A Phase II Trial of Pazopanib in Von Hippel-Lindau Syndrome
Phase: PHASE2
Conditions: Von Hippel-Lindau Syndrome
Sponsor: M.D. Anderson Cancer Center

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Proprietary Information of MD Anderson

Pr ot oc ol 2 0 1 1- 0 4 6 5  
  A Se pte m ber 6, 2 0 1 7 
Pa ge 6 of 5 0 
6 
t he gr eatest i m pact, as d o es t heir treat me nt. 
Ge netic c h ar acterizati o n of t he vari o us m utati o ns has bee n cl assifie d as T y pe 1 ( n o 
p he oc hr o m oc yt o ma) a n d T y pe 2 ( pres e nce of p he o c hr o m oc yt o ma) w hi c h is f urt her 
c haracterize d i nt o 2a, l o w ris k of re n al ca n cer, 2 b, hi g h ris k of re nal ca ncer; a n d 2c, 
p he oc hr o m oc yt o ma o nl y.    
2. 2 Paz o pa ni b 
A n gi o ge n esis, t he pr ocess of ne w bl o o d vessel f or mati o n, pla ys a n i m p orta nt r ole i n t he 
de vel o p me nt of mali g na n c y as well as t he gr o wt h a n d pr o gressi o n of m etastatic lesi o ns.  
T he m olec ular p at h wa ys i n v ol ve d i n a n gi o ge n es is ha ve bee n tar get e d f or a nti-t u m or 
t hera p y.  N u mer o us gr o wt h fact ors a n d c yt o ki n es are i n v ol ve d i n t he a n gi o ge nic pr ocess.  
A m o n g t hes e fact ors, vas c ular e n d ot helial gr o wt h fact or ( V E G F) has a pre d o mi na nt r ole 
as a ce ntral me diat or of t u m or -relate d a n gi oge nesis,  a n d its e x pressi o n has bee n s h o w n t o 
be a n a d v erse pr o g n ostic fact or f or a n u m ber  of s oli d t u m ors 2 ,3 ,4  .
Paz o pa ni b is  a n orall y- bi oa vaila ble, A T P-c o m petiti ve t yr osi ne ki nas e i n hi bit or of 
V E G F R ( - 1, - 2, a n d -3), P D G F R ( -α  a n d -β )
, a n d c
-Kit 5 .  Paz o pa ni b is bei n g de v el o pe d
b y N o v artis P har mace uticals  f or t he treat me nt of a variet y of ca n cers.  I n n o ncli nical 
e x peri me nts, paz o pa ni b has de m o nstrate d e n c o ura gi n g p ote n c y a n d sel ecti vit y f or V E G F 
rece pt ors: f or e x a m ple, p az o pa ni b de m o nstrate d si g nifica nt i n hi biti o n of V E G F-i n d uce d 
V E G F R - 2 p h os p h or yl ati o n i n h u ma n u m bilical vei n e n d ot helial cells a n d w as 3- t o 4 0 0-
f ol d selecti ve f or V E G F r ece pt ors c o m pare d t o 2 3 ot her ki nases teste d.  Paz o pa ni b 
s h o we d si g nifi ca nt gr o wt h i n hi biti o n of a variet y of h u ma n t u m or x e n o grafts i n mice, a n d 
als o i n hi bite d a n gi o ge n esis i n se veral differe nt m o dels of a n gi o ge nesis (e. g., t he Matri gel 
pl u g assa y, t h e c or n ea mi cr o p oc ket, a n d t he laser-i n d uce d c h or oi d al ne o vas c ularizati o n 
m o dels).  
Paz o pa ni b 8 0 0 m g  o nce dail y is t he rec o m me n de d m o n ot hera p y d ose bas e d o n cli nical 
a n d precli nical res ults.  O nce dail y d oses of 5 0 m g t o 2 0 0 0 m g paz o pa ni b were 
i n vesti gate d i n t he “ First Ti me i n H u ma n”, P hase I St u d y V E G 1 0 0 0 3.  I n creases i n t he 
paz o pa ni b d ose a b o ve 8 0 0 m g o nce dail y w he n a d mi nistere d i n t he faste d state di d n ot 
res ult i n a c o nsiste nt i ncr ease i n s yste mic e x p os ure at stea d y-stat e.  T heref ore, n o f urt her 
be nefit is e x pecte d at paz o pa ni b d oses a b o ve 8 0 0 m g o nce dail y.   
P har mac o d y na mic d ata i n dicate t hat paz o pa ni b, at a m o n o t hera p y d ose of 8 0 0 m g o nce 
dail y, r es ults i n effects c o nsiste nt wit h i n hi biti o n of t he V E G F rece pt ors it was desi g ne d 
t o tar get.  C o nce ntrati o n-effect relati o ns hi ps were o bser ve d bet w ee n tr o u g h plas ma 
paz o pa ni b c o nce ntr ati o ns a n d t he de vel o p me nt of h y perte nsi o n i n St u d y V E G 1 0 0 0 3 a n d 
t he perce nt c ha n ge fr o m baseli ne i n s V E G F R 2 na dir i n St u d y V E G 1 0 2 6 1 6.  T he tr o u g h 
plas ma paz o pa ni b c o nce ntrati o ns ass ociate d wit h o ne- half t he m a xi mal effect ( E C 5 0) i n 
b ot h c o nce ntrati o n- eff ect relati o ns hi ps were si milar ( 2 1. 3 µ g/ m L a n d 1 5. 3 µ g/ m L) a n d 
de m o nstrate t hat t her e is a c o nsiste nt i n hi biti o n of V E G F rece pt or(s) i n s u bj ects wit h 
Pr o pri et ar y I nf or m ati o n of M D A n d er s o n

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