Conditions: Renal Cancer Von Hippel Lindau
Keywords: Kidney Tumors Clear Cell Renal Cancer VEGFR Inhibitor EGFR Inhibitor VHL Von Hippel Lindau Kidney Tumor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 37
Healthy volunteers: no

Brief summary:
This study will examine the effectiveness of an investigational drug called ZD6474 (also known as vandetanib or ZACTIMA). Vandetanib is an experimental drug that is designed to prevent the growth and development of new blood vessels on tumors and to prevent the direct growth of cancer cells. It has been tested in a number of clinical trials on adults with cancer, but the United States (U.S.) Food and Drug Administration has not specifically approved it as a cancer treatment. The purpose of this investigational study is to better understand how vandetanib affects humans who have kidney cancer related to von Hippel-Lindau (VHL) disease, and to develop tests that may improve researchers understanding of kidney cancer and its effects.

Volunteers must be at least 18 years old and must have been diagnosed with kidney cancer related to VHL. Candidates must have a life expectancy greater than three months and must have at least one measurable renal tumor for study purposes. Candidates may not be receiving any other investigational agents or have been treated with an investigational drug within the past four weeks. Candidates who have had surgery, chemotherapy, or radiotherapy within the past four weeks will be excluded from the study. Candidates will be screened with a physical examination and medical history.

During the study, participants will receive an oral dose of vandetanib once a day for 28 days (a treatment period known as a cycle). Participants will need to return to the National Institutes of Health every two weeks on the same day of the week as the first dose of vandetanib for a series of tests and procedures, including blood and urine tests and an electrocardiogram. Every 12 weeks, computerized tomography (CT) or magnetic resonance imaging (MRI) scans will be done to assess the size of participants tumors. Participants whose tumors do not grow and who do not have unacceptable side effects may continue to receive vandetanib to maintain the current condition, until researchers conclude the study....

Detailed description:
Background:

Von Hippel Lindau disease is a hereditary cancer syndrome in which affected individuals are at risk for developing tumors in a number of organs, including the kidneys, brain, spine, adrenal glands, eyes and pancreas.

The molecular hallmark of VHL is inactivation of the VHL gene which leads to accumulation of proteins targeted for degradation through the ubiquitin pathway, which includes a group of transcriptionally active proteins called the hypoxia inducible factors (HIF), whose alpha subunits undergo degradation in a VHL-dependent fashion. Accumulation of HIFs results in overexpression of several genes including vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), transforming growth factor (TGF)-alpha, platelet- derived growth factor (PDGF), and erythropoietin, which are believed to play a role in tumorigenesis, tumor progression and metastasis.

ZD6474 is an orally administered receptor tyrosine kinase inhibitor with activity against the Kinase insert domain-containing receptor/vascular endothelial growth factor receptor 2 (KDR/VEGFR2) and the epidermal growth factor receptor (EGFR). Kinase insert domain receptor (KDR)/vascular growth factor receptor 2 (VEGFR2) is an endothelial cell receptor for vascular endothelial growth factor (VEGF) and plays a crucial role in mediating tumor angiogenesis, while epidermal growth factor receptor (EGFR) (a receptor for TGF-alpha and epidermal growth factor (EGF) is believed to mediate tumor growth and proliferation.

Objective:

Primary Objective

To assess the overall response rate in VHL patients with renal tumors treated with single agent ZD6474

Secondary Objectives:

To study the safety and tolerability of ZD6474

To evaluate time to progression and progression-free survival in VHL patients receiving ZD6474

To study the effect of ZD6474 treatment on non-renal tumors associated with von Hippel Lindau disease ( pancreatic tumors, pheochromocytoma, central nervous system (CNS) hemangioblastomas)

To investigate the effect of ZD6474 on circulating endothelial cells and endothelial progenitor cells and to explore the utility of these markers as surrogates of angiogenesis inhibition

To investigate the effect of ZD6474 on biomarkers of angiogenesis such as plasma VEGF and soluble VEGFR2

Eligibility:

Adults with clinical diagnosis of von Hippel Lindau disease

Presence of one or more measurable renal tumors

Age greater than or equal to 18 years

Adequate organ function, performance status (Eastern Cooperative Oncology Group (ECOG) 0-2) and life expectancy (greater than 3 months)

Design:

Single agent ZD6474 administered daily at a starting dose of 300mg per day

Patients will be evaluated for response every 12 weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria

The study is based on an open label two-stage optimal phase II design

Accrual of a maximum of 37 patients.

Arms:
arm 1: 300 mg/day (starting dose) oral dose of vandetanib once a day for 28 days

Interventions: intervention 1: ZACTIMA (Vandetanib) (ZD6474)
Intervention descriptions: intervention 1: None

Protocol document:
Prot_SAP_001.pdf: 
Amendment
Protocol Number:
08C0020-H
Principal Investigator: William Linehan MD NCI 
UOB 
301.496.6353 
linehanm@mail.nih.gov
(NIH Employee Name, Institute/Branch, Telephone and e-mail)
Reference Number:
364849
Protocol Title:
A Phase 2 Study of ZD6474 (vandetanib) in Patients with von Hippel Lindau Disease and Renal Tumors
SIGNATURES
Principal Investigator (*): 
William Linehan MD - applied signature on 12/15/2016 8:14 PM EST
Accountable Investigator:
PI is the Accountable Investigator
Branch Chief/CC Department Head (**):
William Linehan MD - applied signature on 12/15/2016 8:14 PM EST
Medical Advisory Investigator (if applicable):
N/A
Lead Associate Investigator signature:
N/A
Referral Contact signatures:
N/A
Associate Investigators signatures:
N/A
For Institute/Center Scientific Review Committee:
N/A
Other IC Clinical Director signatures:
N/A
APPROVALS
IRB Chair:
Michael Hamilton - applied signature on 01/12/2017 2:42 PM EST
Clinical Director:
N/A
CONCURRENCE
OPS Protocol Specialist:
Signature
Print Name
Date
* Signature signifies that investigators on this protocol have been informed that the collection and use of personally identifiable information at
the NIH are maintained in a system of record governed under provisions of the Privacy Act of 1974. The information provided is mandatory for
employees of the NIH to perform their assigned duties as related to the administration and reporting of intramural research protocols and
used solely for those purposes.  Questions may be addressed to the Protrak System Owner.
** I have reviewed this research project and considered the NIH Policy for Inclusion of Women and Minorities in Clinical Research. Taking into 
account the overall impact that the project could have on the research field involved, I feel the current plans adequately includes both sex/
gender, minorities, children, and special populations, as appropriate. The current enrollment is in line with the planned enrollment report for 
inclusion of individuals on the basis of their sex/gender, race, and ethnicity and is appropriate and of scientific and technical merit. 
IRB Meeting Date:
Expedited
DEC Clearance Date:
11/17/2016
Protocol Version Date:11/16/2016
Michelle Lanham                                                 AM     H                                              01/24/17


Confidential  
1 
 
Abbreviated Title: Phase II of ZD6474 in VHL 
NCI Protocol Number: 08-C-0020 
Version Date: November 16, 2016 
Amendment: H  
   
A Phase II Study of ZD6474 (Vandetanib) in Patients with Von Hippel Lindau Disease and 
Renal Tumors 
   
 
 
NCI Principal Investigator:  
W. Marston Linehan, M.D. A, B, C, D, E, F 
 
 
 
 
 
Branch Chief, UOB, CCR, NCI 
 
 
 
 
 
10 Center Drive 
 
 
 
 
 
10/1-5942 
 
 
 
 
 
Tel: 240-760-6245 
 
 
 
 
 
Email: linehanm@mail.nih.gov 
 
NIH Lead Investigator: 
 
Ramaprasad Srinivasan, M.D., Ph.D. A, B, C, D, E, F 
 
 
 
 
 
Staff Clinician, UOB, CCR, NCI 
 
 
 
 
 
10 Center Drive 
 
 
 
 
 
10/2-5950 
 
 
 
 
 
Tel: 240-760-6251 
 
 
 
 
 
Email: Ramprasad.Srinivasan@nih.gov  
 
Statistician:   
 
 
Joanna H. Shih, Ph.D., BRB, DCTB, NCI E, F 
 
NIH Associate Investigators:  
Peter Pinto, M.D., UOB, CCR, NCI A, B, C, D, E, F 
 
 
 
 
 
Martha Ninos, R.N., OCD, CCR, NC A, B, C, E, F  
 
 
 
 
 
Julia Friend, P.A-C., UOB, CCR, NCI A, B, C, D, E, F 
 
 
 
 
 
Geri Hawks, R.N., OCD, CCR, NCI A, B, C, E, F 
 
 
 
 
 
Jane Trepel, DTB, CCR, NCI E, F 
 
 
 
 
 
Douglas Rosing, M.D., Cardiology, NHLBI A, B, E, F 
 
 
 
 
 
Dave Kohler, Pharm.D., CC Pharmacy B, E 
 
 
 
 
 
Heidi Kong, M.D., DERM, CCR, NCI A, B, C, D, E, F 
 
Referral Contact/ 
 
 
Geri Hawks, R.N., OCD, CCR, NCI 
Study Coordinator:  
 
10 Center Drive 
Building 10 CRC, Room 2-5750 
Bethesda, MD  20892-1208 
Phone:  240-760-6244 
Email: ghawks@mail.nih.gov 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
2 
 
 
A. Obtain information by intervening or interacting with living individuals for research 
purposes 
B. Obtaining identifiable private information about living individuals 
C. Obtaining the voluntary informed consent of individuals to be subjects 
D. Makes decisions about subject eligibility 
E. Studying, interpreting, or analyzing identifiable private information or data/specimens 
for research purposes 
F. Studying, interpreting, or analyzing de-identified data or specimens for research 
purposes 
G. Some/all research activities performed outside NIH 
 
 
 
Investigational Agent:     
Drug Name: 
ZD6474 
IND Number: 
78,970 
Sponsor: 
W. Marston Linehan, M.D. 
 
 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
3 
 
PRÉCIS 
 
Background: 
 
• Von Hippel Lindau disease is a hereditary cancer syndrome in which affected individuals are 
at risk for developing tumors in a number of organs, including the kidneys, brain, spine, 
adrenal glands, eyes and pancreas.  
• The molecular hallmark of VHL is inactivation of the VHL gene which leads to 
accumulation of proteins targeted for degradation through the ubiquitin pathway, which 
includes a group of transcriptionally active proteins called the hypoxia inducible factors 
(HIF), whose alpha subunits undergo degradation in a VHL-dependent fashion. 
Accumulation of HIFs results in overexpression of several genes including VEGF, GLUT-1, 
TGF-, PDGF, and erythropoietin, which are believed to play a role in tumorigenesis, tumor 
progression and metastasis. 
• ZD6474 is an orally administered receptor tyrosine kinase inhibitor with activity against the 
Kinase insert domain-containing receptor/vascular endothelial growth factor receptor 2 
(KDR/VEGFR2) and the epidermal growth factor receptor (EGFR). KDR/VEGFR2 is an 
endothelial cell receptor for vascular endothelial growth factor (VEGF) and plays a crucial 
role in mediating tumor angiogenesis, while EGFR (a receptor for TGF-and EGF) is 
believed to mediate tumor growth and proliferation.   
 
Objective: 
 
Primary Objective 
• To assess the overall response rate in VHL patients with renal tumors treated with single 
agent ZD6474  
 
Eligibility: 
 
• Adults with clinical diagnosis of von Hippel Lindau disease  
• Presence of one or more measurable renal tumors 
• Age ≥ 18 years 
• Adequate organ function, performance status (ECOG 0-2) and life expectancy (>3 months) 
 
Design: 
 
• Single agent ZD6474 administered daily at a starting dose of 300mg/day 
• Patients will be evaluated for response every 12 weeks using RECIST criteria  
• The study is based on an open label two-stage optimal phase II design 
• Accrual of a maximum of 37 patients 
 


9HUVLRQ'DWH
&$PHQGPHQW+
$EEUHYLDWHG7LWOH3KDVH,,RI='LQ9+/

&RQILGHQWLDO


7$%/(2)&217(176

 
,1752'8&7,21 
 
678'<2%-(&7,9(6 
 
%DFNJURXQGDQG5DWLRQDOH 
 
(/,*,%,/,7<$66(660(17$1'(152//0(17 
 
(OLJLELOLW\&ULWHULD 
 
5HVHDUFK(OLJLELOLW\(YDOXDWLRQ 
 
5HJLVWUDWLRQ3URFHGXUHV 
 
678'<,03/(0(17$7,21 
 
6WXG\'HVLJQ 
 
6WXG\'UXJ$GPLQLVWUDWLRQ 
 
'RVLQJ'HOD\V'RVH0RGLILFDWLRQV 
 
5HVHDUFK6WXGLHV 
 
6WXG\(YDOXDWLRQV$QG6FKHGXOH 
 
6WXG\&DOHQGDU 
 
&RQFXUUHQW7KHUDSLHV 
 
6XUJLFDO*XLGHOLQHV 
 
2II6WXG\&ULWHULD2II7UHDWPHQW&ULWHULD 
 
3RVW7UHDWPHQW)ROORZXS 
 
6833257,9(&$5( 
 
'$7$&2//(&7,21$1'(9$/8$7,21 
 
'DWD&ROOHFWLRQ 
 
5HVSRQVH(YDOXDWLRQ 
 
7R[LFLW\&ULWHULD 
 
67$7,67,&$/6(&7,21 
 
7ZRVWDJH'HVLJQ 
 
5HVSRQVH)UHTXHQF\ 
 
$FFUXDO&HLOLQJ 
 
+80$168%-(&763527(&7,21 
 
5DWLRQDOHIRU6XEMHFW6HOHFWLRQ 
 
(YDOXDWLRQRIEHQHILWVDQGULVNVGLVFRPIRUWV 
 
5LVN%HQHILWUHODWLRQVKLS 
 
&RQVHQWDQGDVVHQWSURFHVVHVDQGGRFXPHQWV 
 
3DWLHQWUHFRUGVDQGTXDOLW\DVVXUDQFH 
 
6$)(7<5(3257,1*5(48,5(0(176'$7$$1'6$)(7<021,725L1*3/$1 
 
'HILQLWLRQV 
 
1&,,5%DQG1&,&OLQLFDO'LUHFWRU&'5HSRUWLQJ 
 
)'$5HSRUWLQJ&ULWHULD 
 
'$7$$1'6$)(7<021,72,51*3/$1 
 
&223(5$7,9(5(6($5&+$1''(9(/230(17$*5((0(17
&5$'$&/,1,&$/75,$/6$*5((0(17&7$ 
 
3+$50$&(87,&$/,1)250$7,21 
 
6RXUFH 
 
6ROXELOLW\ 
 
0RGHRI$FWLRQ 


9HUVLRQ'DWH
&$PHQGPHQW+
$EEUHYLDWHG7LWOH3KDVH,,RI='LQ9+/

&RQILGHQWLDO


 
)RUPXODWLRQDQG3UHSDUDWLRQ 
 
&RPSRVLWLRQ 
 
6WDELOLW\DQG6WRUDJH 
 
'RVDJHDQG$GPLQLVWUDWLRQ 
 
5HSRUWHG$GYHUVH(YHQWVDQG3RWHQWLDO5LVNV 
 
3RWHQWLDO'UXJ,QWHUDFWLRQV 
 $YDLODELOLW\ 
 $JHQW2UGHULQJ 
 $JHQW$FFRXQWDELOLW\ 
 
5()(5(1&(6 
 
$33(1',&(6 
 
$SSHQGL[$HFRJSHUIRUPDQFHVWDWXV 
 
$SSHQGL[%1HZ<RUN+HDUW$VVRFLDWLRQ1<+$&DUGLDF&ODVVLILFDWLRQ 
 
$SSHQGL[&0HGLFDWLRQV.QRZQ7R3URORQJ7KH47,QWHUYDO$QG2U,QGXFH
7RUVDGHV'H3RLQWHV7GS8SGDWHG$XJXVW 
 
$SSHQGL['/LVWRIGUXJVLQWHUDFWLQJZLWK&<3$ 
 
$SSHQGL[('LDJQRVWLFFULWHULDIRUYRQKLSSHOOLQGDX 






























Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
6 
 
1 
INTRODUCTION 
 
1.1 
STUDY OBJECTIVES 
  
1.1.1 Primary Objective 
• To assess the overall response rate in VHL patients with renal tumors treated with single agent 
ZD6474  
 
1.1.2 Secondary Objectives:  
• To study the safety and tolerability of ZD6474 
• To evaluate time to progression and progression-free survival in VHL patients receiving 
ZD6474 
• To study the effect of ZD6474 treatment on non-renal tumors associated with von Hippel 
Lindau disease (pancreatic tumors, pheochromocytoma, CNS hemangioblastomas) 
• To investigate the effect of ZD6474 on circulating endothelial cells and endothelial progenitor 
cells and to explore the utility of these markers as surrogates of angiogenesis inhibition 
• To investigate the effect of ZD6474 on biomarkers of angiogenesis such as plasma VEGF and 
soluble VEGFR2 
 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 von Hippel Lindau Disease 
Von Hippel Lindau disease is a hereditary cancer syndrome transmitted in an autosomal 
dominant fashion. The underlying defect is a germline mutation in the VHL gene, which places 
affected individuals at risk for developing tumors in a number of organs, including the brain, 
spine, kidneys, adrenal glands, eyes and pancreas (1-6).   The incidence of VHL is approximately 
one in 36,000 live births (1,7).  
 
1.2.2 VHL Clinical Manifestations 
Bilateral, multifocal clear cell renal carcinoma 
CNS Hemangioblastomas (Cerebellum, Spine) 
Pancreatic neuroendocrine tumor and cysts 
Pheochromocytomas 
Retinal angiomas 
Endolymphatic sac tumors 
 
Renal Tumors in VHL 
 
Affected individuals in VHL kindreds are at risk for the development of bilateral, multifocal 
clear cell renal carcinoma (1-5). 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
7 
 
  
 
 
VHL bilateral, multifocal RCC   
        VHL Renal Tumor 
 
      
Clear Cell RCC 
 
While these tumors can present as localized tumors, they can grow and metastasize.  Historically, 
35-45% of VHL patients died of metastatic renal cell carcinoma. 
 
 
 
 
VHL patient who presented with a large renal mass (left) and pulmonary metastases from the clear cell renal carcinoma 
Non-renal tumors in von Hippel Lindau disease 
 
1) VHL patients are at risk for the development of CNS tumors (cerebellar and spinal 
hemangioblastomas) and retinal angioma (4,5,8-12) 
  
   
  
          
       
 Cerebellar HB         
     Spinal Hemangioblastoma     
        Retinal Angioma 
 
2) These individuals are also at risk for the development of pancreatic cysts and 
neuroendocrine tumors (13-17).   
   
 
 
 
    
Pancreatic neuroendocrine tumor 
      VHL pancreatic cysts 
 
The pancreatic neuroendocrine tumors are malignant and can metastasize. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
8 
 
 
3) These patients are also at risk for the development of pheochromocytomas which can 
occur at an early age (18). 
 
      
 
 
Abdominal CT scan (left) and MRI scan (right) reveal the presence of bilateral pheochromocytomas in a 10 year old boy. 
 
VHL pheochromocytomas can occur at adrenal or extra-adrenal sites and, although the 
pheochromocytomas are usually benign, they can be can be lethal.  They can also be 
malignant and can metastasize. 
 
   
 
 
 
 
       A  
 
 
 
B 
 
 
           C 
VHL associated pheochromocytomas can be extra-adrenal.  Panel A shows a pulmonary 
pheochromocytoma in a VHL patient.  These tumors can also be malignant.  Panel B shows 
a large retroperitoneal, recurrent malignant pheochromocytoma that had spread to the 
lungs (Panel C) in a 24 year old female.                      
 
1.2.3 The VHL Tumor Suppressor Gene 
By studying VHL kindreds here at the NCI we were able to identify the VHL gene (19).  The 
gene is located on the short arm of chromosome 3 (3p25-26). VHL is a classical tumor 
suppressor gene and tumorigenesis due to VHL inactivation conforms to Knudson’s ‘two-hit’ 
hypothesis (20). The gene has three exons that encode the VHL protein (19). Two isoforms of 
the VHL protein have been described. Full length VHL protein has 213 amino acids and 
localizes to the nucleus as well as the cytoplasm. A truncated form, resulting from translation 
initiation at codon 54, has also been characterized and appears to be functionally acive (21,22).  
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
9 
 
 
Genetic linkage analysis at the NCI resulted in the identification of the G7 VHL cDNA, which turned out to be the VHL gene.  
 
We and others have shown that this gene is also the gene for the common form of sporadic renal 
cell carcinoma (viz., clear cell RCC).  
 
VHL germline mutation spectrum 
 
VHL mutations: Functional and Biologic consequences 
While VHL mutations were initially identified as the genetic basis of von Hippel Lindau disease, 
inactivation of the gene by mutation or promoter hypermethylation has also been described in a 
high proportion of sporadic clear cell renal cancers. VHL protein forms a complex with other 
cellular proteins including elongins B and C, and Cullin 2 (the VCB-CUL2 complex) (23). This 
complex plays an important role in the degradation of cellular proteins via the ubiquitin pathway. 
Inactivation of VHL consequently leads to accumulation of proteins targeted for degradation 
through this pathway. This includes a group of transcriptionally active proteins called the 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
10 
 
hypoxia inducible factors (HIF), whose alpha subunits undergo degradation in a VHL-dependent 
fashion (24). Accumulation of HIFs results in overexpression several genes including VEGF, 
GLUT-1, TGF-, PDGF, and erythropoietin (1-4). VEGF is an important regulator of tumor 
angiogenesis and hence is implicated in tumor growth and progression. VEGF exerts its activity 
through several receptor tyrosine kinases expressed on endothelial cells, chief among them being 
the fms-like tyrosine kinase-1/VEGF receptor 1 (Flt-1/VEGFR1) and the kinase insert domain 
containing receptor/VEGF receptor 2 (KDR/VEGFR2) (25). In addition to promoting 
angiogenesis in the tumor microenvironment, VHL inactivation can also directly promote tumor 
growth via the autocrine and paracrine effects of TGF-, and PDGF, which act through receptor 
tyrosine kinases such as the epidermal growth factor receptor (EGFR, a ligand for TGF-a) 
expressed on tumor cell surface. Thus VHL inactivation initiates a series of downstream events 
that promote tumor progression.  
   
        VHL gene pathway 
 
1.2.4 Treatment for VHL-associated tumors 
Although a variety of systemic treatment options including cytokines (IL-2, IFN) as well as 
newer targeted anti-angiogenic agents (e.g. sunitinib, sorafenib) are available for patients with 
sporadic metastatic clear cell RCC, these agents have not been evaluated in the management of 
VHL associated RCC. Consequently, the treatment approach for VHL associated renal tumors 
remains surgical and involves resection of tumors that have reached a size of approximately 3 
cm.   
 
We have estimated that affected VHL individuals may develop up to 600 tumors per kidney (26).  
Over the past 15 years we have observed patients with VHL-associated renal cancer until their 
tumors grew to 3 cm in diameter, whereupon nephron-sparing surgery is recommended.  This 
strategy is used to increase time between operations and decrease patient morbidity.  With this 
treatment approach, we have followed 96 von Hippel-Lindau (VHL) patients for a median of 60 
months.  No patient with maximum renal tumor diameter less than 3 cm has developed 
metastases (27,28).  Tumor diameters greater than 3 cm are associated with increasing frequency 
of metastases. There is no effective standard therapy for VHL patients with metastatic renal 
cancer. Historically 35-45% of patients affected with VHL have died of metastatic renal 
carcinoma. Currently, tumors of non-renal origin are similarly managed by surgical resection to 
relieve symptoms or circumvent potentially dangerous sequelae (29,30) (for e.g. CNS 
hemangioblastomas, pheochromocytomas) or diminish metastatic potential (31) (e.g. pancreatic 
neuroendocrine tumors).  


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
11 
 
1.2.5 ZD6474 
ZD6474 is an orally administered receptor tyrosine kinase inhibitor with potent activity against 
VEGFR2 as well as activity against EGFR (32,33). 
 
Murine preclinical human xenograft models have demonstrated activity of ZD6474 against a 
variety of tumors including those arising in the lung, prostate, ovary, breast and colon. Reduction 
in tumor blood flow, vascular density and vascular permeability have been seen in a mouse 
xenograft model, suggesting inhibition of the VEGF pathway by the drug (34). The following is 
a summary of pre-clinical and clinical studies with ZD6474: 
 
In vitro studies (34) 
In isolated enzyme assays, ZD6474 was found to be a potent inhibitor of KDR tyrosine kinase 
activity (IC50=40nM), with additional activity against Flt-4 (IC50=110nM) and EGFR (IC50= 
500nM. Less potent activity was seen against a range of other tyrosine kinases including 
PDGFR, Tie-2, FGFR1, MEK, CDK2, c-kit, ErbB2, FAK, PDK-1, AKT and IGF-1R, with IC50 
ranging from 1M to >200M.  
 
ZD6474 inhibited the proliferation of both VEGF-stimulated and EGF-stimulated HUVEC cell 
lines (IC50=60nM and 170nM, respectively), while basal HUVEC proliferation was not 
significantly affected. When co-cultured with human fibroblasts, endothelial tube formation by 
HUVEC cells was inhibited at similar concentrations of ZD6474. Direct inhibition of tumor 
growth was demonstrated against established lung, colon, ovarian, breast, and prostate cancer cell 
lines, but only at higher concentrations, with IC50s in the 0.6 to 13.5 M range. 
 
The effect of ZD6474 on cardiovascular function has been investigated in vitro using the human 
ether-a-go-go gene assay as well as by assessment of action potential parameters recorded from 
canine Purkinje fibres. A concentration dependent increase in action potential duration was seen 
in these assays. 
 
The parent compound as well as the N-oxide and N-desmethyl metabolites were active in the 
above assays. 
 
Pre-clinical studies 
Pharmacokinetic Studies and metabolism 
Pharmacokinetic studies were performed in rats and dogs. In both species, >50% of the drug was 
absorbed when administered orally. Time to peak plasma concentration was 3-8 hours. Plasma 
clearance was rapid and was greater in male than in female rats. The drug was rapidly and 
extensively distributed with apparent volumes of distribution of approximately 30L/kg in both 
male and female rats. The highest concentrations were found in the GI tract, liver, adrenal glands, 
Harderian glands, pituitary, spleen and pigmented tissue. Delayed clearance from adrenal, kidney 
and testes was observed. The terminal half life was estimated at 16b hours in male and 31 hours in 
female rats, and at 8.27 hours in dogs.The drug is eliminated both by biliary excretion and in 
urine. Two metabolites have been identified in samples from rats and dogs- the N-oxide of 
ZD6474 and the N-desmethyl of ZD6474. 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
12 
 
ZD6474 underwent minimal metabolism in rat and dog hepatocytes and no metabolism in human 
hepatocytes or human microsomes. No inhibitory effects on the activity of human P450 
isoenzymes CYP1A2, 2C9, 2C19 or 3A4 were observed but the drug inhibited activity of CY 
2D6. 
 
Plasma protein binding ranged from 83% in the rat to 90% in human. ZD6474 was found to bind 
both human serum albumin and alpha-1-glycoprotein. 
 
Toxicology 
Single oral doses of 2000mg/kg in mice and rats were not tolerated. A single oral dose of 
1000mg/kg was tolerated in rats and produced premature death in 1/10 mice. A single IV dose of 
50mg/kg induced early death in 1/10 mice. The following organ-specific toxicities were seen in 
multiple-dose studies: 
 
o Dose-related dysplasia of the epiphyseal growth plates of the femoro-tibial joint was seen in 
rats receiving 25-75mg/kg/day and in dogs dosed at 40mg/kg/day by one month.  
o Elevated ALT, AST and LDH as well as histopathologic changes consistent with 
hepatocellular necrosis and acute cholangitis were seen in the one-month rat study at a dose 
of 75mg/kg/day. Death from acute cholangitis was seen in rats receiving 20mg/kg/day in the 
6-month study. These changes were not observed with the one-month or nine-month dog 
studies. 
o Gastro-intestinal toxicity in the form of emesis, diarrhea and weight loss was observed in the 
1 and 9-month dog studies. No accompanying histopathologic changes were noted, and the 
toxicity was reversible on cessation of drug use. 
o Renal papillary necrosis was seen in the rat 1-month study at doses of 25-75mg/kg/day 
o Decreased numbers of corpora lutea, increased post-implantation loss, embryofetal loss, 
delayed fetal development, heart vessel abnormalities, and precocious ossification of skull 
bones reflect the range of reproductive and embryofetal toxicity observed in rats 
o Reversible histopathologic and ultrastructural changes consistent with phospholipidosis was 
seen in the rat 1-month and 6-month studies, but were not observed in the dog studies 
o Reversible, dose-related acute folliculitis and epidermal microabscess formation in the 
muzzle region of skin was noted in both the 1-month and 6-month rat toxicity studies 
o In dog studies, following single oral doses of 5, 15, or 40mg/kg, an increase in hart rate 75-
360 minutes following the largest dose was observed. In the dose range studies, no clear 
effects on blood pressure, PR interval, QRS duration, RR interval, QT interval, waveform or 
rhythm were seen 
 
Biologic Effects and efficacy against tumors 
 
The following effects consistent with VEGF inhibition were seen in animal studies: 
 
o When administered at a dose of 50mg/kg to Alderley Park rats, ZD6474 inhibited the 
hypotension normally induced by administration of bolus VEGF 
o Dose-dependent increases in the hypertrophic chondrocyte zone of the epiphyseal growth 
plates of growing rats were seen  


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
13 
 
o ZD6474 inhibited tumor-associated angiogenesis in athymic mice intradermally implanted 
with A549 lung cancer cells 
o ZD6474 inhibits tumor vascular flow, volume and permeability as assessed by K trans 
measurements in established PC-3 prostate tumor xenografts using dynamic contrast-
enhanced MRI 
o Antitumor activity 
 In human tumor xenograft models (lung, prostate, ovary, breast, vulval, colon),  ZD6474 
inhibited the growth of established subcutaneous tumors in mice 
 Tumor regression was observed in established PC-3 prostate tumor xenografts, but not in 
a Calu-6 (lung) tumor xenograft model 
 In murine spontaneously metastatic tumor models (melanoma and renal cell cancer) 
administration of ZD6474 reduced both primary tumor growth and the incidence of 
pulmonary metastases 
 Anti-tumor effects of ZD6474 were also identified in a human colon tumor xenograft in 
athymic rats and in two syngeneic tumor models (melanoma, lung) in immunocompetent 
mice 
 Inhibition of angiogenesis as evidenced by changes in microvascular architecture was 
seen in a murine orthotopically implanted renal cell cancer model (35). 
 
Human Studies (34, 36) 
 
Phase I Studies: 
Several phase I trials have been conducted in human subjects. Trial 6474IL/0001 (Western 
study) was conducted as a multicenter, dose escalation phase I trial evaluating 50, 100, 200, 300, 
500 and 600mg doses administered orally as a daily single dose. A total of 77 patients have been 
treated on this trial at various dose levels, including an expanded cohort of 19 and 25 patients 
respectively at the 100mg and 300mg dose levels who were enrolled to better evaluate the effect 
of ZD6474 on QT interval and ST, T wave changes. A second phase I trial conducted in Japan 
(TVE-15-11) followed a dose escalation pattern evaluating 100, 200, 300 and 400mg daily oral 
doses. A total of 18 patients have been accrued on this trial.  
 
Pharmacokinetics 
Pharmacokinetic data obtained from the Western and Japanese studies were comparable. 
Absorption was highly variable, with individual patients having a Tmax as late as 24 hours post-
dose.  Following achievement of maximum plasma concentration, Cmax declined in a biphasic 
manner. Terminal half-life was estimated to be about 4-5 days and appeared to be independent of 
dose. Both mean AUC and Cmax increased with increasing dose in a linear manner with about 2 
to 6 fold in inter-individual variability in AUC for a given dose. A comparison of the mean 
weekly trough levels suggest that steady state was achieved by day 29, with marked 
accumulation between day 1 and 29.  
 
Adverse Events 
The most common adverse events seen on both trials were: 
1) Rash- At least 2 distinct types of rash were seen- A macular erythema and a follicular 
(acneiform) rash. Rash was reported in 54 (72%) patients in the Western and 14 (77.8%) patients 
in the Japanese study. The occurrence of rash appeared to be dose-dependent. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
14 
 
2) Gastrointestinal toxicity- Diarrhea was reported in 42 (56%) of the Western patients and 10 
(56%) of the Japanese patients. Other common GI side effects seen the western and Japanese 
studies included nausea (39% in the Western and 22% in the Japanese studies), vomiting (22% 
and 17% respectively), anorexia (29% and 28% respectively) and constipation (24% in the 
Western study). 
3) Central Nervous System- Headaches were reported by 19 (25%) patients and dizziness by 14 
(17%) patients in the Western study. 27% of the patients in the Japanese study reported 
headaches. 
4) Cardiovascular toxicity-  
a. 
In the western trial, 6 patients (8%) had T-wave or ST-segment changes consistent with 
repolarization abnormalities. 
b. 
QT/QTc prolongation- In the Western study, in the initial 49 patients enrolled, QTc 
prolongation occurred in 0 of 9 patients at 50mg, 1 of 8 patients at 100mg, 2 of 8 patients at 
200mg, 1 of 8 patients at 300mg, 2 of 8 patients at 500mg, and 1 of 8 patients at 600mg. The 
protocol was subsequently amended to include 11 additional patients at the 100mg dose level and 
12 patients at the 300mg dose level, along with the use of extensive ECG monitoring to assess 
QTc prolongation. In the expanded cohorts, 1/11 patients at the 100mg dose level and 2/12 
patients at the 300mg dose level had QTc prolongation. In the Japanese study, 11/18 patients 
(61%) developed QTc prolongation. A PK-PD correlation for QTc prolongation appears to exist. 
The relationship is best described by a direct linear effect model with a concentration of 1ng/ml 
causing an increase of 0.0243 ms in QTc interval. None of the QTc prolongations were 
considered to symptomatic 
c. Hypertension- Hypertension was seen in 21% of the patients in the two trials and on average 
involved a 5mm Hg increase in mean arterial pressure.  
 
Other commonly occurring adverse events (occurring in >10%) include: Fatigue (36%), 
abdominal pain (35%), back pain (15%), fever (14%), cough (14%), peripheral edema (12%), 
insomnia (12%), hematuria (11%), dyspnea (11%), proteinuria (11%).  
 
Dose limiting toxicity 
In Trial 6474IL/0001, dose levels of 50, 100, 200, 300, 500 and 600 mg/day were evaluated.  At 
600 mg/day, 3 of 8 patients developed dose limiting toxicity (DLT): thrombocytopenia, and 
diarrhea.  Because the plasma levels of ZD6474 observed in subjects in the 500 mg overlapped 
considerably with those at 600 mg, it was concluded that doses to take forward into later phases 
of development were less than 500 mg. 
 
In Trial TVE-15-11, dose levels of 100, 200, 300 and 400 mg/day were evaluated.  DLT was seen 
in 2 of 3 subjects in the 400 mg/day cohort (increased alanine aminotransferase and hypertension) 
and 2 of 6 subjects in 300 mg/day cohort (grade 3 diarrhea, hypertension, and headache in one 
patient, and grade 2 rash lasting longer than 7 days in a second subject). 
 
Therefore, in both trials a dose of 300 mg/day was identified as the highest well-tolerated dose of 
ZD6474. 
 
Withdrawal from Study 
67 patients were withdrawn from study in the 6474IL/0001 trial. 56 of these withdrawals were a 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
15 
 
result of disease progression. 6 patients were withdrawn from study due to adverse events. One 
patient was withdrawn because of a rash, one patient due to fatigue, one due to folliculitis, and 
one patient was withdrawn on account of abdominal pain. A 72 year old female with colorectal 
cancer and pre-existing hypertension and edema developed congestive heart failure and was 
withdrawn from study as a consequence. The etiology of the heart failure is unclear and a 
contribution from ZD6474 cannot be ruled out. One patient was withdrawn from protocol due to 
abnormal QTc prolongation. 3 patients withdrew consent and were taken off study consequently. 
 
In the Japanese study, 5/18 patients were withdrawn from study due to disease progression. In 
addition, one patient with QTc prolongation and one with dose limiting alanine aminotransferase 
elevation were withdrawn. 
 
Efficacy 
Phase I study results 
Two phase I studies have been completed in the West and Japan (6474IL/0001 and 6474JP/0001), 
in which 90 (72 Western and 18 Japanese) patients with malignant tumors have been exposed to 
ZD6474 (50 to 600 mg).  By the end of July 2002, safety data were available from 70 patients (40 
males and 30 females).  Cohorts received doses ranging from 50 mg/day to 600 mg/day in the 
Western phase I study and from 15 patients receiving doses ranging from 100 mg/day to 400 
mg/day (9 males and 6 females) in the Japanese trial. In the Japanese Phase I trial, nine patients 
with non-small cell lung cancer (NSCLC) who were heavily pre-treated and failed all prior 
therapy regimens (seven adenocarcinomas, one squamous cell, and one carcinoma not otherwise 
specified) were treated with ZD6474; four achieved partial response at doses ranging from 200 to 
300 mg.  This suggests that ZD6474 may have activity as monotherapy in otherwise 
chemoresistant NSCLC.  Testing this agent in other tumors in light of these results is appropriate.   
 
Summary  
The data from the Phase I studies confirm that ZD6474 is safe for further study in patients with 
cancer.  Dose limiting toxicity in greater than 33% of patients was observed at doses above 300 
mg in both the Western and Japanese Phase I trials.  Plasma concentrations of ZD6474 achieved 
at steady state with 300 mg cover the theoretical IC50 and KDR as extrapolated from in vitro data 
in the VEGF-stimulated umbilical vein endothelial cells in 100% of patients. A dose of 300 mg, 
with options for stepwise dose reductions to ensure tolerability, is therefore recommended.  The 
clinical effect of ZD6474 was shown in preliminary results from the Phase I study in Japan, in 
four of nine patients with NSCLC who received up to 300 mg of ZD6474 had objective responses 
as evaluated by radiographic studies.  
 
 
Phase II Studies: 
Several phase II studies are either currently in progress or have been completed.   
 
Two Phase II studies in NSCLC with ZD6474 have been completed.  A randomized double blind 
Phase II trial comparing ZD6474 monotherapy with gefitinib monotherapy in 168 patients with 
advanced NSCLC as second or third line therapy demonstrated that patients receiving ZD6474 
300mg had a statistically significant prolongation of progression free survival (PFS) compared 
with gefitinib 250mg, with a mean PFS of 11.0 weeks and 8.1 weeks respectively.  The adverse 
event profile of ZD6474 was similar to that seen in previous trials, and included diarrhea (CTC 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
16 
 
grade 3/4, 8.4%), rash (CTC grade 3/4, 4.8%) and asymptomatic QTc prolongation (all CTC 
grade 1, 20.5%). A higher incidence of cardiac, gastrointestinal and respiratory serious adverse 
events was noted in the ZD6474 arm compared with the gefitinib arm, although it is unclear if 
this increase can be attributed to ZD6474 (37) 
 
Another randomized double blind Phase II study evaluated PFS in second-line treatment of 127 
patients with advanced NSCLC, and demonstrated that ZD6474 100mg or 300mg plus docetaxel 
increased median PFS to 19 weeks and 17 weeks respectively, compared with 12.0 weeks for 
docetaxel plus placebo (38). While toxicities were similar to those expected in patients treated 
with docetaxel and those observed in other ZD6474 studies, the ZD6474 arm had more serious 
adverse events compared to the docetaxel/placebo arm.  
 
In an ongoing randomized double-blind phase IIa dose-finding study in 53 Japanese patients with 
NSCLC were given ZD6474 as monotherapy, at doses of 100, 200 or 300 mg/day.  Interim 
results demonstrated a 11% PR rate and a 51% disease control rate (PR+CR+stable disease) (39). 
The toxicity profile was similar to that seen in other trials with ZD6474, although the 
investigators reported a death related to interstitial lung disease that was considered to be related 
to ZD6474. Also reported was a case of cerebellar hemoorhage in a patient receiving the 200mg 
dose. 
 
Results from a phase II trial to assess objective tumor response in patients with hereditary 
metastatic medullary thyroid cancer having mutations in the RET protooncogene receiving 
ZD6474 monotherapy (300mg/day) were recently reported (40). Three of sixteen patients 
enrolled had a partial response, while an additional ten patients demonstrated stable disease >8 
weeks. A >50% reduction in serum tumor markers (calcitonin) was observed in 12 patients. 
Based on these promising data, a randomized phase II study of ZD6474 vs placebo in patients 
with advanced medullary thyroid cancer is currently being planned. 
 
Emerging Safety Profile/ Composite List of Adverse Events 
Notable and/or frequent side effects associated with the above phase I and phase II studies have 
been described along with each study. The following is a system-wise list of adverse events 
encountered on all completed or currently accruing studies as summarized in the most current 
Investigators’ Brochure (version 9) provide by the drug sponsor. 
 
Reported adverse events that may be related to vandetanib are listed below by body system. 
 
• Cardiovascular 
−Abnormal ECG (with or without QT prolongation; ie, either T-wave or 
ST-segment changes consistent with repolarization abnormalities), torsade-de-pointes, 
ventricular tachycardia, and hypertension 
• Central Nervous System 
−Headache or dizziness 
- Reversible posterior leukoencephalopathy syndrome 
- Hydrocephalus 
• Digestive 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
17 
 
−Constipation, diarrhea, non-specific abdominal pain, nausea, gastroesophageal reflux, 
stomatitis esophageal candidiasis, vomiting, and biliary or bowel obstruction or 
perforation,pancreatitis, enteritis, colovesical fistula 
• Haematologic and lymphatic 
−Ecchymosis, anemia, neutropenia, and thrombocytopenia  
• Investigations/Laboratory 
−Elevated liver function tests, generally CTC/CTCAE grade 1-2. Preliminary data 
suggests these are reversible, in some cases even while continuing therapy. 
• Metabolic and nutritional 
−Anorexia, dehydration, hypokalaemia, hypomagnesaemia, hypercalcemia and 
hypophosphataemia 
• Skin and appendages 
Acneiform rash, pruritus, macular or maculopapular rash (generalised or 
localised), localised and generalised erythema, photosensitivity reaction, and sweating. 
On occasion, especially when given with chemotherapy, these have progressed to more 
serious conditions, including exfoliative dermatitis, skin desquamation, erythroderma, 
toxicoderma, toxic epidermal necrolysis, erythema multiforme and necrotizing fasciitis. 
- Wound healing complications 
- Hand-foot syndrome 
• Respiratory 
−Interstitial lung disease, pulmonary effusion and pneumonia. A very small number of 
patients with lung cancer receiving vandetanib have developed shortness of breath and 
cough because of inflammation or scar tissue formation in the lungs, although this could 
be due to the underlying lung cancer. 
• Renal 
−Proteinuria, haematuria and renal failure. 
• Vascular 
−Arterial ischaemic events (including myocardial infarction, stroke, peripheral 
ischaemia), venous thromboembolism (including pulmonary embolism). A small number 
of patients receiving vandetanib have developed blood clots affecting the legs or lungs. 
This may have been due to the patient’s cancer or other illness at the time; however, it is 
considered possible that vandetanib might increase the risk for developing blood clots. 
-- Intracranial bleeding 
• Psychiatric  
−Mood disorders (anxiety, depression, insomnia). It is possible that these events are not 
direct effects of vandetanib, but rather are secondary to symptoms of cancer or to other 
effects of vandetanib (rash, etc). 
• Ophthalmologic 
−Corneal changes, including ulceration 
 
• General 
−Asthenia, fever, weight loss, pain, and fatigue 
 
In addition, a number of other side effects have been reported in clinical trials using ZD6474 
alone, in combination with other chemotherapy agents or radiation. It is unclear whether these 
side effects are related to ZD6474, or are caused by other factors (such as chemotherapy or 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
18 
 
radiation). These side effects include: 
• Infections, including life-threatening bacterial infections 
• Seizures and facial nerve palsies 
• Syncope 
• LV dysfunction 
• Respiratory failure 
• Esophageal fistula 
 
Hemorrhage from both tumor and non-tumor sites have been described with several agents 
targeting the VEGF pathway (such as sunitinib, sorafenib, bevacizumab etc.). Episodes of 
bleeding with the above agents have been occasionally life-threatening or fatal. Experience with 
anti-VEGF agents in VHL patients is limited and largely anecdotal. We are aware of one case of 
cerebellar hemorrhage requiring neurosurgical intervention in a VHL patient receiving the 
experimental VEGFR tyrosine kinase inhibitor (PTK787, Dr. Dan George, Duke University, 
Personal Communication). Gingival bleeding as well as one case each of hemoptysis and 
cerebellar hemorrhage has been described in studies with ZD6474, although it is unclear whether 
these events are attributable to the agent. A risk of serious bleeding events cannot be excluded in 
patients receiving this drug.  
 
1.2.6 Rationale     
Localized clear cell renal carcinoma in VHL patients requires surgical therapy, which often 
needs to be repeated multiple times.  The surgical therapy is not curative, but is recommended in 
order to decrease the likelihood of metastasis.  Once metastasis has occurred, clear cell renal 
cancer is incurable in the majority of VHL patients with currently available therapies.  
 
Insight into the molecular pathways believed to mediate the VHL phenotype has provided the 
impetus for the development of rational targeted therapeutic strategies directed against this 
condition. Inactivation of the VHL gene, the underlying molecular defect in VHL, results in 
decreased ubiquitin-dependent degradation of hypoxia-inducible factors (HIFs), which in turn 
leads to overexpression of VEGF as well as other genes such as transforming growth factor-
(TGF-), platelet derived growth factor (PDGF) and GLUT-1. Overexpression of VEGF is 
responsible for enhanced tumor angiogenesis and leads to the highly vascular renal tumors seen 
in VHL patients. ZD6474 inhibits angiogenesis by inactivation of the tyrosine kinase activity of 
the VEGF receptor KDR/VEGFR2. In addition, ZD6474 may exert direct antitumor activity via 
its inhibition of EGF- R, one of the ligands for which is TGF-. ZD6474 has shown activity in 
several preclinical tumor models and has demonstrated an acceptable toxicity profile in phase I 
and phase II studies. ZD6474 thus provides an exciting opportunity for exploring a targeted 
approach in a hereditary syndrome with a well characterized molecular defect and no available 
curative options. 
 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 ELIGIBILITY CRITERIA  
2.1.1 Inclusion Criteria 
• Patients must satisfy all the following criteria to be eligible for study enrolment 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
19 
 
• Clinical diagnosis of von Hippel Lindau disease (Appendix E) 
• The presence of at least one measurable (as defined by RECIST) renal tumor (RCC). 
Patients with tumors localized to the kidney as well as those with metastatic RCC are 
eligible. 
• Age ≥ 18 years.  
• Life expectancy >3 months 
• Performance status ECOG 0-2 
• Patients must have normal organ and marrow function as defined below: WBC count 
≥ 3,000/uL, absolute neutrophil count ≥ 1,500/L, platelet count ≥100,000/L, 
serum creatinine ≤ 1.5 times upper limit of reference range or measured 24 hr. 
creatinine clearance ≥ 50 ml/min, AST and ALT <2.5 x upper limit of reference 
range, total bilirubin < 1.5x upper limit of reference range ( <3 x upper limit of 
reference range in patients with Gilbert’s disease), alkaline phosphatase ≤ 2.5 x upper 
limit of reference range (or ≤ 5 x upper limit of reference range if considered to be 
related to liver metastases by the PI) 
• No history of serious intercurrent medical illness 
• At least four weeks from completion of any other surgical or investigational therapy 
for von Hippel Lindau and at least 4 weeks from any major surgical procedure. In 
addition, patients who have undergone recent major surgery should have well healed 
surgical incisions. 
• All men and women of childbearing potential must use effective contraception  
• Negative pregnancy test in female patients of childbearing potential within 7 days 
prior to enrolment on study 
• Ability to understand and the willingness to sign a written informed consent 
document. 
 
2.1.2  Exclusion Criteria 
• Prior or concomitant non-von Hippel Lindau associated malignancy with the 
exception of adequately treated basal or squamous cell carcinoma of the skin, cervical 
carcinoma in situ or any other malignancy from which the patient has remained 
disease free for more than five years 
• Known brain metastases (unless adequately resected or irradiated with no evidence of 
recurrence for at least 6 months) 
• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering 
the study or those who have not recovered from adverse events (to ≤ grade 1 CTCAE 
v3.0) due to agents administered more than 4 weeks earlier. 
• Patients may not be receiving any other investigational agents or have received 
treatment with a non-approved or investigational drug within 4 weeks prior to Day 1 
of study treatment except those used for imaging studies. Use of 5HT-3 antagonists 
because of the potential effect on QTc interval 
•  Any concurrent medication that may cause QTc prolongation or induce Torsades de 
Pointes (Appendix C).  Drugs listed in Appendix C, Table 2, that in the investigator’s 
opinion cannot be discontinued, are allowed however, must be monitored closely. 
•  Concomitant medications that are potent inducers of CYP3A4 function, such as 
rifampin, rifabutin, phenytoin, carbamazapine, barbiturates such as phenobarbital, or 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
20 
 
St. John’s Wort (See Appendix D). 
• Clinically significant cardiac event (including symptomatic heart failure, myocardial 
infarction or angina) within 3 months of entry or presence of any cardiac disease that 
in the opinion of the Principal Investigator increases the risk of ventricular arrhythmia 
• History of clinically significant arrhythmia [including multifocal premature 
ventricular contraction (PVC), bigeminy, trigeminy, ventricular tachycardia] that is 
symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained 
ventricular tachycardia 
• Uncontrolled atrial fibrillation.  Atrial fibrillation controlled on medication is not 
excluded. 
• Presence of Left bundle branch block 
• Previous history of QTc prolongation while taking other medications that required 
discontinuation of that medication. 
• Congenital long QT syndrome or first degree relative with unexplained sudden death 
under the age of 40 years 
• QTc with Bazett’s correction that is unmeasurable, or ≥480 msec on screening ECG.  
If a patient has QTc ≥480 msec on screening ECG, the screen ECG may be repeated 
twice (at least 24 hours apart).  The average QTc from the three screening ECGs must 
be <480 msec in order for the patient to be eligible for the study). Patients who are 
receiving a drug that has a risk of QTc prolongation (see Appendix C, Group/Table 2) 
are excluded if QTc is ≥ 460 msec. 
• Potassium concentration less than 4.0 mEq/L, calcium (ionized calcium or adjusted 
for albumin), or magnesium concentrations outside normal limits despite optimal 
supplementation/correction 
• Left ventricular ejection fraction less than 45% measured by multiple gated 
acquisition scan (MUGA) or echocardiogram (ECHO) 
• Hypertension not controlled by medical therapy (systolic blood pressure greater than 
150 mmHg or diastolic blood pressure greater than 100 mmHg). 
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements.  
• Patient known to be HIV positive and requiring antiretroviral therapy  
• Currently active diarrhea that may affect the ability of the patient to absorb ZD6474 
or tolerate further diarrhea. 
• Patients on therapeutic anticoagulation 
• Patients with known bleeding disorders 
• Pregnant women are excluded from this study because ZD6474 is an anti-angiogenic 
agent with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with ZD6474, breastfeeding should be discontinued if the 
mother is treated with ZD6474 
• Any known hypersensitivity to ZD 6474 or other excipients of ZD6474 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
21 
 
2.1.3 Restrictions 
• Patients who are blood donors should not donate blood during the trial and for 3 
months following their last dose of trial treatment. 
• Due to the experimental nature of ZD6474, female patients must be one year post-
menopausal, surgically sterile, or using an acceptable method of contraception during 
and continued after the last dose of study med (oral contraceptives, barrier methods, 
approved contraceptive implant, long-term injectable contraception, intrauterine 
device or tubal ligation.)  Male patients must be surgically sterile or using an 
acceptable method of contraception during their participation in this study.  
Contraceptive use will continue for at least two months, five half-lives, after the last 
dose of study medication. 
• Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
2.2 
RESEARCH ELIGIBILITY EVALUATION 
2.2.1 History and Physical  
Complete history and physical examination and assessment of performance status will be 
obtained at the first clinic visit (screening visit) followed by interim assessments at each visit.  
The H&P and performance status need only be recorded upon the initial assessment and where 
pertinent changes (improvement or deterioration of previously abnormal findings, new findings 
or a change in performance status) are noted. Patients will be asked to keep a diary of their side 
effects, time of occurrence, and medications or interventions for relief.  This will be reviewed 
with the team at each visit. 
 
2.2.2 The following must be performed within 4 weeks of enrollment on study 
• Imaging studies: PA and lateral chest X-ray, CT of the chest, abdomen and pelvis (or 
MRI scans when indicated) 
• MRI of brain to include: pre-contrast T-1 and T-2 weighted images in the axial plane 
and post-contrast (Gadolinium) T-1 weighted images in the axial, sagittal or coronal 
planes (1 hour scan time).  CT imaging with and without contrast may be performed 
if MRI cannot be performed. 
• ECHO 
• 12 lead EKG 
 
2.2.3 The following must be performed within 7 days of enrollment on study 
History and physical - Limited interim evaluation focusing on significant changes or 
deviations from initial H&P 
CBC with differential, Chem 20 panel, urinalysis 
Urine or serum pregnancy test in women of childbearing potential. 
 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
22 
 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) 
must be completed and faxed to 301-480-0757.  After confirmation of eligibility at Central 
Registration Office, CRO staff will call the pharmacy to advise them of the acceptance of the 
patient on the protocol prior to the release of any investigational agents.  Verification of 
Registration will be forwarded electronically via e-mail.  Please note, it is very important for all 
registrars to acquire encrypted e-mail from NIH Help Desk, since the verification of registration 
includes patient’s information.  A recorder is available during non-working hours.  The Central 
Registration Office will be notified when a patient is withdrawn from the study. 
 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
This is a phase II study utilizing a fixed dose of ZD6474 (300mg/day PO). The study will recruit 
patients with von Hippel Lindau disease who have at least one measurable renal tumor (either 
localized to the kidneys and/or metastatic). Based on phase I evaluation, 300mg/day was 
identified as a well tolerated dose and appears to result in serum concentrations of the drug 
compatible with inhibition of target receptor tyrosine kinases. Treatment cycles will consist of 28 
days and the drug will be administered daily on days 1-28. There will be no break between 2 
consecutive cycles (i.e, drug administration will be continuous). Patients will undergo clinical 
and laboratory evaluation in the Urologic Oncology Branch clinic prior to the start of each cycle. 
Patients will be evaluated radiologically for evidence of response or progression approximately 
twelve weeks after initiation of therapy and every twelve weeks thereafter while on study. 
Patients with evidence of stable disease or disease response in renal tumors (CR or PR) will 
continue to receive therapy in the absence of serious toxicity. Patients who demonstrate disease 
progression at any time will be taken off study. Patients who continue to demonstrate at least one 
tumor >3cm following 12 weeks or more of therapy may be taken off study regardless of 
response status, if, in the opinion of the PI, this lesion(s) poses a significant risk of metastasis in 
the absence of surgical intervention or could otherwise compromise patient care. These patients 
will be evaluable for the primary end-point (disease response). 
 
Non-renal VHL associated lesions are usually followed until they reach a certain size or become 
symptomatic, at which point surgical resection or other treatments (such as laser 
photocoagulation of retinal angiomas) of these lesions is pursued. It is also conceivable, although 
unlikely, that patients with pheochromocytomas or pancreatic neuroendocrine tumors may 
develop metastatic disease that may necessitate chemotherapy. Patients with progression of non-
renal lesions requiring systemic antineoplastic therapy or surgical intervention will discontinue 
study drug even in the absence of renal progression or unacceptable toxicity. Vandetanib may be 
restarted in patients undergoing resection of non-renal VHL lesions once the surgical incisions 
have adequately healed, if in the opinion of the PI, this is likely to offer clinical benefit (e.g. 
patients demonstrating an ongoing response in their renal tumors while on vandetanib).  Patients 
with progression of non-renal lesions not requiring intervention but demonstrating stable or 
responding renal lesions will continue ZD6474 at the discretion of the PI/Study Chair. 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
23 
 
3.2 
STUDY DRUG ADMINISTRATION 
ZD6474 Administration  
Treatment will be will be self-administered by the patient on an outpatient basis.  The starting 
dose of ZD6474 is 300mg/day administered PO daily. Patients with moderate renal failure 
defined as creatinine clearance > than or = 30ml/min and <50ml/min should begin vabdetanib at 
a reduced dose of 200mg.  ZD6474 should be taken with some food and water to minimize GI 
effects, ideally at around the same time every morning. ZD6474 is available as 50mg, 100mg, 
200mg and 300mg tablets and as an oral solution (15 mL of 10mg/mL vandetanib in 25 mg oral 
solution bottles). Patient compliance will be tracked using a pill count/administration form which 
the patient will be instructed to complete and which will be reviewed at each clinic visit.   If the 
subject inadvertently does not take the dose in the morning, he or she may take that day’s dose 
any time up to10pm that same day.  However, if a subject misses taking their scheduled dose and 
is unable to take the missed dose on the same day, he or she must take the next scheduled dose 
and the missed dose will not be made up. 
 
Reported adverse events and potential risks are described in Section 8.  Appropriate dose 
modifications for ZD6474 are described in Section 3.3.  No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient’s malignancy.  
 
3.3 
DOSING DELAYS/DOSE MODIFICATIONS 
Patients will be asked to record side effects/symptoms developing or worsening on therapy on a 
Side Effect Diary which will be reviewed by the research nurse/PI/associate investigator during 
clinic visits. Treatment modifications will be made in the event of toxicities (graded based on 
NCI Common Toxicity Criteria for Adverse Events, version 3.0) according to the guidelines 
below, with dose levels as defined below:  
Dose level   0: 300mg/day 
Dose level  -1: 200mg/day 
Dose level  -2: 100mg/day 
Dose level  -3:  100mg every other day 
 
3.3.1 Management of Skin Toxicity 
 
Patients will be instructed to follow a program of sun protective measures while receiving study 
therapy and for 3-4 weeks after discontinuing study therapy.  These measures include 
minimizing sun-exposure, using protective clothing, hats etc., and the use of sunscreens. The aim 
is to reduce the risk of development of skin rash, minimize the severity of skin rash, and to 
minimize the requirement for dose reduction of study therapy. 
 
If a patient develops a skin rash,  
The rash should be graded/assessed by a physician as soon as possible according to the CTCAE 
cutaneous toxicity criteria and documented accordingly 
If a rash of CTCAE grade 2 or higher is detected, symptomatic treatment should be provided. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
24 
 
A variety of agents can be used to manage skin rashes and associated symptoms.  These include 
mild to moderate strength steroid creams or oral corticosteroids, topical or systemic antibiotics, 
topical or systemic antihistamines, emollients and occasionally retinoid creams. 
If a rash of CTCAE grade 3 is detected, ZD6474 should be withheld until recovery to grade 1 or 
below, at which point, the drug may be restarted at one dose level lower 
Patients with CTCAE grade 4 rash will discontinue therapy and will not be retreated. 
If grade 3 higher cutaneous toxicity recurs at reduced dose of ZD6474, the patient will 
permanently discontinue study treatment of ZD6474.  If ZD6474 must be withheld for >3 weeks 
due to cutaneous toxicity, the patient will be taken off study. 
3.3.2 Management of gastrointestinal (GI) toxicity 
If GI toxicity is not appropriately managed this may be associated with a development of 
dehydration.  Electrolytes should be monitored in the event of persistent vomiting or diarrhea. 
 
3.3.2.1 Nausea and/or vomiting 
In subjects who have emesis and are unable to retain study treatment, every attempt should be 
made to obtain control of nausea and vomiting.  The dose of study treatment may be repeated if 
emesis occurs within 30 minutes of taking the tablets or all the tablets are seen in the emesis.  
Nausea, vomiting, or both may be controlled with antiemetic therapy; however, 5HT-3 
antagonists are not permitted because of the potential effect on QTc interval.  
 
3.3.2.2 Diarrhea 
 
Diarrhea should be treated with standard medications to avoid dose modification or interruption, 
if possible.  Diarrhea related to ZD6474 has been successfully managed with anti-diarrheal 
agents such as loperamide. Once diarrhea is determined to be related to ZD6474, an acceptable 
strategy for symptomatic management is initiation of loperamide 2mg po administered following 
the first episode, which can be repeated as frequently as every 2 hours while awake (or 
administered at a dose of 4mg every 4 hours during sleeping hours) (not to exceed a total of 
16mg/24 hours) until the patient is diarrhea-free for 8-12 hours.  
 
No dose modifications will be made for CTCAE grade 1 or 2 nausea, vomiting or diarrhea.  If 
CTCAE grade 3 nausea, vomiting, or diarrhea develops despite optimal pharmacologic 
prophylaxis/treatment, study medication should be withheld until symptoms resolve to less than 
or equal to grade 1.  Once the diarrhea resolves to less than or equal to grade 1, treatment with 
ZD6474 may recommence with a dose reduction of one level.  If the toxicity reoccurs on the 
dose reduction pack, the subject will be withdrawn from the study. Subjects who develop grade 4 
nausea, vomiting, or diarrhea will discontinue therapy with ZD6474. Subjects who are clinically 
unstable because of nausea, vomiting, diarrhea or other intercurrent medical illness must be 
admitted and evaluated using telemetry until clinically stable. 
 
3.3.3 QT prolongation 
QT prolongation will be managed as follows: 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
25 
 
Monitoring for QT prolongation 
All patients on study will get a weekly 12 lead EKG for the first 2 cycles. Thereafter (in the 
absence of QT prolongation), a monthly ECG will be performed while the patient is on the study 
drug. The following algorithm will be used to monitor/manage QTc prolongation. 
 
QTc prolongation is defined as  
A single QTc value of ≥500 msec or an increase of ≥100 msec from baseline;  
OR 
 
Two QTc measurements where either of the following criteria are met for both QTc values (the 
second being the mean of 3 consecutive ECGs):  
A QTc interval ≥500 msec but <550 msec,  OR 
An increase of ≥60 msec, but <100 msec, from baseline QTc to a QTc value ≥480 msec.   
Management of Patients With QTc Prolongation 
 
For a single QTc value of ≥500 msec or an increase of ≥100 msec from baseline, ZD6474 must 
be withheld.  ECGs and electrolytes should be followed 3 times a week until QTc falls below 
480 msec or baseline, whichever is higher.  ZD6474 treatment may be resumed at a lower dose 
after the QTc recovers to <480 msec or baseline. 
 
For a QTc ≥500ms but <550ms (grade 3 CTCAE v3.0) or ≥60ms, but <100ms compared to 
baseline to a QTc value ≥480 msec, further ZD6474 dosing will be withheld and an ECG (in 
triplicate) obtained within 24 hours. If the repeat ECGs confirm a QTc ≥500 (mean calculated 
from 3 ECGs) or prolongation of ≥60ms from baseline to a QTc ≥480ms, QTc and electrolytes 
will be monitored three times a week until the QTc returns to baseline or below 480ms 
(whichever is higher); thereafter, ZD 6474 will be resumed at one lower dose level. If the repeat 
ECG reveals a QTc <500 ms or a prolongation of <60ms from baseline, ZD6474 will be resumed 
at the current dose and an ECG repeated in 48 hours and thereafter as outlined in the study plan 
in the absence of QT prolongation (i.e, ≥500ms or prolongation ≥60ms from baseline to a value 
≥480 msec). A second instance of QTc ≥500ms (but <550ms) or QTc prolongation ≥60ms from 
baseline to a value ≥480 msec will necessitate withholding drug until normalization of QTc and 
resumption thereafter at one lower dose level. 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
26 
 
 
 
3.3.4 Hypertension 
Subjects will be asked to monitor their blood pressure at home at least once a day and contact the 
UOB team for elevated readings. However, elevated BP readings should be confirmed by a 
qualified health care professional and decisions regarding grading of hypertension and 
initiation/intensification of antihypertensive therapy will be driven by BP measurements 
performed by a health care professional. Table 1 outlines the management plan for patients 
developing hypertension on therapy. Although CTCAE criteria will be used to grade 
hypertension, the scheme outlined in Table 1 will be used to guide dose modifications. Early 
treatment of grades 1-2 hypertension to prevent or minimize the risk of developing more 
persistent or clinically significant hypertension is allowed and is not considered a grade 3 event. 
 
Agents typically used to treat hypertension include calcium channel blockers such as amlodipine 
(agents such as verapamil or diltiazem, which are potents inhibitors of CYP3A4 should be 
avoided where possible, as should agents in this category that have the potential to prolont QTc), 
diuretics, ACE inhibitor, beta-blockers and angiotensin receptor antagonists. The choice of 
agents and dosage used may vary based on individual circumstances. 
QTc ≥500 msec OR ∆ in baseline of ≥100 
msec 
Ye
s 
Withhold study drug.  Follow for resolution of QTc  
prolongation and restart at one dose level lower 
following resolution 
 
∆ QTc from baseline ≥60 msec but <100 
msec(to ≥480 msec) 
Ye
s 
No 
Continue study drug  
No 
Repeat ECG 
QTc ≥500 msec and <550 msec OR 
∆ QTc from baseline ≥60 msec but <100 
msec (to ≥480 msec) 
Hold study drug. Repeat 
ECG in triplicate within 24 
hours 
No 
Restart study drug 
at original dose 
 Follow for resolution of QTc 
prolongation and restart at one dose 
level lower following resolution 
Ye
s 
Repeat ECG in 48 hours 
QTc ≥500 msec and <550 msec OR 
∆ QTc from baseline ≥60 msec but <100 
msec (to ≥480 msec) 
Continue at 
current dose 
Withhold study drug.  Follow for 
resolution of QTc  and restart at one 
dose level lower following resolution 
No 
Ye


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
27 
 
 
Table 1 
 
 
BP Measurements - Systolic/Diastolic 
Treatment/Dose Modification 
A 
>150 mmHg (systolic)  
OR 
>100 mmHg (diastolic)  
OR 
Increase of diastolic BP by ≥20 mmHg regardless of 
baseline BP 
• 
Add new or additional antihypertensive 
medications or increase dose of existing 
medications. 
• 
Maintain dose of ZD6474. 
• 
If unable to control BP to <150/100 in 
two weeks, hold ZD6474 and follow 
guidelines under row C 
 
B 
>180 mmHg (systolic) 
OR 
>110 mmHg (diastolic) 
OR 
Symptomatic 
 
• 
Hold ZD6474. 
• 
Add new or additional antihypertensive 
medications or increase dose of existing 
medications. 
• 
Resume treatment at same dose level 
when BP falls to <140/90 or baseline. 
C 
>150 mmHg (systolic) 
OR 
>100 mmHg (diastolic) 
Despite therapy for at least 2 weeks  
• 
Hold ZD6474. 
• 
Maintain or intensify antihypertensive 
therapy 
• 
Resume treatment at one lower dose level 
when BP falls to <140/90 or baseline 
D 
CTCAE Grade 4  
• 
Discontinue ZD647 
• 
No further treatment with ZD 6474 
allowed except in patients benefiting from 
therapy in whom ZD6474 may be 
restarted at one lower dose level if BP is 
controlled to <140/90 within 3 weeks and 
there are no permanent sequelae. Patient 
will be removed from study if a second 
episode of grade 4 hypertension occurs 
 
3.3.5 Other Toxicity 
If any other CTCAE grade 3 or 4 non hematologic toxicity attributable to ZD6474 develops (not 
outlined in Section 3.3.1-3.3.4), study treatment should be interrupted until the toxicity resolves 
to less than or equal to CTCAE grade 1 or baseline.  At the time of resolution, patients with 
grade 3 toxicity may resume study treatment at one dose level lower. Patients with grade 4 
nonhematologic toxicity will discontinue ZD6474 and be taken off study. Patients with grade 3 
or 4 neutropenia or thrombocytopenia attributable to ZD6474 will have their therapy interrupted 
until resolution to less than or equal to CTCAE grade 1 or baseline, at which point treatment may 
be resumed at one dose level lower. If study treatment must be interrupted for more than 3 weeks 
to allow for toxicity to resolve, the subject’s participation in the study will be discontinued. Dose 
reductions or study drug interruptions will not be made for laboratory abnormalities not 
considered clinically significant, regardless of grade. 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
28 
 
3.4 
RESEARCH STUDIES 
Sample acquisition and planned studies 
 
Blood samples for evaluation of basal plasma levels of angiogenesis biomarkers such as VEGF 
and to assess the effect of ZD6474 on these biomarkers will be obtained on study entry and at 
each clinic visit. 5-10 cc of venous blood will be collected into lavender top EDTA tubes and 
thoroughly mixed.  
 
Peripheral blood (four CPT tubes containing sodium citrate) will be obtained pre-treatment and 
post-treatment with ZD6474 and coded samples will be used for analysis of angiogenesis 
markers such as circulating endothelial cells (CEC) and circulating endothelial progenitor cells 
(CEP). The time points may vary as the optimal time vis a vis treatment needs to be empirically 
determined.  Four CPT tubes containing sodium citrate (blue-black speckled top tubes) of 
peripheral blood will be sent to Jane Trepels’s laboratory in the Medical Oncology Branch, CCR, 
NCI.  The CEC and CEP analysis will be performed using multiparameter flow cytometry, and 
may include ancillary studies such as real-time RT-PCR analysis of gene expression and in vitro 
endothelial cell culture.  These studies are exploratory and intended to evaluate the utility of 
CECs and CEPs as surrogates for inhibition of angiogenesis following administration of 
ZD6474.  
 
Although there is no universally accepted surrogate for angiogenesis inhibition, evaluation of 
CECs and CEPs have been proposed and validated by several groups (41-46). Dr. Jane Trepel’s 
lab has collaborated with other groups (Dr. John Heymach, MD Anderson Cancer Center, and 
the Angiogenesis Core at the Beth Israel and Deaconess Medical Center) to standardize flow 
cytometric analyses of peripheral blood for evaluation of CEC/CEP. For this analysis, peripheral 
blood is drawn into 4 CPT citrate tubes. Mononuclear cells are isolated by centrifugation, 
washed with PBS, and FcR solution (Miltenyi) is added to block non-specific binding.  Although 
the entibodies and fluorochromes used may vary, for identification of CECs and CEPs, cells are 
typically stained with FITC- conjugated anti-CD31, PerCP-conjugated anti-CD45, APC-
conjugated anti-CD133, Hoechst 33258 and PE-conjugated CD146 and analysed on an LSR II 
flow cytometer (BD Biosciences), using LSR II-equipped digital data acquisition and FlowJo 
cytometric data analysis software. The CEC and CEP cell concentrations are calculated as a 
percentage of the total number of mononuclear cells or as the number of cells/microliter of whole 
blood after an evaluation of a minimum of 105 cellular events, and preferably 106 cellular events.  
CEC cells are defined by the co-expression, or absence of expression on a single cell of the 
following parameters: CD45-, CD31+, CD133- and CD146+, Hoechst 33258 (viable CEC) or 
CD45-, CD31+, CD133- and CD146+, Hoechst 33258+ (nonviable CEC).  CEP cells are defined 
by the co-expression, or absence of expression on a single cell of the following parameters: 
CD45- or dim, CD31+, CD133+ and CD146-, Hoechst 33258- (viable CEP) or CD45- or dim, 
CD31+, CD133+ and CD146-, Hoechst 33258+ (nonviable CEP). 
 
The outcome measures will be the number of CEC and CEP per 106 mononuclear cells or per 
microliter of peripheral blood, analyzed in samples taken before and after treatment.  These 
numbers will then be examined for correlations with various parameters to assess their potential 
utility as surrogate biomarkers for drug activity, for establishing the optimal biologic dose, for 
patient stratification, and monitoring of therapy-related side effects.  


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
29 
 
In addition to multi-parameter flow CEC and CEP analysis, if there are a sufficient number of 
cells in the mononuclear fraction the cells will be set up in vitro, according to standard methods, 
for the endothelial progenitor cell colony forming assay (47, 48). 
 
Correlative laboratory studies will be performed by investigators in the Urologic Oncology 
Branch and may involve collaboration with other NIH intramural investigators and/or Astra-
Zeneca. Studies listed will be performed wherever possible and as permitted by sample and 
resource availability.  
 
3.4.1 Collection, Storage, Use and Disposition of Human Specimens 
3.4.1.1 Clinical Samples  
Blood and urine samples for clinically relevant, non-research hematology, serum 
chemistry, urinalysis, and skin biopsy tissue will be prepared using standard procedures.  
Routine clinical analyses will be performed by the NIH Clinical Center central 
laboratories or NCI Pathology department.  Samples will be processed and disposed 
according to standard laboratory procedure. 
 
3.4.1.2  Storage and research use of research human specimens  
a) Sample Collection and Planned Research Studies-Research samples will be collected 
with a view to performing a variety of correlative/biomarker studies (as indicated in 
section 3.4).  
b) Sample Processing and Storage-Each patient research sample will be assigned a 
unique patient identifier and relevant sample characteristics (such as timing of sample 
collection, treatment cycle and day identifiers) will be recorded. The location of all 
samples will be carefully tracked in the database.    All stored samples will be coded 
and no identifying patient information will be on placed on sample containers. Stored 
samples will be kept in freezers / refrigerators or secure containers located in the 
Urologic Oncology Branch research laboratories.  
c) Time frame for research studies- Samples will be stored until requested by an 
authorized researcher(s).  All researchers are required to use the samples for research 
purposes associated with this trial (as per the NCI IRB approved protocol). Subjects 
will be given the option of consenting to future use of their research samples per the 
informed consent process with their option declared in the consent document.  
Samples from those patients who consent to this will be stored permanently. 
However, these samples will be used only for research studies on active NCI IRB 
approved protocols covered by a valid informed consent document. Samples will be 
destroyed at the completion of the study from those subjects who decline future use of 
their samples. Once primary research objectives for the protocol are achieved, 
intramural researchers can request access to remaining samples provided they have an 
IRB approved protocol and patient consent. Any unused samples must be returned to 
the UOB laboratories as appropriate. The PI will report destroyed samples to the IRB 
if samples become unsalvageable because of environmental factors (e.g. broken 
freezer or lack of dry ice in a shipping container) or if samples are destroyed because 
a patient withdraws consent. Samples will also be reported as lost if they are lost in 
transit between facilities or misplaced by a researcher.  Any freezer problems, lost 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
30 
 
samples or other problems associated with samples will be reported to the IRB, the 
NCI Clinical Director, and the office of the CCR, NCI. 
 
3.5 
STUDY EVALUATIONS AND SCHEDULE 
3.5.1 Baseline Evaluation  
These studies are intended to evaluate the presence and extent of nonrenal VHL-associated 
tumors and are not meant to determine eligibility. These studies may be performed before (as 
part of routine evaluation of VHL patients) or after eligibility assessment but no more than 3 
months prior to study enrolment. 
 
3.5.1.1 MRI of the spine to include: precontrast T-2 weighted surface coil images of the cervical 
and thoracic cord in the sagittal plane and post contrast (Gadolinium). CT imaging with 
and without contrast may be performed if MRI cannot be performed.  
 
3.5.1.2 24 hour urine collection for catecholamine analysis when clinically indicated. 
 
3.5.1.3 Standard complete audiogram to detect hearing loss and /or the presence of an ELST 
(endolymphatic sac tumor) in patients known or suspected to have these tumors. 
 
3.5.1.4 CT examination of the internal auditory canal to evaluate for potential ELST in patients 
known or suspected to have these tumors. 
 
3.5.1.5 For males, ultrasound of testicles with high resolution (5-7 MHz) transducer to evaluate 
the epididymis (0.75 hour scan time) when clinically indicated.  
 
3.5.1.6 An ophthalmologic exam to screen for retinal angiomas. 
3.5.1.7 Labs: serum erythropoietin, TSH, T3 and FreeT4, parathyroid function tests –spot urine 
phosphorous and spot urine creatinine, vitamin D 1-25, vitamin D 25-OH Serum PTH, 
FGF23 (1-2ml of plasma to be sent to Michael T. Collins, M.D., Chief, Skeletal Clinical 
Studies Unit, CSDB, NIDCR) 
 
3.5.2 On Study Evaluation 
3.5.2.1 Before every cycle: Based on patient’s status and schedule conflicts if deemed warranted 
pt’s may be allowed to reschedule NIH protocol visits at the discretion of the PI, the 
patient and the research team. 
a.   History and physical  
b. CBC, Chem 20, urinalysis and urine protein:creatinine ratio. 
c.   ECG (A 12-lead ECG should be obtained on day 1, cycle 1 before the first dose 
of ZD6474 and repeated 4-8 hours after the first dose) 
d. Urine pregnancy test in women of childbearing potential 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
31 
 
3.5.2.2 Every three cycles (Restaging cycles): Based on patient’s status and schedule conflicts if 
deemed warranted pt’s may be allowed to reschedule NIH protocol visits at the 
discretion of the PI, the patient and the research team. 
e.   History and physical 
f.    CBC, Chem 20 
g. Erythropoeitin 
h. TSH, if elevated, T3 and Free T4, antiTPO and TSI and lipid panel 
i.    Parathyroid function tests – serum PTH, spot urine phosphorus, spot urine 
creatinine, vitamin D 1-25, vitamin D 25-OH and FGF23 (1-2ml of plasma to be 
sent to Michael T. Collins, M.D., Chief, Skeletal Clinical Studies Unit, CSDB, 
NIDCR) 
j.    ECG 
k. Imaging studies: CT/MRI/Ultrasound evaluation of known/suspected disease 
sites (both renal and non-renal VHL associated lesions) 
l.    Ophthalmologic evaluation in patients with baseline retinal angiomas 
m.  Serum and Urine catecholamines in patients with baseline elevations  
 
3.5.2.3 Weekly Monitoring 
n. 12 lead ECG for the first two cycles (within 4-8 hours after dose) 
o. Chem 20 for the first two cycles 
 
3.5.2.4 Daily Monitoring 
Blood Pressure- Patient will be asked to measure and record his blood pressure at least once a 
day and will be provided with a BP monitor. Patients will be instructed to record BP readings on 
a BP monitoring diary which will be provided and will be reviewed by the research nurse/PI/AI 
at each clinic visit. In addition, patients will call the UOB research team for readings above 
150/100mm Hg and may be instructed to have elevated readings confirmed by a local health care 
provider. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
32 
 
3.6 
STUDY CALENDAR 
 
Cycle 
Screening 
 
         1 
 
 
 
2 
 
3 
4 
Daily 
Every 
Cycle  
Every 3 
cycles 
(Cycle 4 
onwards) 
Disease 
Progression/ 
Withdrawal 
from study 
Day (D) of Cycle 
(+/- 3 days) 
 
1 
8 
15 
22 
1 
8 
15 
22 
1 
1 
 
 
 
 
Weeks 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
 
 
 
 
Visit 
1 
2 
 
3 
 
4 
 
 
 
5 
6 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History & Physical 
examination 
Xa 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
ECHO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs/ 
weight 
Xa 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
BP Monitoring 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
12-lead ECG 
Xb 
Xc 
Xd 
Xd 
Xd 
X
d 
X
d 
Xd 
Xd 
Xd 
Xd 
 
Xd 
 
X 
 (Chem 20)/ 
 (CBC) 
Xa 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Chem 20 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
 
 
Thyroid and 
parathyroid  
function  tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urinalysis 
Xa 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
Pregnancy test 
Xa 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
ECOG performance 
status 
Xa 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
X 
RECIST 
Assessment 
Xb 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Dispense ZD6474 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
X 
 
 
Sample for 
Biomarkers 
Xb 
 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Tolerability/ 
AE reporting 
 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
Concurrent 
treatment 
Xb 
X 
 
X 
 
X 
 
 
 
X 
X 
 
X 
 
X 
a Should be performed within 7 days prior to enrolment on study, pregnancy test performed only in women of childbearing potential 
b Should be performed within 4 weeks prior to enrolment on study 
c A 12-lead ECG should be obtained on day 1, cycle 1 before the first dose of ZD6474    and repeated 4-8 hours after the first dose 
d Should be performed 4-8 hours after ZD6474 dose 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
33 
 
3.7 
CONCURRENT THERAPIES 
Coadministration of ZD6474 and drugs with potent CYP3A4 inducer effects are not allowed. 
Agents with potent inhibitory effects on CYP3A4 should be avoided where possible.  (Please see 
Appendix D) Other agents with some modulation of and/or metabolization through CYP3A4 can 
be used with caution at the discretion of the Principal Investigator ZD6474 should also not be 
administered in patients receiving drugs known to prolong QT interval or induce torsades de 
point. (Please see Appendix C). No concurrent systemic anti-neoplastic therapy for VHL-
associated tumors will be allowed. 
 
3.8 
SURGICAL GUIDELINES 
Major elective surgical procedures should not be scheduled during protocol treatment or within 4 
weeks of the last dose of drug. Patients undergoing unexpected major surgical procedures should 
have ZD6474 withheld. Treatment may be resumed at a later date at the discretion of the PI, no 
earlier than 4 weeks post-operatively, with adequately healed incisions.  
 
3.9 
OFF STUDY CRITERIA/OFF TREATMENT CRITERIA 
 In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
• Disease progression per RECIST criteria of targeted renal lesions  
• Disease progression of non-renal lesions requiring surgical intervention or systemic anti-
neoplastic therapy. Vandetanib may be restarted in patients undergoing resection of non-
renal VHL lesions once the surgical incisions have adequately healed, if in the opinion of 
the PI, this is likely to offer clinical benefit (e.g. patients demonstrating an ongoing 
response in their renal tumors while on vandetanib).  
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s) that necessitates discontinuation of ZD6474, including 
most grade 4 and recurrent grade 3 toxicities (CTCAE v3) as outlined in section 3.3 as 
well as any other adverse event that renders further treatment unsafe in the opinion of the 
investigator  
• Patient decides to withdraw from the study, or 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
In the event of a complete radiologic response, treatment will continue for 2 cycles beyond CR. 
Patients may be retreated at the discretion of the PI in the event of disease recurrence. 
3.10 POST-TREATMENT FOLLOW-UP 
Patients with unresolved toxicities (to ≤CTCAE 3.0 grade 1) may be followed to enable 
monitoring and/or management of these toxicities. Patients may be followed-up by telephone or 
other means of communication periodically to determine disease status. 
 
4 
SUPPORTIVE CARE 
Supportive care will be provided in accordance with good medical practice 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
34 
 
5 
DATA COLLECTION AND EVALUATION 
5.1 
DATA COLLECTION 
Data will be prospectively collected and entered in a designated database (C3D). All 
radiographic images will be stored in the Dept. of Radiology, Clinical Center, NIH and will be 
reviewed by a medically responsible investigator and/or a clinical center radiologist. 
 
For the purposes of this study, patients should be reevaluated for response every 12 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 4 weeks following initial 
documentation of objective response. 
 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
 
5.2 
RESPONSE EVALUATION 
5.2.1 Definitions 
Response and progression of renal tumors will be evaluated in this study using the new 
international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee [JNCI 92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Note:  Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy. 
5.2.1.1 Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional techniques (CT, MRI, 
x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters).  
 
5.2.1.2  Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all non-measurable. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
35 
 
5.2.1.3 Target lesions 
All measurable RCC lesions up to a maximum of five lesions per kidney and a total of ten 
lesions should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and their 
suitability for accurate repeated measurements (either by imaging techniques or clinically).  A 
sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as reference by which to characterize the 
objective tumor response. 
 
5.2.1.4 Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline.  Non-target lesions include measurable lesions that exceed the maximum 
numbers per organ or total of all involved organs as well as non-measurable lesions.  
Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. If the lesions are too numerous to list, not all lesions may be listed 
at the discretion of the investigator and/or radiologist. 
 
5.2.2 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. For each restaging study, lesions 
will be recorded in the same order as with the baseline study. 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess the 
antitumor effect of a treatment. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI.  These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and 
neck tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US).  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
36 
 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  
US might also be useful to confirm the complete disappearance of superficial lesions usually 
assessed by clinical examination. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation 
has not yet been fully and widely validated.  Their uses in this specific context require 
sophisticated equipment and a high level of expertise that may only be available in some centers.  
Therefore, the utilization of such techniques for objective tumor response should be restricted to 
validation purposes in reference centers. However, such techniques may be useful to confirm 
complete pathological response when biopsies are obtained. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific additional criteria for standardized usage of prostate-
specific antigen (PSA) and CA-125 response in support of clinical trials are being developed. 
 
Cytology, Histology.  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
5.2.3 Response Criteria 
5.2.3.1 Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking 
as reference the baseline sum LD 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest 
sum LD recorded since the treatment started or 
the appearance of one or more new lesions 
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for PD, taking 
as reference the smallest sum LD since the 
treatment started 
 
5.2.3.2 Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
 
Incomplete Response/ 
Stable Disease (SD):  
Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
37 
 
the normal limits 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target 
lesions 
 
Although a clear progression of “non-target” lesions only is exceptional, in such circumstances 
the opinion of the treating physician should prevail, and the progression status should be 
confirmed at a later time by the review panel (or study chair). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
5.2.3.3 Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
 
Overall Response 
 
CR 
 
CR 
 
No 
 
CR 
 
CR 
 
Incomplete 
response/SD 
 
No 
 
PR 
 
PR 
 
Non-PD 
 
No 
 
PR 
 
SD 
 
Non-PD 
 
No 
 
SD 
 
PD 
 
Any 
 
Yes or No 
 
PD 
 
Any 
 
PD 
 
Yes or No 
 
PD 
 
Any 
 
Any 
 
Yes 
 
PD 
 
Note: 
 
• Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having “symptomatic deterioration.”  Every effort should be made to 
document the objective progression, even after discontinuation of treatment. 
 
• In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
38 
 
5.2.4 Confirmatory Measurement/Duration of Response 
5.2.4.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed ≥ 4 weeks after the criteria for response 
are first met.  In the case of SD, follow-up measurements must have met the SD criteria 
at least once after study entry at a minimum interval of 8 weeks 
 
5.2.4.2 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that recurrent disease is objectively documented. 
 
5.2.4.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started.  
 
5.2.5 Evaluation of non-renal tumors associated with VHL 
Evaluation of the effect of ZD6474 on non-renal tumors associated with VHL disease is one of 
the secondary end-points of this study. Since there is significant interpatient variability in the 
location and number of visceral and non-visceral tumors, each tumor type will be assessed 
individually. In each individual patient, the presence of one or more of the following tumors at 
baseline will be documented and response following treatment with ZD6474 will be assessed: 
 
1) Pancreatic tumors/cysts 
2) CNS Hemangioblastomas 
3) Pheochromocytomas 
 
5.2.5.1 Identification and measurement of lesions to be followed, and response criteria will 
follow the scheme outlined in Sections 5.2.1 to 5.2.4 
 
5.2.5.2 Evaluation of retinal angiomas will include the following:  
a) Measurement of visual acuity 
b) Size-Largest unidimensional measurements will be recorded where 
appropriate 
c) Visual field evaluation 
d) Fluorescein leakage 
Since standard tumor response criteria such as RECIST cannot be applied to ocular 
lesions, changes in the above parameters will be recorded descriptively. 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
39 
 
5.2.5.3 Patients with progressive disease in non-renal lesions which require medical or surgical 
intervention shall be taken off study for progressive disease.  Patients with progressive 
disease in non-renal lesions not requiring intervention but stable disease or responding 
disease in renal lesions will be continued on ZD6474 to the discretion of the PI or Study 
Chair. 
5.3 
TOXICITY CRITERIA 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised 
NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A 
copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov) 
 
6 
STATISTICAL SECTION 
 
This is a phase II study to establish whether treatment of ZD6474 in patients with von Hippel 
Lindau disease and renal tumors results in an adequate fraction of clinical responses (partial 
response plus complete response) to warrant further development. The study will be conducted 
with a Simon two-stage optimal design (Simon R. Controlled Clinical Trials 10:1-10;1989) 
which allows for an early look for futility. For the purposes of phase II evaluation, clinical 
response will be defined as either a partial or complete response occurring at any time after 
initiation of therapy. All responses must be confirmed ≥ 4 weeks after the initial response is 
documented.  Twelve patients will be accrued into the first stage. If 1 or more of the 12 patients 
respond, accrual will proceed to the second stage of the design. Twenty-five additional patients 
will be accrued in the second stage for a total accrual of 37 patients. If 4 or more of 37 respond, 
ZD6474 will be considered worthy of further investigation in this population. If fewer than 4 
patients of 37 respond, the agent will be considered to have insufficient activity for further 
investigation.  If after the first 12 patients have been accrued to the study, no patient has had a 
confirmed response, further accrual will be temporarily suspended for up to a year or until at 
least one response is seen; if no responses are seen within one year of accrual of the twelfth 
patient, no further patients will be accrued and the study will not proceed to the second stage.  
 
6.1 
TWO-STAGE DESIGN 
The optimal two-stage design is based on the following design parameters. The fraction of 
clinical responses is 5% if the agent is ineffective (P0=0.05), while a fraction of clinical 
responses of 20% (P1=0.2) will be considered worthy of further testing.  The probability of 
falsely concluding that the agent is effective when it is truly ineffective is 0.1 (alpha) and the 
probability of falsely concluding that the agent is ineffective when it is truly effective is 0.1 
(beta).  Under this design, the probability of stopping accrual early if the proportion of responses 
is 5% is 54%. 
 
6.2 
RESPONSE FREQUENCY 
The response frequency for non-renal tumors associated with VHL will be estimated as a 
secondary objective. Other secondary objectives (Section 1.1) include examining the effect of 
ZD6474 on, (i) plasma biomarkers of angiogenesis such as VEGF, (ii),endothelial progenitor 
cells and circulating endothelial cells, (iii) time to progression (defined as the time from the start 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
40 
 
of treatment to progression as defined by RECIST criteria, with death being treated as a censored 
event), and (iv) progression free survival (defined as time from initiation of treatment to either 
progression as defined by RECIST criteria, section 5.2.3.3, or death). The follow-up times for 
biomarker endpoints are given in Sections 3.4 and 3.5. Analyses will focus on comparing 
changes in these biomarkers on treatment from the pre-study measurement.  Longitudinal 
changes in continuous biomarkers (eg. plasma VEGF) or imaging outcomes will be analyzed 
using paired Wilcoxon-ranked sum tests (which compares measurements at a single post-
treatment time point with measurements at the pre-treatment time point) as well as with linear 
mixed models (which incorporates all follow-up times when evaluating change).  Evaluation of 
time to progression and progression free survival will be based on restaging studies performed 
approximately every 12 weeks and will be summarized using Kaplan-Meier curves. Available 
pre-treatment data on tumor size and growth rates will be used to determine if parameters such as 
TTP/stability are affected by treatment both within individual patients and in the entire treatment 
group. 
 
6.3 
ACCRUAL CEILING 
The accrual ceiling for this study is 37 patients. With an expected accrual of 10-12 patients per 
year, we expect to complete the accrual within 3-4 years. 
 
 
7 
HUMAN SUBJECTS PROTECTION 
7.1 
RATIONALE FOR SUBJECT SELECTION 
7.1.1  Research subject selection  
 Patients of all races and ethnic origins will be eligible. 
 
7.1.2 Recruitment   
This study will be recruited through internal referral, our physician referral base, and through 
Cancer Hotline information.  
  
7.2 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS  
7.2.1 Potential benefits   
The potential benefit to a patient who enters study is a reduction in the bulk of his/her tumor, 
which may or may not have a favorable impact on symptoms, risk of metastasis and/or survival. 
 
7.2.2 Potential risks  
Potential risks include the possible occurrence of any of a range of side effects that are listed in 
the pharmaceutical section and the consent document.  The procedure for protecting against or 
minimizing risks will be to medically evaluate patients on a regular basis as described in sections 
3 and 8. 
 
 
The agent used in this trial is investigational. Experience with this agent to date suggests that this 
agent is associated with an acceptable toxicity profile. However, VHL patients may be at risk for 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
41 
 
previously undefined or inadequately characterized complications from this agent owing to their 
unique clinical circumstances (e.g. potential risk of bleeding from cerebellar or spinal 
hemangioblastomas, unmasking or exacerbation of hypertension in patients with asymptomatic 
or occult pheochromocytomas etc.); these issues have been addressed in the consent document 
and in the appropriate sections of this protocols. The risk of delaying ‘standard of care’ therapy 
(resection of renal tumors ≥3cm) in favor of an experimental therapy is considered to be 
minimal. The UOB has extensive experience with the management of VHL-associated renal 
tumors over the past 17 years.  These tumors are slow growing tumors and often there is a 3-4 
month time period between when surgery is recommended and is carried out.  All patients 
enrolled on trial will be evaluated for a response of renal lesions following three cycles of 
therapy.  
 
7.2.3 Alternative treatments  
Patients will be apprised of other therapeutic options, both experimental and those of standard 
care (i.e., observation or surgical intervention). 
 
7.3 
RISK/BENEFIT RELATIONSHIP 
VHL patients with renal cell carcinoma or other tumors are at risk for morbidity and mortality 
from complications of local tumor growth and/or metastasis. Standard therapy for these patients 
is restricted to surgical excision, sometimes performed repeatedly. Patients enrolled on this trial 
may benefit from tumor regression which may delay or obviate the need for surgical 
intervention. Although the agent used in this trial is experimental, it has been administered safely 
in prior phase I and phase II trials and the majority of the side effects have been mild to 
moderate.  The mechanism of action of the drug suggests that the drug could potentially render 
benefit in VHL patients with clear cell renal cancer. 
 
7.4 
CONSENT AND ASSENT PROCESSES AND DOCUMENTS  
A medically responsible associate investigator or principal investigator on the trial will inform 
patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this 
trial.  The patient will be provided an IRB-approved consent for review and signature and his/her 
questions will be answered.  After a decision is made to enroll into the study, a signature will be 
obtained from the patient at a subsequent visit.  A copy of the signed informed consent will be 
placed in the patient's medical record and the original held in the Protocol Office. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 
7.5 
PATIENT RECORDS AND QUALITY ASSURANCE  
Complete records must be maintained on each patient treated on the protocol.  These records will 
include primary documentation to confirm that: 
• The patient met all eligibility criteria 
• Signed informed consent was obtained prior to treatment 
• Treatment was given according to protocol. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
42 
 
• Toxicity was assessed according to protocol. 
• Response was assessed according to protocol. 
 
 
8 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
8.1 
DEFINITIONS 
8.1.1 Adverse Events 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the 
course of the clinical trial associated with the use of a drug in humans, whether or not the event 
is considered related to the treatment or clinically significant. For this study, AEs will include 
events reported by the patient, as well as clinically significant abnormal findings on physical 
examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an 
AE.  All AEs must be recorded on the AE case report form. 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution. AEs should be reported up to 30 days 
following the last dose of study drug.   
 
The development of a new cancer or tumor that is not VHL related should be regarded as an AE.  
New cancers are those that are not the primary reason for administration of study treatment and 
have been identified after inclusion of the patient into the clinical study. 
 
8.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
8.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
8.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
43 
 
8.1.5 Serious Adverse Event 
 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse drug experience 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
8.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
 
8.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
 
8.1.8 Protocol Deviation (NIH Definition) 
Any change, divergence, or departure from the IRB-approved research protocol.   
 
8.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
 
8.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
•  Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
44 
 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.1.11 Relatedness of Adverse Event to an Intervention 
The best estimate of the PI at the time of reporting of the causal relationship between an 
experimental intervention and an adverse event; the degree of certainty about causality is graded 
as follows: 
 
Unrelated:  
Adverse event is clearly due to extraneous causes (e.g., underlying disease, environment) 
Unlikely (must have 2):  
Adverse event:  
(1) does not have temporal relationship to intervention,  
(2) could readily have been produced by the subject’s clinical state,  
(3) could have been due to environmental or other interventions,  
(4) does not follow known pattern of response to intervention,  
(5) does not reappear or worsen with reintroduction of intervention 
Possible (must have 2):  
Adverse event:  
(1) has a reasonable temporal relationship to intervention,  
(2) could not readily have been produced by the subject’s clinical state,  
(3) could not readily have been due to environmental or other interventions,  
(4) follows a known pattern of response to intervention 
Probable (must have 3):  
Adverse event:  
(1) has a reasonable temporal relationship to intervention,  
(2) could not readily have been produced by the subject’s clinical state or have been due to 
environmental or other interventions,  
(3) follows a known pattern of response to intervention,  
(4) disappears or decreases with reduction in dose or cessation of intervention 
Definite (must have all 4):  
Adverse event:  
(1) has a reasonable temporal relationship to intervention,  
(2) could not readily have been produced by the subject’s clinical state or have been due to 
environmental or other interventions,  
(3) follows a known pattern of response to intervention,  
(4) disappears or decreases with reduction in dose or cessation of intervention and recurs with re-
exposure 
 
8.1.12 Pregnancy 
Pregnancy in women of childbearing potential should be excluded before randomization.  Should 
a pregnancy occur, it must be reported in accordance with the procedures described in this 
section.  Pregnancy in itself is not regarded as an AE unless there is a suspicion that an 
investigational product may have interfered with the effectiveness of a contraceptive medication. 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
45 
 
8.2 
NCI-IRB AND NCI CLINICAL DIRECTOR (CD) REPORTING 
8.2.1 NCI-IRB and NCI CD Expedited Reporting of Adverse Events, Unanticipated 
Problems, and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI CD: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
 
8.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 
 
The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• 
All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• 
All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
• 
All Grade 5 events regardless of attribution;  
• 
All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
 
8.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
 
8.3 
FDA REPORTING CRITERIA 
8.3.1 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days of initial receipt of the information 
using the MedWatch Form 3500a.  
 
The Sponsor is also responsible for reporting any: 
• 
suspected adverse reaction that is both serious and unexpected  
• 
any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed 
to the drug 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
46 
 
• 
clinically important increase in the rate of a serious suspected adverse reaction over that 
listed in the protocol or investigator brochure  
to the FDA and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting using the MedWatch Form 3500a. If FDA requests any 
additional data or information, the sponsor must submit it to the FDA as soon as possible, but no 
later than 15 calendars days after receiving the request.  
 
8.3.2 FDA Annual Reports (Refer to 21 CFR 312.33) 
The study Sponsor will submit a brief report annually of the progress of the trial within 60 days 
of the anniversary date that the IND went into effect as indicated in 21CFR 312.33, and any 
associated FDA correspondences regarding the IND annual report.  
 
8.3.3 Astra-Zeneca Requirements for Reporting AE 
Investigators and other site personnel must inform the FDA, via a MedWatch form, of any 
serious or unexpected adverse event that occurs in accordance with the reporting obligations of 
21 CFR 312.32, and will concurrently forward all such reports to Astra Zeneca.  A copy of the 
MedWatch report must be faxed to AstraZeneca at the time the event is reported to the FDA.  It 
is the responsibility of the investigator to compile all necessary information and ensure that the 
FDA receives a report according to the FDA reporting requirement timelines and to ensure that 
these reports are also submitted to AstraZeneca at the same time. 
 
A cover page should accompany the MedWatch form indicating the following: 
• ZD6474 Investigator Sponsored Study (ISS) 
• The investigator IND number assigned by the FDA 
• The investigator’s name and address 
• The trial name and AstraZeneca Reference number 
 
Send by way of fax to:  
 
(302) 886-1528,  
 
Attention ZACTIMA ISS Safety Representative 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to AstraZeneca and the FDA. 
 
Serious adverse events that do not require expedited reporting to the FDA need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.  This 
information should be reported on a monthly basis and under no circumstance less frequently 
than quarterly. 
 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented.  The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
47 
 
8.4 
 DATA AND SAFETY MONITOIRNG PLAN  
8.4.1 Principal Investigator/Research Team 
The clinical research team will meet on a regular basis when patients are being actively treated 
on the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
 
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS and if applicable to the 
Sponsor.  
 
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
 
8.4.2 Sponsor Monitoring Plan 
This trial will be monitored by personnel employed by Harris Technical Services on contract to 
the NCI, NIH. Monitors are qualified by training and experience to monitor the progress of 
clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial 
conduct. 
 
At least 25% of enrolled patients’ will be randomly selected and monitored at least biannually, 
based on accrual rate. The patients selected will have 100% source document verification done. 
Additional monitoring activities will include: adherence to protocol specified study eligibility, 
treatment plans, data collection for safety and efficacy, reporting and time frames of adverse 
events to the NCI IRB and FDA, and informed consent requirements. Written reports will be 
generated in response to the monitoring activities and submitted to the Principal investigator and 
Clinical Director or Deputy Clinical Director, CCR, NCI. 
 
9 
COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT 
CRADA)/CLINICAL TRIALS AGREEMENT (CTA) 
 
The agent (ZD6474), supplied by Astra-Zeneca, Inc, used in this protocol is provided to the NCI 
under a Collaborative Research And Development Agreement (CRADA) between tAstra-
Zeneca, Inc) [hereinafter referred to as Collaborator(s)] and W. Marston Linehan, M.D., Chief, 
UOB, CCR, NCI. Therefore, the following obligations/guidelines, in addition to the provisions in 
the Intellectual Property Option to Collaborator@ contained within the terms of award, apply to 
the use of Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be 
maintained as such by the investigators.  The protocol documents for studies utilizing 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
48 
 
investigational agents contain confidential information and should not be shared or distributed 
without the permission of the NCI.  If a copy of this protocol is requested by a patient 
participating on the study or patient’s family member, the individual should sign a confidentiality 
agreement.  A suitable model agreement can be downloaded from http://ctep.cancer.gov. 
 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other investigational Agent(s), each the subject of different collaborative agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”.): 
 
a. NCI must provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator 
to develop, obtain regulatory approval, or commercialize its own investigational agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing prior to the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
investigational agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a collaborative agreement 
will be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate.  All 
data made available will comply with HIPAA regulations. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a DMC 
for this clinical trial.  
 
 
10 PHARMACEUTICAL INFORMATION 
 
10.1 SOURCE 
ZD6474 (Vandetanib)   
 
Chemical Name and Identification N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-
piperidinyl)methoxy]-4-quinazolinamine 
 
Molecular Formula 
C22H24BrFN4O2 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
49 
 
Molecular Weight 
475.36 
 
10.2 SOLUBILITY   
ZD6474 exhibits pH dependent solubility and is relatively insoluble in water with a value of 
0.025mg/ml at 25 C 
 
10.3 MODE OF ACTION 
 
Tyrosine kinase inhibitor with specific activity against KDR (IC50=40nM) and EGFR 
(IC50=500nM) 
 
10.4 FORMULATION AND PREPARATION 
 
The drug product consists of 3 ranges of white film-coated tablets packed in high density 
polyethylene (HDPE) bottles and an oral solution presented in Type 1 glass bottles. The first 
tablet range consisted of a series of tablets containing 25 mg, 100 mg and 200 mg of vandetanib 
drug substance (25 and 100 mg matched, 200 mg size differentiated) and were used in Phase I 
studies. The second range is a matched series containing 100 mg, 200 mg, 300 mg and 400 mg 
tablets. The third range is size differentiated and consists of 50 mg, 100 mg, 200 mg and 300 mg 
tablets. The oral solution is presented in 25ml bottles containing 15 ml of vandetanib (10mg/ml). 
 
The bottles are sealed with ethylene tetrafluoroethylene (ETFE) copolymer coated chlorobutyl 
stoppers secured with screw on caps. Each bottle is intended for single use only. 
 
10.5 COMPOSITION 
The initial 25 mg, 100 mg and 200 mg tablets contain vandetanib, lactose, povidone, 
croscarmellose sodium, sodium lauryl sulphate and magnesium stearate with a film coating 
containing methylhydroxypropylcellulose, polyethylene glycol 300 and titanium dioxide. 
 
The matched second range of tablets (100, 200, 300 and 400 mg) contain vandetanib, calcium 
hydrogen phosphate, microcrystalline cellulose, sodium starch glycollate, povidone, sodium 
lauryl sulphate and magnesium stearate with a film coating containing 
methylhydroxypropylcellulose, polyethylene glycol 300 and titanium dioxide. A placebo to 
match the second range is presented, in which the drug substance is replaced by an appropriate 
amount of calcium hydrogen phosphate and microcrystalline cellulose. 
 
The non-matched third range of tablets (50, 100, 200 and 300 mg) was developed from the 
second range. The compositions are the same with the exception that the sodium starch 
glycollate is replaced with crospovidone and the sodium lauryl sulphate is removed. A placebo to 
match each of the tablets in the third range is presented, in which the drug substance is replaced 
by an appropriate amount of calcium hydrogen phosphate. 
 
The oral solution contains vandetanib, hydrochloric acid and purified water. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
50 
 
10.6 STABILITY AND STORAGE 
 
ZD6474 tablets must be stored at temperatures of up to 25C, and used before the expiry date 
stated on the label. Vandetanib tablets are packaged high density polyethylene (HDPE) bottles 
and oral solution presented in Type 1. Bottles are sealed with ethylene tetrafluoroethylene 
(ETFE) copolymer coated chlorobutyl stoppers secured with screw on caps. Each bottle is 
intended for single use only. 
 
10.7 DOSAGE AND ADMINISTRATION 
 
300mg/day administered orally. The drug should be taken with food and water to minimize GI 
effects. The tablets should not be taken with grapefruit juice. Tablets should not be crushed, 
chewed or otherwise divided and must be swallowed whole. Dose modifications will follow the 
scheme outlined in section 3.3. 
 
10.8 REPORTED ADVERSE EVENTS AND POTENTIAL RISKS  
The following adverse events have been reported in patients treated with ZD6474 in phase I and 
II trials: Rash (including serious complications of progression to desquamation, erythroderma, 
toxicoderma, toxic epidermal necrolysis, and erythema multiforme), pruritis, diarrhea, 
constipation, nausea and vomiting, dyspepsia, anorexia, dehydration, weight loss, colitis, 
intestinal ischemia, intestinal perforation, small bowel obstruction, stomatitis, ECG 
abnormalities (ST and T wave changes, QTc prolongation), hypertension, congestive heart 
failure, increased serum LDH, hypoalbuminemia, elevation of AST/ALT/GGT/alkaline 
phosphatase, electrolyte abnormalities (hypokalemia, hypomagnesemia, hypphosphatemia), 
elevation of serum creatinine hypertriglyceridemia,, headache, dizziness, anxiety, depression, 
insomnia, confusion, tinnitus, hypoacusis, rhinitis, nasopharyngitis, infections, leukopenia, 
anemia, thrombocytopenia, bleeding (gingival bleeding, hemoptysis and intracranial 
hemorrhage), deep venous thromboses and pulmonary embolism, arterial ischemic events 
(myocardial infection, stroke, peripheral arterial ischemia) fatigue, asthenia, arthralgia, 
abdominal pain, back pain,  fever , cough, dyspnea, interstitial lung disease, peripheral edema, 
hematuria, proteinuria, dysuria 
 
10.9 POTENTIAL DRUG INTERACTIONS 
 
 
ZD6474 should not be administered in patients receiving drugs with known significant CYP3A4 
inducer effects or with drugs known to prolong QT interval or torsades de point  
 
10.10 AVAILABILITY 
ZD6474 is an investigational agent supplied to investigators by Astra-Zeneca, Inc under a 
CRADA. 
 
10.11 AGENT ORDERING 
ZD6474 may be requested from Astra-Zeneca, Inc. by the Principal Investigator (or their 
authorized designees).   


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
51 
 
10.12 AGENT ACCOUNTABILITY 
The Investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of drug received from Astra-Zeneca, Inc. using the NCI 
Drug Accountability Record Form.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
52 
 
11 REFERENCES 
 
1 
 Linehan WM, Zbar B, Klausner R. Renal carcinoma. In: Scriver CR, Beaudet AL, Sly 
WS, Valle D, eds. The metabolic and molecular basis of inherited disease. 8th edn. New York: 
McGraw-Hill, 2001:907–29. 
2  
Linehan WM, Zbar B, Klausner R. Renal Carcinoma. In:Vogelstein B, Kinzler K, eds. 
The genetic basis of human cancer. 2 edn. New York: McGraw-Hill, 2002. 
3 
 Linehan WM, Lerman MI, Zbar B. Identification of the von Hippel-Lindau (VHL) gene. 
Its role in renal cancer. JAMA 1995; 273: 564–70. 
4  
Clifford SC, Maher ER. Von Hippel-Lindau disease: clinical and molecular perspectives. 
Adv Cancer Res 2001; 82: 85–105. 
5  
Maher ER, Kaelin WG Jr. von Hippel-Lindau disease. Medicine (Baltimore) 1997; 76: 
381–91. 
6  
Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 
2002; 2: 673–82. 
7  
Maddock IR, Moran A, Maher ER, et al. A genetic register for von Hippel-Lindau 
disease. J Med Genet 1996; 33: 120–27. 
8  
Richard S, Campello C, Taillandier L, Parker F, Resche F. Haemangioblastoma of the 
central nervous system in von Hippel-Lindau disease. French VHL Study Group. J Intern Med 
1998; 243:547–53. 
9  
Lonser RR, Weil RJ, Wanebo JE, DeVroom HL, Oldfield EH. Surgical management of 
spinal cord hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 2003; 
98: 106–116. 
10  
Wanebo JE, Lonser RR, Glenn GM, Oldfield EH. The natural history of central nervous 
system hemangioblastomas in patients with von Hippel-Lindau disease. J Neurosurg 2003; 98: 
82–94. 
11 
 Dollfus H, Massin P, Taupin P, et al. Retinal hemangioblastoma in von Hippel-Lindau 
disease: a clinical and molecular study. Invest Ophthalmol Vis Sci 2002; 43: 3067–74. 
12  
Webster AR, Maher ER, Moore AT. Clinical characteristics of ocular angiomatosis in 
von Hippel-Lindau disease and correlation with germline mutation. Arch Ophthalmol 1999; 117: 
371–78. 
13  
Hammel PR, Vilgrain V, Terris B, et al. Pancreatic involvement in von Hippel-Lindau 
disease. The Groupe Francophone d’Etude de la Maladie de von Hippel-Lindau. 
Gastroenterology 2000; 119: 1087–95. hemangioblastoma: case report. Neurosurgery 1994; 34: 
353–55. 
14  
Lubensky IA, Pack S, Ault D, et al. Multiple neuroendocrine tumours of the pancreas in 
von Hippel-Lindau disease patients: histopathological and molecular genetic analysis. Am J 
Pathol 1998; 153: 223–31. 
15   
Neumann HP, Dinkel E, Brambs H, et al. Pancreatic lesions in the von Hippel-Lindau 
syndrome. Gastroenterology 1991; 101:465–71. 
16 
 Hough DM, Stephens DH, Johnson CD, Binkovitz LA. Pancreatic lesions in von Hippel-
Lindau disease: prevalence, clinical significance, and CT findings. AJR Am J Roentgenol 1994; 
162:1091–94. 
17  
Libutti SK, Choyke PL, Alexander HR, et al. Clinical and genetic analysis of patients 
with pancreatic neuroendocrine tumours associated with von Hippel-Lindau disease. Surgery 
2000; 128:1022–27. 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
53 
 
18  
Walther MM, Reiter R, Keiser HR, et al. Clinical and genetic characterization of 
pheochromocytoma in von Hippel-Lindau families: comparison with sporadic 
pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 1999; 162: 
659–64. 
19  
Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumour 
suppressor gene. Science 1993; 260: 1317–1320. 
20  
Knudson AGJ. Genetics of human cancer. Ann Rev Genet 1986; 20:231–51. 
21 
 Lee S, Chen DY, Humphrey JS, Gnarra JR, Linehan WM, Klausner RD. 
Nuclear/cytoplasmic localization of the von Hippel-Lindau tumour suppressor gene product is 
determined by cell density. Proc Natl Acad Sci USA 1996; 93: 1770–75. 
22  
Ohh M, Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: new 
perspectives. Mol Med Today 1999; 5: 257–63. 
23  
Pause A, Lee S, Worrell RA, et al. The von Hippel-Lindau tumoursuppressor gene 
product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. 
Proc Natl Acad Sci USA 1997;94: 2156–61. 
24  
Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL 
targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399: 271–75. 
25  
Ferrara N. Role of vascular endothelial growth factor in regulation of physiological 
angiogenesis. Am J Physiol Cell Physiol. 280(6):C1358-66 (2001). 
26  
Walther MM, Lubensky IA, Venzon D, Zbar B, Linehan WM. Prevalence of microscopic 
lesions in grossly normal renal parenchyma from patients with von Hippel-Lindau disease, 
sporadic renal cell carcinoma and no renal disease: clinical implications. J Urol 1995; 154: 
2010–14. 
27  
Walther MM, Choyke PL, Glenn G, et al. Renal cancer in families with hereditary renal 
cancer: prospective analysis of a tumour size threshold for renal parenchymal sparing surgery. J 
Urol 1999; 161: 1475–79. 
28  
Pavlovich CP, Walther MM, Choyke PL, et al. Percutaneous radio frequency ablation of 
small renal tumours: initial results. J Urol 2002; 167: 10–15. 
29  
Pavlovich CP, Linehan WM, Walther MM. Partial adrenalectomy in patients with 
multiple adrenal tumours. Curr Urol Rep 2001; 2:19–23. 
30 
 Baghai M, Thompson GB, Young WF Jr, Grant CS, Michels VV, van Heerden JA. 
Pheochromocytomas and paragangliomas in von Hippel-Lindau disease: a role for laparoscopic 
and cortical-sparing surgery. Arch Surg 2002; 137: 682–88. 
31  
Libutti SK, Choyke PL, Bartlett DL, et al. Pancreatic neuroendocrine tumours associated 
with von Hippel-Lindau disease: diagnostic and management recommendations. Surgery 1998; 
124: 1153–59. 
32  
Wedge SR, Ogilvie DJ, Dukes M et al. ZD6474 inhibits vascular endothelial growth 
factor signaling, angiogenesis, and tumor growth following oral administration.Cancer Res. 
4645-55 (2002). 
33  
Ciardiello F, Caputo R, Damiano V et al. Antitumor effects of ZD6474, a small molecule 
vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity 
against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res. 1546-56 (2003). 
34 
ZD6474 Investigator’s brochure. US Drug Development, Astra-Zeneca Pharmaceuticals. 
Wilmington, DE. 
35 
Esser N, Marmé D, Drevs J, Konerding MA, Wolloscheck T, Wedge SR, et al. The 
VEGF receptor tyrosine kinase inhibitor, vandetanib, inhibits angiogenesis and affects  


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
54 
 
microvascular architecture within an orthotopically implanted renal cell carcinoma. Clin Cancer 
Res 2003;9(Pt 2):6150s 
36 
Minami H, Ebi H, Tahara M, et al. A phase I study of oral VEGF receptor tyrosine kinase 
inhibitor ZD6474, in Japanese patients with solid tumors. Proceedings of the American Society 
of Clinical Oncology, Abstract #778 (2003). 
37 
R. B. Natale, D. Bodkin, R. Govindan, B. Sleckman, N. Rizvi, A. Capo, P. Germonpré, P. 
Stockman, S. Kennedy, M. Ranson. JCO; 24, 18S (June 20 Supplement) Abstract 7000, (2006) 
38 
J. V. Heymach, B. E. Johnson, D. Prager, E. Csada, J. Roubec, M. Pešek, I. Špásová, J. 
Hou, S. Kennedy, R. S. Herbst. JCO; 24, 18S (June 20 Supplement), Abstract 7016 (2006) 
39 
K. Nakagawa, K. Kiura, T. Shinkai, K. Eguchi, Y. Ohe, N. Yamamoto, M. Tsuboi, S. 
Yokota, M. Fukuoka, H. Jiang.  JCO; 24, 18S (June 20 Supplement), Abstract 7067 (2006) 
S. Wells, Y. N. You, V. Lakhani, J. Hou, P. Langmuir, D. Headley, M. Skinner, M. Morse, W. 
Burch, M. Schlumberger. JCO; 24, 18S (June 20 Supplement), Abstract 5533 (2006)41
 
Bertolini, F, Shaked, Y, Mancuso, P, and Kerbel, R.S.  The multifaceted circulating 
endothelial cell in cancer: towards marker and target identification.  Nat. Rev. Cancer. 6:835-
845, 2006. 
42 
Chung, E. J., Lee, S., Sausville, E. A., Ryan, Q., Karp, J. E., Gojo, I., Telford, W. G.Lee, 
M.-J., Kong, H. S. and Trepel, J.B.  Histone deacetylase inhibitor pharmacodynamic analysis by 
multiparameter flow cytometry.  Ann. Clin. Lab. Sci. 35:397-406, 2005. 
 
43 
Chung, E. J., Lee, M.-J., Lee, S., Trepel, J. B.  Assays for pharmacodynamic analysis of 
histone deacetylase inhibitors.  Expert Opin. Drug Metab. Toxicol. 2:213-230, 2006. 
44 
Posadas, E. M., Gulley, J., Arlen, P. M., Trout, A., Parnes, H. L., Wright, J., Lee, M. J., 
Chung, E. J., Trepel, J. B., Sparreboom, A., Chen, C., Jones, E., Steinberg, S. M., Daniels, A., 
Figg, W. D., and Dahut, W. L.  A phase II study of perifosine in androgen independent prostate 
cancer.  Cancer Biol. Ther. 4:1133-1137, 2005. 
45 
Gojo, I, Jiemjit, A., Trepel, J. B., Sparreboom, A., Figg, W. D., Rollins, S., Tidwell, M. 
L., Greer, J., Chung, E. J., Lee, M.-J., Gore, S. D., Sausville, E. A., Zwiebel, J., and Karp, J. E.   
Phase I and pharmacological study of MS-275, a histone deacetylase inhibitor, in adults with 
refractory and relapsed acute leukemias. Blood 109:2781-2790, 2007. 
46 
Chung, E. J. and Trepel, J.B.  Pharmacodynamic assays using flow cytometry. E-094-
2004. Patent in National Phase of Foreign Filing in US, EU, Canada and Australia:Approved for 
National Phase filing, 7.21.06.   
47 
Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler 
S:  Number and migratory activity of circulating endothelial progenitors cells inversely correlate 
with risk factors for coronary heart disease. Circ Res 89:e1-e7, 2001. 
48 
Hill JM, Zalos G, Halcox JP, et al.  Circulating endothelial progenitor cells, vascular 
function, and cardiovascular risk. N Engl J Med. 2003;348: 593-600. 
 
 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
55 
 
12 APPENDICES 
12.1 APPENDIX A: ECOG PERFORMANCE STATUS 
Grade  
Scale 
 
0 
 
Fully active, able to carry on all pre-disease performance without restriction. 
 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
 
2 
 
Ambulatory and capable of all self care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
5 
 
Dead 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
56 
 
12.2 APPENDIX B: NEW YORK HEART ASSOCIATION (NYHA) CARDIAC CLASSIFICATION 
 
 
The NYHA classification system relates symptoms to everyday activities and the patient’s 
quality of life. 
 
Class 
Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  
Symptoms of cardiac insufficiency at rest.  If any physical activity is 
undertaken, discomfort is increased. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
57 
 
12.3 APPENDIX C:  MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL AND/OR INDUCE 
TORSADES DE POINTES (TDP) (UPDATED 19 AUGUST 2011) 
 
It has been recognized for a number of years that certain prescription medications can prolong 
the QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug induced 
LQTS.  The drugs that prolong the QT interval and/or have a risk of inducing Torsade de Pointes 
(TdP) are listed below.  We have divided these into two groups based on their known or 
perceived risk of causing TdP: 
Group 1. Drugs that are generally accepted by authorities to have a risk of causing Torsades de 
Pointes 
− 
Concomitant use of these drugs is not allowed during the study or within 2 weeks of 
study entry (at least four weeks for levomethadyl).  These drugs should also be 
avoided for up to 4 weeks following discontinuation of study treatment: 
Table 1 Group 1 Drugs 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
Amiodarone 
Anti-arrhythmic (heart 
rhythm) 
F>M, TdP Cases in 
Literature 
Arsenic trioxide 
Anti-cancer (leukaemia) 
TdP Cases in Literature 
Astermizole 
Antihistamine / Allergic 
rhinitis 
No Longer available in U.S. 
Bepridil 
Anti-anginal (heart pain) 
F>M 
Chlorpromazine 
Anti-psychotic/antiemetic 
(schizophrenia/nausea) 
TdP Cases in Literature 
Chloroquine 
Anti-malaria (malaria 
infection) 
 
Cisapride 
GI stimulant (stimulates GI 
motility) 
Open Prescription 
Restricted F>M 
Clarithromycin 
Antibiotic / bacterial 
infection 
 
Disopyramide 
Anti-arrhythmic (heart 
rhythm) 
F>M 
Dofetilide 
Anti-arrhythmic (heart 
rhythm) 
 
Domperidone 
Anti-nausea (nausea) 
 
Droperidol 
Sedative/hypnotic 
(anaesthesia adjunct) 
TdP Cases in Literature 
Erythromycin 
Antibiotic/GI stimulant 
(infection/GI motility) 
F>M 
Halofantrine 
Anti-malarial (malaria 
infection) 
F>M 
Haloperidol 
Anti-psychotic 
(schizophrenia, agitation) 
 
Ibutilide 
Anti-arrhythmic (heart 
rhythm) 
F>M 
Levomethadyl 
Opiate agonist (narcotic 
dependence) 
 
Mesoridazine 
Anti-psychotic 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
58 
 
Table 1 Group 1 Drugs 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
(schizophrenia) 
Methadone 
Opiate agonist (pain control/ 
narcotic dependence) 
F>M 
Moxifloxacin 
Antibiotic / bacterial 
infection 
 
Pentamidine 
Anti-infective (pneumocystis 
pneumonia) 
F>M 
Pimozide 
Anti-psychotic (Tourette's 
tics) 
F>M, TdP Cases in 
Literature 
Probucol 
Antilipemic / 
Hypercholesterolemia 
No longer available in U.S. 
 
 
 
Procainamide 
Anti-arrhythmic (heart 
rhythm) 
 
Quinidine 
Anti-arrhythmic (abnormal 
heart rhythm) 
F>M 
Sotalol 
Anti-arrhythmic (heart 
rhythm) 
F>M 
Sparfloxacin 
Antibiotic (bacterial 
infection) 
 
Terfenadine 
Antihistamine / Allergic 
rhinitis 
No longer available in U.S. 
Thioridazine8 
Anti-psychotic 
(schizophrenia) 
 
 
Group 2. Drugs that in some reports may be associated with Torsades de Pointes but at this time 
lack substantial evidence of causing Torsades de Pointes 
Concomitant use of these drugs is not allowed at study entry or within 2 weeks of study entry.  
These drugs will be allowed during the study, at the discretion of the Investigator, if considered 
absolutely necessary.  In such cases, the patient must be closely monitored, including regular 
checks of QTc and electrolytes 
 
Table 2 Group 2 Drugs 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Alfuzocin 
Alpha 1-blocker (Benign 
prostatic hyperplasia) 
 
Amantadine 
Dopaminergic/Anti-viral/Anti-
infective (Parkinson’s disease) 
 
Atazanavir 
Protease inhibitor / HIV 
 
Azithromycin 
Antibiotic (bacterial infection) 
 
Chloral hydrate 
Sedative (sedation/insomnia) 
 
Clozapine 
Anti-psychotic (schizophrenia) 
 
Dolastron 
Anti-nausea (nausea and 
vomiting) 
 
Dronedarone 
 
Anti-arrhythmic / Atrial 
Fibrillation 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
59 
 
Table 2 Group 2 Drugs 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Escitalopram 
Anti-depressant / Major 
depression/ Anxiety 
disorders 
 
Famotidine 
H2-receptor antagonist / 
Peptic ulcer/ GERD 
 
Felbamate 
Anti-convulsant (seizures) 
 
Flecainide 
Anti-arrhythmic (heart 
rhythm) 
Association not clear 
Foscarnet 
Antiviral (HIV infection) 
 
Fosphenytoin 
Anticonvulsant (seizures) 
 
Gatifloxacin 
Antibiotic (bacterial infection) 
 
Gemifloxacin 
Antibiotic (bacterial infection) 
 
Granisetron 
Anti-nausea (nausea and 
vomiting) 
 
Indapamide 
Diuretic (stimulates urine & 
salt loss) 
TdP Cases in Literature, QT 
in animals 
Isradipine 
Anti-hypertensive (high blood 
pressure) 
 
Lapatinib 
Anti-cancer / breast cancer, 
metastatic 
 
Levofloxacin 
Antibiotic (bacterial infection) 
Association not clear 
Lithium 
Anti-mania (bipolar disorder) 
 
Moexipril/HCTZ 
Anti-hypertensive (high blood 
pressure) 
 
Nicardipine 
Anti-hypertensive (high blood 
pressure) 
 
Nilotinib 
Anti-cancer / Leukemia 
 
Octreotide 
Endocrine 
(acromegaly/carcinoid 
diarrhoea) 
 
Ofloxacin 
 
 
Ondansetron 
Anti-emetic (nausea and 
vomiting) 
 
Oxytocin 
Oxytocic / Labor stimulation 
 
Paliperidone 
Antipsychotic, atypical / 
Schizophrenia 
 
Perflutren lipid 
microspheres 
Imaging contrast agent / 
Echocardiography 
 
Quetiapine 
Anti-psychotic (schizophrenia) 
 
Ranolazine 
Anti-anginal / chronic angina 
 
Risperidone 
Anti-psychotic (schizophrenia) 
 
Roxithromycin 
Antibiotic (bacterial infection) 
 
Sertindole 
Antipsychotic, atypical / 
Anxiety, Schizophrenia 
 
Sunitinib 
Anti-cancer / RCC, GIST 
 
Tacrolimus 
Immune suppressant 
TdP Cases in Literature 
Tamoxifen 
Anti-cancer (breast cancer) 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
60 
 
Table 2 Group 2 Drugs 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Telithromycin 
Antibiotic (bacterial infection) 
 
Tizanidine 
Muscle relaxant 
 
Vardenafil 
Phosphodiesterase inhibitor 
(vasodilator) 
 
Venlafaxine 
Antidepressant (depression) 
 
Voriconazole 
Anti-fungal (fungal infection) 
 
Ziprasidone 
Anti-psychotic (schizophrenia) 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
61 
 
12.4 APPENDIX D: LIST OF DRUGS INTERACTING WITH CYP3A4 
This list is only intended as a guide. The impact on the CYP3A4 system of each individual drug 
administered to patients on this trial should be independently verified 
 
List of Drugs with known interactions with CYP3A4 
 
SUBSTRATES 
 
INHIBITORS 
 
INDUCERS 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Generic Name 
Trade Name 
Acetaminophen 
Tylenol 
Clotrimazole 
Mycelex 
troches 
Dexamethasone 
Decadron 
Carbamazepine 
Tegretol 
Ketoconazole 
Nizoral 
Phenytoin 
Dilantin 
Quinidine 
Cardioquin 
Troleandomycin TAO 
Rifampin 
Rifadin, 
Rimactane 
Cyclosporin 
Neoral, 
Sandimmune 
Cyclosporine 
Neoral, 
Sandimmune 
Troleandomycin 
TAO 
Digitoxin 
Lanoxin 
Itraconazole 
Sporanox 
St. John’s Wort 
 
Steroids: e.g. 
Dexamethasone 
Hydrocortisone 
Prednisone 
 
Decadron 
Solu-Cortef 
Orasone 
Erythromycin 
Erythrocin 
 
 
Diazepam 
Valium 
Clarithromycin 
Biaxin 
 
 
Erythromycin 
Erythrocin 
Nefazodone 
Serzone 
 
 
Felodipine 
Plendil 
Grapefruit juice 
> 1 quart/day 
 
 
Fluoxetine 
Prozac 
HIV Protease 
Inhibitors:  e.g. 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
 
 
 
Crixivan 
Viracept 
Norvir 
Fortovase, 
Invirase 
 
 
Nifedipine 
Adalat, Procardia 
Grrapefriut 
Juice 
 
 
 
Saquinavir 
Fortovase, 
Invirase 
 
 
 
 
Fexofenadine 
Allegra 
 
 
 
 
Triazolam 
Halcion 
 
 
 
 
Verapamil 
Calan 
 
 
 
 
Warfarin 
Coumadin 
 
 
 
 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
62 
 
Expanded list of drugs interacting with CYP3A4 
Substrates 
Antipyrine 
Astemizole 
Atorvastatin 
Benzphetamine 
Bepridil 
Bexarotene 
Bromazepam 
Bromocriptine 
Budesonide 
Bupropion (minor) 
Buspirone 
Busulfan 
Caffeine 
Cannabinoids 
Carbamazepine 
Cevimeline 
Cerivastatin 
Chlorpromazine 
Cimetidine 
Cisapride 
Cita opram 
Clarithromycin 
Clindamycin 
Clomipramine 
Clonazepam 
Clozapine 
Cocaine 
Codeine (demethylation) 
Cortisol 
Cortisone 
Cyclobenzaprine 
(demethylation) 
Cyclophosphamide 
Cyclosporine 
Dapsone 
Dehydroepiandrostendione 
Delavirdine 
Desmethyldiazepam 
Dexamethasone 
Dextromethorphan (minor, 
 N-demethylation) 
Diazepam(minor;hydroxylation, 
 N-demethylation) 
Digitoxin 
Diltiazem 
Disopyramide 
Docetaxel 
Dolasetron 
Donepezil 
Doxorubicin 
Doxycycline 
Dronabinol 
Enalapril 
Erythromycin 
Estradiol 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemestene 
Dofetilide (minor) 
Felodipine 
Fentanyl 
Fexotenadine 
Finasteride 
Fluoxetine 
Flutamide 
Glyburide 
Granisetron 
Halofantrine 
Hydrocortisone 
Hydroxyarginine 
Ifosfamide 
Imipramine 
Indinavir 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
(minor) 
Letrozole 
Levobupivicaine 
Lidocaine 
Loratadine 
Losartan 
Lovastatin 
 
Methadone 
Mibefradil 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine (N-
demethylation) 
Montelukast  
Navelbine 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Niludipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Omeprazole 
(sulfonation) 
Ondansetron 
Oral contraceptives 
Orphenadrine 
Paclitaxel 
Pantoprazole 
Pimozide 
Pioglitazone 
Pravastatin 
Prednisone 
Progesterone 
Proguanil 
Propafenone 
Quercetin 
Quetiapine 
Quinidine 
Quinine 
Repaglinide 
Retinoic acid 
Rifampin 
Risperidone 
Ritonavir 
 
Salmeterol 
Saquinavir 
Sertindole 
Sertraline 
Sibutramine 
Sildenalfil citrate 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Temazepam 
Teniposide 
Terfenadine 
Testosterone 
Tetrahydrocannabinol 
Theophylline 
Tiagabine 
Tolterodine 
Toremifene 
Trazodone 
Tretinoin 
Triazolam 
Troglitazone 
Troleandomycin 
Venlafaxine (N-
demethylation) 
Verapamil 
Vinblastine Vincristine 
Warfarin (R-warfarin) 
Yohimbine 
Zaleplon 
(minor 
pathway) 
Zatoestron 
Zileuton 
Ziprasidone 
Zolpidem 
Zonisamide 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
63 
 
 
 
Inducers 
Carbamazepine 
Dexamethasone 
Ethosuximide 
Glucocorticoids 
Griseofulvin 
Nafcillin 
Nelfinavir 
Nevirapine 
Oxcarbazepine 
Phenobarbitol 
Phenylbutazone 
Phenytoin 
Primidone 
Progesterone 
Rifabutin 
Rifampin 
Rofecoxib (mild) 
St John’s wort 
Sulfadimidine 
Sulfinpyrazone 
Troglitazone 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inhibitors 
Amiodarone 
Anastrozole 
Azithromycin 
Cannabinoids 
Cimetidine 
Clarithromycin 
Clotrimazole 
Cyclosporine 
Danazol 
Delavirdine 
Dexamethasone 
Diethyldithiocarbamate 
Diltiazam 
Dirithromycin 
Disulfiram 
Entacapone (high 
dose) 
Erythromycin 
Ethinyl estradiol 
Fluconazole (weak) 
Fluoxetine 
Fluvoxamine 
Gestodene 
Grapefruit juice 
Indinavir 
Isoniazid 
Itraconazole 
Metronidazole 
Mibefradil 
Miconazole 
(moderate) 
Nefazodone 
Nelfinavir 
Nevirapine 
Norfloxacin 
Norfluoxetine 
Omeprazole (weak) 
Oxiconazole 
Paroxetine (weak) 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin and 
dalfopristin 
Ranitidine 
Ritonavir 
Saquinavir 
Sertindole 
Sertraline 
Troglitazone 
Troleandomycin 
Valproic acid (weak) 
Verapamil 
Zafirlukast 
Zileuton 


Version Date: 11-16-2016 
08-C-0020 Amendment H 
Abbreviated Title: Phase II of ZD6474 in VHL 
 
Confidential  
64 
 
12.5 APPENDIX E: DIAGNOSTIC CRITERIA FOR VON HIPPEL-LINDAU  
A diagnosis of VHL can be made under the Following Circumstances: 
 
A) Presence of a VHL germline mutation described in VHL families 
 
OR 
 
B) The following clinical circumstances 
 
i) With positive family history 
 
Presence of one or more diagnostic Lesion(s) 
 
CNS hemangioblastoma 
 
Renal Cell Carcinoma, multifocal 
 
Pheochromocytoma 
 
Retinal angioma 
 
Pancreatic cysts 
 
Epididymal cystadenoma 
 
ii) Without VHL family history 
 
Presence of CNS hemangioblastomas  
and/or 
 
  Retinal angiomas 
 
If just one of the above, then one of either: 
 
  Renal Cell carcinoma 
 
  Pheochromocytoma 
 
  Epididymal cystadenoma 
 
 
  Pancreatic cysts / tumor   
 
From: Gladys Glenn, Peter Choyke, Berton Zbar and Marston Linehan. von Hippel-Lindau 
Disease: Clinical Review and Molecular Genetics.  Problems in Urology, 1990, 4 (2):132. 
 

ICF_000.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute   
 
 
STUDY NUMBER: 
08-C-0020 
PRINCIPAL INVESTIGATOR:  Marston Linehan, M.D. 
 
 
STUDY TITLE: 
A Phase 2 Study of ZD6474 (Vandetanib) in Patients with Von Hippel Lindau Disease and Renal 
Tumors 
 
Continuing Review Approved by the IRB on 06/27/11 
Amendment Approved by the IRB on 03/09/12 (F) 
 
 
 
Date Posted to the Web: 03/15/12 
Standard 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
BACKGROUND INFORMATION 
 
What is a Research Study? 
 
A research study is a carefully supervised study that is done in humans to answer specific questions about a study drug or 
a new way of using an approved drug.  Research studies are used to determine whether study drugs or treatments are 
safe and effective in humans. 
 
You are being asked to take part in this study, also known as a clinical trial, because you have kidney cancer related to 
von Hippel-Lindau (VHL) disease.   You are invited to join this phase II study of an investigational (research) drug called 
ZD6474 (also known as vandetanib or ZACTIMA). 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  2  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
What is this document? 
 
This document is an informed consent form that will provide you with information about this research study.  Before you 
can make a decision about whether or not to participate, you should understand what this study involves and the possible 
risks and benefits associated with this study.  If you have any questions after reading this document, please ask the study 
doctor or study nurse to explain any words or information that you do not understand.  If you agree to participate in this 
research study, you should be sure that all your questions are answered and that you understand your rights as a study 
subject.  After you sign this form you will be given a copy to keep. 
 
Why is this study being done? 
 
The purpose of this research study is to determine if the study drug ZD6474 can be used as a treatment for kidney 
tumors in people who have VHL and whether it can safely be given to patients with VHL.   ZD6474 is an experimental 
drug that is being tested as a new medication for a variety of cancers, including clear cell renal carcinoma which is the 
type of kidney cancer seen in VHL patients. ZD6474 is given once daily by mouth as a pill or liquid.  
 
Why might ZD6474 work in cancer patients?  
 
One way tumors are able to grow is by growth and development of new blood vessels which bring nutrients and oxygen 
to the tumor.  This process happens because proteins (called receptors) on the surface of cells lining blood vessels and 
cancer cells receive chemical signals that encourage the growth of new blood vessels.  Cancer cells also have other 
receptors on their surface that promote growth of cancer cells directly in response to proteins called ‘growth factors’. In 
laboratory experiments, ZD6474 works by blocking both these kinds of receptors on the surface of cancer cells or on the 
lining of blood vessels within cancers.  Blocking these receptors may cause cancer cells or the blood vessels to stop 
growing.  
 
ZD6474 has been tested in adults who have a variety of different cancers in clinical trials, but the drug has not been 
approved by the US Food and Drug Administration (FDA) as a cancer treatment.  We do not know whether ZD6474 will 
slow or stop the growth of renal cancer or whether this drug will be effective in your cancer. 
 
One of the goals of this study is to try and understand better how ZD6474 may work in humans with kidney cancer. At 
specific times throughout this study, your blood will be collected and analyzed.   These samples will be studied to look for 
special markers that may help researchers understand how ZD6474 is affecting you and/or your tumor and to develop 
tests that may be helpful in the study of kidney cancer. 
 
How many people will participate in this study? 
 
The study will initially involve 12 patients enrolled at the NIH.  If one or more people in this group have tumors that 
shrink following treatment with ZD6474, another 25 patients can enter the study. The plan is to enter up to 37 patients 
with VHL on to this study.    
 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH  STUDY? 
 
What are the chances that I will get the study drug? 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  3  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
All eligible subjects enrolled in this study will receive the study drug ZD6474.  This study is an open label study, which 
means that both you and your doctor will know what amount of ZD6474 you are taking. 
How often will I need to visit the hospital, clinic, or doctor’s office? 
 
You will visit the NIH clinical center to help your doctors determine whether you are a suitable candidate for this study. 
This visit will involve meetings with doctors, nurses and other staff conducting this study as well as blood and urine tests 
and x-rays. Once you decide to participate in the study, you will need to come to the NIH every 2 weeks during the first 
four weeks of treatment to meet with your doctors and research nurse and also have several tests done. After the first 
four weeks, you will need to return for a visit once every four weeks. The length of each visit will depend upon the 
number of tests that are being done.  Some visits will be longer than other visits. 
 
What will I be responsible for if I participate in this study? 
 
During this study you will not be able to receive any other cancer treatments other than ZD6474.  You will be asked not 
to participate in any other clinical trials involving another experimental treatment while you are being treated in this 
study. 
Several medications (both prescription and non-prescription), ‘alternative/complementary’ or herbal preparations, dietary 
supplements, and foods such as grapefruit juice, can have undesirable interactions with ZD6474. You will not be allowed 
to take certain medications, supplements, and grapefruit juice during your participation in this study.  Your doctor or the 
study staff will review the list of drugs that you are currently taking, as well as those that you took prior to participating in 
this study. Once you are on study, please talk to your NIH doctors prior to starting any new drugs, dietary 
supplements or herbal or complementary medications. 
 
Drugs that affect the normal growth of blood vessels can delay or complicate wound healing following injury or surgical 
procedures. You should not schedule any elective surgeries while you are being treated in this study.  If you have an 
unplanned surgery, inform you doctor immediately, as you may not be able to continue study drug 
treatment. 
 
You need to keep your scheduled NIH visits and follow the instructions of your physicians and study nurse.  If you cannot 
keep one of your planned visits, call your research nurse and reschedule the visit. 
 
You will also be asked to keep a diary of when you take the medication and any side effects that you experience.  You 
will also need to bring your ZD6474 pill bottles with you to every visit for the team to count your remaining ZD6474 pills.  
You will be given a blood pressure cuff and be taught how to take your own blood pressure.  You will be asked to take 
your blood pressure at home periodically and keep a diary of the readings. If you experience any worrisome side 
effects or if your systolic blood pressure (upper or higher number) is above 150, or if your diastolic (lower 
number) is above 100 or above, you should call your doctors at the NIH or seek medical attention from 
your local doctors as soon as possible. 
 
Agents such as ZD6474, which interfere with blood vessel formation or growth may cause developmental problems in 
fetuses and breast-feeding or young children. Therefore, if you are pregnant or breast-feeding you may not participate in 
this study. If you are female and old enough to get pregnant, you will be given a pregnancy test before you are given 
ZD6474.  An appropriate and effective method of birth control (which may include abstinence) must be used by any 
person who is able to become pregnant or father a child and is receiving ZD6474.  Birth control must be continued and 
breast feeding avoided for three months after the last dose of ZD6474 is given to ensure that most of the drug is out of 
your body.  If you become or are found to be pregnant while receiving ZD6474, you must notify one of the doctors listed 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  4  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
on this form right away. If you become pregnant while you are taking ZD6474 you must stop taking ZD6474, and you will 
not be able to continue treatment with ZD6474. If you are a male, you should not attempt to father a child while you are 
on this drug and for at least three  months after stopping the drug. You must use an appropriate and effective method of 
birth control during this period. The effect of this drug on your ability to bear or father children after you discontinue 
treatment is unknown. 
 
WOMEN OF CHILD-BEARING POTENTIAL 
There might be unknown risks to the unborn child if you are or if you become pregnant during the study.  Due to these 
risks, you must not participate in this study if you are pregnant, or plan to become pregnant during the research study 
period, or are breast-feeding a child. 
If you are a woman of child-bearing potential: 
• 
By signing this consent form, you confirm to the best of your knowledge that you are not pregnant now and you 
do not intend to become pregnant during this study 
• 
A pregnancy test will be done to confirm that you are not pregnant before you take part in this study 
• 
You must avoid becoming pregnant and use an acceptable method of birth control during this study. 
If at any time during this study you think you might be pregnant, or later learn that you were pregnant during the study, 
you must contact the study doctor immediately for further instructions about your participation in this study and follow-
up. 
MALE Patients 
The study drug used in this study could affect your sperm and could potentially harm a child that you may father while in 
this study.  You must avoid unprotected sex with a pregnant partner (or woman of child-bearing potential not using birth 
control) or donating sperm during the study and for three months following the last dose, since the potential for problems 
with the fetus has not yet been thoroughly investigated.  Men should use a condom during the trial and for three months 
following the last dose. 
If your partner becomes pregnant, you must notify the study doctor of any outcomes of the pregnancy from the date of 
the first dose until three months after last dose of ZD6474. 
 
TYPES OF TESTS OR PROCEDURES INVOLVED WITH THIS STUDY  
 
Once you meet with your doctors and research team at the NIH and undergo the necessary tests to determine if you are 
a suitable candidate for this study, you can decide whether you want to participate. If you choose to take part, then you 
will be started on ZD6474.  This drug is given by mouth once every day (treatment periods are divided arbitrarily into 
cycles-a cycle of ZD6474 is 28 days). You will be instructed about how to take ZD6474.  
 
During the 1st cycle, you will need to return to the NIH every 2 weeks on the same day of the week as of your first dose 
of ZD6474.  If you stay on the drug after the 1st cycle, you will return to the NIH every four weeks. 
 
At clinic visits during your participation in this study you will have the following tests and procedures.  They are part of 
regular cancer care. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  5  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
● 
Vital signs (pulse rate, respiration rate, oral temperature, and blood pressure), weight, and performance status 
will be taken at each study visit. 
● 
Blood will be collected for chemistry, hematology, and other labs to determine if the study drug is causing any ill 
effects on your body.  These samples will be taken at each study visit.  About 3-5 teaspoons will be taken each 
time you visit the doctor for this study.   
● 
If you are a female and able to get pregnant, a pregnancy test will be done within the week before starting the 
study and once every four weeks during treatment before your continue with each new cycle.  
The following tests and procedures will also be done. Even though they are part of regular cancer care, it is possible they 
are being done more often because you are in this study.   
● 
You will have imaging scans (CT or MRI) done approximately every 12 weeks to assess the size of your tumors 
(or sooner if your doctor feels it is necessary) 
● 
You will have urine collected during the 1st week of every cycle. 
● 
You will have an electrocardiogram (EKG) and routine blood work done every week during the 1st two cycles.  If 
you stay on the drug longer, then EKGs will be performed every four weeks.  This means that some of the EKGs 
and blood work will need to be performed locally near your home and the results sent to the NIH.    
The following research studies will be done to see how ZD6474 is affecting your body. 
● 
Your blood will be taken before and after the ZD6474 dose at weeks 1 and 3 of the 1st cycle, and every four 
weeks after that, as well as the end of treatment to look for special markers affecting you and/or your tumor that 
may be helpful in the study of kidney cancer.  About 8 tablespoons will be collected for this portion of the 
research tests.  
STUDY CHART 
 
The chart below shows what will happen to you during the course of your treatment.  
 
DAY 
WHAT TO DO AND WHAT WILL HAPPEN TO YOU 
Day 1, Week 1 of 
each cycle 
• ZD6474 tablets will be given to you along with a pill diary, blood pressure 
monitor, side effect diary, and blood pressure diary.  
Day 1 of Weeks 1 
and 3 of the 1st cycle, 
and  
Day 1 of every cycle 
(4 weeks) after 1st 
cycle (Week 5, 9, 13, 
etc.) 
 
• NIH visit 
• Have a history taken of how you feel, have a physical examination, and vital 
signs by a Health Care Provider in the Urology (OP3) Clinic 
• Review your blood pressure, side effects and pill diaries 
• Blood draw for research and routine lab tests before ZD6474 dose, and blood 
draw for research tests after ZD6474 dose 
• Urine tests  
• EKG will be done 
Day 1, every week 
for Weeks 2, 4, 6, 7 
& 8,   
 
• EKG and routine blood tests will be done by your local doctor with results sent to 
NIH. 
Every 
12 
weeks 
(starting with week 
13) 
• A CT scan or MRI will determine how your tumor is being affected by the 
therapy. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  6  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or decide to stop.  He 
or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from ZD6474 can be evaluated by 
your doctor.  Another reason to tell your doctor that you are thinking about stopping is to discuss what follow up care and 
testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest; if 
you do not follow the study rules; or if the study is stopped. 
 
When am I finished with the Study? 
 
You may continue to receive ZD6474 treatment in this study until: 
• 
your tumors get larger, or 
• 
your doctor feels you are not benefiting from ZD6474, or  
• 
you experience intolerable side effects or side effects which make it unsafe for you to continue, or   
• 
the doctors taking care of you feel it is not in your best interest to continue, or  
• 
you choose to withdraw from this study, or 
• 
you are unable to keep scheduled medical appointments or take the study medication as instructed, or  
• 
a better therapy becomes available, or 
• 
you are a female and become pregnant, or  
• 
the drug is no longer available or the study closes 
 
Safety Follow-up Visit/End of study visit: 
 
If you come off of the treatment for any of the reasons listed above, we would like to continue to check up on you 
periodically through phone calls to you, your family or your home doctor’s office. 
 
If you experience a side effect or abnormal laboratory results, your study doctor may ask that you come back for 
additional visits until the side effect resolves  
 
SIDE EFFECTS OR RISKS FROM BEING IN THE STUDY 
 
More than 5000 patients with different types of tumors have been treated with ZD6474. A variety of side effects have 
been seen in patients receiving ZD6474 and are described below. In addition to the possible side effects listed below, 
there is always the risk of uncommon or unexpected side effects that you may experience when taking ZD6474.  Your 
doctor will closely monitor you throughout this study and discuss with you any questions regarding risks, discomforts and 
side effects. 
 
The administration of any drug involves a general risk of allergic drug reactions.  The symptoms that may occur include 
headache, rashes/hives, flushing, swollen skin, breathlessness, dizziness, nausea, and sometimes vomiting.  In rare 
cases, life-threatening reactions may develop, including choking attacks, dangerously low blood pressure and loss of 
consciousness, which will require immediate treatment. 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  7  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
To our knowledge, patients with VHL have not received this drug outside this trial and hence it is not known whether 
these patients may develop additional or more severe side effects than non-VHL patients. 
 
If at any time you have any questions about side effects or if you think you have a side effect or a change in your health 
condition, it is important that you speak to your study physician.   
 
Known side effects in patients receiving ZD6474 
 
All drugs have potential side effects.  One of the purposes of this study is to learn about the possible side effects of 
ZD6474.  Many drug-related side effects will go away shortly after stopping the drug, but in some cases side effects may 
be serious, long, lasting, or permanent.  During your study treatment and for at least 30 days after your last dose of 
ZD6474, it will be very important for you to report any possible side effects or symptoms that you develop to your study 
doctor. 
 
Everyone taking part in the study will be watched carefully for any side effects.  However, doctors don’t know all the side 
effects that may occur.  Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen some side effects. It may become necessary to temporarily or permanently discontinue ZD6474 or alter the dose of 
the drugs due to side effects you experience. 
 
Patients in clinical studies using ZD6474 have reported the following symptoms and side effects related to ZD6474:  
 
Likely / Common (> 10%): 
• skin rashes 
• nausea  
• loss of appetite 
• weight loss 
• diarrhea 
• constipation 
• high blood pressure 
• changes on the EKG without any symptoms  
• feeling tired 
• headache 
• dizziness 
• depression and anxiety 
• sleeplessness 
 
Less Likely (1% to 11%) 
• blood in the urine 
• protein in the urine  
• changes in lab values of electrolytes and liver function tests 
• low platelet count, anemia, and low white blood count 
• bruises 
• gum bleeding, mouth sores or yeast infections 
• fever 
• lack of energy and weakness 
• dehydration  


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  8  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• vomiting or heartburn 
• shortness of breath 
• cough 
• pain, including pain associated with tumor 
• itching 
• pain, redness, or peeling of the hands and feet 
• increased blood levels of calcium, a mineral normally found in blood 
• changes in levels of parathormone, a substance made in your body that regulates the levels of calcium and 
phosphorus 
• Inflammation of the pancreas 
• Inflammation/infection of the intestines 
• Abnormal accumulation of fluid in the brain 
• Decrease in thyroid function 
• Stroke 
• Mild nose bleeding 
• Abnormal taste in mouth 
• Dry or irritated eyes 
• Kidney stones 
 
Rare but Serious 
• Life-threatening high blood pressure 
• Symptomatic and / or life threatening heart rhythm changes 
• Formation of clots, such as in the lung or in the legs 
• Bleeding, from tumors or non tumor sites 
• Bleeding in or around the brain 
• Lack of blood flow to heart (heart attack), brain (stroke), eye (blindness),legs, or bowel 
• Serious or life threatening complications from rashes 
• Lung inflammation and stiffening, infections or fluid accumulation around the lungs 
• Blockage or penetration of the bowel or gall bladder duct 
• Kidney failure 
• Problems with wound healing and spreading bacterial infection of the deeper layers of skin and soft tissu 
• Heart Failure, which is the weakening of the heart's ability to pump blood has also been reported and may be related 
to vandetanib. We will be monitoring your heart function with an ekg. If significant changes occur, we may need to 
stop therapy. 
• Seizures, some patients have had seizures while taking vandetanib, and in one case a patient with seizures also 
had swelling in the brain that was found on an MRI scan, which got better after vandetanib was stopped. If you 
develop seizures, dizziness, headache, changes in your vision, or confusion, you should let your study doctor 
know as soon as possible. These may be symptoms of reversible posterior leukoencephalopathy 
syndrome (RPLS). 
 
In addition, a number of other side effects have been reported in clinical trials using ZD6474 alone, in combination with 
other chemotherapy agents or radiation. It is unclear whether these side effects are related to ZD6474, or are caused by 
other factors (such as chemotherapy or radiation). These side effects include: 
• Infections, including life-threatening bacterial infections 
• Facial nerve palsies or reversible confusion, seizures and swelling in the brain 
• Brief loss of consciousness 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  9  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Weakening of the heart muscle or inability of the heart to pump efficiently 
• Severe breathing problems or lung failure 
• Development of an abnormal pathway between the esophagus (tube connecting the throat to the stomach) and 
trachea (windpipe) or surrounding structures 
• Development of an abnormal communication between the intestines and surrounding structures, including the urinary 
bladder 
 
AstraZeneca is monitoring patients receiving vandetanib.  You and your study doctor will be told if we have further 
information about vandetanib that might be relevant to your willingness to continue to take part in the study. 
 
Many side effects, including skin rashes, diarrhea, high blood pressure and EKG changes are often reversible and can 
usually be improved by reducing the dose of ZD6474.  If you develop a skin rash, creams and oral medications can be 
given.  If you develop diarrhea related to the ZD6474, medications to stop the diarrhea can be used. 
 
Your skin will be more sensitive to the sun, and you should minimize your exposure to the sun. This may be done 
by reducing the time you are out in the sun, using a hat and clothing to cover most of your body and applying 
sunscreens with an SPF 45 or higher any time you are outdoors. It is recommended that you take preventative 
action to prevent the rash from occurring while receiving study medication and for 3 to 4 weeks after stopping 
treatment by using the afore mentioned guidelines. 
 
Also, you must notify the study team when the first sign of a rash occurs so that the appropriate steps can be taken in an 
attempt to prevent the rash from becoming severe.   
 
Your eyes may be more dry and changes to your corneas may occur.  In order to prevent corneal ulcers and other eye 
problems, do not wear contact lenses while taking ZD6474. 
 
Your blood pressure will be monitored carefully on the study and, if found to be elevated, medications to lower your blood 
pressure can be used.  If you have uncontrolled high blood pressure, this elevated pressure can cause damage to other 
organs including the heart, kidneys, or brain.  Having uncontrolled blood pressure increases the risk of heart attack and 
stroke in adults.  High blood pressure may be associated with no symptoms; however, dizziness, headache or nose bleed 
can occur in patients with high blood pressure. You will be asked to record your blood pressure at least once a day. If 
your systolic blood pressure (upper or higher number) is above 150, or if your diastolic (lower number) is 
above 100 or above, please call your doctors at the NIH or seek medical attention from your local doctors 
as soon as possible. 
 
We will monitor your heart function closely by performing ECG/EKGs periodically to look at your heart rate and rhythm. 
This procedure is associated with minimal discomfort. Abnormalities on the EKG have been reported in patients taking 
ZD6474 on other trials. Some of these abnormalities can have serious or life-threatening consequences if appropriate 
action is not taken (usually stopping or reducing the dose of ZD6474 and/or ensuring that blood electrolyte levels are 
normal). However, as a result of close monitoring and timely intervention, no serious problems or symptoms related to 
these EKG abnormalities have been reported so far. 
 
AstraZeneca has observed changes in ECGs in some patients being treated with vandetanib. These changes in the 
ECG may be drug-related and usually occur without symptoms; accordingly, frequent safety follow-up visits have 
been built into all studies. Similar changes in the ECGs of patients receiving other medications have led to heart 
rhythm changes, some of which have been life threatening. However, it is estimated that between 0.1 to 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  10  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
1% of patients receiving vandetanib 300 mg have developed heart rhythm changes linked to life-
threatening arrhythmia called Torsades de Pointes. Torsades de Pointes has been associated with 
sudden death. If any such changes are noted on your ECGs, you may need to attend additional visits for further 
safety assessments.  
 
The risk of developing changes in the ECG and serious heart rhythm changes will be greater if you have diarrhea, 
vomiting, high fever, faintness or dizzy spells, or are unable to maintain a normal diet.  You should report any of 
these symptoms to your doctor immediately.  You should review your medications and diet with your doctor at 
each visit while you are continuing to receive study medication. 
 
These changes in the ECG usually occur without you being able to sense it happening, so frequent follow-up has been 
built into the study.  You may be able to sense some changes in the heart rhythm such as rapid or irregular heart 
beating, dizziness, light-headedness, chest discomfort, shortness of breath, and losing consciousness.  These or other 
new symptoms or possible side effects should be reported immediately to your doctor. 
 
A rare side effect of anti-blood vessel agents such as ZD6474 is a risk of bleeding, which can sometimes occur at the site 
of or from tumors.  Although patients taking ZD6474 on other trials have experienced bleeding (including one case of 
bleeding into the brain) it is not clear how frequently bleeding occurs or whether these are related to ZD6474. Other 
drugs (including some drugs that are approved by the FDA for treating kidney cancer) have been associated with 
bleeding, which, in some cases have been life-threatening or fatal. Since patients with VHL have tumors at multiple 
locations within the body, bleeding from tumors can have serious or life-threatening consequences, especially if it involves 
hemangioblastomas in areas such as the brain, the spinal cord or angiomas in the eye. 
 
Drugs that affect the normal growth of blood vessels can delay or complicate wound healing following injury or surgical 
procedures. You should not schedule any elective surgeries while you are being treated in this study.  If you have an 
unplanned surgery, inform you doctor immediately, as you may not be able to continue study drug treatment. 
 
The long-term side effects of ZD6474 are not known.  It is possible that there may be temporary or permanent side 
effects of ZD6474 that have not yet been identified. 
 
The effects of ZD6474 on the human fetus or nursing infant are not known. ZD6474 is harmful to fetal development in 
animals. 
 
Known side effects of the procedures that will be done in this research study 
 
Blood Collection 
 
The risks associated with blood collection include discomfort, pain, bleeding, bruising, redness, swelling and/or bruising 
where the blood is drawn from your arm.  Fainting and infection are rare, but can happen with blood collection.  By 
signing this consent form, you are authorizing NIH investigators to use your blood samples for those procedures identified 
in the study protocol. 
 
ECG 
 
A recording of the normal electrical activity of your heart is taken by placing electrodes (pieces of metal attached to 
wires) on the skin of your chest, arms, and legs.  There is minimal discomfort and there are no risks. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  11  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
Echo 
 
An echocardiogram is an ultrasound of your heart.  An ultrasound is an image made from sound waves.  There is no 
discomfort and there are no risks. 
 
Imaging studies 
 
You will have a CT scan or MRI to measure the size of your cancer(s) before starting the treatment and some or all of 
these scans will be used to periodically monitor the change in the size of your cancer(s) on ZD6474.  These scans are 
common standard imaging tests used in the diagnosis and monitoring of many diseases.  Although these tests have been 
in use for many years, their potential long term effects on the body are still being learned. 
 
MRI Scan  
 
There are no known harmful effects from the strong magnetic field used for MRI. However, the magnet is so powerful 
that it may affect pacemakers, artificial limbs, and other medical devices that contain iron.  You should tell the study staff 
about any metal devices that you may have in your body.  
 
Iron pigments in tattooed eyeliner can cause eye irritation. 
There is slight risk of developing an allergic reaction if contrast material is used during the MRI scan. However, most 
reactions are mild and can be controlled using medication. 
 
The MRI scan is performed in a long narrow tube.  You may experience discomfort related to lying still in an enclosed 
space for a prolonged period of time.  The study staff prior to performing the procedure will provide additional 
instructions to you.  If this occurs, cool air can be blown over you by a fan if desired or your doctor can order a medicine 
to help you relax during this scan.  Keeping the room well lit can also reduce this claustrophobic feeling.  
 
CT Scan  
 
If a contrast agent (the special dye) is given with the scan there is a small risk of having a reaction to the contrast.  
These reactions can include nausea, pain in the vein where the contrast was given, headache, a metallic or bitter taste in 
the mouth, and a warm or flushing feeling that lasts from 1-3 minutes.  Rarely, these symptoms may require treatment.  
In very rare cases, people have had more severe allergic reactions that result in shortness of breath, wheezing, or 
lowering of the blood pressure.  If you have had a reaction in the past, be sure to tell your doctor or nurse about it.   
 
You will be exposed to a limited and medically acceptable dose of radiation during the procedure.  There is always a slight 
risk from being exposed to any radiation, including the low levels of X-rays used for a CT scan. 
 
The radiation dose you receive, if your scans include the use of X-rays or radioactive chemicals, is within the safe limits 
defined by the NIH Radiation Safety Guidelines, and is considered essential for your medical care. 
 
Delay in surgical resection of kidney tumor(s) 
 
Von Hippel-Lindau patients with kidney tumors that have reached a certain size (usually around 3cm) would normally be 
advised to undergo surgery to remove them. Surgical removal of tumors is done to lessen the risk of spread to other 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  12  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
organs.  Removing your kidney tumors does not mean that your cancer has been ‘cured’.  Even if you have surgery to 
remove your kidney tumor(s), it is possible that you will develop new tumors and may need surgery again in the future. 
 
Your tumors may or may not be large enough to require surgical resection in the near future. If they are large enough to 
require surgery, a delay in surgery may result if you choose to participate in this study and your tumors do not decrease 
in size with ZD6474.  We feel that delaying surgery for approximately 12 weeks is unlikely to greatly increase the risk of 
tumor spread from your kidneys. After 12 weeks, depending on the effect of ZD6474 on your tumors, a decision will be 
made about whether it is safe to delay surgery any further. If any of your kidney tumors should be very large, we will 
advise surgery at the earliest possible time and will exclude you from the current study. 
 
Potential Benefits of Participation 
 
You are being offered this experimental drug (ZD6474) because it may be of benefit to you in treating your VHL disease.  
One potential benefit may be shrinkage of your tumors that would enable you to delay or avoid surgery.  Another possible 
benefit might be changes to the tumor environment (such as decreased blood supply) that may make surgical removal of 
your tumor(s) easier.  However, there is no guarantee that this drug is of benefit to humans or that you will benefit from 
taking part in the study.  The drug you receive may even be harmful to you.  
 
Individual patients will not have a benefit from taking part in the investigational procedures such as research done on 
your blood samples or tumor tissue.  However, future patients may benefit from what is learned.   
Your participation in this study is voluntary.   
 
Potential Benefits to Society 
 
The knowledge gained from this study may benefit others.  Your participation may help to determine if ZD6474 treatment 
can be safely and effectively given to other patients with VHL. 
 
Alternative to Participation/ Alternative Approaches or Treatments 
 
You may choose not to participate in this study.  Other treatment options may be available to you.  Your doctor is very 
willing to discuss the benefits and side effects of other ways to treat your tumors including the option of surgical resection 
of your tumor(s), treatment of your symptoms only, and other investigational protocols that may be available for your 
condition. 
 
Your other choices may include: 
 
• 
Getting care for your cancer without being in a study 
 
• 
Taking part in another study 
 
• 
Surgical removal of your tumor(s) 
 
• 
Getting no treatment 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  13  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
If you agree to participate in this study then you and your doctor have determined that there are no other standard 
therapies available that have been shown to improve your chance of survival or cure, or you have refused other 
treatment options available to you.   
 
CONFIDENTIALITY OF MEDICAL INFORMATION 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be kept private.  However, we 
cannot guarantee total privacy.  Your personal information may be given out if required by law.  If information from this 
study is published or presented at scientific meetings, your name and other personal information will not be used.  
 
All patients will be given a number upon signing this informed consent form.  The number will be used throughout the 
study as your main identifier on study documents that will be sent to AstraZeneca (the drug company that provides the 
drug used in this trial).  Every effort will be made to ensure that documents that contain your personal information will be 
crossed out and replaced with your subject identification number if sent to AstraZeneca. 
 
All research samples will be labeled with a unique bar code number.  Only the investigator and designated study site staff 
(i.e. staff at the NIH) will have the key to link the bar-coded samples to the subject to which they correspond. 
 
Neither your results nor your samples will be identified with your name in communications with AstraZeneca.  A number 
will be used in all regulatory documentation related to this study.  It is a requirement that your involvement in this study 
be noted in your medical records. 
 
Since research studies on samples you provide are not expected to benefit you directly or to change your treatment 
course, these results will not be placed in your medical record and will not be made available to you, members of your 
family, your personal physician, or other third parties. 
 
The confidentiality of your medical records will be maintained to the extent permitted by the applicable laws.  If results of 
the trial are published, your identity will remain confidential.  Using your subject number only, the results and other 
information from the study may be submitted to regulatory agencies in countries where the study drug may be submitted 
for approval. 
 
WHAT WILL BE DONE WITH MY BLOOD AND TUMOR SAMPLES? 
 
Consent for Tissue/ Blood (specimen) Banking 
 
During the course of the study, several research studies will be performed on your blood and tissue samples. These 
studies will be done to try to better understand: 
• 
how the drug is handled by your body (i.e, how it is absorbed and broken down) 
• 
what effects the drug has on your body 
• 
whether the drug affects any components of the mechanism that is responsible for formation of new blood 
vessels in or growth of tumors 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  14  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Your research blood samples obtained during your participation in the study will be stored in freezers in research 
laboratories at the NIH and used to test for information required for this study. All samples used for research will be 
coded and no personal information will be included in order to protect your privacy.  
 
 
 
 
Optional Studies 
 
Please read each sentence below and think about your choice. After reading each sentence, circle and initial the answer 
that is right for you.  No matter what you decide to do, it will not affect your care. 
 
1. My tissue, blood, and urine specimens may be kept for use in research to learn about, prevent, or treat cancer.  
 
Yes              No               Initials_________ 
 
2. My specimens may be kept for use in research to learn about, prevent or treat other health problems (for example: 
diabetes, Alzheimer's disease, or heart disease).  
 
Yes              No               Initials_________ 
 
3. Someone may contact me in the future to ask permission to use my specimen(s) in new research not included in this 
consent.  If the risks of the new research are not covered by this consent, you may be asked to sign consent.  
 
Yes              No               Initials_________ 
 
4. I want to be contacted in the future if any information is learned that may direct impact my health or the health of my 
relatives.  I understand that for you to contact me in the future, I need to notify you of any changes in my address.  
Yes              No                Initials _________  
 
 
Will I be compensated for participating in this study? 
 
There will be no financial compensation for participating in this study. 
 
What are the costs of taking part in this study? 
 
The study drug, ZD6474, will be provided to you free of charge by AstraZeneca, Inc. through the NIH.  There is no cost 
to you for the drug itself or for any test or procedure performed solely for research purposes.  NIH will pay for the cost of 
the blood tests, x-rays, scans, drug preparation and pharmacy fees, and other laboratory tests associated with your 
research-related care at NIH while you are enrolled in this study.  You or your insurance company will have to pay for all 
care outside of NIH, which includes non-research related costs that are associated with your routine care for your 
underlying disease.   
 
Drug Sponsor/Manufacturer 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  15  of  18 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
The study drug is provided by AstraZeneca, Inc.  It is possible that the information obtained from your participation on 
this study may become valuable for commercial research and development purposes (including patentable inventions), 
which may be of significant benefit to society, the sponsor of this study, individual researchers, or other third parties.  
You will not receive direct financial benefit from such research and development.  
 
 
 
 
Conflict of Interest 
 
The National Institutes of Health and the research team for this study are using ZD6474 developed by Astra Zeneca 
through a joint study with your researchers and the company.  This means it is possible that the results of this study 
could lead to payments to NIH scientists and to the NIH. By law, government scientists are required to receive such 
payments for their inventions.  You will not receive any money from the development of ZD6474. 
 
What are my rights if I take part in this study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the study.  If you 
decide to take part in this study, you may leave the study at any time.   No matter what decision you make, there will be 
no penalty to you and you will not lose any of your regular benefits.  Leaving the study will not affect your medical care.   
 
We will tell you about new information or changes in the study that may affect your health or your willingness to continue 
in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this 
form.   
 
Participation in this research trial may make you ineligible to participate in other experimental drug trials.   This is 
because researchers may not understand the effect of one research drug on another.  The Principal Investigator or an 
Associate Investigator may end your participation in this study if they feel that termination is medically indicated due to 
side effects, progression of disease or compliance.  Upon completing this study, you may be given the choice of taking 
part in other research protocols that may be appropriate for you or you will be referred to the care of your primary 
physician. 
 
A copy of the informed consent is on file at the Center for Cancer Research, National Cancer Institute and a copy will be 
made available to you.  Your signature on this form indicates that you agree to participate in this medical research study 
under the direction of the principal investigator as listed above.  The Federal Privacy Act protects the confidentiality of 
your NIH medical records.  However, you should know that the Act allows release of some information from your medical 
record without your permission, for example, if it is required by the Food and Drug Administration (FDA), members of 
Congress, law enforcement officials, or other authorized people including representatives of the NCI or drug manufacturer 
(AstraZeneca Pharmaceuticals, LP), and the staff of the National Cancer Institute who may inspect and study your 
medical records.  Your participation in this study does not constitute a promise of long-term care at the NIH Clinical 
Center.  
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  16  of  18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital 
accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator,  W. Marston Linehan, M.D.; 
National Institutes of Health, National Cancer Institute, CRC,1W-5942, 9000 Rockville Pike, Bethesda MD 20892  
Telephone:  301-496-6353.  Other researchers you may call are:  Sally Fowler, R.N. at (301) 435-6255, Dr. Ramaprasad 
Srinivasan, the lead Associate Investigator (301) 496-6353, or the Urologic Oncology Fellow on call at pager (301) 496-
1211 (24-hour phone number).  If you have any questions about the use of your tissue in future research studies, you 
may also contact the Office of the Clinical Director at (301) 496-4251. 
 
You may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
08-C-0020 
CONTINUATION:  page  17  of  18 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 27, 2011 THROUGH JUNE 26, 2012.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name