Conditions: Von Hippel-Lindau Syndrome
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
This phase II trial studies the side effects and how well pazopanib hydrochloride works in treating patients with von Hippel-Lindau syndrome. Pazopanib hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. Evaluate safety and efficacy of treatment with pazopanib hydrochloride (pazopanib) for 6 months in patients with von Hippel-Lindau syndrome (VHL) who have a measurable VHL related lesion.

SECONDARY OBJECTIVES:

I. Evaluate rate of growth over time in target lesions before and after pazopanib treatment.

II. Evaluate need for surgical intervention over time in patients who receive pazopanib and compare to rate prior to receipt of drug.

III. Create an annotated tissue resource from patients with VHL for use in future research related to cancer.

PRECLINICAL OBJECTIVES:

I. Evaluate circulating factors in patients with VHL undergoing treatment with pazopanib.

II. Evaluate relationship between VHL genotype and response to pazopanib.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Treatment repeats every 4 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients benefitting from treatment may continue pazopanib hydrochloride in the absence of disease progression.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 24 weeks.

Arms:
arm 1: Patients receive pazopanib hydrochloride PO QD on days 1-28. Treatment repeats every 4 weeks for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients benefitting from treatment may continue pazopanib hydrochloride in the absence of disease progression.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pazopanib Hydrochloride
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO

Protocol document:
Prot_SAP_000.pdf: 
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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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