Clinical trial NCT01525602
Conditions: Solid Tumors
Keywords: advanced, incurable solid tumors
Sponsor: Daiichi Sankyo
Start date: 2012-05-01; Completion date: 2018-02-01
Enrollment: 74 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was a 3-part study designed to explore the safety and tolerability of escalating doses of PLX3397 with weekly paclitaxel to establish a recommended Phase 2 dose (RP2D), to confirm RP2D in participants with advanced non-resectable solid tumors, and to determine the efficacy of PLX3397 600 mg twice daily (BID) administered in combination with weekly paclitaxel in participants with advanced, metastatic or non-resectable, platinum-resistant or -refractory epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

Detailed description:

Arms: arm 1: Open-label, sequential PLX3397 single-agent dose escalation in combination with paclitaxel in approximately 30 patients with advanced solid tumors. Enrollment completed.

(Closed to recruitment) arm 2: Extension cohort at the RP2D of single-agent PLX3397 in combination with paclitaxel in approximately 30 patients in advanced solid tumors. Enrollment completed.

(Closed to recruitment) arm 3: Extension cohort at the RP2D of single-agent PLX3397 in combination with paclitaxel in approximately 30 patients with advanced, metastatic, or non-resectable, platinum-resistant or -refractory epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

(Closed to recruitment)
Interventions: intervention 1: PLX3397 intervention 2: Paclitaxel
Intervention descriptions: intervention 1: PLX3397 tablets, 200mg intervention 2: Paclitaxel IV

Protocol documents:
Prot_SAP_000.pdf: 




P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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  ......................................................................................................................... 6 
LI S T O F FI G U R E S  ....................................................................................................................... 6 
4. 0  
C O N T A C T S  ....................................................................................................................... 7 
4. 1  
E mer ge nc y C o ntacts ................................................................................................ 7  
4. 2  
A d diti o nal C o ntacts  ................................................................................................. 7 
4. 3  
S A E Re p orti n g C o ntact............................................................................................ 7  
5. 0  
LI S T O F A B B R E VI A TI O N S ........................................................................................... 8  
6. 0  
S T U D Y S Y N O P SI S  ......................................................................................................... 1 1 
7. 0  
I NT R O D U C TI O N ............................................................................................................ 2 6 
7. 1  
Bac k gr o u n d ............................................................................................................ 2 6  
7. 2  
P L X 3 3 9 7 N o ncli nical P har mac o d y na mics ............................................................ 3 0  
7. 2. 1  
I n Vitr o P har mac o d y na mics .................................................................. 3 1 
7. 2. 2  
I n Vi v o P har mac o d y na mics .................................................................. 3 2 
7. 3  
P L X 3 3 9 7 N o ncli nical Meta b olis m a n d P har mac o ki net ics .................................... 3 3 
7. 4  
P L X 3 3 9 7 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 ........ 3 4  
7. 4. 1  
Re peat - D ose T o xicit y i n Rats ............................................................... 3 5 
7. 4. 2  
Re peat - D ose T o xicit y i n D o gs .............................................................. 3 6 
7. 4. 3  
Ge n ot o xicit y .......................................................................................... 3 9  
7. 4. 4  
Safet y P ha r mac ol o g y ............................................................................ 3 9 
7. 5  
P L X 3 3 9 7 N o ncli nical Re pr o d ucti ve T o xic ol o g y .................................................. 3 9  
7. 6  
P L X 3 3 9 7 Pr e vi o us H u ma n E x perie nce ................................................................. 3 9  
8. 0  
S T U D Y O B J E C TI V E S  .................................................................................................... 4 1 
9. 0  
D E SI G N  ............................................................................................................................ 4 2 
9. 1  
Descri pti o n  ............................................................................................................. 4 2 
9. 2  
R o ute a n d Re gi me n ................................................................................................ 4 4  
9. 3  
Paclita xel Pre me dicati o ns  ...................................................................................... 4 5 
9. 4  
N u m ber of Patie nts  ................................................................................................ 4 6 
9. 5  
N u m ber of St u d y Ce nters ....................................................................................... 4 6  
9. 6  
D urati o n of Patie nt Partici pati o n  ........................................................................... 4 6 
9. 7  
D urati o n of St u d y ................................................................................................... 4 7  
1 0. 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  ................................................................... 4 7 
 
C O N FI D E N TI A L  
3 
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1 0. 1  
I ncl usi o n Criteria ................................................................................................... 4 7 
1 0. 2  
E xcl usi o n Criteria  .................................................................................................. 4 9 
1 0. 3  
Scree n Fail ures  ....................................................................................................... 5 0 
1 1. 0  
P RI O R T R E A T M E N T  .................................................................................................... 5 0 
1 2. 0  
C O N C O MI T A N T T R E A T M E N T ................................................................................. 5 0  
1 3. 0  
P R O C E D U R E S  ................................................................................................................ 5 1 
1 3. 1  
Scree ni n g E val uati o n ............................................................................................. 5 1  
1 3. 2  
Pre -Treat me nt ( Baseli ne):  C ycle 1 Da y 1 ............................................................. 5 3  
1 3. 3  
P ost -Treat me nt :  C ycle 1 Da y 1  ............................................................................. 5 3 
1 3. 4  
C ycle 1 Da y 8 ( ± 4 8 h o urs) ..................................................................................... 5 3  
1 3. 5  
Pre -treat me nt C ycle 1 Da y 1 5 ( ± 4 8 h o urs) ............................................................ 5 4 
1 3. 6  
P ost -treat me nt C ycle 1 Da y 1 5 ( ± 4 8 h o urs) .......................................................... 5 5 
1 3. 7  
C ycle 1 Da y 2 2 ( ± 4 8 h o urs) ................................................................................... 5 5  
1 3. 8  
Part 3 O nl y :  C ycle 1 Da y 2 8 ± 7 da ys ( C ycle 1 Da y 2 1 t o C ycle 1 Da y 3 5) ........ 5 5  
1 3. 9  
All S u bse q ue nt C ycles, Da y 1 ( ± 4 8 h o urs) ............................................................ 5 5  
1 3. 1 0  All S u bse q ue nt C ycles, Da ys 8, 1 5 a n d 2 2 ( ± 4 8 h o urs) ........................................ 5 6  
1 3. 1 1  Ot her Sc he d ules  ..................................................................................................... 5 7 
1 3. 1 2  E n d of St u d y .......................................................................................................... 5 7  
1 3. 1 3  D ose -Li miti n g T o xicities ( Part 1 o nl y)  .................................................................. 5 7 
1 3. 1 4  D ose M o dificati o ns  ................................................................................................ 5 8 
1 3. 1 4. 1  
P L X 3 3 9 7 D ose M o dificati o ns .............................................................. 5 8  
1 3. 1 4. 2  
Paclita x el D ose M o dificati o ns .............................................................. 6 1  
1 3. 1 5  Disc o nti n uati o n of Treat me nt a n d Wit h dra wal of Patie nts .................................... 6 2  
1 4. 0  
T E S T A R TI C L E S  ............................................................................................................ 6 2 
1 4. 1  
P L X 3 3 9 7 ................................................................................................................ 6 2  
1 4. 1. 1  
P L X 3 3 9 7 A d mi nistrati o n ...................................................................... 6 2  
1 4. 1. 2  
P L X 3 3 9 7 Pac ka gi n g a n d La beli n g ....................................................... 6 3  
1 4. 1. 3  
P L X 3 3 9 7 St ora ge a n d Sta bilit y ............................................................. 6 3  
1 4. 1. 4  
P L X 3 3 9 7 Acc o u nta bilit y, Rec o nciliati o n, a n d Ret ur n ......................... 6 4  
1 4. 1. 5  
P L X 3 3 9 7 C o m plia nce ........................................................................... 6 4  
1 4. 2  
Paclita xel  ................................................................................................................ 6 4 
1 5. 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 6. 0  
S A F E T Y E V A L U A TI O N  ................................................................................................ 6 4 
1 6. 1  
P h ysical E xa mi nati o n ............................................................................................. 6 5 
1 6. 2  
Vital Si g n s .............................................................................................................. 6 5 
 
C O N FI D E N TI A L  
4 
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1 6. 3  
Electr ocar di o gra ms  ................................................................................................ 6 5 
1 6. 4  
Ec h ocar di o gra ms or M ulti- gate d Ac q uisiti o n Sca ns ............................................. 6 5  
1 6. 5  
Safet y La b orat or y Deter mi nati o ns ......................................................................... 6 5  
1 7. 0  
S T U D Y S T O P PI N G R U L E S  .......................................................................................... 6 6 
1 8. 0  
BI O M A R K E R S A M P L E S  .............................................................................................. 6 6 
1 9. 0  
P H A R M A C O KI N E TI C E V A L U A TI O N ( P A R T 1 A N D P A R T 3)  ............................ 6 6 
1 9. 1  
Bl o o d C ollecti o n .................................................................................................... 6 6  
1 9. 2  
Bi oa nal ytical Met h o d ol o g y .................................................................................... 6 7  
2 0. 0  
S T A TI S TI C A L A N A L Y SI S  ........................................................................................... 6 7 
2 0. 1  
Safet y A nal ysis  ...................................................................................................... 6 7 
2 0. 2  
Efficac y A nal ysis  ................................................................................................... 6 7 
2 0. 3  
Sa m ple Size a n d P o wer .......................................................................................... 6 8  
2 0. 4  
P har mac o ki netic A nal ysis ( Part 1 a n d Part 3)  ....................................................... 6 9 
2 0. 5  
P har mac o d y na mic A nal ysis  ................................................................................... 6 9 
2 1. 0  
P R E C A U TI O N S  .............................................................................................................. 6 9 
2 2. 0  
A D V E R S E E V E N T S  ....................................................................................................... 6 9 
2 2. 1  
Defi niti o ns .............................................................................................................. 7 0 
2 2. 2  
Rec or di n g a n d Re p orti n g ....................................................................................... 7 3  
2 2. 3  
Seri o us A d verse E ve nt Re p orti n g .......................................................................... 7 3  
2 3. 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 4 
2 4. 0  
I N F O R M E D C O N S E N T ................................................................................................. 7 4 
2 5. 0  
P R O T O C O L A M E N D M E N T S  ...................................................................................... 7 4 
2 6. 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 7. 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 5 
2 7. 1  
I n vesti gat or ............................................................................................................ 7 5 
2 7. 2  
S p o ns or .................................................................................................................. 7 5  
2 8. 0  
P R E -S T U D Y D O C U M E N T A TI O N  ............................................................................... 7 5 
2 9. 0  
R E C O R D S R E T E N TI O N  ............................................................................................... 7 6 
3 0. 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  .......................................................................... 8 0 
A T T A C H M E N T 2 :  R E CI S T C RI T E RI A V E R S I O N 1. 1 ....................................................... 8 2 
A T T A C H M E N T 3 :  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  .......................... 9 5 
A T T A C H M E N T 4 :  M E T H O D S O F BI R T H C O N T R O L  ...................................................... 9 6 
A T T A C H M E N T 5 :  A M E N D M E N T 1 S U M M A R Y O F C H A N G E S  .................................... 9 7 
A T T A C H M E N T 6 :  A M E N D M E N T 2 S U M M A R Y O F C H A N G E S  .................................. 1 0 2 
 
C O N FI D E N TI A L  
5 
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 7 :  A M E N D M E N T 3 S U M M A R Y O F C H A N G E S  .................................. 1 0 5 
A T T A C H M E N T 8 :  A M E N D M E N T 4 S U M M A R Y O F C H A N G E S  .................................. 1 0 7 
A T T A C H M E N T 9 :  A M E N D M E N T 5 S U M M A R Y O F C H A N G E S  .................................. 1 1 8 
A T T A C H M E N T 1 0 :  A M E N D M E N T 6 S U M M A R Y O F C H A N G E S  ................................ 1 2 2 
A T T A C H M E N T 1 1 :  A M E N D M E N T 7 S U M M A R Y O F C H A N G E S  ................................ 1 5 2 
A T T A C H M E N T 1 2 :  A M E N D M E N T 8 S U M M A R Y O F C H A N G E S  ................................ 1 5 3 
 
LI S T O F T A B L E S  
Ta ble 1:  
I C5 0 Val ues of P L X 3 3 9 7 A gai nst Selecte d Ki nases  .................................. 3 1 
Ta ble 2:  
Pla n ne d D ose Escalati o n Sc he d ule ............................................................ 4 3  
Ta ble 3:  
D ose M o dificati o ns G ui deli nes f or P L X 3 3 9 7 ........................................... 5 9  
Ta ble  4: 
Pr o ba bilities of Detect i n g D L Ts ( 3 Patie nts) ............................................. 6 8 
Ta ble  5: 
Pr o ba bilities of Detecti n g D L Ts ( 6 Patie nts)  ............................................. 6 9 
Ta ble 6:  
Ti me P oi nt Res p o nse :  Patie nts wit h Tar gets ( ± N o n -Tar get) Disease  ..... 9 2 
Ta ble 7:  
Ti me P oi nt Res p o nse :  Patie nts wit h N o n-Tar get Disease O nl y  ............... 9 2 
Ta ble 8:  
Best O verall Res p o nse W he n C o nfir mati o n of C R a n d P R Re q uire d ....... 9 3  
Ta ble 9:  
List of Per missi ble C o ntrace pti ve Met h o ds  ............................................... 9 6 
 
LI S T O F FI G U R E S  
Fi g ure 1:  
I n Vitr o Paclita xel E x p os ure Res ults i n I ncrease d C S F- 1 a n d 
Macr o p ha ge De nsit y i n Ma m mar y T u m or Str o ma .................................... 2 8  
Fi g ure 2:  
P L X 3 3 9 7 + Paclita xel ................................................................................ 2 9  
Fi g ure 3:  
I m m u n o m o d ulat or y Effects i n T u m ors of P L X 3 3 9 7/ P T X-Treate d 
M M T V -P y M T Mice  .................................................................................. 3 0 
Fi g ure 4:  
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 Ce lls i n P y M T 
M o use M o del of Breast Ca ncer  ................................................................. 3 3 
 
 
C O N FI D E N TI A L  
6 
Ple x xi k o n I nc.  
P R O P RI E T A R Y  




P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 D Ls  
Acti vities of Dail y Li vi n g  
A L T  
Ala ni ne a mi n otra nsferase  
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 6 ( A U C0- 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 6 h o urs after d osi n g 
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 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  
CI  
C o nfi de nce i nter val  
Cl - 
C hl ori de  
C L cr 
Creati ni ne cleara nce  
C ma x  
Ma xi m u m o bs er ve d c o nce ntrati o n  
C N S  
Ce ntral ner v o us s yste 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 X  
C he m ot hera p y  
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 oefficie 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  
D F S  
Disease -Free S ur vi val  
D L T  
D ose Li miti n g T o xicit y  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic Case Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
E F  
Ejecti o n Fracti o n  
E D -5 0  
Effecti ve d ose  
E O R T C  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer  
e. g. 
E xe m pli gratia (f or e xa m ple)  
F A C S  
Fl o w c yt o metr y  
 
C O N FI D E N TI A L  
8 
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A b bre vi ati o n or Ter m a 
Defi niti o n/ E x pl a n ati o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F ms  
C ol o n y sti m ulati n g fact or 1 rece pt or  
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 yltra nsferase  
G L P  
G o o d la b orat or y practice  
H C O 3
- 
Bicar b o nate  
h E R G  
H u ma n Et her -à-G o -G o  
H N S T D  
Hi g hest n o n -se verel y t o xic d ose 
H P L C  
Hi g h -per f 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 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  
M D S C  
M yel oi d -deri ve d s u p press or cell  
M E C  
Micr o vasc ular e n d ot helial cell  
Me d R A  
Me dical Dicti o nar y f or Dr u g Re g ulat or y Acti vities  
M M P -3  
Matri x metall o pe pti dase -3  
M T D  
Ma xi m u m t olerate d d ose  
M U G A  
M ulti -gate d ac q uisiti o n  
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 D G F R  
Platelet deri ve d gr o wt h fact or rece pt or  
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 re missi o n  
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  
P T X  
Paclita xel  
Q C  
Q ualit y c o ntr ol  
 
C O N FI D E N TI A L  
9 
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A b bre vi ati o n or Ter m a 
Defi niti o n/ E x pl a n ati o n  
Q D  
O nce dail y  
Q Tc F  
C orrecte d Q T i nter val, Fre derica’s f or m ula  
Q O L  
Q ualit y Of Life  
R B C  
Re d Bl o o d Cell  
R P 2 D  
Rec o m me n de d P hase 2 D ose  
R x  
Treat me nt  
S A E  
Seri o us a d verse e ve nt  
S C F  
Ste m Cell Fact or  
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  
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 -ass ociate d macr o p ha ges  
T E A E  
Tre at me nt-e mer ge nt a d verse e ve nt  
T KI  
T yr osi ne Ki nase I n hi bit or  
T T E  
Tra ns -t h oracic ec h ocar di o gra m 
U L N  
U p per li mit of n or mal  
V E G F R  
Vasc ular e n d ot helial gr o wt h fact or rece pt or  
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 n -c hil d beari n g p ote ntial  
a 
All of t hese a b bre viati o ns ma y or ma y n ot be use d i n t he pr ot oc ol.  
 
 
C O N FI D E N TI A L  
1 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
6. 0  
S T U D Y S Y N O P SI S  
Title  
A P hase 1 b St u d y t o Assess t he Safet y of P L X 3 3 9 7 a n d Paclita xel i n Patie nts Wit h A d va nce d 
S oli d T u m ors  
St u d y 
O bjecti ve(s)  
T his trial is des i g ne d as a t hree-part st u d y.  
P art 1 :  T he pri mar y o bjecti ve is t o e x pl ore t he safet y a n d t olera bilit y of escalati n g d oses of 
P L X 3 3 9 7 wit h wee kl y paclita xel t o esta blis h a R P 2 D. T he sec o n dar y o bjecti ves are t o 
e x pl ore t he efficac y a n d p har mac o ki netics ( P K) of P L X 3 3 9 7 i n c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d s oli d t u m ors. 
P art 2 :  T he pri mar y o bjecti ve is t o c o nfir m t he safet y a n d t olera bilit y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n c o m bi nati o n wit h paclita xel i n patie nts wit h a d va nce d, n o n-
resecta ble s oli d t u m ors. T he sec o n dar y o bjecti ve is t o e x pl ore t he efficac y of P L X 3 3 9 7 i n 
c o m bi nati o n wit h paclita xel i n patie nts wit h a d va nce d s oli d t u m ors.  
P art 1 a n d 2 :  E x pl orat or y o bjecti ves i ncl u de c orrelati n g t he c ha n ge i n C ol o n y Sti m ulati n g 
Fact or -1 ( C S F -1) le vels d uri n g treat me nt wit h s pecific d ose le vels of P L X 3 3 9 7 a n d 
i de ntif yi n g ne w bi o mar kers of cli nical acti vit y. 
P art 3 :  T he pri mar y o bjecti ve is t o deter mi ne t he efficac y of P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n c o m bi nati o n wit h paclita xel i n patie nts wit h a d va nce d, metastatic or n o n -
resecta ble, plati n u m-resista nt or -refract or y e pit helial o varia n ca ncer, pri mar y perit o neal 
ca ncer, or fall o pia n t u be ca ncer . T he sec o n dar y o bjecti ves are t o e x pl ore t he effect of 
P L X 3 3 9 7 o n ca ncer tiss ue a n d bl o o d bi o mar kers a n d t he safet y a n d t olera bilit y of P L X 3 3 9 7 
i n c o m bi nati o n wit h paclita xel i n t his patie nt p o p ulati o n. 
St u d y Desi g n  
P art 1 : 
T his is a n o nra n d o mize d, o pe n -la bel st u d y e m pl o yi n g a sta n dar d 3 + 3 d ose escalati o n desi g n 
t o deter mi ne t he R P 2 D of P L X 3 3 9 7, a n o vel i n hi bit or of t he C S F-1 rece pt or ( F ms), w he n 
a d mi nistere d i n c o m bi nati o n wit h paclita xel i n patie nts wit h a d va nce d s oli d t u m ors.  
P art 2 : 
T his is a n o nra n d o mize d, o pe n -la bel st u d y of P L X 3 3 9 7 a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n a ppr o xi matel y 3 0 patie nts (i ncl u di n g all R P 2 D -treate d patie nts 
fr o m Part 1  a n d Part 2 ). T he ca n di date p o p ulati o n will be patie nts wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a ta xa ne is c o nsi dere d b y t he i n vesti gat or t o be a p pr o priate. 
P art 3:  
T his is  a n o nra n d o mize d, o pe n -la bel st u d y of P L X 3 3 9 7 6 0 0  m g BI D  a d mi nistere d i n 
c o m bi nati o n wit h paclita xel i n a p pr o xi matel y 3 0  patie nts. T he ca n di date p o p ulati o n will be 
patie nts wit h a d va nce d, metastatic or n o n -resecta ble, plati n u m-resista nt or -refract or y 
e pit helial o varia n ca ncer, pri mar y perit o neal ca ncer, or fall o pia n t u be ca ncer. Patie nts m ust 
be resista nt or refract or y t o pri or plati n u m -base d sta n dar d care s yste mic re gi me ns or 
refract or y t o pri mar y treat me nt wit h a plati n u m-c o ntai ni n g re gi me n.  Patie nts will be 
se q ue ntiall y assi g ne d t o o ne of t hree C ycle 1 ( 2 8 t o 3 5 da y) lea d-i n treat me nt ar ms:  1) dail y 
P L X 3 3 9 7 6 0 0  m g BI D ; 2) wee kl y paclita xel; a n d 3) dail y P L X 3 3 9 7 6 0 0  m g BI D  a n d wee kl y 
paclita xel. Ca ncer tiss ue  ( bi o ps y) f or bi o mar kers  will be o btai ne d d uri n g Scree ni n g a n d at 
C ycle 1 Da y 2 8 ± 7 da ys  ( C ycle 1 Da y 2 1 t o C ycle 1 Da y 3 5). If t he sec o n d bi o ps y i n C ycle 1 
is dela ye d be y o nd Da y 2 8, patie nts  will ha ve a C ycle 1 Da y 2 8 visit, d uri n g w hic h pr oce d ures 
w o ul d be t he sa me as t he C ycle 1 Da y 2 2 visit. F oll o wi n g  t he sec o n d bi o ps y , C ycle 1 e n ds 
a n d all patie nts will start C ycle 2 treat me nt wit h dail y P L X 3 3 9 7 6 0 0  m g BI D  a n d wee kl y 
paclita xel. C ycle 2 a n d all s u bse q ue nt c ycles will be 2 8 -da y c ycles. Bl o o d bi o mar kers will be 
o btai ne d pri or t o treat me nt o n Da y 1 of all s u bse q ue nt c ycles a n d t he  E n d -of -St u d y Visit .  
Patie nts will ha ve efficac y assess me nts e ver y 8 wee ks t o deter mi ne o bjecti ve res p o nse ( C R + 
P R), cli nical be nefit ( C R  + P R + S D), pr o gressi o n -free s ur vi val ( P F S), a n d ti me t o ne xt 
treat me nt. 
 
C O N FI D E N TI A L  
1 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
N u m ber of 
P atie nts/ Sites  
P art 1:  
E nr oll me nt is pla n ne d t o i ncl u de a p pr o xi matel y 3 0 patie nts recr uite d fr o m a p pr o xi matel y  
3 – 4 sites. T he t otal n u m ber of patie nts t o be e nr olle d will de pe n d o n t he n u m ber of c o h orts, 
w het her a c o h ort re q uires 3 or 6 patie nts, a n d w het her patie nts w h o are n ot e val ua ble f or 
D L Ts nee d t o be re place d.  
P art 2:  
E nr oll me nt is pla n ne d t o i ncl u de a p pr o xi matel y 3 0 patie nts (i ncl u di n g R P 2 D -treate d patie nts 
fr o m P art 1  a n d P art 2 ) recr uite d fr o m 3 sites. 
P art 1 a n d P art 2:  
Patie nts w h o d o n ot rece i ve t he re q uisite P L X 3 3 9 7 a n d/ or paclita xel d oses i n C ycle 1 d ue t o 
a n yt hi n g ot her t ha n treat me nt -relate d a n d/ or d ose-li miti n g t o xicit y ma y be re place d. 
Patie nts  w h o e x perie nce a n aller gic reacti o n t o paclita xel t hat precl u des f urt her d osi n g 
(i.e., ≥Gra de  3) will be re m o ve d fr o m t he st u d y a n d ma y als o be re place d.  
P art 3:  
E nr oll me nt is pla n ne d t o i ncl u de u p t o a p pr o xi matel y 3 0  patie nts recr uite d fr o m 
a p pr o xi matel y 9 sites t o accr ue 1 8 patie nts w h o ca n pr o vi de pretreat me nt a n d e n d-of -C ycle  1 
ca ncer tiss ue a n d are e val ua ble f or deter mi ni n g res p o nse usi n g R E CI S T 1. 1 criteria. Patie nts 
u na ble t o pr o vi de t he se q ue ntial ca ncer tiss ue sa m ples or n o n -e val ua ble f or res p o nse usi n g 
R E CI S T criteria will be re place d.  
St u d y 
Tre at me nts  
P art 1:  
P L X 3 3 9 7 will be a d mi nistere d orall y, t wice dail y ( BI D) usi n g a c o nti n u o us d osi n g re gi me n. 
T he starti n g d ose of P L X 3 3 9 7 will be 6 0 0 m g/ da y. D ose escalati o n will occ ur i n i ncre me nts 
of  ≤5 0 %. Paclita xel, 8 0 m g/ m 2 I V will be a d mi nistere d wee kl y (± 4 8 h o urs) o ver 
a p pr o xi matel y 6 0  mi n utes i n eac h 2 8-da y treat me nt c ycle. O ne paclita xel d ose ma y be 
o mitte d per c ycle b y p h ysicia n discreti o n after C ycle 1.  
P art 2:  
P L X 3 3 9 7 will be a d mi nistere d orall y, t wice dail y ( BI D ) usi n g a c o nti n u o us d osi n g re gi me n. 
T he d ose of P L X 3 3 9 7 will be t he R P 2 D. T her e will be n o d ose escalati o n. Paclita xel, 
8 0  m g/ m 2 I V will be a d mi nistere d wee kl y (± 4 8 h o urs) o ver a p pr o xi matel y 6 0  mi n utes i n eac h 
2 8 -da y treat me nt c ycle. O ne paclita xel d ose ma y be o mitte d per c ycle b y p h ysicia n discreti o n 
after C ycle 1.  
P art 3 :  Patie nt s will be se q ue ntiall y assi g ne d t o o ne of t hree C ycle 1 ( 2 8 t o 3 5 da y) lea d-i n 
treat me nt ar ms: 
1)  P L X 3 3 9 7 6 0 0 m g BI D us i n g a c o nti n u o us d osi n g re gi me n 
2)  Paclita xel, 8 0 m g/ m 2 I V wee kl y (± 4 8 h o urs ) o ver a p pr o xi matel y 6 0 mi n utes  
3)  P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel, 8 0 m g/ m 2 
I V wee kl y (± 4 8 h o urs ) o ver a p pr o xi matel y 6 0 mi n utes  
F oll o wi n g t he sec o n d bi o ps y , C ycle 1 e n ds a n d all patie nts will start C ycle 2 treat me nt wit h 
P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8  h o urs) o ver a p pr o xi matel y 6 0  mi n utes . C ycle 2 a n d all s u bse q ue nt c ycles will be 
2 8 -da y c ycles. Starti n g wit h C ycle 2, o ne paclita xel d ose ma y be o mitte d per c ycle b y 
p h ysicia n discreti o n. Patie nts w h o disc o nti n ue paclita xel d ue t o p aclita xel-relate d t o xicit y 
ma y c o nti n ue treat me nt wit h P L X 3 3 9 7.  
P art 1, P art 2, a n d P art 3:  
St u d y treat me nt will be pr o vi de d u ntil disease pr o gressi o n, u nacce pta ble or d ose -li miti n g 
t o xicit y, deat h, wit h dra wal of c o nse nt, st u d y ter mi nati o n b y S p o ns or, or if t he I n vesti gat or 
a n d patie nt a gree t hat it is i n t he patie nt’s best i nterests t o disc o nti n ue.  
 
C O N FI D E N TI A L  
1 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
St u d y 
Pr oce d ures  
P art 1:  
T his n o nra n d o mize d, o pe n -la bel st u d y will e m pl o y a tra diti o nal 3 + 3 P hase 1 desi g n, wit h 
escalati n g d osi n g c o h orts of P L X 3 3 9 7 a n d a fi x e d d ose le vel of paclita xel. Eac h treat me nt 
c ycle will be 2 8 da ys.  
D osi n g of P L X 3 3 9 7 will c o m me nce at t he 6 0 0 m g/ da y d ose le vel. Patie nts s h o ul d fast 
( 1 h o ur) bef ore a n d after P L X 3 3 9 7 a d mi nistr ati o n (see g ui deli nes i n Secti o n 1 4. 1. 1 ). 
O n  n o n -P K/ P D paclita xel a d mi nistrati o n da ys, t he m or ni n g d ose of P L X 3 3 9 7 ma y be 
a d mi nistere d at h o me, pri or t o paclita xel a d mi nistrati o n. D ose escalati o n will occ ur i n 
i ncre me nts of ≤5 0 %. All patie nts at a gi ve n d ose le vel will be f oll o we d o n treat me nt f or at 
least 4 wee ks bef ore accr ual t o t he ne xt c o h ort ca n be gi n. T here will be n o i ntra-patie nt d ose 
escalati o n per mitte d. P L X 3 3 9 7 d ose re d ucti o ns a n d i nterr u pti o ns will be per mitte d d uri n g t he 
first 2 8 da ys of C ycle 1 o nl y if a p atie nt  e x perie nces a D L T.  P L X 3 3 9 7 i nterr u pti o ns d uri n g 
C ycle 1 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 C ycle 1, P L X 3 3 9 7 treat me nt c o nti n uati o n at a l o wer 
d ose ma y be per mitte d a t 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. After C 1 D 2 8, d ose re d ucti o ns or i nterr u pti o ns f or a d verse e ve nts  ( A Es) 
ma y ta ke place at a n y ti me.  
P art 2:  
T his is a n o nra n d o mize d, o pe n -la bel st u d y of P L X 3 3 9 7 a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n a p pr o xi matel y 3 0 patie nts ( R P 2 D -treate d patie nts fr o m P art 1  
a n d P art 2 ). Eac h treat me nt c ycle will be 2 8 da ys.  
D osi n g of P L X 3 3 9 7 will c o m me nce at t he R P 2 D. Patie nts s h o ul d fast ( o ne h o ur) bef ore a n d 
after P L X 3 3 9 7 a d mi nistrati o n (see g ui deli nes i n Secti o n 1 4. 1. 1 ). T here will be n o i ntra-
patie nt d ose escalati o n per mitte d. P L X 3 3 9 7 d ose re d ucti o ns or i nterr u pti o ns f or A Es ma y 
ta ke place at a n y ti me. 
P art 3:  
T he ca n di date  po p ulati o n will be patie nts wit h a d va nce d , metastatic or n o n -resecta ble, 
plati n u m -resista nt or -refract or y e pit helial o varia n ca ncer, pri mar y perit o neal ca ncer or 
fall o pia n t u be ca ncer.  
Patie nts will be se q ue ntiall y assi g ne d t o o ne of t hree C ycle 1 ( 2 8-da y ) lea d-i n treat me nt ar ms: 
1)  P L X 3 3 9 7 6 0 0 m g BI D us i n g a c o nti n u o us d osi n g re gi me n 
2)  Paclita xel, 8 0 m g/ m 2 I V wee kl y (± 4 8 h o urs ) o ver a p pr o xi matel y 6 0 mi n utes  
3)  P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n  a n d paclita xel, 8 0 m g/ m 2 
I V wee kl y (± 4 8 h o urs) o ver  a p pr o xi matel y 6 0  mi n utes 
F oll o wi n g t he sec o n d bi o ps y , C ycle 1 e n ds a n d all patie nts will start C ycle 2 treat me nt wit h 
P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0  mi n utes . C ycle 2 a n d all s u bse q ue nt c ycles will be 
2 8 -da y c ycles. Starti n g wit h C ycle 2, o ne paclita xel d ose ma y be o mitte d per c ycle b y 
p h ysicia n discreti o n. Patie nts w h o disc o nti n ue paclita xel d ue t o paclita xel -relate d t o xicit y 
ma y c o nti n ue treat me nt wit h P L X 3 3 9 7.  
Pati e nts s h o ul d fast ( o ne h o ur) bef ore a n d after P L X 3 3 9 7 a d mi nistrati o n (see g ui deli nes i n 
Secti o n 1 4. 1. 1 ). T here will be n o i ntra-patie nt d ose escalati o n per mitte d. P L X 3 3 9 7 d ose 
re d ucti o ns or i nterr u pti o ns f or A Es may ta ke place at a n y ti me.  
P art 1, P art 2, a n d P art 3:  
Patie nts will recei ve st u d y treat me nt as l o n g as it is well t olerate d a n d b ot h t he I n vesti gat or 
a n d S p o ns or a gree t hat t he patie nt is cli nicall y be nefitti n g. Reas o ns f or st u d y disc o nti n uati o n 
i ncl u de, but are n ot li mite d t o, u nacce pta ble t o xicit y, disease pr o gressi o n, v ol u ntar y 
wit h dra wal of c o nse nt, i n vesti gat or discreti o n, a n d deat h.  
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 
 
C O N FI D E N TI A L  
1 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
i n t he st u d y. Scree ni n g will start wit hi n 2 8 da ys pri or t o t he first st u d y treat me nt d ose. T he 
p h ysical e xa m a n d la b orat or y val ues s h o ul d be o btai ne d wit hi n 1 4 da ys pri or t o C 1 D 1. 
E val uati o ns perf or me d as part of sta n dar d -of -care a n d pri or t o i nf or me d c o nse nt ma y be use d 
if t he y occ ur wit hi n t he pr ot oc ol -s pecifie d ti mefra me.  
All fe male patie nts of c hil d -beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g na nc y test 
wit hi n 1 4 da ys pri or t o C 1 D 1.  
A me dical hist or y, i ncl u di n g c o nc o mita nt me dicati o ns a n d pri or ca ncer treat me nt, will b e 
o btai ne d at Scree ni n g. A re vie w of ne w a n d o n g oi n g c o nc o mita nt me dicati o ns will be 
o btai ne 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), i ncl u di n g Q Tc F, will be perf or me d f or eac h 
patie nt at Scree ni n g, C 1 D 1 5, a n d E n d of St u d y.  
A tra ns -t h oracic ec h ocar di o gra m ( T T E) or m ulti-gate d ac q uisiti o n ( M U G A) sca n will be 
perf or me d f or eac h patie nt at Scree ni n g.  
I ma gi n g f or t u m or stat us will be perf or me d at Scree ni n g, a n d e ver y 8 wee ks or as cli nicall y 
i n dicate d, t hr o u g h o ut st u d y partici pati o n.  
A c o m plete p h ysical e xa mi nati o n, i ncl u di n g hei g ht a n d wei g ht, will be perf or me d f or eac h 
patie nt at Scree ni n g. A s y m pt o m -directe d p h ysical e xa m will be c o m plete d o n Da y 1 ( or 
wit hi n 2 4 h o urs pri or) of eac h c ycle, a n d at E n d of St u d y.  
Cli nical la b orat or y ass ess me nts ( he mat ol o g y a n d c he mistr y) will be perf or me d acc or di n g t o 
t he f oll o wi n g sc he d ule: 
•  
A C B C wit h platelets m ust be perf or me d pri or t o eac h paclita xel a d mi nistrati o n.  
•  
F ull meta b olic pa nel, i ncl u di n g li ver tra nsa mi nases a n d creati ni ne, m ust be 
perf or me d  o n Da ys 1, 8, 1 5 a n d 2 2 ( ± 2 da ys) of C ycle 1 a n d o n Da y 1 f or all 
s u bse q ue nt c ycles.  
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) are re q uire d at 
Scree ni n g, C 1 D 1, C 1 D 1 5, Da y 1 of all s u bse q ue nt c ycles, a n d E n d of St u d y. B o d y wei g ht 
will be meas ure d o n t he first da y of eac h c ycle. T he patie nt’s wei g ht m ust be e val uate d o n 
Da y  1 of eac h c ycle. T he paclita xel d ose m ust be recalc ulate d if t he patie nt’s wei g ht has 
c ha n ge d b y m ore t ha n 1 0 % fr o m baseli ne.  
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 E s a n d c o m plia nce wit h st u d y dr u g 
a d mi nistrati o n.  
P art 1:  
Bl o o d sa m ples f or P L X 3 3 9 7 P K a nal ysis will be o btai ne d pre -P L X 3 3 9 7 a n d paclita xel 
d osi n g o n C 1 D 1, pre -P L X 3 3 9 7 a n d paclita xel d osi n g o n C 1 D 1 5, a n d 2 a n d 4 h o urs p ost -
P L X 3 3 9 7 a n d paclita xel d osi n g o n C 1 D 1 5.  
P art 3 : 
Ca ncer tiss ue [ 2-3 c ore bi o psies of tar get ( ≥2 c m  dia meter)  or n o n -tar get lesi o ns] f or 
bi o mar kers will be o btai ne d d uri n g Scree ni n g after C T i ma gi n g a n d all ot her scree ni n g tests 
a n d pr oce d ures ha ve bee n c o m plete d a n d at C ycle 1 Da y 2 8 ± 7 da ys  ( C ycle 1 Da y 2 1 t o 
C ycle 1 Da y 3 5).  If t he sec on d bi o ps y i n C ycle 1 is dela ye d be y o n d Da y 2 8, patie nts  will 
ha ve a C ycle 1 Da y 2 8 visit, d uri n g w hic h pr oce d ures w ill be t he sa me as t he C ycle 1 Da y 2 2 
visit. F oll o wi n g t he sec o n d bi o ps y , C ycle 1 e n ds a n d all patie nts will start C ycle 2 treat me nt 
wit h dai l y P L X 3 3 9 7 6 0 0  m g BI D  a n d wee kl y paclita xel. C ycle 2 a n d all s u bse q ue nt c ycles 
will be 2 8 -da y c ycles. A b l o o d sa m ple f or plas ma P K a n d bi o mar kers  will be o btai ne d pre -
P L X 3 3 9 7 a n d paclita xel d osi n g o n C ycle 1 Da y 1, C ycle 1 Da y 1 5  a n d o n Da y 1 of all 
s u bse q uent c ycles , a n d E n d-of -St u d y Visit.  Patie nts will ha ve efficac y assess me nts e ver y 8 
wee ks t o deter mi ne o bjecti ve res p o nse ( C R + P R), cli nical be nefit ( C R + P R + S D), 
pr o gressi o n -free s ur vi val ( P F S), a n d ti me t o ne xt treat me nt (after last st u d y treat me nt). 
C A- 1 2 5 sa m pli n g re q uire me nts :  2 pre -treat me nt sa m ples, first sa m ple wit hi n 3 m o nt hs of 
starti n g t hera p y a n d sec o n d sa m ple wit hi n 1 wee k of C 1 D 1 ; s u bse q ue nt sa m ples o n t he first 
 
C O N FI D E N TI A L  
1 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
da y of eac h c ycle starti n g wit h C ycle 2 D a y 1 a n d E n d -of -St u d y Visit.  
P art 1, P a rt 2, a n d P art 3:  
P har mac o d y na mic ( P D) mar kers i ncl u di n g ser u m C S F -1 will be o btai ne d at pre -d ose o n 
Da y  1 of eac h c ycle as o utli ne d i n t he Trial Fl o w C hart . A w h ole bl o o d sa m ple f or circ ulati n g 
C D 1 4/ C D 1 6 p ositi ve m o n oc yte  a nal ysis will als o be o btai ne d pre -d ose o n C 1 D 1 a n d C 1 D 1 5.  
Ke y P atie nt 
Selecti o n 
Criteri a  
I ncl usi o n Criteria 
1.  Patie nts i n  
a. 
P art 1 :  a n a d va nce d, i nc ura ble s oli d t u m or  
a. 
P art 2 :  a n a d va nce d, i nc ura ble s oli d t u m or f or w h o m a ta xa ne  w o ul d be 
c o nsi dere d a reas o na ble c he m ot hera p y o pti o n.  
b.  P art 3 :  a d va nce d , metastatic or n o n -resecta ble e pit helial o varia n ca ncer, 
pri mar y perit o neal ca ncer , or fall o p ia n t u be ca ncer wit h: 
i. plati n u m -resista nt ca ncer, defi ne d as disease t hat res p o n de d t o a 
plati n u m -c o ntai ni n g c he m ot hera p y re gi me n,  b ut de m o nstrate d 
rec urre nce wit hi n si x m o nt hs f oll o wi n g t he c o m pleti o n of t hat 
plati n u m -c o ntai ni n g re gi me n,  
O R  
ii. plati n u m -refract or y ca ncer, defi ne d as disease faile d t o ac hie ve at 
least a partial res p o nse t o a plati n u m-c o ntai ni n g re gi me n  (i.e., 
sta ble disease or act ual disease pr o gressi o n), 
A N D  
iii. ha ve n ot bee n treate d wit h a ta xa ne wit hi n 6 m o nt hs  of C 1 D 1 , 
A N D  
i v. ha ve n ot  bee n treate d wit h wee kl y paclita xel  after first -li ne 
treat me nt i n w hic h wee kl y paclita xel pl us a plati n u m is per mitte d. 
2.  P art 3 :  P atie nts m ust ha ve tar get ( ≥2 c m  dia meter) or n o n -tar get lesi o n ca ncer t hat 
is accessi ble f or 2-3 c ore bi o psies d uri n g Scree ni n g after C T i ma gi n g a n d all ot her 
scree ni n g tests a n d pr oce d ures ha ve bee n c o m plete d a n d d uri n g t he peri o d fr o m 
C ycle 1 Da y 2 1 t o C ycle 1 Da y 3 5.   
3.  Patie nts wit h sta ble brai n metastases are eli gi ble f or t his trial. H o we ver, patie nts 
m ust n ot ha ve re q uire d ster oi d treat me nt f or t heir brai n metastases wit hi n 3 0 da ys of 
Scree ni n g.  
4.  B o ne -directe d t hera p y (e. g., bis p h os p h o nates or de n os u ma b) is per mitte d. H o we ver, 
pa tie nts s h o ul d n ot ha ve starte d b o ne-directe d t hera p y wit hi n 2 wee ks of C 1 D 1, a n d 
ne w b o ne -directe d t hera p y s h o ul d n ot be i nitiate d d uri n g t he first 4 wee ks of st u d y 
(i.e., C ycle 1).  
5.  Was h o ut fr o m a n y pri or i n vesti gati o nal t hera p y of at least fi ve ti mes t he T 1/ 2 pri or t o 
C 1 D 1.  
6.  Was h o ut fr o m a n y pri or bi ol o gic or tar gete d t hera p y at l east 4 wee ks or fi ve ti mes 
t he T1/ 2 ( w hic he ver is s h orter) pri or t o C 1 D 1. 
7.  Was h o ut fr o m pri or c he m ot hera p y of at least 2 wee ks or 1 eli mi nati o n half -life, 
w hic he ver is l o n ger, pri or  t o C 1 D 1. 
8.  Was h o ut fr o m pri or h or m o nal t hera p y of at least 2 wee ks, pri or t o C 1 D 1.  
9.  Was h o ut of at least 2 wee ks fr o m t he m ost rece nt ra diati o n treat me nt pri or t o C 1 D 1.  
1 0.  Res ol uti o n of all pri or treat me nt -relate d t o xicities t o Gra de 1 or less, e xce pt f or 
 
C O N FI D E N TI A L  
1 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Gra de  2 fati g ue or al o pecia pri or t o C 1 D 1  
1 1.  A ge ei g htee n years or ol der.  
1 2.  E C O G perf or ma nce stat us 0 – 2, i ncl usi ve.  
1 3.  A ntici pate d life e x pecta nc y of at least 1 2 wee ks.  
1 4.  A de q uate b o ne marr o w reser ve :  A N C ≥1 5 0 0/ m m 3, platelets ≥1 0 0, 0 0 0/ m m3.  
1 5.  A de q uate re nal f u ncti o n :  ser u m creati ni ne < 1. 5 x U L N or calc ulate d Cr Cl 
> 6 0  m L/ mi n usi n g C oc kcr oft -Ga ult f or m ula  
G F R  = [( 1 4 0-a ge)•( wei g ht i n k g)•( 0. 8 5 if fe male)]/( 7 2• Cr).  
1 6.  A de q uate he patic f u ncti o n :  A S T a n d A L T < 2. 5  x U L N; T otal a n d Direct Bilir u bi n 
< 1. 5  x U L N. H o we ver, i n t he prese nce of li ver metastases, A S T a n d A L T m ust be 
< 5  x U L N.  
1 7.  Car diac ejecti o n fracti o n ≥5 0 %, a n d Q Tc F < 4 5 0 ms ( males) or  
< 4 7 0 ms (fe males) o n E C G at Baseli ne.  
Fri dericia’s F or m ula:  Q Tc F  = ( Q T)/ R R0 3 3 
1 8.  A ble t o s wall o w ca ps ules a n d mai ntai n a de q uate h y drati o n.  
1 9.  A bilit y t o gi ve writte n i nf or me d c o nse nt a n d willi n g t o c o m pl y wit h t he 
re q uire me nts of t he pr ot oc ol; a n d f or P art 3 , a ble t o gi ve writte n i nf or me d c o nse nt 
f or 2 ca ncer bi o ps y pr oce d ures.  
2 0.  W o me n of c hil d -beari n g p ote ntial m ust a gree t o use a n effecti ve met h o d of birt h 
c o ntr ol d uri n g treat me nt a n d f or t hree m o nt h s after recei vi n g t heir last d ose of st u d y 
dr u g. Se x uall y acti ve me n 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 at least 3 m o nt hs after last d ose ( see 
Attac h me nt  4). 
Ke y P atie nt  
Selecti o n 
Criteri a C o nt’ d  
E xcl usi o n Criteria  
1.  Prese nce of a sec o n dar y acti ve mali g na nc y  
•  
Patie nts wit h a n o n -mela n o mat o us, i n sit u mali g na nc y or disease t hat is 
c o m pletel y resecta ble wit h s ur ger y ma y be c o nsi dere d after disc ussi o n wit h t he 
Me dical M o nit or  
•  
P atie nts wit h a c o m pletel y treate d pri or mali g na nc y wit h n o e vi de nce of disease 
f or ≥3 years are eli gi ble  
2.  Refract or y na usea a n d v o miti n g, mala bs or pti o n, e xter nal biliar y s h u nt or si g nifica nt 
s mall 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 P L X 3 3 9 7.  
3.  O n g oi n g treat me nt wit h a n y ot her i n vesti gati o nal t hera p y.  
4.  Pri or a na p h ylactic or se vere h y perse nsiti vit y reacti o n t o paclita xel or Cre ma p h or -
c o ntai ni n g a ge nt.  
5.  Persiste nt Gra de  2 fati g ue at Baseli ne.  
6.  Se vere, c o nc urre nt ill ness i ncl u di n g c o n gesti ve heart fail ure, si g nifica nt car diac 
disease a n d u nc o ntr olle d h y perte nsi o n, t hat w o ul d li kel y pre ve nt t he patie nt fr o m 
bei n g a ble t o c o m pl y wit h t he st u d y pr ot oc ol.  
7.  Acti ve u ntreate d i nfecti o n  
8.  K n o w n c hr o nic acti ve he patitis B or C or HI V i nfecti o n  
9.  T he prese n ce of a me dical or ps yc hiatric c o n diti o n t hat, i n t he o pi ni o n of t he 
Pri nci pal I n vesti gat or, ma kes t he patie nt i na p pr o priate f or i ncl usi o n i n t his st u d y  
D ur ati o n of 
St u d y  
T he d urati o n of t he st u d y will de pe n d o n t he recr uit me nt rate a n d t he d urati o n of tr eat me nt 
f or t h ose patie nts e nr olle d. 
 
C O N FI D E N TI A L  
1 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
D ose Li miti n g 
T o xicities  
P art 1:  
Patie nts m ust recei ve at least 2 1 da ys of P L X 3 3 9 7 A N D at least 3 d oses of paclita xel d uri n g 
t he first 2 8 da y c ycle i n or der t o be c o nsi dere d e val ua ble f or D L T, u nless d oses are misse d 
d ue t o a D L T.  
He mat ol o gic D L Ts  
•  
Gra de 4 ne utr o pe nia lasti n g f or ≥7 da ys i n d urati o n  
•  
Gra de 4 t hr o m b oc yt o pe nia ( platelets ≤2 5. 0/ µ L)  
•  
Gra de 3 t hr o m b oc yt o pe nia ass ociate d wit h blee di n g  
Ot her D L Ts  
•  
A n y C T C A E v 4 Gra de ≥3 ot her t o xicit y, u nless t he e ve nt is cle arl y u nrel ate d  t o 
treat me nt wit h P L X 3 3 9 7 i n c o m bi nati o n wit h wee kl y sta n dar d fi xe d d osi n g of 
paclita xel E X C E P T t he f oll o wi n g:  
o  
Aller gic reacti o n t o paclita xel  
o  
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 
4 8  h o urs, wit h or wit h o ut me dica l i nter ve nti o n or pr o p h yla xis 
o  
Gra de 3 fati g ue t hat res ol ves t o ≤Gra de 2 wit hi n 1 4 da ys  
o  
Gra de ≥3 h y per gl yce mia  
o  
Tra nsie nt ( < 1 4 da ys) i ncrease i n L F Ts of ≤o ne Gra de i n se verit y c o m pare d 
t o baseli ne le vels i n patie nts wit h baseli ne li ver metastases 
o  
Gra de 3 pe ri p heral ne ur o pat h y i n patie nts wit h baseli ne ≥Gra de 1 
peri p heral ne ur o pat h y or a hist or y of c he m ot hera p y -ass ociate d peri p heral 
ne ur o pat h y  
o  
Gra de 3 m yal gia or art hral gia i n patie nts wit h baseli ne ≥Gra de 1 m yal gia or 
art hral gia 
o  
Gra de 3 ras h f or w hic h s y m pt o m s are easil y ma na ge d wit h s u p p orti ve care 
a n d t here is n o e vi de nce of s u peri nfecti o n or li mitati o n of self -care A D Ls 
D os a ge a n d 
Re gi me n  
P L X 3 3 9 7 ( 2 0 0 m g ca ps ules) will be a d mi nistere d orall y, usi n g a d osi n g re gi me n of t wice 
dail y. Patie nts s h o ul d fast ( 1 h o ur) bef ore a n d after P L X 3 3 9 7 a d mi nistrati o n o n a n e m pt y 
st o mac h (see Secti o n 1 4. 1. 1  f or details). T he BI D re gi me n is preferre d t o re d uce ca ps ule l oa d 
per d ose a n d mi ni mize i ntra -da y dr u g le vel fl uct uati o ns. O n n o n- P K or n o n -bl o o d bi o mar ker 
d osi n g da ys, P L X 3 3 9 7 ma y be a d mi nistere d at h o me, pri or t o t he cli nic visit f or paclita xel 
a d mi nistrati o n.  
P art 1:  
At least 3 of 4 pla n ne d paclita xel d oses m ust be a d mi nistere d i n t he D L T peri o d (i.e., C ycle 
1). O n s u bse q ue nt c ycles, 1 paclita xel d ose ma y be s ki p pe d per C ycle per I n vesti gat or 
discreti o n a n d/ or patie nt prefere nce.  
P art 2 :   
Patie nts will be treate d wit h P L X 3 3 9 7 R P 2 D ( 6 0 0 m g BI D) usi n g a c o nti n u o us d osi n g 
re gi me n a n d paclita xel, 8 0 m g/ m 2 I V wee kl y (± 4 8 h o urs) o ver a p pr o xi matel y 6 0  mi n utes i n 
eac h 2 8-da y treat me nt c ycle. O ne paclita xel d ose ma y be o mitte d per c ycle b y p h ysicia n 
discreti o n.   
P art 3 :  Patie nts will be se q ue ntiall y assi g ne d t o o ne of t hree C ycle 1 ( 2 8 t o 3 5 da y) lea d -i n 
treat me nt ar ms: 
•  
P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n.  
•  
Paclita xel, 8 0 m g/ m 2 I V wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0 mi n utes.  
•  
P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0  mi n utes.  
 
C O N FI D E N TI A L  
1 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
F oll o wi n g t he sec o n d bi o ps y , C ycle 1 e n ds a n d all patie nts will start C ycle 2 treat me nt wit h 
P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0  mi n utes . C ycle 2 a n d all s u bse q ue nt c ycles will be 
2 8 - da y c ycles. Starti n g wit h C ycle 2, o ne paclita xel d ose ma y be o mitte d per c ycle b y 
p h ysicia n discreti o n. Patie nts w h o disc o nti n ue paclita xel d ue t o paclita xel -relate d t o xicit y 
ma y c o nti n ue treat me nt wit h P L X 3 3 9 7.  
P art 1, P art 2, a n d P art 3:  
I n or der t o i nitiate eac h wee kl y paclita xel treat me nt, patie nts m ust ha ve a n A N C ≥1 0 0 0/ m m3 
a n d platelets ≥7 5, 0 0 0/ m m 3. 
A paclita xel pre me dicati o n re gi me n, c o nsisti n g of a c ortic oster oi d, a n H 2 a nta g o nist a n d 
di p he n h y dra mi ne, is rec o m me n de d i n or der t o re d uce t he ris k of a n a p h yla xis.  
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, A Es, he mat ol o g y, ser u m c he mistr y, a n d E C Gs will be 
use d t o assess safet y a n d t olera bilit y.  
P art 3 : 
A E a n d seri o us a d verse e ve nt ( S A E)  re p orti n g will c o m me n ce w he n t he 2- 3 c ore bi o psies  are 
o btai ne d d uri n g Scree ni n g .  
St o p pi n g R ules  
P art 1:  
If ≥2 of 6 patie nts i n D ose Le vel -1 eit her e x perie nce a D L T or are u na ble t o recei ve t he 
re q uisite P L X 3 3 9 7 a n d paclita xel d oses i n t he first 2 8 da ys d ue t o treat me nt-relate d a d verse 
e ve nts, 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 b e disc o nti n ue d. 
P art 2 : 
After ~ 5 0 % of t he pla n ne d a p pr o xi matel y 3 0  patie nts ( R P 2 D -treate d patie nts fr o m P art 1  a n d 
P art 2 ) ha ve c o m plete d at least 2 treat me nt C ycles, 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 In 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 o ll me nt, t he st u d y will be disc o nti n ue d. 
P art 3:  
After ~ 5 0 % of t he a p pr o xi matel y pla n ne d 3 0  pati e nts ha ve c o m plete d at least 2 treat me nt 
C ycles, 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  
P art 1  a n d P art 3 : 
P L X 3 3 9 7 le vels will be e val uate d at stea d y state ( C 1 D 1 5).  
P D P ar a meters  
P art 1, P art 2, a n d P art 3:  
E x pl orat or y bi o mar kers f or e val uati n g a nti-t u m or acti vit y, i nfla m mati o n a n d e ner g y 
meta b olis m ma y be meas ure d. Bi o mar kers will i ncl u de, b ut are n ot li mite d t o, C S F -1.  
P art 3 :   
Ca ncer tiss ue bi o mar kers will i ncl u de:  
•  
I m m u n o hist oc he mistr y f or C D 6 8, C D 8, P D-L 1, a n d a d diti o nal mar kers of macr o p ha g e 
a n d T-cell prese nce a n d f u ncti o n  
•  
R N A e x pressi o n a nal ysis f or a n e x pl orat or y pa nel of t u m or micr oe n vir o n me nt mar kers  
•  
Stai ni n g of cells of t he t u m or micr oe n vir o n me nt. Pa nels of I H C mar kers s pecific f or 
macr o p ha ges, T -cells, a n d ot her i m m u ne a n d i nfla m mat or y cells will be e m pl o ye d, f or 
se mi-q ua ntitati ve c ha n ges i n cell n u m ber, l ocati o n wit hi n t he t u m or, a n d de gree of 
acti vati o n. 
 
 
 
C O N FI D E N TI A L  
1 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Bl o o d bi o mar kers will i ncl u de:  
•  
C A -1 2 5  
•  
Plas ma C S F -1 a n d a d diti o nal mar kers of treat me nt effect  
•  
W h ole bl o o d C D 1 4 /C D 1 6 m o n oc yte s u b set b y fl o w c yt o metr y (F A C S ) a nal ysis  
•  
W h ole bl o o d m yel oi d -deri ve d s u p press or cell ( M D S C ) b y F A C S a nal ysis  
 
C O N FI D E N TI A L  
1 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Tri al Fl o w C h art ( P art 1 a n d P art 2) 
 
Scree ni n g  
C ycle 1  
C ycle 2 +  
Ot her 
Sc he d ules  
E n d of 
St u d y  
S T U D Y D A Y ► 
D a y -2 8 
t o - 1 
D a y -1 4 
t o - 1 
D a y 1 
( B aseli ne) 
(-2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
D a y 1 
( ± 2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
E V E N T ▼ 
 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d 
C o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
Pri or Ca ncer 
Treat me nt  
X  
 
 
 
 
 
 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
Wei g ht  
X  
 
X  
 
 
 
X  
 
 
 
 
X  
Vital Si g ns 1 0 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
P h ysical E xa m 1 
 
X  
X  
 
 
 
X  
 
 
 
 
X  
1 2 -lea d E C G1 1 
X  
 
 
 
X  
 
 
 
 
 
 
X  
Ec h ocar di o gra m 
or M U G A  
X  
 
 
 
 
 
 
 
 
 
 
 
C he mistr y 1 4 
 
X  
X  
X  
X  
X  
X  
 
 
 
 
X  
He mat ol o g y 1 2 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
Uri ne Pre g na nc y 
Test 1 3 
 
X  
 
 
 
 
 
 
 
 
 
X  
I ma gi n g 
X  
 
 
 
 
 
 
 
 
 
E ver y 8 
wee ks or as 
i n dicate d 
X 1 6 
C o nc o mita nt 
Me dicati o ns  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
E C O G 
Perf or ma nce 
Stat us 
Assess me nt 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
 
C O N FI D E N TI A L  
2 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
 
Scree ni n g  
C ycle 1  
C ycle 2 +  
Ot her 
Sc he d ules  
E n d of 
St u d y  
S T U D Y D A Y ► 
D a y -2 8 
t o - 1 
D a y -1 4 
t o - 1 
D a y 1 
( B aseli ne) 
(-2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
D a y 1 
( ± 2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
E V E N T ▼ 
 
 
 
 
 
 
 
 
 
 
 
 
P L X 3 3 9 7 
A d mi nistrati o n 2 
 
 
X  
X 
 X 
A d mi nister 
Dail y  
 
P L X 3 3 9 7 
C o m plia nce  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Paclita xel 
Pre me dicati o ns 3 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Paclita xel 
A d mi nistrati o n 4, 6 
 
 
X  
X 
X 
X 
X 5 
X 5 
X 5 
X 5 
 
 
Plas ma f or P K  
( Part 1 o nl y) 
 
 
X 7 
 
X 8 
 
X 7 
 
 
 
 
 
Plas ma f or P D 
bi o mar kers  
 
 
X 1 5 
 
 
 
X 1 5 
 
 
 
 
 
W h ole Bl o o d 
Sa m ple f or 
C D 1 4/ C D 1 6 
a nal ysis  
 
 
X 
 
X 
 
 
 
 
 
 
 
A d verse E ve nts 9 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
E X P L A N A TI O N O F S U P E R S C RI P T S : 
1.  F ull p h ysical e xa m at Scree ni n g o nl y, a n d s y m pt o m -directe d p h ysical e xa m s u bse q ue ntl y.  
2.  O n  cli nic visit da ys, P L X 3 3 9 7  ma y be ta ke n a t a n y ti me pri or t o paclita xel a d mi nistrati o n. T he a  m. d ose of P L X 3 3 9 7 ma y be ta ke n at h o me, pri or t o t he 
cli nic visit o n all cli nic visit da ys E X C E P T  o n C 1 D 1 ( Baseli ne) , C 1 D 1 5 , a n d C 2 + D 1. O n t h ose st u d y da ys, t he m or ni n g d ose of P L X 3 3 9 7 will be 
a d mi niste re d i n t he cli nic after o btai ni n g a pre-d ose bl o o d sa m ple f or P K or P D  bi o mar ker  a nal ysis. P L X 3 3 9 7 s h o ul d be a d mi nistere d at a p pr o xi mate l y 
t he sa me ti me(s) eac h da y, ±2 h o u rs. Patie nts s h o ul d fast f or at least 1 h o ur bef ore a n d after P L X 3 3 9 7 a d mi nistrati o n (see S ecti o n 1 4. 1. 1  f or details) 
3.  Paclita xel pre me dicati o ns are rec o m me n de d, b ut n ot re q uire d. T he pre me dicati o n re gi me n i ncl u des a c ortic oster oi d, H 2 a nta g o nist a n d 
di p he n h y dra mi ne.  
4.  I n vesti gat ors s h o ul d f oll o w sta n dar d i nstit uti o nal g ui deli nes.  
5.  Paclita xel d oses are a d mi nistere d o n t hese sc he d ule d da ys ± 4 8 h o u rs. 
6.  O ne  d ose of paclita xel ma y be s ki p pe d e ver y C ycle  per I n vesti gat or discreti o n a n d patie nt prefere nce  after Cycle 1 . 
 
C O N FI D E N TI A L  
2 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
7.  P art 1 o nl y :  Plas ma sa m ples f or P K o n  C 1 D 1 a n d t he first da y of all s u bse q ue nt c ycles (i.e., C 2 + D 1) are o btai ne d pri or t o t he first d ose of P L X 3 3 9 7.  
8.  P art 1 o nl y :  Plas ma sa m ple f or P K o n C 1 D 1 5 will occ ur pre -P L X 3 3 9 7 a d mi nistrati o n a n d at 2 a n d 4 h o u rs p ost P L X 3 3 9 7 d osi n g. 
9.  M o nit ore d t hr o u g h o ut  t he st u d y via safet y assess me nts, o bser vati o n, a n d partici pa nt re p orti n g. 
1 0.  S h o ul d be ta ke n 3 – 5 mi n utes after sitti n g.  I ncl u des p ulse, res pirat or y rate, te m perat ure a n d bl o o d press ure 
1 1.  S h o ul d be c o m plete d after t he patie nts ha ve  bee n i n a s u pi ne p ositi o n f or  at least 5 mi n utes.  
1 2.  He mat ol o g y e val uati o n m ust i ncl u de C B C wit h differe ntial ( see Attac h me nt 1 ). A N C m ust be ≥1 0 0 0/ m m 3 a n d Platelets m ust be ≥7 5, 0 0 0/ m m 3 f or 
paclita xel a d mi nistrati o n.  
1 3.  Re q uire d f or all fe male patie nts of c hi l d-beari n g p ote ntial.  
1 4.  C he mistr y e val uati o n m ust i ncl u de a f ull meta b olic pa nel ( see Attac h me nt 1 ) 
1 5.  P art 1 a n d P art 2 :  Sa m ples f or P D bi o mar kers t o be o btai ne d pri or t o P L X 3 3 9 7 a d mi nistrati o n. 
1 6.  E n d of St u d y i ma gi n g s h o ul d be o btai ne d f or patie nts w h o g o off  st u d y f or reas o ns ot her t ha n ra di o gra p hic disease pr o gressi o n 
 
 
 
 
C O N FI D E N TI A L  
2 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Tri al Fl o w C h art ( P art 3) 
 
Scree ni n g  
C ycle 1 Le a d -i n P h ase ( 2 8-3 5 d a y c ycle)  
C ycle 2 + ( 2 8 d a y c ycles)  
Ot her 
Sc he d ules  
E n d of 
St u d y  
S T U D Y D A Y ► 
D a y -2 8 
t o - 1 
D a y -1 4 
t o - 1 
D a y 1 
( B aseli ne) 
(-2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
D a y 1 
( ± 2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
E V E N T ▼ 
 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d 
C o nse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
Assi g n me nt of 
Lea d -in 
Treat me nt Ar m  
X  
 
 
 
 
 
 
 
 
 
 
 
Me dical Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
Pri or Ca ncer 
Treat me nt  
X  
 
 
 
 
 
 
 
 
 
 
 
Hei g ht  
X  
 
 
 
 
 
 
 
 
 
 
 
Wei g ht  
X  
 
X  
 
 
 
X  
 
 
 
 
X  
Vital Si g ns 1 
X  
 
X  
 
 
 
X  
 
 
 
 
X  
P h ysical E xa m 2 
 
X  
X  
 
 
 
X  
 
 
 
 
X  
E C O G P S  
X  
 
X  
 
 
 
X  
 
 
 
 
X  
1 2 -lea d E C G3 
X  
 
 
 
X  
 
 
 
 
 
 
X  
Ec h ocar di o gra m 
or M U G A  
X  
 
 
 
 
 
 
 
 
 
 
 
C he mistr y 4 
 
X  
X  
X  
X  
X  
X  
X 2 0 
X 2 0 
X 2 0 
 
X  
He mat ol o g y 5 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
Uri ne Pre g na nc y 
Test 6 
 
X  
 
 
 
 
 
 
 
 
 
X  
I ma gi n g 
X  
 
 
 
 
 
 
 
 
 
E ver y 8 
wee ks or as 
i n dicate d 
X 1 9 
C o nc o mita nt 
Me dicati o ns  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
 
C O N FI D E N TI A L  
2 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
 
Scree ni n g  
C ycle 1 Le a d -i n P h ase ( 2 8-3 5 d a y c ycle)  
C ycle 2 + ( 2 8 d a y c ycles)  
Ot her 
Sc he d ules  
E n d of 
St u d y  
S T U D Y D A Y ► 
D a y -2 8 
t o - 1 
D a y -1 4 
t o - 1 
D a y 1 
( B aseli ne) 
(-2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
D a y 1 
( ± 2 D a ys)  
D a y 8 
( ± 2 D a ys)  
D a y 1 5 
( ± 2 D a ys)  
D a y 2 2 
( ± 2 D a ys)  
E V E N T ▼ 
 
 
 
 
 
 
 
 
 
 
 
 
P L X 3 3 9 7 
A d mi nistrati o n 7 
 
 
X 8, 9 
 X 8, 9 
X 
 X 
A d mi nister 
Dail y  
 
P L X 3 3 9 7 
C o m plia nce  
 
 
X 8, 9 
X 8, 9 
X 8, 9 
X 8, 9 
X 
X 
X 
X 
 
X 
Paclita xel 
A d mi nistrati o n 1 1 
 
 
X 9, 1 0 
X 9, 1 0 
X 9, 1 0 
X 9, 1 0 
X 1 2, 1 3 
X 1 2, 1 3 
X 1 2, 1 3 
X 1 2, 1 3 
 
 
Plas ma f or P K & 
P D Bi o mar kers 1 4 
 
 
X 
 
X 
 
X 
 
 
 
 
X  
Ca ncer Ti ss ue 
Bi o mar kers 1 5 
X 
 
 
 
 
 
X 
 
 
 
 
 
C A -1 2 5  
X 1 6  
 
X 1 6 
 
 
 
X 1 6 
 
 
 
 
X 1 6 
W h ole Bl o o d f or 
C D 1 4/ C D 1 6 
a nal ysis 1 4 
 
 
X 
 
X 
 
 
 
 
 
 
 
W h ole Bl o o d f or 
M D S C a nal ysis
1 4 
 
 
X 
 
X 
 
 
 
 
 
 
 
A d verse E ve nts 1 7 
X 1 8 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
E X P L A N A TI O N O F S U P E R S C RI P T S : 
1.  Vital si g ns s h o ul d be  ta ke n 3– 5 mi n utes after sitti n g. I ncl u des p ulse, res pirat or y rate, te m perat ure a n d bl o o d press ure.  
2.  F ull p h ysical e xa m at Scree ni n g o nl y, a n d s y m pt o m -directe d p h ysical e xa m s u bse q ue ntl y.  
3.  E C Gs s h o ul d be c o m plete d after t he patie nts ha ve bee n i n a s u pi ne p os iti o n f or at least 5 mi n utes. 
4.  C he mistr y e val uati o n m ust i ncl u de a f ull meta b olic pa nel ( see Attac h me nt 1 ). 
5.  He mat ol o g y e val uati o n m ust i ncl u de C B C wit h differe ntial ( see Attac h me nt 1 ). A N C m ust be ≥1 0 0 0/ m m3 a n d Platelets m ust be ≥7 5, 0 0 0/ m m 3 f or 
paclita xel a d mi nistrati o n.  
6.  Re q uire d f or all fe male patie nts of c hil d -beari n g p ote ntial.  
7.  O n cli nic visit da ys, P L X 3 3 9 7 ma y be ta ke n at a n y ti me pri or t o paclita xel a d mi nistrati o n. T he A M d ose of  P L X 3 3 9 7 ma y be ta ke n at h o me pri or t o t he 
cli nic visit o n all cli nic visit da ys E X C E P T  o n C 1 D 1 ( Baseli ne) a n d C 2 + D 1. O n t h ose st u d y da ys, t he m or ni n g d ose of P L X 3 3 9 7 will be a d mi nistere d i n 
 
C O N FI D E N TI A L  
2 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
t he cli nic after o btai ni n g a pre-d ose bl o o d sa m ple f or P D bi o mar k er a nal ysis. P L X 3 3 9 7 s h o ul d be a d mi nistere d at a p pr o xi matel y t he sa me ti me(s) eac h 
da y, ± 2 h o urs. Patie nts s h o ul d fast f or at least 1 h o ur bef ore a n d 1 h o ur after P L X 3 3 9 7 a d mi nistrati o n (see Secti o n 1 4. 1. 1  f or details). 
8.  T his assess me nt sc he d ule is a p plica ble f or all patie nts ra n d o mize d t o t he Le a d -I n P L X 3 3 9 7 Al o ne Ar m. 
9.  T his assess me nt sc he d ule is a p plica ble f or all patie nts ra n d o mize d t o t he Le a d -i n P L X 3 3 9 7 a n d P aclit a xel Ar m. 
1 0.  T his assess me nt sc he d ule is a p plica ble  f or all patie nts ra n d o mize d t o t he Le a d -i n P aclit a xel Al o ne Ar m . 
1 1.  I n vesti gat ors s h o ul d f oll o w sta n dar d i nstit uti o nal g ui deli nes f or paclita xel a d mi nistrati o n. Paclita xel pre me dicati o ns are rec o m me n de d, b ut n ot re q uire d. 
T he pre me dicati o n re gi me n i ncl u des a  c ortic oster oi d, H 2 a nta g o nist a n d di p he n h y dra mi n e.  
1 2.  Paclita xel d oses are a d mi nistere d o n t hese sc he d ule d da ys ± 4 8 h o urs.  
1 3.  O ne d ose of paclita xel ma y be s ki p pe d e ver y C ycle per I n vesti gat or discreti o n a n d patie nt prefere nce after Cycle 1 . 
1 4.  Bl o o d f or plas ma P K a n d P D bi o mar kers will be o btai ne d pri or t o treat me nt o n C ycle 1 Da y 1, C ycle 1 Da y 1 5 a n d o n Da y 1 of all s u bse q ue nt c ycles. 
Plas ma sa m ple f or P K o n C 1 D 1 5 will occ ur pre P L X 3 3 9 7 a d mi nistrati o n a n d at 2, 4, a n d 6 h o urs p ost P L X 3 3 9 7 d osi n g. Se parate w h ole  bl o o d sa m ples 
f or C D 1 4/C D 1 6 a n d M D S C a nal yses will be o btai ne d  pri or t o treat me nt  o n C ycle 1 Da y 1 a n d C ycle 1 Da y 1 5.  
1 5.  Paire d tiss ue bi o psies [ 2-3 c ore bi o psies of tar get ( ≥2 c m  dia meter)  or n o n -tar get lesi o ns] will be o btai ne d at Scree ni n g after C T i ma gi n g a n d all ot her 
scree ni n g tests a n d pr oce d ures ha ve bee n c o m plete d a n d d uri n g t he peri o d fr o m C ycle 1 Da y 2 1 t o C ycle 1 Da y 3 5.  If t he sec o n d bi o ps y i n C ycle 1 is 
dela ye d be y o n d Da y 2 8, patie nts will ha ve a C ycle 1 Da y 2 8 visi t f or paclita xel a d mi nistratio n ( perf or me d wee kl y), d uri n g w hic h st u d y pr oce d ures w ill 
be t he sa me as t he C ycle 1 Da y 2 2 visit.  
1 6.  C A -1 2 5 sa m pli n g re q uire me nts :  t w o pre-treat me nt sa m ples, first sa m ple wit hi n 3 m o nt hs of starti n g t hera p y a n d sec o n d sa m ple wit hi n 1 wee k of 
C 1 D 1 ; s u bse q ue nt sa m ples o n t he first da y of eac h c ycle starti n g wit h Cycle 2 D a y 1 a n d E n d -of -St u d y Visit.  
1 7.  M o nit ore d t hr o u g h o ut t he st u d y via safet y assess me nts, o bser vati o n, a n d partici pa nt re p orti n g.   
1 8.  Seri o us a n d n o n -seri o us a d verse e ve nt re p orti n g will c o m me nce w he n t he 2- 3 c ore bi o psies  are o btai ne d d uri n g Scree ni n g . 
1 9.  E n d of St u d y i ma gi n g s h o ul d be o btai ne d f or patie nts w h o g o off -st u d y f or reas o ns ot her t ha n ra di o gra p hic disease pr o gressi o n. 
2 0.  C ycle 2 o nl y :  ser u m c he mistr y re q uire d pri or t o paclita xel a d mi nistrati o n for P art  3 – all ar ms .  
C ycle 3  o nl y :  ser u m c he mistr y o nl y re q uire d f or P art 3  Le a d -i n P aclit a xel Al o ne Ar m. 
 
C O N FI D E N TI A L  
2 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
7. 0  
I N T R O D U C TI O N 
7. 1  
B ac k gr o u n d 
F or w o me n i n U nite d States, breast ca ncer is t he m ost c o m m o n mali g na nc y, t he sec o n d m ost 
c o m m o n ca use of ca ncer -relate d deat h a n d t he mai n ca use of deat h f or w o me n bet wee n t he a ges 
of 4 0 – 5 9 years ( Je mal 2 0 1 0). A p pr o xi matel y 1 0 % of w o me n dia g n ose d wit h breast ca ncer ha ve 
l ocall y a d va nce d (i.e., Sta ge III) disease , acc o u nti n g f or a p pr o xi matel y 2 3, 00 0 ne w cases i n t he 
U nite d States i n 2 0 1 1 ( Ne w ma n 2 0 0 9 ; A merica n Ca ncer S ociet y 2 0 1 1 ). 
Micr ot u b ule f u ncti o n is vital t o cell s ur vi val a n d pla ys a n i m p orta nt r ole i n pr oliferati o n a n d 
m o tilit y, mai nte na nce of cell s ha pe a n d pr otei n traffic ki n g. Se veral a ge nts affecti n g micr ot u b ule 
d y na mics are acti ve a nti -t u m or a ge nts a n d i n d uce p ol y merizati o n, or ca use n o n-f u ncti o nal 
t u b uli n a g gre gates bl oc ki n g cell di visi o n b y i nterferi n g wit h mit otic s pi n dle f u ncti o n, 
c o nse q ue ntl y res ulti n g i n cell c ycle arrest a n d cell deat h ( H or witz 1 9 9 4 ). Micr ot u b ule  sta bilizers 
are c o nsi dere d o ne of t he m ost effecti ve classes of a ge nts a vaila ble f or treat i n g earl y a n d late 
sta ge B C,  a nd paclita xel ( P T X), w hic h e xerts its a nti -t u m or acti vit y t hr o u g h micr ot u b ule 
sta bilizati o n, is o ne of t he m ost wi del y use d a ge nts i n t his class. Wee kl y paclita xel has bee n 
s h o w n t o be s u peri or t o 3- wee kl y paclita xel i n t he treat me nt of M B C i n b ot h res p o nse rate ( R R) 
a n d ti me- t o-pr o gressi o n ( T T P) ( Sei d ma n 2 0 0 8 ).  
M acr o p h a ges a n d Bre ast C a ncer  
Macr o p ha ges are t he m ost a b u n da nt i n nate i m m u ne cell t y pe prese nt wit hi n  breast ca ncer, w here 
t he y re g ulate a n gi o ge nic pr ocesses via pr o d ucti o n of pr o-a n gi o ge nic fact ors i ncl u di n g vasc ular 
e n d ot helial gr o wt h fact or ( V E G F) a n d pr oteases ( Li n 2 0 0 7 ). I n breast ca ncer patie nts, cyt ot o xic 
t hera pies pr o mi ne ntl y i ncrease t he prese nce of macr o p ha ges i n resi d ual t u m ors a n d alter t he 
t u m or i m m u ne micr oe n vir o n me nt (R uffell 2 0 1 2 ). I n a tra ns ge nic m o use m o del of ma m mar y 
a de n ocarci n o ma de vel o p me nt ( e. g., M M TV- P y M T mice )[ 3 4], i ncrease d macr o p ha ge i nfiltrati o n 
i n pre mali g na nt tiss ue occ urs i m me diately bef ore acti vati o n of a n gi o ge nesis a n d o nset of 
mali g na nc y [ 3 5, 3 6]. C ol o n y sti m ulati n g fact or- 1 ( C S F - 1) is br oa dl y e x presse d b y ma m mar y 
t u m or cells, a n d its e x pressi o n c orrelates wit h e xte nt of macr o p ha ge i nfiltrati o n (G u y 1 9 9 2 ). 
M M T V -P y M T mice carr yi n g t he Csf 1 o p/ o p m utati o n e x hi bit 9 5 % decrease d i nfiltrati o n of 
macr o p ha ges i n t u m ors, i n hi bite d a n gi o ge nesis, si g nifica ntl y dela ye d t u m or pr o gressi o n a n d 
di m i nis he d p ul m o nar y metastasis (Li n  2 0 0 1).  
I n breast ca ncer, macr o p ha ges are re g ulate d i n part b y C S F -1, me diate d b y F ms ( i.e., t he C S F- 1 
rece pt or) (Ta n g 1 9 9 2 ). Paracri ne i nteracti o ns bet wee n macr o p ha ges a n d micr o vasc ular 
e n d ot helial cells ( M E Cs) f or m p ositi ve fee d -f or war d l oo ps i n v ol vi n g macr o p ha ge- e x presse d 
E G F. T o get her wit h C S F - 1 e x presse d b y ne o plastic cells, t hese paracri ne i nteracti o ns  re g ulate 
carci n o ma cell c he m ota xis al o n g c olla ge n fi bers t o war ds bl o o d vessels directe d b y peri vasc ular 
macr o p ha ges (C o n deelis 2 0 0 6 ; C o n deelis 2 0 0 3 ). Base d o n t hese fi n di n gs, it see ms reas o na ble t o 
p ost ulate t hat bl oc ka de of cell ular a n d/ or m olec ular pr o gra ms e n ha nci n g macr o p ha ge recr uit me nt 
 
C O N FI D E N TI A L  
2 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
i n breast ca ncer ma y re prese nt tracta ble tar gets f or a nti-ca ncer t hera p y. I n dee d, bl oc ka de of 
C S F - 1 or F ms  res ults i n decrease d macr o p ha ge prese nce i n tiss ues a n d i n e x peri me ntal t u m ors, 
c orrelates wit h di mi nis he d a n gi o ge nesis, re d uce d t u m or g r o wt h metastasis i n s o me m o dels 
(Li n  2 0 0 1; N o wic ki 1 9 9 6 ; C o n wa y 2 0 0 5 ; Ma nt he y 2 0 0 9 ; Price ma n 2 0 1 0 ; Qia n 2 0 0 9 ). 
C S F -1 Rece pt or I n hi biti o n i n O v ari a n C a ncer  
I n h u ma n e pit helial o varia n ca ncer, C S F- 1 a n d/ or F ms  e x pressi o n has bee n o bser ve d i n t he lar ge 
maj orit y of cases, wit h 7 5 % of pri mar y t u m ors a n d 6 9 % of t he metastases e x pressi n g C S F- 1, a n d 
9 2 % of pri mar y t u m ors a n d 8 3 % of me tastases e x pressi n g F ms  (Kaci ns ki 1 9 9 1 ; C ha m bers 1 9 9 7 ; 
T o y  2 0 0 1). At t he ti me of dia g n osis i n e pit helial o varia n ca ncer patie nts, ele vate d le vels of b ot h 
ser u m a n d ascitic fl ui d C S F- 1 are ass ociate d wit h a p o or o utc o me (Price  1 9 9 3, Sc h oll 1 9 9 4 ). 
D uri n g t he c o urse of t he disease, ele vate d le vels of ser u m C S F -1 ca n heral d disease rec urre nce or 
pr o gressi o n ( Kaci ns ki 1 9 8 9 ). Ele vate d C S F- 1 le vels as part of a pa nel of mar kers, i ncl u di n g 
C A 1 2 5, has rece ntl y bee n s h o w n t o hel p i m pr o ve earl y detecti o n of o varia n ca ncer ( S kates 2 0 0 4 ; 
Z ha n g 2 0 0 7 ). T his str o n g ass ociati o n wit h disease detecti o n a n d pr o g n osis s u g gests a n 
eti ol o gical r ole f or F ms / C S F- 1 i n o varia n ca ncer i nitiati o n a n d ne o plastic pr o gressi o n. 
Base d o n t he fi n di n gs disc usse d a b o ve, it see ms reas o na ble t o p ost ulate t hat b l oc ka de of cell ular 
a n d/ or m olec ular pr o gra ms e n ha nci n g macr o p ha ge recr uit me nt i n e pit helial o varia n ca ncer ma y  
res ult i n decrease d macr o p ha ge prese nce i n e pit helial o varia n t u m ors. 
P L X 3 3 9 7 as a M acr o p h a ge- T ar gete d T u m or Se nsitizer  
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 i nte n de d f or oral a d mi nistrati o n t hat 
tar gets 3 ki nases:  1)  F ms  (als o referre d t o as C S F- 1 R, t he rece pt or f or 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] as well as t he li ga n d i nterle u ki n -3 4 [I L - 3 4]); 2) Kit, t he 
rece pt or f or ste m cell fact or ( S C F); a n d 3) o nc o ge nic Flt 3, t he rece pt or f or Flt 3 li ga n d. H o we ver, 
it ot her wise re mai ns hi g hl y selecti ve i n ter ms of i m pact o n t he acti vit y of ot her rece pt ors a n d 
ki nases. T he p ote nt i n hi biti o n of t hese 3 ki nases ca n be e x pl oite d t o attac k t u m ors t hr o u g h a 
variet y of mec ha nis ms :  1) direct i n hi biti o n of 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 o n of paracri ne l o o ps bet wee n str o mal cells a n d t u m ors; 3)  bl oc ka de 
of mi grati o n a n d a n gi o ge nesis; 4) bl oc ka ge of C S F- 1- de pe n de nt m yel oi d- deri ve d s u p press or 
cells; a n d 5) disr u pti o n of oste ol ytic metastases.  
A n i m p orta nt r ole f or t u m or-i nfiltrati n g macr o p ha ges i n t u m or pr o gressi o n has p oi nte d t o F ms as 
a ke y tar get i n m ulti ple t u m or t y pes ( R uffell 2 0 1 5 ). T he pr o-t u m ori ge nic r ole of C S F 1 a n d F ms 
is s u p p orte d b y a wealt h of st u dies de m o nstrati n g t hat C S F- 1 le vels pre dict a p o or o utc o me i n a 
variet y of o nc ol o g y i n dicati o ns, i ncl u di n g breast, o varia n, n o n- s mall cell lu n g, a n d c ol orectal 
ca ncers.  
 
C O N FI D E N TI A L  
2 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
C yt ot o xics I n d uce E x pressi o n of M acr o p h a ge/ M o n oc yte C he m o attr act a nts 
I n vitr o st u dies of M E Cs fr o m m uri ne ma m mar y a n d h u ma n breast t u m ors de m o nstrate t hat 
le vels of macr o p ha ge a n d i m mat ure m yel oi d s u p press or cell (I M C) c he m oattracta nt m R N A, 
i ncl u di n g C S F- 1, C C L 8/ M C P 2 a n d I L 3 4, i ncrease f oll o wi n g e x p os ure t o paclita xel, cis plati n a n d 
ra diati o n.  
T o re veal t he m olec ular me diat ors i n v ol ve d i n C T X- ass ociate d macr o p ha ge recr uit me nt, we 
e val uate d M E Cs fr o m m uri ne ma m mar y a n d h u ma n br east t u m ors i n vitr o f or m R N A e x pressi o n 
of m o n oc yte/ macr o p ha ge  c yt o ki nes/c he m o ki nes f oll o wi n g e x p os ure t o P T X, cis plati n or 
ra diati o n t hera p y, a n d f o u n d i ncrease d e x pressi o n of i m p orta nt macr o p ha ge/I M C 
c he m oattracta nt m R N As, i ncl u di n g C S F 1, C C L 8/ M C P 2 a n d I L 3 4 ( Fi g ure 1 A ) s h o ws a nal ysis of 
P y M T -deri ve d carci n o ma cells treate d wit h P T X  i n vitr o). A nal ysis of C S F 1  m R N A e x pressi o n 
i n vi v o re veale d t hat ma m mar y t u m ors of M M T V-P y M T mice ha d a 2 -f ol d hi g her e x pressi o n of 
C S F 1 m R N A f oll o wi n g P T X e x p os ure ( Fi g ure 1 B ) t hat c orrelate d wit h i ncrease d de nsit y of 
macr o p ha ge i n t u m or str o ma (Fi g ure 1 C ). 
Fi g ure  1: 
I n Vitr o P aclit a xel E x p os ure Res ults i n I ncre ase d C S F -1 a n d 
M acr o p h a ge De nsit y i n M a m m ar y T u m or Str o m a  
 
A)  Q R T -P C R a nal yses of C S F 1, M C P 1, M C P 2, M C P 3 a n d I L 3 4 e x pressi o n i n P y M T -carci n o ma cell s treate d wit h 
P T X f or 2 4 h o urs; B)  P T X -i n d uce d C S F 1 m R N A e x pressi o n; a n d C)  Macr o p ha ge de nsit y i n ma m mar y t u m ors of 
M M T V -P y M T mice f oll o wi n g P T X treat me nt.  
( *) p < 0. 0 5.  
 
C O N FI D E N TI A L  
2 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  






P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 nslate 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 . 
Please refer t o t he  I n vesti gat or’s Br oc h ure f or a d diti o nal i nf or mati o n o n F ms  a n d Kit i n hi biti o n. 
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 f or F ms ( i.e., C S F - 1 R), Kit  a n d o nc o ge nicall y acti ve Flt 3 
(i.e., Flt 3 -I T D) vers us a pa nel of o ver 2 0 0 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 ai nst Selecte d Ki n ases 
Ki n ase  
F ms  
Kit  
Flt 3 -I T Da 
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  
a 
Flt 3 -I T D i n dicates a ki nase d o mai n acti vate d via tr u ncati o n. 
U nacti vate d ( i.e., wil d -t y pe) Flt 3 has meas ura ble acti vit y t hat is 1 5-f ol d less se nsiti ve t o 
P L X 3 3 9 7. K dr ki nase acti vit y is o nl y m o destl y affecte d, a n d ot he r 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, wit 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, 
Ster oi ds, I o n C ha n nels, Nitric O xi de, 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 c o nce ntrati o n of 1 0 µ M ser u m -free, 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. 
Se veral i n vitr o e x peri me nts ha ve de m o nstrate d t hat P L X 3 3 9 7 s pares t he wil d-t y pe Flt 3 a n d is 
selecti ve f or t he o nc o ge nic Flt 3-I T D. 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 Flt 3 
ki nase acti vit y (tr u ncate d Flt 3 ki nase d o mai n), 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- Flt 3 e x pressi n g Ba F 3 cells are de pe n de nt o n a tr u ncate d Flt 3 ki nase 
acti vit y f or s ur vi val.  I n vitr o, P L X 3 3 9 7 i n hi bits pr oliferati o n of t hat li ne wit h a n I C5 0 of 4 0 0 n M. 
A d diti o n of I L- 3 t o t he Ba F 3 -Flt 3 cells ‘resc ues’ t hese cells a n d s hifts t he I C5 0 t o greater t ha n 
1 0, 0 0 0 n M, reflecti n g a r o b ust t hera pe utic i n de x. 
 
C O N FI D E N TI A L  
3 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
I n R S 4 ; 1 1 cells, Flt 3  a ut o p h os p h or ylati o n a n d pr oliferati 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, ki nase acti vit y a 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 C5 0  val ue of 2 6 n M. 
F or a d diti o nal i nf or mati o n re gar di n g P L X 3 3 9 7 i n vitr o p har mac o d y na mics a n d i n hi biti o n of F ms  
a n d Kit, please refer t o t he I n vesti gat or’s Br oc h ure. 
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 acti 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 duce 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 cells 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 D -5 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 e fficaci 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) be hi 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 xt ra vasati o n i nt o t he bl o o d strea m, re d ucti o n 
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 4 ). 
 
C O N FI D E N TI A L  
3 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Fi g ure 4:  
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  
 
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  
P L X 3 3 9 7 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 P L X 3 3 9 7 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 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 -
lives 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 %). 
 
C O N FI D E N TI A L  
3 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 ( K i) 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 K i 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 ( K i = 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 u ate d f or its a bilit y t o i n hi bit t he maj or 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 C5 0 val ues greater t ha n 3 0 µ M were u nif or ml y 
o btai ne d. 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  
P L X 3 3 9 7 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 
After esta blis hi n g d ose -res p o nse s yste mic e x p os ure data wit h ga vage f or m ulati o ns of P L X 3 3 9 7, 
t he t o xic ol o g y was e val uate d i n n o n- G L P re peat d ose a n d G L P 2 8-da y re peat - d ose t o xicit y 
st u dies i n S pra g ue- Da wle y rats a n d Bea gle d o gs. Sta n dar d G L P batteries of ge n ot o xicit y a n d 
safet y p har mac ol o g y st u dies were als o perf or me d. 
 
C O N FI D E N TI A L  
3 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Res ults of t he st u dies are prese nte d bel o w. I n s u m mar y, a N O A E L f or eit her s pecies was n ot 
deter mi ne d, base d o n b o d y wei g ht l osses a n d se veral hist ol o gical a n d/ or gr oss m or p h ol o gical 
effects. H o we ver, t he si g nifica nt test article -relate d a d verse effects (testes, o varies, b o ne a n d 
b o ne marr o w, he mat ol o g y a n d l y m p h oi d c ha n ges) are c o nsiste nt wit h t he p har mac ol o gical 
mec ha nis m of acti o n of P L X 3 3 9 7. I m p orta ntl y, all of t hese fi n di n gs were partiall y or f ull y 
re versi ble. T here were n o safet y fi n di n gs i n t he ge n ot o xicit y a n d safet y p har mac ol o g y st u dies. 
Please refer t o t he I n vesti gat or’s Br oc h ure f or a m ore detaile d descri pti o n of t he n o n -cli nical 
t o xic ol o g y a n d safet y p har mac ol o g y st u dies. 
7. 4. 1  
Re pe at - d ose T o xicit y i n R ats 
I n rats a d mi nistere d P L X 3 3 9 7 b y oral ga va ge f or 7 da ys at d oses of 3 0, 1 0 0, a n d 3 0 0 m g/ k g/ da y, 
t here were m o dest p ote ntial test article-relate d effects as f oll o ws:  decrease d W B C a n d 
he m o gl o bi n, i ncrease d A S T, A L T, al kali ne p h os p hatase, i ncrease d li ver a n d decrease d s plee n 
wei g hts, b o ne marr o w he mat o p oietic atr o p h y, a n d c ystic c or p ora l utea. U n der t he c o n diti o ns of 
t his st u d y t he N O A E L was 3 0 m g/ k g/ da y f or males a n d fe males. 
I n t he s u bse q ue nt 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. E xp os ure i ncrease d as d osa ge was i ncrease d o ver 
t he 2 0 t o 2 0 0 m g/ k g/ da y ra n ge f or b ot h se xes, wit h e x p os ure i n fe males te n di n g t o be m o destl y 
hi g her ( 9 – 3 4 %, de pe n di n g o n d ose) c o m pare d t o males.  
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 were 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 ups. 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. Alterati o ns i n he mat ol o g y 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. N o effects o n cli nical c he mistr y were c o nsi dere d a d verse.  
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 varies i n t he 6 0 a n d 
2 0 0 m g/ k g/ da y fe males, d ose- relate 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 at st u d y Da y 2 8/ 2 9 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 ofte n c o m pletel 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. T u b ules i n sta ges of el o n gati o n were fre q ue ntl y c haracterize d b y c o m plete 
a bse nce of pre pac h yte ne a n d pac h yte ne s per mat oc ytes a n d sert oli cell vac u olizati o n was 
occasi o nall y o bser ve d. At st u d y Da y 4 3, t he 2 0 0 m g/ k g/ da y gr o u p males ha d de pleti o n of 
s per mat o g o nic e pit heli u m a n d mil d t o se vere atr o p h y c haracterize d b y a de pleti o n of s per mati ds, 
 
C O N FI D E N TI A L  
3 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
h o we ver t here was a n i ncrease i n t he s per mat o g o nial p o p ulati o n, w hic h is reflecte d b y t he 
prese nce of si g nifica nt n u m bers of earl y pre pac h yte ne (le pt ote ne a n d z y g ote ne) s per mat oc ytes.  
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 here were macr osc o pic fi n di n gs of disc ol orati o n/re d areas of t he o varies i n t he 6 0 a n d 
2 0 0 m g/ k g/ da y fe males at pri mar y necr o ps y, a n d s oft/s mall testes i n t he 2 0 0 m g/ k g/ da y gr o u p 
mal es at t he rec o ver y necr o ps y. Micr osc o pic alterati 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 f or t he 6 0 a n d 2 0 0 m g/ k g/ da y gr o u ps, 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 f or t he 6 0 a n d 2 0 0 m g/ k g/ da y gr o u ps, 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). Alterati o ns i n b o ne para meters 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. 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 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 of all test article -treate d gr o u ps, a n d 
l y m p h oi d de pleti o n of t he c orte x i n t he t h y m us i n t he 6 0 a n d 2 0 0 m g/ k g/ da y gr o u ps.  
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. 
L uteal c ysts re d uce d i n se verit y, b ut re mai ne d hi g her t ha n t he c o ntr ol gr o u p i n t he 
2 0 0 m g/ k g/ da y gr o u p fe males. O n t he basis of o bser vati o ns ma de i n t his G L P -c o m plia nt st u d y, a 
n o- o bser ve d a d verse effect le vel ( 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 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 D 1 0). H o we ver f or t he p ur p oses of c alc ulati n g a cli nical starti n g d ose f or 
o nc ol o g y, Ple x xi k o n has ass u me d t he hi g hest d ose teste d i n t his st u d y ( 2 0 0 m g/ k g) t o be t he 
S T D 1 0.  
7. 4. 2  
Re pe at - d ose T o xicit y i n D o gs 
I n t w o pairs of Bea gle d o gs a d mi nistere d P L X 3 3 9 7 at a d ose of 6 0 0 m g/ k g BI D 
( 1 2 0 0 m g/ k g/ da y) f or 7 da ys, fi n di n gs i ncl u de d e mesis a n d mil d t o m o derate re d ucti o n of 
er yt hr o p oiesis i n b o ne marr o w. Mil d b o d y wei g ht l oss was li kel y sec o n dar y t o e mesis.  
I n t he s u bse q ue nt 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 
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. 
 
C O N FI D E N TI A L  
3 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Mea n e x p os ure ge nerall y i ncrease d as d osa ge i ncre ase d o ver t he 5 0 t o 1 0 0 0 m g/ k g/ da y ra n ge, 
b ut t he ra n ge of e x p os ure o bser ve d f or i n di vi d ual a ni mals wit hi n a d ose gr o u p fre q ue ntl y 
o verla p pe d bet wee n t he d osa ges of 5 0 a n d 1 0 0 m g/ k g/ da y a n d 3 0 0 a n d 1 0 0 0 m g/ k g/ da y d oses. 
E x p os ure te n de d t o be si milar i n mal es c o m pare d t o fe males.  
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 1 0 0 0/ 3 0 0 m g/ k g/ da y 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 was 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 3 0 0/ 1 0 0 a n d 1 0 0 0/ 3 0 0 m g/ k g/ da y gr o u ps.  
M o dest b o d y wei g ht decli nes were o bser ve d f or t he 3 0 0/ 1 0 0 a n d 1 0 0 0/ 3 0 0 m g/ k g/ da y gr o u p; 
pri maril y fr o m st u d y Wee k 0 t o 1. 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. 
T here were n o a d verse test article relate d ser u m c he mistr y effects. H y p o p h os p hate mia was n ote d 
i n males at d osa ge le vels > 3 0 0/ 1 0 0 m g/ k g/ da y a n d i n fe males at d oses > 1 0 0/ 5 0 m g/ k g/ da y. 
Ele vate d le vels of P T H i n t he 3 0 0/ 1 0 0 a n d 1 0 0 0/ 3 0 0 m g/ k g/ da y gr o u ps ma y ha ve c o ntri b ute d t o 
t he h y p o p h os p hate mia, b ut was re versi ble a n d n ot se vere e n o u g h t o be c o nsi dere d a d verse. 
A d diti o nall y, F ms i n hi biti o n ca n re d uce oste oclast  differe ntiati o n a n d f u ncti o n, res ulti n g i n 
decrease d b o ne res or pti o n a n d decrease d ser u m p h os p hate.  
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. T he earliest 
c ha n ges, n ote d i n t w o 1 0 0 0/ 3 0 0 m g/ k g/ da y gr o u p males e ut ha nize d i n e xtre mis, were se vere, 
wit h diff use s per mat oc ytes a n d s per mati d de ge nerati o n. At st u d y Wee k 4, t he atr o p hic t u b ules 
c o ntai ne d s mall n u m bers of retai ne d s per mati ds a n d de ge nerate/ m ulti n ucleate i ntra -l u minal 
s per mati ds.  
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.  F ollic ular de ge nerati o n, c haracterize d b y lar ge, dist orte d, a ntral f ollicles wit h 
e xte nsi ve a p o pt osis of gra n ul ose cells a n d a peri p heral str o mal cell pr oliferati o n, was n ote d i n 
t w o of t hree fe males a d mi nistere d 1 0 0 0/ 3 0 0 m g/ k g/ da y. T here a p peare d t o be a n i ncrease d 
n u m ber of atretic f ollicles i n o ne of t w o affecte d d o gs. 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. F oll o wi n g a 1 4- da y 
rec o ver y, t he b o ne marr o w fr o m t he 1 0 0 0/ 3 0 0 m g/ k g/ da y gr o u p was mi ni mall y h y percell ular, 
de m o nstrati n g 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. T he e xtra me d ullar y he mat o p oiesis was a n e x pecte d p h ysi ol o gic 
res p o nse t o t he decrease d R B C mass a n d re ge nerati ve a ne mia.  
 
C O N FI D E N TI A L  
3 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
I n t he fe m ur, mi ni mal t o m oderate s u b p h yseal h y per ost osis was e vi de nt i n d o gs t hat recei ve d 
3 0 0/ 1 0 0 a n d 1 0 0 0/ 3 0 0 m g/ k g/ da y. H y per ost osis was n ot e vi de nt at st u d y Wee k 6. T his lesi o n 
was c haracterize d b y a rete nti o n a n d el o n gati o n of t he pri mar y s p o n gi osa be neat h t he p h ysis a n d 
was 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 o n dar y t o 
P L X 3 3 9 7- relate d n o ns pecific stress fact ors; h o we ver, a n or ga n-s pecific test article-relate d effect 
o n t he l y m p h oi d s yste m ca n n ot be e xcl u de d. 
Mi ni mal t o mil d val v ular  e n d ocar di osis was occasi o nall y n ote d i n place b o- a n d P L X 3 3 9 7-treate d 
d o gs at st u d y Wee ks 4 a n d 6. Beca use t his fi n di n g ca n occ ur s p o nta ne o usl y a n d a clear 
d ose-res p o nse was n ot o bser ve d, it was li kel y n ot a direct P L X 3 3 9 7- relate d effect. A d diti o nall y 
mi ni mal s u be n d ot helial m y x o mat o us c ha n ge was n ote d i n f o ur d o gs treate d wit h P L X 3 3 9 7 at 
t he pri mar y necr o ps y. T his alterati o n was c haracterize d b y f ocal i ncreases i n pr ote o gl yca ns 
near  t he l u mi nal s urface of t he a orta. W hile re gi o nal variati o n i n pr ote o gl yca n c o nte nt was 
c o nsi dere d wit hi n n or mal li mits a n d t he c ha n ge c o ul d ha ve bee n part of t he n or mal s pectr u m, a 
P L X 3 3 9 7-relate d effect ca n n ot be r ule d o ut. I m p orta ntl y, n o e vi de nce of m y x o mat o us c ha n ge i n 
t he a orta was n ote d i n t he 2 8- da y rat G L P t o xic ol o g y st u d y w here hi g h- d ose u n b o u n d P L X 3 3 9 7 
e x p os ure was 1 8-f ol d t hat see n at t he hi g h- d ose i n t he  d o g st u d y. 
I n t he ki d ne ys, bas o p hilic t u b ules were n ote d i n t he 1 0 0/ 5 0 (fe males o nl y) 3 0 0/ 1 0 0 a n d 
1 0 0 0/ 3 0 0 m g/ k g/ da y gr o u ps wit h n o clear relati o ns hi p t o t he P L X 3 3 9 7 d ose a d mi nistere d. 
Bas o p hilic t u b ules are a c o m m o n s p o nta ne o us fi n di n g i n c o ntr ol gr o u p d o gs. T he i nci de nce of 
fi n di n gs was wit hi n t he ra n ge of t h ose n ote d i n t he data base of hist orical c o ntr ol gr o u ps. T h us 
t he ki d ne y fi n di n gs were c o nsi dere d of u ncertai n relati o ns hi p t o t he test article. 
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 at 1 0 0 0/ 3 0 0 a n d 3 0 0/ 1 0 0 m g/ k g/ da y, w hic h c orrelate d wit h b o ne marr o w 
h y p ocell ularit y res ulti n g i n a n o n- re ge nerati ve a ne mia at st u d y Wee k 2. 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 ol ute 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. Alterati o ns i n he mat ol o g y 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. 
Base d o n t he res ults of t his st u d y, s yste mic t o xicit y of P L X 3 3 9 7 a d mi nistere d orall y b y ga va ge 
t wice dail y f or 2 8 c o nsec uti ve da ys was o bser ve d at d osa ge le vels of 3 0 0/ 1 0 0 a n d 
1 0 0 0/ 3 0 0 m g/ k g/ da y, as e vi de nce d b y m ortalit y ( 1 0 0 0/ 3 0 0 m g/ k g/ da y), a d verse cli nical 
o bser vati o ns of e mesis, a n d 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 m p h oi d de pleti o n i n t he t h y m us. T heref ore, 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. F or t he p ur p oses of calc ulati n g a cli nical starti n g 
 
C O N FI D E N TI A L  
3 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
d ose f or o nc ol o g y Ple x xi k o n has defi ne d t he 3 0 0 m g/ k g d ose t o be t he hi g hest n o n- se verel y t o xic 
d ose ( H N S T D) i n d o gs. 
7. 4. 3  
Ge n ot o xicit y 
N o si g ns of ge n ot o xicit y were i de ntifie d i n a sta n dar d batter y of tests (i n vitr o A M E S a n d 
c hr o m os o mal a berrati o n a n d i n vi v o micr o n ucle us assa ys) c o n d ucte d wit h P L X 3 3 9 7. 
7. 4. 4  
S afet y P h ar m ac ol o g y 
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 o n 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). 
7. 5  
P L X 3 3 9 7 N o ncli nic al Re pr o d ucti ve T o xic ol o g y 
T hree G L P e m br y o -fetal de vel o p me nt re pr o d ucti ve t o xic ol o g y st u dies ha ve bee n perf or me d , 
i ncl u di n g d ose-ra n gi n g st u dies i n rats a n d ra b bits, a n d a defi niti ve rat st u d y. I n rats, 
1 0 m g/ k g/ da y was t he N O A E L f or b ot h mater nal a n d fetal t o xicit y. I n ra b bits, b ot h mater nal a n d 
fetal t o xicities were i de ntifie d at d oses ≥6 0 m g/ k g/ da y. 
7. 6  
P L X 3 3 9 7 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 or wa s 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 a d mi nistere d orall y i n or der t o esta blis h a ma xi m u m 
t olerate d d ose ( M T D). 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 
P O , i ncl u di n g 4 1 patie nts i n t he 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 d ose le vels ha ve bee n 2 0 0 m g/ da y ( n = 3), 3 0 0 m g/ da y ( n = 6), 4 0 0 m g/ da y ( n = 6), 
6 0 0 m g/ da y ( n = 6), 9 0 0 m g/ da y ( n = 7), 1 0 0 0 m g/ da y ( n = 7) a n d 1 2 0 0 m g/ da y ( n = 6). 
I n s u m mar y, t he Tma x  is a p pr o xi matel y 2 h o urs, t he mea n eli mi nati o n half-life is a p pr o xi matel y 
2 0 h o urs, a n d t he mea n acc u m ulati o n rati o c o m pare d t o Da y 1 val ues is a p pr o xi matel y 2- f ol d. 
I n ge neral, t here is  g o o d d ose pr o p orti o nalit y, wit h i ncreasi n g e x p os ure wit h i ncreasi n g d ose. 
O n  Da y 1 5, t he A U C0- 2 4 hr was 6 2 u M• hr  f or t he 2 0 0 m g/ da y d ose gr o u p, 1 2 2 u M• hr f or t he 
3 0 0 m g/ da y d ose gr o u p, 9 8 u M• hr f or t he 4 0 0 m g/ da y d ose gr o u p, 2 5 8  u M• hr f o r t he 
6 0 0 m g/ da y d ose gr o u p, 2 5 4 u M• hr f or t he 9 0 0 m g/ da y d ose g r o u p a n d 3 2 9 u M• hr f or t he 
1 2 0 0 m g/ da y d ose gr o u p ( p har mac o ki netic data f or t he 1 0 0 0 m g/ da y c o h ort is n ot c urre ntl y 
a vaila ble). D ose -li miti n g t o xicities ( D L Ts) of Gra de 3 A S T ele vati o n a n d Gra de 4 ne utr o pe nia 
 
C O N FI D E N TI A L  
3 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
occ urre d at 1 2 0 0 m g/ da y. A 1 0 0 0 m g/ da y c o h ort was o pe ne d a n d 1 o ut of 7 patie nts e x perie nce d 
a D L T ( Gra de 3 A S T), esta blis hi n g 1 0 0 0 m g/ da y as t he M T D.  
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 Q T pr ol o n gati o n). A re d ucti o n i n he m o gl o bi n ( us uall y G 1) has 
bee n o bser ve d i n se veral patie nts, b ut t his has n ot res ulte d i n treat me nt disc o nti n uati o n i n a n y 
patie nts. T here ha ve bee n a t otal of 6 p atie nts wit h D L Ts, as f oll o ws:  G 3 i ncrease d I N R 
( 3 0 0 m g/ da y) i n a patie nt o n warfari n; G 3 l y m p h o pe nia ( 6 0 0 m g/ da y), s u bse q ue ntl y e xe m pte d as 
a D L T; G 3 l y m p h o pe nia a n d G 4 h y p o natre mia ( 6 0 0 m g/ da y); G 3 A S T ( 1 0 0 0 m g/ da y); G 3 A S T 
( 1 2 0 0 m g/ da y) w hic h rec o vere d after st u d y dr u g disc o nti n uati o n; a n d G 4 ne utr o pe nia 
( 1 2 0 0 m g/ da y) w hic h rec o vere d after h ol di n g st u d y dr u g a n d ma na ge me nt wit h G-C S F. As t his 
is a p o p ulati o n of patie nts wit h metastatic s oli d t u m ors t hat ha ve bee n hea vil y pretreate d wit h 
c yt ot o xic t hera pies, a d verse e ve nts are a ntici pate d d ue t o eit her t he disease or pre vi o us 
treat me nts. T he m ost c o mm o n a d verse e ve nts ( A Es ) ha ve bee n fati g ue, decrease d a p petite a n d 
na usea. Please see t he I n vesti gat or’s Br oc h ure f or m ore details o n a d verse e ve nts a n d 
t olera bilit y. 
Res p o nse bi o mar kers are bei n g assa ye d i n or der 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 cells ( C T Cs) a n d C D 1 4 +/ C D 1 6 + pr o-i nfla m mat or y m o n oc yte cell n u m bers; I L- 6, I L-1 β, 
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 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 wit h ele vate d C T C  c o u nts at baseli ne, 3 patie nts ha ve s h o w n 
a cli nicall y rele va nt re d ucti o n d uri n g trea t me nt wit h P L X 3 3 9 7. Mar ke d 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 t he maj orit y of patie nts, wit h n o 
c ha n ge i n t he re mai n der.  
 
C O N FI D E N TI A L  
4 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
8. 0  
S T U D Y O B J E C TI V E S  
As descri be d i n Secti o n 7. 1 , t here is a str o ng r ati o nale f or c o m bi ni n g P L X 3 3 9 7 a n d paclita xel f or 
t he treat me nt of a d va nce d s oli d t u m ors, partic ularl y breast ca ncer .  
T his trial is desi g ne d as a 3- part st u d y :  P art 1  ( P hase 1 b), t o e x pl ore t he safet y of escalati n g 
d oses of P L X 3 3 9 7 wit h wee kl y paclita xel  t o esta blis h a R P 2 D; P art 2 , t o deter mi ne t he efficac y 
a n d safet y of t he P L X 3 3 9 7 6 0 0 m g BI D  a d mi nistere d i n c o m bi nati o n wit h paclita xel i n patie nts 
wit h a d va nce d, n o n- resecta ble s oli d t u m ors; a n d P art 3 , t o deter mi ne t he efficac y a n d safet y of 
P L X 3 3 9 7 a d mi nistere d at t he R P 2 D i n c o m bi nati o n wit h paclita xel i n patie nts wit h a d va nce d, 
metastatic or n o n- resecta ble, plati n u m-resista nt or -refract or y e pit helial o varia n ca ncer, pri mar y 
perit o neal ca ncer, or  fall o pia n t u be ca ncer. 
P art 1 ( P h ase 1 b)  
Pri m ar y O bject i ve:   
•  T o e x pl ore t he safet y a n d t olera bilit y of escalati n g d oses of P L X 3 3 9 7 wit h wee kl y 
paclita xel t o esta blis h a R P 2 D   
Sec o n d ar y O bjecti ves:  
•  T o e x pl ore t he efficac y a n d p har mac o ki netics ( P K) of P L X 3 3 9 7 i n c o m bi nati o n wit h 
paclita xel i n patie nts wit h a d va nce d s oli d t u m ors.  
P art 2  
Pri m ar y O bjecti ve :   
•  T o c o nfir m t he safet y a n d t olera bilit y of P L X 3 3 9 7 a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n patie nts wit h a d va nce d, n o n- resecta ble s oli d t u m ors 
Sec o n d ar y O bjecti ve:  
•  T o e x pl ore t he efficac y of P L X 3 3 9 7 i n c o m bi nati o n wit h paclita xel i n patie nts wit h 
a d va nce d s oli d t u m ors 
P arts 1 a n d 2  
E x pl or at or y O bjecti ves: 
•  T o c orrelate t he c ha n ge i n C S F-1 le vels d uri n g treat me nt wit h s pecific d ose le vels of 
P L X 3 3 9 7  
•  T o i de ntif y ne w bi o mar kers of cli nical acti vi t y 
 
C O N FI D E N TI A L  
4 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
P art 3  
Pri m ar y O bjecti ve :   
•  T o deter mi ne t he efficac y of P L X 3 3 9 7 6 0 0 m g BI D  a d mi nistere d i n c o m bi nati o n wit h 
paclita xel i n patie nts wit h a d va nce d, metastatic or n o n -resecta ble, plati n u m-resista nt 
or - refract or y e pit helial  o varia n ca ncer, pri mar y perit o n eal ca ncer, or fall o pia n t u be 
ca ncer 
Sec o n d ar y O bjecti ves :   
•  T o e val uate  t he safet y a n d t olera bilit y of P L X 3 3 9 7 i n c o m bi nati o n wit h paclita xel i n 
patie nts wit h a d va nce d, metastatic or n o n -resecta ble, plati n u m-resista nt or -refract or y 
e pit helial  o varia n ca n cer, pri mar y perit o neal ca ncer, or fall o pia n t u be ca ncer 
•  T o  e x pl ore t he effect of P L X 3 3 9 7 o n ca ncer tiss ue a n d bl o o d bi o mar kers 
 
9. 0  
D E SI G N  
9. 1  
Descri pti o n  
P art 1 : 
T his is a n o nra n d o mize d, P hase 1 b o pe n-la bel, se q ue ntial d ose escalati o n trial of P L X 3 3 9 7 pl us 
pacli ta xel. T he st u d y e m pl o ys a tra diti o nal 3 + 3 desi g n. Treat me nt wit h P L X 3 3 9 7 will c o nsist of 
c o nti n u o us oral a d mi nistrati o n  a n d e nr oll me nt will be gi n at t he 6 0 0 m g/ da y d ose le vel f or 
2 8 da ys . Paclita xel will be a d mi nistere d o nce wee kl y ( ± 4 8 h o u rs). T he pla n ne d sc he d ule f or 
P L X 3 3 9 7 d ose escalati o ns is s h o w n i n Ta ble 2 . F or d oses hi g her t ha n 1 0 0 0 m g/ da y, t he d ose 
escalati o n i ncre me nt ma y be a dj uste d base d o n t he o bser ve d t o xicit y a n d s yste mic e x p os ure at 
t he pre vi o us d ose le vel. H o we ver, t he ma xi m u m d osi n g i ncre me nt will be 5 0 %.  
 
C O N FI D E N TI A L  
4 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T a ble 2: 
Pl a n ne d D ose Esc al ati o n Sc he d ule  
D ose Le vel  
Tre at me nt  
P L X 3 3 9 7 BI D  
P aclit a xel  
Le vel -1  
4 0 0 m g/ da y  
( 2 0 0 m g P O BI D)  
Da ys 1 – 2 8  
8 0 m g/ m 2, ~  -6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Le vel 0  
( St arti n g Le vel) 
6 0 0 m g/ da y  
( 3 0 0 m g P O BI D f or 1 0 0 m g ca ps ules) 
( 4 0 0 m g P O a. m.; 2 0 0 m g P O p. m. f or 
2 0 0 m g ca ps ules)  
Da ys 1 – 2 8  
8 0 m g/ m 2, ~ 6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Le vel 1  
8 0 0 m g/ da y P O  
( 4 0 0 m g P O BI D) 
Da ys 1 – 2 8  
8 0 m g/ m 2, ~ 6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Le vel 2  
1 0 0 0 m g/ da y P O  
( 5 0 0 m g P O BI D f or 1 0 0 m g ca ps ules) 
( 6 0 0 m g P O a. m.; 4 0 0 m g P O p. m. f or 
2 0 0 m g ca ps ules)  
Da ys 1 – 2 8  
8 0 m g/ m 2, ~ 6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Le vel 3  
1 2 0 0 m g/ da y P O  
( 6 0 0 m g P O BI D) 
8 0 m g/ m 2, ~ 6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Le vel 4  
1 6 0 0 m g/ da y P O  
( 8 0 0 m g P O BI D) 
8 0 m g/ m 2, ~ 6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Le vel 5  
2 0 0 0 m g/ da y P O  
(1 0 0 0 m g P O BI D)  
8 0 m g/ m 2, ~ 6 0 mi n I V  
Da ys 1, 8, 1 5 a n d 2 2  
Eac h d ose le vel c o h ort will e nr oll 3 – 6 patie nts per d ose le vel. E nr oll me nt i n t o t he ne xt hi g her 
d ose le vel will be gi n o nl y if t he first t hree patie nts e nr olle d  i nt o t he c o h ort c o m plete t he 2 8- da y 
o bser vati o n peri o d wit h o ut t he occ urre nce of a D ose- Li m iti n g T o xicit y ( D L T) (Secti o n 1 3. 1 2 ). If 
o ne of t he t hree i nitial patie nts at a gi ve n d ose le vel e x perie nces a D L T, t he c o h ort at t his d ose 
le vel will be e x pa n de d t o i ncl u de a n a d diti o nal 3 patie nts ( 6 patie nts t otal). 
Patie nts w h o disc o nti n ue treat me nt i n C ycle 1 f or a n y reas o n ot her t ha n tr eat me nt-relate d or 
d ose- li miti n g t o xicit y ma y be re place d. Patie nts w h o e x perie nce a n aller gic reacti o n t o paclita xel 
t hat precl u des f urt her d osi n g (i.e., ≥Gra de 3) will be re m o ve d fr o m t he st u d y a n d ma y als o be 
re place d. 
I ntra patie nt d ose escalati o ns will n ot be per mitte d . If ≥2/ 6 patie nts e x perie nce a D L T, t he n d ose 
escalati o n will be st o p pe d . T he prece di n g d ose le vel will be c o nsi dere d t he M T D  a n d, t herefore, 
t he R P 2 D . 
P art 2: 
T his is a n o nra n d o mize d, o pe n-la bel st u d y of P L X 3 3 9 7 a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n a p pr o xi matel y 3 0 patie nts (i ncl u di n g all R P 2 D- treate d patie nts 
 
C O N FI D E N TI A L  
4 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
fr o m P art 1  a n d P art 2 ). T he ca n di date p o p ulati o n will be patie nts wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a ta xa ne is c o nsi dere d b y t he i n vesti gat or t o be a p pr o priate. 
P art 3: 
T his is a n o nra n d o mize d, o pe n-la bel st u d y of P L X 3 3 9 7 a d mi nistere d at t he R P 2 D ( 6 0 0 m g BI D) 
i n c o m bi nati o n wit h paclita xel i n a p pr o xi matel y 3 0  patie nts. T he ca n di date p o p ulati o n will be 
patie nts wit h a d va nce d, metastatic or n o n -resecta ble, plati n u m-resista nt or -refract or y e pit helial 
o varia n ca ncer, pri mar y perit o neal ca ncer, or fall o pia n t u be ca ncer. Patie nts m ust be resista nt or  
refract or y t o pri or plati n u m-base d sta n dar d care s yste mic re gi me ns or refract or y t o pri mar y 
treat me nt wit h a plati n u m-c o ntai ni n g re gi me n. Patie nts will be se q ue ntiall y assi g ne d t o o ne of 
t hree C ycle 1 ( 2 8 t o 3 5 da y) lea d-i n treat me nt ar ms:  1) dail y P L X 3 3 9 7 6 0 0 m g BI D ; 2) wee kl y 
paclita xel; a n d 3) dail y P L X 3 3 9 7 6 0 0 m g BI D  a n d wee kl y paclita xel. Ca ncer tiss ue f or 
bi o mar kers will be o btai ne d d uri n g Scree ni n g a n d d uri n g t he peri o d fr o m C ycle 1 Da y 2 1 t o 
C ycle 1 Da y 3 5. If t he sec o n d bi o ps y i n C ycle 1 is dela ye d be y o n d Da y 2 8, patie nts will ha ve a 
C ycle 1 Da y 2 8 visit f or paclita xel a d mi nistrati o n ( perf or me d wee kl y), d uri n g w hic h pr oce d ures 
w ill be t he sa me as t he C ycle 1 Da y 2 2 visit. F oll o wi n g t he sec o n d bi o ps y, C ycle 1 e n ds a n d all 
patie nts will start C ycle 2 treat me nt wit h dail y  P L X 3 3 9 7 6 0 0 m g BI D  a n d wee kl y paclita xel. 
C ycle 2 a n d all s u bse q ue nt c ycles will be 2 8- da y c ycles.  A bl o o d sa m ple f or plas ma P D a n d 
bi o mar kers will be o btai ne d pre- P L X 3 3 9 7 a n d paclita xel d osi n g o n C ycle 1 Da y 1, C ycle 1 
Da y  1 5, Da y 1  of all s u bse q ue nt c ycles, a n d t he E n d - of- St u d y Visit. C A- 1 2 5 sa m pli n g 
re q uire me nts incl u de 2 pre- treat me nt sa m ples:  t he first sa m ple wit hi n 3 m o nt hs of starti n g 
t hera p y a n d a sec o n d sa m ple wit hi n 1 wee k of Cycle 1 Da y 1. S u bse q ue nt sa m ples are c ollecte d 
o n t he first da y of eac h c ycle starti n g wit h C ycle 2 Da y 1 a n d at t he E n d -of - St u d y Visit. 
9. 2  
R o ute a n d Re gi me n  
P art 1: 
P L X 3 3 9 7 will be a d mi nistere d orall y, t wice dail y ( BI D) i n ca ps ule f or m usi n g a c o nti n u o us 
d osi n g re gi me n. T he BI D re gi me n is rec o m me n de d at hi g her d ose le vels (e. g., ≥6 0 0  m g/ da y) t o 
re d uce t he ca ps ule l oa d a n d mi ni mize i ntra- da y dr u g le vel fl uct uati o ns. T he starti n g d ose of 
P L X 3 3 9 7 will be 6 0 0 m g/ da y. D ose escalati o n will occ ur i n i ncre me nts of ≤5 0 %.  
A fi xe d d ose le vel of paclita xel 8 0 m g/ m 2 will be a d mi nistere d i ntra ve n o usl y, o nce wee kl y 
( ± 4 8 h o urs). Patie nts m ust recei ve at least 3 of 4 paclita xel d oses d uri n g t he D L T peri o d 
(i.e., C ycle 1)  i n or der t o be c o nsi dere d e val ua ble f or D L T, u nless d oses are misse d d ue t o a 
D L T . O ne d ose of paclita xel ma y be s ki p pe d per C ycle  f or s u bse q ue nt c ycles (i.e., C ycle 2 +) per 
I n vesti gat or discreti o n a n d/ or patie nt prefere nce. I n ge neral, t w o c o nsec uti ve d oses of paclita xel 
s h o ul d n ot be s ki p pe d. 
 
C O N FI D E N TI A L  
4 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
P art 2: 
P L X 3 3 9 7 will be a d mi nistere d orall y, BI D usi n g a c o nti n u o us d osi n g re gi me n. T he d ose of 
P L X 3 3 9 7 will be t he R P 2 D. T here will be n o d ose escalati o n. Paclita xel, 8 0 m g/ m 2 I V will be 
a d mi nistere d wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0 mi n utes i n eac h 2 8 -da y treat me nt c ycle. 
O ne paclita xel d ose ma y be o mitte d p er c ycle b y p h ysicia n discreti o n after C ycle 1. 
P art 3 :   
Patie nts will be se q ue ntiall y assi g ne d t o o ne of t hree C ycle 1 ( 2 8 t o 3 5 da y) lea d- i n treat me nt 
ar ms: 
1)  P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n 
2)  Paclita xel, 8 0 m g/ m 2 I V wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0  mi n utes 
3)  P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0 mi n utes 
F oll o wi n g t he sec o n d bi o ps y , C ycle 1 e n ds a n d all patie nts will start C ycle 2 treat me nt wit h 
P L X 3 3 9 7 6 0 0 m g BI D usi n g a c o nti n u o us d osi n g re gi me n a n d paclita xel 8 0 m g/ m 2 I V wee kl y 
( ± 4 8 h o urs) o ver a p pr o xi matel y 6 0 mi n utes. C ycle 2 a n d all s u bse q ue nt c ycles will be 2 8- da y 
c ycles. Starti n g wit h C ycle 2, o ne paclita xel d ose ma y be o mitte d per c ycle b y p h ysicia n 
discreti o n. Patie nts w h o disc o nti n ue paclita xel d ue t o paclita xel-relate d t o xicit y ma y c o nti n ue 
treat me nt wit h P L X 3 3 9 7. 
P art 1, P art 2, a n d P art 3: 
St u d y treat me nt will be pr o vi de d u ntil disease pr o gressi o n, u nacce pta ble or d ose -li miti n g 
t o xicit y, deat h, wit h dra wal of c o nse nt, st u d y ter mi nati o n b y S p o ns or, or if t he I n vesti gat or a n d 
patie nt a gree t hat it is i n t he patie nt’s best i nterests t o disc o nti n ue.  
9. 3  
P aclit a xel Pre me dic ati o ns  
A p aclita xel pre me dicati o n re gi me n is rec o m me n de d, b ut n ot re q uire d a n d s h o ul d be pr o vi de d 
per i nstit uti o nal g ui deli nes . T he pre me dicati o n re gi me n ma y  c o nsist of t he f oll o wi n g a ge nts: 
•  I ntra ve n o us de xa met has o ne ( 1 0 m g, or p h ysicia n- selecte d d ose), or ot her e q ui vale nt 
ster oi d, < 6 0 mi n utes pri or t o paclita xel. T his ma y be ta pere d wit h s u bse q ue nt d oses per 
i n vesti gat or discreti o n. 
•  I ntra ve n o us fa m oti di ne, 2 0 m g; or ot her e q ui vale nt H2-a nta g o nist (e. g., ra niti di ne 5 0 m g 
I V or ci meti di ne 3 0 0 m g I V), 3 0 – 6 0 mi n utes pri or t o paclita xel.  
•  I ntra ve n o us di p he n h y dra mi ne, 1 2. 5 – 5 0 m g  I V, 3 0– 6 0 mi n utes pri or t o paclita xel.  
Di p he n h y dra mi ne ca n be e xcl u de d wit h s u bse q ue nt d oses per i n vesti gat or discreti o n. 
 
C O N FI D E N TI A L  
4 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
9. 4  
N u m ber of P atie nts  
P art 1: 
E nr oll me nt is pla n ne d t o i ncl u de a p pr o xi matel y  3 0 patie nts fr o m 3– 4 sites. T he t otal n u m ber of 
patie nts t o be e nr ol le d will de pe n d o n t he n u m ber of c o h orts a n d w het her a c o h ort re q uires 3 or 
6 patie nts. If a patie nt d oes n ot recei ve at least 2 1 da ys of P L X 3 3 9 7 d uri n g t he first c ycle or d oes 
n ot recei ve at least 3 of 4  d oses of paclita xel i n t he first c ycle f or re as o ns ot her t h a n a D L T , t he 
patie nt ma y be re place d.  
P art 2: 
E nr oll me nt is pla n ne d t o i ncl u de a p pr o xi matel y 3 0 patie nts ( i ncl u di n g all R P 2 D-treate d patie nts 
fr o m P art 1  a n d P art 2 ) recr uite d fr o m 3 sites. 
P art 1 a n d P art 2: 
Patie nts w h o d o n ot recei ve t he re q uis ite P L X 3 3 9 7 a n d/ or paclita xel d oses i n C ycle 1 d ue t o 
a n yt hi n g ot her t ha n treat me nt-relate d a n d/ or d ose- li miti n g t o xicit y ma y be re place d. Patie nts w h o 
e x perie nce a n aller gic reacti o n t o paclita xel t hat precl u des f urt her d osi n g (i.e., ≥Gra de 3) will be 
re m o ve d fr o m t he st u d y a n d ma y als o be re place d. 
P art 3: 
E nr oll me nt is pla n ne d t o i ncl u de u p t o a p pr o xi matel y 3 0 patie nts t o accr ue 1 8 patie nts w h o ca n 
pr o vi de pretreat me nt a n d e n d- of- C ycle  1 ca ncer tiss ue a n d are e val ua ble f or deter mi ni n g 
res p o nse usi n g R E CI S T 1. 1 criteria. Patie nts u na ble t o pr o vi de t he se q ue ntial ca ncer tiss ue 
sa m ples or n o n-e val ua ble f or res p o nse usi n g R E CI S T criteria will be re place d.  
9. 5  
N u m ber of St u d y Ce nters  
T he st u d y will be perf or me d at 3 – 4 i n vesti gati o nal sites f or Parts 1 a n d 2 a n d at a p pr o xi matel y 
9 i n vesti gati o nal sites f or Part 3. 
9. 6  
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 t he P L X 3 3 9 7 + paclita xel c o m bi nati o n as 
l o n g as it is well t olerate d a n d b ot h t he I n vesti gat or a n d S p o ns or a gree t hat t he patie nt is 
cli nicall y be nefitti n g fr o m treat me nt.  Reas o ns f or st u d y disc o nti n uati o n i ncl u de, b ut are n ot 
li mite d t o, t he f oll o wi n g: 
•  U nacce pta ble or D ose -Li miti n g T o xicit y  
•  Disease Pr o gressi o n  
 
C O N FI D E N TI A L  
4 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
•  Deat h  
•  V ol u ntar y wit h dra wal of c o nse nt 
•  N o n -c o m plia nce t o st u d y pr oce d ures a n d re q uire me nts 
•  I n vesti gat or decisi o n 
•  S p o ns or decisi o n t o ter mi nate t he st u d y 
9. 7  
D ur ati o n of St u d y  
T he d urati o n of t he st u d y will de pe n d o n t he recr uit me nt rate a n d t he d urati o n of treat me nt f or 
t h ose patie nts e nr olle d.  
1 0. 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 t hat are n ot part of sta n dar d- of-care, 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. Sta n dar d- of-care 
pr oce d ures perf or me d pri or t o i nf o r me d c o nse nt ma y be c ollecte d as part of scree ni n g data if t he 
pr oce d ures occ urre d wit hi n t he pr ot oc ol- s pecifie d ti mefra me. 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 0. 1  
I ncl usi o n Criteri a 
1.  Patie nts wit h:  
a. P art 1 :  a n a d va nce d, i nc ura ble s oli d t u m or 
b.  P art 2 :  a n a d va nce d, i nc ura ble s oli d t u m or f or w h o m a ta xa ne w o ul d be 
c o nsi dere d a reas o na ble c he m ot hera p y o pti o n  
c. P art 3 :  a d va nce d , metastatic  or n o n-resecta ble epit helial o varia n ca ncer, pri mar y 
perit o neal ca ncer o r fall o pia n t u be ca ncer wit h: 
i. plati n u m- resista nt ca ncer, defi ne d as disease t hat res p o n de d t o a plati n u m-
c o ntai ni n g c he m ot hera p y re gi me n, b ut de m o nstrate d rec urre nce wi t hi n si x 
m o nt hs f oll o wi n g t he c o m pleti o n of t h at plati n u m -c o ntai ni n g re gi me n, 
O R  
 
C O N FI D E N TI A L  
4 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
ii. plati n u m-r efract or y ca ncer, defi ne d as disease faile d t o ac hie ve at least a 
partial res p o nse t o a plati n u m-c o ntai ni n g re gi me n  (i.e., sta ble disease or 
act ual disease pr o gr essi o n) , 
A N D  
iii. ha ve n ot bee n treate d wit h a ta xa ne wit hi n 6 m o nt hs of C 1 D 1 , 
A N D  
i v. ha ve n ot bee n treate d wit h wee kl y paclita xel after first -li ne treat me nt i n 
w hic h wee kl y paclita xel pl us a plati n u m is per mitte d  
2.  P art 3 :  Patie nts m ust ha ve tar get ( ≥2  c m dia meter) or n o n -tar get lesi o n ca ncer t hat is 
accessi ble f or 2 - 3 c ore bi o psies d uri n g Scree ni n g after C T i ma gi n g a n d all ot her 
scree ni n g tests a n d pr oce d ures ha ve bee n c o m plete d a n d d uri n g t he peri o d fr o m C ycle 1 
Da y 2 1 t o C ycle 1 Da y 3 5 
3.  Patie nts wit h sta ble brai n metastases are eli gi ble f or t his trial. H o we ver, patie nts m ust n ot 
ha ve re q uire d ster oi d treat me nt f or t heir brai n metastases wit hi n 3 0 da ys of Scree ni n g.  
4.  B o ne- directe d t hera p y (e. g., bis p h os p h o nates or de n os u ma b) is per mitte d. H o we ver, 
patie nts s h o ul d n ot ha ve starte d b o ne- directe d t hera p y wit hi n 2 wee ks of C 1 D 1, a n d ne w 
b o ne- directe d t hera p y s h o ul d n ot be i nitiate d d uri n g t he first 4 wee ks of st u d y (i.e., 
C ycle  1) 
5.  Was h o ut fr o m a n y pri or i n vesti gati o nal t hera p y of at least fi ve ti mes t he T1/ 2 pri or t o 
C 1 D 1  
6.  Was h o ut fr o m a n y pri or bi ol o gic or tar gete d t hera p y at le ast 4 wee ks or fi ve ti mes t he 
T 1/ 2 ( w hic he ver is s h orter) pri or t o C 1 D 1 
7.  Was h o ut fr o m pri or c he m ot hera p y of at least 2 wee ks or 1 eli mi nati o n half- life, 
w hic he ver is l o n ger , pri or t o C 1 D 1 
8.  Was h o ut fr o m pri or h or m o nal t hera p y of at least 2 wee ks pri or t o C 1 D 1 
9.  Was h o ut of at least 2 wee ks fr o m t he m ost rece nt ra diati o n treat me nt  pri or t o C 1 D 1 
1 0.  Res ol uti o n of all pri or treat me nt -relate d t o xicities t o Gra de 1 or less, e xce pt f or Gra de 2 
fati g ue or al o pecia pri or t o C 1 D 1  
1 1.  A ge ei g htee n years or ol der  
 
C O N FI D E N TI A L  
4 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1 2.  E C O G perf or ma nce stat us 0 – 2, i ncl usi ve 
1 3.  A ntici pate d life e x pecta nc y of at least 1 2 wee ks  
1 4.  A de q uate b o ne marr o w reser ve :  A N C ≥1 5 0 0/ m m 3, platelets ≥1 0 0, 0 0 0/ m m 3  
1 5.  A de q uate re nal f u ncti o n :  ser u m creati ni ne < 1. 5 x U L N or calc ulate d Cr Cl  > 6 0 m L/ mi n 
usi n g C oc kcr oft- Ga ult f or m ula  
G F R  = [( 1 4 0-a ge)•( wei g ht i n k g)•( 0. 8 5 if fe male)]/( 7 2•Cr)  
1 6.  A de q uate he patic f u ncti o n :  A S T a n d A L T < 2. 5 x U L N , T otal a n d Direct Bilir u bi n 
< 1. 5 x U L N. H o we ver, i n t he prese nce of li ver metastases, A S T a n d A L T m ust be  
< 5 x  U L N  
1 7.  Car dia c ejecti o n fracti o n ≥5 0 %, a n d Q Tc F < 4 5 0 ms ( males) or < 4 7 0 ms (fe males) o n 
E C G at Baseli ne  
Fri dericia’s F or m ula :  Q Tc F = ( Q T)/ R R 0 . 3 3 
1 8.  A ble t o s wall o w ca ps ules a n d mai ntai n a de q uate h y drati o n  
1 9.  A bilit y t o gi ve writte n i nf or me d c o nse nt a n d willi n g t o c o m pl y wit h t he re q uire me nts of 
t he pr ot oc ol; a n d f or P art 3 , t o gi ve writte n i nf or me d c o nse nt f or 2 ca ncer bi o ps y 
pr oce d ures 
2 0.  W o me n of c hi l d- beari n g p ote ntial m ust a gree t o use a n effecti ve met h o d of birt h c o ntr ol 
d uri n g treat me nt a n d f or t hree m o nt hs after recei vi n g t heir last d ose of st u d y dr u g. Fertile 
me n 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 at least 3 m o nt hs after last d ose (see Attac h me nt 4 ). 
1 0. 2  
E xcl usi o n Criteri a  
1.  Prese nce of a n acti ve sec o n dar y mali g na nc y 
•  Patie nts wit h a n o n -mela n o mat o us, i n sit u mali g na nc y or disease t hat is 
c o m pletel y resecta ble wit h s ur ger y ma y be c o nsi dere d after disc ussi o n wit h t he 
Me dical M o nit or  
•  Patie nts wit h a c o m pletel y treate d pri or mali g na nc y wit h n o e vi de nce of disease 
f or ≥3 years are eli gi ble 
2.  Refract or y na usea a n d v o miti n g, mala bs or pti o n, e xter nal biliar y s h u nt or si g nifica nt s mall 
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 P L X 3 3 9 7 
 
C O N FI D E N TI A L  
4 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
3.  O n g oi n g treat me nt wit h a n y ot her i n vesti gati o nal t hera p y  
4.  Pri or a na p h ylactic or se vere h y perse nsiti vit y reacti o n t o paclita xel  or Cre m o p h or-
c o ntai ni n g a ge nt 
5.  Persiste nt gra de 2 fati g ue at Baseli ne  
6.  Se vere, c o nc urre nt ill ness i ncl u di n g c o n gesti ve heart fail ure, si g nifica nt car diac disease 
a n d u nc o ntr olle d h y perte nsi o n, t hat w o ul d li kel y pre ve nt t he patie nt fr o m bei n g a ble t o 
c o m pl y wit h t he st u d y pr ot oc ol 
7.  Acti ve u ntreate d i nfecti o n  
8.  K n o w n c hr o nic acti ve He patitis B or C, or HI V i nfecti o n  
9.  T he prese nce of a me dical or ps yc hiatric c o n diti o n t hat, i n t he o pi ni o n of t he Pri nci pal 
I n vesti gat or, ma kes t he patie nt i na p pr o priate f or i ncl usi o n i n t his st u d y 
 
1 0. 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 
test article are defi ne d as scree n fail ures. F or all scree n fail ures, t he i n vesti gat or will e nter 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 i nt o a scree n fail ure l o g . T his 
data will als o be retai ne d i n t he i n vesti gat or’s s t u d y files a n d ca n be pri nte d b y t he site i n l o g 
f or mat at t he e n d of t he st u d y.  
I n Part 3, patie nt data will be c ollecte d i n t he electr o nic data ca pt ure ( E D C) s yste m fr o m t he date 
t he bi o ps y is perf or me d d uri n g scree ni n g. Data will n ot be c ollecte d i n t he E D C f or patie nts w h o 
are scree n fail ures a n d ha ve n ot ha d a bi o ps y assess me nt.  
1 1. 0  
P RI O R T R E A T M E N T  
Reas o na ble eff orts will be ma de t o deter mi ne all rele va nt treat me nt recei ve d b y t he patie nt 
wit hi n 2 8 da ys bef ore a d mi nistrati o n of t he test article.  All pre vi o us ca ncer treat me nts s h o ul d be 
rec or de d. Rele va nt i nf or mati o n m ust be rec or de d o n t he patie nt's electr o nic case re p ort f or m 
(e C R F). T his s h o ul d i ncl u de t he na me of t he pr oce d ure or dr u g a n d ot her i nf or mati o n re q uire d o n 
t he eC R F.  
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 
 
C O N FI D E N TI A L  
5 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 start a n d st o p dates of a d mi nistrati o n. 
Pr o p h yla xis or me dical ma na ge me nt f or na usea a n d v o miti n g wit h a ntie metics is e nc o ura ge d, 
partic ularl y i n patie nts wit h a hist or y of na usea or v o miti n g wit h pri or ta xa ne t hera p y.  
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 d r 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. N ota bl y, t w o 
mi n or meta b olites of paclita xel , 3'-p -h y dr o x y paclita xel a n d 6 α, 3' -p di h y dr o x y paclita xel, are 
meta b olize d b y C Y P 3 A 4. 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 (i.e., first pass) 
meta b olis m of P L X 3 3 9 7, wit h p ossi bl y C Y P 1 A 2 pla 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 o ul 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 3  f or a list of c o m m o n 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 cli nicall y necessar y  a n d wit h o ut effecti ve alter nati ves . T hese i ncl u de 
a ntic o n v ulsa nts, m yci n a nti micr o bials, a n d a ntiretr o virals. S o me c o m m o n  e xa m ples 
i ncl u de i n hi bit ors s uc h as er yt hr o m yci n, fl u o xeti ne, ge mfi br ozil, a n d i n d ucers s uc h as  rifa m pici n, 
car ba maze pi ne, p he n yt oi n, efa vire nz, a n d ne vira pi ne. 
Fil grasti m gr o wt h fact or s u p p ort is e nc o ura ge d f or A N C < 1 5 0 0/ m m 3 a n d ma y be use d at t he 
discreti o n of t he Pri nci pal I n vesti gat or i n c o ns ultati o n wit h t he Me dical M o nit or. Gr o wt h fact ors 
ma y be a d mi nistere d t hr o u g h o ut t he st u d y, i ncl u di n g d uri n g C ycle 1, i n or der t o mai ntai n 
a de q uate bl oo d c o u nts. F or patie nts w h ose A N C is bet wee n 1 5 0 0 – 2 0 0 0 cells/ m m 3, Fil grasti m 
ma y be a d mi nistere d fr o m da ys 2 – 5 (t otal of 4 da ys) after t he m ost rece nt paclita xel i nf usi o n. 
Fil grasti m is n ot per mitte d wit hi n 2 4 h o urs pri or t o or f oll o wi n g a n y paclita xel i nf usi o n. 
Pe gfil grasti m ( Ne ulasta) is n ot per mitte d i n t his st u d y.  
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  
T he f oll o wi n g Scree ni n g assess me nts m ust be perf or me d wit hi n 2 8 d a ys  bef ore st u d y dr u g 
a d mi nistrati o n  o n C 1 D 1: 
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 n t 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.  De m o gra p hic i nf or mati o n i ncl u di n g date of birt h, se x a n d et h nic ori gi n 
 
C O N FI D E N TI A L  
5 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
3.  Me dical hist or y i ncl u di n g si g nifica nt me dical pr oce d ures 
4.  Pri or treat me nt f or  ca ncer 
5.  Hei g ht (c m) a n d wei g ht ( k g) 
6.  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 [° F]) 
7.  Sta n dar d 1 2- lea d E C G, i ncl u di n g Q Tc F 
8.  Tra ns -t h oracic ec h ocar di o gra m or M U G A 
9.  I ma gi n g f or baseli ne t u m or stat us 
1 0.  P art 3 o nl y :  Ca ncer tiss ue [ 2- 3 c ore bi o psies of tar get ( ≥2 c m dia meter ] or n o n-tar get 
lesi o ns) f or bi o mar kers after C T i ma gi n g  a n d all ot her scree ni n g tests a n d pr oce d ures 
ha ve bee n c o m plete d  
1 1.  P art 3 o nl y :  C A - 1 2 5 sa m pli n g wit hi n 3 m o nt hs of starti n g t hera p y  
1 2.  Rec or di n g of c o nc o mita nt me dicati o ns 
1 3.  E C O G Perf or ma nce stat us assess me nt  
1 4.  P art 3 o nl y :  A E a n d s eri o us a d verse e ve nt  ( S A E) re p orti n g will c o m me nce w he n t he 2- 3 
c ore bi o psies are o btai ne d d uri n g Scree ni n g . 
T he f oll o wi n g Scree ni n g assess me nts m ust be perf or me d wit hi n 1 4 d a ys  bef ore st u d y dr u g 
a d mi nistrati o n o n C 1 D 1: 
•  F ull p h ysical e xa mi nati o n 
•  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d c he mistr y) 
•  F or w o me n of c hil d- beari n g p ote ntial, uri ne pre g na nc y test 
T he f oll o wi n g Scree ni n g assess me nts m ust be perf or me d wit hi n 7 d a ys  bef ore st u d y dr u g 
a d mi nistrati o n o n C ycle 1 Da y 1: 
•  P art 3 o nl y :  C A - 1 2 5 sa m pli n g  
A patie nt w h o meets all of t he i ncl usi o n criteria will c o nti n ue o n i n t he st u d y. Scree n fail ures will 
be mar ke d i n t he E D C s yste m . 
 
C O N FI D E N TI A L  
5 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1 3. 2  
Pre -Tre at me nt ( B aseli ne) :  C ycle 1 D a y 1 
Patie nts will ret ur n t o t he cli nic o n C 1 D 1 a n d w ill u n der g o t he f oll o wi n g pr oce d ures pri or t o 
d osi n g: 
1.  Rec or di n g of c o nc o mita nt me dicati o ns 
2.  Vital si g ns  a n d wei g ht 
3.  S y m pt o m -directe d p h ysical e xa m  
4.  E C O G Perf or ma nce stat us  
5.  Cli nical la b orat or y e val uati o n ( he mat ol o g y a n d c he mistr y) 
6.  Pre - P L X 3 3 9 7 d ose bl o o d sa m ple c ollecti o n f or plas ma P K ( P art 1 a n d P art 3 o nl y)  a n d 
P D bi o mar ker a nal yses 
7.  Pre - P L X 3 3 9 7 d ose w h ole bl o o d sa m ple c ollecti o n f or C D 1 4/ C D 1 6 m o n oc yte a nal ysis. 
Per i nstr ucti o ns i n t he La b orat or y Ma n ual, t his sa m ple is ti me se nsiti ve a n d m ust be 
s hi p pe d o ut t he sa me da y as t he c ollecti o n , refri gerate d b ut n ot fr oze n.  
8.  P art 3 o nl y :  Pre - P L X 3 3 9 7 d ose w h ole bl o o d sa m ple c ollecti o n f or m yel oi d- deri ve d 
s u p press or cell ( M D S C)  
9.  P art 1 , P art 2 , a n d P art 3 ( P L X 3 3 9 7 o nl y a n d P L X 3 3 9 7 + p aclit a x el ar ms):  
P L X 3 3 9 7 a d mi nistrati o n. Patie nts s h o ul d fast f or at least 1 h o ur pri or t o a n d after 
P L X 3 3 9 7 a d mi nistrati o n ( see S ecti o n 1 4. 1. 1). 
1 0.  P art 1, P art 2, a n d  P art 3 ( p aclit a xel o nl y a n d P L X 3 3 9 7 + p aclit a x el ar ms):  
Paclita xel pre me dic ati o n a d mi nistrati o n (rec o m me n de d, b ut n ot re q uire d . I n vesti gat or 
s h o ul d f oll o w sta n dar d i nstit uti o nal p olicies) 
1 1.  P art 1, P art 2, a n d P art 3 ( p aclit a xel o nl y a n d P L X 3 3 9 7 + p aclit a x el ar ms) :  
Paclita xel a d mi nistrati o n  
1 3. 3  
P ost -Tre at me nt :  C ycle 1 D a y 1 
F oll o wi n g recei pt of all st u d y dr u gs, patie nts will be e val uate d f or a d verse e ve nts a n d P L X 3 3 9 7 
c o m plia nce. 
1 3. 4  
C ycle 1 D a y 8 ( ± 4 8 h o u rs) 
At t he C 1 D 8 visit, 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: 
 
C O N FI D E N TI A L  
5 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1.  A E m o nit ori n g  
2.  Rec or di n g of c o nc o mita nt me dica ti o ns 
3.  P L X 3 3 9 7 c o m plia nce e val uati o n 
4.  Cli nical la b orat or y val ues ( he mat ol o g y a n d c he mistr y) 
5.  P L X 3 3 9 7 a d mi nistrati o n ( ma y be ta ke n pri or t o t he cli nic visit; patie nts m ust fast f or at 
least 1 ho u r pri or t o a n d after a d mi nistrati o n per i nstr ucti o ns i n Secti o n 1 4. 1. 1 ) 
6.  Paclita xel pre me dic ati o n a d mi nistrati o n ( rec o m me n de d, b ut n ot re q uire d . I n vesti gat or 
s h o ul d f oll o w sta n dar d i nstit uti o nal p olicies) 
7.  Paclita xel a d mi ni strati o n 
1 3. 5  
Pre -tre at me nt C ycle 1 D a y 1 5 ( ± 4 8 h o u rs) 
At t he C 1 D 1 5 visit, 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.  Pre - P L X 3 3 9 7 d ose bl o o d sa m ple f or P K ( P art 1 a n d P art 3 o nl y)  
2.  A E  m o nit ori n g 
3.  Rec or di n g of c o nc o mita nt me dicati o ns 
4.  P L X 3 3 9 7 c o m plia nce e val uati o n 
5.  Cli nical la b orat or y val ues ( he mat ol o g y a n d c he mistr y) 
6.  1 2- lea d sta n dar d E C G, i ncl u di n g Q Tc F 
7.  Pre - P L X 3 3 9 7 d ose w h ole bl o o d sa m ple c ollecti o n f or C D 1 4/ C D 1 6 m o n oc yte a nal ysis. 
Per i nstr ucti o ns i n t he La b orat or y Ma n ual, t his sa m ple is ti me se nsiti ve a n d m ust be 
s hi p pe d o ut t he sa me da y as t he c ollecti o n, refri gerate d b ut n ot fr oze n. 
8.  P art 3 o nl y :  Pre - P L X 3 3 9 7 d ose w h ole bl o o d sa m ple c ollecti o n f or M D S C  
9.  P art 3 o nl y :  Pre - P L X 3 3 9 7 d ose bl o o d f or plas ma P K a n d bi o mar kers 
1 0.  P L X 3 3 9 7 a d mi nistrati o n  ( m ust be a d mi nistere d i n t he cli nic; patie nts m ust fast f or at 
least 1 h o ur pri or t o a n d after a d mi nistrati o n per i nstr ucti o ns i n Secti o n 1 4. 1. 1 ). 
1 1.  Paclita xel pre me dic ati o n a d mi nistrati o n ( rec o m me n de d, b ut n ot re q uire d . I n vesti gat or 
s h o ul d f oll o w sta n dar d i nstit uti o nal p olicies). 
 
C O N FI D E N TI A L  
5 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1 2.  Paclita xel a d mi nistrati o n . 
1 3. 6  
P ost -tre at me nt C ycle 1 D a y 1 5 ( ± 4 8 h o urs) 
F oll o wi n g recei pt of all st u d y dr u gs, patie nts will u n der g o t he f oll o wi n g: 
1.  P ost - d ose bl o o d sa m ple f or P K ( P art 1 o nl y) at 2 a n d 4 h o urs f oll o wi n g P L X 3 3 9 7 
a d mi nistrati o n  
2.  P ost- d ose bl o o d sa m ple f or P K ( P art 3 o nl y ) at 2, 4, a n d 6 h o urs f oll o wi n g P L X 3 3 9 7 
a d mi nistrati o n  
3.  A E m o nit ori n g  
1 3. 7  
C ycle 1 D a y 2 2 ( ± 4 8 h o u rs) 
At t he C 1 D 2 2  visit, 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.  A E m o nit ori n g  
2.  Rec or di n g o f c o nc o mita nt me dicati o ns 
3.  P L X 3 3 9 7 c o m plia nce e val uati o n 
4.  Cli nical la b orat or y val ues ( he mat ol o g y a n d c he mistr y) 
5.  P L X 3 3 9 7 a d mi nistrati o n ( ma y be ta ke n pri or t o t he cli nic visit; patie nts m ust fast f or at 
least 1 h o ur pri or t o a n d after a d mi nistrati o n per i nstr ucti o ns i n Secti o n 1 4. 1. 1 ) 
6.  Paclita xel pre me dicati o n a d mi nistrati o n (rec o m me n de d , b ut n ot re q uire d . I n vesti gat or 
s h o ul d f oll o w sta n dar d i nstit uti o nal p olicies) 
7.  Paclita xel a d mi nistrati o n . 
1 3. 8  
P art 3 O nl y:  C ycle 1 D a y 2 8 ± 7 d a ys ( C ycle 1 D a y 2 1 t o C ycle 1 D a y 3 5) 
•  Ca ncer tiss ue [ 2- 3 c ore bi o psies of tar get ( ≥2 c m dia meter)  or n o n- tar get lesi o ns] f or 
bi o mar kers 
1 3. 9  
All S u bse q ue nt C ycles, D a y 1 ( ± 4 8 h o u rs) 
At all s u bse q ue nt D 1 visits, 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.  A E m o nit ori n g  
 
C O N FI D E N TI A L  
5 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
2.  Rec or di n g of c o nc o mita nt me dicati o ns 
3.  P L X 3 3 9 7 c o m plia nce 
4.  Vital si g ns a n d wei g ht 
5.  S y m pt o m- directe d p h ysical e xa m  
6.  Cli nical la b orat or y val ues ( h e mat ol o g y a n d c he mistr y) 
7.  Bl o o d sa m pl e f or plas ma P K  ( P art 1 a n d P art 3 o nl y)  a n d P D b i o mar ker a nal yses ta ken 
pri or t o P L X 3 3 9 7 d ose 
8.  P art 3 o nl y :  C A - 1 2 5 sa m pli n g  
9.  E C O G perf or ma nce stat us  
1 0.  P L X 3 3 9 7 a d mi nistrati o n( ma y be ta ke n pri or t o t he cli nic visit; patie nts m ust fast f or at 
least 1 ho u r pri or t o a n d after a d mi nistrati o n per i nstr ucti o ns i n Secti o n 1 4. 1. 1 ) 
1 1.  Paclita xel pre me dicati o n a d mi nistrati o n ( rec o m me n de d, b ut n ot re q uire d. I n vesti gat or 
s h o ul d f oll o w sta n dar d i nstit uti o nal p olicies) 
1 2.  Paclita xel a d mi nistrati o n  ( ma y be s ki p pe d base d o n 3- wee k a d mi nistrati o n sc he d ule) 
1 3. 1 0  All S u bse q ue nt C ycles,  D a y s 8, 1 5 a n d 2 2  ( ± 4 8 h o urs) 
At all s u bse q ue nt Da y 8, 1 5a n d 2 2 visits, 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.  A E m o nit ori n g  
2.  Rec or di n g of c o nc o mita nt me dicati o ns 
3.  P L X 3 3 9 7 c o m plia nce 
4.  Cli nical la b orat or y val ues ( he mat ol o g y o nl y re q uire d pri or t o paclita xel a d mi nistrati o n ) 
5.  C ycle 2 o nl y :  ser u m c he mistr y o nl y re q uire d pri or t o paclita xel a d mi nistrati o n f or 
P art 3 – all ar ms  
6.  C ycle 3 o nl y :  ser u m c he mistr y o nl y re q uire d f or Pa rt 3  Le a d -i n P aclit a xel Al o ne Ar m  
7.  P L X 3 3 9 7 a d mi nistrati o n ( ma y be ta ke n pri or t o t he cli nic visit; patie nts m ust fast f or at 
least 1 ho u r pri or t o a n d after a d mi nistrati o n per i nstr ucti o ns i n Secti o n 1 4. 1. 1 ) 
 
C O N FI D E N TI A L  
5 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
8.  Paclita xel pre me dicati o n a d mi nistrati o n ( rec o m me n de d, b ut n ot re q uire d. I n vesti gat or 
s h o ul d f oll o w sta n dar d i nstit uti o nal p olicies) 
9.  Paclita xel a d mi nistrati o n  ( ma y be s ki p pe d base d o n 3- wee k a d mi nistrati o n sc he d ule) 
1 3. 1 1  Ot her Sc he d ules  
P L X 3 3 9 7 will be a d mi nistere d t wice dail y ( BI D) i n eac h 2 8- da y c ycle. I ma gi n g f or t u m or 
assess me nts will be perf or me d eit her e ver y 8 wee ks or as cli nicall y i n dicate d.  
1 3. 1 2  E n d of St u d y  
All patie nts  disc o nti n ui n g st u d y treat me nt f or a n y reas o n s h o ul d ret ur n t o t he cli nic wit hi n 
2 8 da ys f oll o wi n g t heir last d ose of t he st u d y dr u g c o m bi nati o n a n d pri or t o recei vi n g ne w 
a ntit u m or t hera p y f or t he f oll o wi n g pr oce d ures: 
1.  A E m o nit ori n g  
2.  Rec or di n g of c o nc o mita nt me dicati o ns 
3.  P L X 3 3 9 7 c o m plia nce 
4.  Vital si g ns a n d wei g ht 
5.  S y m pt o m -directe d  p h ysical e xa mi nati o n 
6.  E C O G perf or ma nce stat us  
7.  Cli nical la b orat or y val ues ( he mat ol o g y, c he mistr y, a n d uri ne  pre g na nc y test f or w o me n 
of c hil d- beari n g p ote ntial) 
8.  P art 3 o nl y :  Bl o o d f or plas ma P K a n d bi o mar kers 
9.  P art 3 o nl y :  C A - 1 2 5 sa m pli n g  
1 0.  1 2- lea d E C G, i ncl u di n g Q Tc F 
1 1.  E n d of St u d y i ma gi n g f or t u m or assess me nts s h o ul d be o btai ne d f or patie nts w h o g o off 
st u d y f or reas o ns ot her t ha n ra di o gra p hic disease pr o gressi o n 
1 3. 1 3  D ose -Li miti n g T o xicities  ( P art 1 o nl y) 
A D ose Li miti n g T o xicit y ( D L T) is a n y treat me nt-relate d a d verse e ve nt t hat meets t he criteria 
bel o w t hat occ urs wit hi n t he first 2 8 d a ys of c o m bi n ati o n t her a p y . Patie nts m ust recei ve at 
 
C O N FI D E N TI A L  
5 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
least 2 1 da ys of P L X 3 3 9 7 a n d at least 3 of 4 d oses of paclita xel d uri n g t he first c ycle i n or der t o 
be c o nsi dere d e val ua ble f or D L T ( u nless t he misse d d oses are d ue t o a D L T).  
He mat ol o gic D L Ts 
•  Gr a de 4 ne utr o pe nia lasti n g f or ≥7 da ys i n d urati o n 
•  Gra de 4  t hr o m b oc yt o pe nia ( platelets ≤2 5. 0/ µ L)  
•  Gra de 3 t hr o m b oc yt o pe nia wit h blee di n g 
Ot her  D L Ts  
A n y C T C A E v 4 Gra de ≥3 ot her t o xicit y, u nless t he e ve nt is cle arl y u nrel ate d  t o treat me nt wit h 
P L X 3 3 9 7 i n c o m bi nati o n wit h wee kl y sta n dar d fi xe d d osi n g of paclita xel E X C E P T t he 
f oll o wi n g: 
•  Aller gic reacti o n t o paclita xel  
•  Gra de ≥3 na usea, v o miti n g, or di arr hea t hat res ol ves t o Gra de ≤2 wit hi n 4 8 h o urs, wit h or 
wit h o ut me d ical i nter ve nti o n or pr o p h yla xis 
•  Gra de 3 fati g ue t hat res ol ves t o Gra de ≤2 wit hi n 1 4 da ys  
•  Gra de ≥3 h y per gl yce mia 
•  Tra nsie nt ( < 1 4 da ys) i ncrease i n L F Ts ( of ≤o ne Gra de i n se verit y) c o m pare d t o baseli ne 
le vels i n patie nts wit h baseli ne li ver metastases. 
•  Gra de  3 peri p heral ne ur o pat h y i n patie nts wit h baseli ne ≥Gra de 1 peri p heral ne ur o pat h y 
or a hist or y of c he m ot hera p y- ass ociate d peri p heral ne ur o pat h y  
•  Gra de 3 m yal gia or art hral gia i n patie nts wit h baseli ne ≥Gra de 1 m yal gia or art hral gia  
•  Gra de 3 ras h f or w hic h s y m pt o ms are easil y ma na ge d wit h s u p p orti ve care a n d n o 
e vi de nce of s u peri nfecti o n or li mitati o n of self- care A D Ls.  
1 3. 1 4  D ose M o dific ati o ns 
1 3. 1 4. 1  
P L X 3 3 9 7 D ose M o dific ati o ns  
D uri n g P art 1  P L X 3 3 9 7 d ose re d ucti o ns a n d i nterr u pti o ns will be per mitte d d uri n g t he first 
2 8 da ys of C ycle 1 o nl y if a p atie nt e x perie nces a D L T.  P L X 3 3 9 7 i nterr u pti o ns d uri n g C ycle 1 
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 C ycle 1, P L X 3 3 9 7 treat me nt c o nti n uati o n at a l o wer d ose ma y  be 
 
C O N FI D E N TI A L  
5 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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. 
After C 1 D 2 8 , d ose re d ucti o ns or i nterr u pti o ns f or a d verse e ve nts ma y ta ke place at a n y ti me. 
D uri n g P art 2  a n d P art 3 :  P L X 3 3 9 7 d ose re d ucti o n s or i nterr u pti o ns f or a d verse e ve nts ma y 
ta ke place at a n y ti me.  
F or P art 1 , P art 2 , a n d P art 3,  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 are n ote d i n Ta ble 3 . Please c o ntact t he 
Me dical M o nit or pri or t o ma ki n g a n y d ose m o dificati o ns. 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.  T hese para meters are o nl y s u g gesti o ns  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 ph 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.  
T a ble 3: 
D ose M o dific ati o ns G ui deli nes f or P L X 3 3 9 7  
T o xicit y Gr a de   
( C T C A E v 4) 
P L X 3 3 9 7 D ose C h a n ges D uri n g 
C urre nt Tre at me nt Peri o d  
D ose A dj ust me nts for  
Res u m pti o n of Tre at me nt a 
He m at ol o gic T o xicit y  
Gr a de 3 or 4 ne utr o pe ni a  
1 st A p peara nce  
I nterr u pt u ntil A N C rec o vers t o ≥1 × 
1 0 9/ L; 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 ×  1 0 9/ L i n ≤7 
da ys, res u me at sa me d ose.  
If A N C d oes n ot rec o ver t o ≥1 ×  1 0 9/ L 
after 7 da ys, re d uce d ose b y 2 0 0 m g per 
da y.  
2 n d A p peara nce  
I nterr u pt u ntil A N C rec o vers t o ≥1 × 
1 0 9/ L; 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 × 1 09/ L i n ≤7 
da ys, re d uce d ose b y 2 0 0 m g.  
If A N C d oes n ot rec o ver t o ≥1 ×  1 0 9/L 
after 7 da ys, re d uce d ose b y a n a d diti o nal 
2 0 0 m g per da y.  
3 r d A p peara nce  
I nterr u pt u ntil A N C rec o vers t o ≥1 × 
1 0 9/ L; 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 × 1 0 9/ L i n ≤7 
da ys, re d uce d ose b y 2 0 0 m g.  
If A N C d oes n ot rec o ver t o ≥1 ×  1 0 9/L 
after 7 da ys, disc o nti n ue per ma ne ntl y.  
4 t h A p peara nce  
Disc o nti n ue per ma ne ntl y  
N /A  
Gr a de 3 or Gr a de 4 fe brile ne utr o pe ni a  
1 st A p peara nce  
I nterr u pt u ntil A N C a n d fe ver 
rec o very ; pr o vi de gr o wt h fact or 
s u p p ort 
O nce res ol ve d t o A N C ≥1 0 0 0  ×  1 0 6/ L 
a n d T ≤3 8 °C, re d uce d ose b y 2 0 0 m g  per 
da 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  
O nce res ol ve d t o A N C ≥1 0 0 0  ×  1 0 6/ L 
a n d T ≤3 8 °C, re d uce d ose b y a n 
a d diti o nal 2 0 0 m g  per da y .  
3 r d A p peara nce  
Disc o nti n ue per ma ne ntl y  
N/ A  
 
C O N FI D E N TI A L  
5 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T o xicit y Gr a de   
( C T C A E v 4) 
P L X 3 3 9 7 D ose C h a n ges D uri n g 
C urre nt Tre at me nt Peri o d  
D ose A dj ust me nts for  
Res u m pti o n of Tre at me nt a 
Gr a de 4 t hr o m b oc yt o pe ni a  
1 st A p peara nce  
I nterr u pt u ntil P L T ≥7 5 x 1 0 9/ L 
Rei ntr o d uce at sa me d ose  
2 n d A p peara nce  
I nterr u pt u ntil P L T ≥7 5 x 1 0 9/ L 
If P L T d oes n ot rec o ver t o ≥7 5  ×  1 0 9/ L 
after 7 da ys, re d uce d ose b y 2 0 0 m g.  
3 r d A p peara nce  
I nterr u pt u ntil P L T ≥7 5 x 1 0 9/ L 
Re d uce d ose b y a n a d diti o nal 2 0 0 m g  per 
da y  
4 t h A p peara nce  
Disc o nti n ue per ma ne ntl y  
N/ A  
Ot her Rel ate d T o xicities ( ≥Gr a de 3), wit h t he e xce pti o n of li ver -e nz y me a b n or m alities  
(f or w hic h, see Tra ns a mi n ase i ncre ases b o x bel o w)  
Ot her Rel ate d Gr a de 3 (st art s y m pt o m atic tre at me nt w he n p ossi ble)  
1 st A p peara nce  b 
I nterr u pt u ntil res ol ve d ( gra de 0-1)  
If rec o ver < 5 da ys, res u me at sa me d ose. 
Re d uce b y 2 0 0 m g 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  c 
2 n d A p peara nce  
I nterr u pt u ntil res ol ve d ( gra de 0 -1)  
Re d uce b y a n a d diti o nal 2 0 0 m g.  
3 r d A p peara nce  
Disc o nti n ue per ma ne ntl y  
N/ A  
Ot her Rel ate d Gr a de 4 (st art s y m pt o m atic tre at me nt w he n p ossi ble)  
1 st A p peara nce  
I nterr u pt u ntil res ol ve d 
( gra de 0-1)  
Re d uce b y 2 0 0 m g  
2 n d A p peara nce  
Disc o nt i n ue per ma ne ntl y 
N/ A  
Tr a ns a mi n ase i ncre ases a n d e nz y me a b n or m alities  
•  
A L T or A S T > 8  × U L N  
•  
A L T or A S T > 5 × U L N 
f or m ore t ha n 2 wee ks  
•  
A L T or A S T > 3 × U L N 
a n d t otal bilir u bi n  
> 2 × U L N or I N R > 1. 5  
•  
A L T or A S T > 3 × U L N 
wit h t he a p peara nce of 
fati g ue, na usea, vo 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 %).  
D ose h ol d a n d i m me diatel y disc uss 
wit h Me dical M o nit or.  
N/ A  
 
C O N FI D E N TI A L  
6 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T o xicit y Gr a de   
( C T C A E v 4) 
P L X 3 3 9 7 D ose C h a n ges D uri n g 
C urre nt Tre at me nt Peri o d  
D ose A dj ust me nts for  
Res u m pti o n of Tre at me nt a 
Pr ol o n ge d Q Tc F  
Q Tc F > 5 0 0 msec o n at least 
2 se parate E C Gs 
(i.e., Gra de  3).  
H ol d P L X 3 3 9 7 u ntil rec o ver y t o 
Q Tc F ≤5 0 0 msec.  
U p o n rec o ver y t o Q Tc F ≤5 0 0 msec 
( Gra de ≤2), restart at a re d uce d d ose 
( mi ni m u m re d ucti o n decre me nt of 
2 0 0  m g). M o nit or E C G a n d 
electr ol ytes, i ncl u di n g p otassi u m, 
ma g nesi u m, a n d calci u m, after d ose 
m o dificati o n of P L X 3 3 9 7 f or Q Tc F 
pr ol o n gati o n  
Q Tc F i nter val re mai ns 
> 5 0 0  msec a n d i ncrease d 
> 6 0  msec fr o m pretreat me nt 
val ues after c o ntr olli n g 
car diac ris k fact ors f or Q T 
pr ol o n gati o n (e. g., 
electr ol yte a b n or malities, 
c o n gesti ve heart fail ure, a n d 
bra d yarr h yt h mias).  
Per ma ne ntl y disc o nti n ue P L X 3 3 9 7.  
N/ A.  
A N C = a bs ol ute ne utr o p hil c o u nt; A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase;  
E C G = electr ocar di o gra m; 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(s);  
Q Tc F = Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula; T = te m perat ure = U L N = u p per li mit of n or mal 
a 
T hr o u g h o ut t he st u d y, d ose decre me nts of 2 0 0 m g/ da y of P L X 3 3 9 7 are per mitte d f or ma na ge me nt of t o xicit y.  
b 
E xce pt f or cases of Gra de 3 e mesis.  
c 
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. 
F or Gra de 3 e me sis t hat persists des pite o pti mal s u p p orti ve care, P L X 3 3 9 7 d oses s h o ul d be hel d 
u ntil res ol uti o n t o Gra de 2 or less.  
F or cases of Gra de 3 s y m pt o matic ras h t hat persists des pite me dical i nter ve nti o n, P L X 3 3 9 7 
d oses s h o ul d be hel d u ntil res ol uti o n t o Gra de 2 or less. U p o n rei ntr o d ucti o n of P L X 3 3 9 7, t he 
d ose le vel s h o ul d be re d uce d b y 2 0 0 m g/ da y.  
1 3. 1 4. 2  
P aclit a xel D ose M o dific ati o ns  
D ose m o dificati o ns or i nterr u pti o ns of paclita xel are n ot per mitte d i n P art 1 , C ycle 1 u nless t he 
patie nt e x perie nces a D L T. Patie nts m u st recei ve t he first 4 sc he d ule d Paclita xel d oses, b ut ma y 
s ki p 1 d ose per C ycle be gi n ni n g at C ycle 2 per I n vesti gat or discreti o n  a n d/ or patie nt prefere nce . 
I n or der t o recei ve wee kl y paclita xel treat me nt, t he f oll o wi n g criteria m ust be met: 
•  A N C ≥1 0 0 0/ m m 3 
 
C O N FI D E N TI A L  
6 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
•  Platelets ≥7 5, 0 0 0/ m m 3 
If t hese criteria are n ot met, treat me nt m ust be dela ye d u ntil c o u nts rec o ver t o t his le vel. 
Paclita xel s h o ul d be hel d f or all i nsta nces of fe brile ne utr o pe n ia ( A N C <1 0 0 0/ m m 3). Fil grasti m 
gr o wt h fact or s u p p ort is e nc o ura ge d f or A N C <1 5 0 0/ m m 3 a n d ma y be use d at t he discreti o n of 
t he treati n g p h ysicia n i n or der t o mai ntai n a de q uate bl o o d c o u nts E X C E P T d uri n g t he first c ycle. 
Fil grasti m is n ot per mitte d wit hi n 2 4 h o urs pri or t o or f oll o wi n g a n y paclita xel i nf usi o n. 
Pe gfil grasti m ( Ne ulasta) is n ot per mitte d i n t his st u d y.  
If paclita xel is hel d d ue t o ne utr o pe nia, P L X 3 3 9 7 s h o ul d still be a d mi nistere d. At least 2 1 da ys 
of P L X 3 3 9 7 a n d 3 of t he 4 d oses of paclita xel m ust be a d mi nistere d i n t he first c ycle  u nless t he 
patie nt e x perie nces a D L T . 
F or P art 1, C ycle 2 a n d s u bse q ue nt c ycles  a n d f or P art 2  a n d P art 3 , ot her d ose m o dificati o ns 
f or paclita xel will be i n acc or da nce wit h t he pr o d uct la bel. 
1 3. 1 5  Disc o nti n u ati o n of Tre at me nt a n d Wit h dr a w al of P atie nts  
T he reas o ns a patie nt ma y disc o nti n ue or be w it h dra 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 ( or desi g nee) 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 St u d y c ol u m n i n t he st u d y fl o w c hart wit hi n 
2 8 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 ne w a nti-t u m or t hera py. 
If a patie nt is wit h dra w n o n a n o n- P K da y, a P K sa m ple s h o ul d be o btai ne d. All eff orts s h o ul d be 
ma de t o o btai n f oll o w- u p i nf or mati o n f or patie nts w h o disc o nti n ue t heir partici pati o n i n or are 
wit h dra w n fr o m t he st u d y. 
Patie nts wit h dra w n fr o m t he st u d y 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. P L X 3 3 9 7 a n d/ or Paclita xel 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. Patie nts w h o disc o nti n ue treat me nt f or reas o ns ot her 
t ha n treat me nt-relate d a n d/ or d ose-li miti n g t o xicit y or wit h a cli nicall y si g nifica nt aller gic 
reacti o n t o paclita xel t hat precl u des f urt her treat me nt (i.e., ≥Gra de 3) ma y  be re place d.  
1 4. 0  
T E S T A R TI C L E S  
1 4. 1  
P L X 3 3 9 7 
1 4. 1. 1  
P L X 3 3 9 7 A d mi nistr ati o n  
P L X 3 3 9 7 will be a d mi nistere d orall y usi n g a ca ps ule f or m ulati o n (eit her 1 0 0 m g or 2 0 0 m g per 
ca ps ule).  P L X 3 3 9 7 will be a d mi nistere d o nl y t o patie nts  w h o ha ve si g ne d a n d date d a n i nf or me d 
c o nse nt f or m. P L X 3 3 9 7  will be a d mi nistere d o n Da ys 1 t hr o u g h 2 8 of eac h 2 8- da y c ycle, 
be gi n ni n g o n C 1 D 1 ( baseli ne). P L X 3 3 9 7 s h o ul d be ta ke n orall y  wit h 2 4 0 m L ( 8 oz.) of water i n 
t he fasti n g state. T he  p atie nt s h o ul d f ast at le ast 1 h o ur bef ore a d mi nist r ati o n a n d 1 h o ur 
 
C O N FI D E N TI A L  
6 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
after a d mi nistr ati o n of P L X 3 3 9 7 . Patie nts will be per mitte d t o eat a l o w -fat, bla n d 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. Q uesti o ns relate d t o per mitte d  pre- or 
p ost- d ose s nac ks s h o ul d be directe d t o t he Me dical M o nit or.  
P L X 3 3 9 7 s h o ul d be ta ke n b y t he patie nt at a p pr o xi matel y t he sa me ti me of da y. T he ti me 
bet wee n BI D  d oses s h o ul d be a p pr o xi matel y 1 2 h o urs. D osi n g ma y occ ur o nce dail y ( Q D) u n der 
certai n circ u msta nces ( e. g., d ose re d ucti o ns) a n d at t he disc reti o n of t he I n vesti gat or i n 
c o ns ultati o n wit h t he Me dical M o nit or. Q D d osi n g s h o ul d be a p pr o xi matel y 2 4 h o urs a part. 
F or P art 1  o nl y o n C 1 D 1 , C 1 D 1 5 , a n d t he first da y of all s u bse q ue nt c ycles, t he patie nts s h o ul d 
ta ke t he m or ni n g d ose of P L X 3 3 9 7 at t he cli nical site after t he pre - d ose P K bl o o d sa m ple is 
o btai ne d – patie nts s h o ul d be i nstr ucte d n ot t o ta ke t he st u d y dr u g at h o me pri or t o t he se cli nic 
visits. T he ti me of d osi n g will be rec or de d i n t he cli nic. T he e ve ni n g d ose of P L X 3 3 9 7 s h o ul d be 
ta ke n b y t he patie nt at h o me. F or P art 1  o n all ot her visit da ys a n d f or all P art 2 a n d P art 3  visit 
da ys, patie nts ma y a d mi nister 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 i n t he 
P L X 3 3 9 7a d mi nistrati o n diar y.  
Misse d d oses  of gre ater t h a n 2 h o urs after t he a p pr o pri ate d osi n g ti me  s h o ul d be s ki p pe d 
a n d n ot t a ke n  as a d o u ble  d ose at t he ne xt d osi n g ti me  p oi nt . F or e xa m ple, a patie nt w h o 
ta kes t heir P L X 3 3 9 7 at 8 a. m. a n d 8 p. m. eac h da y s h o ul d n ot ta ke t heir d ose if it has bee n 1 4 or 
m ore h o urs si nce t heir last  d ose. T his a p plies t o b ot h BI D a n d a p pr o ve d Q D d osi n g. 
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 ma ke u p t hat d ose.  
1 4. 1. 2  
P L X 3 3 9 7 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 ( 1 0 0 m g or 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 (f or merl y A pt uit) 
1 0 2 4 5 Hic k ma n Mills Dri ve 
Ka nsas Cit y, M O 6 4 1 3 7 
1 4. 1. 3  
P L X 3 3 9 7 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 nica l 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 ( bet wee n 1 5 – 3 0° C, or 5 9 – 8 6° F). 
Patie nts  will be re q ueste d t o st ore P L X 3 3 9 7 at t he rec o m me n de d st ora 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. 
 
C O N FI D E N TI A L  
6 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
1 4. 1. 4  
P L X 3 3 9 7 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 test article s u p plie d b y t he S p o ns or. C o pies of t he 
c o m plete d s o urce dis pe nsi n g a n d i n ve nt or y rec or d (s) will be ret ur ne d t o t he S p o ns or ( or 
desi g nee) after t he S p o ns or ( or desi g nee) has perf or me d acc o u nta bilit y pr oce d ures. P L X 3 3 9 7 
acc o u nta bilit y will als o be ca pt ure d i n t he E D C t hr o u g h o ut t he c o urse of t he trial. 
All P L X 3 3 9 7 ca ps ules m ust be ret ur ne d t o t he c o ntract distri b uti o n ce nter wit h t he a p pr o priate 
f or m if t here is e vi de nce t hat t he pr o d uct has bee n ta m pere d wit h i n tra nsit.  
Ret ur ne d a n d u n use d P L X 3 3 9 7 ca ps ules ma y als o be destr o ye d a n d d oc u me nte d at t he 
i n vesti gati ve site i n acc or da nce wit h G C P. T he q ua ntit y a n d dates of destr ucti o n of all P L X 3 3 9 7 
ca ps ules m ust be rec or de d o n t he P L X 3 3 9 7 acc o u nta bilit y l o g.  
1 4. 1. 5  
P L X 3 3 9 7 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 P L X 3 3 9 7 c o m plia nce.  P L X 3 3 9 7 
c o m plia nce will als o be trac ke d t hr o u g h a patie nt diar y.  
1 4. 2  
P aclit a xel  
Paclita xel will be a d mi nistere d i ntra ve n o usl y o ver a p pr o xi matel y 6 0 mi n utes. Paclita xel will be 
a d mi nistere d o nl y t o patie nts w h o ha ve si g ne d a n d date d a n i nf or me d c o nse nt f or m. Per 
I n vesti gat or a n d/ or patie nt prefere nce, 1 d ose of paclita xel ma y be s ki p pe d e ver y f o ur wee ks.  
1 5. 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 6. 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 ort e d si g ns a n d 
s y m pt o ms, sc he d ule d a n d s y m pt o m-directe 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 TcF 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 if 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  or pri or t o start of ne w a nti-t u m or t hera p y, w hic he ver 
occ urs first . 
 
C O N FI D E N TI A L  
6 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
F or P art 3 o nl y :  A E a n d S A E re p orti n g will c o m me nce w he n t he 2- 3 c ore bi o psies are o btai ne d 
d uri n g Scree ni n g. 
1 6. 1  
P h ysic al E x a mi n ati o n  
P h ysical e xa mi nati o ns 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) at Scree ni n g a n d at all ti me  p oi nts i n dicate d i n t he Trial Fl o w C hart . 
P h ot o gra p h y ma y be i ncl u de d as part of t he p h ysical e xa m f or t h ose patie nts w h o c o nse nt t o t he 
pr oce d ure. 
1 6. 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. All patie nts s h o ul d be sitti n g f or 3 – 5 mi n utes pri or t o o btai ni n g vital si g ns. 
1 6. 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 rec or di n gs m ust be perf or me d usi n g a sta n dar d, hi g h-q u alit y, 
hi g h- fi delit y electr ocar di o gra p h mac hi ne e q ui p pe d wit h c o m p uter- base d i nter val meas ure me nts.  
F or safet y m o nit ori n g p ur p oses, t he E C G m ust be re vie we d , si g ne d a n d date d pr o m ptl y 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 eC 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, P R i nter val, Q R S 
i nter val, Q T i nter val, a n d Q TcF i nter val (c orrecte d Q T i nter val, Fre derica’s f or m ula). If 
c o nsi dere d a p pr o priate b y t he S p o ns or, E C Gs ma y be retr os pecti vel y a nal yze d at a ce ntral 
facilit y. 
1 6. 4  
Ec h oc ar di o gr a ms or M ulti- g ate d Ac q uisiti o n Sc a ns  
Eit her a tra nst h oracic ec h ocar di o gra m ( T T E) or m ulti- gate d ac q uisiti o n sca n ( M U G A) will be 
o btai ne d t o e val uate car diac ejecti o n fracti o n. 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 pri or t o t he e val uati o n. T he Ec h o or M U G A m ust be re vie we d, si g ne d a n d date d 
pr o m ptl y 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. 
1 6. 5  
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 Trial Fl o w C hart. 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. 
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 or tl 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 
 
C O N FI D E N TI A L  
6 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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.  
1 7. 0  
S T U D Y S T O P PI N G R U L E S  
P art 1: 
If ≥2 of 6 patie nts i n D ose Le vel -1 eit her e x perie nce a D L T or are u na ble t o recei ve t he re q uisite 
P L X 3 3 9 7 a n d paclita xel d oses i n t he first 2 8 da ys d ue t o treat me nt- relate d a d verse e ve nts, 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 b e disc o nti n ue d.  
P art 2: 
After ~ 5 0 % of t he pla n ne d a p pr o xi matel y 3 0 patie nts ( R P 2 D- treate d patie nts fr o m Part 1 a n d 
Part 2) ha ve c o m plete d at least 2 treat me nt c ycles, 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 In 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 l me nt, t he st u d y will be disc o nti n ue d. 
P art 3: 
After ~ 5 0 % of t he a p pr o xi matel y pla n ne d 3 0 pati e nts ha ve c o m plete d at least 2 treat me nt c ycles, 
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. 
1 8. 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 Trial Fl o w C hart. Sa m ples 
will be c ollecte d,  pr ocesse d a n d st ore d acc or di n g t o t he st u d y- s pecific la b orat or y ma n ual.  
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. 
1 9. 0  
P H A R M A C O KI N E TI C E V A L U A TI O N ( P A R T 1 A N D P A R T 3)  
1 9. 1  
Bl o o d C ollecti o n  
A p pr o xi matel y 5 m L of bl o o d will be c ollecte d via peri p heral ve ni p u nct ure i nt o a lit hi u m 
he pari n t u be. T his bl o o d sa m ple will be use d t o meas ure c o nce ntrati o ns of P L X 3 3 9 7 f or eac h P K 
bl o o d c ollecti o n, as n ote d i n t he Trial Fl o w C hart. Sa m ples will be c ollecte d, pr ocesse d a n d 
st ore d acc or di n g t o t he st u d y-s pecific la b orat or y ma n ual.  
 
C O N FI D E N TI A L  
6 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 0 mi n ute 
wi n d o w of t he re q ueste d ti me. 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 . 
1 9. 2  
Bi o a n al ytic al Met h o d ol o g y 
T he plas ma 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 ple mass s pectr o metric 
detecti o n) of a p pr o priate s pecificit y a n d se nsiti vit y. 
2 0. 0  
S T A TI S TI C A L A N A L Y SI S  
2 0. 1  
S afet y A n al ysis 
All patie nts i n all c o h orts w h o recei ve  st u d y me dicati o n will be c o nsi dere d e val ua ble f or safet y 
re gar dless of t heir d urati o n of treat me nt. 
T he o bjecti ve of t he d ose escalati o n is t o deter mi ne a d ose of P L X 3 3 9 7 ( pl us p aclita xel) f or 
w hic h t he rate of D L Ts is less t ha n 3 3 %. 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, cli nical c he mistr y a n d uri nal ysis), E C G, a n d vital si g ns. A d verse e ve nt 
ter ms rec or de d o n t he 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 7. 1 or hi g her. All A Es will be s u m marize d f or 
eac h d ose gr o u p 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 tal lie d f or o verall fre q ue nc y ( n u m ber a n d perce nta ge of patie nts), 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 patie nt. 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. I n 
a d diti o n, all e ve nts meeti n g t he criteria of a D L T will be ta b ulate d as a se parate listi n g b y patie nt  
a n d d ose gr o u p. La b orat or y varia bles will be s u m marize 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 f or eac h d ose le vel gr o u p a n d 9 5 % c o nfi de nce i nter val. 
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 a n d d ose le vel gr o u p. 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 st u d y 
treat me nt d ose. C o nc o mita nt me dicati o ns will als o be s u m marize d. 
2 0. 2  
Effic ac y A n al ysis  
All patie nts wit h meas ura ble disease b y R E CI S T versi o n 1. 1 criteria (see Attac h me nt 2 ) at 
Baseli ne w h o c o m plete at least o ne p ost -baseli ne ra di o gra p hic assess me nt or disc o nti n ue st u d y 
me dicati o n earl y d ue t o disease pr o gressi o n will be c o nsi dere d e val ua ble f or efficac y.  
R es p o nse t o treat me nt acc or di n g t o t he R E CI S T criteria will be re p orte d via descri pti ve statistics 
b y d ose le vel. T he a bs ol ute a n d perce nt c ha n ge fr o m baseli ne f or t he e xte nt of disease (s u m of 
 
C O N FI D E N TI A L  
6 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
t he l o n gest dia meters) will be s u m marize d at eac h sc he d ule d e val uati o n usi n g descri pti ve 
statistics i ncl u di n g mea n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m val ues. 
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 pr o gressi o n – free 
s ur vi val, re gar dless of t he prese nce or a bse nce of meas ura ble disease. Pr o gressi o n -free s ur vi val 
will be calc ulate d f or eac h patie nt  a n d s h o w n f or all patie nts o n a Ka pla n -Meier pl ot . 
Pr o gressi o n-free s ur vi val is defi ne d as t he n u m ber of da ys fr o m t he first da y of treat me nt 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. 
F or eac h patie nt 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 (c o nf ir me d at least 
2 8 da ys later) 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. If t he i nf or mati o n is a vaila ble, t he pre-st u d y sta bilit y of disease will als o be rec or de d t o 
assist t he i nter pretati o n of t he o n -treat me nt pr o gressi o n-free s ur vi val. 
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 p y, pr o gressi o n-free s ur vi val 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. E x pl orat or y a nal yses 
ma y be c o n d ucte d t o e val uate p ossi ble relati o ns hi ps bet wee n a ntit u m or acti vit y, 
p har mac o d y na mic mar kers, a n d dr u g e x p os ure le vels. 
2 0. 3  
S a m ple Size a n d P o wer  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he safet y of c o m bi nati o n P L X 3 3 9 7 + Paclita xel 
t hera p y i n a li mite d n u m ber of patie nts wit h s oli d t u m ors. T he n u m ber of patie nts is n ot base d o n 
statistical p o wer c o nsi derati o ns. 
P art 1.  T hree -t o-si x patie nts will be accr ue d per d ose le vel i n or der t o ins ure t he safet y a n d 
t olera bilit y. T he pr o ba bilities of detecti n g D L Ts i n t his st u d y are s h o w n i n Ta ble  4 a n d Ta ble  5. 
T a ble  4: 
Pr o b a bilities of Detecti n g D L Ts ( 3 P atie nts)  
N u m ber D L Ts i n a C o h ort of 3  P atie nts  
I nci de nce of D L Ts i n P atie nt P o p ul ati o n 
0. 1 0  
0. 2 0  
0. 3 0  
0. 4 0  
0. 5 0  
0 a 
0. 7 2 9  
0. 5 1 2  
0. 3 4 3  
0. 2 1 6  
0. 1 2 5  
1 b 
0. 2 4 3  
0. 3 8 4  
0. 4 4 1  
0. 4 3 2  
0. 3 7 5  
2 or m ore c 
0. 0 2 8  
0. 1 0 4  
0. 2 1 6  
0. 3 5 2  
0. 5 0 0  
a 
N u m ber of D L T s lea ds t o a d va nci n g t o t he ne xt c o h ort. 
b 
N u m ber of D L Ts lea di n g t o e nr olli n g a n a d diti o nal 3 patie nts i n t he C o h ort.  
c 
N u m ber of D L Ts lea di n g t o st o p pi n g t he st u d y a n d defi ni n g t he M T D.  
 
 
C O N FI D E N TI A L  
6 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T a ble  5: 
Pr o b a bilities of Detecti n g D L Ts ( 6 P atie nts)  
N u m ber D L Ts i n a C o h ort of 3  P atie nts  
I nci de nce of D L Ts i n P atie nt P o p ul ati o n 
0. 1 0  
0. 2 0  
0. 3 0  
0. 4 0  
0. 5 0  
0  
N A  
N A  
N A  
N A  
N A  
1 a 
0. 1 7 7  
0. 1 9 7  
0. 1 5 1  
0. 0 9 3  
0. 0 4 7  
2 or m ore b 
0. 0 6 6  
0. 1 8 7  
0. 2 9 0  
0. 3 3 9  
0. 3 2 8  
a 
N u m ber of D L Ts lea di n g t o a d va nci n g t o t he  ne xt c o h ort [ Pr o b ( 1 i n first 3 a n d 0 i n sec o n d 3)].  
b 
N u m ber of D L Ts lea di n g t o st o p pi n g t he st u d y a n d defi ni n g t he M T D [ Pr o b ( 1 i n first 3 a n d 1 i n sec o n d 3) + 
Pr o b ( 1 i n first 3 a n d 2 i n sec o n d 3)].  
 
2 0. 4  
P h ar m ac o ki netic A n al ysis  ( P art 1 a n d P art 3 ) 
A n o n- c o m part me ntal met h o d of a nal ysis will be use d t o a nal yze t he plas ma c o nce ntrati o ns of 
P L X 3 3 9 7 C ma x  at stea d y state (i.e., C 1 D 1 5) a n d t he ti me t o attai n t he Cma x  ( Tma x ) will be 
deter mi ne d directl y fr o m t he o bser ve d data. A partial A U C ( A U C 0- 4) will be calc ulate d o n 
Da y  1 5 i n C ycle 1.  
2 0. 5  
P h ar m ac o d y n a mic A n al ysis 
N o f or mal statistical a nal ysis of p har mac o d y na mic e n d p oi nts will be perf or me d. 
P har mac o d y na mic data fr o m eac h assa y will be liste d b y d ose.  P ossi ble relati o ns hi ps bet wee n 
P K a n d p har mac o d y na mic varia bles will be e x pl ore d, as a p pr o priate. A n y bi ol o gical acti vit y will 
be descri be d.  
2 1. 0  
P R E C A U TI O N S  
Al t 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 us t 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 . F or a c o m plete descri pti o n of paclita xel, please refer t o t he 
pr o d uct la bel’s i n dicati o ns a n d usa ge i nstr ucti o ns. 
2 2. 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 o r’s 
Br oc h ure. F or safet y i nf or mati o n o n paclita xel, refer t o t he pr o d uct la bel’s i n dicati o ns a n d usa ge. 
 
C O N FI D E N TI A L  
6 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
2 2. 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 test 
article 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 test article. 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 d iti 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 test article, 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 test article. 
•  A n A E t hat has bee n ass oc iate d wit h t he disc o nti n uati o n of t he use of a test article. 
A n y treat 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) 
•  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 
treat 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. 
 
C O N FI D E N TI A L  
7 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 ve nt 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 pitali zati 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.  
•  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 pree xisti 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. Visits t o t he E mer ge nc y R o o m t hat d o n ot res ult i n 
h os pital a d missi o n are n ot c o nsi dere d h os pitalizati o ns.  
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 ei t her “ pr o ba bl y”, “ p ossi bl y”, or “n ot relate d ”, 
as f oll o ws: 
 
C O N FI D E N TI A L  
7 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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 stu d y t hat is n ot relate d 
t o t he test article, 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:   
•  A case i n v ol vi n g a pre g na nc y e x p os ure t o a test article, 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 ur se 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, test 
article 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 ut 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.  
 
C O N FI D E N TI A L  
7 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
2 2. 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 f irst d ose of st u d y dr u g 
u p t o 2 8 da ys after t he last d ose  a n d pri or t o starti n g a n ot her t hera p y. F or P art 3 o nl y , A E a n d 
S A E  re p orti n g will c o m me nce w he n t he 2- 3 c ore bi o psies are o btai ne d d uri n g Scree ni n g. 
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 her 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. 
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 E D C . 
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 2. 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 mpleti n g t he S A E e C R F  i n t he electr o nic data ca pt ure 
( E D C) s yste m. As a bac k- u p, t he site ma y fa x a c o m plete 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 ved. 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. 
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 pe a n Cli nic al Tri als Directive ( Directive 2 0 0 1/ 2 0/ E C), a n d/ or l ocal 
re g ulat or y re q uire me nts. T o meet t his re q uire me nt, Ple x xi k o n ( or desi g nee) ma y re q uest 
a d diti o nal i nf or mati o n fr o m t he sites, i ncl u di n g b ut n ot li mite d t o, h os pitalizati o n rec or ds . A n y 
re q uests f or s uc h i nf or mati o n s h o ul d be a d dresse d i n a ti mel y ma n ner. 
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. 
 
C O N FI D E N TI A L  
7 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
2 3. 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 test article, c o ntai ners, a n d ot her st u d y materials t o t he S p o ns or’s 
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 4. 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 po 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. 
* = Data fr o m sta n dar d - of-care pr oce d ures perf or me d pri or t o i nf or me d c o nse nt ma y be use d f or 
scree ni n g p ur p oses if t he pr oce d ure occ urre d wit hi n t he pr ot oc ol-s pecifie d ti mefra me. 
2 5. 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 vesti 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, 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 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 process as t he ori gi nal pr ot oc ol.  
2 6. 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 
 
C O N FI D E N TI A L  
7 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
re vie w t he pr ot oc ol, t he i n vesti gat or’s br oc h ure, t he eC 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 7. 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 7. 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 ulator 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 eC 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 st u d y-relate d la 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 nts’ 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 7. 2  
S p o ns or  
T he data will be c hec ke d f or c o m plete ness a n d c orrect ness i n real -ti me o nli ne. 
Data are c hec ke d as t he y are e ntere d i nt o t he electr o nic data ca pt ure s yste m ( E D C ). Off-li ne 
c hec ks will als o be r u n t o assess t he nee d f or a d diti o nal data re vie w. Discre pa nc y re p orts will be 
ge nerate d 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 his/ her 
desi g nee.  
2 8. 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 
patie 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 O N FI D E N TI A L  
7 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
•  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 b  i 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 b e 
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 plica 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 n ci pal I n vesti gat or, a n y s u b i n vesti gat ors 
a n d a n y ot her i n di vi d ual s ha vi n g si g nifica nt res p o nsi bilit y as liste d i n t he 1 5 7 2. 
•  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 Pri nci pal I n vesti gat or a n d a n y ot her 
pers o ns liste d i n t he 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 1 5 7 2 a n d t he 
la b orat or y direct or’s c urric ula 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. 
 
2 9. 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 
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. 
 
C O N FI D E N TI A L  
7 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
3 0. 0  
R E F E R E N C E S  
A merica n Ca ncer S ociet y ( A C S). Ca ncer Facts & Fi g ures 2 0 1 1. A vaila ble at 
htt p:// w w w.ca ncer. or g/acs/ gr o u ps/c o nte nt/ @e pi de mi ol o g ys ur veila nce/ d oc u me nts/ d oc u me nt/ 
acs pc- 0 2 9 7 7 1. p df. Accesse d Ja n uar y 2 0 1 2. 
Car d os o F, Be dar d P L, Wi ner E P, Pa ga ni O, Se n k us- K o nef ka E, Fall o wfiel d LJ, et al. 
I nter nati o nal g ui deli nes f or ma na ge me nt of metastatic breast ca ncer:  c o m bi nati o n vs se q ue ntial 
si n gle-a ge nt c he m ot hera p y. J Natl Ca ncer I nst. 2 0 0 9; 1 0 1( 1 7): 1 1 7 4 – 1 1 8 1. 
C ha m bers S K, Kaci ns ki B M, I vi ns C M, Carca n gi u M L. O vere x pressi o n of e pit helial 
macr o p ha ge c ol o n y- sti m ulati n g fact or ( C S F- 1) a n d C S F- 1 rece pt or:  a p o or pr o g n ostic fact or i n 
e pit helial o varia n ca ncer, c o ntraste d wit h a pr otecti ve effect of str o mal C S F - 1. Cli n Ca ncer Res. 
1 9 9 7; 3( 6): 9 9 9 – 1 0 0 7. 
C o n deelis J, Se gall J E. I ntra vital i ma gi n g of cell m o ve me nt i n t u m o urs. Nat Re v Ca ncer. 
2 0 0 3; 3( 1 2): 9 2 1 – 9 3 0. 
C o n deelis J, P ollar d J W. Macr o p ha ges :  o bli gate part ners f or t u m or cell mi grati o n, i n vasi o n, a n d 
metastasis. Cell. 2 0 0 6; 1 2 4( 2): 2 6 3 – 2 6 6. 
C o nli n A K, Sei d ma n A D. Ta xa nes i n breast ca ncer :  a n u p date. C urr O nc ol Re p.  
2 0 0 7; 9( 1): 2 2 – 3 0. 
C o n wa y J G, Mc D o nal d B, Par ha m J, Keit h B, R us na k D W, S ha w E, et al. I n hi biti o n of c ol o n y-
sti m ulati n g-fact or- 1 si g nali n g i n vi v o wit h t he orall y bi oa vaila ble c F M S ki nase i n hi bit or 
G W 2 5 8 0. Pr oc Natl Aca d Sci U S A. 2 0 0 5; 1 0 2( 4 4): 1 6 0 7 8 – 1 6 0 8 3. 
De Nar d o D G, Bre n na n DJ, Re x he paj E, R uffell B, S hia o S L, Ma d de n S F, et al. Le u k oc yte 
c o m ple xit y pre dicts breast ca ncer s ur vi val a n d f u ncti o nall y re g ulates res p o nse t o c he m ot hera p y. 
Ca ncer Disc o v. 2 0 1 1; 1( 1): 5 4 – 6 7. 
G u y C T, Car diff R D, M uller WJ. I n d ucti o n of ma m mar y t u m ors b y e x pressi o n of p ol y o ma vir us 
mi d dle T o nc o ge ne :  a tra ns ge nic m o use m o del f or metastatic disease. M ol Cell Bi ol. 
1 9 9 2; 1 2( 3): 9 5 4 – 9 6 1. 
H or witz S B. Ta x ol ( paclita xel):  mec ha nis ms of acti o n. A n n O nc ol. 1 9 9 4; 5( S u p pl 6): S 3 – S 6.  
Je mal A, Sie gel R, X u J, War d E. Ca ncer statistics, 2 0 1 0. C A Ca ncer J Cli n. 2 0 1 0; 6 0: 2 7 7 – 3 0 0. 
Kaci ns ki B M, St a nle y E R, Carter D, C ha m bers J T, C ha m bers S K, K o h or n EI, et al. Circ ulati n g 
le vels of C S F- 1 ( M- C S F) a l y m p h o he mat o p oietic c yt o ki ne ma y be a usef ul mar ker of disease 
stat us i n patie nts wit h mali g na nt o varia n ne o plas ms. I nt J Ra diat O nc ol Bi ol P h ys. 
1 9 8 9; 1 7( 1): 1 5 9 – 1 6 4. 
 
C O N FI D E N TI A L  
7 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Kaci ns ki B M, Scata K A, Carter D, Yee L D, Sa pi E, Ki n g B L, et al. F M S ( C S F - 1 rece pt or) a n d 
C S F - 1 tra nscri pts a n d pr otei n are e x presse d b y h u ma n breast carci n o mas i n vi v o a n d i n vitr o. 
O nc o ge ne. 1 9 9 1; 6( 6): 9 4 1 – 9 5 2. 
Li n E Y, N g u ye n A V, R ussell R G, P ollar d J W. C ol o n y-sti m ulati n g fact or 1 pr o m otes pr o gressi o n 
of ma m mar y t u m ors t o mali g na nc y. J E x p Me d. 2 0 0 1; 1 9 3( 6): 7 2 7 – 7 3 9. 
Li n E Y, P ollar d J W. T u m or- ass ociate d macr o p ha ges press t he a n gi o ge nic s witc h i n breast 
ca ncer. Ca ncer Res. 2 0 0 7; 6 7( 1 1): 5 0 6 4 – 5 0 6 6. 
Ma nt he y C L, J o h ns o n D L, Illi g C R, T u ma n R W, Z h o u Z, Ba ker J F, et al. J NJ- 2 8 3 1 2 1 4 1, a n o vel 
orall y acti ve c ol o n y- sti m ulati n g fact or-1 rece pt or/ F M S -relate d rece pt or t yr osi ne ki nase- 3 
rece pt or t yr osi ne ki nase i n hi bit or wit h p ote ntial utilit y i n s oli d t u m ors, bo ne metastases, a n d 
ac ute m yel oi d le u ke mia. M ol Ca ncer T her. 2 0 0 9; 8( 1 1): 3 1 5 1 – 3 1 6 1. 
Ne w ma n L A. E pi de mi ol o g y of l ocall y a d va nce d breast ca ncer. Se mi n Ra diat O nc ol. 
2 0 0 9; 1 9( 4): 1 9 5 – 2 0 3. 
N o wic ki A, et al. I m paire d t u m or gr o wt h i n c ol o n y- sti m ulati n g fact or 1 ( C SF- 1)- deficie nt, 
macr o p ha ge- deficie nt o p/ o p m o use :  e vi de nce f or a r ole of C S F- 1- de pe n de nt macr o p ha ges i n 
f or mati o n of t u m or str o ma. I nt J Ca ncer. 1 9 9 6; 6 5( 1): 1 1 2 – 1 1 9. 
Ple x xi k o n P L X 3 3 9 7 I n vesti gat or’s Br oc h ure. 
Price F V, C ha m bers S K, C ha m bers J T, Carca n gi u M L, Sc h wartz P E, K o h or n EI, et al. C ol o n y-
sti m ulati n g fact or-1 i n pri mar y ascites of o varia n ca ncer is a si g nifica nt pre dict or of s ur vi val. A m 
J O bstet G y nec ol. 1 9 9 3; 1 6 8( 2): 5 2 0 – 5 2 7. 
Price ma n SJ, S u n g J L, S ha p os h ni k Z, B urt o n J B, T orres- C olla d o A X, M o u g h o n D L, et al. 
Tar geti n g disti nct t u m or-i nfiltrati n g m yel oi d cells b y i n hi biti n g C S F- 1 rece pt or :  c o m bati n g 
t u m or e vasi o n of a ntia n gi o ge nict hera p y. Bl o o d. 2 0 1 0; 1 1 5( 7): 1 4 6 1 – 1 4 7 1. 
Qia n B, De n g Y, I m J H, M usc hel RJ, Z o u Y, Li J, et al. A disti nct macr o p ha ge p o p ulati o n 
me diates metastatic breast ca ncer cell e xtra vasati o n, esta blis h me nt a n d gr o wt h. P L o S O ne. 
2 0 0 9; 4( 8):e 6 5 6 2. 
R uffell B, A u A, R u g o H S, Esser ma n LJ, H wa n g E S, C o usse ns L M. Le u k oc yte c o m p ositi o n of 
h u ma n breast ca ncer. Pr oc Natl Aca d Sci U S A. 2 0 1 2; 1 0 9( 8): 2 7 9 6 – 2 8 0 1. 
R uffell B, C o usse ns L M. Macr o p ha ges a n d t hera pe utic resista nce i n ca ncer. Ca ncer Cell. 
2 0 1 5; 2 7( 4): 4 6 2 – 4 7 2. 
 
C O N FI D E N TI A L  
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Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Sc h oll S M, Basc o u C H, M osseri V, Oli vares R, Ma g dele nat H, D or val T, et al. Circ ulati n g le vels 
of c ol o n y-sti m ulati n g fact or 1 as a pr o g n o stic i n dicat or i n 8 2 patie nts wit h e pit helial o varia n 
ca ncer. Br J Ca ncer. 1 9 9 4; 6 2( 2): 3 4 2 – 3 4 6. 
Sei d ma n A D, Berr y D, Cirri nci o ne C, Harris L, M uss H, Marc o m P K, et al. Ra n d o mize d p hase 
III trial of wee kl y c o m pare d wit h e ver y- 3-wee ks paclita xel f or metastati c breast ca ncer, wit h 
trastaz u ma b f or all H E R- 2 o vere x press ors a n d ra n d o m assi g n me nt t o tra nst uz u ma b or n ot i n 
H E R - 2 n o n o vere x press ors:  fi nal res ults of Ca ncer a n d Le u ke mia Gr o u p B Pr ot oc ol 9 8 4 0. J Cli n 
O nc ol. 2 0 0 8; 2 6( 1 0): 1 6 4 2 – 1 6 4 9. 
S kates SJ, H oric k N, Y u Y, X u FJ, Berc h uc k A, Ha vriles k y LJ, et al. Pre o perati ve se nsiti vit y a n d 
s pecificit y f or earl y-sta ge o varia n ca ncer w he n c o m bi ni n g ca ncer a nti ge n C A- 1 2 5II, C A 1 5- 3, 
C A 7 2 - 4, a n d macr o p ha ge c ol o n y-sti m ulati n g fact or usi n g mi xt ures of m ulti variate n or mal 
distri b uti o ns. J Cli n O nc ol. 2 0 0 4; 2 2( 2 0): 4 0 5 9 – 4 0 6 6. 
Ta n g R, Be u v o n F, Oje da M, M osseri V, P o uillart P, Sc h oll S. M- C S F ( m o n oc yte c ol o n y 
sti m ulati n g fact or) a n d M- C S F rece pt or e x pressi o n b y breast t u m o ur cells:  M- C S F me diate d 
recr uit me nt of t u m o ur i nfiltrati n g m o n oc ytes? J Cell Bi oc he m. 1 9 9 2; 5 0( 4): 3 5 0 – 3 5 6. 
T o y E P, C ha m bers J T, Kaci ns ki B M, Flic k M B, C ha m bers S K. T he acti vate d macr o p ha ge 
c ol o n y sti m ulati n g fact or ( C S F- 1) rece pt or as a pre dict or of p o or o utc o me i n a d va nce d e pit helial 
o varia n carci n o ma. G y nec ol  O nc ol. 2 0 0 1; 8 0( 2): 1 9 4 – 2 0 0. 
Tr ussell J. C o ntrace pti ve Efficac y. I n :  Hatc her R A, Tr ussell J, Nels o n A L, Cates W Jr., Ste wart 
F H, K o wal D, e dit ors. C o ntrace pti ve Tec h n ol o g y. 1 9t h e d. Ne w Y or k, N Y :  Ar de nt Me dia, I nc.; 
2 0 0 7. 
Z ha n g Z, Y u Y, X u F, Berc h uc k A, va n Haafte n - Da y C, Ha vriles k y LJ, et al. C o m bi ni n g 
m ulti ple ser u m t u m or mar kers i m pr o ves detecti o n of sta ge I e pit helial o varia n ca ncer. G y nec ol 
O nc ol. 2 0 0 7; 1 0 7( 3): 5 2 6 – 5 3 1. 
 
 
 
C O N FI D E N TI A L  
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P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
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  
H E M A T O L O G Y  ( Peri p heral Bl o o d Sa m ple) 
•  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  
S E R U M C H E MI S T R Y  ( Peri p heral Bl o o d Sa m ple) 
•  S o di u m 
•  P otassi u m  
•  C hl ori de 
•  C O 2  
•  Ma g nesi u m  
•  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 d irect bilir u bi n 
•  As partate 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)  
•  Creati ne ki nase ( C P K)  
* = Fasti n g Gl uc ose ( 8 – 1 0 h o ur fast) is rec o m me n de d, b ut n ot re q uire d  
Pre g n a nc y test ( uri ne β -H C G) :  W o me n of c hil d- beari n g p ote ntial 
P art 1, P art 2, a n d P art 3: 
Bl o o d Res p o nse Bi o m ar kers  (s a m ples):   
•  C S F - 1 
•  C D 1 4/ C D 1 6 p ositi ve m o n oc ytes  
(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, a defi niti ve list of a nal yses re mai ns t o be deter mi ne d.) 
P art 3: 
C a ncer tiss ue bi o m ar kers will i ncl u de:  
•  I H C f or C D 6 8, C D 8, P D- L 1, a n d a d diti o nal mar kers of macr o p ha ge a n d T-cell prese nce a n d 
f u ncti o n 
 
C O N FI D E N TI A L  
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Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
•  R N A e x pressi o n a nal ysis f or a n e x pl orat o r y pa nel of t u m or micr oe n vir o n me nt mar kers 
•  Stai ni n g of cells of t he t u m or micr oe n vir o n me nt. Pa nels of I H C mar kers s pecific f or 
macr o p ha ges, T-cells, a n d ot her i m m u ne a n d i nfla m mat or y cells will be e m pl o ye d, f or se mi-
q ua ntitati ve c ha n ges i n cell n u m ber, l ocati o n wit hi n t he t u m or, a n d de gree of acti vati o n. 
Bl o o d bi o m ar kers will i ncl u de:  
•  C A - 1 2 5 sa m pli n g re q uire me nts:  2 pre- treat me nt sa m ples, first sa m ple wit hi n 3 m o nt hs of 
starti n g t hera p y a n d sec o n d sa m ple wit hi n 1 wee k of C ycle 1 Da y 1; s u bse q ue nt sa m ples on 
t he first da y of eac h c ycle starti n g wit h C ycle 2 Da y 1 a n d E n d- of-St u d y Visit.  
•  Plas ma C S F -1 a n d a d diti o nal mar kers of treat me nt effect  
•  W h ole bl o o d C D 1 4/ C D 1 6 m o n oc yte s u bset b y F A C S a nal ysis 
•  W h ole bl o o d M D S C b y F A C S a nal ysis 
 
 
C O N FI D E N TI A L  
8 1  
Ple x xi k o n I nc.  
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P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 2 :  R E CI S T C RI T E R I A V E R SI O N 1. 1 
Me as ur a bilit y of T u m or at B aseli ne  
Defi niti o ns  
At baseli ne, t u m or lesi o ns/l y m p h n o des will be cate g orize d meas ura ble or n o n- meas ura ble as 
f oll o ws. 
Me as ur a ble t u m or lesi o ns  
T u m or lesi o ns m ust be acc uratel y meas ure d i n at least o ne di me nsi o n ( l o n gest dia meter i n t he 
pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of :   
•  1 0 m m b y C T sca n ( C T sca n slice t hic k ness n o greater t ha n 5 m m)  
•  1 0 m m cali per meas ure me nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h cali pers s h o ul d be rec or de d as n o n-meas ura ble)  
•  2 0 m m b y c hest X- ra y 
Mali g na nt l y m p h n o des :  T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a l y m p h 
n o de m ust be ≥ 1 5 m m i n s h ort a xis w he n assesse d b y C T sca n ( C T sca n slice t hic k ness 
rec o m me n de d t o be n o greater t ha n 5 m m). At baseli ne a n d i n f oll o w- u p, o nl y t he s h ort a xis will 
be meas ure d a n d f oll o we d. See als o secti o n bel o w o n ‘ Baseli ne d oc u me ntati o n of tar get a n d 
n o n-tar get lesi o ns’ f or i nf or mati o n o n l y m p h n o de meas ure me nt. 
N o n -me as ur a ble t u m or lesi o ns  
N o n- meas ura ble t u m or lesi o ns e nc o m pass s mall lesi o ns (l o n gest dia meter < 1 0 m m or 
pat h ol o gical l y m p h n o des wit h ≥1 0 t o < 1 5 m m s h ort a xis) as well as tr ul y n o n- meas ura ble 
lesi o ns. Lesi o ns c o nsi dere d tr ul y n o n- meas ura ble i ncl u de:  le pt o me ni n geal disease, ascites, 
ple ural or pericar dial eff usi o n, i nfla m mat or y breast disease, l y m p ha n gitic i n v ol ve me nt of s ki n or 
l u n g, perit o neal s prea d, a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysical e xa m 
t hat is n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues. 
S pe ci al c o nsi der ati o ns re g ar di n g lesi o n me as ur a bilit y  
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y treate d wit h l ocal t hera p y re q uire partic ular 
c o m me nt : 
 
 
 
C O N FI D E N TI A L  
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Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
B o ne lesi o ns:  
•  B o ne sca n, P E T sca n or plai n fil ms are n ot c o nsi dere d a de q uate i ma gi n g tec h ni q ues  t o 
meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be use d t o c o nfir m t he prese nce or 
disa p peara nce of b o ne lesi o ns.  
•  L ytic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de ntifia ble s oft tiss ue c o m p o ne nts, 
t hat ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T or M RI ca n be 
c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of 
meas ura bilit y descri be d a b o ve.  
•  Blastic b o ne lesi o ns are n o n -meas ura ble.  
C ystic lesi o ns:  
•  Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be 
c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble n or n o n- meas ura ble) si nce t he y are, 
b y defi niti o n, si m ple c ysts 
•  ‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble 
lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. H o we ver, if 
n o n- c ystic lesi o ns are prese nt i n t he sa me patie nt, t hese are preferre d f or selecti o n as 
tar get lesi o ns 
Lesi o ns wit h pri or l oc al tre at me nt :   
•  T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her 
l oc o-re gi o nal t hera p y, are us uall y n ot c o nsi dere d meas ura ble u nless t here has bee n 
de m o nstrate d pr o gressi o n i n t he lesi o n. St u d y pr ot oc ols s h o ul d detail t he c o n diti o ns 
u n der w hic h s uc h lesi o ns w o ul d be c o nsi dere d meas ura ble.  
S pecific ati o ns b y met h o ds of me as ure me nts  
Me as ure me nt of lesi o ns  
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y assesse d. All 
baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o  t he treat me nt start a n d ne ver 
m ore t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt. 
 
 
 
C O N FI D E N TI A L  
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Ple x xi k o n I nc.  
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P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Met h o d of assess me nt  
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w- u p. I ma gi n g base d e val uati o n s h o ul d 
al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot be 
i ma ge d b ut are assessa ble b y cli nical e xa m. 
Cli nical lesi o ns:  Cli nical lesi o ns will o nl y be c o nsi dere d meas ura ble w he n t he y are s u perficial 
a n d ≥ 1 0 m m dia meter as assesse d usi n g cali pers (e. g., s ki n n o d ules). F or t he case of s ki n 
lesi o ns, d oc u me ntati o n b y c ol or p h ot o gra p h y i ncl u di n g a r uler t o esti mate t he size of t he lesi o n is 
s u g geste d. As n ote d a b o ve, w he n lesi o ns ca n be e val uate d b y b ot h cli nical e xa m a n d i ma gi n g, 
i ma gi n g e val uati o n s h o ul d be u n derta ke n si nce it is m ore o bjecti ve a n d ma y als o be re vie we d at 
t he e n d of t he st u d y. 
C hest X -ra y:  C hest C T is preferre d o ver c hest X -ra y, partic ularl y w he n pr o gressi o n is a n 
i mp orta nt e n d p oi nt, si nce C T is m ore se nsiti ve t ha n X-ra y, partic ularl y i n i de ntif yi n g ne w 
lesi o ns. H o we ver, lesi o ns o n c hest X-ra y ma y be c o nsi dere d meas ura ble if t he y are clearl y 
defi ne d a n d s urr o u n de d b y aerate d l u n g. Still, n o n- c o ntrast C T is preferre d o ver c hest X -ra y. 
C T, M RI :  C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns 
selecte d f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n 
base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. W he n C T sca ns ha ve slice 
t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice 
t hic k ness. M RI is als o acce pta ble i n certai n sit uati o ns (e. g., f or b o d y sca ns). 
If pri or t o e nr ol me nt it is k n o w n t hat a patie nt is n ot a ble t o u n der g o C T sca ns wit h I V c o ntrast 
d ue t o aller g y or re nal i ns ufficie nc y, t he decisi o n as t o w het her a n o n- c o ntrast C T or M RI ( wit h 
or wit h o ut I V c o ntrast) will be use d t o e val uate t he s u bject at baseli ne a n d f oll o w- u p, s h o ul d be 
g ui de d b y t he t u m or t y pe u n der i n vesti gati o n a n d t he a nat o mic l ocati o n of t he disease. F or 
patie nts w h o de vel o p c o ntrai n dicati o ns t o c o ntrast after baseli ne c o ntrast C T is d o ne, t he 
decisi o n as t o w het her n o n-c o ntrast C T or M RI (e n ha nce d or n o n-e n ha nce d) will be perf or me d, 
s h o ul d als o be base d o n t he t u m or t y pe, a nat o mic l ocati o n of t he disease a n d s h o ul d be o pti mize d 
t o all o w f or c o m paris o n t o t he pri or st u dies if p ossi ble. Eac h case s h o ul d be disc usse d wit h t he 
ra di ol o gist t o deter mi ne if s u bstit uti o n of t hese ot her a p pr oac hes is p ossi ble a n d, if n ot, t he 
p atie nt s h o ul d be c o nsi dere d n ot e v al u a ble fr o m t h at p oi nt f or w ar d.  
Ultras o u n d :  Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure me nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vie w at a later date a n d, beca use t he y are o perat or de pe n de nt, it ca n n ot be 
g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure me nts will be ta ke n fr o m o ne assess me nt t o t he 
ne xt. If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n b y C T or 
M RI is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure at C T, M RI ma y be use d i nstea d of 
C T i n selecte d i nsta nces.  
 
C O N FI D E N TI A L  
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P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
E n d osc o p y, la par osc o p y :  T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n is 
n ot a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n 
bi o psies are o btai ne d or t o deter mi ne rela pse i n trials w here rec urre nce f oll o wi n g c o m plete 
res p o nse or s ur gical resecti o n is a n e n d p oi nt.  
T u m or mar kers :  T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. If 
mar kers are i nitiall y a b o ve t he u p per n or mal li mit, h o we ver, t he y m ust n or malize f or a patie nt t o 
be c o nsi dere d i n c o m plete res p o nse. Beca use t u m or mar kers are disea se s pecific, i nstr ucti o ns f or 
t heir meas ure me nt s h o ul d be i nc or p orate d i nt o pr ot oc ols o n a disease s pecific basis. S pecific 
g ui deli nes f or b ot h C A- 1 2 5 res p o nse (i n rec urre nt o varia n ca ncer) a n d P S A res p o nse (i n 
rec urre nt pr ostate ca ncer), ha ve bee n p u blis he d. I n a d diti o n, t he G y nec ol o gic Ca ncer I nter gr o u p 
has de vel o pe d C A 1 2 5 pr o gressi o n criteria w hic h are t o be i nte grate d wit h o bjecti ve t u m or 
assess me nt f or use i n first -li ne trials i n o varia n ca ncer. 
C yt ol o g y, hist ol o g y :  T hese tec h ni q ues ca n be use d t o dif fere ntiate bet wee n P R a n d C R i n rare 
cases if re q uire d b y pr ot oc ol (f or e xa m ple, resi d ual lesi o ns i n t u m or t y pes s uc h as ger m cell 
t u m ors, w here k n o w n resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n t o be a 
p ote ntial a d verse effect of treat me n t (e. g., wit h certai n ta xa ne c o m p o u n ds or a n gi o ge nesis 
i n hi bit ors), t he c yt ol o gical c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or 
w orse ns d uri n g treat me nt ca n be c o nsi dere d if t he meas ura ble t u m or has met criteria f or res p o nse 
or st a ble disease i n or der t o differe ntiate bet wee n res p o nse ( or sta ble disease) a n d pr o gressi ve 
disease . 
T u m or res p o nse e v al u ati o n  
Assess me nt of o ver all t u m or b ur de n a n d me as ur a ble dise ase  
T o assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mate t he o verall t u m or 
b ur de n at baseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts. O nl y patie nts wit h 
meas ura ble disease at baseli ne s h o ul d be i ncl u de d i n pr ot oc ols w here o bjecti ve t u m or res p o nse is 
t he pri mar y e n d p oi nt. Meas ura ble disease is defi ne d b y t he prese nce of at least o ne meas ura ble 
lesi o n (as detaile d a b o ve i n t his Attac h me nt 2 ). I n st u dies w here t he pri mar y e n d p oi nt is t u m or 
pr o gressi o n (eit her ti me t o pr o gressi o n or pr o p orti o n wit h pr o gressi o n at a fi xe d date), t he 
pr ot oc ol m ust s pecif y if e ntr y is restricte d t o t h ose wit h meas ura ble disease or w het her patie nts 
ha vi n g n o n- meas ura ble disease o nl y are als o eli gi ble.  
 
 
 
C O N FI D E N TI A L  
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P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
B aseli ne d oc u me nt ati o n of ‘t ar get’ a n d ‘ n o n -t ar get’ lesi o ns 
W he n m ore t ha n o n e meas ura ble lesi o n is prese nt at baseli ne all lesi o ns u p t o a ma xi m u m of fi ve 
lesi o ns t otal (a n d a ma xi m u m of t w o lesi o ns per or ga n) re prese ntati ve of all i n v ol ve d or ga ns 
s h o ul d be i de ntifie d as tar get lesi o ns a n d will be rec or de d a n d meas ure d at baseli ne. 
T his mea ns i n i nsta nces w here patie nts ha ve o nl y o ne or t w o or ga n sites i n v ol ve d a ma xi m u m of 
t w o ( o ne site) a n d f o ur lesi o ns (t w o sites), res pecti vel y, will be rec or de d. Ot her lesi o ns i n t hat 
or ga n will be rec or de d as n o n- meas ura ble lesi o ns (e ve n if siz e is greater t ha n 1 0 m m b y C T 
sca n). 
Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re prese ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o 
re pr o d uci ble re pe ate d m e as ure me nts . It ma y be t he case t hat, o n occasi o n, t he lar gest lesi o n 
d oes n ot le n d itself t o re pr o d uci ble meas ure me nt i n w hic h circ u msta nce t he ne xt lar gest lesi o n 
w hic h ca n be meas ure d re pr o d uci bl y s h o ul d be selecte d. 
L y m p h n o des merit s pecial me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h ma y be 
visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or. Pat h ol o gical n o des w hic h are defi ne d as 
meas ura ble a n d ma y be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort a xis 
of ≥1 5 m m b y C T sca n.  O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne s u m. 
T he s h ort a xis of t he n o de is t he dia meter n or mall y use d b y ra di ol o gists t o j u d ge if a n o de is 
i n v ol ve d b y s oli d t u m or. N o dal size is n or mall y re p orte d as t w o di me nsi o ns i n t he pla ne i n w hic h 
t he i ma ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; f or M RI t he pla ne of 
ac q uisiti o n ma y be a xial, sa g gital or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. 
F or e xa m ple, a n a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m x 3 0 m m has a s h ort a xis of 
2 0 m m a n d q ualifies as a mali g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s h o ul d be 
rec or de d as t he n o de meas ure me nt. All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥1 0 m m 
b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n- tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are 
c o nsi dere d n o n- pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.  
A s u m of t he di a meters (l o n gest f or n o n- n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p orte d as t he b aseli ne s u m di a meters . If l y m p h n o des are t o be 
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. T he baseli ne 
s u m dia meters will be use d as refere nce t o f urt her c haracterize a n y o bjecti ve t u m or re gressi o n i n 
t he meas ura ble di me nsi o n of t he disease.  
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l y m p h n o des s h o ul d be i de ntifie d as 
n o n- tar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne. Meas ure me nts are n ot re q uire d a n d 
t hese lesi o ns s h o uld be f oll o we d as ‘ prese nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal 
pr o gressi o n.’ I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g t he sa me 
or ga n as a si n gle ite m o n t he case re p ort f or m (e. g., ‘ m ulti ple e nlar ge d pel vic l y m p h n o d es’ or 
‘ m ulti ple li ver metastases’).  
 
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Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Res p o nse criteri a  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne o bjecti ve t u m or res p o nse 
f or tar get lesi o ns. 
E v al u ati o n of t ar get lesi o ns 
•  C o m plete Res p o nse ( C R) :  Disa p peara nce of all tar get l esi o ns. A n y pat h ol o gical l y m p h 
n o des ( w het her tar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
•  Partial Res p o nse ( P R) :  At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, 
ta ki n g as refere nce t he baseli ne s u m dia meters.  
•  Pr o gressi ve Disease ( P D) :  At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get 
lesi o ns, ta ki n g as refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if 
t hat is t he s mallest o n st u d y). I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust 
als o de m o nstrate a n a bs ol ute i ncrease of at least 5 m m. ( N ote :  t he a p peara nce of o ne or 
m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n). 
•  Sta ble Disease ( S D) :  Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt 
i ncrease t o q ualif y f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u d y.  
S peci al n otes o n t he assess me nt of t ar get lesi o ns  
L y m p h n o des :  L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e xa mi nati o n), 
e ve n if t he n o des re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l y m p h n o des are 
i ncl u de d as tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot be zer o e ve n if c o m plete res p o nse criteria 
are met, si nce a n or mal  l y m p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. Case re p ort 
f or ms or ot her data c ollecti o n met h o ds ma y t heref ore be desi g ne d t o ha ve tar get n o dal lesi o ns 
rec or de d i n a se parate secti o n w here, i n or der t o q ualif y f or C R, eac h n o de m ust ac hie ve a s hort 
a xis < 1 0 m m. F or P R, S D a n d P D, t he act ual s h ort a xis meas ure me nt of t he n o des is t o be 
i ncl u de d i n t he s u m of tar get lesi o ns.  
Tar get lesi o ns t hat bec o me ‘t o o s mall t o meas ure’ :  w hile o n st u d y, all lesi o ns ( n o dal a n d 
n o n- n o dal) rec or de d at baseli ne s h o ul d ha ve t heir act ual meas ure me nts rec or de d at eac h 
s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e. g., 2 m m). H o we ver, s o meti mes lesi o ns or 
l y m p h n o des w hic h are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat t he 
ra di ol o gist ma y not feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as bei n g 
‘t o o s mall t o meas ure’. W he n t his occ urs it is i m p orta nt t hat a val ue be rec or de d o n t he case 
re p ort f or m: 
 
C O N FI D E N TI A L  
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P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
•  If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, t he 
meas ure me nt s h o ul d be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is 
fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d a n d 
B M L ( bel o w meas ura ble li mit) s h o ul d be tic ke d ( N ote:  It is less li kel y t hat t his r ule will 
be use d f or l y m p h n o des si nce t he y us uall y ha ve a defi na ble size w he n n or mal a n d are 
fre q ue ntl y s urr o u n de d b y fat s uc h as i n t he retr o perit o ne u m; h o we ver, if a l y m p h n o de 
is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue 
of 5 m m s h o ul d be assi g ne d i n t his circ u msta nce as well a n d B M L s h o ul d als o be tic ke d).  
T his defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h 
var yi n g C T slice t hic k ness). T he meas ure me nt of t h ese lesi o ns is p ote ntiall y n o n -re pr o d uci ble, 
t heref ore pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses or pr o gressi o ns base d u p o n 
meas ure me nt err or.  
T o reiter ate, h o we ver, if t he r a di ol o gist is a ble t o pr o vi de a n act u al me as ure, t h at s h o ul d be 
rec or de d, e ve n if it is bel o w 5 m m a n d i n t h at c ase B M L s h o ul d n ot be tic ke d. ( B M L is 
e q ui v ale nt t o a less t h a n si g n <)  
Lesi o ns t hat s plit or c oalesce o n treat me nt :  w he n n o n- n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d b e a d de d t o get her t o calc ulate t he tar get lesi o n s u m. 
Si milarl y, as lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat w o ul d ai d i n 
o btai ni n g ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr ul y 
c oalesce d s uc h t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n t his 
i nsta nce s h o ul d be t he ma xi mal l o n gest dia meter f or t he ‘c oalesce d lesi o n’. 
E v al u ati o n of n o n- t ar get lesi o ns 
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne t he t u m or res p o nse f or t he 
gr o u p of n o n- tar get lesi o ns. W hile s o me n o n-tar get lesi o ns ma y act uall y be meas ura ble, t he y 
nee d n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q ualitati vel y at t he ti me p oi nts 
s pecifie d i n t he pr ot oc ol.  
C o m plete Res p o nse ( C R) :  Disa p peara nce of all n o n- tar get lesi o ns a n d n or malizati o n of t u m or 
mar ker le vel. All l y m p h n o des m ust be n o n- pat h ol o gical i n size ( < 1 0 m m s h ort a xis). 
N o n -C R/ N o n -P D :  Persiste nce of o ne or m ore n o n -tar get lesi o n(s) a n d/ or mai nte na nce of t u m or 
mar ker le v el a b o ve t he n or mal li mits.  
Pr o gressi ve Disease ( P D) :  U ne q ui v ocal pr o gressi o n of e xisti n g n o n- tar get lesi o ns. ( N ote:  t he 
a p peara nce of o ne or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).  
S peci al n otes o n assess me nt of pr o gressi o n of n o n -t ar get disease 
 
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Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T he c o nce pt of pr o gressi o n of n o n- tar get disease re q uires a d diti o nal e x pla nati o n as f oll o ws:   
W he n t he patie nt als o has meas ura ble disease :  i n t his setti n g, t o ac hie ve ‘ u ne q ui v oc al 
pr o gressi o n’ o n t he b asis of t he n o n -t ar get dise ase, t here m ust be a n o ver all le vel of 
s u bst a nti al w orse ni n g i n n o n-t ar get dise ase i n a m a g nit u de t h at, e ve n i n prese nce of S D or 
P R i n t ar get dise ase, t he o ver all t u m or b ur de n h as i ncre ase d s ufficie ntl y t o merit 
disc o nti n u ati o n of t her a p y. A m o dest ‘i ncrease’ i n t he size of o ne or m ore n o n- tar get lesi o ns is 
us uall y n ot s ufficie nt t o q ualif y f or u ne q ui v oc al pr o gressi o n stat us. T he desi g nati o n of o verall 
pr o gressi o n s olel y o n t he basis of c ha n ge i n n o n- tar get disease i n t he face of S D or P R of tar get 
disease will t heref ore be e x tre mel y rare. 
W he n t he patie nt has o nl y n o n- meas ura ble disease :  t his circ u msta nce arises i n s o me p hase III 
trials w he n it is n ot a criteri o n of st u d y e ntr y t o ha ve meas ura ble disease. T he  sa me ge neral 
c o nce pts a p pl y here as n ote d a b o ve, h o we ver, i n t his i nsta nce t here is n o meas ura ble disease 
assess me nt t o fact or i nt o t he i nter pretati o n of a n i ncrease i n n o n -meas ura ble disease b ur de n. 
Beca use  w orse ni n g i n n o n -tar get disease ca n n ot be easil y q ua ntifie d ( b y defi niti o n:  if all lesi o ns 
are tr ul y n o n- meas ura ble) a usef ul test t hat ca n be a p plie d w he n assessi n g patie nts f or 
u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o verall disease b ur de n base d o n t he 
c ha n ge i n n o n- meas ura ble disease is c o m para ble i n ma g nit u de t o t he i ncrease t hat w o ul d be 
re q uired t o declare P D f or meas ura ble disease :  i.e., a n i ncrease i n t u m or b ur de n re prese nti n g a n 
a d diti o nal 7 3 % i ncrease i n ‘ v ol u me’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a 
meas ura ble lesi o n). E xa m ples i ncl u de a n i ncrease i n a ple ural eff usi o n fr o m ‘ trace’ t o ‘lar ge’, a n 
i ncrease i n l y m p ha n gitic disease fr o m l ocalize d t o wi des prea d, or ma y be descri be d i n pr ot oc ols 
as ‘s ufficie nt t o re q uire a c h a n ge i n t her a p y’. If ‘ u ne q ui v ocal pr o gressi o n’ is see n, t he patie nt 
s h o ul d be c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it w o ul d be i deal t o ha ve 
o bjecti ve criteria t o a p pl y t o n o n- meas ura ble disease, t he ver y nat ure of t hat disease ma kes it 
i m p ossi ble t o d o s o; t heref ore t he i ncrease m ust be s u bst a nti al. 
Ne w lesi o ns  
T he a p peara nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt. T here are n o s pecific criteria f or t he 
i de ntificati o n of ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be 
u ne q ui v ocal :  i.e., n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g 
m o dalit y or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her t ha n t u m or (f or e xa m ple, s o me ‘ ne w’ 
b o ne lesi o ns ma y be si m pl y heali n g or flare of pre-e xisti n g lesi o ns). T his is partic ularl y i m p orta nt 
w he n t he patie nt’s baseli ne lesi o ns s h o w partial or c o m plete res p o nse. F or e xa m ple, necr osis of a 
li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as a ‘ ne w’ c ystic lesi o n, w hic h it is n ot. 
A lesi o n i de ntifie d o n a f oll o w- u p st u d y i n a n a nat o mica l l ocati o n t hat was n ot sca n ne d at 
baseli ne is c o nsi dere d a ne w lesi o n a n d will i n dicate disease pr o gressi o n . A n e xa m ple of t his is 
t he patie nt w h o has visceral disease at baseli ne a n d w hile o n st u d y has a brai n C T or M RI 
 
C O N FI D E N TI A L  
8 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
or dere d w hic h re veals metastases. T he  patie nt’s brai n metastases are c o nsi dere d t o be e vi de nce 
of P D e ve n if he/s he di d n ot ha ve brai n i ma gi n g at baseli ne. 
If a ne w lesi o n is e q ui v ocal, f or e xa m ple beca use of its s mall size, c o nti n ue d t hera p y a n d 
f oll o w-u p e val uati o n will clarif y if it re p rese nts tr ul y ne w disease. If  re peat sca ns c o nfir m t here 
is defi nitel y a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n. 
( 1 8) F- Fl u or o de o x y gl uc ose P ositr o n E missi o n T o m o gr a p h y ( F D G-P E T)  
W hile F D G -P E T res p o nse assess me nts nee d a d diti o nal st u d y, it is s o meti mes reas o na ble t o 
i nc or p orate t he use of F D G-P E T sca n ni n g t o c o m ple me nt C T sca n ni n g i n assess me nt of 
pr o gressi o n ( partic ularl y p ossi ble ‘ ne w’ disease). Ne w lesi o ns o n t he basis of F D G- P E T i ma gi n g 
ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m :   
•  Ne gati ve F D G -P E T at baseli ne, wit h a p ositi ve F D G -P E T at f oll o w - u p is a si g n of P D 
base d o n a ne w lesi o n.  
•  N o F D G - P E T at baseli ne a n d a p ositi ve F D G-P E T at f oll o w - u p: 
•  If t he p ositi ve F D G-P E T at f oll o w - u p c orres p o n ds t o a ne w site of disease 
c o nfir me d b y C T, t his is P D. 
•  If t he p ositi ve F D G-P E T at f oll o w -u p is n ot c o nfir me d as a ne w site of disease o n 
C T, a d diti o nal f oll o w- u p C T sca ns are nee de d t o deter mi ne if t here is tr ul y 
pr o gressi o n occ urri n g at t hat site (if s o, t he date of P D will be t he date of t he 
i nitial a b n or mal F D G-P E T sca n).  
•  If t he p ositi ve F D G-P E T at f oll o w - u p c orres p o n ds t o a pre-e xisti n g site of disease 
o n C T t hat is n ot pr o gressi n g o n t he basis of t he a nat o mic i ma ges, t his is n ot P D.  
E v al u ati o n of best o ver all res p o nse  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y treat me nt u ntil 
t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire me nt f or c o nfir mati o n. O n occasi o n a 
res p o nse ma y n ot be d oc u me nte d u ntil after t he e n d of t hera p y s o pr ot oc ols s h o ul d be clear if 
p ost- treat me nt assess me nts are t o be c o nsi dere d i n deter mi nati o n of best o verall res p o nse. 
Pr ot oc ols m ust s pecif y h o w a n y ne w t hera p y i ntr o d uce d bef ore pr o gressi o n will affect best 
res p o nse desi g nati o n. T he patie nt’s best o verall res p o nse assi g n me nt will de pe n d o n t he fi n di n gs 
of b ot h tar get a n d n o n- tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w 
lesi o ns. F urt her m ore, de pe n di n g o n t he nat ure of t he st u d y a n d t he pr ot oc ol re q uire me nts, it ma y 
also re q uire c o nfir mat or y meas ure me nt. S pecificall y, i n n o nra n d o mize d trials w here res p o nse is 
t he pri mar y e n d p oi nt, c o nfir mati o n of P R or C R is nee de d t o dee m eit her o ne t he ‘ best o verall 
res p o nse’. T his is descri be d f urt her bel o w. 
 
C O N FI D E N TI A L  
9 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Ti me p oi nt res p o nse  
It is ass u me d t hat at eac h pr ot oc ol s pecifie d ti me p oi nt, a res p o nse assess me nt occ urs. Ta ble 6  
pr o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at eac h ti me p oi nt f or patie nts w h o 
ha ve meas ura ble disease at  baseli ne.  
W he n patie nts ha ve n o n- meas ura ble (t heref ore n o n -tar get) disease o nl y, Ta ble 7  is t o be use d.  
Missi n g assess me nts a n d n ot -e v al u a ble desi g n ati o n 
W he n n o i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me p oi nt, t he patie nt is n ot 
e val ua ble at t hat ti me p oi nt. If o nl y a s u bset of lesi o n meas ure me nts are ma de at a n assess me nt, 
us uall y t he case is als o c o nsi dere d n ot e val ua ble at t hat ti me p oi nt, u nless a c o n vi nci n g ar g u me nt 
ca n be ma de t hat t he c o ntri b uti o n of t he i n di vi d ual missi n g lesi o n(s) w o ul d n ot c ha n ge t he 
assi g ne d ti me p oi nt res p o nse. T his w o ul d be m ost li kel y t o ha p pe n i n t he case of P D.  
F or e xa m ple, if a patie nt ha d a baseli ne s u m of 5 0 m m wit h t hree meas ure d lesi o ns a n d at 
f oll o w- u p o nl y t wo lesi o ns were assesse d, b ut t h ose ga ve a s u m of 8 0 m m, t he patie nt will ha ve 
ac hie ve d P D stat us, re gar dless of t he c o ntri b uti o n of t he missi n g lesi o n.  
If o ne or m ore tar get lesi o ns were n ot assesse d eit her beca use t he sca n was n ot d o ne, or c o ul d n ot 
be a ssesse d beca use of p o or i ma ge q ualit y or o bstr ucte d vie w, t he Res p o nse f or Tar get Lesi o ns 
s h o ul d be “ U na ble t o Assess” si nce t he patie nt is n ot e val ua ble. Si milarl y, if o ne or m ore 
n o n- tar get lesi o ns are i n dicate d as ‘ n ot assesse d’, t he res p o nse f or n o n-tar get lesi o ns s h o ul d be 
“ U na ble t o Assess” (e xce pt w here t here is clear pr o gressi o n). O verall res p o nse w o ul d be 
“ U na ble t o Assess” if eit her t he tar get res p o nse or t he n o n -tar get res p o nse is “ U na ble t o Assess” 
(e xce pt w here t his is clear e vi de nce of pr o gressi o n) as t his e q uates wit h t he case bei n g n ot 
e val ua ble at t hat ti me p oi nt.  
Best o ver all res p o nse :  all ti me p oi nts 
T he best o verall res p o nse will be deter mi ne d b y statistical pr o gra m mi n g o nce all t he data f or t he 
patie nt is k n o w n. 
 
C O N FI D E N TI A L  
9 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T a ble 6: 
Ti me P oi nt Res p o nse :  P atie nts wit h T ar gets ( ± N o n -T ar get) Dise ase  
T ar get Lesi o ns  
N o n -T ar get Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N ot e val uate d  
N o  
P R  
P R  
N o n -P D or n ot all e val uate d  
N o  
P R  
S D  
N o n -P D or n ot all e val uate d  
N o  
S D  
N ot all e val uate d  
N o n -P D  
N o  
N E  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gre ssi ve disease, N E =  i ne val ua ble 
 
T a ble 7: 
Ti me P oi nt Res p o nse :  P atie nts wit h N o n-T ar get Dise ase O nl y  
N o n -T ar get Lesi o ns  
Ne w Lesi o ns  
O ver all Res p o nse  
C R  
N o  
C R  
N o n -C R/ N o n -P D  
N o  
N o n -C R/ n o n -P D a 
N ot all e val uate d  
N o  
N E  
U ne q ui v ocal P D  
Yes or N o  
P D  
A n y  
Yes  
P D  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gressi ve disease, N E =  i ne val ua ble 
a  
‘N o n -C R/ n o n -P D’ is preferre d o ver ‘sta ble disease’ f or n o n -tar get disease si nce S D is i ncreasi n gl y use d as 
e n d p oi nt f or assess me nt of efficac y i n s o me trials s o t o assi g n t his cate g or y w he n n o lesi o ns ca n be meas ure d 
is n ot a d vise d. 
 
 
C O N FI D E N TI A L  
9 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
T a ble 8: 
Best O ver all Res p o nse W he n C o nfir m ati o n of C R a n d P R Re q uire d  
O ver all 
Res p o nse First 
Ti me P oi nt  
O ver all Res p o nse 
S u bse q ue nt  
Ti me P oi nt  
B E S T O ver all Res p o nse  
C R  
C R  
C R  
C R  
P R  
S D, P D or P R a 
C R  
S D  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, P D  
C R  
P D  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, P D  
C R  
N E  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, N E  
P R  
C R  
P R  
P R  
P R  
P R  
P R  
S D  
S D  
P R  
P D  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, P D  
P R  
N E  
S D pr o vi de d mi ni m u m criteria f or S D d urati o n met, ot her wise, N E  
N E  
N E  
N E  
C R = c o m plete res p o nse, P R = partial res p o nse, S D = sta ble disease, P D = pr o gre ssi ve disease, NE  =  i ne val ua ble 
a 
If a C R is tr ul y met at first ti me p oi nt, t he n a n y disease see n at a s u bse q ue nt ti me p oi nt, e ve n disease meeti n g 
P R criteria relati ve t o baseli ne, ma kes t he disease P D at t hat p oi nt (si nce disease m ust ha ve rea p peare d after 
C R). Best res p o nse w o ul d de pe n d o n w het her mi ni m u m d urati o n f or S D was met. H o we ver, s o meti mes ‘ C R’ 
ma y be clai me d w he n s u bse q ue nt sca ns s u g gest s mall lesi o ns were li kel y still prese nt a n d i n fact t he patie nt 
ha d P R, n ot C R at t he first ti me p oi nt. U n der t hese circ u msta nces, t he ori gi nal C R s h o ul d be c ha n ge d t o P R 
a n d t he best res p o nse is P R.  
 
S peci al n otes o n res p o nse assess me nt  
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o ‘ n or mal’ 
size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns. T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstate pr o gressi o n s h o ul d it be 
base d o n i ncrease i n size of t he n o des. As n ote d earlier, t his mea ns t hat patie nts wit h C R ma y n ot 
ha ve a t otal s u m  of ‘zer o’ o n t he case re p ort f or m ( C R F).  
I n trials w here c o nfir mati o n of res p o nse is re q uire d, re peate d ‘ N E’ ti me p oi nt assess me nts ma y 
c o m plicate best res p o nse deter mi nati o n. T he a nal ysis pla n f or t he trial m ust a d dress h o w missi n g 
data/assess me nts will  be a d dresse d i n deter mi nati o n of res p o nse a n d pr o gressi o n. F or e xa m ple, 
i n m ost trials it is reas o na ble t o c o nsi der a patie nt wit h ti me p oi nt res p o nses of P R-N E -P R as a 
c o nfir me d res p o nse.  
Patie nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g d isc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as 
‘s y m pt o matic deteri orati o n’. E ver y eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n 
e ve n after disc o nti n uati o n of treat me nt. S y m pt o matic  deteri orati o n is n ot a descri pt or of a n 
 
C O N FI D E N TI A L  
9 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
o bjecti ve res p o nse :  it is a reas o n f or st o p pi n g st u d y t hera p y. T he o bjecti ve res p o nse stat us of 
s uc h patie nts is t o be deter mi ne d b y e val uati o n of tar get a n d n o n-tar get disease as s h o w n i n 
Ta ble 6 , Ta ble 7 , a n d Ta ble 8 .  
C o n diti o ns t hat defi ne ‘earl y pr o gressi o n, earl y deat h a n d n o n- e val ua bilit y’ are st u d y s pecific 
a n d s h o ul d be clearl y descri be d i n eac h pr ot oc ol ( de pe n di n g o n treat me nt d urati o n, treat me nt 
peri o dicit y).  
I n s o me circ u msta nces it ma y be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. 
W he n t he e val uati o n of c o m plete res p o nse de pe n ds u p o n t his deter mi nati o n, it is r ec o m me n de d 
t hat t he resi d ual lesi o n be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y) bef ore assi g ni n g a stat us of 
c o m plete res p o nse. F D G- P E T ma y be use d t o u p gra de a res p o nse t o a C R i n a ma n ner si milar t o 
a bi o ps y i n cases w here a resi d ual ra di o gra p hic a b n or malit y is t h o u g ht t o re prese nt fi br osis or 
scarri n g. T he use of F D G- P E T i n t his circ u msta nce s h o ul d be pr os pecti vel y descri be d i n t he 
pr ot oc ol a n d s u p p orte d b y disease s pecific me dical literat ure f or t he i n dicati o n. H o we ver, it m ust 
be ac k n o wle d ge d t hat b ot h a p pr oac hes ma y lea d t o false p ositi ve C R d ue t o li mitati o ns of 
F D G -P E T a n d bi o ps y res ol uti o n/se nsiti vit y.  
F or e q ui v ocal fi n di n gs of pr o gressi o n (e. g., ver y s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at 
t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he 
earlier date w he n pr o gressi o n was s us pecte d.  
 
C O N FI D E N TI A L  
9 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 3 :  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 b it 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 g a 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) 
 
 
C O N FI D E N TI A L  
9 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 4 :  M E T H O D S O F BI R T H C O N T R O L  
All W O C B P a n d se x uall y acti ve me n m ust a gree t o use acce pt a ble met h o ds of c o ntrace pti o n 
t hr o u g h o ut t he c o urse of t heir partici pati o n i n t his st u d y a n d f or at least 3 m o nt hs after t heir last 
d ose of st u d y dr u g. W O C B P m ust a gree t o use t w o f or ms of c o ntrace pti o n. Se x uall y acti ve male 
partici pa nts m ust a gree t o use a p h ysical barrier met h o d ( male late x r u b ber c o n d o m wit h or 
wit h o ut s per mici de).  
T a ble 9: 
List of Per missi ble C o ntr ace pti ve Met h o ds  
Met h o d  
W o me n E x perie nci n g U ni nte n de d Pre g n a nc y  
Wit hi n t he First Ye ar of  Use ( %)  
T y pic al Use 1 
Perf ect Use 2 
S per mici des 3 
2 9  
1 8  
C o n d o m 4  
- 
- 
 Male  
1 5  
2  
C o m bi ne d pill a n d pr o gesti n -o nl y pill  
8  
0. 3  
E vra Patc h  
8  
0. 3  
N u va Ri n g  
8  
0. 3  
De p o -Pr o vera  
3  
0. 3  
I ntra uteri ne de vice (I U D) 
- 
- 
 Para Gar d (c o p per T)  
0. 8  
0. 6  
 Mire na ( L N G -I U S) 
0. 2  
0. 2  
I m pla n o n 
0. 0 5  
0. 0 5  
Fe male Sterilizati o n  
0. 5  
0. 5  
Male Sterilizati o n  
0. 1 5  
0. 1 0  
S o urce :  Tr ussell J. C o ntrace pti ve Efficac y. I n :  Hatc her R A, Tr ussell J, Nels o n A L, Cates W Jr., Ste wart F H, K o wal 
D, e dit ors. C o ntrace pti ve Tec h n ol o g y . 1 9t h e d. Ne w Y or k, N Y:  Ar de nt Me di a, I nc.; 2 0 0 7. 
1.  A m o n g ty pic al c o u ples w h o i nitiate use of a met h o d ( n ot necessaril y f or t he first ti me), t he perce nta ge w h o 
e x perie nce a n acci de ntal pre g na nc y d uri n g t he first year if t he y d o n ot st o p use f or a n y ot her reas o n. Esti mates 
of t he pr o ba bilit y of pre g na nc y d uri n g t he first year of t y pical use f or s per mici des, wit h dra wal, peri o dic 
a bsti ne nce, t he dia p hra g m, t he male c o n d o m, t he pill, a n d De p o -Pr o vera are ta ke n fr o m t he 1 9 9 5 Nati o nal 
S ur ve y of Fa mil y Gr o wt h c orrecte d f or u n derre p orti n g of a b orti o n; see t he te xt f or t he deri vati o n of esti mates 
f or t he ot her met h o ds. 
2.  A m o n g c o u ples w h o i nitiate use of a met h o d ( n ot necessaril y f or t he first ti me) a n d w h o use it perfectly  ( b ot h 
c o nsiste ntl y a n d c orrectl y), t he perce nta ge w h o e x perie nce a n acci de nt al pre g na nc y d uri n g t he first year if t he y 
d o n ot st o p use f or a n y ot her reas o n.  
3. 
S per mici des are o nl y per mitte d w he n use d i n c o m bi nati o n wit h a male p h ysical barrier met h o d  
4.  Wit h o ut s per mici des.  
 
C O N FI D E N TI A L  
9 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 5 :  A M E N D M E N T 1 S U M M A R Y O F C H A N G E S  
N ote :  C ha n ges t hr o u g h o ut t he pr ot oc ol t hat are re petiti ve, self -e vi de nt or gra m matical ma y n ot be i n di vi d uall y 
liste d i n t his S u m mar y of C ha n ges.  
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 1  
R ati o n ale  
M aj or M o dific ati o ns  
S y n o psis a n d 
Secti o n 1 0. 1  
1 2.  A de q uate b o ne  marr o w 
reser ve:  A N C ≥1 0 0 0/ m m 3, 
platelets ≥1 0 0, 0 0 0/ m m 3 
1 2.  A de q uate b o ne marr o w 
reser ve:  A N C ≥1 5 0 0/ m m 3, 
platelets ≥1 0 0, 0 0 0/ m m 3 
M o dificati o n t o e ns ure 
patie nts ha ve a de q uate b o ne 
marr o w reser ves t o recei ve 
paclita xel  
S y n o psis a n d 
Secti o n 1 0. 1  
1 4.  A de q ua te he patic f u ncti o n:  
A S T a n d A L T < 2. 5 x U L N; 
T otal a n d Direct Bilir u bi n 
< 1. 5 x  U L N.  H o we ver, i n 
t he prese nce of li ver 
me tastases, A S T a n d A L T 
m ust be < 5 x U L N a n d 
T ot al  a n d Direct Bilir u bi n 
m ust be < 3 x U L N.  
1 4.  A de q uate he patic f u ncti o n :  
A S T a n d A L T < 2. 5 x U L N. 
T otal a n d Direct Bilir u bi n 
< 1. 5 x U L N. H o we ver, i n t he 
prese nce of li ver metastases, 
A S T a n d A L T m ust be < 5 x 
U L N.  
M o dificati o n t o e ns ure 
patie nts ha ve a de q uate 
he patic f u ncti o n pri or t o 
e nr oll me nt i nt o t he trial . 
Patie nts wit h li ver metastases 
m ust meet  t he sa me T otal a n d 
Direct Bilir u bi n le vels as 
patie nts wit h o ut li ver t u m or 
i n v ol ve me nt. 
S y n o psis a n d 
Secti o n 1 0. 1  
1 5.  Car diac ejecti o n fracti o n 
≥5 0 %, a n d Q Tc F < 4 5 0 ms 
o n E C G at Baseli ne  
1 5.  Car diac ejecti o n fracti o n  
≥5 0 %, a n d Q Tc F < 4 5 0 ms 
( m ales) or < 4 7 0 ms 
(fe m ales) o n E C G at 
Baseli ne  
M o dificati o n t o acc o m m o date 
fe male n or mal ra n ge f or 
Q Tc F  
S y n o psis a n d 
Secti o ns 1 3. 2 
a n d 1 3. 5  
 
A w h ole bl o o d sa m ple f or 
circ ulati n g C D 1 4/ C D 1 6 p ositi ve 
m o n oc yte a nal ysis will be 
o btai ne d pre  d ose [ o n C 1 D 1 a n d 
C 1 D 1 5  
A d diti o n t o gat her a d diti o nal 
p har mac o d y na mic data 
P L X 3 3 9 7 + paclita xel 
c o m bi nati o n 
S y n o psis a n d 
Secti o n 1 3. 1 2  
[ N o n-he mat ol o gic D L Ts - 
e xe m pti o ns]  
•  Gra de 3 fati g ue t hat res ol ves 
wit hi n 1 4 da ys, wit h or 
wit h o ut me dical i nter ve nti o n 
or pr o p h yla xis  
[ N o n-he mat ol o gic D L Ts -
e xe m pti o ns] 
•  Gra de 3 fati g ue t hat res ol ves 
t o ≤Gr a de 2  wit hi n 1 4 da ys  
A d diti o n of res ol uti o n t o 
Gra de 2 f or m ore s pecificit y 
i n t he Gra de 3 fati g ue D L T 
e xe m pti o n defi niti o n .  
 
C O N FI D E N TI A L  
9 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 1  
R ati o n ale  
S y n o psis a n d 
Secti o n 1 3. 1 2  
 
[ N o n-he mat ol o gic D L Ts]  
•  Gr a de 3 peri p her al 
ne ur o p at h y  i n p atie nts wit h 
b aseli ne ≥Gr a de 1 
peri p her al ne ur o p at h y or a 
hist or y of c he m ot her a p y -
ass oci ate d peri p her al 
ne ur o p at h y  
•  Gr a de 3 m y al gi a or 
art hr al gi a i n p atie nts wit h 
b aseli ne ≥Gr a de 1 m y al gi a 
or art hr al gi a  
•  Gr a des 3 r as h f or w hic h 
s y m pt o ms are e asil y 
m a n a g e d wit h s u p p orti ve 
c are a n d t here is n o 
e vi de nce of s u peri nfecti o n 
or li mit ati o n of self -c are 
A D Ls.  
A d diti o n of Gra de 3 
peri p heral ne ur o pat h y i n 
patie nts will Gra de 1 
s y m pt o ms as a D L T 
e xe m pti o n beca use peri p heral 
ne ur o pat h y is a c o m m o n 
t o xicit y ass ociate d wit h 
ta xa nes a n d ot her 
c he m ot hera pies. Ac ute 
s y m pt o ms or w orse ni n g of 
peri p heral ne ur o pat h y wit h 
paclita xel i n t his patie nt 
p o p ulati o n is e x pecte d.  
A d diti o n of Gra de 3 m yal gia 
or art hra gia beca use t hese are 
c o m m o n t o xicities ass ociate d 
wit h paclita xel tre at me nt a n d 
e x pecte d i n t his p o p ulati o n.  
A d diti o n of Gra de 3 
ma na gea ble ras h beca use t his 
is a c o m m o n t o xicit y 
ass ociate d wit h paclita xel 
treat me nt a n d e x pecte d i n t his 
p o p ulati o n.  
S y n o psis a n d 
Secti o n 1 3. 1 2  
A tre at me nt del a y of gre ater 
t h a n 7 d a ys f or P L X 3 3 9 7 or 
missi n g m ore t h a n 1 o ut of t he 
4 wee kl y d oses of p aclit a xel i n 
t he first c ycle d ue t o t o xicit y 
t h at is n ot rel ate d t o c a ncer 
w orse ni n g or i nterc urre nt 
ill ness will be c o nsi dere d a 
D L T.  
 
Re m o ve d as t his is c o vere d 
b y t he D L T defi niti o ns. 
Patie nts w h o miss d oses of 
eit her P L X 3 3 9 7 or paclita xel 
d uri n g C ycle 1 f or reas o ns 
ot her t ha n a D L T will be 
re place d.  
 
C O N FI D E N TI A L  
9 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 1  
R ati o n ale  
Secti o n 1 2. 0  
Fil grasti m gr o wt h fact or s u p p ort 
is e nc o ura ge d f or A N C 
< 1 5 0 0/ m m 3 a n d ma y be use d at 
t he discreti o n of t he treati n g 
p h ysicia n i n or der t o mai ntai n 
a de q uate bl o o d c o u nts 
E X C E P T d uri n g t he first 
c ycle. Fil grasti m is n ot 
per mitte d wit hi n 2 4 h o urs pri or 
t o or f oll o wi n g a n y paclita xel 
i nf usi o n. Pe gfil grasti m 
( Ne ulasta) is n ot per mitte d i n 
t his st u d y. 
Fil grasti m gr o wt h fact or s u p p ort 
is e nc o urage d f or A N C 
< 1 5 0 0/ m m 3 a n d ma y be use d at 
t he discreti o n of t he Pri nci p al 
I n vesti g at or i n c o ns ult ati o n 
wit h t he Me dic al M o nit or. 
Gr o wt h f act ors m a y be 
a d mi nistere d t hr o u g h o ut t he 
st u d y, i ncl u di n g d uri n g C ycle 
1, i n or der t o m ai nt ai n 
a de q u ate bl o o d c o u nts. F or 
p atie nts w h ose A N C is bet wee n 
1 5 0 0 – 2 0 0 0 cells/ m m 3, 
Fil gr asti m m a y be 
a d mi nistere d fr o m d a ys 2 – 5 
(t ot al of 4 d a ys) after t he m ost 
rece nt p aclit a xel i nf usi o n. 
Fil grasti m is n ot per mitte d wit hi n 
2 4 h o urs pri or t o or f oll o wi n g 
a n y paclita xel i nf usi o n. 
Pe gfi l grasti m ( Ne ulasta) is n ot 
per mitte d i n t his st u d y.  
M o dificati o n. Gr o wt h fact or 
s u p p ort is re g ularl y use d i n 
r o uti ne practice t o hel p 
patie nts ac hie ve a de q uate 
ne utr o p hil c o u nts i n or der t o 
recei ve paclita xel. T his 
m o dificati o n was ma de i n 
or der t o ma ke t h is pr ot oc ol 
c o nsiste nt wit h t he sta n dar d -
of -care f or wee kl y paclita xel.  
S y n o psis, 
Secti o ns 9. 2 
a n d 1 3. 1 5  
O ne d ose of paclita xel ma y be 
s ki p pe d e ver y [t hree/f o ur] 
wee ks  f or s u bse q ue nt c ycles 
(i.e., C ycle 2 +) per I n vesti gat or 
discreti o n a n d/ or patie nt 
prefe re nce.  
O ne d ose of paclita xel ma y be 
s ki p pe d per C ycle  f or 
s u bse q ue nt c ycles (i.e., C ycle 2 +) 
per I n vesti gat or discreti o n a n d/ or 
patie nt prefere nce . I n ge ner al, 
t w o c o nsec uti ve d oses of 
p aclit a xel s h o ul d n ot be 
s ki p pe d. 
M o dificati o n a n d 
clarificati o n. T he  ori gi nal 
pr ot oc ol was i nc o nsiste nt 
bet wee n stati n g e ver y t hree 
wee ks or e ver y f o ur wee ks. 
T he m o dificati o n was a d de d 
t o clarif y t he per mitte d 
fre q ue nc y f or s ki p pi n g a 
paclita xel d ose.  
Secti o n 7. 6  
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 …[  
]..As of J u ne 2 0 1 1 , a t otal of 4 1  
patie nts ha ve bee n treate d wit h 
P L X 3 3 9 7 P O …[  ] …t he mea n 
acc u m ulati o n rati o c o m pare d t o 
Da y 1 val ues is a p pr o xi matel y 
1. 6 . I n ge neral, t here is 
i ncreasi n g e x p os ure wit h 
i ncreasi n g d ose …[ ] … T he 
m ost c o m m o n A Es ha ve bee n 
n a use a  a n d f ati g ue . 
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 …[  
] … 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 P O , i ncl u di n g 4 1 
p atie nts i n t he d ose esc al ati o n 
c o h orts a n d 2 1 p atie nts i n t he 
E xte nsi o n c o h orts …[ ] … t he 
mea n acc u m ulati o n rati o 
c o m pare d t o Da y 1 val ues is 
a p pr o xi matel y 2: 1 . I n ge neral, 
t here is g o o d d ose 
pr o p orti o n alit y,  wit h i ncreasi n g 
e x p os ure wit h i ncreasi n g d ose …[  
] … T he m ost c o m m o n A Es ha ve 
bee n f ati g ue, decre ase d a p petite 
a n d n a use a . 
 
Ge neral u p dates base d o n ne w 
data  
 
C O N FI D E N TI A L  
9 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 1  
R ati o n ale  
Secti o n 1 2. 0  
 
Pr o p h yl a xis or me dic al 
m a n a ge me nt f or n a use a a n d 
v o miti n g wit h a ntie metics is 
e nc o ur a ge d, p artic ul arl y i n 
p atie nts wit h a hist or y of 
n a use a or v o miti n g wit h pri or 
t a x a ne t her a p y. 
A d diti o n  t o pr o vi de g ui da nce 
f or pre ve nti n g a n d ma na gi n g 
na usea a n d v o miti n g.  
Secti o n 1 3. 1 4  
P L X 3 3 9 7 d ose re d ucti o ns a n d 
i nterr u pti o ns will be per mitte d 
d uri n g t he first 2 8 da ys of C ycle 
1 o nl y if a patie nt e x perie nces a 
D L T . If a patie nt e x perie nces a 
D L T d uri n g C ycle 1, P L X 3 3 9 7 
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. After C 1 D 2 8, 
d ose re d ucti o ns or i nterr u pti o ns 
f or a d verse e ve nts ma y ta ke 
place at a n y ti me.  
P L X 3 3 9 7 d ose re d ucti o ns a n d 
i nterr u pti o ns will be per mitte d 
d uri n g t he first 2 8 da ys of C ycle 
1 o nl y if a patie nt e x perie nces a 
D L T . P L X 3 3 9 7 i nterr u pti o ns 
d uri n g C ycle 1 are als o 
per mitte d f or Gr a de 3 v o miti n g 
t h at persists des pite o pti m al 
s u p p orti ve c are. If a patie nt 
e x perie nces a D L T d uri n g C ycle 
1, P L X 3 3 9 7 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. After C 1 D 2 8, d ose 
re d ucti o ns or i nterr u pti o ns f or 
a d verse e ve nts ma y ta ke place at 
a n y ti me.  
A d diti o n t o clar if y patie nt 
ma na ge me nt of Gra de 3 
e mesis i n C ycle 1.  
Secti o n 1 3. 1 4  
 
F or Gr a de 3 e mesis t h at 
persists des pite o pti m al 
s u p p orti ve c are, P L X 3 3 9 7 
d oses s h o ul d be hel d u ntil 
res ol uti o n t o Gr a de 2 or less.  
A d diti o n f or clarificati o n o n 
t he ma na ge me nt of e mesis 
Secti o n 1 3. 1 4  
 
F or c ases of Gr a de 3 
s y m pt o m atic r as h t h at persists 
des pite me dic al i nter ve nti o n, 
P L X 3 3 9 7 d oses s h o ul d be hel d 
u ntil res ol uti o n t o Gr a de 2 or 
less. U p o n rei ntr o d ucti o n of 
P L X 3 3 9 7, t he d ose le vel s h o ul d 
be re d uce d b y 2 0 0 m g/ d a y.  
A d diti o n f or  clarificati o n o n 
t he ma na ge me nt of ras h 
Secti o n 1 3. 1 6  
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 ( or 
desi g nee) 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 st u d y 
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. 
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 ( or desi g nee) 
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 h e st u d y fl o w 
c hart wit hi n 2 8  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.  
M o dificati o n f or c o nsiste nc y 
wit h pre vi o us secti o ns  
 
C O N FI D E N TI A L  
1 0 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 1  
R ati o n ale  
Secti o n 1 4. 1. 2  A pt uit  
1 0 2 4 5 Hic k ma n Mills Dri ve 
Ka nsas Cit y, M O 6 4 1 3 7  
Catale nt  P har ma S ol uti o ns  
(f or merl y A pt uit) 
1 0 2 4 5 Hic k ma n Mills Dri ve  
Ka nsas Cit y, M O 6 4 1 3 7  
U p date  
Secti o n 2 1. 3  
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 e C R F.  
All S A Es, ot he r 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 
e C R F i n T E M P O. 
Clarificati o n  
T a ble 3 :  D ose 
M o dific ati o n 
G ui deli nes f or 
P L X 3 3 9 7  
[ He mat ol o gical t o xicit y d ose 
re d ucti o ns occurre d i n 3 0 0 
m g/ da y i ncre me nts]  
[ He mat ol o gical t o xicit y d ose 
re d ucti o ns c ha n ge d t o occ ur i n 
2 0 0 m g/ da y i ncre me nts]  
M o dificati o n f or c o nsiste nc y 
wit h n o n -he mat ol o gical 
t o xicit y d ose re d ucti o n 
i ncre me nts 
 
 
 
C O N FI D E N TI A L  
1 0 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 6 :  A M E N D M E N T 2 S U M M A R Y O F C H A N G E S  
N ote :  C ha n ges t hr o u g h o ut t he pr ot oc ol t hat are re petiti ve, self -e vi de nt or gra m matical ma y n ot be i n di vi d uall y 
liste d i n t his S u m mar y of C ha n ges.  
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 2  
R ati o n ale  
M aj or M o dific ati o ns  
S y n o psis a n d 
Secti o n 8. 0  
T he pri mar y o bj ecti ve of t his 
P hase 1 b st u d y is t o esta blis h 
t he d ose li miti n g t o xicities 
( D L Ts) a n d m a xi m u m 
t oler ate d d ose ( M T D) of 
P L X 3 3 9 7 w he n gi ve n i n 
c o m bi nati o n wit h wee kl y 
sta n dar d d ose paclita xel i n 
patie nts wit h a d va nce d s oli d 
t u m ors. 
T he pri mar y o bjecti ve of t h is 
P hase 1 b st u d y is t o esta blis h t he 
d ose li miti n g t o xicities ( D L Ts) 
a n d rec o m me n de d P h ase 2 d ose 
( R 2 P D) of P L X 3 3 9 7 w he n gi ve n 
i n c o m bi nati o n wit h wee kl y 
sta n dar d d ose paclita xel i n 
patie nts wit h a d va nce d s oli d 
t u m ors. 
M o dificati o n t o per mit t he 
selecti o n of t he R P 2 D base d 
o n eit her P K data or reac hi n g 
a n M T D. If a bs or pti o n a n d 
s yste mic e x p os ure of 
P L X 3 3 9 7 reac hes a platea u 
pri or t o esta blis h me nt of a n 
M T D, it w o ul d n ot be 
necessar y t o c o nti n ue 
escalati n g P L X 3 3 9 7 d osa ge.  
S y n o psis  
T his is a n o nra n d o mize d,  o pe n -
la bel p hase 1 b st u d y e m pl o yi n g 
a sta n dar d 3 + 3 d ose escalati o n 
desi g n t o deter mi ne t he M T D  
of P L X 3 3 9 7, a n o vel i n hi bit or 
of t he C S F -1 rece pt or ( F ms), 
w he n a d mi nistere d i n 
c o m bi nati o n wit h paclita xel i n 
patie nts wit h a d va nce d s oli d 
t u m ors. 
T his is a n o nra n d o mize d, o pe n -
la bel p hase 1 b st u d y e m pl o yi n g 
a sta n dar d 3 + 3 d ose escalati o n 
desi g n t o deter mi ne t he R P 2 D  of 
P L X 3 3 9 7, a n o vel i n hi bit or of 
t he C S F-1 rece pt or ( F ms), w he n 
a d mi nistere d i n c o m bi nati o n 
wit h paclita xel i n patie nts wit h 
a d va nce d s oli d t u m ors.  
M o dificati o n t o per mit t he 
selecti o n of t he R P 2 D base d 
o n eit her P K data or reac hi n g 
a n M T D. If a bs or pti o n a n d 
s yste mic e x p os ure of 
P L X 3 3 9 7 reac hes a platea u 
pri or t o esta blis h me nt of a n 
M T D, it w o ul d n ot be 
necessar y t o c o nti n ue 
escalati n g P L X 3 3 9 7 d osa ge . 
S y n o psis  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y ( BI D) usi n g a 
c o nti n u o us d osi n g re gi me n. T he 
pl a n ne d c o h orts are C o h ort 1 :  
6 0 0 m g/ d a y, C o h ort 2 :  8 0 0 
m g/ d a y  a n d C o h ort 3 :  1 0 0 0 
m g/ d a y  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y ( BI D) us i n g a 
c o nti n u o us d osi n g re gi me n. T he 
st arti n g d ose of P L X 3 3 9 7 will 
be 6 0 0 m g/ d a y. D ose esc al ati o n 
will occ ur i n i ncre me nts of 
≤5 0 %.   
M o dificati o n t o per mit 
escalati o n of P L X 3 3 9 7 
be y o n d 1 0 0 0 m g/ da y base d 
o n safet y a n d t olera bilit y data.  
 
C O N FI D E N TI A L  
1 0 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 2  
R ati o n ale  
Secti o n 9. 1  
Pr ot oc ol P L X 1 0 8 -0 7 is a P hase 
1 b o pe n -la bel, se q ue ntial d ose 
escalati o n trial of P L X 3 3 9 7 pl us 
paclita xel. T he st u d y e m pl o ys a 
tra diti o nal 3 + 3 desi g n. 
Treat me nt wit h P L X 3 3 9 7 will 
c o nsist of c o nti n u o us oral 
a d mi nistrati o n a n d e nr oll me nt 
will be gi n at t he 6 0 0 m g/ da y 
d ose le vel f or 2 8 da ys. 
Paclita xel will be a d mi nistere d 
o nce wee kl y ( ± 4 8 h o urs).  
Pr ot oc ol P L X 1 0 8 -0 7 is a P hase 
1 b o pe n -la bel, se q ue ntial d ose 
escalati o n trial of P L X 3 3 9 7 pl us 
paclita xel. T he st u d y e m pl o ys a 
tra diti o nal 3 + 3 desi g n. Treat me nt 
wit h P L X 3 3 9 7 will c o nsist of 
c o nti n u o us oral a d mi nistrati o n 
a n d e nr oll me nt will be gi n at t he 
6 0 0 m g/ da y d ose le vel f or 2 8 
da ys. Paclita xel will b e 
a d mi nistere d o nce wee kl y 
( ± 4 8 h o urs). T he pl a n ne d 
sc he d ule f or P L X 3 3 9 7 d ose 
esc al ati o ns is s h o w n i n T a ble 2. 
F or d oses hi g her t h a n 1 0 0 0 
m g/ d a y, t he d ose esc al ati o n 
i ncre me nt m a y be a dj uste d 
b ase d o n t he o bser ve d t o xicit y 
a n d s yste mic e x p os ure at t he 
pre vi o us d ose le vel. H o we ver, 
t he m a xi m u m d osi n g i ncre me nt 
will be 5 0 %.  
M o dificati o n t o per mit 
escalati o n of P L X 3 3 9 7 
be y o n d 1 0 0 0  m g/ da y base d 
o n safet y a n d t olera bilit y data.  
Secti o n 9. 1 
T a ble 2  
 
[ P L X 3 3 9 7 D ose Le vels 3 ( 1 2 0 0 
m g/ da y, 4 ( 1 6 0 0 m g/ da y) a n d 5 
2 0 0 0 m g/ da y) a d de d t o D ose 
Escalati o n Sc he d ule]  
M o dificati o n t o pr o vi de 
d osi n g pla n a n d i nstr ucti o ns 
f or P L X 3 3 9 7 d ose le vels 
a b ove 1 0 0 0 m g/ da y  
S y n o psis  
T he t otal n u m ber of patie nts t o 
be e nr olle d will de pe n d o n t he 
n u m ber of c o h orts a n d w het her 
a c o h ort re q uires 3 or 6 patie nts  
T he t otal n u m ber of patie nts t o 
be e nr olle d will de pe n d o n t he 
n u m ber of c o h orts, w het her a 
c o h ort re q u ires 3 or 6 patie nts 
a n d w het her p atie nts w h o are 
n ot e v al u a ble f or D L Ts nee d t o 
be re pl ace d.  
 
U p date d t o ta ke i nt o acc o u nt 
t he e nr oll me nt of a d diti o nal 
patie nts i n a gi ve n c o h ort t o 
re place patie nts w h o are n ot 
e val ua ble f or D L Ts  
 
C O N FI D E N TI A L  
1 0 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 2  
R ati o n ale  
Secti o n 9. 2  
A fi xe d d ose  of paclita xel, 8 0 
m g/ m 2, will be a d mi nistere d 
i ntra ve n o usl y, o nce wee kl y 
( ± 4 8 h o urs). Patie nts m ust 
recei ve at least 3 of 4 paclita xel 
d oses d uri n g t he D L T peri o d 
(i.e., C ycle 1). O ne d ose of 
paclita xel ma y be s ki p pe d per 
C ycle f or s u bse q ue nt c ycles 
(i.e., C ycle 2 +) per I n vesti gat or 
discreti o n a n d/ or patie nt 
prefere nce. I n ge neral, t w o 
c o nsec uti ve d oses of paclita xel 
s h o ul d n ot be s ki p pe d. 
A fi xe d d ose le vel of paclita xel, 
8 0 m g/ m 2, will be a d mi nistere d 
i ntra ve n o usl y, o nce wee kl y 
( ± 4 8 h o urs). Patie nts m ust  
recei ve at least 3 of 4 paclita xel 
d oses d uri n g t he D L T peri o d 
(i.e., C ycle 1) i n or der t o be 
c o nsi dere d e v al u a ble f or D L T, 
u nless d oses are misse d d ue t o 
a D L T. O ne d ose of paclita xel 
ma y be s ki p pe d per C ycle f or 
s u bse q ue nt c ycles (i.e., C ycle 2 +) 
per I n vesti gat or discreti o n a n d/ or 
patie nt prefere nce. I n ge neral, 
t w o c o nsec uti ve d oses of 
paclita xel s h o ul d n ot be s ki p pe d.  
Ge neral clarificati o ns  f or 
re q uire d d osi n g i n C ycle 1 
Secti o n 9. 2  
T he P L X 3 3 9 7 + paclita xel 
c o m bi nati o n will be offere d t o 
eac h patie nt as l o n g as b ot h t he 
patie nt a n d I n vesti gat or a gree 
t hat it c o nti n ues t o be well 
t olerate d a n d t he patie nt is 
cli nicall y be nefitti n g  
[ para gra p h delete d] 
Re d u n da nt wit h state me nt i n 
Secti o n 9. 6  
Secti o n 1 4. 1. 1  P L X 3 3 9 7 s h o ul d be ta ke n orall y 
wit h 2 4 0 m L ( 8 oz ) of r o o m 
te m per at ure water i n t he 
fasti n g state. 
P L X 3 3 9 7 s h o ul d be ta ke n orall y 
wit h 2 4 0 m L ( 8 oz) of water i n 
t he fasti n g state. 
M o dificati o n of i nstr ucti o ns. 
Water te m perat ure is n ot 
rec or de d a n d is n ot necessar y 
f or t he pr o per a d mi nistrati o n 
of P L X 3 3 9 7  
Secti o n 1 4. 1. 1  Misse d d oses of greater t h a n 2 
h o urs bef ore or after t he 
a p pr o pri ate d osi n g  ti me s h o ul d 
be s ki p pe d a n d n ot ta ke n as a 
d o u ble d ose at t he ne xt d osi n g 
ti me p oi nt. F or e xa m ple, a 
patie nt w h o ta kes t heir 
P L X 3 3 9 7 at 8 a  m. a n d 8 p. m. 
eac h da y s h o ul d n ot ta ke t heir 
d ose if t he y are o utsi de of t he 
± 2 hr wi n d o w peri o d.  T his 
a p plies t o b ot h BI D a n d 
a p pr o ve d Q D d osi n g.  
Misse d d oses of greater t ha n 2 
h o urs after t he a p pr o pri ate 
d osi n g ti me  s h o ul d be s ki p pe d 
a n d n ot ta ke n as a d o u ble d ose at 
t he ne xt dosi n g ti me p oi nt. F or 
e xa m ple, a patie nt w h o ta kes 
t heir P L X 3 3 9 7 at 8 a  m. a n d 8 
p  m. eac h da y s h o ul d n ot ta ke 
t heir d ose if it h as bee n 14 or 
m ore h o urs si nce t heir l ast 
d ose.  T his a p plies t o b ot h BI D 
a n d a p pr o ve d Q D d osi n g.  
M o dificati o n of i nstr ucti o ns. 
A misse d d ose w o ul d n ot 
occ ur pri or t o t he sc he d ule d 
d osi n g ti me.  
 
 
 
C O N FI D E N TI A L  
1 0 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  




P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n(s)  
Ori gi n al Pr ot oc ol  
A me n d me nt 3  
R ati o n ale  
Trial Fl o w C hart  S u perscri pt err ors:  
Paclita xel A d mi nist rati o n4 
Vital Si g ns 9 
1 2 -Lea d E C G 1 0 
C he mistr y 1 3 
He mat ol o g y 1 1 
Uri ne Pre g na nc y Test 1 2 
A d verse E ve nts 8 
S u perscri pt C orrecti o ns:  
Paclita xel A d mi nistrati o n 4, 6 
Vital Si g ns 1 0 
1 2 -lea d E C G1 1 
C he mistr y 1 4 
He mat ol o g y 1 2 
Uri ne Pre g na nc y Test 1 3 
A d verse E ve nts 9 
C orrecti o n of n u m beri n g 
err ors 
Plas ma f or P K:  
Da y 1 :  X 6 
C ycle 1 Da y 1 5 :  X 7 
C ycle 2 Da y 1 :  X 1 4 
Plas ma f or P D bi o mar kers : 
Da y 1 :  X 1 4 
C ycle 2 Da y 1 :  X 1 4 
Plas ma f or P K:  
Da y 1 :  X 7 
C ycle 1 Da y 1 5 :  X 8 
C ycle 2 Da y 1 :  X 7 
Plas ma f or P D bi o mar kers : 
Da y 1 :  X 1 5 
C ycle 2  Da y 1 :  X 1 5 
Trial Fl o w C hart  E x pla nati o n of S u perscri pt # 2:  
T he a  m. d ose of P L X 3 3 9 7 
ma y be ta ke n at h o me, pri or t o 
t he cli nic visit o n all cli nic visit 
da ys e xce pt o n C 1 D 1 
( Baseli ne) a n d C 1 D 1 5. O n 
t h ose t w o st u d y da ys, t he 
m or ni n g d ose of P L X 3 3 9 7 will 
be a d mi nistere d i n t he cli nic 
after o btai ni n g a pre -d ose 
bl o o d sa m ple f or P K a nal ysis.  
E x pla nati o n of S u perscri pt # 2:  
T he a. m. d ose of P L X 3 3 9 7 ma y 
be ta ke n at h o me, pri or t o t he 
cli nic visit o n all cli nic visit da ys 
e xce pt o n C 1 D 1 ( Baseli ne) a n d 
C 1 D 1 5 , a n d C 2 + D 1 . O n t h ose 
t w o st u d y da ys, t he m or ni n g d ose 
of P L X 3 3 9 7 will be a d mi nistere d 
i n t he cli nic after o btai ni n g a pre-
d ose bl o o d sa m ple f or P K 
a nal ysis.  
M o dificati o n f or c o nsiste nc y 
wit h pr ot oc ol secti o n 1 3. 8  
Secti o n 9. 1, 
Ta ble 2  
Le vel 5  
P L X 3 3 9 7 BI D D ose  
( 8 0 0 m g P O BI D) 
Le vel 5  
P L X 3 3 9 7 BI D D ose  
(1 0 0 0  8 0 0  m g P O BI D)  
C orrecti o n of t y p o gra p hical 
err or. 
 
 
 
 
C O N FI D E N TI A L  
1 0 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 8 :  A M E N D M E N T 4 S U M M A R Y O F C H A N G E S  
N ote :  C ha n ges t hr o u g h o ut t he pr ot oc ol t hat are re petiti ve, self-e vi de nt or gra m matical ma y n ot 
be i n di vi d uall y liste d i n t his S u m mar y of C ha n ges.  
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
6. 0 S Y N O P SI S :  
St u d y 
O bjecti ve(s)  
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
T his tri al is desi g ne d as a t w o -
p art st u d y :  P art 1 ( P h ase 1 b), 
t o e x pl ore t he s afet y of 
esc al ati n g d oses of P L X 3 3 9 7 
wit h wee kl y p aclit a xel t o 
est a blis h a R P 2 D; a n d, P art 2, 
t o deter mi ne t he effic ac y a n d 
s afet y of t he P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi n ati o n wit h p aclit a xel i n 
p atie nts wit h a d v a nce d, n o n -
resect a ble s oli d t u m ors.  
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n patie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
6. 0 S Y N O P SI S :  
St u d y Desi g n  
T his is a n o nra n d o mize d, o pe n -
la bel.... 
 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
P art 1:  
T his is a n o n -ra n d o mize d, o pe n 
la bel …. 
P art 2:  
T his is a n o nr a n d o mize d, 
o pe n -l a bel st u d y of P L X 3 3 9 7 
a d mi nist ere d at t he R P 2 D i n 
c o m bi n ati o n wit h p aclit a xel i n 
a p pr o xi m atel y 1 5 p atie nts 
(i ncl u di n g all R P 2 D-tre ate d 
p atie nts fr o m P art 1 a n d P art 
2). T he p atie nt p o p ul ati o n will 
be p atie nts wit h a d v a nce d 
s oli d t u m ors i n w hic h 
tre at me nt wit h a t a x a ne is 
c o nsi dere d b y t he i n vesti g at or 
t o be a p pr o pri ate. 
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n patie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
6. 0 S Y N O P SI S :  
N u m ber of 
Patie nts/ Sites  
E nr oll me nt is pla n ne d t o 
i ncl u de... 
 
 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
P art 1:  
E nr oll me nt is pla n ne d t o 
i ncl u de  
 
P art 2:  
E nr oll me nt is pl a n ne d  t o 
i ncl u de a p pr o xi m atel y 1 5 
p atie nts ( i ncl u di n g R P 2 D -
tre ate d p atie nts fr o m P art 1 
a n d P art 2) recr uite d fr o m 3  
sites. 
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n patie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
 
C O N FI D E N TI A L  
1 0 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
6. 0 S Y N O P SI S :  
N u m ber of 
Patie nts/ Sites  
(c o nti n ue d) 
Patie nts w h o d o n ot recei ve t he 
re q uisite P L X 3 3 9 7 a nd/ or 
paclita xel d oses....  
P art 1 a n d P art 2:  
Patie nts w h o d o n ot recei ve t he 
re q uisite P L X 3 3 9 7 a n d/ or 
paclita xel d oses ….  
T his state me nt a p plies t o 
b ot h Parts 1 a n d 2.  
6. 0 S Y N O P SI S :  
St u d y 
Treat me nts  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y....  
 
 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
P art 1:  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y ….  
 
P art 2:  
P L X 3 3 9 7 will be a d mi nistere d 
or all y, t wice d ail y ( BI D) usi n g 
a c o nti n u o us d osi n g re gi me n. 
T he d ose of P L X 3 3 9 7 will be 
t he R P 2 D. T here will be n o 
d ose es c al ati o n.  
 
P art 1 a n d P art 2:  
P aclit a xel, 8 0 m g/ m 2 I V will 
be a d mi nistere d wee kl y ( ± 4 8 
h o urs) o ver a p pr o xi m atel y 
6 0  mi n utes i n e ac h 2 8 -d a y 
tre at me nt c ycle. 
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n pat ie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
6. 0 S Y N O P SI S :  
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 2 8 
da ys pri or t o t he first st u d y 
treat me nt d ose. T he p h ysical 
e xa m a n d la b orat or y val ues 
s h o ul d be o btai ne d wit hi n 1 4 
da ys pri or t o d osi n g. 
E val uati o ns  perf or me d as part 
of sta n dar d -of -care a n d pri or t o 
i nf or me d c o nse nt ma y be use d 
if t he y occ ur wit hi n t he 
pr ot oc ol -s pecifie d ti mefra me.  
All fe male patie nts of c hil d -
beari n g p ote ntial m ust ha ve a 
ne gati ve uri ne pre g na nc y test 
wit hi n 1 4 da ys of C 1 D 1.  
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 2 8 
da ys pri or t o t he first st u d y 
treat me nt d ose. T he p h ysical 
e xa m a n d la b orat or y val ues 
s h o ul d be o btai ne d wit hi n 1 4 
da ys  pri or t o d osi n g. 
E val uati o ns perf or me d as part 
of sta n dar d of care a n d pri or t o 
i nf or me d c o nse nt ma y be use d 
if t he y occ ur wit hi n t he 
pr ot oc ol s pecifie d ti mefra me.  
All fe male patie nts of c hil d
beari n g p ote ntial m ust ha ve a 
ne gati ve uri ne pre g na nc y test 
w it hi n 1 4 da ys of C 1 D 1.  
Para gra p hs m o ve d u n der ne w 
Part 1 a n d 2.  
 
C O N FI D E N TI A L  
1 0 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
6. 0 S Y N O P SI S :  
St u d y 
Pr oce d ures  
(c o nti n ue d) 
T his st u d y will e m pl o y a 
tra diti o nal 3 + 3 P hase 1 desi g n, 
wit h escalati n g d osi n g c o h orts 
of P L X 3 3 9 7 a n d a fi xe d d ose 
le vel of paclita xel. Eac h 
treat me nt c ycle will be 2 8 da ys. 
P art 1 :  T his n o n -r a n d o mize d, 
o pe n -l a bel st u d y will e m pl o y a 
tra diti o nal 3 + 3 P hase 1 desi g n, 
wit h escalati n g d osi n g c o h orts 
of P L X 3 3 9 7 a n d a fi xe d d ose 
le vel of paclita xel. Eac h 
treat me nt c ycle will be 2 8 da ys. 
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he 6 0 0 m g/ d a y 
d ose le vel. P atie nts s h o ul d f ast 
( o ne h o ur) bef ore a n d after 
P L X 3 3 9 7 a d mi nistr ati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1). 
O n n o n -P K/ P D p aclit a xel 
a d mi nistr ati o n d a ys, t he 
m or ni n g d ose of P L X 3 3 9 7 
m a y be a d mi nistere d at h o me, 
pri or t o p aclit a xel 
a d mi nistr ati o n. T he st arti n g 
d ose le vel of P L X 3 3 9 7 will be 
6 0 0  m g/ d a y. D ose esc al ati o n 
will occ ur i n i ncre me nts of 
≤5 0 %. All p atie nts at a gi ve n 
d ose le vel will be f oll o we d o n 
tre at me nt f or at le ast 4 wee ks 
bef ore accr u al t o t he ne xt 
c oh ort c a n be gi n. T here will 
be n o i ntr a -p atie nt d ose 
esc al ati o n per mitte d. 
P L X 3 3 9 7 d ose re d ucti o ns a n d 
i nterr u pti o ns will be 
per mitte d d uri n g t he first 2 8 
d a ys of C ycle 1 o nl y if a 
p atie nt e x perie nces a D L T.  
P L X 3 3 9 7 i nterr u pti o ns 
d uri n g C ycle 1 are als o 
pe r mitte d f or Gr a de 3 
v o miti n g t h at persists des pite 
o pti m al s u p p orti ve c are. If a 
p atie nt e x perie nces a D L T 
d uri n g C ycle 1, P L X 3 3 9 7 
tre at me nt c o nti n u ati o n at a 
l o wer d ose m a y be per mitte d 
at t he discreti o n of t he 
I n vesti g at or a n d i n 
c o ns ult ati o n wit h t he Me dic al 
M o nit or. After C 1 D 2 8, d ose 
re d ucti o ns or i nterr u pti o ns 
f or a d verse e ve nts m a y t a ke 
pl ace at a n y ti me.  
Clarif y t hat t his is 
n o nra n d o mize d, o pe n la bel 
a n d ela b orati o n o n Part 1 
pr oce d ures.  
 
C O N FI D E N TI A L  
1 0 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
6. 0 S Y N O P SI S :  
St u d y 
Pr oce d ures  
(c o nti n ue d) 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
P art 2:  
T his is a n o nr a n d o mize d, 
o pe n -l a bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi n ati o n wit h p aclit a xel i n 
a p pr o xi m atel y 1 5 p atie nts 
(R P 2 D -tre ate d p atie nts fr o m 
P art 1 a n d P art 2). E ac h 
tre at me nt c ycle will be 2 8 
d a ys.  
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he R P 2 D. 
P atie nts s h o ul d f ast ( o ne 
h o ur) bef ore a n d after 
P L X 3 3 9 7 a d mi nistr ati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1). 
T here will be n o i ntr a -p atie nt 
d ose esc al ati o n per mitte d.  
P L X 3 3 9 7 d ose re d ucti o ns or 
i nterr u pti o ns f or a d verse 
e ve nts m a y t a ke pl ace at a n y 
ti me. 
A d de d Part 2 st u d y 
pr oce d ures f or clarit y.  
6. 0 S Y N O P SI S :  
St u d y 
Pr oce d ures  
(c o nti n ue d) 
Patie nts will recei ve st u d y 
treat me nt as l o n g as it is well 
t olerate d a n d b ot h t he 
I n vesti gat or a n d S p o ns or a gree 
t hat t he patie nt is cli nicall y 
be nefitti n g. Reas o ns f or st u d y 
disc o nti n uati o n i ncl u de, b ut are 
n ot li mite d t o, u nacce pta ble 
t o xicit y, disease pr o gressi o n, 
v ol u ntar y wit h dra wal of 
c o nse nt, I n vesti gat or discreti o n 
a n d deat h. 
Patie nts will recei ve st u d y 
treat me nt as l o n g as it is well 
t olerate d a n d b ot h t he 
I n vesti gat or a n d S p o ns or a gree 
t hat t he patie nt is cli nicall y 
be nefitti n g. Reas o ns f or st u d y 
disc o nti n uati o n i ncl u de, b ut are 
n ot li mite d t o, u nacce pta ble 
t o xicit y, disease pr o gressi o n, 
v ol u ntar y wit h dra wal of 
c o nse nt, I n v esti gat or discreti o n 
a n d deat h. 
Para gra p h m o ve d u n der Part 
1 a n d Part 2  
6. 0 S Y N O P SI S :  
St u d y 
Pr oce d ures  
(c o nti n ue d) 
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he 6 0 0 m g/ da y 
d ose le vel. Patie nts s h o ul d fast 
( o ne h o ur) bef ore a n d after 
P L X 3 3 9 7 a d mi nistrati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1). 
O n n o n -P K/ P D paclita xel 
a d mi nistrati o n da ys, t he 
m or ni n g d ose of P L X 3 3 9 7 ma y 
be a d mi nistere d at h o me, pri or 
t o paclita xel a d mi nistrati o n. 
T he starti n g d ose le vel of 
P L X 3 3 9 7 will be 6 0 0  m g/ da y. 
D ose escalati o n will occ ur i n 
i ncre me nts of ≤5 0 %. All 
patie nts at a gi ve n d ose le vel 
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he 6 0 0 m g/ da y 
d ose le vel.  Patie nts s h o ul d fast 
( o ne h o ur) bef ore a n d after 
P L X 3 3 9 7 a d mi nistrati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1). 
O n n o n P K/ P D paclita xel 
a d mi nistrati o n da ys, t he 
m or ni n g d ose of P L X 3 3 9 7 ma y 
be a d mi nistere d at h o me, pri or 
t o paclita xel a d mi nistrati o n. 
T he start i n g d ose le vel of 
P L X 3 3 9 7 will be 6 0 0  m g/ da y. 
D ose escalati o n will occ ur i n 
i ncre me nts of ≤5 0 %. All 
patie nts at a gi ve n d ose le vel 
Para gra p h m o ve d u n der Part 
1.  
 
C O N FI D E N TI A L  
1 1 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
will be f oll o we d o n treat me nt 
f or at least 4 wee ks bef ore 
accr ual t o t he ne xt c o h ort ca n 
be gi n. T here will be n o i ntra -
patie nt d ose escalati o n 
per mitte d.  
will be f oll o we d o n treat me nt 
f or at least 4 wee ks bef ore 
accr ual t o t he ne xt c o h ort ca n 
be gi n. T here will be n o i ntra
patie nt d ose escalati o n 
per mitte d.  
P art 1 a n d P art 2:  
P atie nts will recei ve st u d y 
tre at me nt as lo n g as it is well 
t oler ate d a n d b ot h t he 
I n vesti g at or a n d S p o ns or 
a gree t h at t he p atie nt is 
cli nic all y be nefitti n g. Re as o ns 
f or st u d y disc o nti n u ati o n 
i ncl u de, b ut are n ot li mite d t o, 
u n acce pt a ble t o xicit y, dise ase 
pr o gressi o n, v ol u nt ar y 
wit h dr a w al of c o nse nt, 
i n vesti g at or discreti o n, a n d 
de at h.  
After pr o vi di n g i nf or me d 
c o nse nt, p atie nts will u n der g o 
scree ni n g f or eli gi bilit y t o 
p artici p ate i n t he st u d y. 
Scree ni n g will st art wit hi n 2 8 
d a ys pri or t o t he first st u d y 
tre at me nt d ose. T he p h ysic al 
e x a m a n d l a b or a t or y v al ues 
s h o ul d be o bt ai ne d wit hi n 1 4 
d a ys pri or t o C 1 D 1. 
E v al u ati o ns perf or me d as 
p art of st a n d ar d -of -c are a n d 
pri or t o i nf or me d c o nse nt 
m a y be use d if t he y occ ur 
wit hi n t he pr ot oc ol -s pecifie d 
ti mefr a me.  
6. 0 S Y N O P SI S :  
S t u d y 
Pr oce d ures  
(c o nti n ue d) 
All fe male patie nts of c hil d -
beari n g p ote ntial m ust ha ve a 
ne gati ve uri ne pre g na nc y test 
wit hi n 1 4 da ys of C 1 D 1  
All fe male patie nts of c hil d -
beari n g p ote ntial m ust ha ve a 
ne gati ve uri ne pre g na nc y test 
wit hi n 1 4 da ys pri or t o  C 1 D 1.  
Clarificati o n t hat uri ne 
pre g na nc y test m ust be d o ne 
pri or t o C 1 D 1.  
6. 0 S Y N O P SI S :  
St u d y 
Pr oce d ures  
(c o nti n ue d) 
Bl o o d sa m ples f or P L X 3 3 9 7 
P K a nal ysis....  
 
P har mac o d y na mic ( P D) 
mar kers....  
P art 1:  
Bl o o d sa m ples f or P L X 3 3 9 7 
P K a nal ysis will be o btai ne d … . 
P art 1 a n d P art 2:  
P har mac o d y na mic ( P D) 
mar kers....  
P K sa m ples are c ollecte d 
o nl y i n Part 1 w hile P D 
sa m ples will be o btai ne d i n 
b ot h Parts 1 a n d 2.  
6. 0 S Y N O P SI S :  
Ke y Patie nt 
Selecti o n 
I ncl usi o n Criteria 
1.  A d va nce d, i nc ura ble s oli d 
I ncl usi o n Criteria 
1.  P atie nts i n :   
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of P L X 3 3 9 7 will be 
 
C O N FI D E N TI A L  
1 1 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
Criteria  
t u m or. 
 
A m e n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
 
P art 1 :  a n a d v a nce d,  
i nc ura ble s oli d t u m or 
P art 2 :  a n a d v a nce d, 
i nc ur a ble s oli d t u m or a n d 
h a ve recei ve d ≤2 pri or 
c he m ot her a p y re gi me ns f or 
t he tre at me nt of t heir 
pri m ar y m ali g n a nc y a n d f or 
w h o m a t a x a ne w o ul d be 
c o nsi dere d a re as o n a ble 
c he m ot her a p y o pti o n.  
deter mi ne d i n patie nts wit h 
a d va nce d s oli d t u m ors i n 
w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
6. 0 S Y N O P SI S  
D ose Li miti n g 
T o xicities  
Patie nts m ust recei ve at least 2 1 
da ys of P L X 3 3 9 7 A N D at least 
3 d oses of paclita xel d uri n g t he 
first 2 8 da y c ycle i n or der t o be 
c o nsi dere d e val ua ble f or D L T, 
u nless d oses are misse d d ue t o a 
D L T.  
P art 1:  
Patie nts m ust recei ve at least 2 1 
da ys of P L X 3 3 9 7 A N D at least 
3 d oses of paclita xel d uri n g t he 
first 2 8 da y c ycle i n or der t o be 
c o nsi dere d e val ua ble f or D L T, 
u n less d oses are misse d d ue t o a 
D L T.  
Criteria f or D ose Li miti n g 
T o xicities refer o nl y t o 
Part  1.  
6. 0 S Y N O P SI S  
D osa ge a n d 
Re gi me n  
At least 3 or 4 pla n ne d 
paclita xel d oses m ust be 
a d mi nistere d ….  
 
I n or der t o i nitiate eac h wee kl y 
paclita xel treat me nt, patie nt s …. 
P art 1:  
At least 3 or 4 pla n ne d 
paclita xel d oses m ust be 
a d mi nistere d ….  
P art 1 a n d P art 2:  
I n or der t o i nitiate eac h wee kl y 
paclita xel treat me nt, patie nts ….  
T he D L T peri o d o nl y a p plies 
t o Part 1. 
6. 0 S Y N O P SI S :  
St o p pi n g R ules  
If ≥2 of 6 patie nts i n D ose 
Le vel -1 eit her e x perie nce a 
D L T or are u na ble t o recei ve 
t he re q uisite P L X 3 3 9 7 a n d 
paclita xel d oses i n t he first 2 8 
da ys d ue t o treat me nt -relate d 
a d verse e ve nts, 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  
P art 1 :  If ≥2 of 6 patie nts i n 
D ose Le vel -1 eit her e x perie nce 
a D L T or are u na ble t o recei ve 
t he re q uisite P L X 3 3 9 7 a n d 
paclita xel d oses i n t he first 2 8 
da ys d ue t o treat me nt -relate d 
a d verse e ve nts, 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. 
Clarificati o n t hat t he 
st o p pi n g r ules f or Part 1 a n d 
Part 2 are differe nt.  
6. 0 S Y N O P SI S :  
St o p pi n g R ules  
(c o nti n ue d) 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2 . 
P art 2 :  After ~ 5 0 % of t he 
pl a n ne d a p pr o xi m atel y 1 5 
p atie nts (R P 2 D -tre ate d 
p atie nts fr o m P art 1 a n d P art 
2) h a ve c o m plete d at le ast 2 
tre at me nt C ycles, a n o ver all 
i nteri m s afet y s u m m ar y will 
be re vie we d b y t he Me dic al 
M o nit or a n d Pri nci p al 
I n vesti g at ors t o e ns ure t h at 
t he p ote nti al cli nic al be nefit 
o ut wei g hs t he o bs er ve d 
cli nic al ris k t o d ate. If t he 
s afet y o bser v ati o ns d o n ot 
Nee de d st o p pi n g r ules f or 
Part 2.  
 
C O N FI D E N TI A L  
1 1 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
w arr a 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. 
6. 0 S Y N O P SI S  
P K Para meters  
 
P art 1:  
P K sa m ples will o nl y be 
c ollecte d i n part 1.  
6. 0 S Y N O P SI S  
P D  Para meters  
 
P art 1 a n d P art 2:  
Sa m ples f or e x pl orat or y 
bi o mar kers will be c ollecte d 
i n b ot h Parts 1 & 2. 
8. 0 S T U D Y 
O BJ E C TI V E S 
 
T his trial is desi g ne d t o e x pl ore 
t he safet y of escalati n g d oses of 
P L X 3 3 9 7 wit h wee kl y 
paclita xel.  
T his trial is desi g ne d  as a  t w o-
p art st u d y :  P art 1 ( P h ase 1 b), 
t o e x pl ore t he safet y of 
escalati n g d oses of P L X 3 3 9 7 
wit h wee kl y paclita xel  t o 
est a blis h a R P 2 D; a n d, P art 2, 
t o deter mi ne t he effic ac y a n d 
s afet y of t he P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi n ati o n wit h p aclit a xel i n 
p atie nts wit h a d v a nce d, n o n -
resect a ble s oli d t u m ors.  
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n patie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
9. 0 D E SI G N  
9. 1 Descri pti o n  
Pr ot oc ol P L X 1 0 8 -0 7 is a P hase 
1 b o pe n -la bel, se q ue ntial d ose 
escalati o n trial of P L X 3 3 9 7 
pl us paclita xel.  
P art 1:  
Pr ot oc ol P L X 1 0 8 0 7  T his is  a 
n o nr a n d o mize d P hase 1 b 
o pe n -la bel, se q ue ntial d ose 
escalati o n trial of P L X 3 3 9 7 
pl us paclita xel.  
Disti ncti o n ma de t hat Part 1 
is t he d ose escalati o n p hase 
of t he trial.  
9. 0 D E SI G N  
9. 1 Descri pti o n 
(c o nti n ue d) 
 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
P art 2 :   
T his is a n o nr a n d o mize d, 
o pe n -l a bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi n ati o n wit h p aclit a xel i n 
a p pr o xi m atel y 1 5 p atie nts 
(i ncl u di n g R P 2 D -tre ate d 
p atie nts fr o m P art 1 a n d P art 
2). T he p atie nt p o p ul ati o n will 
be p atie nts wit h a d v a nce d 
s oli d t u m ors i n w hic h 
tre at me nt wit h a t a x a ne is 
c o nsi dere d b y t he i n vesti g at or 
t o be a p pr o pri ate. 
O nce t he R P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n patie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
taxa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. Efficac y a n d 
safet y si g nals will be use d t o 
g ui de s u bse q ue nt st u dies.  
9. 0 D E SI G N  
9. 4  
N u m ber of 
Patie nts  
 
E nr oll me nt is pla n ne d t o 
i ncl u de.... 
 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
P art 1 :   
E nr oll m e nt is pla n ne d t o 
i ncl u de.... 
P art 2 :   
E nr oll me nt is pl a n ne d t o 
i ncl u de a p pr o xi m atel y 1 5 
p atie nts ( i ncl u di n g all R P 2 D -
tre ate d p atie nts fr o m P art 1 
a n d P art 2) recr uite d fr o m 
Clarifie d n u m ber of patie nts 
t o be treate d at R P 2 D a n d 
patie nt re place me nt r ules.  
 
C O N FI D E N TI A L  
1 1 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
a p pr o xi m atel y 3 – 4  sites. 
P art 1 a n d P art 2 :   
P atie nts w h o d o n ot recei ve 
t he re quisite P L X 3 3 9 7 a n d/ or 
p aclit a xel d oses i n C ycle 1 d ue 
t o a n yt hi n g ot her t h a n 
tre at me nt-rel ate d a n d/ or 
d ose- li miti n g t o xicit y m a y be 
re pl ace d. P atie nts w h o 
e x perie nce a n aller gic 
re acti o n t o p aclit a xel t h at 
precl u des f urt her d osi n g (i.e., 
≥Gr a de 3) will be re m o ve d 
fr o m t he st u d y a n d m a y als o 
be re pl ace d.  
1 0. 1  
I ncl usi o n 
Criteria  
 
A d va nce d, i nc ura ble s oli d 
t u m or 
 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
1. P atie nts wit h:  
a. P art 1 :  a n a d v a nce d, 
i nc ur a ble s oli d t u m or 
b. P art 2 :  a n a d v a nce d, 
i nc ur a ble s oli d t u m or a n d 
h a ve recei ve d ≤2 pri or 
c he m ot her a p y re gi me ns f or 
t he tre at me nt of t heir 
pri m ar y m ali g n a nc y a n d f or 
w h o m a t a x a ne w o ul d be 
c o nsi dere d a re as o n a ble 
c he m ot her a p y o pti o n.  
O nce t he P P 2 D has bee n 
deter mi ne d, t he efficac y a n d 
safet y of t he P L X 3 3 9 7 will 
be deter mi ne d i n patie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be a p pr o priate. 
Efficac y a n d safet y si g nals 
will be use d t o g ui de 
s u bse q ue nt st u dies. 
1 0. 2  
E xcl usi o n 
Criteria  
8. K n o w n c hr o nic He patitis B 
or C, or HI V i nfecti o n  
 
8. K n o w n c hr o nic acti ve  
He patitis B or C, or HI V 
i nfecti o n 
Clarifie d t hat c hr o nic acti ve 
he patitis was e xcl u de d, n ot a 
hist or y of he patitis B or C.  
1 3. 1 2  
D ose- Li miti n g 
T o xicities  
1 3. 1 2 D ose -L i miti n g T o xicities 1 3. 1 2 D ose -Li miti n g T o xicities 
( P art 1 o nl y) 
Deter mi nati o n of d ose -
li miti n g t o xicit y is li mite d t o 
Part 1; Part 2 occ urs after t he 
R P 2 D has bee n deter mi ne d.  
1 3. 1 4  
P L X 3 3 9 7 D ose 
M o dificati o ns  
 
P L X 3 3 9 7 d ose re d ucti o ns a n d 
i nterr u pti o ns will be per mitte d 
d uri n g t he first 2 8 da ys of 
C ycle 1 …. 
A me n d me nt 3 d oes n ot c o nt ai n 
P art 2.  
 
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 are n ote d i n Ta ble 
3. 
D uri n g P art 1,  P L X 3 3 9 7 d ose 
re d ucti o ns a n d i nterr u pti o ns 
will be per mitte d d uri n g t he 
first 2 8 da ys of C ycle 1 ….  
D uri n g P art 2 :  P L X 3 3 9 7 
d ose re d ucti o ns or 
i nterr u pti o ns f or a d verse 
e ve nts m a y t a ke pl ace at a n y 
ti me.  
F or P art 1 a n d P art 2, 
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 
A d de d i nf or mati o n o n Part 2.  
 
C O N FI D E N TI A L  
1 1 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
ma na ge me nt are n ote d i n Ta ble 
3. 
1 3. 1 5  
Paclita xel D ose 
M o dificati o ns  
 
D ose m o dificati o ns or 
i nterr u pti o ns of paclita xel are 
n ot per mitte d i n C ycle 1 u nless 
t he patie nt e x perie nces a D L T. 
Ot her d ose m o dificati o ns f or 
paclita xel will be i n acc or da nce 
t o t he pr o d uct la bel. 
D ose m o dificati o ns or 
i nterr u pti o ns of paclita xel are 
n ot per mitte d i n P art 1 , C ycle 1 
u nless t he patie nt e x perie nces a 
D L T.  
F or P art 1, C ycle 2 a n d 
s u bse q ue nt c ycles a n d P art 2, 
ot her d ose m o dificati o ns f or 
paclita xel will be i n acc or da nce 
t o t he pr o d uct la bel. 
Clarifie d w he n paclita xel 
d ose re d ucti o ns ca n be ma de . 
1 4. 0 T E S T 
A R TI C L E S  
1 4. 1. 1  
P L X 3 3 9 7 
A d mi nistrati o n  
 
O n C 1 D 1 a n d C 1 D 1 5, t he 
patie nts s h o ul d ta ke t he 
m or ni n g d ose of P L X 3 3 9 7 at 
t he cli nical site after t he pre-
d ose P K bl o o d sa m ple is 
o btai ne d – patie nts s h o ul d be 
i nstr ucte d n ot t o ta ke t he st u d y 
dr u g at h o me pri or t o t hese 
cli nic visits. T he ti me of d osi n g 
will be rec or de d i n t he cli nic. 
T he e ve ni n g d ose of P L X 3 3 9 7 
s h o ul d be ta ke n b y t he patie nt 
at h o me. O n all ot her visit da ys 
a n d f or all visit da ys, patie nts 
ma y a d mi nister 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 i n t he P L X 3 3 9 7 
a d mi nistrati o n diar y.  
F or P art 1 o nl y  o n C 1 D 1, a n d 
C 1 D 1 5, a n d  t he first d a y of all 
s u bse q ue nt c ycles, t he patie nts 
s h o ul d ta ke t he m or ni n g d ose of 
P L X 3 3 9 7 at t he cli nical site 
after t he pre-d ose P K bl o o d 
sa m ple is o btai ne d– patie nts 
s h o ul d be i nstr ucte d n ot t o ta ke 
t he st u d y dr u g at h o me pri or t o 
t hese cli nic visits. T he ti me of 
d osi n g will be rec or de d i n t he 
cli nic. T he e ve ni n g d ose of 
P L X 3 3 9 7 s h o ul d be ta ke n b y 
t he patie nt at h o me. F or P art 1  
o n all ot her visit da ys a n d f or 
all P art 2 visit d a ys,  patie nts 
ma y a d mi nister 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 i n t he P L X 3 3 9 7 
a d mi nistrati o n diar y.  
Clarifie d P L X 3 3 9 7 d ose 
a d mi nistrati o n ti mes o n da ys 
of Part 1 bl o o d sa m ples f or 
P K.  
 
 
 
C O N FI D E N TI A L  
1 1 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Mi n or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
Trial Fl o w C hart  
Plas ma f or P K  
Plas ma f or P K  
( P art 1 o nl y) 
T here is n o P K i n Part 2.  
Trial Fl o w C hart  
P har mac o d y na mic ( P D) 
mar kers.....  
P D bi o m ar kers  
( P art 1 a n d P art 2) 
Clarifie d t hat P D bi o mar kers 
will be assesse d i n Part 1 a n d 
Part 2.  
1 3. 0 
P R O C E D U R E S  
 
M ulti ple l ocati o ns i n t his 
secti o n:   
bl o o d sa m ple c ollecti o n f or 
P K  
M ulti ple l ocati o ns i n t his 
secti o n:   
bl o o d sa m ple c ollecti o n f or P K  
( P art 1 o nl y) 
T here is n o P K i n Part 2.  
1 4. 1. 4  
P L X 3 3 9 7 
Acc o u nta bilit y, 
Rec o nciliati o n, 
a n d Ret ur n 
 
T he d ates of destr ucti o n of all 
P L X 3 3 9 7 c a ps ules m ust be 
rec or de d o n t he P L X 3 3 9 7 
acc o u nt a bilit y l o g.  
Clarificati o n f or dr u g 
acc o u nta bilit y..  
1 8. 0 
P H A R M A C O -
KI N E TI C 
E V A L U A TI O N  
1 8. 0 
P H A R M A C O KI N E TI C 
E V A L U A TI O N  
1 8. 0  
P H A R M A C O KI N E TI C 
E V A L U A TI O N ( P art 1 o nl y) 
Clarifie d t hat P K is o nl y i n 
Part 1.  
1 9. 1 Safet y 
A nal ysis  
La b orat or y varia ble s 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 f or eac h d ose le vel 
gr o u p.  
La b orat or y varia bles will be 
e xa mi ne d  s u m m arize 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 
f or eac h d ose le vel gr o u p a n d  
9 5 % c o nfi de nce i nter v al . 
Clarificati o n.  
1 9. 2 Efficac y 
A nal ysis  
 
Res p o nse t o treat me nt 
acc or di n g t o t he R E CI S T 
criteria will be re p orte d via 
descri pti ve statistics b y 
d ose le vel. T he a bs ol ute 
a n d perce nt c ha n ge fr o m 
baseli ne f or t he e xte nt of 
disease (s u m  of t he l o n gest 
dia meters) will be 
s u m marize d at eac h 
sc he d ule d e val uati o n usi n g 
descri pti ve statistics.  
Res p o nse t o treat me nt acc or di n g 
t o t he R E CI S T criteria will be 
re p orte d via descri pti ve statistics 
b y d ose le vel. T he a bs ol ute a n d 
perce nt c ha n ge fr o m baseli ne f or 
t he e xte nt of disease (s u m of t he 
l o n gest dia meters) will be 
s u m marize d at eac h sc he d ule d 
e val uati o n usi n g descri pti ve 
statistics i ncl u di n g me a n, 
st a n d ar d de vi ati o n, mi ni m u m 
a n d m a xi m u m v al ues.  
Clarificati o n.  
1 9. 2 Efficac y 
A nal ysis  
(c o nti n ue d) 
 
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 pr o gressi o n-free 
s ur vi val, re gar dless of t he 
prese nce or a bse nce of 
meas ura ble disease. 
Pr o gressi o n -free s ur vi val 
will be calc ulate d f or eac h 
patie nt. Pr o gressi o n -free 
s ur vi val is defi ne d as t he 
n u m ber of da ys fr o m t he 
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 pr o gressi o n free -
s ur vi val, re gar dless of t he 
prese nce or a bse nce of 
meas ura ble disease. Pr o gressi o n -
free s ur vi val will be calc ulate d 
f or eac h patie nt a n d s h o w n f or 
all p atie nts o n a K a pl a n -Meier 
pl ot . Pr o gressi o n -free s ur vi val is 
defi ne d as t he n u m ber of da ys 
fr o m t he first day of treat me nt t o 
Clarificati o n.  
 
C O N FI D E N TI A L  
1 1 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Mi n or M o dific ati o ns  
Secti o n  
A me n d me nt 3  
A me n d me nt 4  
R ati o n ale  
first da y of treat me nt 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 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 . 
1 9. 2 Efficac y 
A nal ysis  
(c o nti n ue d) 
I n a d diti o n, relati o ns hi ps 
bet wee n a ntit u m or acti vit y, 
p har mac o d y na mic mar kers, 
a n d dr u g e x p os ure le vels 
will be e x pl ore d.  
I n a d diti o n, E x pl or at or y 
a n al yses m a y be c o n d ucte d t o 
e v al u ate p ossi ble  relati o ns hi ps 
bet wee n a ntit u m or acti vit y, 
p har mac o d y na mic mar kers, a n d 
dr u g e x p os ure le vels  will be 
e x pl ore d . 
Clarificati o n.  
1 9. 4 P har mac o -
ki netic A nal y sis  
1 9. 4 P har mac o ki netic 
A nal ysis  
1 9. 4 P har mac o ki netic A nal ysis 
( P art 1 o nl y) 
Clarifie d t hat P K is o nl y i n 
Part 1.  
 
 
 
 
C O N FI D E N TI A L  
1 1 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 9 :  A M E N D M E N T 5 S U M M A R Y O F C H A N G E S  
N ote :  C ha n ges t hr o u g h o ut t he pr ot oc ol t hat are re petiti ve, self -e vi de nt or gra m matical ma y n ot be 
i n di vi d uall y liste d i n t his S u m mar y of C ha n ges.  
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 4  
A me n d me nt 5  
R ati o n ale  
6. 0 S Y N O P SI S :  
Ke y Patie nt 
Selecti o n 
Criteria  
I ncl usi o n Criteria 
P art 2 :  a n a d v a nce d, 
i nc ur a ble s oli d t u m or a n d 
ha ve recei ve d ≤2 pri or 
c he m ot hera p y re gi me ns f or t he 
treat me nt of t heir pri mar y 
mali g na nc y a n d  f or w h o m a 
t a x a ne w o ul d be c o nsi dere d a 
re as o n a ble c he m ot her a p y 
o pti o n.  
I ncl usi o n Criteria 
Part 2 :  a n a d va nce d, i nc ura ble 
s oli d t u m or a n d h a ve recei ve d 
≤2 pri or c he m ot her a p y 
re gi mens f or t he tre at me nt of 
t heir pri m ar y m ali g n a nc y a n d 
f or w h o m a ta xa ne w o ul d be 
c o nsi dere d a reas o na ble 
c he m ot hera p y o pti o n.  
T he rati o nale f or t his 
m o dificati o n is t o all o w 
e nr oll me nt of a si milar patie nt 
p o p ulati o n i n Part 2 as t hat f or 
Part 1 a n d f or w h o m t here 
ma y be t he p ote ntial f or 
treat me nt be nefit. T here is n o 
safet y c o ncer n wit h t his 
c ha n ge. T his m o dificati o n 
was disc usse d wit h t he 
pri nci pal i n vesti gat ors at all 
partici pati n g trial sites a n d all 
were i n a gree me nt wit h t his 
pr o p ose d c ha n ge.  T his 
m o d ificati o n is base d o n N ote 
T o File 0 4 Fe br uar y 2 0 1 4.  
6. 0 S Y N O P SI S :  
St u d y Desi g n  
Part 2:  
T his is a n o nra n d o mize d, 
o pe n -la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 1 5 patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 
2). T he patie nt p o p ulati o n will 
be patie nts wit h a d va nce d s oli d 
t u m ors i n w hic h treat me nt wit h 
a ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be a p pr o priate. 
Part 2:  
T his is a n o nra n d o mize d, o pe n -
la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 1 5  3 0 p atie nts  
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 2). 
T he patie nt p o p ulati o n will be 
patie nts wit h a d va nce d s oli d 
t u m ors i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be a p pr o priate. 
Patie nts w h o wit h dra w fr o m 
t he st u d y d ue t o disease 
pr o gressi o n or f or a n y reas o n 
ot her t ha n P L X 3 3 9 7 -relate d 
a d verse e ve nts nee d t o be 
re place d, beca use at least 1 5 
( Part 1 + Part 2) patie nts 
treate d at t he 1 6 0 0 m g/ da y 
R P 2 D wit h 2 -c ycle P L X 3 3 9 7 
e x p os ure a n d safet y data are 
re q uire d t o e na ble P L X 3 3 9 7 
t o be st u die d i n t he I-S P Y 2 
trial. T his m o dificati o n is 
base d o n N ote T o File 1 4 
A pril 2 0 1 4.  
 
C O N FI D E N TI A L  
1 1 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 4  
A me n d me nt 5  
R ati o n ale  
6. 0 S Y N O P SI S :  
N u m ber of 
Patie nts/ Sites  
Part 2:  
E nr oll me nt is pla n ne d t o 
i ncl u de a p pr o xi matel y 1 5 
patie nts (i ncl u di n g R P 2 D -
treate d patie nts fr o m Part 1 a n d 
Part 2) recr uite d fr o m 3 sites. 
Part 1 a n d Part 2:  
Patie nts w h o d o n ot recei ve t he 
re q uisite P L X 3 3 9 7 a n d/ or 
paclita xel d oses i n C ycle 1 d ue 
t o a n yt hi n g ot her t ha n 
treat me nt-relate d a n d/ or d ose -
li miti n g t o xicit y ma y be 
re place d. Patie nts w h o 
e x perie nce a n aller gic reacti o n 
t o paclita xel t hat precl u des 
f urt her d osi n g (i.e., ≥Gra de 3) 
will be re m o ve d fr o m t he st u d y 
a n d ma y als o be re place d.  
Part 2:  
E nr oll me nt is pla n ne d t o i ncl u de 
a p pr o xi matel y 1 5  3 0 p atie nts  
(i ncl u di n g R P 2 D-treate d patie nts 
fr o m Part 1 a n d Part 2) recr uite d 
fr o m 3 sites. 
Part 1 a n d Part 2:  
Patie nts w h o d o n ot  recei ve t he 
re q uisite P L X 3 3 9 7 a n d/ or 
paclita xel d oses i n C ycle 1 d ue t o 
a n yt hi n g ot her t ha n treat me nt -
relate d a n d/ or d ose-li miti n g 
t o xicit y ma y be re place d. Patie nts 
w h o e x perie nce a n aller gic 
reacti o n t o paclita xel t hat 
precl u des f urt her d osi n g (i.e., 
≥G ra de 3) will be re m o ve d fr o m 
t he st u d y a n d ma y als o be 
re place d. 
Patie nts w h o wit h dra w fr o m 
t he st u d y d ue t o disease 
pr o gressi o n or f or a n y reas o n 
ot her t ha n P L X 3 3 9 7 -relate d 
a d verse e ve nts nee d t o be 
re place d, beca use at least 1 5 
( Part 1 + Part 2) patie nts 
treate d at t he 1 6 0 0 m g/ da y 
R P 2 D wit h 2 -c ycle P L X 3 3 9 7 
e x p os ure a n d safet y data are 
re q uire d t o e na ble P L X 3 3 9 7 
t o be st u die d i n t he I-S P Y 2 
trial. T his m o dificati o n is 
base d o n N ote T o File 1 4 
A pril 2 0 1 4.  
6. 0 S Y N O P SI S :  
St u d y 
Pr oce d ures  
Part 2:  
T his is a n o nra n d o mize d, 
o pe n -la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 1 5 patie nts 
( R P 2 D-treate d patie nts fr o m 
Part 1 a n d Part 2). Eac h 
treat me nt c ycle will be 2 8 
da ys.  
 
Part 2:  
T his is a n o nra n d o mize d, o pe n -
la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 1 5  3 0 p atie nts  
( R P 2 D-treate d patie nts fr o m Part 
1 a n d Part 2). Eac h treat me nt 
c ycle will be 2 8 da ys.  
 
Patie nts w h o wit h dra w fr o m 
t he st u d y d ue t o disease 
pr o gressi o n or f or a n y reas o n 
ot her t ha n P L X 3 3 9 7 -relate d 
a d verse e ve nts nee d t o be 
re place d, beca use at least 1 5 
( Part 1 + Part 2) patie nts 
treate d at t he 1 6 0 0 m g/ da y 
R P 2 D wit h 2 -c ycle P L X 3 3 9 7 
e x p os ure a n d safet y data are 
re q uire d t o e na ble P L X 3 3 9 7 
t o be st u die d i n t he I-S P Y 2 
trial. T his m o dificati o n is 
base d o n N ote T o File 1 4 
A pril 2 0 1 4.  
 
C O N FI D E N TI A L  
1 1 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 4  
A me n d me nt 5  
R ati o n ale  
9. 0 D E SI G N  9. 1 
Descri pti o n  
Part 2 :  T his is a 
n o nra n d o mize d, o pe n -la bel 
st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 1 5  patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 
2). T he patie nt p o p ulati o n will 
be patie nts wit h a d va nce d s oli d 
t u m ors i n w hic h treat me nt wit h 
a ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be a p pr o priate. 
Part 2 :  T his is a n o nra n d o mize d, 
o pe n -la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 1 5  3 0  patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 2). 
T he patie nt p o p ulati o n will be 
patie nts wit h a d va nce d s oli d 
t u m ors i n w hic h treat me nt with a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be a p pr o priate. 
Patie nts w h o wit h dra w fr o m 
t he st u d y d ue t o disease 
pr o gressi o n or f or a n y reas o n 
ot her t ha n P L X 3 3 9 7 -relate d 
a d verse e ve nts nee d t o be 
re place d, beca use at least 1 5 
( Part 1 + Part 2) patie nts 
treate d at t he 1 6 0 0 m g/ da y 
R P 2 D wit h 2 -c ycle P L X 3 3 9 7 
e x p os ure a n d safet y data are 
re q uire d t o e na ble P L X 3 3 9 7 
t o be st u die d i n t he I-S P Y 2 
trial. T his m o dificati o n is 
base d o n N ote T o File 1 4 
A pril 2 0 1 4.  
9. 0 D E SI G N  9. 4 
N u m ber of 
Patie nts  
E nr oll me nt is pla n ne d t o 
i ncl u de a p pr o xi matel y 1 5 
patie nts (i ncl u di n g all R P 2 D -
treate d patie nts fr o m Part 1 a n d 
Part 2) recr uite d fr o m 3 sites. 
 
E nr oll me nt is pla n ne d t o i ncl u de 
a p pr o xi matel y 1 5  3 0  patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 2) 
recr uite d fr o m 3 sites. 
 
Patie nts w h o wit h dra w fr o m 
t he st u d y d ue t o disease 
pr o gressi o n or f or a n y reas o n 
ot her t ha n P L X 3 3 9 7 -relate d 
a d verse e ve nts nee d t o be 
re place d, beca use at least 1 5 
( Part 1 + Part 2) patie nts 
treate d at t he 1 6 0 0 m g/ da y 
R P 2 D wit h 2 -c ycle P L X 3 3 9 7 
e x p os ure a n d safet y data are 
re q uire d t o e na ble P L X 3 3 9 7 
t o be st u die d i n t he I-S P Y 2 
trial. T his m o dificati o n is 
base d o n N ote T o File 1 4 
A pril 2 0 1 4.  
1 0. 1  
I ncl usi o n 
Criteria  
 
I ncl usi o n Criteria 
P art 2 :  a n a d v a nce d, 
i nc ur a ble s oli d t u m or a n d 
ha ve  recei ve d ≤2 pri or 
c he m ot hera p y re gi me ns f or t he 
treat me nt of t heir pri mar y 
mali g na nc y a n d  f or w h o m a 
t a x a ne w o ul d be c o nsi dere d a 
re as o n a ble c he m ot her a p y 
o pti o n.  
I ncl usi o n Criteria 
P art 2 :  a n a d v a nce d, i nc ur a ble 
s oli d t u m or a n d ha ve recei ve d 
≤2 pri or c he m ot hera p y re gi me ns 
f or t he treat me nt of t heir pri mar y 
mali g na nc y a n d  f or w h o m a 
t a x a ne w o ul d be c o nsi dere d a 
re as o n a ble c he m ot her a p y 
o pti o n.  
T he rati o nale f or t his 
m o dificati o n is t o all o w 
e nr oll me nt of a si milar patie nt 
p o p ulati o n i n Part 2 as t hat f or 
Pa rt 1 a n d f or w h o m t here 
ma y be t he p ote ntial f or 
treat me nt be nefit. T here is n o 
safet y c o ncer n wit h t his 
c ha n ge. T his m o dificati o n 
was disc usse d wit h t he 
pri nci pal i n vesti gat ors at all 
partici pati n g trial sites a n d all 
were i n a gree me nt wit h t his 
pr o p ose d c ha n ge. T his 
m o dificati o n is base d o n N ote 
T o File 0 4 Fe br uar y 2 0 1 4.  
 
C O N FI D E N TI A L  
1 2 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
M aj or M o dific ati o ns  
Secti o n  
A me n d me nt 4  
A me n d me nt 5  
R ati o n ale  
1 6. 5 Safet y 
La b orat or y 
Deter mi nati o ns  
 
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 or e 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.  
Re v ie w of p har mac o ki netic 
data a n d I N R data i n a s mall 
n u m ber of patie nts ta ki n g 
P L X 3 3 9 7 a n d warfari n is 
i nc o ncl usi ve as t o w het her 
t here is a dr u g-dr u g 
i nteracti o n; h o we ver, a 
p ote ntial dr u g- dr u g 
i nteracti o n bet wee n P L X 3 3 9 7 
a n d warfari n c o ul d e xist . T his 
m o dificati o n is base d o n N ote 
T o File 0 7 Oct o ber 2 0 1 3.  
 
 
C O N FI D E N TI A L  
1 2 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  




P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
t his st u d y are t o 1) e val uate 
t he o verall safet y a n d 
t olera bilit y of P L X 3 3 9 7 i n 
c o m bi nati o n wit h paclita xel, 
2) e x pl ore t he efficac y of 
P L X 3 3 9 7 i n c o m bi nati o n 
wit h paclita xel i n pa tie nts 
wit h a d va nce d s oli d t u m ors, 
a n d 3) deter mi ne t he 
p har mac o ki netics ( P K) of 
P L X 3 3 9 7 w he n a d mi nistere d 
i n c o m bi nati o n wit h 
paclita xel.  
E x pl orat or y o bjecti ves 
i ncl u de c orrelati n g t he 
c ha n ge i n C ol o n y Sti m ulati n g 
Fact or -1  
( C S F-1) le vels d uri n g 
treat me nt wit h s pecific d ose 
le vels of P L X 3 3 9 7 a n d 
i de ntif yi n g ne w bi o mar kers 
of cli nical acti vit y.  
p atie nts wit h a d v a n ce d s oli d 
t u m ors. 
T he pri mar y o bjecti ve of t his 
P hase 1 b st u d y is t o esta blis h t he 
d ose li miti n g t o xicities ( D L Ts)  
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 gi ve n 
i n c o m bi nati o n wit h wee kl y 
sta n dar d d ose paclita xel i n 
patie nts wit h a d va nce d s oli d 
t u mors. T he sec o n dar y o bjecti ves 
of t his st u d y are t o 1) e val uate t he 
o verall safet y a n d t olera bilit y of 
P L X 3 3 9 7 i n c o m bi nati o n wit h 
paclita xel, 2) e x pl ore t he efficac y 
of P L X 3 3 9 7 i n c o m bi nati o n wit h 
paclita xel i n patie nts wit h 
a d va nce d s oli d t u m ors, a n d 3) 
de ter mi ne t he p har mac o ki netics 
( P K) of P L X 3 3 9 7 w he n 
a d mi nistere d i n c o m bi nati o n wit h 
paclita xel.  
P art 1 a n d 2 :  E x pl orat or y 
o bjecti ves i ncl u de c orrelati n g t he 
c ha n ge i n C ol o n y Sti m ulati n g 
Fact or -1 ( C S F -1) le vels d uri n g 
treat me nt wit h s pecific d ose le vels 
of P L X 3 3 9 7 a n d i de ntif yi n g ne w 
bi o mar kers of cli nical acti vit y.  
P art 3 :  T he pri m ar y o bjecti ve is 
t o deter mi ne t he effic ac y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n c o m bi n ati o n 
wit h p aclit a xel i n p atie nts wit h 
a d v a nce d, met ast atic or n o n -
resect a ble, pl ati n u m -resist a nt or 
-refr act or y e pit heli al o v ari a n 
c a ncer, pri m ar y perit o ne al 
c a ncer, or f all o pi a n t u be c a ncer . 
T he sec o n d ar y o bjecti ves are t o 
e x pl ore t he effect of P L X 3 3 9 7 
o n c a ncer tiss ue a n d bl o o d 
bi o m ar kers a n d t he s afet y a n d 
t oler a bilit y of P L X 3 3 9 7 i n 
c o m bi n at i o n wit h p aclit a xel i n 
t his p atie nt p o p ul ati o n. 
 
C O N FI D E N TI A L  
1 2 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
6. 0 S Y N O P SI S  
St u d y Desi g n  
P art 1 : 
T his is a n o nra n d o mize d, 
o pe n -la bel p hase 1 b st u d y 
e m pl o yi n g a sta n dar d 3 + 3 
d ose escalati o n desi g n t o 
deter mi ne t he R P 2 D of 
P L X 3 3 9 7, a n o vel i n h i bit or 
of t he C S F -1 rece pt or ( F ms), 
w he n a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d 
s oli d t u m ors. 
P art 2 : 
T his is a n o nra n d o mize d, 
o pe n -la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel 
i n a p pr o xi mate l y 3 0 patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 
2). T he patie nt p o p ulati o n 
will be patie nts wit h 
a d va nce d s oli d t u m ors i n 
w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate.  
P art 1 : 
T his is a n o nra n d o mize d, o pe n -
la bel p hase 1 b  st u d y e m pl o yi n g a 
sta n dar d 3 + 3 d ose escalati o n 
desi g n t o deter mi ne t he R P 2 D of 
P L X 3 3 9 7, a n o vel i n hi bit or of t he 
C S F -1 rece pt or ( F ms), w he n 
a d mi nistere d i n c o m bi nati o n wit h 
paclita xel i n patie nts wit h 
a d va nce d s oli d t u m ors.  
P art 2 : 
T his is a n o nra n d o mize d, o pe n -
la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 3 0 patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m Part 1 a n d Part 2). 
T he patie nt  c a n di d ate  p o p ulati o n 
will be patie nts wit h a d va nce d 
s oli d t u m ors i n w hic h treat me nt 
wit h a ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be a p pr o priate. 
T his is a n o nr a n d o mize d, o pe n -
l a bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi n ati o n wit h p aclit a xel i n 
a p pr o xi m atel y 3 0 p atie nts. T he 
c a ndi d ate p o p ul ati o n will be 
p atie nts wit h a d v a nce d , 
met ast atic or n o n -resect a ble , 
pl ati n u m -resist a nt 
or -refr act or y  e pit heli al o v ari a n 
c a ncer, pri m ar y perit o ne al 
c a ncer, or f all o pi a n t u be c a ncer. 
P atie nts m ust be resist a nt or 
refr act or y t o pri or pl ati n u m -
b as e d st a n d ar d c are s yste mic 
re gi me ns or refr act or y t o 
pri m ar y tre at me nt wit h a 
pl ati n u m -c o nt ai ni n g re gi me n.  
P atie nts will be se q ue nti all y 
assi g ne d t o o ne of t hree C ycle 1 
( 2 8 t o 3 5 d a y) le a d-i n tre at me nt 
ar ms :  1) d ail y P L X 3 3 9 7 at t he 
R P 2 D; 2)  wee kl y p aclit a xel; a n d 
3) d ail y P L X 3 3 9 7 at t he R P 2 D 
a n d wee kl y p aclit a xel. C a ncer 
tiss ue ( bi o ps y) a n d bl o o d f or 
bi o m ar kers will be o bt ai ne d 
d uri n g Scree ni n g a n d at C ycle 1 
T o a d d Part 3 t o e x pl ore t he 
efficac y a n d safet y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
metastatic or n o n -
resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer, 
pri mar y perit o neal ca ncer, 
or fall o pia n t u be ca ncer  
 
C O N FI D E N TI A L  
1 2 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
D a y 2 8 ±  7 d a ys  ( C ycle 1 D a y 2 1 
t o C ycle 1 D a y 3 5). 
F oll o wi n g t he sec o n d bi o ps y, 
C ycle 1 e n ds a n d all p atie nts will 
st art C ycle 2 tre at me nt wit h 
d ail y P L X 3 3 9 7 at t he R P 2 D a n d 
wee kl y p aclit a xel. C ycle 2 a n d 
all s u bse q ue nt c ycles will be 2 8 -
d a y c ycles. Bl o o d bi o m ar kers 
will be o bt ai ne d pri or t o 
tre at me nt o n D a y 1 of all 
s u bse q ue nt c ycles a n d t he E n d -
of - St u d y Visit. P atie nts will h a ve 
effic ac y assess me nts e ver y 8 
wee ks t o deter mi ne o bjecti ve 
res p o nse ( C R + P R), cli nic al 
be nefit ( C R  + P R + S D), 
pr o gressi o n -free s ur vi v al ( P F S), 
a n d ti me t o ne xt tre at me nt.  
6. 0 S Y N O P SI S  
N u m ber of 
Patie nts/ Sites  
A me n d me nt 5 d oes n ot 
c o nt ai n P art 3.  
P art 3:  
E nr oll me nt is pl a n ne d t o i ncl u de 
u p t o a p pr o xi m atel y 3 0 p atie nts 
recr uite d fr o m a p pr o xi m atel y 
3 – 6 sites t o accr ue 1 8 p atie nts 
w h o c a n pr o vi de pretre at me nt 
a n d e n d -of -C ycle  1 c a ncer tiss ue 
a n d are e v al u a ble f or 
deter mi ni n g res p o nse usi n g 
R E CI S T 1. 1 criteri a. P atie nts 
u n a ble t o pr o vi de t he se q ue nti al 
c a ncer tiss ue s a m ples or n o n -
e v al u a ble f or res p o nse usi n g 
R E CI S T criteri a will be 
re pl ace d. 
T o a d d Part 3 t o e x pl ore t he 
efficac y a n d safet y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
metastatic or n o n -
resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer, 
pri mar y perit o neal ca ncer, 
or fall o pia n t u be ca ncer  
6. 0 S Y N O P SI S  
St u d y Treat me nts  
P art 1:  
P L X 3 3 9 7 will be 
a d mi nistere d orall y, t wice 
dail y ( BI D) usi n g a 
c o nti n u o us d osi n g re gi me n. 
T he starti n g d ose of 
P L X 3 3 9 7 will be 6 0 0 
m g/ da y. D ose escalati o n will 
occ ur i n i ncre me nts of  ≤5 0 %.  
P art 2:  
P L X 3 3 9 7 will be 
a d mi nistere d orall y, t wice 
dail y ( B I D) usi n g a 
c o nti n u o us d osi n g re gi me n. 
T he d ose of P L X 3 3 9 7 will be 
P art 1:  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y ( BI D) usi n g a 
c o nti n u o us d osi n g re gi me n. T he 
starti n g d ose of P L X 3 3 9 7 will be 
6 0 0 m g/ da y. D ose escalati o n will  
occ ur i n i ncre me nts of  ≤5 0 %. 
P art 1 a n d P art 2:  
Paclita xel, 8 0 m g/ m 2 I V will be 
a d mi nistere d wee kl y ( ± 4 8 h o urs) 
o ver a p pr o xi matel y 6 0  mi n utes i n 
eac h 2 8-da y treat me nt c ycle. O ne 
p aclit a xel d ose m a y be o mitte d 
per c ycle b y p h ysici a n discreti o n 
after C ycle 1.  
T o a d d Part 3 t o e x pl ore t he 
efficac y a n d safet y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
metastatic or n o n -
resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer, 
pri mar y perit o neal ca ncer, 
or fall o pia n t u be ca ncer  
 
C O N FI D E N TI A L  
1 2 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
t he R P 2 D. T here will be n o 
d ose escalati o n.  
P art 1 a n d P art 2:  
Paclita xel, 8 0 m g/ m 2 I V will 
be a d mi nistere d wee kl y ( ± 4 8 
h o urs) o ver a p pr o xi matel y 
6 0  mi n utes i n eac h 2 8 -da y 
treat me nt c ycle. 
O ne paclita xel d ose ma y be 
o mitte d per c ycle b y 
p h ysicia n discreti o n after 
C ycle 1.  
St u d y treat me nt will be 
pr o vi de d u ntil disease 
pr o gressi o n, u nacce pta ble or 
d ose -li miti n g t o xicit y, deat h, 
wit h dra wal of c o nse nt, st u d y 
ter mi nati o n b y S p o ns or, or if 
t he I n vesti gat or a n d patie nt 
a gree t hat it is i n t he patie nt’s 
best i nterests t o disc o nti n ue.  
P art 2:  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y ( BI D usi n g a 
c o nti n u o us d osi n g re gi me n. T he 
d ose of P L X 3 3 9 7 will be t he 
R P 2 D. T here will be n o d ose 
escalati o n. P aclit a xel, 8 0 m g/ m 2 
I V will be a d mi nistere d wee kl y 
( ±4 8 h o urs) o ver a p pr o xi m atel y 
6 0  mi n utes i n e ac h 2 8 -d a y  
tre at me nt c ycle. O ne paclita xel 
d ose ma y be o mitte d per c ycle b y 
p h ysicia n discreti o n after C ycle 1.  
P art 3 :  P atie nts will be 
se q ue nti all y assi g ne d t o o ne of 
t hree C ycle 1 ( 2 8 t o 3 5 d a y) 
le a d-i n tre at me nt ar ms: 
4)  P L X 3 3 9 7 6 0 0 m g BI D 
usi n g a c o nti n u o us 
d osi n g re gi me n  
5)  P aclit a xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver 
a p pr o xi m atel y 
6 0  mi n utes  
6)  P L X 3 3 9 7 6 0 0 m g BI D 
usi n g a c o nti n u o us 
d osi n g re gi me n a n d 
p aclit a xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver 
a p pr o xi m atel y 
6 0  mi n utes  
F oll o wi n g t he sec o n d c a ncer 
tiss ue a n d bl o od f or bi o m ar ker 
s a m pli n g d uri n g t he peri o d 
fr o m St u d y D a y 2 8 - 3 5, C ycle 1 
e n ds a n d all p atie nts will st art 
C ycle 2 tre at me nt wit h 
P L X 3 3 9 7 6 0 0 m g BI D usi n g a 
c o nti n u o us d osi n g re gi me n a n d 
p aclit a xel 8 0 m g/ m 2 I V wee kl y 
( ±4 8  h o urs) o ver a p pr o xi m atel y 
6 0  mi n u tes. C ycle 2 a n d all 
s u bse q ue nt c ycles will be 2 8-d a y 
c ycles. St arti n g wit h C ycle 2, 
o ne p aclit a xel d ose m a y be 
o mitte d per c ycle b y p h ysici a n 
discreti o n. P atie nts w h o 
disc o nti n ue p aclit a xel d ue t o 
p aclit a xel -rel ate d t o xicit y m a y 
c o nti n ue tre at me nt wit h 
 
C O N FI D E N TI A L  
1 2 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
P L X 3 3 9 7.  
P art 1, P art 2, a n d P art 3:  
St u d y treat me nt will be pr o vi de d 
u ntil disease pr o gressi o n, 
u nacce pta ble or d ose -li miti n g 
t o xicit y, deat h, wit h dra wal of 
c o nse nt, st u d y ter mi nati o n b y 
S p o ns or, or if t he I n vesti gat or a n d 
patie nt a gree t hat it is i n t he 
pa tie nt’s best i nterests t o 
disc o nti n ue.  
6. 0 S Y N O P SI S  
St u d y Pr oce d ures  
P art 1:  
T his n o nra n d o mize d, o pe n -
la bel st u d y will e m pl o y a 
tra diti o nal 3 + 3 P hase 1 
desi g n, wit h escalati n g 
d osi n g c o h orts of P L X 3 3 9 7 
a n d a fi xe d d ose le vel o f 
paclita xel. Eac h treat me nt 
c ycle will be 2 8 da ys.  
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he 6 0 0 m g/ da y 
d ose le vel. Patie nts s h o ul d 
fast ( o ne h o ur) bef ore a n d 
after P L X 3 3 9 7 
a d mi nistrati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1 ). 
O n n o n -P K/ P D paclita xel 
a d mi nistra ti o n da ys, t he 
m or ni n g d ose of P L X 3 3 9 7 
ma y be a d mi nistere d at 
h o me, pri or t o paclita xel 
a d mi nistrati o n. T he starti n g 
d ose le vel of P L X 3 3 9 7 will 
be 6 0 0  m g/ da y. D ose 
escalati o n will occ ur i n 
i ncre me nts of ≤5 0 %. All 
patie nts at a gi ve n d ose le vel 
will be f oll o we d o n treat me nt 
f or at least 4 wee ks bef ore 
accr ual t o t he ne xt c o h ort ca n 
be gi n. T here will be n o i ntra -
patie nt d ose escalati o n 
per mitte d. P L X 3 3 9 7 d ose 
re d ucti o ns a n d i nterr u pti o ns 
will be per mitte d d uri n g t he 
first 2 8 da ys of C ycle 1 o nl y 
if a p atie nt e x perie nces a 
D L T.  P L X 3 3 9 7 i nterr u pti o ns 
d uri n g C ycle 1 are als o 
P art 1:  
T his n o nra n d o mize d, o pe n -la bel 
st u d y will e m pl o y a tra diti o nal 
3 + 3 P hase 1 desi g n, wit h 
escalati n g d osi n g c o h orts of 
P L X 3 3 9 7 a n d a fi xe d d ose le vel of 
paclita xel. Eac h treat me nt c ycle 
will be 2 8 da ys.  
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he 6 0 0 m g/ da y d ose 
le vel. Patie nts s h o ul d fast ( 1 h o ur) 
bef ore a n d after P L X 3 3 9 7 
a d mi nistrati o n (see g ui deli nes i n 
Secti o n 1 4. 1. 1 ). O n n o n -P K/ P D 
paclita xel a d mi nistrati o n da ys, t he 
m or ni n g d ose of P L X 3 3 9 7 ma y be 
a d mi nistere d at h o me, pri or t o 
paclita xel a d mi nistrati o n. T he 
starti n g d ose le vel of P L X 3 3 9 7 
will be 6 0 0  m g/ da y. D ose 
escalati on will occ ur i n i ncre me nts 
of ≤5 0 %. All patie nts at a gi ve n 
d ose le vel will be f oll o we d o n 
treat me nt f or at least 4 wee ks 
bef ore accr ual t o t he ne xt c o h ort 
ca n be gi n. T here will be n o i ntra -
patie nt d ose escalati o n per mitte d. 
P L X 3 3 9 7 d ose re d ucti o ns a n d 
i nterr u pti o ns will be per mitte d 
d uri n g t he first 2 8 da ys of C ycle 1 
o nl y if a p atie nt e x perie nces a 
D L T.  P L X 3 3 9 7 i nterr u pti o ns 
d uri n g C ycle 1 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 C ycle 1, P L X 3 3 9 7 
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 
T o a d d Part 3 t o e x pl ore t he 
efficac y a n d safet y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
metastatic or n o n -
resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer, 
pri mar y perit o neal ca ncer, 
or fall o pia n t u be ca ncer  
 
C O N FI D E N TI A L  
1 2 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
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 C ycle 1, P L X 3 3 9 7 
treatme 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. After C 1 D 2 8, d ose 
re d ucti o ns or i nterr u pti o ns 
f or a d verse e ve nts ma y ta ke 
place at a n y ti me.  
P art 2:  
T his is a n o nra n d o mi ze d, 
o pe n -la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel 
i n a p pr o xi matel y 3 0 patie nts 
( R P 2 D-treate d patie nts fr o m 
P art 1  a n d P art 2 ). Eac h 
treat me nt c ycle will be 2 8 
da ys.  
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he R P 2 D. 
Patie nt s s h o ul d fast ( o ne 
h o ur) bef ore a n d after 
P L X 3 3 9 7 a d mi nistrati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1 ). 
T here will be n o i ntra -patie nt 
d ose escalati o n per mitte d. 
P L X 3 3 9 7 d ose re d ucti o ns or 
i nterr u pti o ns f or a d verse 
e ve nts ma y ta k e place at a n y 
ti me. 
P art 1 a n d P art 2: 
Patie nts will recei ve st u d y 
treat me nt as l o n g as it is well 
t olerate d a n d b ot h t he … 
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 e ve nts  a n d 
c o m plia nce wit h st u d y dr u g 
a d mi nistrati o n.  
P art 1:  
Bl o o d sa m ples f or P L X 3 3 9 7 
P K a nal ysis will be o btai ne d 
pre -P L X 3 3 9 7 a n d paclita xel 
d osi n g o n C 1 D 1, pre -
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. After C 1 D 2 8, d ose 
re d ucti o ns or i nterr u pti o ns f or 
a d verse e ve nts ( A Es) ma y ta ke 
place at a n y ti me.  
P art 2:  
T his is a n o nra n d o mize d, o pe n -
la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y 3 0 patie nts ( R P 2 D -
treate d patie nts fr o m P art 1  a n d 
P art 2 ). Eac h treat me nt c ycle will 
be 2 8 da ys.  
D osi n g of P L X 3 3 9 7 will 
c o m me nce at t he R P 2 D. Patie nts 
s h o ul d fast ( o ne h o ur) bef ore a n d 
after P L X 3 3 9 7 a d mi nistrati o n (see 
g ui deli nes i n Secti o n 1 4. 1. 1 ). 
T here will be n o i ntra -patie nt d ose 
escalati o n per mitte d. P L X 3 3 9 7 
d ose re d ucti o ns or i nterr u pti o ns 
f or a d verse e ve nts  A Es  ma y ta ke 
place at a n y ti me.  
P art 3:  
T he c a n di d ate p o p ul ati o n will 
be p atie nts wit h a d v a nce d , 
met ast atic or n o n -resect a ble , 
pl ati n u m -resist a nt 
or -refr act or y  e pit heli al o v ari a n 
c a ncer, pri m ar y perit o ne al 
c a ncer or f all o pi a n t u be c a ncer.  
P atie nts will be  se q ue nti all y 
assi g ne d t o o ne of t hree C ycle 1  
( 2 8-d a y) le a d -i n tre at me nt 
ar ms:  
4)  P L X 3 3 9 7 6 0 0 m g BI D 
usi n g a c o nti n u o us 
d osi n g re gi me n  
5)  P aclit a xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver 
a p pr o xi m atel y 
6 0  mi n utes  
6)  P L X 3 3 9 7 6 0 0 m g BI D 
usi n g a c o nti n u o us 
d osi n g re gi m e n a n d 
p aclit a xel, 8 0 m g/ m 2 I V 
wee kl y ( ± 4 8 h o urs) o ver 
a p pr o xi m atel y 
 
C O N FI D E N TI A L  
1 2 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
P L X 3 3 9 7 a n d paclita xel 
d osi n g o n C 1 D 1 5, a n d 2 a n d 
4 h o urs p ost -P L X 3 3 9 7 a n d 
paclita xel d osi n g o n C 1 D 1 5.  
P art 1 a n d P art 2: 
P har mac o d y na mic ( P D) 
mar kers i ncl u di n g ser u m 
C S F -1 will be o btai ne d at  
pre -d ose o n Da y  1 of eac h 
c ycle as o utli ne d i n t he Trial 
Fl o w C hart . A w h ole bl o o d 
sa m ple f or circ ulati n g 
C D 1 4/ C D 1 6 p ositi ve 
m o n oc yte a nal ysis will als o 
be o btai ne d pre -d ose o n 
C 1 D 1 a n d C 1 D 1.  
6 0  mi n utes  
F oll o wi n g t he sec o n d c a ncer 
bi o ps y, C ycle 1 e n ds a n d all 
p atie nts will st art C ycle 2 
tre at me nt wit h P L X 3 3 9 7 6 0 0 m g 
BI D usi n g a c o nti n u o us d osi n g 
re gi me n a n d p aclit a xel, 8 0 
m g/ m
2 I V wee kl y ( ± 4 8 h o urs) 
o ver a p pr o xi m atel y 6 0  mi n utes. 
C ycle 2 a n d all s u bse q ue nt 
c ycles will be 2 8 -d a y c ycles. 
St arti n g wit h C ycle 2, o ne 
p aclit a xel d ose m a y be o mitte d 
per c ycle b y p h ysici a n 
discreti o n. P atie nts w h o 
disc o nti n ue p aclit a xel d ue t o 
p aclit a x el-rel ate d t o xicit y m a y 
c o nti n ue tre at me nt wit h 
P L X 3 3 9 7.  
P atie nts s h o ul d f ast ( o ne h o ur) 
bef ore a n d after P L X 3 3 9 7 
a d mi nistr ati o n (see g ui deli nes i n 
Secti o n 1 4. 1. 1 ). T here will be n o 
i ntr a-p atie nt d ose esc al ati o n 
per mitte d. P L X 3 3 9 7 d ose 
re d ucti o ns or i nterr u pti o ns f or 
A Es  m a y t a ke pl ace at a n y ti me.  
P art 1, P art 2, a n d P art 3 : 
Patie nts will recei ve st u d y 
treat me nt as l o n g as it is well 
t olerate d a n d b ot h t he … 
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 
e ve ntsA Es  a n d c o m plia nce wit h 
st u d y dr ug a d mi nistrati o n.  
P art 1:  
Bl o o d sa m ples f or P L X 3 3 9 7 P K 
a nal ysis will be o btai ne d pre -
P L X 3 3 9 7 a n d paclita xel d osi n g o n 
C 1 D 1, pre -P L X 3 3 9 7 a n d 
paclita xel d osi n g o n C 1 D 1 5, a n d 2 
a n d 4 h o urs p ost -P L X 3 3 9 7 a n d 
paclita xel d osi n g o n C 1 D 1 5.  
P art 1 , P art 2, a n d P art  3: 
P har mac o d y na mic ( P D) mar kers 
i ncl u di n g ser u m C S F-1 will be 
o btai ne d at pre -d ose o n Da y  1 of 
eac h c ycle as o utli ne d i n t he Trial 
Fl o w C hart . A w h ole bl o o d 
sa m ple f or circ ulati n g 
 
C O N FI D E N TI A L  
1 2 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
C D 1 4/ C D 1 6 p ositi ve m o n oc yte 
a nal ysis will als o be o btai ne d pre -
d ose o n C 1 D 1  a n d C 1 D 1 5. 
P art 3 :   
C a ncer tiss ue [ 2- 3 c ore bi o psies 
of t ar get ( ≥2 c m  di a meter) or 
n o n -t ar get lesi o ns] a n d bl o o d f or 
bi o m ar kers will be o bt ai ne d 
d uri n g Scree ni n g after C T 
i m a gi n g a n d at C ycle 1 D a y 2 8 ± 
7 d a ys  ( C ycle 1 D a y 2 1 t o C ycle 
1 D a y 3 5).. F oll o wi n g t he sec o n d 
bi o ps y, C ycle 1 e n ds a n d all 
p atie nts will st art C ycle 2 
tre at me nt wit h d ail y P L X 3 3 9 7 
at t he R P 2 D a n d wee kl y 
p aclit a xel. C ycle 2 a n d all 
s u bse q ue nt c ycles will be 2 8-d a y 
c ycles. A bl o o d s a m ple f or 
pl as m a P K a n d bi o m ar kers  will 
be o bt ai ne d pre -P L X 3 3 9 7 a n d 
p aclit azel d osi n g o n C ycle 1 D a y 
1, C ycle 1 D a y 1 5 a n d  o n D a y 1 
of all s u bse q ue nt c ycles a n d t he 
E n d -of -St u d y Visit. P atie nts will 
h a ve effic ac y assess me nts e ver y 
8 wee ks t o deter mi ne o bjecti ve 
res p o nse ( C R + P R), cli nic al 
be nefit ( C R + P R + S D) , 
pr o gressi o n -free s ur vi v al ( P F S), 
a n d ti me t o ne xt tre at me nt 
( after l ast st u d y tre at me nt). 
C A -1 2 5 s a m pli n g re q uire me nts :  
2 pre -tre at me nt s a m ples, first 
s a m ple wit hi n 3 m o nt hs of 
st arti n g t her a p y a n d sec o n d 
s a m ple wit hi n 1 wee k of st arti n g 
t her a p y; s u bse q ue nt s a m ples o n 
t he first d a y of e ac h c ycle 
st arti n g wit h C 2 D 1 a n d E n d-of -
St u d y Visit.  
 
C O N FI D E N TI A L  
1 3 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
6. 0 S Y N O P SI S  
Ke y Patie nt 
Selecti o n Criteria  
I ncl usi o n Criteria 
A N D  
1 0. 1 I ncl usi o n 
Criteria  
I ncl usi o n Criteria 
1.  Patie nts i n  
a. Part 1 :  a n a d vance d, 
i nc ura ble s oli d t u m or 
b.  Part 2 :  a n a d va nce d, 
i nc ura ble s oli d t u m or 
f or w h o m a ta xa ne 
w o ul d be c o nsi dere d a 
reas o na ble 
c he m ot hera p y o pti o n.  
2.  Patie nts wit h sta ble 
brai n metastases are 
eli gi ble f or t his trial. 
H o we ver, patie nts m ust 
n ot ha ve re q uire d 
steroi d treat me nt f or 
t heir brai n metastases 
wit hi n 3 0 da ys of 
Scree ni n g.  
3.  B o ne -directe d t hera p y 
(e. g., bis p h os p h o nates 
or de n os u ma b) is 
per mitte d. H o we ver, 
patie nts s h o ul d n ot ha ve 
starte d b o ne-directe d 
t hera p y wit hi n 2 wee ks 
of C 1 D 1, a n d ne w b o ne -
directe d t he ra p y s h o ul d 
n ot be i nitiate d d uri n g 
t he first 4 wee ks of 
st u d y (i.e., C ycle 1).  
4.  Was h o ut fr o m a n y pri or 
i n vesti gati o nal t hera p y 
of at least 2 8 da ys pri or 
t o C 1 D 1. 
 
1 7. A bilit y t o gi ve writte n 
i nf or me d c o nse nt a n d 
willi n g t o c o m pl y wit h 
t he re q uire me nts of the 
pr ot oc ol  
 
I ncl usi o n Criteria 
1.  Patie nts i n  
a. Part 1 :  a n a d va nce d, 
i nc ura ble s oli d t u m or 
b.  Part 2 :  a n a d va nce d, 
i nc ura ble s oli d t u m or f or 
w h o m a ta xa ne w o ul d be 
c o nsi dere d a reas o na ble 
c he m ot hera p y o pti o n.  
c. P art 3 :  a d v a nce d , 
met ast atic or n o n -
resect a ble e pit heli al 
o v ari a n c a ncer, pri m ar y 
perit o ne al c a ncer , or 
f all o pi a n t u be c a ncer 
w it h: 
i. pl ati n u m -resist a nt 
c a ncer, defi ne d as 
dise ase t h at res p o n de d 
t o a pl ati n u m -
c o nt ai ni n g 
c he m ot her a p y re gi me n, 
b ut  de m o nstr ate d 
rec urre nce wit hi n si x 
m o nt hs f oll o wi n g t he 
c o m plet i o n of t hat 
pl ati n u m -c o nt ai ni n g 
re gi me n ,  
O R  
ii. pl ati n u m -refr act or y 
c a ncer, defi ne d as 
dise ase f aile d t o ac hie ve 
at le ast a p arti al 
res p o nse t o a pl ati n u m -
c o nt ai ni n g re gi me n  (i.e., 
st a ble dise ase or act u al 
dise ase pr o gressi o n),  
A N D  
iii. h a ve n ot bee n tre ate d 
wit h a t a x a ne wit hi n o ne 
ye ar of C 1 D 1 , 
A N D  
i v. h a ve  n ot  bee n tre ate d 
wit h wee kl y p aclit a xel  
after first -li ne tre at me nt 
i n w hic h wee kl y 
p aclit a xel pl us a 
pl ati n u m is per mitte d . 
2.  P art 3 :  P atie nts m ust h a ve 
T o a d d Part 3 i ncl usi o n 
criteria 
 
C O N FI D E N TI A L  
1 3 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
t ar get (≥2 c m  di a meter) or 
n o n -t ar get lesi o n c a ncer 
t h at is accessi ble f or 2-3 
c ore bi o psies d uri n g 
Scree ni n g after C T i m a gi n g 
a n d all ot her scree ni n g tests 
a n d pr oce d ures h a ve bee n 
c o m plete d a n d d uri n g t he 
peri o d fr o m C ycle 1 D a y 2 1 
t o C ycle 1 D a y 3 5.  
2 3. Patie nts wit h sta ble brai n 
metastases are eli gi ble f or 
t his trial. H o we ver, patie nts 
m ust n ot ha ve re q uire d 
ster oi d treat me nt f or t heir 
brai n metastases wit hi n 3 0 
da ys of Scree ni n g.  
3 4. B o ne -directe d t hera p y (e. g., 
bis p h os p h o nates or 
de n os u ma b) is per mitte d. 
H o we ver, patie nts s h o ul d 
n ot ha ve starte d b o ne -
directe d t hera p y wit hi n 2 
wee ks of C 1 D 1, a n d ne w 
b o ne -directe d t hera p y 
s h o ul d n ot be i nitiate d 
d uri n g t he first 4 wee ks of 
st u d y (i.e., C ycle 1). \ 
4 5.  Was h o ut fr o m a n y pri or 
i n vesti gati o nal t hera p y of at 
least 2 8 da ys fi ve ti mes t he 
T 1/ 2 pri or t o C 1 D 1.  
5 6. W as h o ut fr o m a n y pri or 
bi ol o gic or t ar gete d 
t her a p y at least 4 wee ks or 
fi ve ti mes t he T 1/ 2 
( w hic he ver is s h orter) 
pri or t o C 1 D 1.  
1 7 1 9. A bilit y t o gi ve writte n 
i nf or me d c o nse nt a n d 
willi n g t o c o m pl y wit h t he  
re q uire me nts of t he 
pr ot oc ol; a n d f or P art  3, 
a ble t o gi ve writte n 
i nf or me d c o nse nt f or 2 
c a ncer bi o ps y pr oce d ures.  
 
C O N FI D E N TI A L  
1 3 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
6. 0 S Y N O P SI S  
D ose Li miti n g 
T o xicities  
N o n -he mat ol o gic D L Ts  
•  
A n y C T C A E v 4 Gra de 
≥3 n o n -he mat ol o gic 
t o xicit y, u nless t he 
e ve nt is cle arl y 
u nrel ate d  t o treat me nt 
wit h P L X 3 3 9 7 i n 
c o m bi nati o n wit h wee kl y 
sta n dar d fi xe d d osi n g of 
paclita xel E X C E P T t he 
f oll o wi n g: 
N o n he mat ol o gic Ot her  D L Ts  
•  
A n y C T C A E v 4 Gra de ≥3 
n o n he mat ol o gic ot her  D L Ts 
t o xicit y, u nless t he e ve nt is 
cle arl y u nrel ate d  t o 
treat me nt wit h P L X 3 3 9 7 i n 
c o m bi nati o n wit h wee kl y 
sta n dar d fi xe d d osi n g of 
paclita xel E X C E P T t he 
f oll o wi n g:   
 
6. 0 S Y N O P SI S 
D osa ge a n d 
Re gi me n  
P L X 3 3 9 7 ( 1 0 0 or 2 0 0 m g 
ca ps ules) will be 
a d mi n istere d orall y, usi n g a 
d osi n g re gi me n of t wice dail y 
o n a n e m pt y st o mac h (see 
Secti o n 1 4. 1. 1  f or details). 
T he BI D re gi me n is preferre d 
t o re d uce ca ps ule l oa d per 
d ose a n d mi ni mize i ntra -da y 
dr u g le vel fl uct uati o ns. O n 
n o n -P K paclita xel d osi n g 
da ys, P L X 3 3 9 7 ma y be 
a d mi nistere d at h o me, pri or 
t o t he cli nic visit f or 
paclita xel a d mi nistrati o n.  
Paclita xel at a fi xe d d ose of 
8 0 m g/ m 2 will be 
a d mi nistere d I V o ver 
a p pr o xi matel y 6 0 mi n utes 
o nce wee kl y ( ± 4 8 h o urs).  
P art 1:  
At least 3 of 4 pla n ne d 
paclita xel d oses  m ust be 
a d mi nistere d i n t he D L T 
peri o d (i.e., C ycle 1). O n 
s u bse q ue nt c ycles, 1 
paclita xel d ose ma y be 
s ki p pe d per C ycle per 
I n vesti gat or discreti o n a n d/ or 
patie nt prefere nce.  
P art 1 a n d P art 2:  
I n or der t o i nitiate eac h 
wee kl y paclita xel treat me nt, 
pati e nts m ust ha ve a n A N C 
≥1 0 0 0/ m m 3 a n d platelets 
≥7 5, 0 0 0/ m m 3. 
A paclita xel pre me dicati o n 
re gi me n, c o nsisti n g of a 
c ortic oster oi d, a n H 2 
P L X 3 3 9 7 ( 1 0 0 or  2 0 0 m g 
ca ps ules)  will be a d mi nistere d 
orall y, usi n g a d osi n g re gi me n of 
t wice dail y. P atie nts s h o ul d f ast 
( o ne h o ur) bef ore a n d after 
P L X 3 3 9 7 a d mi nistr ati o n  o n a n 
e m pt y st o mac h (see Secti o n 1 4. 1. 1  
f or details). T he BI D re gi me n is 
preferre d t o re d uce ca ps ule l oa d 
per d ose a n d mi ni mize i ntra -da y 
dr u g le vel fl uct uati o ns. O n n o n -
P K paclita xel or n o n -bl o o d 
bi o m ar ker d osi n g da ys, P L X 3 3 9 7 
ma y be a d mi nistere d at h o me, 
pri or t o t he cli nic visit f or 
paclita xel a d mi nistrati o n.  
Paclita xel at a fi xe d d ose of 8 0 
m g/ m 2 will be a d mi nister e d I V 
o ver a p pr o xi matel y 6 0 mi n utes 
o nce wee kl y ( ± 4 8 h o urs).  
P art 1:  
At least 3 of 4 pla n ne d paclita xel 
d oses m ust be a d mi nistere d i n t he 
D L T peri o d (i.e., C ycle 1). O n 
s u bse q ue nt c ycles, 1 paclita xel 
d ose ma y be s ki p pe d per C ycle 
per I n vesti gat or discret i o n a n d/ or 
patie nt prefere nce.  
P art 1 a n d  P art 2 :   
P atie nts will be tre ate d wit h 
P L X 3 3 9 7 R P 2 D ( 6 0 0 m g BI D) 
usi n g a c o nti n u o us d osi n g 
re gi me n a n d p aclit a xel, 8 0 
m g/ m
2 I V wee kl y (± 4 8 h o urs) 
o ver a p pr o xi m atel y 6 0  mi n utes 
i n e ac h 2 8-d a y tre at me nt c ycle. 
O ne p aclit a xel d ose m a y be 
o mitte d per c ycle b y p h ysici a n 
discreti o n.   
T o a d d Part 3 t o d osa ge a n d 
re gi me n 
 
C O N FI D E N TI A L  
1 3 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
a nta g o nist a n d 
di p he n h y dra mi ne, is 
rec o m me n de d i n or der t o 
re d uce t he ris k of 
a na p h yla xis. 
P art 3 :  P atie nts will be 
se q ue nti all y assi g ne d t o o ne of 
t hree C ycle 1 ( 2 8 t o 3 5 d a y) 
le a d-i n tre at me nt ar ms: 
•  
P L X 3 3 9 7 6 0 0 m g BI D usi n g 
a c o nti n u o us d osi n g 
re gi me n. 
•  
P aclit a xel, 8 0 m g/ m 2 I V 
w ee kl y ( ± 4 8 h o urs) o ver 
a p pr o xi m atel y 6 0  mi n utes.  
•  
P L X 3 3 9 7 6 0 0 m g BI D usi n g 
a c o nti n u o us d osi n g 
re gi me n a n d p aclit a xel, 8 0 
m g/ m
2 I V wee kl y ( ± 4 8 
h o urs) o ver a p pr o xi m atel y 
6 0  mi n utes.  
F oll o wi n g t he sec o n d c a ncer 
tiss ue a n d bl o o d f or bi o m ar ker 
s a m pli n g d uri n g the peri o d 
fr o m St u d y D a y 2 8 - 3 5, C ycle 1 
e n ds a n d all p atie nts will st art 
C ycle 2 tre at me nt wit h 
P L X 3 3 9 7 6 0 0 m g BI D usi n g a 
c o nti n u o us d osi n g re gi me n a n d 
p aclit a xel, 8 0 m g/ m 2 I V wee kl y 
( ±4 8 h o urs) o ver a p pr o xi m atel y 
6 0  mi n utes . C ycle 2 a n d all 
s u bse q ue nt c ycles will be 2 8 -d a y 
c ycles. St arti n g wit h C ycle 2, 
o ne p aclit a xel d ose m a y be 
o mitte d per c ycle b y p h ysici a n 
discreti o n. P atie nts w h o 
disc o nti n ue p aclit a xel d ue t o 
p aclit a xel -rel ate d t o xicit y m a y 
c o nti n ue tre at me nt wit h 
P L X 3 3 9 7.  
P art 1, P art 2, a n d P art 3:  
I n or der t o i nitiate eac h wee kl y 
paclita xel treat me nt, patie nts m ust 
ha ve a n A N C ≥1 0 0 0/ m m 3 a n d 
platelets ≥7 5, 0 0 0/ m m 3. 
A paclita xel pre me dicati o n 
re gi me n, c o nsisti n g of a 
c ortic oster oi d, a n H 2 a nta g o nist 
a n d di p he n h y dra mi ne, is 
rec o m me n de d i n or der t o red uce 
t he ris k of a na p h yla xis. 
6. 0 S Y N O P SI S  
Safet y a n d 
A me n d me nt 5 d oes n ot 
c o nt ai n P art 3.  
P art 3 :  A E a n d seri o us a d verse 
e ve nt ( S A E) re p orti n g will 
T o a d d start of A E 
c ollecti o n f or Part 3 of t he 
 
C O N FI D E N TI A L  
1 3 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
T olera bilit y 
Assess me nts 
c o m me nce w he n t he 2 -3 c ore 
bi o psies  are o bt a i ne d d uri n g 
Scree ni n g.  
st u d y 
6. 0 S Y N O P SI S 
St o p pi n g R ules  
A me n d me nt 5 d oes n ot 
c o nt ai n P art 3.  
P art 3:  
After ~ 5 0 % of t he pl a n ne d 
a p pr o xi m atel y 1 8  p atie nts h a ve 
c o m plete d at le ast 2 tre at me nt 
C ycles, a n o ver al l i nteri m s afet y 
s u m m ar y will be re vie we d b y 
t he Me dic al M o nit or a n d 
Pri nci p al I n vesti g at ors t o e ns ure 
t h at t he p ote nti al cli nic al be nefit 
o ut wei g hs t he o bser ve d cli nic al 
ris k t o d ate. If t he s afet y 
o bser v ati o ns d o n ot w arr a 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 . 
T o a d d st o p pi n g r ules f or 
Part 3 of t he st u d y  
6. 0 S Y N O P SI S  
P K Para meters  
P art 1:  
P art 1 a n d P art 3:  
T o a d d P K para meters f or 
Part 3 of t he st u d y  
6. 0 S Y N O P SI S  
P D Para meters  
P art 1 a n d P art 2:  
E x pl orat or y bi o mar kers f or 
e val uati n g anti -t u m or 
acti vit y, i nfla m mati o n a n d 
e ner g y meta b olis m ma y be 
meas ure d. Bi o mar kers will 
i ncl u de, b ut are n ot li mite d 
t o, C S F-1.  
P art 1, P art 2, a n d P art 3:  
E x pl orat or y bi o mar kers f or 
e val uati n g a nti -t u m or acti vit y, 
i nfla m mati o n a n d e ner g y 
meta b olis m ma y be  meas ure d. 
Bi o mar kers will i ncl u de, b ut are 
n ot li mite d t o, C S F -1.  
P art 3 :   
C a ncer tiss ue bi o m ar kers will 
i ncl u de: 
•  
I H C f or C D 6 8, C D 8, P D-L 1, 
a n d a d diti o n al m ar kers of 
m acr o p h a ge a n d T -cell 
prese nce a n d f u ncti o n  
•  
R N A e x pressi o n a n al ysis f or 
a n e x pl or at or y p a nel of 
t u m or micr oe n vir o n me nt 
m ar kers  
•  
St ai ni n g of cells of t he 
t u m or micr oe n vir o n me nt. 
P a nels of I H C m ar kers 
s pecific f or m acr o p h a ges, T-
cells, a n d ot her i m m u ne a n d 
i nfl a m m at or y cells will be 
e m pl o ye d, f or se mi -
q u a ntit ati ve c h a n ges i n cell 
n u m ber, l oc ati o n wit hi n t he 
t u m or, a n d de gree of 
acti v ati o n.  
T o a d d P D para m eters f or 
Part 3 of t he st u d y  
 
C O N FI D E N TI A L  
1 3 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
Bl o o d bi o m ar kers will i ncl u de:  
•  
C A -1 2 5 s a m pli n g 
re q uire me nts :  t w o pre-
tre at me nt s a m ples, first 
s a m ple wit hi n 3 m o nt hs of 
st arti n g t her a p y a n d sec o n d 
s a m ple wit hi n 1 wee k of 
C 1 D 1; s u bse q ue nt s a m ples 
o n t he first  d a y of e ac h c ycle 
st arti n g wit h C 2 D 1 a n d 
E n d -of -St u d y Visit.  
•  
Pl as m a C S F -1 a n d 
a d diti o n al m ar kers of 
tre at me nt effect 
•  
W h ole bl o o d C D 1 4/ C D 1 6 
m o n oc yte s u bset b y F A C S 
a n al ysis  
•  
W h ole bl o o d m yel oi d -
deri ve d s u p press or cell 
(M D S C) b y F A C S a n al ysis  
6. 0 S Y N O P SI S  
Trial Fl o w C hart 
( Part 1 a n d 2) 
 
1 6.  E n d of St u d y i m a gi n g 
s h o ul d be o bt ai ne d f or 
p atie nts w h o g o off 
st u d y f or re as o ns ot her 
t h a n r a di o gr a p hic 
dise ase pr o gressi o n.  
T o clarif y w hic h s u bjects 
s h o ul d recei ve ra di o gra p hic 
assess me nts s h o ul d be 
o btai ne d f or E n d of St u d y 
i ma gi n g. 
6. 0 S Y N O P SI S  
Trial Fl o w C hart  
A me n d me nt 5 d oes n ot 
c o nt ai n a Tri al Fl o w C h art 
f or P art 3. 
Tri al Fl o w C h art ( P art 3)  
T o a d d Trial Fl o w C hart or 
Part 3 of t he st u d y  
7. 0 
I N T R O D U C TI O N 
 
C S F -1 Rece pt or  I n hi biti o n i n 
O v ari a n C a ncer   
I n h u m a n e pit heli al o v ari a n 
c a ncer, C S F -1 a n d/ or F ms 
e x pressi o n h as bee n o bser ve d i n 
t he l ar ge m aj orit y of c ases, wit h 
7 5 % of pri m ar y t u m ors a n d 
6 9 % of t he met ast ases 
e x pressi n g C S F -1, a n d 9 2 % of 
pri m ar y t u m ors a n d 8 3 % of 
met ast ases e x pressi n g F ms  
(K aci ns ki 1 9 9 1 , C h a m bers 1 9 9 7 , 
T o y 2 0 0 1 ). At t he ti me of 
di a g n osis i n e pit heli al o v ari a n 
c a ncer p atie nts, ele v ate d le vels 
of b ot h ser u m a n d ascitic fl ui d 
C S F -1 are ass oci ate d wit h a 
p o or o utc o me ( Price 1 9 9 3 , 
Sc h oll 1 9 9 4 ). D uri n g t he c o urse 
of t he dise ase, ele v ate d le vels of 
T o a d d rati o nale f or t he 
a d diti o nal i n dicati o n of 
o varia n ca ncer.  
 
C O N FI D E N TI A L  
1 3 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
ser u m C S F-1 c a n her al d dise ase 
rec urre nce or pr o gressi o n 
(K aci ns ki 1 9 8 9) . Ele v ate d C S F-1 
le vels as p art of a p a nel of 
m ar kers, i ncl u di n g C A 1 2 5, h as 
rece ntl y bee n s h o w n t o hel p 
i m pr o ve e arl y detecti o n of 
o v ari a n c a n cer (S k ates 2 0 0 4 , 
Z h a n g 2 0 0 7 ). T his str o n g 
ass oci ati o n wit h dise ase 
detecti o n a n d pr o g n osis s u g gests 
a n eti ol o gic al r ole f or F ms/ C S F -
1 i n o v ari a n c a ncer i niti ati o n 
a n d ne o pl astic pr o gressi o n.  
B ase d o n t he fi n di n gs disc usse d 
a b o ve, it see ms re as o n a ble t o 
p o st ul ate t h at bl oc k a de of 
cell ul ar a n d/ or m olec ul ar 
pr o gr a ms e n h a nci n g 
m acr o p h a ge recr uit me nt i n 
e pit heli al o v ari a n c a ncer m a y 
res ult i n decre ase d m acr o p h a ge 
prese nce i n e pit heli al o v ari a n 
t u m ors. 
P L X 3 3 9 7 as a m acr o p h a ge -
t ar gete d t u m or se nsitizer 
P L X 3 3 9 7 is  a n o vel, or all y 
acti ve, s m all m olec ule i n hi bit or 
i nte n de d f or or al a d mi nistr ati o n 
t h at t ar gets 3 ki n ases:  
1)  F ms  ( als o referre d t o as C S F-
1 R, t he rece pt or f or C S F -1 [ als o 
k n o w n as m acr o p h a ge -c ol o n y 
sti m ul ati n g f act or] as well as t he 
li g a n d i nterle u ki n-3 4  [I L-3 4]); 
2) Kit, t he rece pt or f or ste m cell 
f act or ( S C F); a n d 3) o nc o ge nic 
Flt 3, t he rece pt or f or Flt 3 
li g a n d. H o we ver, it ot her wise 
re m ai ns hi g hl y selecti ve i n ter ms 
of i m p act o n t he acti vit y of ot her 
rece pt ors a n d ki n ases. T he 
p ote nt i n hi biti o n of t hes e 3 
ki n ases c a n be e x pl oite d t o 
att ac k t u m ors t hr o u g h a v ariet y 
of mec h a nis ms :  1) direct 
i n hi biti o n of o nc o ge nic dri vers 
s uc h as o nc o ge nic Kit a n d Flt 3 
m ut a nt pr otei ns; 2) i n hi biti o n of 
p ar acri ne l o o ps bet wee n str o m al 
cells a n d t u m ors; 3)  bl oc k a de of 
 
C O N FI D E N TI A L  
1 3 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
mi gr ati o n a n d a n gi o ge nesis; 4) 
bl oc k a ge of C S F - 1-de pe n de nt 
m yel oi d -deri ve d s u p press or 
cells; a n d 5) disr u pti o n of 
oste ol ytic met ast ases.  
A n i m p ort a nt r ole f or t u m or -
i nfiltr ati n g m acr o p h a ges i n 
t u m or pr o gressi o n h as p oi nte d 
t o F ms as a ke y t ar get i n 
m ulti ple t u m or t y pes ( R uffell 
2 0 1 5). T he pr o -t u m ori ge nic r ole 
of C S F 1 a n d F ms is s u p p orte d 
b y a we alt h of st u dies 
de m o nstr ati n g t h at C S F -1 le vels 
pre dict a p o or o utc o me i n a 
v ariet y of o nc ol o g y i n dic ati o ns, 
i ncl u di n g bre ast, o v ari a n, n o n-
s m all cell l u n g, a n d c ol orectal 
c a ncers.  
8. 0 S T U D Y 
O BJ E C TI V E S 
T his trial is desi g ne d as a 
t w o-part st u d y:  P art 1  
( P hase 1 b), t o e x pl ore t he 
safet y of escalati n g d oses of 
P L X 3 3 9 7 wit h wee kl y 
paclita xel t o esta blis h a 
R P 2 D; a n d, P art 2 , t o 
deter mi ne t he efficac y a n d 
safet y of t he P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
n o n -resecta ble s oli d t u m ors. 
Pri m ar y O bjecti ve :   
•  
Esta blis h t he d ose 
li miti n g t o xicities 
( D L Ts) a n d 
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 
gi ve n i n 
c o m bi nati o n wit h 
wee kl y sta n dar d 
d ose paclita xel i n 
patie nts wit h 
a d va nce d s oli d 
t u m ors. 
•  
Sec o n d ar y 
O bjecti ves: E val uate 
t he o verall safet y 
a n d t olera bilit y of 
T his trial is de si g ne d as a t w o 3 -
part st u d y :  P art 1  ( P hase 1 b), t o 
e x pl ore t he safet y of escalati n g 
d oses of P L X 3 3 9 7 wit h wee kl y 
paclita xel t o esta blis h a R P 2 D; 
a n d, P art 2 , t o deter mi ne t he 
efficac y a n d safet y of t he 
P L X 3 3 9 7 a d mi nistere d at t he 
R P 2 D i n c o m bi nati o n wit h 
paclita xel i n patie nts wit h 
a d va nce d, n o n -resecta ble s oli d 
t u m ors; a n d P art 3, t o deter mi ne 
t he effic ac y a n d s afet y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n c o m bi n ati o n 
wit h p aclit a xel i n p atie nts wit h 
a d v a nce d, met ast atic or n o n -
resect a ble, pl ati n u m -resist a n t 
or -refr act or y e pit heli al o v ari a n 
c a ncer, pri m ar y perit o ne al 
c a ncer, or f all o pi a n t u be c a ncer. 
P art 1 ( P h ase 1 b)  
Pri m ar y O bjecti ve :   
•  
T o e x pl ore t he safet y a n d 
t olera bilit y of escalati n g 
d oses of P L X 3 3 9 7 wit h 
wee kl y paclita xel t o 
esta blis h a R P 2 D  
Esta bli s h t he d ose 
li miti n g t o xicities ( D L Ts) 
a n d rec o m me n de d P hase 
T o a d d Part 3 t o e x pl ore t he 
efficac y a n d safet y of 
P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
metastatic or n o n -
resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer, 
pri mar y perit o neal ca ncer, 
or fall o pia n t u be ca ncer  
 
C O N FI D E N TI A L  
1 3 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
P L X 3 3 9 7 i n 
c o m bi nati o n wit h 
paclita xel  
1.  
E x pl ore t he efficac y 
of P L X 3 3 9 7 i n 
c o m bi nati o n wit h 
paclita xel i n patie nts 
wit h a d va nce d s oli d 
t u m ors 
2.  
Deter mi ne t he 
p har mac o ki netics 
( P K) of P L X 3 3 9 7 
w he n a d mi nistere d 
i n c o m bi nati o n wit h 
paclita xel.  
E x pl or at or y O bjecti ves:  
•  
C orrelate t he c ha n ge 
i n C ol o n y 
Sti m ulati n g Fact or -
1 ( C S F -1) le vels 
d uri n g treat me nt 
wit h s pecific d ose 
le vels of P L X 3 3 9 7  
•  
I de ntif yi n g ne w 
bi o mar kers of 
cli nical acti vit y. 
 
2 d ose ( R P 2 D) of 
P L X 3 3 9 7 w he n gi ve n i n 
c o m bi nati o n wit h wee kl y 
sta n dar d d ose paclita xel 
i n patie nts wit h a d va nce d 
s oli d t u m ors. 
Sec o n d ar y O bjecti ves:  
•  
T o e x pl ore t he  effic ac y 
a n d p h ar m ac o ki netics 
( P K) of P L X 3 3 9 7 i n 
c o m bi n ati o n wit h 
p aclit a xel i n p atie nts 
wit h a d v a nce d s oli d 
t u m ors. 
P art 2  
Pri m ar y O bjecti ve :   
•  
T o c o nfir m t he s afet y 
a n d t oler a bilit y of 
P L X 3 3 9 7 a d mi nistere d 
at t he R P 2 D i n 
c o m bi n ati o n wit h 
p aclit a xel i n p atie nts 
wit h a d v a nce d, n o n -
resect a ble s oli d t u m ors  
Sec o n d ar y O bjecti ve:  
•  
T o e x pl ore t he effic ac y 
of  E val uate t he o verall 
safet y a n d t olera bilit y of 
P L X 3 3 9 7 i n c o m bi nati o n 
wit h paclita xel i n 
p atie nts wit h a d v a nce d 
s oli d t u m ors 
•  
E x pl ore t he efficac y of 
P L X 3 3 9 7 i n c o m bi nati o n 
wit h paclita xel  i n patie nts 
wit h a d va nce d s oli d 
t u m ors 
•  
Deter mi ne t he 
p har mac o ki netics ( P K) of 
P L X 3 3 9 7 w he n 
a d mi nistere d i n 
c o m bi nati o n wit h 
paclita xel.  
P arts 1 a n d 2  
E x pl or at or y O bjecti ves:  
•  
T o c orrelate t he c ha n ge 
i n C ol o n y Sti m ulati n g 
Fact or 1 ( C S F - 1) le vels 
d uri n g tre at me nt wit h 
 
C O N FI D E N TI A L  
1 3 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
s pecific d ose le vels of 
P L X 3 3 9 7  
•  
T o  i de ntif y i n g ne w 
bi o mar kers of cli nical 
acti vit y  
P art 3  
Pri m ar y O bjecti ve :   
•  
T o deter mi ne t he efficac y 
of P L X 3 3 9 7 6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h 
paclita xel i n patie nts wit h 
a d va nce d, metastatic o r 
n o n -resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer, 
pri mar y perit o neal 
ca ncer, or fall o pia n t u be 
ca ncer 
Sec o n d ar y O bjecti ves :   
•  
T o e val uate t he safet y 
a n d t olera bilit y of 
P L X 3 3 9 7 i n c o m bi nati o n 
wit h paclita xel i n patie nts 
wit h a d va nce d, metastatic 
or n o n -resecta ble, 
plati n u m -resista nt 
or -refract or y e pit helial 
o varia n ca ncer, pri mar y 
perit o neal ca ncer, or 
fall o pia n t u be ca ncer 
•  
T o e x pl ore t he effect of 
P L X 3 3 9 7 o n ca ncer 
tiss ue a n d bl o o d 
bi o mar kers  
 
C O N FI D E N TI A L  
1 4 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
9. 1  Descri pti o n  
…  P art 2:  
T his is a n o nra n d o mize d, 
o pe n -la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel 
i n a p pr o xi matel y 3 0 patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m P art 1  a n d 
P art 2 ). T he patie nt 
p o p ulati o n will be pa tie nts 
wit h a d va nce d s oli d t u m ors 
i n w hic h treat me nt wit h a 
ta xa ne is c o nsi dere d b y t he 
i n vesti gat or t o be 
a p pr o priate. 
 
… P art 2:  
T his is a n o nra n d o mize d, o pe n -
la bel st u d y of P L X 3 3 9 7 
a d mi nistere d at t he R P 2 D i n 
c o m bi nati o n wit h paclita xel i n 
a p pr o xi matel y  3 0 patie nts 
(i ncl u di n g all R P 2 D-treate d 
patie nts fr o m P art 1  a n d P art 2 ). 
T he patie nt p o p ulati o n c a n di d ate 
p o p ul ati o n  will be patie nts wit h 
a d va nce d s oli d t u m ors i n w hic h 
treat me nt wit h a ta xa ne is 
c o nsi dere d b y t he i n vesti gat or t o 
be a p pr o priate.  
P art 3:  
T his is a n o nr a n d o mize d, o pe n -
l a bel st u d y of P L X 3 3 9 7 6 0 0  m g 
BI D  a d mi nistere d i n 
c o m bi n ati o n wit h p aclit a xel i n 
a p pr o xi m atel y 3 0 p atie nts. T he 
c a n di d ate p o p ul ati o n will be 
p atie nts wit h a d v a nce d , 
met ast atic or n o n -resect a ble, 
pl ati n u m -resist a nt 
or -refr actor y e pit heli al o v ari a n 
c a ncer, pri m ar y perit o ne al 
c a ncer, or f all o pi a n t u be c a ncer. 
P atie nts m ust be resist a nt or 
refr act or y t o pri or pl ati n u m -
b ase d st a n d ar d c are s yste mic 
re gi me ns or refr act or y t o 
pri m ar y tre at me nt wit h a 
pl ati n u m -c o nt ai ni n g re gi me n. 
P ati e nts will be se q ue nti all y 
assi g ne d t o o ne of t hree C ycle 1 
( 2 8 t o 3 5 d a y) le a d-i n tre at me nt 
ar ms :  1) d ail y P L X 3 3 9 7  6 0 0  m g 
BI D ; 2) wee kl y p aclit a xel; a n d 
3) d ail y P L X 3 3 9 7 6 0 0  m g BI D  
a n d wee kl y p aclit a xel. C a ncer 
tiss ue a n d bl o o d f or bi o m ar kers 
will be o bt a i ne d d uri n g 
Scree ni n g a n d d uri n g t he peri o d 
fr o m C ycle 1 D a y 2 1 t o C ycle 1 
D a y 3 5. F oll o wi n g t he sec o n d 
bi o ps y, C ycle 1 e n ds a n d all 
p atie nts will st art C ycle 2 
tre at me nt wit h d ail y P L X 3 3 9 7 
6 0 0  m g BI D  a n d wee kl y 
p aclit a xel. C ycle 2 a n d all 
s u bse q ue nt c ycles will be 2 8-d a y 
T o a d d Part 3 t o e x pl ore t he 
efficac y a n d safet y of 
P L X 3 3 9 7  6 0 0  m g BI D  
a d mi nistere d i n 
c o m bi nati o n wit h paclita xel 
i n patie nts wit h a d va nce d, 
metastatic or n o n -
resecta ble, plati n u m-
resista nt or -refract or y 
e pit helial o varia n ca ncer , 
pri mar y perit o neal ca ncer, 
or fall o pia n t u be ca ncer  
 
C O N FI D E N TI A L  
1 4 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
c ycles. 
9. 2 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.e., BI D) i n ca ps ule 
f or m at t he d ose le vels 
descri be d i n Secti o n 9. 1. T he 
BI D re gi me n is 
rec o m me n de d at hi g her d ose 
le vels (e. g., ≥6 0 0  m g/ da y) t o 
re d uce t he ca ps ule l oa d a n d 
mi ni mize i ntra -da y dr u g le vel 
fl uct uati o ns. 
A fi xe d d ose le vel of 
paclita xel, 8 0 m g/ m 2, will be 
a d mi nistere d i ntra ve n o usl y, 
o nce wee kl y ( ± 4 8  h o urs). 
Patie nts m ust recei ve at least 
3 of 4 paclita xel d oses d uri n g 
t he D L T peri o d (i.e., C ycle 1) 
i n or der t o be c o nsi dere d 
e val ua ble f or D L T, u nless 
d oses are misse d d ue t o a 
D L T. O ne d ose of paclita xel 
ma y be s ki p pe d per C ycle f or 
s u bse q ue nt c ycles (i.e., C ycle 
2 +) per I n vesti gat or 
discreti o n a n d/ or patie nt 
prefere nce . I n ge neral, t w o 
c o nsec uti ve d oses of 
paclita xel s h o ul d n ot be 
s ki p pe d. 
P art 1:  
P L X 3 3 9 7 will be a d mi nistere d 
orall y, t wice dail y ( i.e., BI D) i n 
ca ps ule f or m usi n g a c o nti n u o us 
d osi n g re gi me n  at t he d ose le vels 
descri be d i n Secti o n 9. 1 . T he BI D 
re gi me n is rec o m me n de d at hi g her 
d ose le vels (e. g.,  ≥6 0 0  m g/ da y) t o 
re d uce t he ca ps ule l oa d a n d 
mi ni mize i ntra -da y dr u g le vel 
fl uct uati o ns. T he st arti n g d ose of 
P L X 3 3 9 7 will be 6 0 0 m g/ d a y. 
D ose esc al ati o n will occ ur i n 
i ncre me nts of ≤5 0 %.   
A fi xe d d ose le vel of pacli ta xel 8 0 
m g/ m 2 will be a d mi nistere d 
i ntra ve n o usl y, o nce wee kl y 
( ± 4 8 h o urs). Patie nts m ust recei ve 
at least 3 of 4 paclita xel d oses 
d uri n g t he D L T peri o d (i.e.,  C ycle 
1) i n or der t o be c o nsi dere d 
e val ua ble f or D L T, u nless d oses 
are misse d d ue t o a D L T. O ne 
d ose of paclita xel ma y be s ki p pe d 
per C ycle f or s u bse q ue nt c ycles 
(i.e., C ycle 2 +) per I n vesti gat or 
discreti o n a n d/ or patie nt 
prefere nce. I n ge neral, t w o 
c o nsec uti ve d oses of paclita xel 
s h o ul d n ot be s ki p pe d. 
P art 2:  
P L X 3 3 9 7 will be a d mi nistere d 
or all y, BI D usi n g a c o nti n u o us 
d osi n g re gi me n. T he d ose of 
P L X 3 3 9 7 will be t he R P 2 D. 
T here will be n o d ose esc al ati o n. 
P aclit a xel, 8 0 m g/ m 2 I V will be 
a d mi nistere d wee kl y ( ± 4 8 h o urs) 
o ver a p pr o xi m atel y 6 0  mi n utes 
i n e ac h 2 8-d a y tre at me nt c ycle. 
O ne p aclit a xel d ose m a y be 
o mitte d per c ycle b y p h ysici a n 
discreti o n after C ycle 1.  
P art 3 :   
P atie nts will be se q ue nti all y 
assi g ne d t o o ne of t hree C ycle 1 
( 2 8 t o 3 5 d a y) le a d-i n tre at me nt 
ar ms:  
1)  P L X 3 3 9 7 6 0 0 m g BI D usi n g 
T o a d d Part 3 t o r o ute a n d 
re gi me n 
 
C O N FI D E N TI A L  
1 4 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
a c o nti n u o us d osi n g 
re gi me n 
2)  P aclit a xel, 8 0 m g/ m 2 I V 
wee k l y ( ± 4 8 h o urs) o ver 
a p pr o xi m atel y 6 0  mi n utes  
3)  P L X 3 3 9 7 6 0 0 m g BI D usi n g 
a c o nti n u o us d osi n g 
re gi me n a n d p aclit a xel, 8 0 
m g/ m
2 I V wee kl y ( ± 4 8 
h o urs) o ver a p pr o xi m atel y 
6 0  mi n utes  
F oll o wi n g t he sec o n d bi o ps y, 
C ycle 1 e n ds a n d all p atie nts will 
st art C ycle 2 treat me nt wit h 
P L X 3 3 9 7 6 0 0  m g BI D usi n g a 
c o nti n u o us d osi n g re gi me n a n d 
p aclit a xel 8 0 m g/ m 2 I V wee kl y 
( ±4 8  h o urs) o ver a p pr o xi m atel y 
6 0  mi n utes . C ycle 2 a n d all 
s u bse q ue nt c ycles will be 2 8-d a y 
c ycles. St arti n g wit h C ycle 2, 
o ne p aclit a xel d ose m a y be 
o mitte d  per c ycle b y p h ysici a n 
discreti o n. P atie nts w h o 
disc o nti n ue p aclit a xel d ue t o 
p aclit a xel -rel ate d t o xicit y m a y 
c o nti n ue tre at me nt wit h 
P L X 3 3 9 7.  
P art 1, P art 2, a n d P art 3:  
St u d y tre at me nt will be 
pr o vi de d  u ntil dise ase 
pr o gressi o n, u n acce pt a ble or 
d ose- li miti n g t o xicit y, de at h, 
wit h dr a w al of c o nse nt, st u d y 
ter mi n ati o n b y S p o ns or, or if 
t he I n vesti g at or a n d p atie nt 
a gree t h at it is i n t he p atie nt’s 
best i nterests t o disc o nti n ue.  
9. 4 N u m ber of 
Patie nts  
A me n d me nt 5 d oes n ot 
c o nt ai n P art 3.  
P art 3:  
E nr oll me nt is pl a n ne d t o i ncl u de 
u p t o a p pr o xi m atel y 3 0 p atie nts 
t o accr ue 1 8 p atie nts w h o c a n 
pr o vi de pretre at me nt a n d 
e n d-of -C ycle  1 c a ncer tiss ue a n d 
are e v al u a ble f or deter mi ni n g 
res p o nse usi n g R E CI S T 1. 1 
criteri a. P atie nts u n a b le t o 
pr o vi de t he se q ue nti al c a ncer 
tiss ue s a m ples or n o n-e v al u a ble 
f or res p o nse usi n g R E CI S T 
T o a d d Part 3 t o n u m ber of 
s u bjects 
 
C O N FI D E N TI A L  
1 4 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
criteri a will be re pl ace d.  
1 0. 3 Scree n 
Fail 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 test article 
are defi ne d as scree n fail ures. 
F or all scree n fail ures, t he 
i n vesti gat or will e nter 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 i nt o t he 
electr o nic data ca pt ure 
s yste m ( E D C). T hese data 
will als o  be retai ne d i n t he 
i n vesti gat or’s st u d y files a n d 
ca n be pri nte d b y t he site i n 
l o g f or mat at t he e n d of t he 
st u d y. 
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 test 
article are defi ne d as scree n 
fail ures. F or all scree n fail ures, t he 
i n vesti gat or will e nter 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 
i nt o t he electr o nic data ca pt ure 
s yste m ( E D C) a scree n f ail ure 
l o g. T his data will als o be retai ne d 
i n t he i n vesti gat or’s st u d y files 
a n d ca n be pri nte d b y t he site i n 
l o g f or mat at t he e n d of t he st u d y. 
I n P art 3, p atie nt d at a will be 
c ollecte d i n t he electr o nic d at a 
c a pt ure ( E D C) s yste m fr o m t he 
d ate t he bi o ps y is perf or me d 
d uri n g scree ni n g. D at a will n ot 
be c ollecte d i n t he E D C f or 
p atie nts w h o are scree n f ail ures 
a n d h a ve n ot h a d a bi o ps y 
assess me nt. 
T o u p date scree n fail ure 
pr oce d ures f or Part 3  
1 3. 1 Scree ni n g  
A me n d me nt 5 d oes n ot 
c o nt ai n P art 3 f or t his 
secti o n. 
1 0.  P art 3 o nl y :  C a ncer 
tiss ue [ 2-3 c ore bi o psies 
of t ar get ( ≥2 c m  
d i a meter) or n o n-t ar get 
lesi o ns] f or bi o m ar kers 
after C T i m a gi n g a n d 
all ot her scree ni n g tests 
a n d pr oce d ures h a ve 
bee n c o m plete d  
1 1.  P art 3 o nl y :  C A -1 2 5 
s a m pli n g wit hi n 3 
m o nt hs of st arti n g 
t her a p y  
1 4.  P art 3 o nl y :  Seri o us 
a d verse e ve nt re p orti n g 
will c o m me nce w he n 
t he 2-3 c ore bi o psies are 
o bt ai ne d d uri n g 
Scree ni n g.  
T he f oll o wi n g Scree ni n g 
assess me nts m ust be perf or me d 
wit hi n 7 d a ys bef ore st u d y dr u g 
a d mi nistr ati o n o n C ycle 1 D a y 1:  
•  
P art 3 o nl y :  C A -1 2 5 
s a m pli n g  
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
 
C O N FI D E N TI A L  
1 4 4  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
1 3. 2 Pre -treat me nt 
( Baseli ne) 
6.  Pre -P L X 3 3 9 7 d ose 
bl o o d sa m ple 
c ollecti o n f or P K 
( P art 1 o nl y) a n d 
P D a nal yses.  
7.  Pre -P L X 3 3 9 7 d ose 
w h ole bl o o d sa m ple 
c ollecti o n f or 
C D 1 4/ C D 1 6 
m o n oc yte a nal ysis. 
Per i nstr ucti o ns i n 
t he La b orat or y 
Ma n ual, t his sa m ple 
is ti me se nsiti ve a n d 
m ust be s hi p pe d o ut 
t he sa me da y as t he 
c ollecti o n, 
refri gerate d b ut n ot 
fr oze n.  
8.  P L X 3 3 9 7 
a d mi nistrati o n. 
Patie nts s h o ul d fast 
f or at least 1 hr pri or 
t o a n d after 
P L X 3 3 9 7 
a d mi nistrati o n (see 
Secti o n 1 4. 1. 1 ). 
9.  Paclita xel 
pre me dicati o n 
a d mi nistrati o n 
(rec o m me n de d, b ut 
n ot re q uire d. 
I n vesti gat or s h o ul d 
f oll o w sta n dar d 
i nstit uti o nal 
p olicies).  
1 0.  Paclita xel 
a d mi nistrati o n. 
6.  Pre -P L X 3 3 9 7 d ose bl o o d 
sa m ple c ollecti o n f or 
plas ma P K ( P art 1 a n d 
P art 3 o nl y)  a n d P D 
bi o m ar ker a nal yses.  
7.  Pre -P L X 3 3 9 7 d ose w h ole 
bl o o d sa m ple c ollecti o n 
f or C D 1 4/ C D 1 6 
m o n oc yte a nal ysis. Per 
i nstr ucti o ns i n t he 
La b orat or y Ma n ual, t his 
sa m ple is ti me se nsiti ve 
a n d m ust be s hi p pe d o ut 
t he sa me da y as t he 
c ollecti o n, refri gerate d 
b ut n ot fr oze n.  
8.  P art 3 o nl y :  Pre -
P L X 3 3 9 7 d ose w h o le 
bl o o d s a m ple c ollecti o n 
f or m yel oi d-deri ve d 
s u p press or cell ( M D S C)  
9.  P art 1, P art 2, a n d P art 
3 ( P L X 3 3 9 7 o nl y a n d 
P L X 3 3 9 7 + p aclit a xel 
ar ms) :  P L X 3 3 9 7 
a d mi nistrati o n. Patie nts 
s h o ul d fast f or at least 1 
h o ur pri or t o a n d after 
P L X 3 3 9 7 a d mi nistrati o n 
(see Secti o n 1 4. 1. 1 ). 
1 0.  P art 1, P art 2, a n d P art 
3 ( p aclit a xel o nl y a n d 
P L X 3 3 9 7 + p aclit a xel 
ar ms) :  Paclita xel 
pre me dicati o n 
a d mi nistrati o n 
(rec o m me n de d, b ut n ot 
re q uire d. I n vesti gat or 
s h o ul d f oll o w sta n dar d 
i nstit uti o nal p olicies). 
1 1.  P art 1, P art 2, a n d P art 
3 ( p a clit a xel o nl y a n d 
P L X 3 3 9 7 + p aclit a xel 
ar ms) :  Paclita xel 
a d mi nistrati o n.  
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
1 3. 5 Pre -treat me nt 
C ycle 1 Da y 1 5  
1.  Pre -P L X 3 3 9 7 d ose 
bl o o d sa m ple f or P K 
(P art 1 o nl y ) 
 
•  
Pre -P L X 3 3 9 7 d ose bl o o d 
sa m ple f or P K (P art 1 
a n d P art 3 o nl y ) 
8.  P art 3 o nl y :  Pre -
P L X 3 3 9 7 d ose w h ole 
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
 
C O N FI D E N TI A L  
1 4 5  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
bl o o d s a m ple c ollecti o n 
f or M D S C  
9.  P art 3 o nl y :  Pre -
P L X 3 3 9 7 d ose bl o o d f or 
pl as m a P K a n d 
bi o m ar kers  
1 3. 6 P ost -treat me nt 
C ycle 1 Da y 1 5 
( ± 4 8 h o urs)  
F oll o wi n g recei pt of all st u d y 
dr u gs, patie nts will u n der g o 
t he f oll o wi n g: 
1.  P ost- d ose bl o o d 
sa m ple f or P K ( Part 
1 o nl y) at 2 a n d 4 
h o urs f oll o wi n g 
P L X 3 3 9 7 
a d mi nistrati o n  
2.  A E m o nit ori n g  
F oll o wi n g recei pt of all st u d y 
dr u gs, patie nts will u n der g o t he 
foll o wi n g:  
1. P ost -d ose bl o o d sa m ple f or P K 
( Part 1 o nl y) at 2 a n d 4 h o urs 
f oll o wi n g P L X 3 3 9 7 
a d mi nistrati o n  
2. P ost -d ose bl o o d s a m ple f or 
P K ( P art 3 o nl y) at 2, 4, a n d 6 
h o urs f oll o wi n g P L X 3 3 9 7 
a d mi nistr ati o n  
2 3. A E m o nit ori n g  
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
1 3. 8 Part 3 O nl y :  
C ycle 1 Da y 2 8 ± 7 
da ys ( C ycle 1 Da y 
2 1 t o C ycle 1 Da y 
3 5)  
A me n d me nt 5 d oes n ot 
c o nt ai n t his secti o n.  
1 3. 8 P art 3 O nl y :  C ycle 1 D a y 
2 8 ± 7 d a ys ( C ycle 1 D a y 2 1 t o 
C ycle 1 D a y 3 5)  
•  
C a ncer tiss ue [ 2 -3 c ore 
bi o ps ies of t ar get ( ≥2 
c m di a meter) or n o n -
t ar get lesi o ns] f or 
bi o m ar kers   
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
1 3. 9 ( Pre vi o usl y 
1 3. 8) All 
S u bse q ue nt C ycles, 
Da y 1  
7.  Bl o o d sa m ple f or 
plas ma P K ( P art 1 
o nl y ) a n d P D 
bi o mar ker a nal yses 
ta ke n pri or t o 
P L X 3 3 9 7 d ose  
7.  Bl o o d sa m ple f or plas ma 
P K ( P art 1 a n d P art 3 
o nl y ) a n d P D bi o mar ker 
a nal yses ta ke n pri or t o 
P L X 3 3 9 7 d ose  
8.  P art 3 o nl y :  C A -1 2 5 
s a m pli n g  
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
1 3. 1 2 ( Pre vi o usl y 
1 3. 1 1) E n d of 
St u d y  
9.  I ma gi ng f or t u m or 
assess me nts 
8.  P art 3 o nl y :  Bl o o d f or 
pl as m a P K a n d 
bi o m ar kers  
9.  P art 3 o nl y :  C A -1 2 5 
s a m pli n g  
 9.  1 1 . I ma gi n g f or t u m or 
assess me nts E n d of St u d y 
i m a gi n g f or t u m or 
assess me nts s h o ul d be 
o bt ai ne d f or p atie nts w h o 
g o off st u d y f or re as o ns 
ot her t h a n  r a di o gr a p hic 
dise ase pr o gressi o n  
T o u p date st u d y pr oce d ures 
t o i ncl u de Part 3 pr oce d ures 
 
C O N FI D E N TI A L  
1 4 6  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
1 3. 1 3 ( Pre vi o usl y 
1 3. 1 2) D ose -
Li miti n g T o xicities 
( Part 1 O nl y) 
N o n -he mat ol o gic D L Ts  
A n y C T C A E v 4 Gra de ≥3 
n o n -he mat ol o gic t o xicit y, 
u nless t he e ve nt is cle arl y 
u nrel ate d  t o treat me nt wit h 
P L X 3 3 9 7 i n c o m bi nati o n 
wit h wee kl y sta n dar d fi xe d 
d osi n g of paclita xel E X C E P T 
t he f oll o wi n g 
N o n he mat ol o gic  Ot her D L Ts  
A n y C T C A E v 4 Gra de ≥3 n o n
he mat ol o gic  ot her t o xicit y, u nless 
t he e ve nt is cle arl y u nrel ate d t o 
treat me nt wit h P L X 3 39 7 i n 
c o m bi nati o n wit h wee kl y sta n dar d 
fi xe d d osi n g of paclita xel 
E X C E P T t he f oll o wi n g : 
T o sta n dar dize defi niti o n of 
a n y D L T t hat is n ot 
ot her wise discreetl y 
defi ne d  
1 3. 1 4. 1 
( Pre vi o usl y 1 3. 1 4) 
P L X 3 3 9 7 D ose 
M o dificati o ns  
D uri n g P art 2 :  P L X 3 3 9 7 
d ose re d uc ti o ns or 
i nterr u pti o ns f or a d verse 
e ve nts ma y ta k e place at a n y 
ti me.  
F or P art 1  a n d P art 2  
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 are n ote d i n 
Ta ble 3 . 
D uri n g P art 2 a n d P art 3 :  
P L X 3 3 9 7 d ose re d ucti o ns or 
i nterr u pti o ns f or a d verse e ve nts 
ma y ta ke place at a n y ti me.  
F or P art 1  a n d P art 2, a n d P art 
3,  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 are n ote d i n 
Ta ble 3 . 
T o a d d  Part 3 t o d ose 
m o dificati o ns.  
1 3. 1 4. 1 
( Pre vi o usl y 1 3. 1 4) 
P L X 3 3 9 7 D ose 
M o dificati o ns  
Ta ble 3  
Re place Ta ble 3  
T o u p date d ose 
m o dificati o n r ules f or 
t o xicit y a n d a p pl y 
u nif or mit y acr oss st u dies.  
1 3. 1 4. 2 
( Pre vi o usl y 1 3. 1 5) 
Paclita xel D ose 
M o dificati o ns  
F or P art 1, C ycle 2 a n d 
s u bse q ue nt c ycles a n d P art 
2 , ot her d ose m o dificati o ns 
f or paclita xel will be i n 
acc or da nce t o t he pr o d uct 
la bel. 
F or P art 1, C ycle 2 a n d 
s u bse q ue nt c ycles a n d f or P art 2 
a n d P art 3,  ot her d ose 
m o dificati o ns f or paclita xel will 
be i n ac c or da nce t o wit h t he 
pr o d uct la bel.  
T o a d d Part 3 t o d ose 
m o dificati o ns.  
1 6. 0 S A F E T Y 
E V A L U A TI O N  
A me n d me nt 5 d oes n ot 
c o nt ai n P art 3 f or t his 
secti o n. 
F or P art 3 o nl y :  A E a n d S A E 
re p orti n g will c o m me nce w he n 
t he 2-3 c ore bi o psies are 
o bt ai ne d d uri n g Scree ni n g.  
T o a d d start of A E 
c ollecti o n f or Part 3 of t he 
st u d y 
1 6. 1 P h ysical 
E xa mi nati o n  
P h ysical e xa mi nati o ns 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) at Scree ni n g a n d 
at all ti me p oi nts i n dicate d i n 
t he Trial Fl o w C hart. 
P h ysical e xa mi nati o ns 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) at Scree ni n g a n d at 
all ti me p oi nts i n dicate d i n t he 
Trial Fl o w C hart.  P h ot o gr a p h y 
m a y be i ncl u de d as p art of t he 
p h ysic al e x a m f or t h ose p atie nts 
w h o c o nse nt t o t he pr oce d ure.  
T o a d d o pti o n f or 
p h ot o gra p h y d uri n g 
p h ysical e xa mi nati o n  
1 8. 0 
P H A R M A C O -
KI N E TI C 
1 8. 0 P H A R M A C O KI N E TI C 
E V A L U A TI O N ( P A R T 1 
O N L Y)  
1 8. 0 P H A R M A C O KI N E TI C 
E V A L U A TI O N ( P A R T 1 O N L Y  
A N D P A R T 3 ) 
T o a d d Part  3 t o P K 
e val uati o n 
 
C O N FI D E N TI A L  
1 4 7  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
E V A L U A TI O N  
1 9. 4 
P har mac o ki netic 
A nal ysis  
1 9. 4 P har mac o ki netic 
A nal ysis ( Part 1 o nl y)  
1 9. 4 P har mac o ki netic A nal ysis 
( Part 1 o nl y  a n d P art 3)  
T o a d d Part 3 t o P K 
e val uati o n 
2 1. 1 Defi niti o ns  
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 “ u nli kel y”, as f oll o ws:  
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 
“u nli kel y n ot rel ate d ”, as f oll o ws: 
T o ali g n wit h t he s pecifie d 
defi niti o ns liste d  
2 1. 2 Rec or di n g 
a n d Re p orti n g  
A patie n t’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 a n d pri or t o 
starti n g a n ot her t hera p y.  
 
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 dru g u p t o 
2 8 da ys after t he last d ose a n d 
pri or t o starti n g a n ot her t hera p y . 
F or P art 3 o nl y,  A E a n d S A E 
re p orti n g will c o m me nce w he n 
t he 2- 3 c ore bi o psies  are 
o bt ai ne d d uri n g Scree ni n g.  
T o a d d start of A E 
c ollecti o n f or Part 3 of t he 
st u d y 
2 1. 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 e C R F T E M P O.  
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 rep 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 
e C R F i n t he electr o nic d at a 
c a pt ure s yste m T E M P O. 
T o all o w f or S A Es t o be 
re p orte d i n a n electr o nic 
data ca pt ure s yste m ot her 
t ha n T E M P O 
2 6. 2 S p o ns or  
Data are c hec ke d as t he y are 
e ntered i nt o t he electr o nic 
data ca pt ure s yste m 
( T E M P O). 
Data are c hec ke d as t he y are 
e ntere d i nt o t he electr o nic data 
ca pt ure s yste m E D C (T E M P O)..  
T o all o w f or data t o be 
e ntere d i n a n electr o nic 
data ca pt ure s yste m ot her 
t ha n T E M P O 
2 9. 0 
R E F E R E N C E S  
All refere n ces 
U p d ate t o f ull cit ati o n  
T o gi ve f ull a n d c orrect 
citati o n f or all refere nces  
2 9. 0 
R E F E R E N C E S  
A me n d me nt 5 d oes n ot 
c o nt ai n t hese refere nces  
C ha m bers S K, Kaci ns ki B M, I vi ns 
C M, Carca n gi u M L. 
O vere x pressi o n of e pit helial 
macr o p ha ge c ol o n y -sti m ulati n g 
fact or ( C S F-1) a n d C S F -1 
rece pt or:  a p o or pr o g n ostic fact or 
i n e pit helial o varia n ca ncer, 
c o ntraste d wit h a pr otecti ve effect 
of str o mal C S F -1. Cli n Ca ncer 
Res. 1 9 9 7; 3( 6): 9 9 9 – 1 0 0 7.  
Kaci ns ki B M, Scata K A, Carter D, 
Yee L D, Sa pi E, Ki n g B L, et al. 
F M S ( C S F -1 r ece pt or) a n d C S F -1 
tra nscri pts a n d pr otei n are 
e x presse d b y h u ma n breast 
carci n o mas i n vi v o a n d i n vitr o. 
O nc o ge ne. 1 9 9 1; 6( 6): 9 4 1 – 9 5 2.  
T o i ncl u de ne w refere nces 
use d i n Sect i o n 7. 0 
 
C O N FI D E N TI A L  
1 4 8  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
Kaci ns ki B M, Sta nle y E R, Carter 
D, C ha m bers J T, C ha m bers S K, 
K o h or n EI, et al. Circ ulati n g 
le vels of C S F-1 ( M -C S F) a 
l y m ph o he mat o p oietic c yt o ki ne 
ma y be a usef ul mar ker of disease 
stat us i n patie nts wit h mali g na nt 
o varia n ne o plas ms. I nt J Ra diat 
O nc ol Bi ol P h ys. 1 9 8 9; 1 7( 1): 1 5 9 –
1 6 4.  
Price F V, C ha m bers S K, 
C ha m bers J T, Carca n gi u M L, 
Sc h wartz P E, K o h or n EI, et al. 
C ol o n y -sti m ulati n g fact or -1 i n 
pri mar y ascites of o varia n ca ncer 
is a si g nifica nt pre dict or of 
s ur vi val. A m J O bstet G y nec ol. 
1 9 9 3; 1 6 8( 2): 5 2 0 – 5 2 7.  
R uffell B, C o usse ns L M. 
Macr o p ha ges a n d t hera pe utic 
resista nce i n ca ncer. Ca ncer Cell. 
2 0 1 5; 2 7( 4): 4 6 2 – 4 7 2.  
Sc h oll S M, Basc o u C H, M osseri 
V, Oli vares R, Ma g dele nat H, 
D or val T, et al. Circ ulati n g le vels 
of c ol o n y -sti m ulati n g fact or 1 as a 
pr o g n ostic i n dicat or i n 8 2 patie nts 
wit h e pit helial o varia n ca ncer. Br 
J Ca ncer. 1 9 9 4; 6 2( 2): 3 4 2– 3 4 6.  
S kates SJ, H oric k N, Y u Y, X u FJ, 
Berc h uc k A, Ha vriles k y LJ, et al. 
Pre o perati ve se nsiti vit y a n d 
s pecificit y f or earl y-sta ge o varia n 
ca ncer w he n c o m bi ni n g ca ncer 
a nti ge n C A-1 2 5II, C A 1 5 -3, C A 
7 2 -4, a n d macr o p ha ge c ol o n y -
sti m ulati n g fact or usi n g mi xt ures 
of m ulti variate n or mal 
distri b uti o ns. J C li n O nc ol. 
2 0 0 4; 2 2( 2 0): 4 0 5 9 – 4 0 6 6.  
T o y E P, C ha m bers J T, Kaci ns ki 
B M, Flic k M B, C ha m bers S K. 
T he acti vate d macr o p ha ge c ol o n y 
sti m ulati n g fact or ( C S F-1) 
rece pt or as a pre dict or of p o or 
o utc o me i n a d va nce d e pit helial 
o varia n carci n o ma. G y nec ol 
O nc ol. 2 0 0 1; 8 0( 2 ): 1 9 4– 2 0 0.  
Z ha n g Z, Y u Y, X u F, Berc h uc k 
A, va n Haafte n -Da y C, Ha vriles k y 
LJ, et al. C o m bi ni n g m ulti ple 
 
C O N FI D E N TI A L  
1 4 9  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
ser u m t u m or mar kers i m pr o ves 
detecti o n of sta ge I e pit helial 
o varia n ca ncer. G y nec ol O nc ol. 
2 0 0 7; 1 0 7( 3): 5 2 6 – 5 3 1.  
A T T A C H M E N T 
1 :  La b orat or y 
Tests 
Bl o o d Res p o nse 
Bi o m ar kers (s a m ples) :   
•  
C S F - 1 
•  
C D 1 4/ C D 1 6 
p ositi ve m o n oc ytes  
(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, a defi niti ve 
list of a nal yses re mai ns t o be 
deter mi ne d.)  
P art 1, P art 2, a n d P art 3:  
Bl o o d Res p o nse Bi o m ar kers 
(s a m ples):   
•  
C S F - 1 
•  
C D 1 4/ C D 1 6 p ositi ve 
m o n oc ytes  
(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, a defi niti ve list of a nal yses 
re mai ns t o be deter mi ne d.) 
P art 3:  
C a ncer tiss ue bi o m ar kers will 
i ncl u de: 
•  
I H C f or C D 6 8, C D 8, P D-L 1, 
a n d a d diti o n al m ar kers of 
m acr o p h a ge a n d T -cell 
prese nce a n d f u ncti o n  
•  
R N A e x pressi o n a n al ysis f or 
a n e x pl or at or y p a nel of 
t u m or micr oe n vir o n me nt 
m ar kers  
•  
St ai ni n g of cells of t he 
t u m or micr oe n vir o n me nt. 
P a nels of I H C m ar kers 
s pecific f or m acr o p h a ges, T-
cells, a n d ot her i m m u ne a n d 
i nfl a m m at or y cells will be 
e m pl o ye d, f or se mi -
q u a ntit ati ve c h a n ges i n cell 
n u m ber, l oc ati o n wit hi n t he 
t u m or, a n d de gree of 
acti v ati o n.  
Bl o o d bi o m ar kers will i ncl u de:  
•  
C A -1 2 5 s a m pli n g 
re q uire me nts :  2 pre -
tre at me nt s a m ples, first 
s a m ple wit hi n 3 m o nt hs of 
st arti n g t her a p y a n d sec o n d 
s a m ple wit hi n 1 wee k of 
C ycle 1 D a y 1 ; s u bse q ue nt 
s a m ples o n t he first d a y of 
e ac h c ycle st arti n g wit h 
T o i ncl u de sa m pli n g f or 
Part 3  
 
C O N FI D E N TI A L  
1 5 0  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
Secti o n  
A me n d me nt 5  
A me n d me nt 6  
R ati o n ale  
C ycle 2 D a y 1 a n d E n d -of -
St u d y Visit.  
•  
Pl as m a C S F -1 a n d 
a d diti o n al m ar kers of 
tre at me nt effect 
•  
W h ole bl o o d C D 1 4/ C D 1 6 
m o n oc yte s u bset b y F A C S 
a n al ysis  
•  
W h ole bl o o d M D S C b y 
F A C S a n al ysis  
 
 
 
 
C O N FI D E N TI A L  
1 5 1  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
 
A T T A C H M E N T 1 1 :  A M E N D M E N T 7 S U M M A R Y O F C H A N G E S  
T he f oll o wi n g c ha n ges were ma de fr o m A me n d me nt 6 ( 2 7 Ma y 2 0 1 5) t o A me n d me nt 7 of t he 
pr ot oc ol: 
•  T he i ncl usi o n criteri o n was re vise d t o c ha n ge t he d urati o n t hat patie nts c o ul d be 
pre vi o usl y treate d wit h a ta xa ne fr o m 1 year t o 6 m o nt hs. 
Rati o nale :  T o i ncrease patie nt e nr oll me nt.  
•  T he n u m ber of sites e nr olli n g patie nts i n Part 3 of t he st u d y was i ncrease d fr o m 3 -6 sites t o 
a p pr o xi matel y 9 sites. 
Rati o nale :  T o i ncrease patie nt e nr oll me nt.  
•  Cla rificati o n was a d de d t hat if a bi o ps y d uri n g C ycle 1 is dela ye d be y o n d Da y 2 8, patie nts 
will ha ve a Da y  2 8 visit a d de d i n C ycle 1 f or paclita xel a d mi nistrati o n.  Visit pr oce d ures 
w o ul d be t he sa me as t he Da y 2 2 visit.    
Rati o nale :  T o pr o vi de pr oce d ures f or a bi o ps y dela y i n C ycle 1.  
•  A secti o n was a d de d i n t he mai n b o d y of t he pr ot oc ol t o descri be st u d y st o p pi n g r ules ( n o w 
Secti o n 1 7. 0). 
Rati o nale :  St u d y st o p pi n g r ules were pre vi o usl y i ncl u de d i n t he s y n o psis b ut n ot i n t he mai n 
b o d y of t he pr ot oc ol. 
•  Pr ot oc ol te xt was c orrecte d  t o re m o ve bl o o d bi o mar ker c ollecti o n o n C ycle 1 Da y 2 1- 3 5.  
Rati o nale :  T he st u d y fl o w c hart was c orrect t hat o nl y ca ncer tiss ue s h o ul d be o btai ne d o n 
C ycle 1 Da y 2 1- 3 5 a n d n ot bl o o d bi o mar kers.  
A d diti o nal mi n or c ha n ges ha ve bee n ma de t o i m pr o ve clarit y a n d c o nsiste nc y. 
 
C O N FI D E N TI A L  
1 5 2  
Ple x xi k o n I nc.  
P R O P RI E T A R Y  


P L X 3 3 9 7  
Pr ot oc ol P L X 1 0 8 -0 7  
A me n d me nt 8  
A T T A C H M E N T 1 2 :  A M E N D M E N T 8 S U M M A R Y O F C H A N G E S  
•
A d diti o nal ser u m c he mistr y testi n g was a d de d o n Da ys 8, 1 5, a n d 2 2 f or t he f oll o wi n g:
•
C ycle 2 o nl y :  ser u m c he mistr y re q uire d pri or t o paclita xel a d mi nistrati o n  f or P art  3 –
all ar ms .
•
C ycle 3  o nl y :  ser u m c he mistr y re q uire d f or P art 3 - Le a d -i n P aclit a xel Al o ne Ar m
o nl y.
Rati o nale :  T o i ncrease m o nit ori n g of li ver f u ncti o n d uri n g t he first 8 wee ks of P L X 3 3 9 7 t hera p y 
d ue t o u p date d safet y i nf or mati o n.  
A d diti o nal mi n or c ha n ges ha ve bee n ma de t o i m pr o ve clarit y a n d c o nsiste nc y. 
C O N FI D E N TI A L  
1 5 3  
Ple x xi k o n I nc.  
P R O P RI E T A R Y