Clinical trial NCT01790503
Conditions: Patients With Newly Diagnosed Glioblastoma
Keywords: glioblastoma GBM
Sponsor: Daiichi Sankyo
Start date: 2013-07-18; Completion date: 2020-03-04
Enrollment: 65 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The study objectives are to assess the potential for PLX3397 to improve the efficacy of standard of care radiation therapy (RT) + temozolomide in patients with newly diagnosed glioblastoma (GBM).

Detailed description:
Study drug will be administered twice daily for 7 days prior to the initiation of RT (radiation therapy)and will continue twice daily during the course of RT. The RT schedule will be once daily for 5 days per week for 6 weeks (total radiation dose of 60 Gy. Oral temozolomide will be administered once daily (7 days per week) for the duration of RT. Four weeks after the completion of the course of RT, patients will be started on once-daily adjuvant temozolomide (Day 1-5 of a 28 day cycle) and PLX3397 twice daily (28 days of a 28 day cycle) for up to 12 cycles in the absence of progressive disease or unacceptable toxicities. After discontinuation of study drug, patients will continue to be followed for OS every 6 months. For patients participating in the run-in Phase 1b of the study, intra patient dose escalation will be permitted after a RP2D has been established. The Phase 2 portion of the study will enroll patients to be treated with PLX3397 at RP2D.

For the Phase 1b portion of the study, 2 cohorts (800 mg/day and 1000 mg/day) are planned to be enrolled at approximately 7-10 sites. Each cohort will consist of approximately 7 patients. Therefore, a minimum of 14 patients are planned to be enrolled in Phase 1b. Additional patients may be required for replacement patients, or if lower dose cohorts (600 mg or 400 mg) are required. For the Phase 2 portion of the study, enrollment is planned to include approximately 44 patients.

Arms: arm 1: 600mg/day PLX3397, Radiation Therapy, and Temozolomide arm 2: 800mg/day PLX3397, Radiation Therapy, and Temozolomide arm 3: 1000 mg/day PLX3397, Radiation Therapy, and Temozolomide arm 4: Recommended phase 2 dose of PLX3397 (800mg/day), Radiation therapy, and Temozolomide
Interventions: intervention 1: PLX3397 intervention 2: Radiation Therapy intervention 3: Temozolomide
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_SAP_000.pdf: 




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