ve nt or seri o us 
a d verse e ve nt.  Fi n di n gs t hat are clearl y c o nsiste nt  wit h t he e x pecte d pr o gressi o n of t he 
u n derl yi n g ca ncer s h o ul d n ot be re p orte d as a n a d verse e ve nt, a n d h os pitalizati o ns d ue t o t he 
pr o gressi o n of ca ncer d o n ot necessaril y q ualif y f or a seri o us a d verse e ve nt. S u d de n a n d 
u ne x plai ne d deat h s h o ul d be re p orte d as a n S A E. If t here is a n y u ncertai nt y a b o ut a fi n di n g bei n g 
d ue s olel y t o pr o gressi o n of ne o plasia, t he fi n di n g s h o ul d be re p orte d as a n a d verse e ve nt or 
seri o us a d verse e ve nt as a p pr o priate. 
Life -t hre ate ni n g refers t o i m me diate ris k of deat h as t he e vent occ urre d per t he re p orter. A life-
t hreate ni n g e x perie nce d oes n ot i ncl u de a n e x perie nce, ha d it occ urre d i n a m ore se vere f or m, 
w hic h mi g ht ha ve ca use d deat h, b ut as it act uall y occ urre d, di d n ot create a n i m me diate ris k of 
deat h. F or e xa m ple, he patitis t hat res ol ve d wit h o ut e vi de nce of he patic fail ure w o ul d n ot be 
c o nsi dere d life-t hreate ni n g, e ve n t h o u g h he patitis of a m ore se vere nat ure ca n be fatal. Si milarl y, 
a n aller gic reacti o n res ulti n g i n a n gi oe de ma of t he face w o ul d n ot be life -t hreate ni n g, e ve n 
t h o u g h a n gi oe de ma of t he lar y n x, aller gic br o nc h os pas m, or a na p h yla xis ca n be fatal. 
H os pit aliz ati o n  is official a d missi o n t o a h os pital. H os pitalizati o n or pr ol o n gati o n of a 
h os pitalizati o n c o nstit utes criteria f or a n A E t o be seri o us; h o we ver, it is n ot  i n itself c o nsi dere d 
a seri o us a d verse e ve nt ( S A E). I n a bse nce of a n A E, a h os pitalizati o n or pr ol o n gati o n of a 
h os pitalizati o n s h o ul d n ot be re p orte d as a n S A E. T his is t he case i n t he f oll o wi n g sit uati o ns: 
•  T he h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n is nee de d f or a pr oce d ure re q uire d b y 
t he pr ot oc ol. Da y or ni g ht s ur ve y visits f or bi o ps y or s ur ger y re q uire d b y t he pr ot oc ol are n ot 
c o nsi dere d seri o us. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 1  
Ple x xi k o n I nc.  
•  T he h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n is part of a r o uti ne pr oce d ure f oll o we d 
b y t he ce nter (e. g., ste nt re m o val after s ur ger y). T his s h o ul d be rec or de d i n t he st u d y file. 
•  H os pitalizati o n f or s ur ve y visits or a n n ual p h ysicals falls i n t he sa me cate g or y. 
I n a d diti o n, h os pitalizati o ns pla n ne d bef ore t he start of t he st u d y, f or a preexisti n g c o n diti o n t hat 
has n ot w orse ne d, d o n ot c o nstit ute a n S A E. A n e mer ge nc y r o o m visit is n ot c o nsi dere d a 
h os pitalizati o n u nless it res ults i n a h os pitalizati o n.  
Dis a bilit y  is defi ne d as a s u bsta ntial disr u pti o n i n a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
If t here is a n y d o u bt a b o ut w het her t he i nf or mati o n c o nstit utes a n S A E, t he i nf or mati o n is treate d 
as a n S A E.  
Relate d ness t o st u d y me dicati o n will be gra de d as eit her “ pr o ba bl y”, “ p ossi bl y”, or “ n ot relate d”, 
as f oll o ws: 
Pr o b a bl y  – T he a d verse e ve nt 
•  F oll o ws a reas o na ble te m p oral se q ue nce fr o m dr u g a d mi nistrati o n 
•  A bates u p o n disc o nti n uati o n of t he dr u g 
•  Ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n c haracteristics of t he patie nt’s cli nical state  
P ossi bl y  – T he a d verse e ve nt 
•  F oll o ws a reas o na ble te m p oral se q ue nce fr o m dr u g a d mi nistrati o n 
•  C o ul d ha ve bee n pr o d uce d b y t he patie nt’s cli nical state or b y ot her m o des of t hera p y 
a d mi nistere d t o t he patie nt 
N ot Rel ate d  – T he a d verse e ve nt  
•  D oes n ot f oll o w a reas o na ble se q ue nce fr o m dr u g a d mi nistrati o n  
•  Is rea dil y e x plai ne d b y t he patie nt’s cli nical state or b y ot her m o des of t hera p y a d mi nistere d 
t o t he patie nt 
A pr ot oc ol- rel ate d a d verse e ve nt  is a n A E occ urri n g d uri n g a cli nical st u d y t hat is n ot relate d 
t o t he st u d y dr u g, b ut is c o nsi dere d b y t he i n vesti gat or or t he me dical m o nit or ( or desi g nee) t o be 
relate d t o t he researc h c o n diti o ns, i.e., relate d t o t he fact t hat a patie nt is partici pati n g i n t he 
st u d y. F or e xa m ple, a pr ot oc ol-relate d A E ma y be a n u nt o war d e ve nt occ urri n g d uri n g a was h o ut 
peri o d or a n e ve nt relate d t o a me dical pr oce d ure re q uire d b y t he pr ot oc ol. 
Ot her  Re p ort a ble I nf or m ati o n :  certai n i nf or mati o n, alt h o u g h n ot c o nsi dere d a n S A E, m ust be 
rec or de d, re p orte d, a n d f oll o we d u p as i n dicate d f or a n S A E. T his i ncl u des:  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 2  
Ple x xi k o n I nc.  
•  A case i n v ol vi n g a pre g na nc y e x p os ure t o a st u d y dr u g, u nless t he pr o d uct is i n dicate d f or 
use d uri n g pre g na nc y e. g., pre natal vita mi ns. I nf or mati o n a b o ut use i n pre g na nc y 
e nc o m passes t he e ntire c o urse of pre g na nc y a n d deli ver y a n d peri natal a n d ne o natal 
o utc o mes, e ve n if t here were n o a b n or mal fi n di n gs. If a pre g na nc y is c o nfir me d, st u d y dr u g 
m ust be disc o nti n ue d i m me diatel y. All re p orts of pre g na nc y m ust be f oll o we d f or 
i nf or mati o n a b o ut t he c o urse of t he pre g na nc y a n d deli ver y, as well as t he c o n diti o n of t he 
ne w b or n. W he n t he ne w b or n is healt h y, a d diti o nal f oll o w- u p is n ot nee de d. Pre g na ncies 
occ urri n g u p t o 6 m o nt hs after c o m pleti o n of t he st u d y treat me nt m ust als o be re p orte d t o t he 
i n vesti gat or. 
•  O ver d ose (e. g., a d ose hi g her t ha n t hat i n dicate d i n t he pr ot oc ol) wit h or wit h o u t a n A E. 
•  A b use (e. g., use f or n o ncli nical reas o ns) wit h or wit h o ut a n A E. 
•  I na d verte nt or acci de ntal e x p os ure wit h or wit h o ut a n A E. 
•  De vice malf u ncti o n wit h or wit h o ut a n A E. 
2 3. 2  
Rec or di n g a n d Re p orti n g  
A patie nt’s A E or S A E ca n occ ur fr o m t he ti me t he patie nt recei ves t he first d ose of st u d y dr u g 
u p t o 2 8 da ys after t he last d ose. 
T he i n vesti gat or m ust f oll o w- u p o n all dr u g-relate d A Es, S A Es, a n d ot her re p orta ble i nf or mati o n 
u ntil t he e ve nts ha ve s u bsi de d, ret ur ne d t o baseli ne, t he patie nt has i nitiate d a n y ot h er a ntica ncer 
treat me nt, or i n case of per ma ne nt i m pair me nt, u ntil t he c o n diti o n sta bilizes. Pre g na ncies a n d 
o ver d oses are n ot c o nsi dere d A Es b ut m ust be re p orte d t o t he S p o ns or. 
All A E a n d S A Es m ust be rec or de d o n s o urce d oc u me nts a n d c ollecte d i n T E M P O. All A Es a n d 
S A Es f or patie nts w h o are n ot scree n fail ures will be rec or de d i n t he e C R Fs.  
A Es s h o ul d be base d o n t he si g ns or s y m pt o ms detecte d d uri n g t he p h ysical e xa mi nati o n a n d o n 
cli nical e val uati o n of t he patie nt. I n a d diti o n t o t he i nf or mati o n o btai ne d fr o m t h ose s o urces, t he 
patie nt s h o ul d be as ke d t he f oll o wi n g n o ns pecific q uesti o n:  " H o w ha ve y o u bee n feeli n g si nce 
y o ur last visit?" Si g ns a n d s y m pt o ms s h o ul d be rec or de d usi n g sta n dar d me dical ter mi n ol o g y. 
A n y u na ntici pate d ris ks t o t he patie nts m ust be re p orte d pr o m ptl y t o t he I R B/I E C. 
2 3. 3  
Seri o us A d verse E ve nt Re p orti n g  
All S A Es, ot her re p orta ble i nf or mati o n, a n d f oll o w - u p i nf or mati o n m ust be re p orte d wit hi n 
2 4 h o urs of lear ni n g of t he e ve nt b y c o m pleti n g t he S A E f or m wit hi n t he e C R F. As a bac k- u p, 
t he site ma y fa x a c o m pl ete d seri o us a d verse e ve nt f or m t o t he fa x n u m ber i n dicate d i n t he 
E mer ge nc y C o ntacts secti o n a n d c o nfir mi n g b y p h o ne or e- mail t hat t he fa x was recei ve d. 
Ple x xi k o n ( or desi g nee) will pr ocess a n d e val uate all S A Es as s o o n as t he re p orts are recei ve d. 
F or eac h S A E recei ve d, Ple x xi k o n will ma ke a deter mi nati o n as t o w het her t he criteria f or 
e x pe dite d re p orti n g ha ve bee n met. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 3  
Ple x xi k o n I nc.  
Ple x xi k o n ( or desi g nee) is res p o nsi ble f or re p orti n g rele va nt S A Es t o t he rele va nt re g ulat or y 
a ut h orities a n d partici pati n g i n vesti gat ors, i n acc or da nce wit h F D A re g ulati o ns 2 1 C F R 3 1 2. 3 2, 
I C H g ui deli nes, E ur o pea n Cli nical Trials Directi ve ( Directi ve 2 0 0 1/ 2 0/ E C), a n d/ or l ocal 
re g ulat or y re q uire me nts. 
Re p orti n g of S A Es b y t he i n vesti gat or t o t he I nstit uti o nal Re vie w B oar d (I R B) or Et hics 
C o m mittee ( E C) will be d o ne i n acc or da nce wit h t he sta n dar d o perati o n pr oce d ures a n d p olicies 
of t he I R B/ E C. A de q uate d oc u me ntati o n m ust be mai ntai ne d s h o wi n g t hat t he I R B/ E C was 
pr o perl y n otifie d. 
2 4. 0  
S T U D Y S U S P E N SI O N, T E R MI N A TI O N, A N D C O M P L E TI O N  
T he S p o ns or ma y s us pe n d or ter mi nate t he st u d y or a n y part of t he st u d y at a n y ti me f or a n y 
reas o n. If t he i n vesti gat or s us pe n ds or ter mi nates t he st u d y, t he i n vesti gat or will pr o m ptl y i nf or m 
t he S p o ns or a n d t he I R B/I E C a n d pr o vi de t he m wit h a detaile d writte n e x pla nati o n. T he 
i n vesti gat or will als o ret ur n all st u d y dr u g, c o ntai ners, a n d ot her st u d y materials t o t he c o ntract 
distri b uti o n ce nter, or destr o y t he materials at t he i n vesti gati ve site. U p o n st u d y c o m pleti o n, t he 
i n vesti gat or will pr o vi de t he S p o ns or, I R B/I E C, a n d re g ulat or y a ge nc y wit h fi nal re p orts a n d 
s u m maries as re q uire d b y re g ulati o ns. F or I N D st u dies, t he i n vesti gat or m ust s u b mit a writte n 
re p ort t o t he S p o ns or a n d t he I R B/I E C wit hi n 3 m o nt hs after t he c o m pleti o n or ter mi nati o n of t he 
st u d y. 
2 5. 0  
I N F O R M E D C O N S E N T 
T he i n vesti gat or will pr o vi de f or t he pr otecti o n of t he patie nts b y f oll o wi n g all a p plica ble 
re g ulati o ns. T hese re g ulati o ns are a vaila ble u p o n re q uest fr o m t he S p o ns or. T he i nf or me d 
c o nse nt f or m use d d uri n g t he i nf or me d c o nse nt pr ocess m ust be re vie we d b y t he S p o ns or a n d 
a p pr o ve d b y t he I R B/I E C. 
Bef ore a n y pr oce d ures s pecifie d i n t he pr ot oc ol are perf or me d, a patie nt m ust: 
•  Be i nf or me d of all perti ne nt as pects of t he st u d y a n d all ele me nts of i nf or me d c o nse nt. 
•  Be gi ve n ti me t o as k q uesti o ns a n d ti me t o c o nsi der t he decisi o n t o partici pate. 
•  V ol u ntaril y a gree t o partici pate i n t he st u d y.  
•  Si g n a n d date a n I R B/I E C a p pr o ve d i nf or me d c o nse nt f or m. 
 
2 6. 0  
P R O T O C O L A M E N D M E N T S  
A n y si g nifica nt c ha n ge i n t he st u d y re q uires a pr ot oc ol a me n d me nt. A n i n ve sti gat or m ust n ot 
ma ke a n y c ha n ges t o t he st u d y wit h o ut I R B/I E C a n d S p o ns or a p pr o val e xce pt w he n necessar y t o 
eli mi nate a p pare nt i m me diate hazar ds t o t he patie nts. A pr ot oc ol c ha n ge i nte n de d t o eli mi nate a n 
a p pare nt i m me diate hazar d t o patie nts ma y be i m ple me nte d i m me diatel y, b ut t he c ha n ge m ust 
t he n be d oc u me nte d i n a n a me n d me nt, 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, a n d 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 4  
Ple x xi k o n I nc.  
s u b mitte d t o t he a p pr o priate re g ulat or y a ge nc y i n t he re q uire d ti me fra me. All pr ot oc ol 
a me n d me nts m ust be re vie we d a n d a p pr o ve d f oll o wi n g t he sa me pr ocess as t he ori gi nal pr ot oc ol. 
2 7. 0  
Q U A LI T Y C O N T R O L A N D A S S U R A N C E  
T he S p o ns or perf or ms q ualit y c o ntr ol a n d ass ura nce c hec ks o n all cli nical st u dies t hat it 
s p o ns ors. Bef ore e nr olli n g a n y patie nts i n t his st u d y, S p o ns or pers o n nel a n d t he i n vesti gat or 
re vie w t he pr ot oc ol, t he i n vesti gat or’s br oc h ure, t he e C R Fs a n d i nstr ucti o ns f or t heir c o m pleti o n, 
t he pr oce d ure f or o btai ni n g i nf or me d c o nse nt, a n d t he pr oce d ure f or re p orti n g A Es a n d S A Es. A 
q ualifie d re prese ntati ve of t he S p o ns or will m o nit or t he c o n d uct of t he st u d y. D uri n g t hese site 
visits, i nf or mati o n rec or de d i n t he e C R Fs is verifie d a gai nst s o urce d oc u me nts. 
2 8. 0  
DI R E C T A C C E S S, D A T A H A N D LI N G, A N D R E C O R D K E E PI N G  
2 8. 1  
I n vesti g at or 
T he i n vesti gat or will per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y 
i ns pecti o ns b y pr o vi di n g direct access t o s o urce data a n d d oc u me nts. 
All st u d y -relate d i nf or mati o n will be rec or de d o n s o urce d oc u me nts. All re q uire d data will be 
rec or de d i n t he e C R Fs. All e C R F data m ust be s u b mitte d t o t he S p o ns or t hr o u g h o ut a n d at t he 
e n d of t he st u d y. 
If a n i n vesti gat or retires, rel ocates, or ot her wise wit h dra ws fr o m c o n d ucti n g t he st u d y, t he 
i n vesti gat or m ust n otif y t he S p o ns or t o a gree u p o n a n acce pta ble st ora ge s ol uti o n. Re g ulat or y 
a ge ncies will be n otifie d wit h t he a p pr o priate d oc u me ntati o n. 
All l a b orat or y a n d cli nical data gat here d i n t his pr ot oc ol will be st ore d i n a pass w or d- pr otecte d 
data base. All patie nt i nf or mati o n will be ha n dle d usi n g a n o n y m o us i de ntifiers. Li n ka ge t o patie nt 
st u d y data is o nl y p ossi ble after accessi n g a pass w or d-pr otecte d data base. Access t o t he data base 
is o nl y a vaila ble t o i n di vi d uals directl y i n v ol ve d i n t he st u d y. 
Patie nt pers o nal healt h i nf or mati o n t hat is accesse d f or t his st u d y will n ot be re use d or discl ose d 
t o a n y ot her pers o n or e ntit y, or f or ot her researc h. 
2 8. 2  
S p o n s or 
T he data will be c hec ke d f or c o m plete ness a n d c orrect ness b y real -ti me o nli ne c hec ks as it is 
e ntere d i nt o t he electr o nic data ca pt ure s yste m [ Te m p o] use d t o c ollect t he data. Off -li ne c hec ks 
will als o be r u n t o perf or m a n y a d diti o nal data re vie w re q ui re d. Discre pa nc y re p orts will be 
ge nerate d acc or di n gl y a n d tra nsferre d t o t he st u d y ce nter f or res ol uti o n b y t he i n vesti gat or or 
desi g nee.  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 5  
Ple x xi k o n I nc.  
2 9. 0  
P R E -S T U D Y D O C U M E N T A TI O N  
T he i n vesti gat or m ust pr o vi de t he S p o ns or wit h t he f oll o wi n g d oc u me nts B E F O R E e nr olli n g a n y 
p atie nts: 
•  C o m plete d a n d si g ne d f or m 1 5 7 2. 
•  All a p plica ble c o u ntr y-s pecific re g ulat or y f or ms. 
•  C urre nt si g ne d a n d date d c urric ula vitae f or t he i n vesti gat or, s u bi n vesti gat ors, a n d ot her 
i n di vi d uals ha vi n g si g nifica nt i n vesti gat or res p o nsi bilit y w h o are liste d o n t he F or m 1 5 7 2 or 
e q ui vale nt, or t he cli nical st u d y i nf or mati o n f or m. 
•  C o p y of t he I R B/I E C  a p pr o val letter f or t he pr ot oc ol a n d i nf or me d c o nse nt. All a d vertisi n g, 
recr uit me nt, a n d ot her writte n i nf or mati o n pr o vi de d t o t he patie nt m ust be a p pr o ve d b y t he 
I R B/I E C. Writte n ass ura nce of c o nti n ui n g a p pr o val (at least a n n uall y) as well as a c o p y of 
t he a n n ual pr o gress re p ort s u b mitte d t o t he I R B/I E C m ust als o be pr o vi de d t o t he S p o ns or. 
•  C o p y of t he I R B/I E C-a p pr o ve d i nf or me d c o nse nt d oc u me nt t o be use d. 
•  W here a p p lica ble, a list of t he I R B/I E C me m bers or a F W A/ D H H S n u m ber. 
•  C o p y of t he pr ot oc ol si g n- off pa ge si g ne d b y t he i n vesti gat or. 
•  C o p y of t he c urre nt me dical lice nse of t he pri nci pal I n vesti gat or a n d a n y s u bi n vesti gat ors. 
•  F ull y e xec ute d Cli nical Trial A gree me nt.  
•  W here a p plica ble, a fi na ncial discl os ure f or m f or t he i n vesti gat or, s u bi n vesti gat ors, a n d ot her 
i n di vi d uals w h o ha ve si g nifica nt i n vesti gat or res p o nsi bilit y a n d are liste d o n t he F or m 1 5 7 2. 
•  A writte n d oc u me nt c o ntai ni n g t he na me, l ocati o n, certificati o n n u m ber, a n d date of 
certificati o n of t he la b orat or y t o be use d f or la b orat or y assa ys a n d t h ose of ot her facilities 
c o n d ucti n g tests. T his d oc u me nt s h o ul d be ret ur ne d al o n g wit h t he la b direct or’s c urric ul u m 
vitae a n d acti ve me dical lice nse. T he S p o ns or m ust  be n otifie d if t he la b orat or y is c ha n ge d or 
if a n y a d diti o nal la b orat or y is t o be use d. 
•  List of n or mal la b orat or y val ues a n d u nits of meas ure f or all la b orat or y tests re q uire d b y t he 
pr ot oc ol. T his is re q uire d f or eac h la b orat or y t o be use d d uri n g t he st u d y. T he S p o ns or m ust 
be n otifie d if n or mal val ues or u nits of meas ure me nt c ha n ge. 
 
3 0. 0  
R E C O R D S R E T E N TI O N  
T he i n vesti gat or s hall retai n a n d preser ve 1 c o p y of all data ge nerate d i n t he c o urse of t he st u d y, 
s pecificall y i ncl u di n g b ut n ot li mite d t o t h ose defi ne d b y G C P as esse ntial, f or t he l o n ger of:  (i) 
2 years after t he last mar keti n g a ut h orizati o n f or t he st u d y dr u g has bee n a p pr o ve d or t he 
S p o ns or has disc o nti n ue d its researc h wit h res pect t o s uc h dr u g or (ii) s uc h l o n ger peri o d as 
re q uire d b y a p plica ble gl o bal re g ulat or y re q uire me nts. At t he e n d of s uc h peri o d, t he i n vesti gat or 
s hall n otif y t he S p o ns or i n writi n g of its i nte nt t o destr o y all s uc h material. T he S p o ns or s hall 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 6  
Ple x xi k o n I nc.  
ha ve 3 0 da ys t o res p o n d t o t he i n vesti gat or’s n otice, a n d t he S p o ns or s hall ha ve a f urt her 
o p p ort u nit y t o retai n s uc h materials at t he S p o ns or’s e x pe nse. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 7  
Ple x xi k o n I nc.  
3 1. 0  
R E F E R E N C E S  
A dair J E. ( 2 0 1 4). Ge ne t hera p y e n ha nces c he m ot hera p y t olera nce a n d efficac y i n gli o blast o ma 
patie nts. J Cli n I n vest. 1 2 4( 9): 4 0 8 2 – 4 0 9 2. 
Bal d oc k A L, et al. ( 2 0 1 3). Fr o m Patie nt- S pecific Mat he matical Ne ur o - O nc ol o g y t o Precisi o n 
Me dici ne. Fr o ntiers i n O nc ol o g y. 3( 6 2): 1- 1 1. 
Ple x xi k o n P L X 3 3 9 7 I n vesti gat or’s Br oc h ure. 
A h n G O et al. ( 2 0 1 0). I n hi biti o n of Mac- 1 ( C D 1 1 b/ C D 1 8) e n ha nces t u m or res p o nse t o ra diati o n 
b y re d uci n g m yel oi d cell recr uit me nt. Pr oc Natl Aca d Sci U S A. 1 0 7( 1 8): 8 3 6 3- 8. 
C o ni gli o et al. ( 2 0 1 2). Micr o glial sti m ulati o n of gli o blast o ma i n vasi o n i n v ol ves e pi der mal 
gr o wt h fact or rece pt or ( E G F R) a n d c ol o n y sti m ulati n g fact or 1 rece pt or ( C S F - 1 R) si g nali n g. M ol 
Me d. 1 8( 1): 5 1 9- 2 7. 
K o m o hara, Y. et al. ( 2 0 0 8). P ossi ble i n v ol ve me nt of t he M 2 a nti- i nfla m mat or y macr o p ha ge 
p he n ot y pe i n gr o wt h of h u ma n gli o mas. J Pat h ol. 2 1 6: 1 5- 2 4.  
La m b or n, K. R. et al. ( 2 0 0 8) Pr o gressi o n-free s ur vi val:  A n i m p orta nt e n d p oi nt i n e val uati n g 
t hera p y f or rec urre nt hi g h-gra de gli o mas. Ne ur o - o nc ol o g y 1 0:  1 6 2- 1 7 0. 
Mar k o vic D S et al. ( 2 0 0 9). Gli o mas i n d uce a n d e x pl oit micr o glial M T 1- M M P e x pressi o n f or 
t u m or e x pa nsi o n. Pr oc Natl Aca d Sci U S A. 1 0 6: 1 2 5 3 0- 1 2 5 3 5. 
Neal M L. ( 2 0 1 3a). Discri mi nati n g S ur vi val O utc o mes i n Patie nts wit h Gli o blast o ma Usi n g a 
Si m ulati o n -Base d, Patie nt - S pecific Res p o nse Metric. P L o S O N E 8( 1):e 5 1 9 5 1. 
Neal M L. ( 2 0 1 3 b). Pr o gressi o n fr o m Pse u d o pr o gressi o n Gr o wt h is Pr o g n ostic f or Cli nical 
O utc o mes a n d Disti n g uis hes Res p o nse Classificati o n Base d o n  a Mi ni mal M o del of 
Gli o blast o ma Ca ncer Res. 7 3: 2 9 7 6- 2 9 8 6. 
P hilli ps, H. S. et al. ( 2 0 0 6). M olec ular s u bclasses of hi g h- gra de gli o ma pre dict pr o g n osis, 
deli neate a patter n of disease pr o gressi o n, a n d rese m ble sta ges i n ne ur o ge nesis. Ca ncer Cell 
9: 1 5 7 – 1 7 3. 
R o d er o, M. et al. ( 2 0 0 8). P ol y m or p his m i n t he Micr o glial Cell- M o bilizi n g C X 3 C R 1 Ge ne Is 
Ass ociate d Wit h S ur vi val i n Patie nts Wit h Gli o blast o ma. J Cli n O nc ol 2 6: 5 9 5 7 - 5 9 6 4. 
Ver haa k, R. G. W. et al. ( 2 0 1 0). I nte grate d Ge n o mic A nal ysis I de ntifies Cli nicall y Rele va n t 
S u bt y pes of Gli o blast o ma C haracterize d b y A b n or malities i n P D G F R A, I D H 1, E G F R, a n d N F 1. 
Ca ncer Cell 1 7:  9 8 – 1 1 0. 
We n, P. Y. et al. ( 2 0 1 0). U p date d Res p o nse Assess me nt Criteria f or Hi g h- Gra de Gli o mas:  
Res p o nse Assess me nt i n Ne ur o - O nc ol o g y W or ki n g Gr o u p. J Cli n O nc ol 2 8:  1 9 6 3- 1 9 7 2. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 8  
Ple x xi k o n I nc.  
Zi m mer ma n HJ. ( 1 9 9 9). He pat ot o xicit y:  T he A d verse Effects of Dr u g a n d Ot her C he micals o n 
t he He patic, 2 n d e diti o n, P hila del p hia, Li p pi nc ott Willia ms a n d Wil ki ns, C ha pters 4, 5 a n d 1 6. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
7 9  
Ple x xi k o n I nc.  
A T T A C H M E N T 1:  L A B O R A T O R Y T E S T S  
He m at ol o g y  
He m o gl o bi n a n d he mat ocrit  
 
W hite bl o o d cell c o u nt wit h differe ntial  
 
Platelet c o u nt  
 
Ser u m C he mistr y  
S o di u m  
P otassi u m  
C hl ori de 
C O 2 
Calci u m  
P h os p h or us 
Gl uc ose  
Bl o o d urea nitr o ge n  
Creati ni ne  
Uric aci d  
T otal pr otei n  
Al b u mi n  
T otal a n d direct bilir u bi n  
As pa rtate a mi n otra nsferase ( A S T) 
Ala ni ne a mi n otra nsferase ( A L T)  
Al kali ne p h os p hatase ( A P)  
Lactate de h y dr o ge nase ( L D H)  
 
Ser u m pre g n a nc y test ( β -H C G) :  w o me n of c hil d- beari n g p ote ntial 
Bl o o d Res p o nse Bi o m ar kers:  
•  C S F - 1 
•  Bi o mar kers of ki nase i n hi biti o n a n d m yel oi d cell recr uit me nt  
•  C D 1 4/ C D 1 6 m o n o n uclear cells 
Tiss ue Res p o nse Bi o m ar kers i n F or m ali n -Fi xe d S ur gic al Tiss ue  
•  M G M T met h ylati o n  
•  C S F 1 R a n d C S F 1  
•  T u m or -ass ociate d macr o p ha ges  
•  Ot her pr o g n ostic mar kers as a p pr o priate  
Beca use t he i de ntificati o n of ne w res p o nse pre dicti o n or earl y res p o nse bi o mar kers of disease 
acti vit y is a ra pi dl y de vel o pi n g fiel d, t he defi niti ve list of a nal yses re mai ns t o be deter mi ne d, a n d 
ma y i ncl u de a d diti o nal mar kers of macr o p ha ge acti vit y, i n a d diti o n t o a nti- t u m or bi o mar kers t hat 
ma y be rel ate d t o P L X 3 3 9 7 treat me nt. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
8 0  
Ple x xi k o n I nc.  
A T T A C H M E N T 2:  S T R O N G C Y P 3 A 4 I N HI BI T O R S A N D I N D U C E R S  
Str o n g I n hi bit ors  
Str o n g I n d ucers  
Pr otease i n hi bit ors  
•  Rit o na vir 
•  I n di na vir 
•  Nelfi na vir  
Macr oli de a nti bi otics  
•  Er yt hr o m yci n 
•  Telit hr o m yci n  
•  Clarit hr o m yci n  
Az ole a ntif u n gals 
•  Fl uc o naz ole  
•  Ket oc o naz ole 
•  Itrac o naz ole 
C hl ora m p he nic ol (a nti bi otic)  
Nefaz o d o ne (a nti de pressa nt) 
Ber ga m otti n (c o nstit ue nt of gra pefr uit j uice) 
A pre pita nt (a ntie metic)  
Vera pa mil (calci u m c ha n nel bl oc ker)  
A ntic o n v ulsa nts, m o o d sta bilizers  
•  P he n yt oi n 
•  Car ba maze pi ne  
•  O xcar baze pi ne  
N o n -n ucle osi de re verse tra nscri ptase 
i n hi bit ors 
•  Efa vire nz 
•  Ne vira pi ne  
•  Etra viri ne  
P he n o bar bital ( bar bit urate) 
Rifa m pici n ( bacterici dal)  
M o dafi nil (sti m ula nt)  
H y perf ori n (c o nstit ue nt of St J o h ns W ort) 
C y pr oter o ne (a ntia n dr o ge n, pr o gesti n)  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
8 1  
Ple x xi k o n I nc.  
A T T A C H M E N T  3:  R A N O R E S P O N S E C RI T E RI A  
Patie nts wit h meas ura ble disease ( bi di me nsi o nal meas ure me nts) will be assesse d b y t he R A N O 
(ra di o gra p hic assess me nt i n ne ur o o nc ol o g y) criteria. F or t he p ur p oses of t his st u d y, patie nts 
s h o ul d be re-e val uate d e ver y 8 wee ks wit h a  c o ntrast-e n ha nce d cra nial M RI sca n. T he res p o nse 
will be deter mi ne d as o utli ne d i n t he R A N O criteria bel o w.  
C o m plete Res p o nse  (re q uires all of t he f oll o wi n g): 
a) C o m plete disa p peara nce of all e n ha nci n g meas ura ble a n d n o n -meas ura ble disease 
s ustai ne d f or at least 4 wee ks. I n t he a bse nce of a c o nfir mi n g sca n 4 wee ks later, t his sca n 
will be c o nsi dere d o nl y sta ble disease.  
b)  N o ne w lesi o ns. 
c) All meas ura ble a n d n o n- meas ura ble lesi o ns m ust be assesse d usi n g t he sa me tec h ni q ues 
as baseli ne. 
d)  Patie nts m ust be o n n o ster oi ds. 
e) Sta ble or i m pr o ve d n o n- e n ha nci n g ( T 2/ F L AI R) lesi o ns.  
f) Sta ble or i m pr o ve d cli nicall y.  
N ote:  Patie nts wit h n o n -meas ura ble disease ca n n ot ha ve a c o m plete res p o nse. T he best res p o nse p ossi ble 
is sta ble disease. 
P arti al Res p o nse  (re q uires all of t he f oll owi n g): 
a) Greater t ha n or e q ual t o 5 0 % decrease c o m pare d t o baseli ne i n t he s u m of pr o d ucts of 
per pe n dic ular dia meters ( bi- di me nsi o nal meas ure me nts) of all meas ura ble e n ha nci n g 
lesi o ns s ustai ne d f or at least 4 wee ks. I n t he a bse nce of a c o nfir mi n g sca n 4 wee ks later, 
t his sca n will be c o nsi dere d o nl y sta ble disease. 
b)  N o pr o gressi o n of n o n- meas ura ble disease.  
c) N o ne w lesi o ns. 
d)  All meas ura ble a n d n o n meas ura ble lesi o ns m ust be assesse d usi n g t he sa me tec h ni q ues as 
baseli ne.  
e) T he ster oi d d ose at t he ti me of t he sca n e val uati o n s h o ul d be n o greater t ha n t he d ose at 
ti me of baseli ne sca n. 
f) Sta ble or i m pr o ve d n o n-e n ha nci n g ( T 2/ F L AI R) lesi o ns o n sa me or l o wer d ose of 
c ortic oster oi ds c o m pare d t o baseli ne sca n.  
g)  Sta ble or i m pr o ve d cli nicall y.  
N ote:  Patie nts wit h n o n -meas ura bl e disease ca n n ot ha ve a partial res p o nse. T he best res p o nse p ossi ble is 
sta ble disease. 

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
8 2  
Ple x xi k o n I nc.  
St a ble Dise ase  (re q uires all of t he f oll o wi n g): 
a) D oes n ot q ualif y f or C R, P R, or pr o gressi o n. 
b)  T he desi g nati o n of sta ble disease re q uires a mi ni m u m of 4 - wee k d urati o n. 
c) Al l meas ura ble a n d n o n-meas ura ble sites m ust be assesse d usi n g t he sa me tec h ni q ues as 
baseli ne.  
d)  Sta ble n o n-e n ha nci n g ( T 2/ F L AI R) lesi o ns o n sa me or l o wer d ose of c ortic oster oi ds 
c o m pare d t o baseli ne sca n. I n t he e ve nt t hat t he c ortic oster oi d d ose has bee n i nc rease d, 
t he last sca n c o nsi dere d t o s h o w sta ble disease will be t he sca n o btai ne d w he n t he 
c ortic oster oi d d ose was e q ui vale nt t o t he baseli ne d ose.  
e) Sta ble cli nicall y.  
Pr o gressi ve Dise ase ( defi ne d b y a n y of t he f oll o wi n g): 
a) > 2 5 % i ncrease i n s u m of t he pr o d uc ts of per pe n dic ular dia meters ( bi- di me nsi o nal 
meas ure me nts) of e n ha nci n g lesi o ns ( o ver baseli ne if n o decrease) o n sta ble or i ncreasi n g 
d oses of c ortic oster oi ds. a n d/ or 
b)  Si g nifica nt i ncrease i n T 2/ F L AI R n o n-e n ha nci n g lesi o n o n sta ble or i ncreasi n g d oses of 
c ortic oster oi ds c o m pare d t o baseli ne sca n or best res p o nse f oll o wi n g i nitiati o n of t hera p y, 
n ot d ue t o c o- m or bi d e ve nts (ra diati o n t hera p y, de m yeli nati o n, isc he mic i nj ur y, i nfecti o n, 
seiz ures, p ost o perati ve c ha n ges, or ot her treat me nt effects). 
c) A n y ne w lesi o n. 
d)  Clear cli nical deteri orati o n n ot attri b uta ble t o ot her ca uses a part fr o m t he t u m or (e. g., 
seiz ures, me dicati o n si de effects, c o m plicati o ns of t hera p y, cere br o vasc ular e ve nts, 
i nfecti o n, etc.). T he defi niti o n of cli nical deteri orati o n is left t o t he discreti o n of t he 
treati n g p h ysicia n, b ut it is rec o m me n de d t hat a decrease i n 2 0 % of K P S or fr o m a n y 
baseli ne t o 5 0 % or less be c o nsi dere d, u nless attri b uta ble t o c o m or bi d e ve nts. 
e) Fail ure t o ret ur n f or e val uati o n d ue t o deat h or deteri orati n g c o n diti o n. 
Ass ess me nt of Res p o nse  ( Efficac y) 
Ti mi n g of t he E val uati o n of Res p o nse:  Assess me nt of res p o nse will be gi n wit h t he pre vi o us 
M RI. All sca ns are t o be c o m pare d t o t he s mallest meas ure me nt sca n t o date.  

P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 8 A me n d me nt 5  
C o nfi de nti al  
8 3  
Ple x xi k o n I nc.  
A T T A C H M E N T 4:  T E M O Z O L O MI D E P R E S C RI BI N G I N F O R M A TI O N  
 
 

 
1  
HI G H LI G H T S O F P R E S C RI BI N G I N F O R M A TI O N  
T h e s e hi g hli g ht s d o n ot i n cl u d e all t h e i nf or m ati o n n e e d e d t o u s e 
T E M O D A R s af el y a n d eff e cti v el y. S e e f ull pr e s cri bi n g i nf or m ati o n 
f or T E M O D A R. 
 
T E M O D A R ®  (t e m o z ol o mi d e) C a p s ul e s 
T E M O D A R ®  (t e m o z ol o mi d e) f or I nj e cti o n 
a d mi ni st er e d vi a i ntr a v e n o u s i nf u si o n  
I niti al U. S. A p pr o v al: 1 9 9 9 
 ----------------------------I N DI C A TI O N S A N D U S A G E ---------------------------- 
T E M O D A R  i s  a n  al k yl ati n g  dr u g  i n di c at e d  f or  t h e  tr e at m e nt  of  a d ult  
p ati e nt s wit h:  
•  
N e wl y  di a g n o s e d  gli o bl a st o m a  m ultif or m e  ( G B M)  c o n c o mit a ntl y  
wit h r a di ot h er a p y a n d t h e n  a s m ai nt e n a n c e tr e at m e nt. ( 1. 1)  
•  
R efr a ct or y a n a pl a sti c a str o c yt o m a p ati e nt s w h o h a v e e x p eri e n c e d 
di s e a s e  pr o gr e s si o n  o n  a  dr u g  r e gi m e n  c o nt ai ni n g  nitr o s o ur e a  
a n d pr o c ar b a zi n e. ( 1. 2)  
 ----------------------- D O S A G E A N D A D MI NI S T R A TI O N  ----------------------- 
•  
N e wl y Di a g n o s e d G B M : 7 5 m g/ m 2  f or 4 2 d a y s c o n c o mit a nt wit h 
f o c al  r a di ot h er a p y  f oll o w e d  b y  i niti al  m ai nt e n a n c e  d o s e  of  1 5 0  
m g/ m
2  o n c e d ail y f or D a y s 1 -5 of a 2 8 -d a y c y cl e of T E M O D A R f or 
6 c y cl e s. ( 2. 1)  
•  
R efr a ct or y A n a pl a sti c A str o c yt o m a: I niti al d o s e 1 5 0 m g/ m 2  o n c e 
d ail y f or 5 c o n s e c uti v e d a y s p er 2 8 -d a y tr e at m e nt c y cl e. ( 2. 1)  
•  
T h e  r e c o m m e n d e d  d o s e  f or  T E M O D A R  a s  a n  i ntr a v e n o u s  
i nf u si o n  o v er  9 0  mi n ut e s  i s  t h e  s a m e  a s  t h e  d o s e  f or  t h e  or al  
c a p s ul e  f or m ul ati o n.  Bi o e q ui v al e n c e  h a s  b e e n  e st a bli s h e d  o nl y  
w h e n T E M O D A R f or I nj e cti o n w a s gi v e n o v er 9 0 mi n ut e s. ( 2 . 1, 
1 2. 3)  
 --------------------- D O S A G E F O R M S A N D S T R E N G T H S  --------------------- 
•   
5-m g,  2 0 -m g,  1 0 0 -m g,  1 4 0 -m g,  1 8 0 -m g,  a n d  2 5 0 -m g c a p s ul e s. 
( 3) 
•  
1 0 0 -m g p o w d er f or i nj e cti o n. ( 3)  
 ------------------------------- C O N T R AI N DI C A TI O N S  ------------------------------- 
•  
K n o w n  h y p er s e n siti vit y  t o  a n y  T E M O D A R  c o m p o n e nt  or  t o  
d a c ar b a zi n e ( D TI C). ( 4. 1)  
 ----------------------- W A R NI N G S A N D P R E C A U TI O N S  ------------------------ 
•  
M y el o s u p pr e s si o n — 
m o nit or  A b s ol ut e  N e utr o p hil  C o u nt  ( A N C)  
a n d  pl at el et  c o u nt  pri or  t o  d o si n g  a n d  t hr o u g h o ut  tr e at m e nt.  
G eri atri c  p ati e nt s  a n d  w o m e n  h a v e  a  hi g h er  ri s k  of  d e v el o pi n g  
m y el o s u p pr e s si o n. ( 5. 1)  
•  
C a s e s of m y el o d y s pl a sti c s y n dr o m e a n d s e c o n d ar y m ali g n a n ci e s, 
i n cl u di n g m y el oi d l e u k e mi a, h a v e b e e n o b s er v e d. ( 5. 2) 
•  
P n e u m o c y sti s c ari nii  p n e u m o ni a ( P C P) – pr o p h yl a xi s r e q uir e d f or 
all p ati e nt s r e c ei vi n g c o n c o mit a nt T E M O D A R a n d r a di ot h er a p y f or 
t h e  4 2-d a y  r e gi m e n  f or  t h e  tr e at m e nt  of  n e wl y  di a g n o s e d  
gli o bl a st o m a m ultif or m e. ( 5. 3)  
•  
All  p ati e nt s,  p arti c ul arl y  t h o s e  r e c ei vi n g  st er oi d s,  s h o ul d  b e  
o b s er v e d cl o s el y f or t h e d e v el o p m e nt of l y m p h o p e ni a a n d P C P. 
( 5. 4) 
•  
C o m pl et e  bl o o d  c o u nt s  s h o ul d  b e  o bt ai n e d  t hr o u g h o ut  t h e  
tr e at m e nt c o ur s e a s s p e cifi e d. ( 5. 4) 
•  
F e t al h ar m c a n o c c ur w h e n a d mi ni st er e d t o a pr e g n a nt w o m a n. 
W o m e n  s h o ul d  b e  a d vi s e d  t o  a v oi d  b e c o mi n g  pr e g n a nt  w h e n  
r e c ei vi n g T E M O D A R. ( 5. 5) 
•  
A s bi o e q ui v al e n c e h a s b e e n e st a bli s h e d o nl y w h e n gi v e n o v er 9 0 
mi n ut e s,  i nf u si o n  o v er  a  s h ort er  or  l o n g er  p eri o d  of  t i m e  m a y  
r e s ult  i n  s u b o pti m al  d o si n g;  t h e  p o s si bilit y  of  a n  i n cr e a s e  i n  
i nf u si o n-r el at e d a d v er s e r e a cti o n s c a n n ot b e r ul e d o ut. ( 5. 6) 
 ------------------------------ A D V E R S E R E A C TI O N S  ------------------------------ 
•  
T h e  m o st  c o m m o n  a d v er s e  r e a cti o n s  ( ≥1 0 %  i n ci d e n c e)  ar e: 
al o p e ci a,  f ati g u e,  n a u s e a,  v o miti n g,  h e a d a c h e,  c o n sti p ati o n, 
a n or e xi a,  c o n v ul si o n s,  r a s h,  h e mi p ar e si s,  di arr h e a,  a st h e ni a,  
f e v er, di z zi n e s s, c o or di n ati o n a b n or m al, vir al i nf e cti o n, a m n e si a, 
a n d i n s o m ni a. ( 6. 1)  
•  
T h e  m o st  c o m m o n  Gr a d e  3  t o  4  h e m at ol o gi c  l a b or at or y  
a b n or m aliti e s  ( ≥1 0 %  i n ci d e n c e)  t h at  h a v e d e v el o p e d  d uri n g  
tr e at m e nt
 wit h
 t e m o z ol o mi d e
 ar e:
 l y m p h o p e ni a,
 
t hr o m b o c yt o p e ni a, n e utr o p e ni a, a n d l e u k o p e ni a. ( 6. 1) 
•  
All er gi c r e a cti o n s h a v e al s o b e e n r e p ort e d. ( 6)  
 
T o  r e p ort  S U S P E C T E D  A D V E R S E  R E A C TI O N S,  c o nt a ct  M er c k 
S h ar p & D o h m e C or p. , a s u b si di ar y of M er c k & C o., I n c., at 1- 8 7 7 -
8 8 8 -4 2 3 1  or F D A at 1 -8 0 0 -F D A -1 0 8 8 or w w w.f d a. g o v/ m e d w at c h.  
 ------------------------------- D R U G I N T E R A C TI O N S  ------------------------------- 
•  
V al pr oi c a ci d: d e cr e a s e s or al cl e ar a n c e of t e m o z ol o mi d e. ( 7. 1)  
 ----------------------- U S E I N S P E CI FI C P O P U L A TI O N S  ----------------------- 
•  
N ur si n g m ot h er s: N ot r e c o m m e n d e d. ( 8. 3)  
•  
P e di atri c u s e: N o  e st a bli s h e d u s e. ( 8. 4)  
•  
H e p ati c/ R e n al  I m p air m e nt:  C a uti o n  s h o ul d  b e  e x er ci s e d  w h e n  
T E M O D A R  i s  a d mi ni st er e d  t o  p ati e nt s  wit h  s e v er e  r e n al  or  
h e p ati c i m p air m e nt. ( 8. 6, 8. 7)  
 
S e e  1 7  f or  P A TI E N T  C O U N S E LI N G  I N F O R M A TI O N  a n d  F D A -
a p pr o v e d p ati e nt l a b eli n g.  
 
R e vi s e d: 0 6/ 2 0 1 3
F U L L P R E S C RI BI N G I N F O R M A TI O N: C O N T E N T S*
1 
I N DI C A TI O N S A N D U S A G E 
1. 1  N e wl y Di a g n o s e d Gli o bl a st o m a M ultif or m e  
1. 2  R efr a ct or y A n a pl a sti c A str o c yt o m a  
2 
D O S A G E A N D A D MI NI S T R A TI O N  
2. 1  R e c o m m e n d e d D o si n g a n d D o s e M o difi c ati o n G ui d eli n e s  
2. 2  Pr e p ar ati o n a n d A d mi ni str ati o n  
3 
D O S A G E F O R M S A N D S T R E N G T H S  
4 
C O N T R AI N DI C A TI O N S  
4. 1  H y p er s e n siti vit y  
5 
W A R NI N G S A N D P R E C A U TI O N S  
5. 1  M y el o s u p pr e s si o n  
5. 2  M y el o d y s pl a sti c S y n dr o m e  
5. 3  P n e u m o c y sti s c ari nii  P n e u m o ni a  
5. 4  L a b or at or y T e st s  
5. 5  U s e i n Pr e g n a n c y  
5. 6  I nf u si o n Ti m e 
6 
A D V E R S E R E A C TI O N S  
6. 1  Cli ni c al Tri al s E x p eri e n c e  
6. 2  P o st m ar k eti n g E x p eri e n c e  
7 
D R U G I N T E R A C TI O N S  
7. 1  V al pr oi c A ci d  
8 
U S E I N S P E CI FI C P O P U L A TI O N S  
8. 1  Pr e g n a n c y  
8. 3  N ur si n g M ot h er s  
8. 4  P e di atri c U s e  
8. 5  G eri atri c U s e  
8. 6  R e n al I m p air m e nt  
8. 7  H e p ati c I m p air m e nt  
1 0  O V E R D O S A G E  
1 1  D E S C RI P TI O N  
1 2  C LI NI C A L P H A R M A C O L O G Y  
1 2. 1  M e c h a ni s m of A cti o n  
1 2. 3  P h ar m a c o ki n eti c s  
1 3  N O N C LI NI C A L T O XI C O L O G Y  
 
1 3. 1  C ar ci n o g e n e si s, M ut a g e n e si s, I m p air m e nt of F ertilit y  
 
1 3. 2  A ni m al T o xi c ol o g y a n d/ or P h ar m a c ol o g y  
1 4  C LI NI C A L S T U DI E S  
 
1 4. 1  N e wl y Di a g n o s e d Gli o bl a st o m a M ultif or m e  
 
1 4. 2  R efr a ct or y A n a pl a sti c A str o c yt o m a  
1 5  R E F E R E N C E S  
1 6  H O W S U P P LI E D/ S T O R A G E A N D H A N D LI N G  
1 6. 1  S af e H a n dli n g a n d Di s p o s al  
1 6. 2  H o w S u p pli e d  
1 6. 3  St or a g e  
1 7  P A TI E N T C O U N S E LI N G I N F O R M A TI O N  
 
1 7. 1  I nf or m ati o n f or t h e P ati e nt 
 
* S e cti o n s or s u b s e cti o n s o mitt e d fr o m t h e f ull pr e s cri bi n g i nf or m ati o n 
ar e n ot li st e d.  

 
2  
F U L L P R E S C RI BI N G I N F O R M A TI O N  
 
1 
I N DI C A TI O N S A N D U S A G E 
 
1. 1  N e wl y Di a g n o s e d Gli o bl a st o m a M ultif or m e  
T E M O D A R ®  (t e m o z ol o mi d e)  i s  i n di c at e d  f or  t h e  tr e at m e nt  of  a d ult  p ati e nt s  wit h  n e wl y  di a g n o s e d  gli o bl a st o m a  m ultif or m e  c o n c o mit a ntl y  wit h 
r a di oth er a p y a n d t h e n a s m ai nt e n a n c e tr e at m e nt.  
 
1. 2  R efr a ct or y A n a pl a sti c A str o c yt o m a  
T E M O D A R i s  i n di c at e d f or t h e tr e at m e nt  of  a d ult  p ati e nt s  wit h r efr a ct or y a n a pl a sti c a str o c yt o m a, i. e.,  p ati e nt s  w h o h a v e e x p eri e n c e d di s e a s e 
pr o gr e s si o n o n a dr u g r e gi m e n c o nt ai ni n g nitr o s o ur e a a n d pr o c ar b a zi n e.  
 
2 
D O S A G E A N D A D MI NI S T R A TI O N  
 
2. 1  R e c o m m e n d e d D o si n g a n d D o s e M o difi c ati o n G ui d eli n e s  
T h e r e c o m m e n d e d d o s e f or T E M O D A R a s a n i ntr a v e n o u s i nf u si o n o v er 9 0 mi n ut e s i s t h e s a m e a s t h e d o s e f or t h e or al c a p s ul e f or m ul ati o n.  
Bi o e q ui v al e n c e h a s b e e n e st a bli s h e d o nl y w h e n T E M O D A R f or I nj e cti o n w a s gi v e n o v er 9 0 mi n ut e s [ s e e Cli ni c al P h ar m a c ol o g y ( 1 2. 3)]. D o s a g e of 
T E M O D A R m u st b e a dj u st e d a c c or di n g t o n a dir n e utr o p hil a n d pl at el et c o u nt s i n t h e pr e vi o u s c y cl e a n d t h e n e utr o p hil  a n d pl at el et c o u nt s at t h e ti m e of 
i niti ati n g t h e n e xt c y cl e. F or T E M O D A R d o s a g e c al c ul ati o n s b a s e d o n b o d y s urf a c e ar e a ( B S A) s e e T a bl e 5 . F or s u g g e st e d c a p s ul e c o m bi n ati o n s o n a 
d ail y d o s e s e e  T a bl e 6 . 
P ati e nt s wit h N e wl y Di a g n o s e d Hi g h Gr a d e Gli o m a: C o n c o mit a nt P h a s e:  T E M O D A R i s a d mi ni st er e d at 7 5 m g/ m 2  d ail y f or 4 2 d a y s c o n c o mit a nt 
wit h f o c al r a di ot h er a p y ( 6 0 G y a d mi ni st er e d i n 3 0 fr a cti o n s) f oll o w e d b y m ai nt e n a n c e T E M O D A R f or 6 c y cl e s. F o c al R T i n cl u d e s t h e t u m or b e d or 
r e s e cti o n  sit e  wit h  a  2- t o  3- cm  m ar gi n.  N o  d o s e  r e d u cti o n s  ar e  r e c o m m e n d e d  d uri n g  t h e  c o n c o mit a nt  p h a s e;  h o w e v er,  d o s e  i nt err u pti o n s  or  
di s c o nti n u ati o n m a y o c c ur b a s e d o n t o xi cit y. T h e T E M O D A R d o s e s h o ul d b e c o nti n u e d t hr o u g h o ut t h e 4 2 -d a y c o n c o mit a nt p eri o d u p t o 4 9 d a y s if all of 
t h e f oll o wi n g c o n diti o n s ar e m et: a b s ol ut e n e utr o p hil c o u nt gr e at er t h a n or e q u al t o 1. 5  x 1 0 9 / L, pl at el et c o u nt gr e at er t h a n or e q u al t o 1 0 0 x 1 0 9 / L, 
c o m m o n t o xi cit y crit eri a ( C T C) n o n h e m at ol o gi c al t o xi cit y l e s s t h a n or e q u al t o Gr a d e 1 ( e x c e pt f or al o p e ci a,  n a u s e a, a n d v o miti n g). D uri n g tr e at m e nt a 
c o m pl et e bl o o d c o u nt s h o ul d b e o bt ai n e d w e e kl y. T e m o z ol o mi d e d o si n g s h o ul d b e i nt err u pt e d or di s c o nti n u e d d uri n g c o n c o mit a nt p h a s e a c c or di n g t o 
t h e h e m at ol o gi c al a n d n o n h e m at ol o gi c al t o xi cit y crit eri a a s n ot e d i n T a bl e 1 . P n e u m o c y sti s c ari nii  p n e u m o ni a  (P C P ) pr o p h yl a xi s i s r e q uir e d d uri n g t h e 
c o n c o mit a nt  a d mi ni str ati o n of  T E M O D A R a n d r a di ot h er a p y , a n d s h o ul d b e c o nti n u e d i n p ati e nt s  w h o d e v el o p l y m p h o c yt o p e ni a u ntil r e c o v er y fr o m  
l y m p h o c yt o p e ni a ( C T C Gr a d e l e s s t h an or e q u al t o 1).  
 
T A B L E 1: T e m o z ol o mi d e D o si n g I nt err u pti o n or Di s c o nti n u ati o n  
D uri n g C o n c o mit a nt R a di ot h er a p y a n d T e m o z ol o mi d e  
T o xi cit y  
T M Z I nt err u pti o n*  
T M Z Di s c o nti n u ati o n  
A b s ol ut e N e utr o p hil C o u nt  
gr e at er t h a n or e q u al t o 0. 5 
a n d l e s s t h a n 1. 5 x 1 0 9 / L 
l e s s t h a n 0. 5 x 1 0 9 / L 
Pl at el et C o u nt  
gr e at er t h a n or e q u al t o 1 0 
a n d l e s s t h a n 1 0 0 x 1 0 9 / L 
l e s s t h a n 1 0 x 1 0 9 / L 
C T C N o n h e m at ol o gi c al T o xi cit y  
( e x c e pt f or al o p e ci a, n a u s e a, v o miti n g) 
C T C Gr a d e 2  
C T C Gr a d e 3 or 4  
*Tr e at m e nt wit h c o n c o mit a nt T M Z c o ul d b e c o nti n u e d w h e n all of t h e f oll o wi n g c o n diti o n s w er e m et: a b s ol ut e 
n e utr o p hil c o u nt gr e at er t h a n or e q u al t o 1. 5 x 1 0 9 / L; pl at el et c o u nt gr e at er t h a n or e q u al t o 1 0 0 x 1 09 / L; C T C 
n o n h e m at ol o gi c al t o xi cit y l e s s t h a n or e q u al t o Gr a d e 1 ( e x c e pt f or al o p e ci a, n a u s e a, v o miti n g).  
T M Z =t e m o z ol o mi d e; C T C = C o m m o n T o xi cit y Crit eri a.  
 
M ai nt e n a n c e P h a s e:  
C y cl e 1: F o ur w e e k s aft er c o m pl eti n g t h e T E M O D A R + R T p h a s e, T E M O D A R i s a d mi ni st er e d f or a n a d diti o n al 6 c y cl e s of m ai nt e n a n c e tr e at m e nt . 
D o s a g e i n C y cl e 1  ( m ai nt e n a n c e) i s 1 5 0 m g/ m
2 o n c e d ail y f or 5 d a y s f oll o w e d b y 2 3 d a y s wit h o ut tr e at m e nt.  
C y cl e s 2 -6: At t h e st art of C y cl e 2, t h e d o s e c a n b e e s c al at e d t o 2 0 0 m g/ m 2 , if t h e C T C n o n h e m at ol o gi c t o xi cit y f or C y cl e 1 i s Gr a d e l e s s t h a n or 
e q u al t o  2 ( e x c e pt f or al o p e ci a, n a u s e a, a n d v o miti n g), a b s ol ut e n e utr o p hil c o u nt ( A N C) i s gr e at er t h a n or e q u al t o  1. 5  x 1 0 9 / L, a n d t h e pl at el et c o u nt i s 
gr e at er t h a n or e q u al t o 1 0 0  x 1 0 9 / L. T h e d o s e r e m ai n s at 2 0 0 m g/ m2  p er d a y f or t h e fir st 5 d a y s of e a c h s u b s e q u e nt c y cl e e x c e pt if t o x i cit y o c c ur s. If t h e 
d o s e w a s n ot e s c al at e d at C y cl e 2, e s c al ati o n s h o ul d n ot b e d o n e i n s u b s e q u e nt c y cl e s.  
D o s e R e d u cti o n or Di s c o nti n u ati o n D uri n g M ai nt e n a n c e: D o s e r e d u cti o n s d uri n g t h e m ai nt e n a n c e p h a s e s h o ul d b e a p pli e d a c c or di n g t o T a bl e s 2 
a n d  3. 
D u ri n g tr e at m e nt, a c o m pl et e bl o o d c o u nt s h o ul d b e o bt ai n e d o n D a y 2 2 ( 2 1 d a y s aft er t h e fir st d o s e of T E M O D A R) or wit hi n 4 8 h o ur s of t h at d a y, 
a n d w e e kl y u ntil t h e A N C i s a b o v e 1. 5 x 1 0 9 / L ( 1 5 0 0/ µ L) a n d t h e pl at el et c o u nt e x c e e d s 1 0 0 x 1 09 / L ( 1 0 0, 0 0 0/ µ L). T h e n e xt c y cl e of T E M O D A R s h o ul d 
n ot b e st art e d u ntil t h e A N C a n d pl at el et c o u nt e x c e e d t h e s e l e v el s. D o s e r e d u cti o n s d uri n g t h e n e xt c y cl e s h o ul d b e b a s e d o n  t h e l o w e st bl o o d c o u nt s 
a n d w or st n o n h e m at ol o gi c t o xi cit y d uri n g t h e pr e vi o u s c y cl e. D o s e r e d u cti o n s or di s c o nti n u ati o n s d uri n g t h e m ai nt e n a n c e p h a s e s h o ul d b e a p pli e d 
a c c or di n g t o T a bl e s 2 a n d  3. 
 
T A B L E  2: T e m o z ol o mi d e D o s e L e v el s f or M ai nt e n a n c e Tr e at m e nt  
D o s e L e v el  
D o s e ( m g/ m 2 / d a y) 
R e m ar k s  
-1  
1 0 0  
R e d u cti o n f or pri or t o xi cit y  
0  
1 5 0  
D o s e d uri n g C y cl e 1  
1  
2 0 0  
D o s e d uri n g C y cl e s 2 -6 i n a b s e n c e of t o xi cit y  
 

 
4  
T A B L E 6: S u g g e st e d C a p s ul e C o m bi n ati o n s B a s e d o n D ail y D o s e i n A d ult s  
N u m b er of D ail y C a p s ul e s b y Str e n gt h  ( m g) 
T ot al D ail y D o s e ( m g)  
2 5 0 m g  
1 8 0 m g  
1 4 0 m g  
1 0 0 m g  
2 0 m g  
5 m g  
 
 
 
 
 
 
 
7 5  
0  
0  
0  
0  
3  
3  
8 2. 5  
0  
0  
0  
0  
4  
0  
9 0  
0  
0  
0  
0  
4  
2  
9 7. 5  
0  
0  
0  
1  
0  
0  
1 0 5  
0  
0  
0  
1  
0  
1  
1 1 2. 5  
0  
0  
0  
1  
0  
2  
1 2 0  
0  
0  
0  
1  
1  
0  
1 2 7. 5  
0  
0  
0  
1  
1  
1  
1 3 5  
0  
0  
0  
1  
1  
3  
1 4 2. 5  
0  
0  
1  
0  
0  
0  
1 5 0  
0  
0  
1  
0  
0  
2  
1 5 7. 5  
0  
0  
1  
0  
1  
0  
1 6 5  
0  
0  
1  
0  
1  
1  
1 7 2. 5  
0  
0  
1  
0  
1  
2  
1 8 0  
0  
1  
0  
0  
0  
0  
1 8 7. 5  
0  
1  
0  
0  
0  
1  
1 9 5  
0  
1  
0  
0  
0  
3  
2 0 0  
0  
1  
0  
0  
1  
0  
2 1 0  
0  
0  
0  
2  
0  
2  
2 2 0  
0  
0  
0  
2  
1  
0  
2 2 5  
0  
0  
0  
2  
1  
1  
2 4 0  
0  
0  
1  
1  
0  
0  
2 5 5  
1  
0  
0  
0  
0  
1  
2 6 0  
1  
0  
0  
0  
0  
2  
2 7 0  
1  
0  
0  
0  
1  
0  
2 8 0  
0  
0  
2  
0  
0  
0  
2 8 5  
0  
0  
2  
0  
0  
1  
3 0 0  
0  
0  
0  
3  
0  
0  
3 1 5  
0  
0  
0  
3  
0  
3  
3 2 0  
0  
1  
1  
0  
0  
0  
3 3 0  
0  
1  
1  
0  
0  
2  
3 4 0  
0  
1  
1  
0  
1  
0  
3 4 5  
0  
1  
1  
0  
1  
1  
3 6 0  
0  
2  
0  
0  
0  
0  
3 7 5  
0  
2  
0  
0  
0  
3  
3 8 0  
0  
1  
0  
2  
0  
0  
4 0 0  
0  
0  
0  
4  
0  
0  
4 2 0  
0  
0  
3  
0  
0  
0  
4 4 0  
0  
0  
3  
0  
1  
0  
4 6 0  
0  
2  
0  
1  
0  
0  
4 8 0  
0  
1  
0  
3  
0  
0  
5 0 0  
2  
0  
0  
0  
0  
0  
 
2. 2  Pr e p ar ati o n a n d A d mi ni str ati o n  
T E M O D A R C a p s ul e s: I n cli ni c al tri al s, T E M O D A R w a s a d mi ni st er e d u n d er b ot h f a sti n g a n d n o nf a sti n g c o n diti o n s; h o w e v er, a b s or pti o n i s aff e ct e d 
b y f o o d [ s e e Cli ni c al P h ar m a c ol o g y ( 1 2. 3)], a n d c o n si st e n c y of a d mi ni str ati o n wit h r e s p e ct t o f o o d i s r e c o m m e n d e d. T h er e ar e n o di et ar y r e stri cti o n s wit h 
T E M O D A R. T o r e d u c e n a u s e a a n d v o miti n g, T E M O D A R s h o ul d b e t a k e n o n a n e m pt y st o m a c h. B e dti m e a d mi ni str ati o n m a y b e a d vi s e d. A nti e m eti c 
t h er a p y m a y b e a d mi ni st er e d pri or t o a n d/ or f oll o wi n g a d mi ni str ati o n of T E M O D A R.  
T E M O D A R (t e m o z ol o mi d e) C a p s ul e s s h o ul d n ot b e o p e n e d or c h e w e d. T h e y s h o ul d b e s w all o w e d w h ol e wit h a gl a s s of w at er.  
If c a p s ul e s ar e a c ci d e nt all y o p e n e d or d a m a g e d, pr e c a uti o n s s h o ul d b e t a k e n t o a v oi d i n h al ati o n or c o nt a ct wit h t h e s ki n or m u c o u s m e m br a n e s 
[ s e e H o w S u p pli e d/ St or a g e a n d H a n dli n g ( 1 6. 1)]. 

 
5  
T E M O D A R  f or  I nj e cti o n:  E a c h  vi al  of  T E M O D A R  f or  I nj e cti o n  c o nt ai n s  st eril e  a n d  p yr o g e n -fr e e  t e m o z ol o mi d e  l y o p hili z e d  p o w d er.  W h e n  
r e c o nstit ut e d wit h 4 1 m L St eril e W at er f or I nj e cti o n, t h e r e s ulti n g s ol uti o n will c o nt ai n 2. 5 m g/ m L t e m o z ol o mi d e. Bri n g t h e vi al t o r o o m t e m p er at ur e pri or 
t o r e c o n stit uti o n wit h St eril e W at er f or I nj e cti o n. T h e vi al s s h o ul d b e g e ntl y s wirl e d a n d n ot s h a k e n. Vi al s s h o ul d b e i n s p e ct e d, a n d a n y vi al c o nt ai ni n g 
vi si bl e p arti c ul at e m att er s h o ul d n ot  b e u s e d.  D o n ot  f urt h er dil ut e t h e r e c o n stit ut e d s ol uti o n.  Aft er r e c o n stit uti o n, st or e at  r o o m  t e m p er at ur e ( 2 5° C 
[ 7 7° F]). R e c o n stit ut e d pr o d u ct m u st b e u s e d wit hi n 1 4 h o ur s, i n cl u di n g i nf u si o n ti m e.  
U si n g a s e pti c t e c h ni q u e, wit h dr a w u p t o 4 0 m L fr o m e a c h vi al t o m a k e u p t h e t ot al d o s e b a s e d o n T a bl e 5  a b o v e a n d tr a n sf er i nt o a n e m pt y 2 5 0 
m L i nf u si o n b a g  { 2}. T E M O D A R f or I nj e cti o n s h o ul d b e i nf u s e d i ntr a v e n o u sl y u si n g a p u m p o v er a p eri o d of 9 0 mi n ut e s. T E M O D A R f or I nj e cti o n s h o ul d 
b e a d mi ni st er e d o nl y b y i ntr a v e n o u s i nf u si o n.  Fl u s h t h e li n e s b ef or e a n d aft er e a c h T E M O D A R i nf u si o n.  
T E M O D A R f or I nj e cti o n m a y b e a d mi ni st er e d i n t h e s a m e i ntr a v e n o u s li n e wit h 0. 9 % S o di u m C hl ori d e i nj e cti o n o nl y.  
B e c a u s e n o d at a ar e a v ail a bl e o n t h e c o m p ati bilit y of T E M O D A R f or I nj e cti o n wit h ot h er i ntr a v e n o u s s u b st a n c e s or a d diti v e s, o t h er m e di c ati o n s 
s h o ul d n ot b e i nf u s e d si m ult a n e o u sl y t hr o u g h t h e s a m e i ntr a v e n o u s li n e.  
 
3 
D O S A G E F O R M S A N D S T R E N G T H S  
•  
T E M O D A R (t e m o z ol o mi d e) C a p s ul e s f or or al a d mi ni str ati o n  
-   
5-m g c a p s ul e s h a v e o p a q u e w hit e b o di e s wit h gr e e n c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, 
a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R."  
-  
2 0 -m g  c a p s ul e s  h a v e  o p a q u e  w hit e  b o di e s  wit h  y ell o w  c a p s.  T h e  c a p s ul e  b o d y  i s  i m pri nt e d  wit h  t w o  stri p e s,  t h e  d o s a g e  
str e n gt h, a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R."  
-  
1 0 0 -m g  c a p s ul e s  h a v e  o p a q u e  w hit e  b o di e s  wit h  pi n k  c a p s.  T h e  c a p s ul e  b o d y  i s  i m pri nt e d  wit h  t w o  stri p e s,  t h e  d o s a g e  
str e n gt h, a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R."  
-  
1 4 0 -m g  c a p s ul e s  h a v e  o p a q u e  w hit e  b o di e s  wit h  bl u e  c a p s.  T h e  c a p s ul e  b o d y  i s  i m pri nt e d  wit h  t w o  stri p e s,  t h e  d o s a g e  
str e n gt h, a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R."  
-  
1 8 0 -m g c a p s ul e s h a v e o p a q u e w hit e b o di e s wit h or a n g e c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e 
str e n gt h, a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R."  
-  
2 5 0 -m g  c a p s ul e s  h a v e  o p a q u e  w hit e  b o di e s  wit h  w hit e  c a p s.  T h e  c a p s ul e  b o d y  i s  i m pri nt e d  wit h  t w o  stri p e s,  t h e  d o s a g e 
str e n gt h, a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R."  
•  
T E M O D A R (t e m o z ol o mi d e) i s a v ail a bl e a s 1 0 0 -m g/ vi al p o w d er f or i nj e cti o n. T h e l y o p hili z e d p o w d er i s w hit e t o li g ht t a n/li g ht pi n k.  
 
4 
C O N T R AI N DI C A TI O N S  
 
4. 1  H y p er s e n siti vit y  
T E M O D A R  (t e m o z ol o mi d e)  i s  c o ntr ai n di c at e d  i n  p ati e nt s  w h o  h a v e  a  hi st or y  of  h y p er s e n siti vit y  r e a cti o n  ( s u c h  a s  urti c ari a,  all er gi c  r e a cti o n 
i n cl u di n g a n a p h yl a xi s,  t o xi c  e pi d er m al n e cr ol y si s,  a n d St e v e n s-J o h n s o n s y n dr o m e) t o a n y of  it s c o m p o n e nt s.  T E M O D A R i s  al s o c o ntr ai n di c at e d i n 
p ati e nt s  w h o  h a v e  a  hi st or y  of  h y p er s e n siti vit y  t o  d a c ar b a zi n e   (D TI C ),  si n c e  b ot h  dr u g s  ar e  m et a b oli z e d  t o  5-( 3-m et h yltri a z e n - 1-yl) -i mi d a z ol e- 4-
c ar b o x a mi d e ( M TI C).  
 
5 
W A R NI N G S A N D P R E C A U TI O N S  
 
5. 1  M y el o s u p pr e s si o n  
P ati e nt s tr e at e d wit h T E M O D A R m a y e x p eri e n c e m y el o s u p pr e s si o n,  i n cl u di n g pr ol o n g e d p a n c yt o p e ni a, w hi c h m a y r e s ult i n a pl a sti c a n e mi a, w hi c h 
i n  s o m e  c a s e s h a s  r e s ult e d  i n  a  f at al  o ut c o m e.  I n  s o m e  c a s e s,  e x p o s ur e  t o  c o n c o mit a nt  m e di c ati o n s  a s s o ci at e d  wit h  a pl a sti c  a n e mi a,  i n cl u di n g 
c ar b a m a z e pi n e, p h e n yt oi n, a n d s ulf a m et h o x a z ol e/tri m et h o pri m, c o m pli c at e s a s s e s s m e nt. Pri or t o d o si n g, p ati e nt s m u st h a v e a n a b s o l ut e n e utr o p hil 
c o u nt ( A N C) gr e at er t h a n or e q u al t o 1. 5 x 1 0 9 / L a n d a pl at el et c o u nt gr e at er t h a n or e q u al t o 1 0 0 x 1 09 / L. A c o m pl et e bl o o d c o u nt s h o ul d b e o bt ai n e d o n 
D a y 2 2 ( 2 1 d a y s aft er t h e fir st d o s e) or wit hi n 4 8 h o ur s of t h at d a y, a n d w e e kl y u ntil t h e A N C i s a b o v e 1. 5 x 1 0
9 / L a n d pl at el et c o u nt e x c e e d s 1 0 0 x 
1 0 9 / L. G eri atri c p ati e nt s a n d w o m e n h a v e b e e n s h o w n i n cli ni c al tri al s t o h a v e a hi g h er ri s k of d e v el o pi n g m y el o s u p pr e s si o n. 
 
5. 2  M y el o d y s pl a sti c S y n dr o m e  
C a s e s of m y el o d y s pl a sti c s y n dr o m e a n d s e c o n d ar y m ali g n a n ci e s, i n cl u di n g m y el oi d l e u k e mi a, h a v e b e e n o b s er v e d.  
 
5. 3  P n e u m o c y sti s c ari nii  P n e u m o ni a  
F or tr e at m e nt of n e wl y di a g n o s e d gli o bl a st o m a m ultif or m e: Pr o p h yl a xi s a g ai n st P n e u m o c y sti s c ari nii  p n e u m o ni a ( P C P) i s r e q uir e d f or all p ati e nt s 
r e c eivi n g c o n c o mit a nt T E M O D A R a n d r a di ot h er a p y f or t h e 4 2 -d a y r e gi m e n.  
T h er e m a y b e a hi g h er o c c urr e n c e of P C P w h e n t e m o z ol o mi d e i s a d mi ni st er e d d uri n g a l o n g er d o si n g r e gi m e n. H o w e v er, all p ati e nt s r e c ei vi n g 
t e m o z ol o mi d e, p arti c ul arl y p ati e nt s r e c ei vi n g st er oi d s, s h o ul d b e o b s er v e d cl o s el y f or t h e d e v el o p m e nt of P C P r e g ar dl e s s of t h e r e gi m e n. 
 
5. 4  L a b or at or y T e st s  
F or  t h e  c o n c o mit a nt  tr e at m e nt  p h a s e  wit h  R T,  a  c o m pl et e  bl o o d  c o u nt  s h o ul d  b e  o bt ai n e d  pri or  t o  i niti ati o n  of  tr e at m e nt  a n d  w e e kl y  d uri n g  
tr e at m e nt. 
F or t h e 2 8 -d a y tr e at m e nt c y cl e s,  a c o m pl et e bl o o d c o u nt s h o ul d b e o bt ai n e d pri or t o tr e at m e nt o n D a y 1 a n d o n D a y 2 2 ( 2 1 d a y s aft er t h e fir st 
d o s e) of e a c h c y cl e. Bl o o d c o u nt s s h o ul d b e p erf or m e d w e e kl y u ntil r e c o v er y if t h e A N C f all s b el o w 1. 5 x 1 0 9 / L a n d t h e pl at el et c o u nt f all s b el o w 1 0 0 x 
1 0 9 / L [ s e e R e c o m m e n d e d D o si n g a n d D o s e M o difi c ati o n G ui d eli n e s ( 2. 1)]. 
 
5. 5  U s e i n Pr e g n a n c y  
T E M O D A R c a n c a u s e f et al h ar m w h e n a d mi ni st er e d t o a pr e g n a nt w o m a n. A d mi ni str ati o n of T E M O D A R t o r at s a n d r a b bit s d uri n g or g a n o g e n e si s 
at 0. 3 8 a n d 0. 7 5 ti m e s t h e m a xi m u m r e c o m m e n d e d h u m a n d o s e ( 7 5 a n d 1 5 0 m g/ m 2 ), r e s p e cti v el y, c a u s e d n u m er o u s f et al m alf or m ati o n s of t h e e xt er n al 
or g a n s, s oft ti s s u e s, a n d s k el et o n i n b ot h s p e ci e s [ s e e U s e i n S p e cifi c P o p ul ati o n s ( 8. 1)]. 
 
5. 6  I nf u si o n Ti m e 
A s bi o e q ui v al e n c e h a s b e e n e st a bli s h e d o nl y w h e n T E M O D A R f or I nj e cti o n w a s gi v e n o v er 9 0 mi n ut e s, i nf u si o n o v er a s h ort er  or  l o n g er p eri o d of 
ti m e m a y r e s ult i n s u b o pti m al d o si n g. A d diti o n all y, t h e p o s s bilit y of a n i n cr e a s e i n i nf u si o n-r el at e d a d v er s e r e a cti o n s c a n n ot b e r ul e d o ut.  
 
6 
A D V E R S E R E A C TI O N S  
 
6. 1  Cli ni c al Tri al s E x p eri e n c e  
B e c a u s e cli ni c al tr ial s ar e c o n d u ct e d u n d er wi d el y v ar yi n g c o n diti o n s, a d v er s e r e a cti o n r at e s o b s er v e d i n t h e cli ni c al tri al s  of a dr u g c a n n ot b e 
dir e ctl y c o m p ar e d t o  r at e s i n t h e cli ni c al tri al s of a n ot h er dr u g a n d m a y n ot r efl e ct t h e r at e s o b s er v e d i n pr a cti c e. 

 
6  
N e wl y  Di a g n o s e d  Gli o bl a st o m a  M ultif or m e:  D uri n g  t h e  c o n c o mit a nt  p h a s e  ( T E M O D A R +r a di ot h er a p y),  a d v er s e  r e a cti o n s  i n cl u di n g  
t hr o m b o c yt o p e ni a,  n a u s e a,  v o miti n g,  a n or e xi a,  a n d  c o n sti p ati o n  w er e  m or e  fr e q u e nt  i n  t h e  T E M O D A R + R T  ar m.  T h e  i n ci d e n c e  of  ot h er  a d v er s e  
r e a cti o n s w a s c o m p ar a bl e i n t h e t w o ar m s. T h e m o st c o m m o n a d v er s e r e a cti o n s a cr o s s t h e c u m ul ati v e T E M O D A R e x p eri e n c e w er e al o p e ci a, n a u s e a, 
v o miti n g, a n or e xi a, h e a d a c h e, a n d c o n sti p ati o n ( s e e T a bl e 7 ). F ort y-ni n e p er c e nt ( 4 9 %) of p ati e nt s tr e at e d wit h T E M O D A R r e p ort e d o n e or m or e s e v er e 
or  lif e -t hr e at e ni n g  r e a cti o n s,  m o st  c o m m o nl y  f ati g u e  ( 1 3 %),  c o n v ul si o n s  ( 6 %),  h e a d a c h e  ( 5 %),  a n d  t hr o m b o c yt o p e ni a  ( 5 %).  O v erall,  t h e  p att er n  of  
r e a cti o n s d uri n g t h e m ai nt e n a n c e p h a s e w a s c o n si st e nt wit h t h e k n o w n s af et y pr ofil e of T E M O D A R. 
 
T A B L E 7: N u m b er ( %) of P ati e nt s wit h A d v er s e R e a cti o n s:  
All a n d S e v er e/ Lif e T hr e at e ni n g (I n ci d e n c e of 5 % or Gr e at er)  
 
C o n c o mit a nt P h a s e  
R T Al o n e  
( n = 2 8 5) 
C o n c o mit a nt P h a s e 
R T + T M Z  
( n = 2 8 8)* 
M ai nt e n a n c e P h a s e  
T M Z  
( n = 2 2 4) 
All  
Gr a d e ≥3  
All  
Gr a d e ≥3  
All  
Gr a d e ≥3  
S u bj e ct s R e p orti n g a n y 
A d v er s e R e a cti o n  
2 5 8  
( 9 1) 
7 4  
( 2 6) 
 
2 6 6  
 
( 9 2) 
 
8 0  
 
( 2 8) 
 
2 0 6  
 
( 9 2) 
 
8 2  
 
( 3 7) 
B o d y a s a W h ol e —  G e n er al 
Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
A n or e xi a  
2 5  
( 9) 
1  
( < 1) 
5 6  
( 1 9) 
2  
( 1) 
6 1  
( 2 7) 
3  
( 1) 
Di z zi n e s s  
1 0  
( 4) 
0  
 
1 2  
( 4) 
2  
( 1) 
1 2  
( 5) 
0  
 
F ati g u e  
1 3 9  
( 4 9) 
1 5  
( 5) 
1 5 6  
( 5 4) 
1 9  
( 7) 
1 3 7  
( 6 1) 
2 0  
( 9) 
H e a d a c h e  
4 9  
( 1 7) 
1 1  
( 4) 
5 6  
( 1 9) 
5  
( 2) 
5 1  
( 2 3) 
9  
( 4) 
W e a k n e s s  
9  
( 3) 
3  
( 1) 
1 0  
( 3) 
5  
( 2) 
1 6  
( 7) 
4  
( 2) 
C e ntr al a n d P eri p h er al 
N er v o u s S y st e m Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
C o nf u si o n  
1 2  
( 4) 
6  
( 2) 
1 1  
( 4) 
4  
( 1) 
1 2  
( 5) 
4  
( 2) 
C o n v ul si o n s  
2 0  
( 7) 
9  
( 3) 
1 7  
( 6) 
1 0  
( 3) 
2 5  
( 1 1) 
7  
( 3) 
M e m or y I m p air m e nt  
1 2  
( 4) 
1  
( < 1) 
8  
( 3) 
1  
( < 1) 
1 6  
( 7) 
2  
( 1) 
Di s or d er s of t h e E y e  
 
 
 
 
 
 
 
 
 
 
 
 
Vi si o n Bl urr e d  
2 5  
( 9) 
4  
( 1) 
2 6  
( 9) 
2  
( 1) 
1 7  
( 8) 
0  
 
Di s or d er s of t h e I m m u n e 
S y st e m  
 
 
 
 
 
 
 
 
 
 
 
 
All er gi c R e a cti o n  
7  
( 2) 
1  
( < 1) 
1 3  
( 5) 
0  
 
6  
( 3) 
0  
 
G a str oi nt e sti n al S y st e m 
Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
A b d o mi n al P ai n  
2  
( 1) 
0  
 
7  
( 2) 
1  
( < 1) 
1 1  
( 5) 
1  
( < 1) 
C o n sti p ati o n  
1 8  
( 6) 
0  
 
5 3  
( 1 8) 
3  
( 1) 
4 9  
( 2 2) 
0  
 
Di arr h e a  
9  
( 3) 
0  
 
1 8  
( 6) 
0  
 
2 3  
(1 0)  
2  
( 1) 
N a u s e a  
4 5  
( 1 6) 
1  
( < 1) 
1 0 5  
( 3 6) 
2  
( 1) 
1 1 0  
( 4 9) 
3  
( 1) 
St o m atiti s  
1 4  
( 5) 
1  
( < 1) 
1 9  
( 7) 
0  
 
2 0  
( 9) 
3  
( 1) 
V o miti n g  
1 6  
( 6) 
1  
( < 1) 
5 7  
( 2 0) 
1  
( < 1) 
6 6  
( 2 9) 
4  
( 2) 
I nj ur y a n d P oi s o ni n g 
 
 
 
 
 
 
 
 
 
 
 
 
R a di ati o n I nj ur y N O S  
1 1  
( 4) 
1  
( < 1) 
2 0  
( 7) 
0  
 
5  
( 2) 
0  
 
M u s c ul o s k el et al S y st e m 
Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
Art hr al gi a  
2  
( 1) 
0  
 
7  
( 2) 
1  
( < 1) 
1 4  
( 6) 
0  
 
Pl at el et, Bl e e di n g a n d 
Cl otti n g Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
T hr o m b o c yt o p e ni a  
3  
( 1) 
0  
 
1 1  
( 4) 
8  
( 3) 
1 9  
( 8) 
8  
( 4) 
P s y c hi atri c Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
I n s o m ni a 
9  
( 3) 
1  
( < 1) 
1 4  
( 5) 
0  
 
9  
( 4) 
0  
 
R e s pir at or y S y st e m 
Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
C o u g hi n g  
3  
( 1) 
0  
 
1 5  
( 5) 
2  
( 1) 
1 9  
( 8) 
1  
( < 1) 
D y s p n e a  
9  
( 3) 
4  
( 1) 
1 1  
( 4) 
5  
( 2) 
1 2  
( 5) 
1  
( < 1) 
S ki n a n d S u b c ut a n e o u s 
Ti s s u e Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
Al o p e ci a  
1 7 9  
( 6 3) 
0  
 
1 9 9  
( 6 9) 
0  
 
1 2 4  
( 5 5) 
0  
 
Dr y S ki n  
6  
( 2) 
0  
 
7  
( 2) 
0  
 
1 1  
( 5) 
1  
( < 1) 
Er yt h e m a  
1 5  
( 5) 
0  
 
1 4  
( 5) 
0  
 
2  
( 1) 
0  
 
Pr urit u s  
4  
( 1) 
0  
 
1 1  
( 4) 
0  
 
1 1  
( 5) 
0  
 
R a s h  
4 2  
( 1 5) 
0  
 
5 6  
( 1 9) 
3  
( 1) 
2 9  
( 1 3) 
3  
( 1) 
S p e ci al S e n s e s Ot h er, 
Di s or d er s  
 
 
 
 
 
 
 
 
 
 
 
 
T a st e P er v er si o n  
6  
( 2) 
0  
 
1 8  
( 6) 
0  
 
1 1  
( 5) 
0  
 
* O ne p ati e nt w h o w a s r a n d o mi z e d t o R T o nl y ar m r e c ei v e d R T +t e m o z ol o mi d e.  
R T + T M Z =r a di ot h er a p y pl u s t e m o z ol o mi d e; N O S = n ot ot h er wi s e s p e cifi e d.  
N ot e:  Gr a d e 5 (f at al) a d v er s e r e a cti o n s ar e i n cl u d e d i n t h e Gr a d e ≥3 c ol u m n.  
 
M y el o s u p pr e s si o n ( n e utr o p e ni a a n d t hr o m b o c yt o p e ni a), w hi c h i s a k n o w n d o s e -li miti n g t o xi cit y f or m o st c yt ot o xi c a g e nt s, i n cl u di n g T E M O D A R, 
w a s o b s er v e d. W h e n l a b or at or y a b n or m aliti e s a n d a d v er s e r e a cti o n s w er e c o m bi n e d, Gr a d e 3 or Gr a d e 4 n e utr o p hil a b n or m aliti e s i n cl u di n g n e utr o p e ni c 

 
7  
r e a cti o n s w er e o b s er v e d i n 8 % of t h e p ati e nt s, a n d Gr a d e 3 or Gr a d e 4 pl at el et a b n or m aliti e s, i n cl u di n g t hr o m b o c yt o p e ni c r e a cti o n s, w er e o b s er v e d i n 
1 4 % of t h e p ati e nt s tr e at e d wit h T E M O D A R.  
R efr a ct or y A n a pl a sti c A str o c yt o m a: T a bl e s 8 a n d  9 s h o w t h e i n ci d e n c e of a d v er s e r e a cti o n s i n t h e 1 5 8 p ati e nt s i n t h e a n a pl a sti c a str o c yt o m a 
st u d y f or w h o m d at a ar e a v ail a bl e. I n t h e a b s e n c e of a c o ntr ol gr o u p, it i s n ot cl e ar i n m a n y c a s e s w h et h er t h e s e r e a cti o n s s h o ul d b e attri b ut e d t o 
t e m o z ol o mi d e or t h e p ati e nt s’ u n d erl yi n g c o n diti o n s, b ut n a u s e a, v o miti n g, f ati g u e, a n d h e m at ol o gi c eff e ct s a p p e ar t o b e cl e arl y dr u g-r el at e d. T h e m o st 
fr e q u e ntl y o c c urri n g a d v er s e r e a cti o n s w er e n a u s e a, v o miti n g, h e a d a c h e, a n d f ati g u e. T h e a d v er s e r e a cti o n s w er e u s u all y N CI C o m m o n T o xi cit y Crit eri a 
( C T C) Gr a d e 1 or 2 ( mil d t o m o d er at e i n s e v erit y) a n d w er e s elf-li miti n g, wit h n a u s e a a n d v o miti n g r e a dil y c o ntr oll e d wit h a nti e m eti c s. T h e i n ci d e n c e of 
s e v er e n a u s e a a n d v o miti n g ( C T C Gr a d e 3 or 4) w a s 1 0 % a n d 6 %, r e s p e cti v el y. M y el o s u p pr e s si o n (t hr o m b o c yt o p e ni a a n d n e utr o p e ni a) w a s t h e d o s e -
li miti n g a d v er s e r e a cti o n. It u s u all y o c c urr e d wit hi n t h e fir st f e w c y cl e s of t h er a p y a n d w a s n ot c u m ul ati v e. 
M y el o s u p pr e s si o n o c c urr e d l at e i n t h e tr e at m e nt c y cl e a n d r et ur n e d t o n or m al, o n a v er a g e, wit hi n 1 4 d a y s of n a dir c o u nt s. T h e m e di a n n a dir s 
o c c urr e d at 2 6 d a y s f or pl at el et s (r a n g e: 2 1 -4 0 d a y s) a n d 2 8 d a y s f or n e utr o p hil s (r a n g e: 1 -4 4 d a y s). O nl y 1 4 % ( 2 2/ 1 5 8) of p ati e nt s h a d a n e utr o p hil 
n a dir  a n d  2 0 %  ( 3 2/ 1 5 8)  of  p ati e nt s  h a d  a  pl at el et  n a dir,  w hi c h  m a y  h a v e  d el a y e d  t h e  st art  of  t h e  n e xt  c y cl e.  L e s s  t h a n  1 0 %  of  p ati e nt s  r e q uir e d 
h o s pit ali z ati o n, bl o o d tr a n sf u si o n, or di s c o nti n u ati o n of t h er a p y d u e t o m y el o s u p pr e s si o n.  
I n  cli ni c al  tri al  e x p eri e n c e  wit h  1 1 0  t o  1 1 1  w o m e n  a n d  1 6 9  t o  1 7 4  m e n  ( d e p e n di n g  o n  m e a s ur e m e nt s),  t h er e  w er e  hi g h er  r at e s  of  Gr a d e  4 
n e utr o p e ni a ( A N C l e s s t h a n 5 0 0 c ell s/ µ L) a n d t hr o m b o c yt o p e ni a (l e s s t h a n 2 0, 0 0 0 c ell s/ µ L) i n w o m e n t h a n m e n i n t h e fir st c y cl e of t h er a p y ( 1 2 % v s. 5 % 
a n d 9 % v s. 3 %, r e s p e cti v el y).  
I n t h e e ntir e s af et y d at a b a s e f or w hi c h h e m at ol o gi c d at a e xi st ( N = 9 3 2), 7 % ( 4/ 6 1) a n d 9. 5 % ( 6/ 6 3) of p ati e nt s o v er a g e 7 0 e x peri e n c e d Gr a d e 4 
n e utr o p e ni a or t hr o m b o c yt o p e ni a i n t h e fir st c y cl e, r e s p e cti v el y . F or p ati e nt s l e s s t h a n or e q u al t o a g e 7 0, 7 % ( 6 2/ 8 7 1) a n d 5. 5 % ( 4 8/ 8 7 9) e x p eri e n c e d 
Gr a d e 4 n e utr o p e ni a or t hr o m b o c yt o p e ni a i n t h e fir st c y cl e, r e s p e cti v el y. P a n c yt o p e ni a, l e u k o p e ni a, a n d a n e mi a h a v e al s o b e e n  r e p ort e d. 
 

 
8  
T A B L E 8: A d v er s e R e a cti o n s i n t h e A n a pl a sti c A str o c yt o m a Tri al i n A d ult s ( ≥5 %)  
 
N o. ( %) of T E M O D A R P ati e nt s  
( N = 1 5 8) 
 
All R e a cti o n s  
Gr a d e 3/ 4  
A n y A d v er s e R e a cti o n  
1 5 3 ( 9 7)  
7 9 ( 5 0)  
B o d y a s a W h ol e  
 
 
H e a d a c h e  
6 5 ( 4 1)  
1 0 ( 6)  
F ati g u e  
5 4 ( 3 4)  
7 ( 4)  
A st h e ni a  
2 0 ( 1 3)  
9 ( 6)  
F e v er  
2 1 ( 1 3)  
3 ( 2)  
B a c k p ai n  
1 2 ( 8)  
4 ( 3)  
C ar di o v a s c ul ar  
 
 
E d e m a p eri p h er al  
1 7 ( 1 1)  
1 ( 1)  
C e ntr al a n d P eri p h er al N er v o u s S y st e m  
 
 
C o n v ul si o n s  
3 6 ( 2 3)  
8 ( 5)  
H e mi p ar e si s  
2 9 ( 1 8)  
1 0 ( 6)  
Di z zi n e s s  
1 9 ( 1 2)  
1 ( 1)  
C o or di n ati o n a b n or m al  
1 7 ( 1 1)  
2 ( 1)  
A m n e si a  
1 6 ( 1 0)  
6 ( 4)  
I n s o m ni a 
1 6 ( 1 0)  
0  
P ar e st h e si a  
1 5 ( 9)  
1 ( 1)  
S o m n ol e n c e  
1 5 ( 9)  
5 ( 3)  
P ar e si s  
1 3 ( 8)  
4 ( 3)  
Uri n ar y i n c o nti n e n c e  
1 3 ( 8)  
3 ( 2)  
At a xi a  
1 2 ( 8)  
3 ( 2)  
D y s p h a si a  
1 1 ( 7)  
1 ( 1)  
C o n v ul si o n s l o c al  
9 ( 6)  
0  
G ait a b n or m al  
9 ( 6)  
1 ( 1)  
C o nf u si o n  
8 ( 5)  
0  
E n d o cri n e  
 
 
A dr e n al h y p er c orti ci s m  
1 3 ( 8)  
0  
G a str oi nt e sti n al S y st e m  
 
 
N a u s e a  
8 4 ( 5 3)  
1 6 ( 1 0)  
V o miti n g  
6 6 ( 4 2)  
1 0 ( 6)  
C o n sti p ati o n  
5 2 ( 3 3)  
1 ( 1)  
Di arr h e a  
2 5 ( 1 6)  
3 ( 2)  
A b d o mi n al p ai n  
1 4 ( 9)  
2 ( 1)  
A n or e xi a  
1 4 ( 9)  
1 ( 1)  
M et a b oli c  
 
 
W ei g ht i n cr e a s e  
8 ( 5)  
0  
M u s c ul o s k el et al S y st e m  
 
 
M y al gi a  
8 ( 5)  
 
P s y c hi atri c Di s or d er s  
 
 
A n xi et y  
1 1 ( 7)  
1 ( 1)  
D e pr e s si o n  
1 0 ( 6)  
0  
R e pr o d u cti v e Di s or d er s  
 
 
Br e a st p ai n, f e m al e  
4 ( 6)  
 
R e si st a n c e M e c h a ni s m Di s or d er s  
 
 
I nf e cti o n vir al 
1 7 ( 1 1)  
0  
R e s pir at or y S y st e m  
 
 
U p p er r e s pir at or y tr a ct i nf e cti o n  
1 3 ( 8)  
0  
P h ar y n giti s  
1 2 ( 8)  
0  
Si n u siti s  
1 0 ( 6)  
0  
C o u g hi n g  
8 ( 5)  
0  
S ki n a n d A p p e n d a g e s  
 
 
R a s h  
1 3 ( 8)  
0  
Pr urit u s  
1 2 ( 8)  
2 ( 1)  
Uri n ar y S y st e m  
 
 
Uri n ar y tr a ct i nf e cti o n  
1 2 ( 8)  
0  
Mi ct uriti o n i n cr e a s e d fr e q u e n c y  
9 ( 6)  
0  
V i si o n 
 
 
Di pl o pi a  
8 ( 5)  
0  
Vi si o n a b n or m al*  
8 ( 5)  
 
* Bl urr e d vi si o n; vi s u al d efi cit; vi si o n c h a n g e s; vi si o n tr o u bl e s 
 

 
9  
T A B L E 9: A d v er s e H e m at ol o gi c Eff e ct s ( Gr a d e 3 t o 4) i n t h e A n a pl a sti c A str o c yt o m a Tri al i n A d ult s  
 
T E M O D A R*  
H e m o gl o bi n  
7/ 1 5 8 ( 4 %)  
L y m p h o p e ni a  
8 3/ 1 5 2 ( 5 5 %)  
N e utr o p hil s  
2 0/ 1 4 2 ( 1 4 %)  
Pl at el et s  
2 9/ 1 5 6 ( 1 9 %)  
W B C  
1 8/ 1 5 8 ( 1 1 %)  
* C h a n g e fr o m Gr a d e 0 t o 2 at b a s eli n e t o Gr a d e 3 or 4 d uri n g tr e at m e nt. 
 
T E M O D A R  f or  i nj e cti o n  d eli v er s  e q ui v al e nt  t e m o z ol o mi d e  d o s e  a n d  e x p o s ur e  t o  b ot h  t e m o z ol o mi d e  a n d  5 -( 3-m et h yltri a z e n - 1-yl) -i mi d a z ol e- 4-
c ar b o x a mi d e ( M TI C) a s t h e c orr e s p o n di n g T E M O D A R c a p s ul e s. A d v er s e r e a cti o n s pr o b a bl y r el at e d t o tr e at m e nt t h at w er e r e p ort e d fr o m t h e 2 st u di e s 
wit h t h e i ntr a v e n o u s f or m ul ati o n ( n = 3 5) t h at w er e n ot r e p ort e d i n st u di e s u si n g t h e T E M O D A R c a p s ul e s w er e: p ai n, irrit ati o n, pr urit u s, w ar mt h, s w elli n g, 
a n d er yt h e m a at i nf u si o n sit e a s w ell a s t h e f oll o wi n g a d v er s e r e a cti o n s: p et e c hi a e a n d h e m at o m a.  
 
6. 2  P o st m ar k eti n g E x p eri e n c e  
T h e f oll o wi n g a d v er s e r e a cti o n s h a v e b e e n i d e ntifi e d d uri n g p o st a p pr o v al u s e of T E M O D A R. B e c a u s e t h e s e r e a cti o n s ar e r e p ort e d v ol u nt aril y fr o m 
a p o p ul ati o n of u n c ert ai n si z e, it i s n ot al w a y s p o s si bl e t o r eli a bl y e sti m at e t h eir fr e q u e n c y or e st a bli s h a c a u s al r el ati o n s hi p t o t h e dr u g e x p o s ur e.  
T E M O D A R C a p s ul e s: all er gi c r e a cti o n s, i n cl u di n g a n a p h yl a xi s, h a v e b e e n r e p ort e d. Er yt h e m a m ultif or m e h a s b e e n r e p ort e d, w hi c h r e s ol v e d aft er 
di s c o nti n u ati o n of T E M O D A R a n d, i n s o m e c a s e s, r e c urr e d u p o n r e c h all e n g e. C a s e s of t o xi c e pi d er m al n e cr ol y si s a n d St e v e n s - Jo h n s o n s y n dr o m e h a v e 
b e e n r e p ort e d.   
T h er e h a v e b e e n r e p ort e d c a s e s of h e p at ot o xi cit y, i n cl u di n g el e v ati o n s of li v er e n z y m e s, h y p er bilir u bi n e mi a, c h ol e st a si s, a n d  h e p atiti s.  
O p p ort u ni sti c i nf e cti o n s i n cl u di n g P n e u m o c y sti s c ari nii  p n e u m o ni a ( P C P) h a v e al s o  b e e n r e p ort e d. C a s e s of i nt er stiti al p n e u m o niti s/ p n e u m o niti s, 
al v e oliti s, a n d p ul m o n ar y fi br o si s h a v e b e e n r e p ort e d. Pr ol o n g e d p a n c yt o p e ni a, w hi c h m a y r e s ult i n a pl a sti c a n e mi a, h a s b e e n r e p ort e d, a n d i n s o m e 
c a s e s h a s r e s ult e d i n a f at al o ut c o m e.  
 
7 
D R U G  I N T E R A C TI O N S 
 
7. 1  V al pr oi c A ci d  
A d mi ni str ati o n  of  v al pr oi c  a ci d  d e cr e a s e s  or al  cl e ar a n c e  of  t e m o z ol o mi d e  b y  a b o ut  5 %.  T h e  cli ni c al  i m pli c ati o n  of  t hi s  eff e ct  i s n ot k n o w n [ s e e 
Cli ni c al P h ar m a c ol o g y ( 1 2. 3)].  
 
8 
U S E I N S P E CI FI C P O P U L A TI O N S  
 
8. 1  Pr e g n a n c y  
Pr e g n a n c y C at e g or y D. S e e W ar ni n g s a n d Pr e c a uti o n s s e cti o n.  
T E M O D A R c a n c a u s e f et al h ar m w h e n a d mi ni st er e d t o a pr e g n a nt w o m a n. Fi v e c o n s e c uti v e d a y s of or al t e m o z ol o mi d e a d mi ni str ati o n  of 0. 3 8 a n d 
0. 7 5 ti m e s t h e hi g h e st r e c o m m e n d e d h u m a n d o s e ( 7 5 a n d 1 5 0 m g / m2 ) i n r at s a n d r a b bit s, r e s p e cti v el y, d uri n g t h e p eri o d of or g a n o g e n e si s c a u s e d 
n u m er o u s m alf or m ati o n s of t h e e xt er n al a n d i nt er n al s oft ti s s u e s a n d s k el et o n i n b ot h s p e ci e s. D o s e s e q ui v al e nt t o 0. 7 5 ti m e s  t h e hi g h e st r e c o m m e n d e d 
h u m a n d o s e ( 1 5 0 m g/ m 2 ) ca u s e d e m br y ol et h alit y i n r at s a n d r a b bit s a s i n di c at e d b y i n cr e a s e d r e s or pti o n s. T h er e ar e n o a d e q u at e a n d w ell -c o ntr oll e d 
st u di e s i n pr e g n a nt w o m e n. If t hi s dr u g i s u s e d d uri n g pr e g n a n c y, or if t h e p ati e nt b e c o m e s pr e g n a nt w hil e t a ki n g t hi s dr u g, t h e p ati e nt s h o ul d b e 
a p pri s e d  of  t h e  p ot e nti al  h a z ar d  t o  a  f et u s.  W o m e n  of  c hil d b e ari n g  p ot e nti al  s h o ul d  b e  a d vi s e d  t o  a v oi d  b e c o mi n g  pr e g n a nt  d uri n g  t h er a p y  wit h  
T E M O D A R.  
 
8. 3  N ur si n g M ot h er s  
It i s n ot k n o w n w h et h er t hi s dr u g i s e x cr et e d i n h u m a n mil k. B e c a u s e m a n y dr u g s ar e e x cr et e d i n h u m a n mi k a n d b e c a u s e of t h e p ot e nti al f or 
s eri o u s  a d v er s e r e a cti o n s  i n  n ur si n g  i nf a nt s  a n d  t u m ori g e ni cit y  s h o w n  f or  t e m o z ol o mi d e  i n  a ni m al  st u di e s,  a  d e ci si o n  s h o ul d  b e  m a d e  w h et h er  t o  
di s c o nti n u e n ur si n g or t o di s c o nti n u e t h e dr u g, t a ki n g i nt o a c c o u nt t h e i m p ort a n c e of T E M O D A R  t o t h e m ot h er. 
 
8. 4  P e di atri c U s e  
S af et y  a n d  eff e cti v e n e s s  i n  p e di atri c  p ati e nt s  h a v e  n ot  b e e n  e st a bli s h e d.  T E M O D A R  C a p s ul e s  h a v e  b e e n  st u di e d  i n  2  o p e n -l a b el  st u di e s  i n  
p e di atri c p ati e nt s ( a g e d 3 -1 8 y e ar s) at a d o s e of 1 6 0 t o 2 0 0 m g/ m 2  d ail y f or 5 d a y s e v er y 2 8 d a y s. I n o n e tri al, 2 9 p ati e nt s wit h r e c urr e nt br ai n st e m 
gli o m a a n d 3 4 p ati e nt s wit h r e c urr e nt hi g h gr a d e a str o c yt o m a w er e e nr oll e d. All p ati e nt s h a d r e c urr e n c e f oll o wi n g s ur g er y a n d  r a di ati o n t h er a p y, w hil e 
3 1 % al s o h a d di s e a s e pr o gr e s si o n f oll o wi n g c h e m ot h er a p y. I n a s e c o n d st u d y c o n d u ct e d b y t h e C hil dr e n’ s O n c ol o g y Gr o u p ( C O G), 1 2 2 p ati e nt s w er e 
e nr oll e d,  i n cl u di n g  p ati e nt s  wit h  m e d ull o bl a st o m a/ P N E T  ( 2 9),  hi g h  gr a d e  a str o c yt o m a  ( 2 3),  l o w  gr a d e  a str o c yt o m a  ( 2 2),  br ai n  st e m  gli o m a  ( 1 6),  
e p e n d y m o m a ( 1 4), ot h er C N S t u m or s ( 9), a n d n o n -C N S t u m or s ( 9). T h e T E M O D A R t o xi cit y pr ofil e i n p e di atri c p ati e nt s i s si mil ar t o a d ult s. T a bl e 1 0  
s h o w s t h e a d v er s e r e a cti o n s i n 1 2 2 c hil dr e n i n t h e C O G st u d y.  
 

 
1 0  
T A B L E 1 0 : A d v er s e R e a cti o n s R e p ort e d i n t h e P e di atri c C o o p er ati v e Gr o u p Tri al ( ≥1 0 %) 
 
N o. ( %) of T E M O D A R P ati e nt s 
( N = 1 2 2)* 
B o d y S y st e m/ Or g a n Cl a s s  
 
A d v er s e R e a cti o n  
All R e a cti o n s  
Gr a d e 3/ 4  
S u bj e ct s R e p orti n g a n A E  
1 0 7 ( 8 8)  
6 9 ( 5 7)  
B o d y a s a W h ol e  
 
 
C e ntr al a n d P eri p h er al N er v o u s S y st e m  
 
 
C e ntr al  c er e br al C N S c ort e x  
2 2 ( 1 8)  
1 3 ( 1 1)  
G a str oi nt e sti n al S y st e m  
 
 
N a u s e a  
5 6 ( 4 6)  
5 ( 4)  
V o miti n g  
6 2 ( 5 1)  
4 ( 3)  
Pl at el et, Bl e e di n g a n d Cl otti n g  
 
 
T hr o m b o c yt o p e ni a  
7 1 ( 5 8)  
3 1 ( 2 5)  
R e d Bl o o d C ell Di s or d er s  
 
 
D e cr e a s e d H e m o gl o bi n  
6 2 ( 5 1)  
7 ( 6)  
W hit e C ell a n d R E S Di s or d er s  
 
 
D e cr e a s e d W B C  
7 1 ( 5 8)  
2 1 ( 1 7)  
L y m p h o p e ni a  
7 3 ( 6 0)  
4 8 ( 3 9)  
N e utr o p e ni a  
6 2 ( 5 1)  
2 4 ( 2 0)  
* T h e s e v ari o u s t u m or s i n cl u d e d t h e f oll o wi n g: P N E T-m e d ull o bl a st o m a, gli o bl a st o m a, l o w gr a d e 
a str o c yt o m a, br ai n st e m t u m or, e p e n d y m o m a, mi x e d gli o m a , oli g o d e n dr o gli o m a, n e ur o bl a st o m a, 
E wi n g' s s ar c o m a, pi n e o bl a st o m a, al v e ol ar s oft p art s ar c o m a, n e ur ofi br o s ar c o m a, o pti c gli o m a, 
a n d o st e o s ar c o m a.  
 
8. 5  G eri atri c U s e  
Cli ni c al st u di e s of t e m o z ol o mi d e di d n ot i n cl u d e s uffi ci e nt n u m b er s of s u bj e ct s a g e d 6 5 a n d o v er t o d et er mi n e w h et h er t h e y r e s p o n d e d diff er e ntl y 
fr o m  y o u n g er s u bj e ct s.  Ot h er r e p ort e d cli ni c al  e x p eri e n c e h a s  n ot i d e ntifi e d diff er e n c e s  i n r e s p o n s e s  b et w e e n t h e el d erl y a n d y o u n g er p ati e nt s.  I n 
g e n er al, d o s e s el e cti o n f or a n el d erl y p ati e nt s h o ul d  b e c a uti o u s, r efl e cti n g t h e gr e at er fr e q u e n c y of d e cr e a s e d h e p ati c, r e n al, or c ar di a c f u n cti o n, a n d of 
c o n c o mit a nt di s e a s e or ot h er dr u g t h er a p y.  
I n t h e a n a pl a sti c a str o c yt o m a st u d y p o p ul ati o n, p ati e nt s 7 0 y e ar s of a g e or ol d er h a d a hi g h er i n ci d e n c e of Gr a d e 4 n e utr o p e ni a a n d Gr a d e 4 
t hr o m b o c yt o p e ni a ( 2/ 8; 2 5 %, P = 0. 3 1 a n d 2/ 1 0; 2 0 %, P = 0. 0 9, r e s p e cti v el y) i n t h e fir st c y cl e of t h er a p y t h a n p ati e nt s u n d er 7 0 y e ar s of a g e [ s e e W ar ni n g s 
a n d Pr e c a uti o n s ( 5 . 1) a n d A d v er s e R e a cti o n s ( 6. 1)]. 
I n n e wl y di a g n o s e d p ati e nt s wit h gli o bl a st o m a m ultif or m e, t h e a d v er s e r e a cti o n pr ofil e w a s si mil ar i n y o u n g er p ati e nt s ( < 6 5 y e ar s) v s. ol d er ( ≥6 5 
y e ar s).  
 
8. 6  R e n al I m p air m e nt  
C a uti o n s h o ul d b e e x er ci s e d w h e n T E M O D A R i s a d mi ni st er e d t o p ati e nt s wit h s e v er e r e n al i m p air m e nt [ s ee Cli ni c al P h ar m a c ol o g y ( 1 2. 3)].  
 
8. 7  H e p ati c I m p air m e nt  
C a uti o n s h o ul d b e e x er ci s e d w h e n T E M O D A R i s a d mi ni st er e d t o p ati e nt s wit h s e v er e h e p ati c i m p air m e nt [ s e e Cli ni c al P h ar m a c ol o g y ( 1 2. 3)]. 
 
1 0  
O V E R D O S A G E  
D o s e s of 5 0 0, 7 5 0, 1 0 0 0, a n d 1 2 5 0 m g/ m 2 (t ot al d o s e p er c y cl e o v er 5 d a y s) h a v e b e e n e v al u at e d cli ni c all y i n p ati e nt s. D o s e -li miti n g t o xi cit y w a s 
h e m at ol o gi c a n d w a s r e p ort e d wit h a n y d o s e b ut i s e x p e ct e d t o b e m or e s e v er e at hi g h er d o s e s. A n o v er d o s e of 2 0 0 0 m g p er d a y f or 5 d a y s w a s t a k e n 
b y o n e p ati e nt a n d t h e a d v er s e r e a cti o n s r e p ort e d w er e p a n c yt o p e ni a, p yr e xi a, m ulti -or g a n f ail ur e, a n d d e at h. T h er e ar e r e p ort s of p ati e nt s w h o h a v e 
t a k e n m or e t h a n 5 d a y s of tr e at m e nt ( u p t o 6 4 d a y s), wit h a d v er s e r e a cti o n s r e p ort e d i n cl u di n g b o n e m arr o w s u p pr e s si o n, w hi c h i n s o m e c a s e s w a s 
s e v er e a n d pr ol o n g e d, a n d i nf e cti o n s a n d r e s ult e d i n d e at h. I n t h e e v e nt of a n o v er d o s e, h e m at ol o gi c e v al u ati o n i s n e e d e d. S u p p orti v e m e a s ur e s s h o ul d 
b e pr o vi d e d a s n e c e s s ar y.  
 
1 1  
D E S C RI P TI O N  
T E M O D A R c o nt ai n s t e m o z ol o mi d e, a n i mi d a z ot etr a zi n e d eri v ati v e. T h e c h e mi c al n a m e of t e m o z ol o mi d e i s 3, 4 -di h y dr o - 3-m et h yl - 4-o x oi mi d a z o[ 5, 1 -
d] -a s -t etr a zi n e- 8-c ar b o x a mi d e. T h e str u ct ur al f or m ul a i s:  
 
T h e m at eri al i s a w hit e t o li g ht t a n/li g ht pi n k p o w d er wit h a m ol e c ul ar f or m ul a of C 6 H 6 N 6 O
2  a n d a m ol e c ul ar w ei g ht of 1 9 4. 1 5. T h e m ol e c ul e i s 
st a bl e at a ci di c p H ( < 5) a n d l a bil e at p H > 7; h e n c e T E M O D A R c a n b e a d mi ni st er e d or all y a n d i ntr a v e n o u sl y. T h e pr o dr u g, t e m o z ol o mi d e, i s r a pi dl y 
h y dr ol y z e d t o t h e a cti v e 5 -( 3-m et h yltri a z e n - 1-yl) i mi d a z ol e - 4-c ar b o x a mi d e ( M TI C) at n e utr al a n d al k ali n e p H v al u e s, wit h h y dr ol y si s t a ki n g pl a c e e v e n 
f a st er at a k ali n e p H. 
T E M O D A R C a p s ul e s:  
E a c h c a p s ul e f or or al u s e c o nt ai n s eit h er 5 m g, 2 0 m g, 1 0 0 m g, 1 4 0 m g, 1 8 0 m g, or 2 5 0 m g of t e m o z ol o mi d e.  
T h e i n a cti v e i n gr e di e nt s f or T E M O D A R C a p s ul e s ar e a s f oll o w s:  
T E M O D A R  5 m g : l a ct o s e a n h y dr o u s ( 1 3 2. 8 m g), c oll oi d al sili c o n di o xi d e ( 0. 2 m g), s o di u m st ar c h gl y c ol at e ( 7. 5 m g), t art ari c a ci d ( 1. 5 m g), an d 
st e ari c a ci d ( 3 m g).  

 
1 1  
T E M O D A R 2 0 m g:  l a ct o s e a n h y dr o u s ( 1 8 2. 2 m g), c oll oi d al sili c o n di o xi d e ( 0. 2 m g), s o di u m st ar c h gl y c ol at e ( 1 1 m g), t art ari c a ci d ( 2. 2 m g), a n d 
st e ari c a ci d ( 4. 4 m g).  
T E M O D A R 1 0 0 m g:  l a ct o s e a n h y dr o u s ( 1 7 5. 7 m g), c oll oi d al sili c o n di o xi d e ( 0. 3 m g), s o di u m st ar c h gl y c ol at e ( 1 5 m g), t art ari c a ci d ( 3 m g), a n d 
st e ari c a ci d ( 6 m g).  
T E M O D A R 1 4 0 m g:  l a ct o s e a n h y dr o u s ( 2 4 6 m g), c oll oi d al sili c o n di o xi d e ( 0. 4 m g), s o di u m st ar c h gl y c ol at e ( 2 1 m g), t art ari c a ci d ( 4. 2 m g), a n d 
st e ari c a ci d ( 8. 4 m g).  
T E M O D A R 1 8 0 m g:  l a ct o s e a n h y dr o u s ( 3 1 6. 3 m g), c oll oi d al sili c o n di o xi d e ( 0. 5 m g), s o di u m st ar c h gl y c ol at e ( 2 7 m g), t art ari c a ci d ( 5. 4 m g), a n d 
st e ari c a ci d ( 1 0. 8 m g).  
T E M O D A R 2 5 0 m g:  l a ct o s e a n h y dr o u s ( 1 5 4. 3 m g), c oll oi d al sili c o n di o xi d e ( 0. 7 m g), s o di u m st ar c h gl y c ol at e ( 2 2. 5 m g), t art ari c a ci d ( 9 m g), a nd 
st e ari c a ci d ( 1 3. 5 m g).  
T h e b o d y of t h e c a p s ul e s i s m a d e of g el ati n, a n d i s o p a q u e w hit e. T h e c a p i s al s o m a d e of g el ati n, a n d t h e c ol or s v ar y b a s e d o n t h e d o s a g e 
str e n gt h. T h e c a p s ul e b o d y a n d c a p ar e i m pri nt e d wit h p h ar m a c e uti c al br a n di n g i n k, w hi c h c o nt ai n s s h ell a c, d e h y dr at e d al c o h ol, i s o pr o p yl al c o h ol, b ut yl 
al c o h ol, pr o p yl e n e gl y c ol, p urifi e d w at er, str o n g a m m o ni a s ol uti o n, p ot a s si u m h y dr o xi d e, a n d f erri c o xi d e.  
T E M O D A R 5 m g: T h e gr e e n c a p c o nt ai n s g el ati n, tit a ni u m di o xi d e, ir o n o xi d e y ell o w, s o di u m l a ur yl s ulf at e, a n d F D & C Bl u e # 2.  
T E M O D A R 2 0 m g:  T h e y ell o w c a p c o nt ai n s g el ati n, s o di u m l a ur yl s ulf at e, a n d ir o n o xi d e y ell o w.  
T E M O D A R 1 0 0 m g:  T h e pi n k c a p c o nt ai n s g el ati n, tit a ni u m di o xi d e, s o di u m l a ur yl s ulf at e, a n d ir o n o xi d e r e d.  
T E M O D A R 1 4 0 m g: T h e bl u e c a p c o nt ai n s g el ati n, s o di u m l a ur yl s ulf at e, a n d F D & C Bl u e # 2.  
T E M O D A R 1 8 0 m g: T h e or a n g e c a p c o nt ai n s g el ati n, ir o n o xi d e r e d, ir o n o xi d e y ell o w, tit a ni u m di o xi d e, a n d s o di u m l a ur yl s ulf at e.  
T E M O D A R 2 5 0 m g:  T h e w hit e c a p c o nt ai n s g el ati n, tit a ni u m di o xi d e, a n d s o di u m l a ur y l s ulf at e. 
T E M O D A R f or I nj e cti o n: E a c h vi al c o nt ai n s 1 0 0 m g of st eril e a n d p yr o g e n -fr e e t e m o z ol o mi d e l y o p hili z e d p o w d er f or i ntr a v e n o u s i nj e cti o n. T h e 
i n a cti v e i n gr e di e nt s ar e: m a n nit ol ( 6 0 0 m g), L-t hr e o ni n e ( 1 6 0 m g), p ol y s or b at e 8 0 ( 1 2 0 m g), s o di u m citr at e di h y dr at e ( 2 3 5 m g), a n d h y dr o c hl ori c a ci d 
( 1 6 0 m g).  
 
1 2  
C LI NI C A L P H A R M A C O L O G Y  
 
1 2. 1  M e c h a ni s m of A cti o n  
T e m o z ol o mi d e i s n ot dir e ctl y a cti v e b ut u n d er g o e s r a pi d n o n e n z y m ati c c o n v er si o n at p h y si ol o gi c p H t o t h e r e a cti v e c o m p o u n d 5 -( 3-m et h yltri a z e n -
1- yl) -imi d a z ol e - 4-c ar b o x a mi d e ( M TI C).  T h e c yt ot o xi cit y of  M TI C i s t h o u g ht  t o b e pri m aril y d u e t o al k yl ati o n of  D N A.  Al k yl ati o n ( m et h yl ati o n) o c c ur s 
m ai nl y at t h e O
6  a n d N 7  p o siti o n s of g u a ni n e.  
 
1 2. 3  P h ar m a c o ki n eti c s  
A b s or pti o n: T e m o z ol o mi d e i s r a pi dl y a n d c o m pl et el y a b s or b e d aft er or al a d mi ni str ati o n wit h a p e a k pl a s m a c o n c e ntr ati o n ( C m a x ) a c hi e v e d i n a 
m e di a n T
m a x  of 1 h o ur. F o o d r e d u c e s t h e r at e a n d e xt e nt of t e m o z ol o mi d e a b s or pti o n. M e a n p e a k pl a s m a c o n c e ntr ati o n a n d A U C d e cr e a s e d b y 3 2 % 
a n d 9 %, r e s p e cti v el y, a n d m e di a n T m a x  i n cr e a s e d b y 2-f ol d (fr o m 1-2. 2 5 h o ur s) w h e n t e m o z ol o mi d e w a s a d mi ni st er e d aft er a m o difi e d hi g h -f at br e a kf a st.  
A p h ar m a c o ki n eti c st u d y c o m p ari n g or al a n d i ntr a v e n o u s t e m o z ol o mi d e i n 1 9 p ati e nt s wit h pri m ar y C N S m ali g n a n ci e s s h o w e d t h at 1 5 0 m g/ m 2  
T E M O D A R f or i nj e cti o n a d mi ni st er e d o v er 9 0 mi n ut e s i s bi o e q ui v al e nt t o 1 5 0 m g/ m 2  T E M O D A R or al c a p s ul e s wit h r e s p e ct t o b ot h C m a x  a n d A U C of 
t e m o z ol o mi d e a n d M TI C. F oll o wi n g a si n gl e 9 0-mi n ut e i ntr a v e n o u s i nf u si o n of 1 5 0 m g/ m
2 , t h e g e o m etri c m e a n Cm a x  v al u e s f or t e m o z ol o mi d e a n d M TI C 
w er e 7. 3 m c g/ m L a n d 2 7 6 n g/ m L, r e s p e cti v el y. F oll o wi n g a si n gl e or al d o s e of 1 5 0 m g/ m 2 , t h e g e o m etri c m e a n Cm a x  v al u e s f or t e m o z ol o mi d e a n d M TI C 
w er e 7. 5 m c g/ m L a n d 2 8 2 n g/ m L, r e s p e cti v el y. F oll o wi n g a si n gl e 9 0 -mi n ut e i ntr a v e n o u s i nf u si o n of 1 5 0 m g/ m
2 , t h e g e o m etri c m e a n A U C v al u e s f or 
t e m o z ol o mi d e a n d M TI C w er e 2 4. 6 m c g· hr/ m L a n d 8 9 1 n g· hr/ m L, r e s p e cti v el y. F oll o wi n g a si n gl e or al d o s e of 1 5 0 m g/ m2 , t h e g e o m etri c m e a n A U C 
v al u e s f or t e m o z ol o mi d e a n d M TI C w er e 2 3. 4 m c g· hr/ m L a n d 8 6 4 n g· hr/ m L, r e s p e cti v el y.  
Di stri b uti o n: T e m o z ol o mi d e h a s a m e a n a p p ar e nt v ol u m e of di stri b uti o n of 0. 4 L/ k g ( % C V = 1 3 %). It i s w e a kl y b o u n d t o h u m a n pl a s m a pr ot ei n s; t h e 
m e a n p er c e nt b o u n d of dr u g -r el at e d t ot al r a di o a cti vit y i s 1 5 %. 
M et a b oli s m a n d  Eli mi n ati o n: T e m o z ol o mi d e i s s p o nt a n e o u sl y h y dr ol y z e d at p h y si ol o gi c p H t o t h e a cti v e s p e ci e s, M TI C a n d t o t e m o z ol o mi d e a ci d 
m et a b olit e. M TI C i s f urt h er h y dr ol y z e d t o 5 -a mi n o -i mi d a z ol e- 4-c ar b o x a mi d e ( AI C), w hi c h i s k n o w n t o b e a n i nt er m e di at e i n p uri n e a n d n u cl ei c a ci d 
bi o s y nt h e si s, a n d t o m et h yl h y dr a zi n e, w hi c h i s b eli e v e d t o b e t h e a cti v e al k yl ati n g s p e ci e s. C yt o c hr o m e P 4 5 0 e n z y m e s pl a y o nl y a mi n or r ol e i n t h e 
m et a b oli s m of t e m o z ol o mi d e a n d M TI C. R el ati v e t o t h e A U C of t e m o z ol o mi d e, t h e e x p o s ur e t o M TI C  a n d AI C i s 2. 4 % a n d 2 3 %, r e s p e cti v el y.  
E x cr eti o n: A b o ut 3 8 % of t h e a d mi ni st er e d t e m o z ol o mi d e t ot al r a di o a cti v e d o s e i s r e c o v er e d o v er 7 d a y s: 3 7. 7 % i n uri n e a n d 0. 8 % i n f e c e s.  T h e 
m aj orit y of t h e r e c o v er y of r a di o a cti vit y i n uri n e i s u n c h a n g e d t e m o z ol o mi d e ( 5. 6 %), AI C ( 1 2 %), t e m o z ol o mi d e a ci d m et a b olit e ( 2. 3 %), a n d u ni d e ntifi e d 
p ol ar m et a b olit e( s) ( 1 7 %). O v er all cl e ar a n c e of t e m o z ol o mi d e i s a b o ut 5. 5 L/ hr/ m 2 . T e m o z ol o mi d e i s r a pi dl y eli mi n at e d, wit h a m e a n eli mi n ati o n h alf-lif e 
of 1. 8 h o ur s, a n d e x hi bit s l i n e ar ki n eti c s o v er t h e t h er a p e uti c d o si n g r a n g e of 7 5 t o 2 5 0 m g/ m2 / d a y. 
Eff e ct  of  A g e:  A  p o p ul ati o n  p h ar m a c o ki n eti c  a n al y si s  i n di c at e d  t h at  a g e  (r a n g e:  1 9 -7 8  y e ar s)  h a s  n o  i nfl u e n c e  o n  t h e  p h ar m a c o ki n eti c s  of  
t e m o z ol o mi d e. 
Eff e ct of G e n d er: A p o p ul ati o n p h ar m a c o ki n eti c  a n al y si s  i n di c at e d  t h at  w o m e n  h a v e  a n  a p pr o xi m at el y  5 %  l o w er  cl e ar a n c e  ( a dj u st e d  f or  b o d y 
s urf a c e ar e a) f or t e m o z ol o mi d e t h a n m e n.  
Eff e ct of R a c e: T h e eff e ct of r a c e o n t h e p h ar m a c o ki n eti c s of t e m o z ol o mi d e h a s n ot b e e n st u di e d.  
T o b a c c o U s e: A p o p ul ati o n p h ar m a c o ki n eti c a n al y si s i n di c at e d t h at t h e or al cl e ar a n c e of t e m o z ol o mi d e i s si mil ar i n s m o k er s a n d n o n s m o k er s.  
Eff e ct of R e n al I m p air m e nt: A p o p ul ati o n p h ar m a c o ki n eti c a n al y si s i n di c at e d t h at cr e ati ni n e cl e ar a n c e o v er t h e r a n g e of 3 6 t o 1 3 0 m L/ mi n/ m
2  h a s 
n o eff e ct o n t h e cl e ar a n c e of t e m o z ol o mi d e aft er or al a d mi ni str ati o n. T h e p h ar m a c o ki n eti c s of t e m o z ol o mi d e h a v e n ot b e e n st u di e d i n p ati e nt s wit h 
s e v er el y i m p air e d r e n al f u n cti o n ( C L cr < 3 6 m L/ mi n/ m 2 ). C a uti o n s h o ul d b e e x er ci s e d w h e n T E M O D A R i s a d mi ni st er e d t o p ati e nt s wit h s e v er e r e n al 
i m p air m e nt [ s e e U s e i n S p e ci al P o p ul ati o n s ( 8. 6)]. T E M O D A R h a s n ot b e e n st u di e d i n p ati e nt s o n di al y si s.  
Eff e ct of H e p ati c I m p air m e nt: A st u d y s h o w e d t h at t h e p h ar m a c o ki n eti c s of t e m o z ol o mi d e i n p ati e nt s wit h m il d-t o-m o d er at e h e p ati c i m p air m e nt 
( C hil d-P u g h Cl a s s I - II) w er e si mil ar t o t h o s e o b s er v e d i n p ati e nt s wit h n or m al h e p ati c f u n cti o n. C a uti o n s h o ul d b e e x er ci s e d w h e n t e m o z ol o mi d e i s 
a d mi ni st er e d t o p ati e nt s wit h s e v er e h e p ati c i m p air m e nt [ s e e U s e i n S p e ci fi c P o p ul ati o n s ( 8. 7)].  
Eff e ct of Ot h er Dr u g s o n T e m o z ol o mi d e P h ar m a c o ki n eti c s: I n a m ulti pl e-d o s e s tu d y, a d mi ni str ati o n of T E M O D A R C a p s ul e s wit h r a niti di n e di d 
n ot c h a n g e t h e C m a x  or A U C v al u e s f or t e m o z ol o mi d e or M TI C.  
A p o p ul ati o n a n al y si s i n di c at e d t h a t a d mi ni str ati o n of v al pr oi c a ci d d e cr e a s e s t h e cl e ar a n c e of t e m o z ol o mi d e b y a b o ut 5 % [ s e e Dr u g I nt er a cti o n s 
( 7. 1)]. 
A  p o p ul ati o n  a n al y si s  di d  n ot  d e m o n str at e  a n y  i nfl u e n c e  of  c o a d mi ni st er e d  d e x a m et h a s o n e,  pr o c hl or p er a zi n e,  p h e n yt oi n,  c ar b a m a z e pi n e, 
o n d a n s etr o n, H 2 -r e c e pt or a nt a g o ni st s, or p h e n o b ar bit al o n t h e cl e ar a n c e of or all y a d mi ni st er e d t e m o z ol o mi d e. 
 
1 3  
N O N C LI NI C A L T O XI C O L O G Y  
 
1 3. 1  C ar ci n o g e n e si s, M ut a g e n e si s, I m p air m e nt of F ertilit y  
T e m o z ol o mi d e i s c ar ci n o g e ni c i n r at s at d o s e s l e s s t h a n t h e m a xi m u m  r e c o m m e n d e d h u m a n d o s e. T e m o z ol o mi d e i n d u c e d m a m m ar y c ar ci n o m a s 
i n b ot h m al e s a n d f e m al e s at d o s e s 0. 1 3 t o 0. 6 3 ti m e s t h e m a xi m u m h u m a n d o s e ( 2 5-1 2 5 m g/ m 2 ) w h e n a d mi ni st er e d or all y o n 5 c o n s e c uti v e d a y s e v er y 
2 8 d a y s f or 6 c y cl e s. T e m o z ol o mi d e al s o i n d u c e d fi br o s ar c o m a s of t h e h e art, e y e, s e mi n al v e si cl e s, s ali v ar y gl a n d s, a b d o mi n al c a vit y, ut er u s, a n d 

 
1 2  
pr o st at e, c ar ci n o m a s of t h e s e mi n al v e si cl e s, s c h w a n n o m a s of t h e h e art, o pti c n er v e, a n d h ar d eri a n gl a n d, a n d a d e n o m a s of t h e  s ki n, l u n g, pit uit ar y, 
a n d t h yr oi d at d o s e s 0. 5 ti m e s t h e m a xi m u m  d ail y d o s e. M a m m ar y t u m or s w er e al s o i n d u c e d f oll o wi n g 3 c y cl e s of t e m o z ol o mi d e at t h e m a xi m u m 
r e c o m m e n d e d d ail y d o s e. 
T e m o z ol o mi d e  i s  a  m ut a g e n  a n d  a  cl a st o g e n.  I n  a  r e v er s e  b a ct eri al  m ut a g e n e si s  a s s a y  ( A m e s  a s s a y),  t e m o z ol o mi d e  i n cr e a s e d  r e v ert a nt  
fr e q u e n c y i n t h e a b s e n c e a n d pr e s e n c e of m et a b oli c a cti v ati o n. T e m o z ol o mi d e w a s cl a st o g e ni c i n h u m a n l y m p h o c yt e s i n t h e pr e s e n c e a n d a b s e n c e of 
m et a b oli c a cti v ati o n.  
T e m o z ol o mi d e  i m p air s  m al e  f ertilit y.  T e m o z ol o mi d e  c a u s e d  s y n c yti al  c ell s/i m m at ur e  s p er m  f or m ati o n  at  0. 2 5  a n d  0. 6 3  ti m e s  t h e  m a xi m u m  
r e c o m m e n d e d h u m a n d o s e ( 5 0 a n d 1 2 5 m g/ m2 ) i n r at s a n d d o g s, r e s p e cti v el y, a n d t e sti c ul ar atr o p h y i n d o g s at 0. 6 3 ti m e s t h e m a xi m u m r e c o m m e n d e d 
h u m a n d o s e ( 1 2 5 m g/ m 2 ). 
 
1 3. 2  A ni m al T o xi c ol o g y a n d/ or P h ar m a c ol o g y  
T o xi c ol o g y st u di e s i n r at s a n d d o g s i d e ntifi e d a l o w i n ci d e n c e of h e m orr h a g e, d e g e n er ati o n, a n d n e cr o si s of t h e r eti n a at t e m o z ol o mi d e d o s e s 
e q u al t o or gr e at er t h a n 0. 6 3 ti m e s t h e m a xi m u m r e c o m m e n d e d h u m a n d o s e ( 1 2 5 m g/ m 2 ). T he s e c h a n g e s w er e m o st c o m m o nl y s e e n at d o s e s w h er e 
m ort alit y w a s o b s er v e d.  
 
1 4  
C LI NI C A L S T U DI E S  
 
1 4. 1  N e wl y Di a g n o s e d Gli o bl a st o m a M ultif or m e  
Fi v e h u n dr e d a n d s e v e nt y -t hr e e p ati e nt s w er e r a n d o mi z e d t o r e c ei v e eit h er T E M O D A R ( T M Z) + R a di ot h er a p y ( R T) ( n = 2 8 7)  or R T al o n e ( n = 2 8 6). 
P ati e nt s i n t h e T E M O D A R + R T ar m r e c ei v e d c o n c o mit a nt T E M O D A R ( 7 5  m g/ m
2 ) o n c e d ail y, st arti n g t h e fir st d a y of R T u ntil t h e l a st d a y of R T, f or 4 2 
d a y s ( wit h a m a xi m u m of 4 9  d a y s). T hi s w a s f oll o w e d b y 6 c y cl e s of T E M O D A R al o n e ( 1 5 0  or 2 0 0  m g/ m
2 ) o n D a y s 1 t o 5 of e v er y 2 8 -d a y c y cl e, st arti n g 
4 w e e k s aft er t h e e n d of R T. P ati e nt s i n t h e c o ntr ol ar m r e c ei v e d R T o nl y. I n b ot h ar m s, f o c al r a di ati o n t h er a p y w a s d eli v er e d a s 6 0 G y/ 3 0 fr a cti o n s. 
F o c al R T i n cl u d e s t h e t u m or b e d or r e s e cti o n sit e wit h a 2 - t o 3-c m m ar gi n. P n e u m o c y sti s c ari nii p n e u m o ni a ( P C P) pr o p h yl a xi s w a s r e q uir e d d uri n g t h e 
T M Z + R T, r e g ar dl e s s of l y m p h o c yt e c o u nt, a n d w a s t o c o nti n u e u ntil r e c o v er y of l y m p h o c yt e c o u nt t o l e s s t h a n or e q u al t o Gr a d e  1.  
At t h e ti m e of di s e a s e pr o gr e s si o n, T E M O D A R w a s a d mi ni st er e d a s s al v a g e t h er a p y i n 1 6 1 p ati e nt s of t h e 2 8 2 ( 5 7 %) i n t h e R T al o n e ar m, a n d 6 2 
p ati e nt s of t h e 2 7 7 ( 2 2 %) i n t h e T E M O D A R + R T ar m.  
T h e  a d diti o n  of  c o n c o mit a nt  a n d  m ai nt e n a n c e  T E M O D A R  t o  r a di ot h er a p y  i n  t h e  tr e at m e nt  of  p ati e nt s  wit h  n e wl y  di a g n o s e d  G B M  s h o w e d  a  
st ati sti c all y  si g nifi c a nt  i m pr o v e m e nt  i n  o v er all  s ur vi v al  c o m p ar e d  t o  r a di ot h er a p y  al o n e  ( Fi g ur e  1 ).  T h e  h a z ar d  r ati o  ( H R)  f or  o v er all  s ur vi v al  w a s  
0. 6 3  ( 9 5 %  CI  f or  H R = 0. 5 2-0. 7 5) wit h a l o g -r a n k P < 0. 0 0 0 1 i n f a v or of t h e T E M O D A R ar m. T h e m e di a n s ur vi v al w a s i n cr e a s e d b y 2. 5 m o nt h s i n t h e 
T E M O D A R ar m.  
 
FI G U R E 1: K a pl a n -M ei er C ur v e s f or O v er all S ur vi v al (I T T P o p ul ati o n)  
 
1 4. 2  R efr a ct or y A n a pl a sti c A str o c yt o m a  
A si n gl e -ar m, m ulti c e nt er st u d y w a s c o n d u ct e d i n 1 6 2 p ati e nt s w h o h a d a n a pl a sti c a str o c yt o m a at fir st r el a p s e a n d w h o h a d a b a s eli n e K ar n of s k y 
p erf or m a n c e st at u s of 7 0 or gr e at er. P ati e nt s h a d pr e vi o u sl y r e c ei v e d r a di ati o n t h er a p y a n d m a y al s o h a v e pr e vi o u sl y r e c ei v e d  a nitr o s o ur e a wit h or 
wit h o ut ot h er c h e m ot h er a p y.  Fift y -f o ur p ati e nt s h a d di s e a s e pr o gr e s si o n o n pri or t h er a p y wit h b ot h a nitr o s o ur e a a n d pr o c ar b a zi n e, a n d t h eir m ali g n a n c y 
w a s c o n si d er e d r efr a ct or y t o c h e m ot h er a p y (r efr a ct or y a n a pl a sti c a str o c yt o m a p o p ul ati o n). M e di a n a g e of t hi s s u b gr o u p of 5 4 p ati e nt s w a s 4 2 y e ar s ( 1 9 -
7 6). Si xt y -fi v e p er c e nt w er e m al e. S e v e nt y-t w o p er c e nt of p ati e nt s h a d a K P S of > 8 0. Si xt y-t hr e e p er c e nt of p ati e nt s h a d s ur g er y ot h er t h a n a bi o p s y at 
t h e ti m e of i niti al di a g n o si s. Of t h o s e p ati e nt s u n d er g oi n g r e s e cti o n, 7 3 % u n d er w e nt  a s u bt ot al r e s e cti o n a n d 2 7 % u n d er w e nt a gr o s s t ot al r e s e cti o n. 
Ei g ht e e n p er c e nt of p ati e nt s h a d s ur g er y at t h e ti m e of fir st r el a p s e. T h e m e di a n ti m e fr o m i niti al di a g n o si s t o fir st r el a p s e w a s 1 3. 8 m o nt h s ( 4. 2 -7 5. 4).  
T E M O D A R C a p s ul e s w er e gi v e n f or t h e fir st 5 c o n s e c uti v e d a y s of a 2 8 -d a y c y cl e at a st arti n g d o s e of 1 5 0 m g/ m 2 / d a y. If t h e n a dir a n d d a y of 
d o si n g ( D a y 2 9, D a y 1 of n e xt c y cl e) a b s ol ut e n e utr o p hil c o u nt w a s gr e at er t h a n or e q u al t o 1. 5 x 1 0 9 / L ( 1 5 0 0/ µ L) a n d t h e n a dir a n d D a y 2 9, D a y 1 of 
n e xt  c y cl e pl at el et c o u nt w a s gr e at er t h a n or e q u al t o 1 0 0 x 1 0 9 / L ( 1 0 0, 0 0 0/ µ L), t h e T E M O D A R d o s e w a s i n cr e a s e d t o 2 0 0 m g/ m2 / d a y f or t h e fir st 5 
c o n s e c uti v e d a y s of a 2 8 -d a y c y cl e.  
I n t h e r efr a ct or y a n a pl a sti c a str o c yt o m a p o p ul ati o n, t h e o v er all t u m or r e s p o n s e r at e ( C R + P R) w a s 2 2 % ( 1 2/ 5 4 p ati e nt s) a n d t h e c o m pl et e r e s p o n s e 
r at e w a s 9 % ( 5/ 5 4 p ati e nt s). T h e m e di a n d ur ati o n of all r e s p o n s e s w a s 5 0 w e e k s (r a n g e: 1 6-1 1 4 w e e k s) a n d t h e m e di a n d ur ati o n of c o m pl et e r e s p o n s e s 

 
1 3  
w a s 6 4 w e e k s (r a n g e: 5 2 -1 1 4 w e e k s). I n t hi s p o p ul ati o n, pr o gr e s si o n -fr e e  s ur vi v al  at  6  m o nt h s  w a s  4 5 %  ( 9 5 %  CI:  3 1 %-5 8 %)  a n d  pr o gr e s si o n -fr e e 
s ur vi v al at 1 2 m o nt h s w a s 2 9 % ( 9 5 % CI: 1 6 % -4 2 %). M e di a n pr o gr e s si o n -fr e e s ur vi v al w a s 4. 4 m o nt h s. O v er all s ur vi v al at 6 m o nt h s w a s 7 4 % ( 9 5 % CI: 
6 2 % -8 6 %) a n d 1 2 -m o nt h o v er all s ur vi v al w a s 6 5 % ( 9 5 % CI: 5 2 % -7 8 %). M e di a n o v er all s ur vi v al w a s 1 5. 9 m o nt h s.  
 
1 5  
R E F E R E N C E S  
1.  
O S H A T e c h ni c al M a n u al, T E D 1 -0. 1 5 A, S e cti o n VI: C h a pt er 2. C o ntr olli n g O c c u p ati o n al E x p o s ur e t o H a z ar d o u s Dr u g s. O S H A, 1 9 9 9.  
2.  
A m eri c a n S o ci et y of H e a lt h-S y st e m P h ar m a ci st s. A S H P g ui d eli n e s o n h a n dli n g h a z ar d o u s dr u g s. A m J H e alt h -S y st P h ar m.  2 0 0 6; 6 3: 1 1 7 2 -
1 1 9 3.  
3.  
NI O S H Al ert: Pr e v e nti n g o c c u p ati o n al e x p o s ur e s t o a nti n e o pl a sti c a n d ot h er h a z ar d o u s dr u g s i n h e alt h c ar e s etti n g s. 2 0 0 4. U. S.  D e p art m e nt of 
H e a lt h a n d H u m a n S er vi c e s, P u bli c H e alt h S er vi c e, C e nt er s f or Di s e a s e C o ntr ol a n d Pr e v e nti o n, N ati o n al I n stit ut e f or O c c u p ati o n al S af et y 
a n d H e alt h, D H H S ( NI O S H) P u bli c ati o n N o. 2 0 0 4 -1 6 5.[ 3]    
4.  
P ol o vi c h, M., W hit e, J. M., & K ell e h er, L. O. ( e d s.) 2 0 0 5. C h e m ot h er a p y a n d bi ot h er a p y g ui d eli n e s a n d r e c o m m e n d ati o n s f or pr a cti c e ( 2 n d. e d.) 
Pitt s b ur g h, P A: O n c ol o g y.  
 
1 6  
H O W S U P P LI E D/ S T O R A G E A N D H A N D LI N G  
 
1 6. 1  S af e H a n dli n g a n d Di s p o s al  
C ar e  s h o ul d  b e  e x er ci s e d  i n  t h e  h a n dli n g  a n d  pr e p ar ati o n  of  T E M O D A R.  Vi al s  a n d  c a p s ul e s  s h o ul d  n ot  b e  o p e n e d.  If  vi al s  or  c a p s ul e s  ar e 
a c ci d e nt all y  o p e n e d  or  d a m a g e d,  ri g or o u s  pr e c a uti o n s  s h o ul d  b e  t a k e n  wit h  t h e  c o nt e nt s  t o  a v oi d  i n h al ati o n  or  c o nt a ct  wit h  t h e  s ki n  or  m u c o u s  
m e m br a n e s. T h e u s e of gl o v e s a n d s af et y gl a s s e s i s r e c o m m e n d e d t o a v oi d e x p o s ur e i n c a s e of br e a k a g e of t h e vi al or c a p s ul e s. Pr o c e d ur e s f or pr o p er 
h a n dli n g a n d di s p o s al of a nti c a n c er dr u g s s h o ul d b e c o n si d er e d  { 1-4} . S e v er al g ui d eli n e s o n t hi s s u bj e ct h a v e b e e n p u bli s h e d. 
 
1 6. 2  H o w S u p pli e d  
T E M O D A R  C a p s ul e s:  T E M O D A R (t e m o z ol o mi d e)  C a p s ul e s  ar e  s u p pli e d  i n  a m b er  gl a s s  b ottl e s  wit h  c hil d-r e si st a nt  p ol y pr o p yl e n e  c a p s  or  c hil d-
r e si st a nt s a c h et s c o nt ai ni n g t h e f oll o wi n g c a p s ul e str e n gt h s: 
T E M O D A R C a p s ul e s 5 m g:  h a v e o p a q u e w hit e b o di e s wit h gr e e n c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, a n d 
t h e S c h eri n g-Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R ". 
T h e y ar e s u p pli e d a s f oll o w s:  
B ottl e s:  
5- c o u nt – N D C 0 0 8 5 -3 0 0 4 -0 2  
1 4 -c o u nt – N D C 0 0 8 5 -3 0 0 4 -0 1  
S a c h et s:  
5- c o u nt – N D C 0 0 8 5 -3 0 0 4 -0 3  
1 4 -c o u nt – N D C 0 0 8 5 -3 0 0 4 -0 4  
T E M O D A R C a p s ul e s 2 0 m g:  h a v e o p a q u e w hit e b o di e s wit h y ell o w c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, a n d 
t h e S c h eri n g-Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R".  
T h e y ar e s u p pli e d a s f oll o w s:  
B ot tl e s: 
5- c o u nt – N D C 0 0 8 5 -1 5 1 9 -0 2  
1 4 -c o u nt – N D C 0 0 8 5 -1 5 1 9 -0 1  
S a c h et s:  
5- c o u nt – N D C 0 0 8 5 -1 5 1 9 -0 3  
1 4 -c o u nt – N D C 0 0 8 5 -1 5 1 9 -0 4  
T E M O D A R C a p s ul e s 1 0 0 m g:  h a v e o p a q u e w hit e b o di e s wit h pi n k c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, a n d 
t h e S c h eri n g-Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R".  
T h e y ar e s u p pli e d a s f oll o w s:  
B ottl e s:  
5- c o u nt – N D C 0 0 8 5 -1 3 6 6 -0 2  
1 4 -c o u nt – N D C 0 0 8 5 -1 3 6 6 -0 1  
S a c h et s:  
5- c o u nt – N D C 0 0 8 5 -1 3 6 6 -0 3  
1 4 -c o u nt – N D C 0 0 8 5 -1 3 6 6 -0 4  
T E M O D A R C a p s ul e s 1 4 0 m g:  h a v e o p a q u e w hit e b o di e s wit h bl u e c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, a n d 
t h e S c h eri n g-Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R".  
T h e y ar e s u p pli e d a s f oll o w s:  
B ottl e s:  
5- c o u nt – N D C 0 0 8 5 -1 4 2 5 -0 1  
1 4 -c o u nt – N D C 0 0 8 5 -1 4 2 5 -0 2  
S a c h et s:  
5- c o u nt – N D C 0 0 8 5 -1 4 2 5 -0 3  
1 4 -c o u nt –  N D C 0 0 8 5 -1 4 2 5 -0 4  
T E M O D A R C a p s ul e s 1 8 0 m g:  h a v e o p a q u e w hit e b o di e s wit h or a n g e c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, 
a n d t h e S c h eri n g -Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R" . 
T h e y ar e s u p pli e d a s f oll o w s:  
B ottl e s:  
5- c o u nt – N D C 0 0 8 5 -1 4 3 0 -0 1  
1 4 -c o u nt – N D C 0 0 8 5 -1 4 3 0 -0 2  
S a c h et s:  
5- c o u nt – N D C 0 0 8 5 -1 4 3 0 -0 3  
1 4 -c o u nt – N D C 0 0 8 5 -1 4 3 0 -0 4  
T E M O D A R C a p s ul e s 2 5 0 m g:  h a v e o p a q u e w hit e b o di e s wit h w hit e c a p s. T h e c a p s ul e b o d y i s i m pri nt e d wit h t w o stri p e s, t h e d o s a g e str e n gt h, a n d 
t h e S c h eri n g-Pl o u g h l o g o. T h e c a p i s i m pri nt e d wit h " T E M O D A R ".  
T h e y ar e s u p pli e d a s f oll o w s:  
B ottl e s:  
5- c o u nt – N D C 0 0 8 5 -1 4 1 7 -0 1  
S a c h et s:  
5- c o u nt – N D C 0 0 8 5 -1 4 1 7 -0 2  

 
1 4  
T E M O D A R f or I nj e cti o n: T E M O D A R (t e m o z ol o mi d e) f or I nj e cti o n i s s u p pli e d i n si n gl e -u s e gl a s s vi al s c o nt ai ni n g 1 0 0 m g t e m o z ol o mi d e. T h e l y o p hili z e d 
p o w d er i s w hit e  t o li g ht t a n/li g ht pi n k. 
T E M O D A R f or I nj e cti o n 1 0 0 m g:  
 
N D C 0 0 8 5 - 13 8 1 -0 1  
 
1 6. 3  St or a g e  
St or e T E M O D A R C a p s ul e s at 2 5° C ( 7 7° F); e x c ur si o n s p er mitt e d t o 1 5 -3 0° C ( 5 9 -8 6° F) [ s e e U S P C o ntr oll e d R o o m T e m p er at ur e].  
St or e T E M O D A R f or I nj e cti o n r efri g er at e d at 2 -8° C ( 3 6 -4 6° F). Aft er r e c o n stit uti o n, st or e r e c o n stit ut e d pr o d u ct at r o o m t e m p er at ur e ( 2 5° C 
[ 7 7° F]). R e c o n stit ut e d pr o d u ct m u st b e u s e d wit hi n 1 4 h o ur s, i n cl u di n g i nf u si o n ti m e.  
 
1 7  
P A TI E N T C O U N S E LI N G I N F O R M A TI O N  
S e e F D A -A p pr o v e d P ati e nt L a b eli n g ( P ati e nt I nf or m ati o n).  
 
1 7. 1  I nf or m ati o n f or t h e P ati e nt 
P h y si ci a n s s h o ul d di s c u s s t h e f oll o wi n g wit h t h eir p ati e nt s:  
•  
N a u s e a a n d v o miti n g ar e t h e m o st fr e q u e ntl y o c c urri n g a d v er s e r e a cti o n s. N a u s e a a n d v o miti n g ar e u s u all y eit h er s elf-li miti n g or r e a dil y 
c o ntr oll e d wit h st a n d ar d a nti e m eti c t h er a p y.  
•  
C a p s ul e s s h o ul d n ot b e o p e n e d. If c a p s ul e s ar e a c ci d e nt all y o p e n e d or d a m a g e d, ri g or o u s pr e c a uti o n s s h o ul d b e t a k e n wit h t h e c a p s ul e 
c o nt e nt s t o a v oi d i n h al ati o n or c o nt a ct wit h t h e s ki n or m u c o u s m e m br a n e s.  
•  
T h e m e di c ati o n s h o ul d b e k e pt a w a y fr o m c hil dr e n a n d p et s.  
 
T E M O D A R C a p s ul e s  
 
 
 
T E M O D A R f or I nj e cti o n  
 
 
 
M a n uf a ct ur e d b y:  
B a xt er O n c ol o g y G m b H, H all e  3 3 7 9 0 , G er m a n y 
 
F or p at e nt i nf or m ati o n: w w w. m er c k. c o m/ pr o d u ct/ p at e nt/ h o m e. ht ml  
 
C o p yri g ht © 1 9 9 9, 2 0 0 8 M er c k S h ar p & D o h m e C or p., a s u b si di ar y of M er c k & C o., I n c . 
All ri g ht s r e s er v e d.  
 
R e v i s e d: 0 6/ 2 0 13 
 
u s pi -m k 7 3 6 5 -mtl -1 3 0 6 r0 1 5  
 

Acti o n Letter 
Att ac h me nt 4 :  Se vere li ver t o xicit y ass oci ate d wit h te m oz ol o mi de ( Te m o d al ®) letter f r o m M S D