Phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents With Hereditary Medullary Thyroid Carcinoma
Phase: PHASE1
Conditions: Medullary Thyroid Carcinoma, Multiple Endocrine Neoplasia Type 2A, Multiple Endocrine Neoplasia Type 2B
Sponsor: National Cancer Institute (NCI)

Abbreviated Title: Vandetanib in Hereditary MTC 
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Abbreviated Title: Vandetanib in Hereditary MTC 
CC Protocol: # 07-C-0189 L 
AstraZeneca Protocol #IRUSZACT0098 
Version Date: 06/27/2017 
NCT Number: NCT00514046 
 
Title: Phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents with 
Hereditary Medullary Thyroid Carcinoma 
 
NCI Principal Investigator: 
Brigitte Widemann, M.D., POB, NCI A-E 
10 Center Drive, MSC 1104 
Bldg. 10 CRC, Rm. 1-3750 
Bethesda, MD 20814-1104 
Phone: 240-760-6203 
Email: widemanb@pbmac.nci.nih.gov 
 
 
NIH Associate Investigators: 
Trish Whitcomb, R.N., OCD, CCR, NCIA-C,E  
 
Andy Gillespie, R.N. OCD, CCR, NCIA-C,E 
 
Andrea Baldwin, P.N.P. POB, CCR, NCIA-E 
 
Joanne Derdak, N.P. POB, CCR, NCIA-E 
 
Eva Dombi, M.D., POB, CCR, NCIE 
 
John Glod, M.D., Ph.D., POB, CCR, NCIA-E 
 
Paul Jarosinski, PharmD, Pharmacy, CC, NIHA,B 
 
Seth Steinberg, Ph.D., BDMS, CCR, NCIE,F 
 
Paul Meltzer, M.D., Ph.D., CGB, CCR, NCIE,F 
 
Maria Merino-Neumann, M.D., LP, CCR, NCIE,F 
 
Clara Chen, M.D., Nuclear Medicine Dept, CCA,B,E 
 
Constantine A. Stratakis, M.D., OSD, NICHDA-E 
 
Jaydira Del Rivero, M.D., OCD, CCR, NCIA-E 
 
 
Non-NIH Associate Investigators: 
Samuel A. Wells, Jr M.D., Volunteer, CGB, CCRF-G 
 
Srivandana Akshintala, M.D., Volunteer, POB, 
CCR, NCIE-G 

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Claudia Derse-Anthony, R.N. Contractor, Leidos 
Biomedical Research Inc.E,G 
 
Referral Contact/Study Coordinator: 
Claudia Derse-Anthony, R.N., Contractor, Leidos 
Biomedical Research, Inc. 
10 Center Drive, Room 1C244 
Bethesda, MD 20982 
Office Phone: (240) 760-6102  
Email: derseanthonycp@mail.nih.gov 
 
 
Investigator Roles: 
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 Agents:     
Drug Name: 
Vandetanib (ZD6474, Zactima) 
IND Number: 
77570 
Sponsor: 
Center for Cancer Research, NCI 
Manufacturer: 
AstraZeneca 
 
Commercial Agents: None 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................ 3 
1 
INTRODUCTION .............................................................................................................................................. 7 
1.1 
STUDY OBJECTIVES .................................................................................................................................... 7 
1.2 
BACKGROUND AND RATIONALE ................................................................................................................. 7 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ................................................................................ 17 
2.1 
ELIGIBILITY CRITERIA .............................................................................................................................. 17 
2.2 
SCREENING EVALUATION ......................................................................................................................... 20 
2.3 
REGISTRATION PROCEDURES .................................................................................................................... 21 
3 
STUDY IMPLEMENTATION ....................................................................................................................... 21 
3.1 
STUDY DESIGN ......................................................................................................................................... 21 
3.2 
DRUG ADMINISTRATION ........................................................................................................................... 28 
3.3 
DOSE MODIFICATIONS FOR VANDETANIB-RELATED DLT ........................................................................ 29 
3.4 
VANDETANIB PHARMACOKINETIC STUDIES .............................................................................................. 30 
3.5 
VANDETANIB PHARMACODYNAMIC STUDIES ........................................................................................... 31 
3.6 
STUDY CALENDAR .................................................................................................................................... 33 
4 
CONCOMITANT MEDICATIONS/MEASURES  ...................................................................................... 38 
5 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA.......... 38 
5.2 
POST-TREATMENT EVALUATIONS ............................................................................................................ 40 
6 
SUPPORTIVE CARE ISSUES ....................................................................................................................... 40 
6.1 
MANAGEMENT OF HYPERTENSION (HTN) ................................................................................................ 40 
6.2 
MANAGEMENT OF QTC PROLONGATION ................................................................................................... 43 
6.3 
MANAGEMENT OF SKIN TOXICITY ............................................................................................................ 43 
6.4 
MANAGEMENT OF GASTROINTESTINAL TOXICITY .................................................................................... 44 
6.5 
MANAGEMENT OF MTC-RELATED DIARRHEA ......................................................................................... 44 
7 
DATA COLLECTION AND EVALUATION ............................................................................................... 44 
7.1 
DATA COLLECTION ................................................................................................................................... 44 
7.2 
GENOMIC DATA SHARING PLAN ............................................................................................................... 46 
7.3 
RESPONSE CRITERIA ................................................................................................................................. 46 
7.4 
TOXICITY CRITERIA .................................................................................................................................. 49 
8 
STATISTICAL CONSIDERATIONS ............................................................................................................ 49 
8.2 
DATA SAFETY AND MONITORING PLAN .................................................................................................... 51 
8.3 
SAMPLE STORAGE, TRACKING AND DISPOSITION ..................................................................................... 52 
9 
COLLABORATIVE AGREEMENTS ........................................................................................................... 53 
9.1 
CLINICAL TRIAL AGREEMENT (00720-07) ................................................................................................ 53 
10 
HUMAN SUBJECTS PROTECTION ........................................................................................................... 53 
10.1 
RATIONALE FOR SUBJECT SELECTION ...................................................................................................... 53 

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10.2 
PARTICIPATION OF CHILDREN ................................................................................................................... 53 
10.3 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT ....................................................................... 53 
10.4 
RISKS AND BENEFITS ................................................................................................................................ 53 
10.5 
RISKS/BENEFITS ANALYSIS ...................................................................................................................... 54 
10.6 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION ......................................................................... 56 
11 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .................. 57 
11.1 
DEFINITIONS ............................................................................................................................................. 57 
11.2 
NCI-IRB AND CLINICAL DIRECTOR REPORTING ...................................................................................... 59 
11.3 
IND SPONSOR REPORTING CRITERIA ........................................................................................................ 60 
11.4 
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS .......................................... 61 
12 
PHARMACEUTICAL INFORMATION ...................................................................................................... 62 
12.1 
VANDETANIB (IND #77570) ..................................................................................................................... 62 
12.2 
ENALAPRIL ............................................................................................................................................... 66 
13 
REFERENCES ................................................................................................................................................. 68 
14 
APPENDIX 1: PERFORMANCE STATUS SCALES/SCORES ................................................................ 71 
15 
APPENDIX 2: NORMAL BLOOD PRESSURE RANGE FOR CHILDREN ........................................... 72 
16 
APPENDIX 3: PHARMACOKINETIC WORKSHEET FOR VANDETANIB ........................................ 75 
17 
APPENDIX 4: MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL OR INDUCE 
TORSADES DE POINTES ....................................................................................................................................... 77 
18 
APPENDIX 5: AS OF AMENDMENT J: CARE, MONITORING AND MANAGEMENT OF ALL 
PATIENTS REMAINING ON STUDY ON LONG TERM VANDETANIB THERAPY .................................. 82 
19 
APPENDIX 6: VANDETANIB PACKAGE INSERT .................................................................................. 87 
 
 
 

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PRECIS 
Background 
x Hereditary medullary thyroid carcinoma (MTC), which is a rare calcitonin-producing 
tumor arising from the parafollicular C cells of the thyroid, is often a manifestation of 
multiple endocrine neoplasia (MEN) types 2A and 2B and can be detected in children as 
young as 5 years in MEN 2A and 1 year in those with MEN 2B. 
x MEN results from an activating mutation in the RET proto-oncogene resulting in a 
constitutively activated receptor tyrosine kinase (RTK). 
x Vandetanib is an orally bioavailable multi-RTK inhibitor that blocks the mutant RET 
gene product and has anti-tumor activity in adults with hereditary MTC. 
Objectives 
x To assess the activity of vandetanib in children and adolescents with hereditary MTC 
using RECIST (primary endpoint), tumor biomarkers and tumor-related diarrhea. 
x To assess the safety and tolerance of vandetanib in children and adolescents at a dose 
equivalent to the recommended dose in adults. 
x To assess the pharmacokinetics of vandetanib at steady state in children and adolescents. 
x Secondary objectives include monitoring progression-free and overall survival, assessing 
RET, EGFR, VEGFR and somatostatin receptor expression in archival tumor tissue, 
assessing changes in DNA mutations in RET in tumor tissue vs. germ line in PBMC and 
after treatment; assessing gene expression and gains/losses of DNA in tumor tissue at 
baseline, during treatment and at the time of progression; establishment of pediatric MTC 
cell lines to assess the effects of vandetanib on RET activation and signaling pathways in 
sensitive and resistant cells lines in vitro. 
Eligibility 
x Children and adolescents 5 to 18 years of age (inclusive) with unresectable, recurrent or 
metastatic hereditary medullary thyroid carcinoma. 
x Measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors). 
Design 
x Vandetanib will be administered as a once daily dose, continuously (1 cycle = 28 days) at 
a dose of 150 mg/m2/d. 
x To ensure the safety of the adult dose in children and adolescents, a limited intra-patient 
dose escalation will be performed in the initial cohort of patients, with older patients (13-
18 yrs) being studied before younger patients (5-12 yrs). 
x Patients will be enrolled at a dose of 100 mg/m2/d (180 mg/d in adults) for two 28 day 
cycles and escalated to 150 mg/m2/d (270 mg/d in adults) on cycle 3, if dose-limiting 
toxicity was not observed at the lower dose.  If the 150 mg/m2/d dose level is tolerable on 
cycles 3 and 4, all subsequent patients will be enrolled at this dose level. 
x Pharmacokinetics of vandetanib will be studied at steady state at the end of cycle 2 and 
trough levels will be obtained prior to the second dose on cycle 1, and on day 1 of cycles 
2-5. 
x Response of measurable tumors will be assessed by RECIST. Biomarker and clinical 
response will also be monitored.  Twenty-one patients will be studied to determine if the 

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response rate in children and adolescents with hereditary MTC is consistent with the 28% 
objective response rate in adults. 

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1 
 
INTRODUCTION 
1.1 
 Study Objectives 
1.1.1 PRIMARY OBJECTIVES 
x To assess the activity of daily oral vandetanib in children and adolescents with hereditary 
medullary thyroid carcinoma (MTC) by measuring: 
o change in tumor size compared to baseline using RECIST (primary endpoint); 
o change in tumor biomarkers (calcitonin and CEA) compared to baseline; and  
o change in tumor-related diarrhea (frequency and consistency), compared to 
baseline. 
x To assess the safety and tolerance of vandetanib in children and adolescents at a dose that 
is equivalent to the recommended dose in adults using a limited intra-patient dose 
escalation. 
x To assess the pharmacokinetics of vandetanib at steady state (end of cycle 2) in children 
and adolescents with hereditary MTC. 
1.1.2 EXPLORATORY OBJECTIVES 
x To determine the progression-free survival and overall survival in children and 
adolescents with hereditary MTC treated with vandetanib. 
x To assess the expression of RET, EGFR, VEGFR and somatostatin receptor by 
immunohistochemistry in archival tissue blocks from children and adolescents enrolled 
on this protocol. 
x To assess gene expression by microarray prior to and during treatment with vandetanib. 
x To screen for gains or losses of DNA sequences in tumor tissue using comparative 
genomic hybridization. 
x To perform RET gene mutational analysis in tumor and peripheral blood mononuclear 
cells prior to treatment and in tumor at the time of disease progression on treatment with 
vandetanib to discover tumor-specific somatic mutations that may be responsible for drug 
resistance. 
x To establish pediatric MTC cell lines and investigate the effects of vandetanib on cell 
proliferation, RET activation and signaling pathways in vitro in cell lines from patients 
with sensitive and resistance tumors. 
1.2 
 Background and Rationale 
1.2.1 HEREDITARY MEDULLARY THYROID CARCINOMA (MTC) 
Medullary thyroid carcinoma (MTC) is a rare, calcitonin (CTN)-producing tumor that arises 
from neural crest derived parafollicular C cells of the thyroid gland. MTC accounts for <10% of 
thyroid cancers in the U.S., and hereditary MTC, which is usually bilateral and multicentric, 
accounts for 25% to 30% of MTC cases.1,2 
Hereditary MTC is divided into three distinct clinical subtypes.  Multiple endocrine neoplasia 
(MEN) 2A, or Sipple’s syndrome, is the most common subtype, accounting for approximately 
70% to 80% of patients with hereditary MTC.  MEN 2A is characterized by MTC in 100% of 
affected individuals, by pheochromocytoma in 50%, and by primary hyperparathyroidism in 
20%. MTC is usually the first manifestation of the syndrome. Patients typically present with a 

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thyroid nodule or neck mass by 15 to 20 years of age, but MTC can appear as early as 5 years of 
age.1-3 
MEN 2B is less common than MEN 2A, accounting for approximately 5% of MTC cases. It is 
characterized by a clinically more aggressive form of MTC that is manifest at a younger age 
(second decade) and that occurs in 100% of affected individuals, by pheochromocytoma in 50%, 
and by characteristic dysmorphic features including distinctive mucosal neuromas on the tongue, 
lips, and subconjunctival areas, diffuse ganglioneuromas of the gastrointestinal tract, and 
marfanoid habitus. Hyperparathyroidism is not associated with MEN 2B.1,3,4  
Familial MTC is the third clinical subtype of inherited MTC.  It accounts for 10% to 20% of 
hereditary MTC cases and is defined by the presence of MTC in kindreds with four to 10 or more 
affected members and with objective evidence of the absence of adrenal and parathyroid gland 
involvement. This form of hereditary MTC is less aggressive and has an older age at onset, 
usually between 20 and 40 years, compared to MEN 2A and 2B.5,6 
MTC is the most common cause of death in patients with MEN 2a, MEN 2b, or FMTC, and the 
tumor is relatively unresponsive to conventional doses of radiation therapy and to standard or 
novel chemotherapeutic regimens.2,7-13 Surgery is the only standard treatment. Patients with 
MTC can be cured only by thyroidectomy, but only when it is performed at a time when the 
tumor is confined to the thyroid gland.  Early recognition through genetic screening and 
detection of one of the characteristic mutations (see below) followed by prophylactic 
thyroidectomy has become the standard of care.14,15  The timing and extent of the prophylactic 
surgery is determined by germline mutational analysis.2,16,17  In three large series, patients who 
were detected by screening and who subsequently had prophylactic total thyroidectomy had 5 
and 10 years survival rates approaching 100%.7,8,18  However, genetic screening is only 
applicable to those with a family history of MEN or FMTC.  There is no treatment (apart from 
complete surgical removal) that has been shown to be effective for recurrent or persistent 
MTC.19  
In published series, which span many years, over half of patients with MEN 2A and 2B present 
with advanced (stage 3) or metastatic disease, and a majority of the patients with MEN 2B 
represent new mutations, that could not have been detected early by genetic screening.7,8  MTC 
metastasizes to local and regional lymph nodes, lung, bone and liver.  The survival in patients 
with advanced or residual local tumor or metastatic disease can be prolonged and even patients 
with metastatic MTC can remain asymptomatic and live for many years.2,8  Survival in patients 
who are not cured by thyroidectomy and have persistent local or metastatic disease is 80% and 
70% at 5 and 10 years, and 5-year survival rate for patients with stage 4 disease exceeds 50%.7,8 
1.2.2 MTC BIOMARKERS 
The primary secretory product of thyroid C cells and MTC is CTN, which is an excellent tumor 
marker that correlates well with tumor bulk.20-22 Basal or stimulated CTN values are almost 
always elevated with MTC.2,22 Similarly, elevated CTN values after surgery are generally the 
first sign of persistent or recurrent disease. The physiologic role of CTN remains unclear.23  It 
may play a role in calcium regulation through its effects on 3 target organs: bone (resorption), 
kidney (calcium excretion), and gastrointestinal (GI) tract,24 but an excess or deficiency of CTN 
does not appear to have a significant pathologic effect and some believe that it is vestigial and 
has no function.  Extremely high levels (>30,000 pg/ml) of serum CTN can cause symptomatic, 
intractable diarrhea and are usually associated with metastatic MTC.25 

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MTC cells also secrete carcinoembryonic antigen (CEA) and several biogenic amines, in 
addition to CTN. As with CTN, CEA levels are generally proportional to tumor burden and, as a 
result, CEA is a useful, although nonspecific, tumor biomarker.26 
1.2.3 GENETICS OF MEN 2 AND MTC 
MEN 2 syndrome is an autosomal dominant inherited disorder that is caused by germline 
activating mutations in the RET (REarranged during Transfection) proto-oncogene, which has 21 
exons.26,27 MEN 2 mutations are localized in exons 10, 11, and 13 to 16 (see Table below). 
Missense mutations at one of six cysteine codons (609, 611, 618, 620, 630 at exon 10 and 634 at 
exon 11), which result in the substitution of any one of these extracytoplasmic cysteines by a 
different amino acid, are responsible for the majority of cases of MEN 2A (93–98%).3,14 In more 
than 95% of cases, MEN 2B is associated with a point mutation in the methionine residue in 
exon 16 (codon 918) in the intracellular tyrosine kinase receptor domain of RET.28 Mutations are 
de novo in about 50% of MEN 2B cases; therefore, many patients with MEN 2B lack a family 
history of the disease and thus would not otherwise be targeted to undergo early screening and 
prophylactic thyroidectomy. These MEN 2B patients often experience a delay in diagnosis until 
signs of mucosal neuromas or palpable thyroid tumors are obvious.  
Domain 
Exon 
Codons 
Syndrome 
Cadherin-like 
 
 
 
Cysteine-rich 
10 
609, 611, 618, 620, 630 
MEN 2A, FMTC 
11 
634 
MEN 2A, FMTC 
Transmembrane 
 
 
 
Tyrosine kinase 1 
13 
768, 790, 791 
MEN 2A, FMTC 
14 
804, 844 
MEN 2A, FMTC 
Tyrosine kinase 2 
15 
883 
MEN 2B 
16 
918 
MEN 2B 
The RET protooncogene is located on chromosome 10 and encodes for a receptor tyrosine kinase 
module.  The RET protein contains an extracellular ligand  binding domain, a transmembrane 
region, and an  intracellular tyrosine kinase region. The ligands known to interact with RET 
include Glial-derived neurotrophic  factor (GDNF), neuturin, persephin, and artemin.  There is 
also a family of membrane bound co-receptors  termed GFRa-1, -2, -3, and -4. To activate RET, 
the ligand first binds with the requisite co-receptor, which then interacts on the cell membrane 
with the RET protein to cause receptor dimerization and initiation of  intracellular signaling 
through the tyrosine kinase  domains.17  Because the mutations to RET in MEN and MTC are 
activating, the RET RTK is a potential direct therapeutic target in this disease. 
1.2.4 VANDETANIB (ZD6474, ZACTIMA) 
Mechanism of Action 

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Vandetanib is a small molecule receptor tyrosine kinase (RTK) inhibitor (see Table below) that 
potently inhibits vascular endothelial growth factor receptor-2 (VEGFR-2, KDR) tyrosine kinase 
activity (IC50 = 40 nM), and it also inhibits RET receptor tyrosine kinase (IC50 = 100 nM), Flt-4 
(VEGF receptor-3: IC50 = 110 nM) and EGF receptor tyrosine kinases (IC50 = 500 nM).29,30  
Vandetanib also inhibits the kinase activity of RET oncoproteins (although its affinity for all of 
the known mutated forms of RET in MEN 2A and 2B has not been studied) and blocks in vivo 
phosphorylation and signaling of the RET/papillary thyroid carcinoma and RET/MEN2B 
activated oncoproteins.29,31 Notably, RET/MEN2B phosphorylation and RET/ MEN2B-
dependent MAPK activation were inhibited by vandetanib in vivo at tolerable doses.  The growth 
of cells expressing the RET/PTC oncoprotein was also inhibited in vitro and in vivo.29 
Vandetanib inhibition of VEGF receptor tyrosine 
kinase activity and selectivity profile32,33 
Kinase 
Mean (± SE) 
IC50 (μM)* 
Fold selectivity 
versus KDR† 
KDR 
0.04 ± 0.01 
- 
Flt-4 
0.11 ± 0.02 
2.7 
RET 
0.13 
2.5 
Flt-1 
1.6 ± 0.4 
40 
EGFR 
0.5 ± 0.1 
12.5 
PDGFRβ 
1.1 ± 0.3 
27.5 
Tie-2 
2.5 ± 1.2 
62.5 
FGFR1 
3.6 ± 0.9 
90 
MEK 
>10 
>250 
CDK2 
>10 
>250 
c-Kit 
>20 
>500 
ErbB2 
>20 
>500 
FAK 
>20 
>500 
PDK1 
>20 
>500 
AKT 
>100 
>2500 
IGF-1R 
>200 
>5000 

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* 
Data represent the mean ± SE of at least 3 separate determinations. IC50 values quoted as 
“greater than” denote the inability to reach an IC50 value with the highest concentration tested. 
† 
Ratio for the IC50 obtained with a given kinase compared to that achieved versus KDR. 
Vandetanib also has broad-spectrum antitumor activity in vivo, in a range of models 
(subcutaneous or orthotopically implanted human tumor xenografts or syngeneic murine tumors) 
and histological types (lung, colon, breast, prostate, ovarian, vulval).33  Vandetanib has also been 
shown to inhibit tumor metastases in liver, lung and lymph nodes with a variety of tumors 
types.33  Reduced CD31 (endothelial cell) staining and increased tumor cell necrosis has been 
observed in human tumor xenografts from mice treated chronically with vandetanib (once-daily, 
orally, for 24 days), consistent with inhibition of angiogenesis and tumor vascular permeability.  
This is supported by dynamic contrast-enhanced MRI 24 hours post-vandetanib demonstrating a 
dose-dependent reduction in tumor ktrans, consistent with a reduction in vascular permeability, in 
mice bearing human prostate tumor xenografts.34 
Preclinical Toxicology 
The preclinical safety evaluation of vandetanib revealed: 
x Elevated plasma alanine transaminase (ALT), aspartate transaminase (AST), and GLDH 
activities; hepatocellular necrosis; and acute cholangitis were seen at the highest doses 
used in the rat 1-month and 6-month studies. 
x Gastrointestinal tract toxicity (body weight loss, emesis, and diarrhea) was the dose-
limiting in dogs, but there were no associated histopathological findings. 
x Renal papillary necrosis was observed at the higher doses in the 1-month rat study, but 
this finding was not seen in the 6-month rat study or in any dog study. 
x Histopathological and ultrastructural changes, consistent with the induction of 
phospholipidosis, were observed in rats at the 1- and 6-month studies. No histological 
evidence of phospholipidosis was observed in dogs in any study.  Vandetanib has 
physiochemical properties, which have been shown to induce excessive accumulation of 
intracellular phospholipids. 
x The muzzle region of the skin of rats receiving the higher doses of vandetanib in the 1- 
and 6-month studies showed dose-related acute folliculitis and epidermal microabscess 
formation. 
x As expected from its antiangiogenic properties, vandetanib has shown significant effects 
on all stages of female reproduction in rats. These effects were characterized by the 
following: 
o decreased numbers of corpora lutea in the ovaries of rats. 
o increased estrus cycle irregularity and a dose-related increase in early intrauterine 
deaths, resulting in reduced number of live embryos and increased post-
implantation loss. 
o embryofetal developmental toxicity in the rat, indicated by embryofetal loss, 
delayed fetal development, heart vessel abnormalities and precocious ossification 
of some skull bones. 
x Vandetanib produced a dose-dependent increase in the femorotibial epiphyseal zone 
of hypertrophy in growing rats when dosed daily for 14 days (an observation 
consistent with an ability to inhibit VEGF signaling and also angiogenesis in vivo). 
x Vandetanib elevated systolic and diastolic blood pressure in telemetered rats. 

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x Vandetanib shows evidence of phototoxicity potential 
x Vandetanib had no effect on male fertility in rats and no mutagenic or clastogenic 
potential. 
Preclinical Pharmacology 
The pharmacokinetics and metabolism of vandetanib was studied in animals after oral and 
intravenous (IV) administration in the rat and dog and revealed: 
x The bioavailability after oral dosing was high (>90% in the rat and >33% in the dog). 
There was evidence of slightly lower bioavailability in the rat at higher doses (72 to 
78%). The absorption was not rapid, with peak concentrations occurring 3-8 hours post 
dose. At higher doses in rats and dogs, C x T profiles were flat, indicating prolonged 
absorption. 
x After an IV dose of 5 mg/kg in rats, the clearance rate was 30 L/kg and the terminal half-
life was 16 to 31 h. After a single IV dose (5 mg/kg) in dogs, the clearance was 85 
ml/min/kg and the half-life was 8 h.  The volume of distribution was 45 L/kg.  
x Plasma protein binding ranged from 83% in rats to 90% in human plasma. Vandetanib 
was shown to bind to both human serum albumin and human α-1- acid glycoprotein. 
x Toxicokinetic monitoring in rats showed dose proportional increases between 1 and 10 
mg/kg, but a less than proportional increase in exposure between 25 and 75 mg/kg. 
Administration to rats for 6 months at 5 mg/kg resulted in a 3-fold increase in exposure 
(accumulation). There was evidence of a small degree of accumulation in the dog (13%) 
in the 1-month toxicity study that was confirmed in the 9-month toxicology study. 
x After 14C-vandetanib administration to rats, radioactivity (parent drug + metabolites) was 
rapidly and extensively distributed, with the highest concentrations in the gastrointestinal 
tract, liver, spleen, adrenal glands and other glandular tissues. 
x Two metabolites have been identified in samples from rats and dogs: the N-oxide of 
vandetanib and N-desmethyl vandetanib. These metabolites and a vandetanib glucuronide 
have been identified in humans. N-desmethyl vandetanib is primarily produced by 
CYP3A4 and N-oxide vandetanib by flavine-containing mono-oxygenase enzymes 
FMO1 and FMO3. 
x Vandetanib had no inhibitory effect on the activity of human CYP1A2, 2C9, 2C19, or 
3A4, but did inhibit 2D6 activity (ki of 13 μg/ml). 
x Urinary recoveries after 14C-vandetanib in rat and dog ranged from 4-12% of the dose. 
The majority of the radioactivity was recovered in the feces. Studies in rat demonstrated 
both biliary excretion and enterohepatic recirculation of vandetanib-related material. 
Clinical Trials 
Vandetanib has been administered to over 500 adults who were enrolled in 16 clinical trials, 
including 2 phase I trials in cancer patients,35,36 6 phase I/pharmacokinetic studies in healthy 
volunteers, and 8 phase II trials in NSCLC, SCLC, breast cancer, multiple myeloma and MTC 
(see Section 1.2.5). 
The recommended adult dose of vandetanib is a fixed dose of 300 mg/d, administered 
continuously. The most common adverse events related to vandetanib are skin rashes, diarrhea, 
hypertension, and asymptomatic prolongation of the electrocardiogram QTc interval. These 
events are dose-dependent. At a dose of 300 mg/d, QTc prolongation resulting in dose reduction 

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has been seen in less than 15% of patients. No patient with QTc prolongation reported symptoms 
or developed cardiac arrhythmia that could be exclusively attributed to QTc prolongation or 
other cardiac arrhythmia. 
In the U.S. phase I trial conducted in adult patients with refractory solid tumors, patients received 
once-daily oral vandetanib (50-600 mg) in 28-day cycles. Seventy-seven patients were treated at 
doses of 50 mg (n=9), 100 mg (n=19), 200 mg (n=8), 300 mg (n=25), 500 mg (n=8), and 600 mg 
(n=8). Adverse events were generally mild. The most common drug-related adverse events were 
diarrhea (n = 29), rash (n = 26), nausea (n = 15), hypertension (n = 14), fatigue (n = 14), anorexia 
(n = 10), acneiform rash (n = 9), and maculopapular rash (n = 8). Drug-related adverse events 
that led to treatment discontinuation were congestive cardiac failure, follicular rash, folliculitis 
and prolonged QT interval (all n = 1). The most common dose-limiting toxicities (DLT) were 
diarrhea (n=4), hypertension (n=4), and rash (n=3). The incidence of most adverse events 
appeared to be dose-dependent. In the 500 mg/day cohort, 3/8 patients experienced DLT and this 
dose was therefore considered to exceed the maximum tolerated dose. Once-daily oral dosing of 
vandetanib at 300 mg/d was generally well tolerated in patients with advanced solid tumors, and 
this dose was recommended phase II trials.35 
In the largest monotherapy vandetanib study conducted to date comparing vandetanib to 
gefitinib,37 the most frequent adverse events observed with vandetanib were diarrhea (55.4%, 
grade 3 or 4, 8.4%), fatigue (36.1%), rash (27.7%, grade 3 or 4, 4.8%), nausea (24.1%), and 
grade 1 QTc prolongation (20.5%). Approximately 10% of subjects who received vandetanib 
developed hypertension, the majority of which was CTC grade 1 or 2. Three subjects  developed 
CTC grade 3 hypertension, and none were CTC grade 4. The median increase in systolic blood 
pressure for subjects who  received vandetanib was 10 mmHg; the median increase in diastolic 
blood pressure was  6 mmHg. 
An increased incidence of SAEs was noted in subjects who received vandetanib compared to 
those who received gefitinib (44.6% vs. 35.3%). Cardiac disorders (6.0% vs. 1.2%),  
gastrointestinal disorders (6% vs. 2.4%, mainly diarrhea), and respiratory disorders (13.3% vs.  
8.2%) did occur more frequently in subjects receiving vandetanib. The cardiac events included a  
variety of terms without any apparent pattern. Respiratory events were primarily those that  
would be anticipated in subjects with advanced lung cancer. Three subjects receiving vandetanib  
developed pulmonary embolism and 3 subjects developed interstitial lung disease, but cases  
were confounded by such factors as smoking, reduced mobility, infection, lung cancer  
progression and previous chemotherapy or radiation therapy. One subject in each arm  developed 
a serious skin disorder. One subject who received vandetanib developed a  hematologic event, as 
did 2 subjects who received gefitinib. No subjects who received  vandetanib developed serious 
hepatotoxicity. 
Thirteen adverse events on study were followed by an outcome of death, 7 in the vandetanib arm 
(ARDS, pneumonia, pneumonitis, dyspnea, interstitial lung disease, respiratory failure and 
carcinomatous meningitis) and 6 in the gefitinib arm (breathlessness, bone pain, cellulitis, acute 
respiratory failure (2 cases) and pleural effusion). 
There were 12 subjects with confirmed QTc prolongation. Of these, 6 occurred in the first 28 
days, and 2 in the following 28 days. The remaining 4 occurred sporadically, with the longest 
time to occurrence of 323 days. There were 3 events of CTC grade 1 reversible dizziness in 
subjects with a confirmed QTc prolongation occurring within the first 4 weeks. Subjects with 

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14 
dizziness had other events that might have caused dizziness and the events were not well 
correlated in time with the actual QTc prolongation. There were no other potentially relevant 
adverse events in subjects with confirmed QTc prolongation within the first 4 weeks, and no 
relevant adverse events in subjects whose first confirmed QTc  prolongation occurred more than 
4 weeks after randomization. 
Evidence of an advantage for progression-free survival in NSCLC was seen with vandetanib 300 
mg compared with gefitinib, and in the combination of vandetanib 100 mg and docetaxel 
compared to docetaxel alone. These progression advantages did not translate into a 
corresponding advantage for overall survival in preliminary data.  These observations have led to 
phase III trials of vandetanib in NSCLC.32,37 
In April 2011, the U.S. Food and Drug Administration (FDA) approved vandetanib for the 
treatment of advanced (metastatic or unresectable locally advanced) medullary thyroid cancer 
under the orphan drug designation at a recommended daily dose of 300 mg.  
Human Pharmacokinetics and Metabolism 
In healthy subjects, vandetanib absorption appeared to be relatively slow with a median tmax of 6 
h (range, 4-10 h). From the Cmax, plasma levels declined in a biexponentially with a terminal 
half-life of about 10 days. In population pharmacokinetic modeling, vandetanib was best 
described by a two-compartment, first order absorption, first order elimination with lag-time 
model, with a CL/F of 14 L/h and a volume of distribution of 4590 L. After single doses over the 
dose range 300-1200 mg, exposure appeared to increase in proportion to the dose. There was no 
effect of food on the either AUC or Cmax. There was no pharmacokinetic interaction with the 
potent inhibitor of CYP3A4 itraconazole or with the 5HT3 antagonist ondansetron. 
The recovery of [14C]-vandetanib was slow and both biliary (44%) and renal (25%) routes of 
excretion were important in its elimination. Vandetanib and its N-desmethyl and N-oxide 
metabolites were detected in the systemic circulation. Vandetanib, the N-oxide, the N-desmethyl, 
and a glucuronide metabolite were identified in urine and feces. 
The inhibitory activity of N-desmethyl and N-oxide metabolites of vandetanib, were examined in 
a growth factor stimulated HUVEC proliferation assay. N-desmethyl vandetanib retained similar 
potency against VEGFR and selectivity (versus EGF and bFGF) to the parent drug, whereas the 
N-oxide of vandetanib had relatively weak activity in cells (IC50 >3 μM) against the growth 
factor stimuli examined. 
In patients,35,36 the absorption of vandetanib appeared to be more variable and prolonged than in 
healthy subjects, with median tmax of 4-10 h and a larger range of 1-24 h. Population 
pharmacokinetic modeling showed a CL/F of 6.43 
L/h, a volume of distribution of 6260 L, and an 
estimated terminal half-life of about 20 days. Over 
the dose range 100-600 mg, exposure appeared to 
increase in a dose-proportional manner. Trough 
levels indicate that a minimum of 28 days of daily 
dosing is required to achieve steady state plasma 
concentrations, with about a 10-fold (range, 3- to 
30-fold) accumulation compared to a single dose. 
N
N
N
O
O
CH3
N
Br
F
H
CH3
HN
N
O
O
H3C O-
Vandetanib
Desmethyl vandetanib
Vandetanib N-oxide

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15 
1.2.5 PHASE I AND II TRIALS OF VANDETANIB IN CHILDREN AND ADULTS WITH MTC 
A phase II single arm, open label trial of daily oral vandetanib at a dose of 300 mg is ongoing in 
adults with hereditary MTC (MEN 2a, MEN 2B, and FMTC).26  Patients enrolled on this trial are 
required to have a characteristic germline RET mutation.  The most common adverse events 
observed in the first 14 patients enrolled on the trial include diarrhea (11), rash (10), headache 
(9), dysphagia (8), and fatigue (8), dizziness (7), and urinary tract infection (7).  Four SAEs were 
observed in 3 of the first 14 subjects that included a GI obstruction and GI hemorrhage in 1 
subject (unrelated to study drug) and a grade 3 dysphagia (n=1) and grade 3 diarrhea (n=1) that 
were both attributed to study drug.  Four subjects experienced QTc prolongation on study. 
Response data are available in the 30 patients enrolled on the adult phase II trial.  Seven (23%) 
of 30 have had an objective response (see the example in the Figure below), 3 have progressed 
and the remainder have stable disease (<30% decrease in tumor size).  Reduction in tumor size is 
gradual (up to 2 years to achieve a PR) and responses have been durable.  All patients have had a 
>50% reduction in CTN levels and 70% have had a >50% reduction in plasma CEA. 
As on 7/16/08, five children have been enrolled on this trial, including 3 in older age group and 2 
in the younger age group.  One of the older patients had progressive disease after 2 cycles and 
was removed from the study.  The other two older patients tolerated the 2 cycles at 100 mg/m2/d 
and their dose was escalated to 150 mg/m2/d on cycle 3.  One of these two patients experienced 
dose-limiting diarrhea requiring a dose reduction.  The two younger patients have been treated at 
the 100 mg/m2/d dose and have tolerated it well.  The patient experiencing progressive disease 
did not have the codon 918 mutation typical for MEN-2B.  The remaining 4 patients have this 
mutation and the phenotypic features of MEN-2B. Three of the 4 have been restaged on 
treatment at least once and all have a >80% reduction in serum CTN, a >40% reduction in serum 
CEA and a 15 to 19% reduction in tumor size by RECIST. 
1.2.6 STUDY RATIONALE 
Vandetanib is a molecularly targeted RTK inhibitor that blocks the mutant RET oncoprotein, 
which is believed to play a key role in the pathogenesis of hereditary MTC.  In adults with 
hereditary MTC, vandetanib at a dose of 300 mg/d has an objective response rate of 28% in a 
tumor that has been refractory to standard chemotherapy and radiation therapy, and the drug has 
been well tolerated. The purpose of this trial is to confirm this response rate in children and 
adolescents with hereditary MTC.  This trial is likely to enroll a much higher fraction of patients 
with MEN 2B-related MTC than the adult trial, because the tumors occur at a younger age in 
MEN 2B and because most patients with this syndrome represent new mutations and, as a result, 
usually present with advanced (stage 3) or metastatic disease. 
A phase I, dose finding component is built into this trial, because there are no completed phase I 
trials of this agent in children.  The trial uses an intra-patient dose escalation design in order to 
ensure that all patients receive the equivalent dose to that used on the adult phase II trial (if it is 
tolerated) and that all patients are evaluable for the phase II portion of the trial.  The dose 
escalation portion of the trial will be performed in the initial cohort of 3 to 6 patients who are 13 
to 18 years old followed by the first 3 to 6 patients who are 5 to 12 years old. Two dose levels 
(100 and 150 mg/m2/d) will be studied and the drug will be dosed based on body surface area in 
children and adolescents.  The first dose level (100 mg/m2/d) is equivalent to 60% of the adult 
MTD and the second dose level (150 mg/m2/d) is equivalent to 90% of the adult MTD of 300 
mg/d.  In a recent review comparing the results of pediatric and adult phase I trials,38 the MTD in 

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16 
children exceeded the adult MTD for two-thirds of the agents, and in all but one case (all-trans-
retinoic acid), the pediatric MTD was at least 60% of the adult MTD.  These authors also 
evaluated the ratio of pediatric to adult drug clearance for a variety of agents in this meta-
analysis and the median ratio was 1 (clearances were equivalent when normalized to BSA).  
Pharmacokinetic studies will be performed at steady state (end of cycle 2) on this trial. 
The phase II portion of the trial was designed to have similar eligibility criteria and response 
criteria as the ongoing phase II trial in adults with hereditary MTC (Section 1.2.5).  Although 
objective radiographic response using RECIST is the primary endpoint, biomarker (CTN and 
CEA) and clinical response (diarrhea) will also be monitored.  Because the drug has 
demonstrated activity in adults with the same cancer, the trial uses a single-stage design – 
without an early futility evaluation. 
The trial includes several secondary objectives to document progression-free and overall 
survival, to assess expression of the molecular targets of vandetanib and somatostatin receptor in 
archival tumor tissue, and to assess gene expression, secondary genetic changes and RET 
mutational status in tumor tissue prior to the start of therapy and at the time of response and 
progression in selected patients who are over 12 years of age and who have easily accessible 
tumors for biopsy, and to establish pediatric MTC cell lines from biopsy or surgical specimens to 
study the effects of vandetanib on proliferation, RET activation and signaling pathways in cell 
lines from patients with clinically sensitive and resistant tumors.  Although exploratory, these 
studies will be critical to assess the effect of treatment on signaling pathways in the tumor and to 
determine if somatic mutations to RET in the tumor are responsible for de novo or acquired 
resistance to vandetanib. 
Dr. Frank Balis served as the Adjunct Principal Investigator on this trial until June 27, 2017.  Dr. 
Balis designed and has led this phase I/II trial of vandetanib in children.   
Update on trial status July 2012: Since initiation of the trial 16 patients were enrolled, 10 in the 
adolescent cohort (age 13-18 years) and 6 in childhood cohort (age 5-12 years). Vandetanib has 
been well tolerated without evidence of cumulative toxicity.  One of 6 patients 5-12 years old 
enrolled at 100 mg/m2/dose developed dose-limiting diarrhea. Of 8 adolescents 13-18 years old, 
who were eligible to receive vandetanib at 150 mg/m2/dose, one developed dose-limiting 
diarrhea, one had a dose reduction for non dose-limiting diarrhea, and one patient had a dose 

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17 
reduction for non-dose-limiting hypertension in presence of baseline bradycardia. Common non-
dose-limiting toxicities included prolonged QTc interval, hypertension, diarrhea, rash and TSH 
elevation necessitating an increase in levothryroxine dosage in athyrotic patients who were 
previously on a stable dose. Patients received a median (range) of 27 (2-52) cycles. For subjects 
with M918T RET germline mutations (n=15) the confirmed objective partial response rate was 
47% (95%CI, 34%, 60%). Durable responses were achieved in children and adolescents at 150 
mg/m2/d (n=2, duration 40-52 cycles), 100 mg/m2/d (n=4, duration 20-44 cycles) and 67 
mg/m2/d (n=1, 48 cycles). While both dose levels were tolerated in the patients studied, the 
activity of vandetanib at the 100 mg/m2 dose level combined with the better tolerability of 
vandetanib was recommended for pediatric patients with MTC.  
Update on trial status Amendment J:  This trial is closed to further accrual as an adequate  
number of subjects have been enrolled to allow us to meet the study objectives.  Eleven subjects 
remain on study drug, which has been approved by the FDA for treatment of symptomatic or 
progressive MTC in adults with unresectable locally advanced or metastatic disease.  All patients 
remaining on the trial have received vandetanib for more than 2 years. In conjunction with 
AstraZeneca, vandetanib will continue to be supplied to subjects on this study as long as they 
meet requirements for continued therapy.  Vandetanib package insert recommendations and 
standard of care clinical practice will be followed in managing these patients.  Data collection 
will be limited to serious adverse events and to data required to make a decision about continued 
treatment, such as response data, while drug accountability will be maintained.  
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
Eligibility Criteria 
2.1.1 INCLUSION CRITERIA 
x Age:  Participants must be 5 to 18 years of age, inclusive. The first cohort of 3 to 6 
participants enrolled on the trial will be at least 13 years of age. 
x Diagnosis:  Hereditary (MEN 2A or MEN 2B) medullary thyroid carcinoma 
(histologically confirmed) that is unresectable, recurrent or metastatic. Participants must 
have previously had a characteristic germline mutation in the RET proto-oncogene 
documented.  Results of the germline mutation testing will be obtained from the referring 
institution. 
x Participants must have measurable disease as defined in RECIST as the presence of at 
least one lesion that can be accurately measured in at least one dimension with longest 
diameter of at least 20 mm using conventional techniques or at least 10 mm with spiral 
CT scan. Superficial (easily palpable) lymph nodes will be considered measurable. 
x Participants must be able to take one of the oral formulations of vandetanib. 
Administration of the liquid formulation via a nasogastric tube or gastrostomy is allowed. 
x Prior therapy:  There are no standard chemotherapy regimens known to be effective for 
MTC.  Therefore, previously untreated participants are eligible if their tumor(s) are not 
surgically resectable. 
o Participants must be at least 4 weeks from prior surgical procedures and surgical 
incisions must be healed. 
o Participants must have had their last fraction of external beam radiation therapy at least 4 
weeks prior to enrollment. 

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o Participants must have had their last dose of cytotoxic chemotherapy at least 28 days 
prior to enrollment, their last dose of biological therapy, such as biological response 
modifiers (e.g., cytokines), immunomodulatory agents, vaccines, differentiating agents, 
used to treat their cancer at least 7 days prior to enrollment, their last dose of a 
monoclonal antibody at least 30 days prior to enrollment, and their last dose of any 
investigational agent at least 30 days prior to enrollment. 
o Participants must have received their last dose of short acting colony stimulating factor, 
such as filgrastim or sargramostim at least 72 hours prior to enrollment and their last dose 
of long-acting colony stimulating factors, such as PEG-filgrastim at least 7 days prior to 
enrollment. 
o Participants must have recovered from the acute toxic effects of prior therapy to a grade 1 
(CTCAE v.3.0) level prior to enrollment. 
x Performance Status:  Lansky (for participants 10 years of age or younger) or Karnofsky 
(for participants older than 10 years) performance score greater than 50 (Appendix 1: 
Performance Status Scales/Scores) 
x Concomitant Medications: 
o Participants who have previously had a thyroidectomy should be on thyroid 
hormone replacement therapy. 
x Hematological Function:  The peripheral absolute neutrophil count must be at least 
1,500/μL and the platelet count must be at least 100,000/μL within 72 hours prior to 
enrollment. 
x Coagulation:  PT and PTT must not be more than 1.5 x ULN within 72 hours prior to 
enrollment. PT and PTT should be drawn by venipuncture, rather than from a central 
venous catheter when feasible. 
x Hepatic Function: Bilirubin must not be more than 1.5 x ULN and the AST and ALT 
must not be more than 2.5 x ULN within 72 hours prior to enrollment. AST and ALT 
may be up to 5 x ULN within 72 hours prior to enrollment in participants with hepatic 
metastases. 
x Renal Function: Participants must have an age-adjusted normal serum creatinine (see 
Table) or a creatinine clearance of at least 60 ml/min/1.73 m2. 
 
Maximum Serum Creatinine 
(mg/dL) 
Age (years) 
Male 
Female 
5 to <10 
1 
1 
10 to <13 
1.2 
1.2 
13 to <16 
1.5 
1.4 
16 and older 
1.7 
1.4 
x Birth Control: Participants of child-bearing or child-fathering potential must be willing to 
use a medically effective form of birth control, which includes abstinence, while taking 
vandetanib and for 2 months after the last dose. 

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19 
x Negative pregnancy test for women of childbearing potential. 
x Informed Consent: Participants who are 18 years of age or legal guardians of participants 
who are younger than 18 years must sign an informed consent for the POB Screening 
Protocol prior to participating in studies required to determine eligibility for this trial. 
After confirmation of eligibility, participants or legal guardians of minor participants 
must sign an informed consent document for this trial, indicating that they are aware of 
the investigational nature of the proposed treatment, the risks and benefits of participating 
and the alternatives to participating. 
2.1.2 EXCLUSION CRITERIA 
x Pregnant or breast feeding females because the anti-angiogenic properties of vandetanib may 
be harmful to the developing fetus or nursing infant.  
x Participants with pheochromocytoma as evidenced by elevated plasma free metanephrines. 
x Electrolytes: Participants with a serum potassium less than 3.5 mmol/L or a serum calcium or 
magnesium below the lower limits of normal.  Correction of these electrolyte abnormalities 
with supplements is allowed. 
x Cardiac:  
o Participants with a history of arrhythmia (multifocal premature ventricular contractions, 
bigeminy, trigeminy, ventricular tachycardia, uncontrolled atrial fibrillation, left bundle 
branch block) that is symptomatic or requires treatment (except for controlled atrial 
fibrillation) 
o Participants with a history of congenitally prolonged QTc, a first degree relative with 
unexplained sudden death under 40 years of age, or a measured QTc (Bazett’s correction) 
longer than 480 msec on ECG.  ECGs should be performed after correction of electrolyte 
abnormalities. Participants with a prolonged QTc should have a repeat ECG at least 24 hour 
after the first, and the mean of the 2 QTcs should not exceed 480 msec. 
o Participants who experienced QTc prolongation with other medications requiring 
discontinuation of that medication 
o Participants receiving a medication that has a known risk of QTc prolongation (Appendix 4: 
Medications Known to Prolong the QT Interval or Induce Torsades de Pointes, Group 1) 
within 14 days (28 days for levomethadyl) of enrollment. 
x Hypertension: Diastolic blood pressure above the 95% for age (Appendix 2: Normal Blood 
Pressure Range for Children) on at least 2 of 3 measurements with an appropriate-size cuff or 
patients who are currently taking anti-hypertensive therapy. 
x Other clinically severe or uncontrolled systemic illness that could compromise the 
participant’s ability to tolerate vandetanib or could compromise study procedures or 
endpoints. 
2.1.3 ELIGIBILITY CRITERIA FOR OPTIONAL BIOPSY TO OBTAIN TUMOR FOR RESEARCH 
x Age: Participants must be older than 12 years of age 
x Tumor Location: Easily accessible tumor site that is 
o Superficial 
o Extra-cavitary (i.e., not within the chest or abdominal cavity) 
o Sufficiently distant from vital structures to avoid direct damage from insertion of the biopsy 
needle 
o The biopsy must be taken from within a site that has NOT been previously radiated 

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20 
x Coagulation Studies: Participant must have a platelet count >100,000/mcL and a normal PT 
and PTT within 72 hours of each biopsy 
x Anesthesia: Must be able to perform the biopsy under local anesthesia. 
x Consent/Assent:  The parent/guardian must sign a separate biopsy consent and the participant 
must sign an assent describing the biopsy. 
2.2 
Screening Evaluation 
2.2.1 GENERAL 
x HISTORY AND PHYSICAL EXAMINATION: including vital signs with blood pressure, 
documentation of palpable, measurable disease (longest diameter and location), and a 
description of signs and symptoms is required. Daily stool frequency over the prior 7 
days and consistency (formed, loose or partially formed, watery) should be documented.  
A family history of endocrine neoplasia should also be recorded. 
x HEIGHT, WEIGHT AND BODY SURFACE AREA: The BSA should be calculated from the 
average of 3 repeated measurements of weight and height on the same day by the 
standard formula in use at the NCI: 
BSA Weight  (kg)0.425 Height  (cm)0.725
139.315
 
2.2.2 LABORATORY EVALUATION 
Pre-treatment blood tests should be performed within 72 hours prior to enrollment on the trial 
unless otherwise stated. 
x HEMATOLOGY: complete blood count, differential, platelet count, PT, PTT. 
x CHEMISTRIES: ALT, alkaline phosphatase, bilirubin (total and direct), GGT, BUN, 
creatinine, electrolytes, calcium, magnesium, phosphorus, uric acid, total protein, and 
albumin. 
x Thyroid Stimulating Hormone 
x PLASMA FREE METANEPHRINE AND NOR-METANEPHRINE: Patients must be NPO 8 h prior 
to sampling. No acetaminophen, attention deficit disorder medications, caffeine, alcohol, 
or smoking within 24 hrs prior to the sample. Patient should be supine for 15 min after 
PIV placement and prior to sample being drawn. Draw sample into prechilled tubes and 
place on ice immediately. Values obtained within 8 weeks of trial entry and outside 
values are acceptable. 
x BIOMARKERS: Serum calcitonin (CTN) and CEA.  CTN and CEA should be measured 
during screening.  Serum CTN should be drawn after a 12 hour fast and sent to the lab 
immediately at room temperature. 
x URINE OR SERUM PREGNANCY TEST: required for females of childbearing potential.  
2.2.3 PERFORMANCE SCORE 
Lansky (for participants 10 years of age or younger) or Karnofsky (for participants older than 10 
years). 
2.2.4 ECG WITH CALCULATION OF QTC 
Use Bazett’s correction (QTc = QT/RR0.5). 

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21 
2.2.5 RADIOGRAPHIC EVALUATION 
Scans should be performed within 28 days prior to enrollment of the study. 
x CT scans of the neck, chest and abdomen 
x MRI of the brain and neck 
x 
99mTc-Bone scan 
x MRI of the knee to assess the growth plates.  Open growth plates will be assessed with 
volumetric measurements prior to and during therapy until the growth plate is closed, as 
documented by MRI or plain x-ray. 
2.2.6 TUMOR BIOPSY 
Percutaneous core needle (16 or 18 gauge) biopsy of superficial (e.g., cervical lymph nodes) 
tumors (not within a body cavity) will be performed if it can be done under local anesthesia with 
minimal risk to surrounding vital structures (see Section 2.1.3 for complete eligibility criteria to 
participate in the part of the trial).  A single tumor will be biopsied, and the number of needle 
passages to obtain a core biopsy of tumor tissue for research purposes will be limited to two.  
The biopsy will be used to document RET gene mutations and gene expression in the tumor at 
baseline and to establish pediatric MTC cell lines.  Whole blood will also be obtained to assess 
RET germ line mutation status (see Section 3.5.2).  If a biopsy is required for clinical indications 
(e.g., to make or confirm the diagnosis), then the two additional passages to obtain a tumor 
specimen for research purposes will be obtained after the biopsy for clinical indications.  If a 
tumor is resected, residual tissue remaining after processing for diagnostic tests will be processed 
for research studies as outlined in Section 3.5. 
Research specimen labels will include the protocol number (07-C-0189), the two digit 
participant’s study number and NIH medical record number.  
2.3 
Registration Procedures 
When registering a patient, information about all entry criteria (e.g., laboratory results) must be 
available to allow for verification of eligibility (see Section 2.1 ). Dr. Brigitte Widemann 240-
760-6203  must be contacted to discuss the patient prior to entry onto the trial. 
The research nurse will register patients by FAXing the completed eligibility checklist to the 
Central Registration Office at (301) 480-0757 within 24 hours of signing consent. 
3 
STUDY IMPLEMENTATION 
3.1 
Study Design 
3.1.1 OVERALL TRIAL DESIGN 
This phase II trial is designed to determine whether daily oral vandetanib, which has activity in 
adults with hereditary MTC, is also active against hereditary MTC in children and adolescents.  
Vandetanib activity will be primarily assessed by response of measurable disease using RECIST, 
but change in biomarkers (calcitonin and CEA) and tumor-related symptoms (diarrhea) from 
baseline will also be monitored to assess drug effect (see Section 7.2). 
Vandetanib is administered to adults continuously in a fixed daily dose of 300 mg/d and has not 
been previously studied in children.  In this trial, children will be dosed based on body surface 
area (BSA).  The adult dose of 300 mg/d is equivalent to approximately 150 mg/m2/d.  In 

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22 
addition, a limited intra-patient dose escalation study will be performed to assess the safety of the 
equivalent to the recommended adult dose of vandetanib in this pediatric population, which is 
likely to be less heavily pretreated with cytotoxic chemotherapy than children with other types of 
refractory cancers that are typically treated on pediatric phase I trials.  Initially three adolescents 
13-18 years will be enrolled and started on a dose of 100 mg/m2/d (equivalent to an adult fixed 
dose of 180 mg/d).  The dose will be escalated to 150 mg/m2/d on cycle 3 in these three older 
patients if the lower dose was tolerable (no dose-limiting toxicity [defined in Section 3.1.4] that 
was possibly, probably or definitely related to vandetanib) on cycles 1 and 2.  The dose is 
escalated after 2 cycles because steady state levels are not achieved until at least 4 weeks of 
continuous daily dosing.  If the first cohort of older (13-18 years) children tolerate the cycles 1 
and 2 at a dose of 100 mg/m2/d, then a cohort of three children who are 5-12 years of age will be 
enrolled and treated with 100 mg/m2/d of vandetanib on cycles 1 and 2 and escalated to 150 
mg/m2/d on cycle 3 if they tolerated (no dose-limiting toxicity that was possibly, probably or 
definitely related to vandetanib) the lower dose on the cycles 1 and 2.  If the 150 mg/m2/d dose is 
tolerated for 2 cycles, then subsequent patients will be enrolled at the 150 mg/m2/d dose level.  
Detailed pharmacokinetics of vandetanib will be performed in children and adolescents at steady 
state at the end of the second 28 day cycle of treatment (end of cycle 2). 
Patients will be staged to assess measurable disease by RECIST, biomarkers and disease-related 
symptoms prior to the start of therapy, after every 2 cycles x 4 (prior to cycles 1, 3, 5, 7 and 9), 
prior to cycle 13, and then after every 6 cycles (prior to cycles 19, 25, etc.).  There will be no 
limit on the duration of therapy.  The drug will be discontinued if there is evidence of tumor 
progression clinically or by RECIST or biomarkers (CTN or CEA) or there is intolerable toxicity 
that is not alleviated by dose reduction.   
As of March 2014 (amendment J): Clinical restaging for all patients remaining on study 
receiving long term therapy will be performed as per Appendix 5: As of Amendment J: Care, 
Monitoring and Management of all Patients Remaining on Study on Long Term Vandetanib 
Therapy. 
Secondary endpoints on this trial include progression-free and overall survival, assessment of 
target (RET, EGFR, VEGFR) expression and somatostatin receptor expression in archival tissue, 
RET mutational status in tumor vs. peripheral blood mononuclear cells at entry, and changes in 
gene expression and RET mutational status in tumor tissue with treatment at the time of tumor 
response and progression on treatment. 
3.1.2 DOSE LEVELS AND INTRA-PATIENT DOSE ESCALATION 
In order to ensure that children and adolescents can tolerate a dose that is equivalent to the 300 
mg fixed dose used in adults, a limited intra-patient dose escalation will be performed in the 
initial subset of patients enrolled on this trial.  The two dose levels that will be studied are 100 
mg/m2/d, which equivalent to 180 mg/d in adults (60% of the adult recommended dose), and 150 
mg/m2/d, which is equivalent to 270 mg/d in adults (90% of the recommended dose of 300 
mg/d).  These doses will be studied in older patients (13-18 yo) before being administered to 
younger patients (5-12 yo).  The dose will not be escalated beyond 150 mg/m2/d.  Intra-patient 
dose escalation is permitted in patients who tolerate (do not experience a vandetanib-related 
DLT) the 100 mg/m2/d dose level of vandetanib on cycles 1 and 2.  
 

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13-18 yo Cohort (see the algorithm): 
x Initially, three 13-18 yo patients will be treated at the 100 mg/m2/d dose level for two 
cycles.  Those who do not experience a vandetanib-related DLT (see Section 3.1.4) 
during cycles 1 and 2 (56 days) at the 100 mg/m2/d dose level will have their dose 
escalated to 150 mg/m2/d for their third and subsequent cycles. 
x If 0/3 of 13-18 yo cohort experience a vandetanib-related DLT on cycles 1 and 2 at the 
100 mg/m2/d dose level, then these 3 patients will be evaluated for toxicity on their 
third and fourth cycles at the 150 mg/m2/d dose level (patients who come off treatment 
before completing cycle 2 for reasons other than a vandetanib-related DLT can be 
replaced on the intra-patient dose escalation component of the trial).  New 13-18 yo 
patients can be enrolled on the trial at the 150 mg/m2/d dose level if none of the first 3 
patients enrolled at the 100 mg/m2/d dose level experienced a vandetanib-related DLT 
on cycles 1 and 2, but no more than 6 patients should be receiving the 150 mg/m2/d 
dose until 3 patients have completed 2 cycles at this dose level. 
x If 1/3 of 13-18 yo cohort experiences a vandetanib-related DLT on cycle 1 or 2 at the 
100 mg/m2/d dose level, then three additional 13-18 yo patients will be enrolled at the 
dose 100 mg/m2/d level. If 1/6 of the expanded 13-18 yo cohort experience a 
vandetanib-related DLT on cycle 1 or 2 at the 100 mg/m2/d dose level, then the 5 
patients who tolerated the drug will be evaluated for toxicity on their third and fourth 
cycles at the 150 mg/m2/d dose level (patients who come off treatment before 
completing cycle 2 for reasons other than DLT can be replaced on the intra-patient dose 
escalation component of the trial). Additional new 13-18 yo patients can be enrolled on 

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the trial at the 150 mg/m2/d dose level if no more than 1 of the first 6 patients enrolled 
in the expanded cohort at the 100 mg/m2/d dose level experienced a vandetanib-related 
DLT on cycles 1 and 2, but no more than 6 patients should be receiving the 150 
mg/m2/d dose until 3 patients have completed 2 cycles at this dose level. 
x If 2 or more of the initial 3 to 6 13-18 yo patients experience a vandetanib-related DLT 
on cycle 1 or 2 at the 100 mg/m2/d cohort, accrual to the trial will be suspended until 
the protocol can be amended to include a new lower dose level. 
x If the 100 mg/m2/d dose level is tolerable (0/3 or 1/6 with a vandetanib-related DLT) on 
cycles 1 and 2 in 13-18 yo population and none of the 3 to 6 patients experience a 
vandetanib-related DLT on 2 cycles at the 150 mg/m2/d dose level, then subsequent 13-
18 yo patients will be enrolled at the 150 mg/m2/d dose level. 
x If the 100 mg/m2/d dose level is tolerable (0/3 or 1/6 with a vandetanib-related DLT) on 
cycles 1 and 2 in 13-18 yo cohort and one of the 3 to 6 patients experiences a drug-
related DLT on 2 cycles at the 150 mg/m2/d dose level, then additional 13-18 yo 
patients (if necessary) will be enrolled at the 150 mg/m2/d dose level until there are 6 
evaluable patients who have received 150 mg/m2/d for 2 cycles. If 1/6 patients 
experience a vandetanib-related DLT at the 150 mg/m2/d dose level, then subsequent 
13-18 yo patients will be enrolled at the 150 mg/m2/d dose level. 
x If 2 or more of the initial 3 to 6 13-18 yo patients experience a vandetanib-related DLT 
at the 150 mg/m2/d dose level, then all subsequent patients will be treated at the 100 
mg/m2/d dose without intra-patient dose escalation. 
5-12 yo Cohort: 
x If 0/3 or 1/6 of 13-18 yo cohort experience a vandetanib-related DLT on cycles 1 and 2 
at the 100 mg/m2/d dose level, then three 5-12 yo patients can be enrolled at this dose 
level. Those patients in the 5-12 yo patients who do not experience a vandetanib-related 
DLT during cycles 1 and 2 at the 100 mg/m2/d dose level will have their dose escalated 
to 150 mg/m2/d for their third and subsequent cycles. 
x The dose escalation for the 5-12 yo cohort follows the same rules described above for 
the 13-18 yo patient cohort (see the algorithm above). 
x If the 150 mg/m2/d dose level is found to be intolerable in the 13-18 yo cohort (i.e., 2 or 
more patients experience vandetanib-related DLTs out of 3 to 6 patients), then the 5-12 
yo cohort will be treated at the 100 mg/m2/d dose level without intra-patient dose 
escalation to 150 mg/m2/d. 
x If 0/3 of 5-12 yo cohort experience a vandetanib-related DLT on cycles 1 and 2 at the 
100 mg/m2/d dose level, then these 3 patients will be evaluated for toxicity on their 
third and fourth cycles at the 150 mg/m2/d dose level (patients who come off treatment 
before completing cycle 2 for reasons other than a vandetanib-related DLT can be 
replaced on the intra-patient dose escalation component of the trial). New 5-12 yo 
patients can be enrolled on the trial at the 150 mg/m2/d dose level if none of the first 3 
patients enrolled at the 100 mg/m2/d dose level experienced a vandetanib-related DLT 
on cycles 1 and 2, but no more than 6 patients should be receiving the 150 mg/m2/d 
dose until 3 patients have completed 2 cycles at this dose level. 
x If 1/3 of 5-12 yo cohort experiences a vandetanib-related DLT on cycle 1 or 2 at the 
100 mg/m2/d dose level, then three additional 5-12 yo patients will be enrolled at the 
100 mg/m2/d dose level. If 1/6 of the expanded 5-12 yo cohort experience a vandetanib-

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related DLT on cycle 1 or 2 at the 100 mg/m2/d dose level, then the 5 patients who 
tolerated the drug will be evaluated for toxicity on their third and fourth cycles at the 
150 mg/m2/d dose level (patients who come off treatment before completing cycle 2 for 
reasons other than DLT can be replaced on the intra-patient dose escalation component 
of the trial). Additional new 5-12 yo patients can be enrolled on the trial at the 150 
mg/m2/d dose level if no more than 1 of the first 6 patients enrolled in the expanded 
cohort at the 100 mg/m2/d dose level experienced a vandetanib-related DLT on cycles 1 
and 2, but no more than 6 patients should be receiving the 150 mg/m2/d dose until 3 
patients have completed 2 cycles at this dose level. 
x If 2 or more of the initial 3 to 6 5-12 yo patients experience a vandetanib-related DLT 
on cycle 1 or 2 at the 100 mg/m2/d dose level, accrual to the trial will be suspended 
until the protocol can be amended to include a new lower dose level. 
x If the 100 mg/m2/d dose level is tolerable (0/3 or 1/6 with a vandetanibs-related DLT) 
on cycles 1 and 2 in 5-12 yo population and none of the 3 to 6 patients experience a 
vandetanib-related DLT on 2 cycles at the 150 mg/m2/d dose level, then subsequent 5-
12 yo patients will be enrolled at the 150 mg/m2/d dose level.   
x If the 100 mg/m2/d dose level is tolerable (0/3 or 1/6 with a vandetanib-related DLT) on 
cycles 1 and 2 in 5-12 yo cohort and one of the 3 to 6 patients experiences a drug-
related DLT on 2 cycles at the 150 mg/m2/d dose level, then additional 5-12 yo patients 
(if necessary) will be enrolled at the 150 mg/m2/d dose level until there are 6 evaluable 
patients who have received 150 mg/m2/d for 2 cycles. If 1/6 patients experience a 
vandetanib-related DLT at the 150 mg/m2/d dose level, then subsequent 5-12 yo 
patients will be enrolled at the 150 mg/m2/d dose level. 
x If 2 or more of the initial 3 to 6 5-12 yo patients experience a vandetanib-related DLT 
at the 150 mg/m2/d dose level, then all subsequent patients will be treated at the 100 
mg/m2/d dose without intra-patient dose escalation. 
As of Amendment J: The recommended dose of vandetanib has been established at 100 mg/m2/ 
day and the dose escalation portion of the study is complete. Eleven subjects remain on study 
receiving long-term (> 2 years) therapy with vandetanib.  All subjects will remain on their 
current dose level, while dose reductions may be made in 30% increments based on 
investigator’s judgment (with guidance from the vandetanib package insert) following evaluation 
of side effects and quality of life measures (See Appendix 6: Vandetanib Package Insert).  
3.1.3 DEFINITION OF MAXIMUM TOLERATED DOSE (MTD) OR RECOMMENDED DOSE 
A MTD for vandetanib will be determined if DLT is observed in 2 or more patients at one of the 
2 dose levels (100 and 150 mg/m2/d) being evaluated in the limited, intra-patient dose escalation 
portion of the study.  However, the purpose of this dose escalation is to ensure that the adult 
recommended dose of 300 mg/d (approximately equivalent to 150 mg/m2/d) is tolerable in 
children and adolescents, and the dose will not be escalated beyond the 150 mg/m2/d, even if no 
DLT is observed at this dose level.  If 150 mg/m2/d is tolerable in the two age-based cohorts, 
then this dose will be the recommended dose for children and adolescents with MTC. 
If vandetanib-related DLT is observed in 2 or more of the 3 to 6 patients who are treated for 2 
cycles with 150 mg/m2/d, then the MTD will be 100 mg/m2/d, if 5 or 6 of the first 6 patients from 
each of the 2 age-based cohorts do not experience a vandetanib-related DLT on their first 2 cycles 
at this dose level.  If 2 or more out of the first 3 to 6 patients in a cohort experience a vandetanib-

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26 
related DLT at the 100 mg/m2/d dose level on cycle 1 or 2, then accrual to the trial will be 
suspended until the protocol can be amended to include a new lower dose level. 
At the MTD or recommended dose fewer than 33% of patients in each age-based cohort (13-18 
yo and 5-12 yo) should experience DLT on the first two treatment cycles at that dose level. 
3.1.4 DEFINITION OF DOSE-LIMITING TOXICITY (DLT) 
This study will utilize the CTEP Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 for toxicity and Adverse Event grading and reporting.  A copy of the CTCAE 
version 3.0 can be viewed or downloaded from the CTEP website 
(http://ctep.info.nih.gov/reporting/ctc_v30.html).  An adverse event must be judged to be 
possibly, probably, or definitely related to vandetanib to be a dose-limiting toxicity. 
Dose-limiting toxicity is defined as: 
x Hematologic Dose-Limiting Toxicity (H-DLT):  
o Neutrophil count below 1,000/μL (grade 3) on 2 consecutive measurements 
drawn at least 72 hours apart OR a single neutrophil count below 500/μL (grade 
4). 
o Platelet count below 50,000/μL (grade 3) on 2 consecutive measurements drawn 
at least 72 hours apart OR a single platelet count below 25,000/μL (grade 4). A 
platelet transfusion administered when platelet count is below 50,000/μL is dose-
limiting thrombocytopenia, unless the transfusion is being administered for peri-
operative coverage. 
o Grade 3 or 4 decrease in hemoglobin that can be corrected to at least 8.0 g/dl 
(grade 2) by transfusion of red blood cells is not a dose-limiting toxicity.  
However, grade 3 or 4 hemolysis is a dose-limiting toxicity if it is judged to be 
vandetanib-related. 
o Grade 3 or 4 leucopenia is not a dose-limiting toxicity. 
o Grade 3 or 4 lymphopenia is not a dose-limiting toxicity. 
x Non-Hematologic Dose-Limiting Toxicity (NH-DLT): NH-DLT is any grade 3 or 
higher non-hematologic toxicity, with the exception of:  
o Grade 3 nausea that is controlled by symptomatic treatment with anti-emetics (see 
Appendix 4: Medications Known to Prolong the QT Interval or Induce Torsades de 
Pointes to avoid agents that can prolong the QTc) within 48 hours. 
o Grade 3 vomiting that is controlled by symptomatic treatment with anti-emetics (see 
Appendix 4: Medications Known to Prolong the QT Interval or Induce Torsades de 
Pointes to avoid agents that can prolong the QTc)  within 48 hours. 
o Any grade of diarrhea that is tumor-related (present at baseline and associated with 
elevated calcitonin levels) or grade 3 diarrhea that is related to vandetanib and is 
controlled by symptomatic treatment within 48 hours.  
o Grade 3 serum transaminase elevation (ALT/AST) that returns to grade 2 or less 
within 7 days.  The drug may be held until the transaminase elevation subsides, but 
if the grade 3 transaminase elevation recurs when the drug is re-instituted, this will 
be considered dose-limiting toxicity. 
o Grade 3 electrolyte abnormalities that are asymptomatic and correctable to grade 2 
or less within 48 hours. 

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27 
o Grade 3 infection, with neutropenia, without neutropenia, or with unknown ANC 
o Grade 3 febrile neutropenia (fever with ANC ≤1000/μL) 
x Hypertension (HTN):  For pediatric patients, the ULN for blood pressure is defined 
as a diastolic BP at the 95th percentile from age and gender-appropriate normal 
values (see Appendix 2: Normal Blood Pressure Range for Children). Patients with 
a diastolic blood pressure >95% for age and gender should have blood pressure 
measurement repeated x2 with an appropriate size cuff, and hypertension (HTN) is 
defined as at least 2 (of 3) measurements exceeding the ULN.  Dose-limiting 
hypertension is defined as: 
o A diastolic BP on at least 2 of 3 measurements that is more than 25 mm Hg 
above the ULN for age and gender. 
o A diastolic BP on at least 2 of 3 measurements that is above the ULN but not 
more than 25 mm Hg above the ULN and that does not return to within the 
normal range after 14 days on single agent antihypertensive therapy. 
o Grade ≥4 (CTCAE v.3) hypertension. 
x QTc Prolongation:  Participants with QTc prolongation should have serum 
electrolytes (including calcium and magnesium) measured.  If serum electrolytes are 
outside the normal range, the abnormality should be corrected before determining 
whether a patient has dose-limiting QTc prolongation.  Dose-limiting QTc 
prolongation is defined as: 
o A single QTc value ≥550 msec OR an increase of ≥100 msec from baseline, 
OR 
o Two consecutive ECG measurements, which are within 48 hours of one 
another and which meet either of the following criteria: 
 QTc ≥500 msec but <550 msec OR 
 A ≥60 msec but <100 msec increase in the QTc from baseline QTc to 
a QTc value ≥480 msec. 
3.1.5 CRITERIA FOR STARTING SECOND AND SUBSEQUENT TREATMENT CYCLES 
Patients who complete a treatment cycle (28 days) may receive another cycle if: 
x DISEASE STATUS: The patient does not have radiographic or clinical evidence of 
progressive disease (see Section 7.2) for cycles prior to which the patient is re-staged, or 
in the opinion of the investigator the patient is benefiting from the therapy with vandetanib 
as evidenced by stable or decreased tumor-related symptoms such as diarrhea or pain or 
stable or decreased tumor biomarkers (CEA, CTN) for cycles that are not proceeded by 
restaging. 
x TOXICITY: Patients who experienced dose-limiting toxicity in the previous cycle should 
have the dose modified (see Section 3.3).  
x Criteria for discontinuation of protocol treatment or off-study criteria (see Section 5) have 
not been met. 
As of Amendment J: All patients who continue on the trial receiving long term therapy may 
continue to receive additional cycles until clinical data warrants stopping for unacceptable 

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28 
toxicity or progression of disease, as determined by the principal investigator.  There is no limit 
on the number of cycles that a patient may receive. 
3.1.6 EVALUATION OF RESPONSE TO VANDETANIB 
The primary objective of this trial is to assess the activity of vandetanib in children and 
adolescents with MTC.  Patients are required to have measurable disease at study entry 
according to the RECIST.  Measurable disease will be quantified on physical exam for palpable 
tumors in the neck and by CT scan or MRI scan.  Lesion detected on bone scan will be 
considered to be non-target lesions by RECIST.  Patients will be evaluated for response after 
every 2 cycles x 4 (prior to cycles 1, 3, 5, 7, and 9) and then after every 4 cycles X 1 (prior to 
cycle 13) and then every 6 cycles (prior to cycle 19, 25, 31, etc) using the same method (type of 
scan) used to document the size target lesions at baseline (prior to treatment).  RECIST criteria to 
assess response are summarized in Section 7.3.1. If a response (PR or CR) is achieved for by 
RECIST, a confirmatory restaging should be performed 4 weeks later.  Patients will be 
considered evaluable for response if they have at least one on treatment restaging performed 
(after cycle 2).  Patients removed from study for clinical disease progression prior to the post-
cycle 2 evaluation will also be considered evaluable for response. 
Patients participating on the dose escalation portion of the trial will receive a lower dose (100 
mg/m2/d) for the first 2 28-day treatment cycles.  Those who are eligible for dose escalation (no 
vandetanib-related DLT on cycles 1 and 2) may continue on treatment at the 150 mg/m2/d dose 
level starting on cycle 3 and beyond as long as the sum of the longest diameters of target lesions 
has not increased by more than 40% compared to baseline and no new lesions have appeared, in 
order to ensure that these patients have an opportunity to receive the equivalent to the adult 
recommended dose (150 mg/m2/d) of vandetanib. 
If CEA or CTN levels are elevated prior to the start of treatment, these biomarkers will be 
measured after every 2 cycles x 4 (prior to cycles 1, 3, 5, 7 and 9), prior to cycle 13, and then 
every 6 cycles (prior to cycle 19, 25, 31, etc).  Criteria for defining biomarker response are in 
Section 7.3.2.  If a response (PR or CR) is achieved for CTN or CEA, a confirmatory level 
should be drawn 4 weeks later.  The frequency and consistency of bowel movements will also be 
monitored on treatment in patients presenting with MTC-related diarrhea.   
As of Amendment J: All patients remaining on trial in long term therapy will be evaluated for 
clinical response status according to Appendix 5: As of Amendment J: Care, Monitoring and 
Management of all Patients Remaining on Study on Long Term Vandetanib Therapy. 
3.2 
Drug Administration 
Vandetanib is administered orally, once daily continuously.  Patients can receive the liquid 
formulation through a nasogastric tube or gastrostomy.  A cycle of vandetanib is defined as 28 
consecutive days starting with the first day of treatment (day 1). The dose of vandetanib is 
determined from the patient’s body surface area using the dosing nomogram below. The BSA 
should be recalculated prior to each treatment cycle and the dose should be adjusted if necessary 
based on the nomogram.  Treatment will be administered in an outpatient setting.  
As of Amendment J:  For all patients remaining on trial in long term therapy, refer to Appendix 
5: As of Amendment J: Care, Monitoring and Management of all Patients 
Remaining on Study on Long Term Vandetanib Therapy. 

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Dose 
Level 
[mg/m2] 
 
 
 
 
 
 
 
100 
BSA 
[m2] 
0.50-
0.62 
0.63-
0.87 
0.88-
1.12 
1.13-
1.37 
1.38-
1.75 
>1.75- 
Dose 
[mg] 
50 
75 
100 
125 
150 
200 
150 
BSA 
[m2] 
0.50-
0.75 
0.76-
0.91 
0.92-
1.16 
1.17-
1.50 
1.51-
1.83 
>1.83 
Dose 
[mg] 
100 
125 
150 
200 
250 
300 
Vandetanib is supplied as 10 mg/ml suspension and 50 and 100 mg tablets.  A combination of 
tablets and suspension can be used. For example, a dose of 75 mg could be one 50 mg tablet plus 
2.5 ml of suspension. 
Vandetanib is supplied as a 10 mg/ml suspension and 50 and 100 mg tablets.  Vandetanib should 
be stored at room temperature in the original pack until use. 
Patients will receive their assigned dose of vandetanib once daily at the same time of the day (An 
every other day dosing schedule can be used to achieve lower dose levels in patients requiring a 
dose reduction, see Section 3.3.1). Vandetanib absorption is not affected by a meal,39 so it need 
not be administered in the fasted state.  The tablet should be swallowed whole. If a patient misses 
a scheduled dose of vandetanib and less than 6 hours have passed since the scheduled dosing time, 
the dose should be taken immediately. If more than 6 hours have passed since the scheduled dosing 
time, the patient should not take the missed dose but should wait and take the next regularly 
scheduled dose. 
If the patient vomits within 15 minutes of taking vandetanib, then another dose can be 
administered. The dose may only be repeated once.  If more than 15 minutes has passed from the 
time of oral dosing then no additional doses should be given. 
Patients or their guardians will document missed vandetanib doses, and vandetanib toxicities on 
the study calendar. 
3.3 
Dose Modifications for Vandetanib-Related DLT 
As of Amendment J: For dose modifications for all patients in long term therapy, refer to 
Appendix 5: As of Amendment J: Care, Monitoring and Management of all Patients Remaining 
on Study on Long Term Vandetanib Therapy.  
3.3.1 DOSE-LIMITING TOXICITY 
x Vandetanib should be held for any dose-limiting toxicity (see Section 3.1.4). 
For DLTs that include a duration in the definition, such as a neutrophil count 
below 1,000/μL (grade 3) on 2 consecutive measurements drawn at least 72 
hours, the drug will be held after the toxicity becomes dose limiting (e.g., after 
the second ANC <1,000/μL). 

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30 
x If vandetanib-related DLT resolves to grade ≤1 or baseline in ≤14 days of 
drug free period, vandetanib may be restarted at a reduced dose. 
x If the vandetanib-related DLT does not resolve to grade ≤1 or baseline in ≤14 
days of a drug free period the patient should discontinue protocol therapy and 
be monitored until the toxicity resolves. 
x The cycle duration remains 28 consecutive days in patients who have dose 
interruptions. 
x The NCI Principal Investigator should be consulted for all dose reductions. 
x Patients who experience a DLT (Section 3.1.4) that is possibly, probably, or definitely 
related to vandetanib should have a 30% dose reduction of their dose of vandetanib 
(e.g., from 300 mg/d to 200 mg/d) for the remainder of the current course and for the 
subsequent ≥2 cycles of treatment.  All dose reductions must be at least 30% of the 
administered dose rounded down to the nearest 25 mg (e.g., for patients receiving 150 
mg/d, a 30% reduction would be a decrease in the dose by 45 mg to 105 mg/d, which 
is rounded down to 100 mg/d). 
x Patients who experience DLT after a dose reduction can have additional dose 
reductions according to the guidelines above.  An every other day dosing schedule can 
be used to achieve lower dose levels if the calculated daily dose is <50 mg/d. 
x Once the dose-finding (phase I) portion of the trial is completed and the MTD is 
established in the two age groups, patients who have a dose reduction for a non-life-
threatening DLT (diarrhea, nausea, vomiting, constipation, anorexia, weight loss, 
fatigue or skin rash) and who tolerate ≥2 cycles at the reduced dose can have their dose 
re-escalated to the prior dose level.  The toxicity type that was previously dose-limiting 
at the higher dose level must not have exceeded grade 1 at the reduced dose level in 
order to re-escalate the dose. The dose will not be escalated above the MTD. 
3.3.2 WOUND HEALING 
x For patients who require elective surgery, vandetanib should be held for 2 weeks prior 
to the procedure and for 2 weeks after surgery.  The treatment should resume only after 
the surgeon has determined that the wound is healed.  Patients should have restaging 
studies performed prior to restarting the treatment or within a month of restarting 
treatment. 
x For patients who require emergency surgery or who experience a significant injury, 
the vandetanib should be held for at least 2 weeks and only resumed when the wounds 
are judged to be healed.  If the vandetanib is held for 4 or more weeks, then restaging 
studies should be performed prior to restarting the treatment. 
3.4 
Vandetanib Pharmacokinetic Studies 
x A pretreatment sample will be drawn prior to the start of therapy (prior to cycle 1). 
x A single trough sample will be drawn 24 hours after the first dose of Vandetanib on 
cycle 1. 
x A single trough sample will be drawn 24 hours after the last dose of Vandetanib on 
cycle 1 (before the first dose on cycle 2). 

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x A detailed pharmacokinetic (PK) evaluation of vandetanib will be performed for each 
patient at the end of treatment cycle 2 (cycle 2, day 28±5 days).  See Appendix 3: 
Pharmacokinetic Worksheet for Vandetanib for details of sample collection, 
handling, shipping, and PK Worksheet. 
x Patients who have their dosing of vandetanib interrupted for toxicity during cycle 1 or 
2 will have the PK sampling performed on a subsequent cycle.  At least 42 days of 
continuous dosing is required to ensure that patients are at steady state at the time of 
the PK study. 
x On cycle 2, day 28±5 days, 2 mL blood samples will be collected in tubes containing 
lithium heparin and mixed thoroughly prior to the dose and then 1, 2, 4, 6, 8, 10, and 
24 hours after the dose. Trough samples (24 h after the previous dose) should be drawn 
on the first day of cycles 4 and 5 for patients who undergo a dose escalation on cycle 
3.  Plasma will be separated by centrifugation at 1,000 g for 10 min at room temperature 
within 30 min of collection, and the plasma sample should be taken off immediately 
and stored frozen in a plain plastic tube at -20qC or -70qC. Samples will be shipped 
frozen (see Appendix 3: Pharmacokinetic Worksheet for Vandetanib). The 
label on the tube should contain the following information: 
Study number  
Vandetanib PK 
Day number 
Cycle number 
Nominal time point (hours post-dose) 
x Plasma concentrations of vandetanib will be determined in human plasma samples 
using solvent extraction followed by reverse phase high performance liquid 
chromatography with tandem mass spectrometric detection (HPLC-MS/MS).  
Samples spiked with [13C,d3]-vandetanib internal standard are extracted into methyl-t-
butyl ether at a basic pH.  Extracts are evaporated to dryness, reconstituted in HPLC 
eluent and subjected to HPLC using an Inertsil ODS3 column.  Vandetanib is 
detected using a Perkin Elmer Sciex quadrupole mass spectrometer using a 
turboionspray source (multiple reaction monitoring in positive ion mode).  
Concentrations are determined by reference to a calibration curve prepared over a 
range of 5 to 1000 ng/mL vandetanib in 100 Pl aliquots of heparinized human plasma.   
This method will be performed at Bioanalytical Systems Inc (BASi), West Lafayette, 
Indiana, US.  
3.5 
Vandetanib Pharmacodynamic Studies 
3.5.1 RET, VEGFR, EGFR, AND SOMATOSTATIN RECEPTOR EXPRESSION IN ARCHIVAL TUMOR 
TISSUE 
When available, paraffin embedded tumor from diagnostic biopsies or prior surgical resections 
will be obtained and examined for the expression of RET, VEGFR and EGFR (and the phospho-
forms of these proteins) and somatostatin receptor by immunohistochemistry (IHC).  In the event 
that a biopsy or surgical procedure is performed for clinical indications or research purposes 

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while a patient is on this study, tumor may also be obtained and examined for expression of these 
targets by IHC.  Pathology report should accompany each specimen and the specimen should be 
labeled with the patient ID number. 
Tumor should be shipped to: 
Brigitte Widemann, MD 
10-CRC, 1-3750, MSC 1101 
10 Center Drive 
Bethesda, MD 20892-1206 
Phone: 301-496-7387 
Page  301-496-1121 
Email  widemanb@mail.nih.gov 
3.5.2 GENE EXPRESSION AND RET GENE MUTATIONAL STATUS IN TUMOR 
Participants over the age of 12 years with superficial tumors (e.g., cervical lymph nodes 
metastases) that are not located in a body cavity and that are accessible to percutaneous core 
needle (16 or 18 gauge) biopsy with minimal risk to surrounding vital structures will be asked to 
voluntarily undergo a core needle biopsy of the tumor under local anesthesia prior to the 
initiation of treatment and at the time of documented tumor progression by RECIST (see Section 
2.1.3 for eligibility).  In those who have a partial response (by RECIST), residual superficial 
tumors will also be biopsied while the participants are in partial remission. 
x A portion of the biopsy will be processed for histologic and immunohistochemical 
evaluation by Dr. Maria Merino in the Laboratory of Pathology 
x A portion will be snap frozen in OCT and sent to:   
Paul Meltzer, M.D. 
Bldg. 37/Rm. 6138 
Phone: 
(301) 496-5266 
Email: 
pmeltzer@mail.nih.gov 
x A small portion will be placed into RPMI media to establish a cell line and sent to: 
Maya Lodish, M.D. 
Bldg. 10/Rm. 1-3216 (East labs) 
Phone: 
(301) 451-7175 
Email: 
lodishma@mail.nih.gov 
x A 5 ml blood sample in EDTA (purple top tube) should also be obtained and sent 
with the frozen tumor sample to Dr. Meltzer. 
Research samples will be used to evaluate gene expression by microarray and to assess 
secondary genetic changes (gains or losses of DNA sequences) by comparative genomic 
hybridization (CGH) in the tumor, and to sequence and identify mutations in the RET gene and 
compare these mutations to germ line mutations in nucleated peripheral blood cells.  These 
studies of the RET mutation status in peripheral blood and tumor will not be used to determine 
protocol eligibility or inform clinical decisions on the trial.  They will be used for research 

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purposes only.  Information about the development of somatic mutations in tumors that lead to 
resistance to vandetanib is not currently available in adults.  Identification of such mutations in 
the active site or the drug binding site of the RET RTK in even one patient would provide 
valuable information to understand the mechanism of resistance to vandetanib and to identify 
new RET inhibitors that could circumvent the resistance. Pediatric MTC cell lines will be used to 
assess the effects of vandetanib on cell proliferation, RET activation, and cell signaling pathways 
in cell lines from patients with clinically sensitive and resistant tumors. 
If a biopsy is required for clinical indications (e.g., to make or confirm the diagnosis), then the 
two additional passages to obtain a tumor specimen for research purposes will be obtained after 
the biopsy for clinical indications.  If a tumor is resected, residual tissue remaining after 
processing for diagnostic tests will be processed for research studies as above. 
Research specimen labels will include the protocol number (07-C-0189), the two digit 
participant’s study number and NIH medical record number. 
If archival tissue blocks in paraffin are available, a core sample may be taken from the block for 
extraction of DNA and sequencing of the RET gene to assess mutation status in the tumor and 
for CGH. 
3.6 
Study Calendar 
As of Amendment J: See Appendix 5: As of Amendment J: Care, Monitoring and Management 
of all Patients Remaining on Study on Long Term Vandetanib Therapy for Evaluations of all 
patients receiving long term therapy. 
OBSERVATION 
Prior to Cycle†% 
During Cycle 1 
only 
During Cycle 2 
Post 
Study 
History & Physical 
1-9 then 13, 16++,19, 
22++, 25, etc. 
Weekly 
Midcycle+ 
X 
Assessment of toxicity 
1-9 then 13, 19, 25, etc 
Weekly 
Midcycle+ 
X 
BP Monitoring 
1-9 then 13, 16++,19, 
22++ 25,, etc 
Days 1, 2, 3, 7§, 
then Weekly 
Midcycle+ 
X 
Performance status 
(document changes only) 
1-3 then 5, 7, 9, 13, 19, 
25, etc. 
 
 
X 
 Height, Weight, Body 
Surface Area 
1-9 then 13, 19, 25, etc 
 
 
 
Urinalysis 
1-9 then 13, 16++, 19, 
22++, 25, etc 
 
 
X 

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OBSERVATION 
Prior to Cycle†% 
During Cycle 1 
only 
During Cycle 2 
Post 
Study 
Urine/Serum pregnancy 
test* 
1-9 then 13, 19, 25, etc 
 
 
 
CBC, differential, platelets 
1-9 then 13, 16++, 19,  
22++, 25, etc 
Weekly 
Midcycle+ 
X 
PT, PTT 
1-3 then 5,7,9,13, 19, 
25, etc. 
 
 
X 
Electrolytes, glucose, BUN 
and Creat 
1-9 then 13, 16++, 19,  
22++, 25, etc 
Weekly 
Midcycle+ 
X 
Ca+2, Mg+2, PO4-, uric acid 
1-9 then 13, 16++, 19, 
22++, 25, etc 
Weekly 
Midcycle+ 
X 
LDH, AST, ALT, 
bilirubin&, Alk Phos 
1-9 then 13, 16++,19, 
22++, 25, etc 
Weekly 
Midcycle+ 
X 
Total protein, albumin, 
GGT 
1-9 then 13, 16++, 19, 
22++, 25, etc 
 
 
X 
Plasma free metanephrine 
and nor-metanephrine 
Vitamin D 25-OH 
Cycle 1, then every year 
(at NIH) 
 
 
 
Thyroid Stimulating 
Hormone (TSH),  
Free thyroxine (T4), Free-
T3 
Cycle 1-3, 5, 7, 9, 13, 
16++, 19, 22++, 25 etc 
 
 
X 
Pharmacokinetic monitoring 
Cycle 1 
24 h after 1st 
dose 
Cycles 2, 3, 4, 5 
(trough) ^ 
 

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OBSERVATION 
Prior to Cycle†% 
During Cycle 1 
only 
During Cycle 2 
Post 
Study 
Serum calcitonin and CEA¶ 
Cycle 1, 2, 3, 5, 7, 9, 13, 
19, 25 etc 
 
 
X 
ECG 
1-9 then 13, 16++, 19, 
22++, 25, etc 
Day 3, 7, then 
Weekly 
 
X 
CT neck, chest, abdomen 
Cycle 1, 3, 5, 7, 9, 13, 
19, 25, etc 
 
 
X 
MRI neck  
Cycle 1 then as 
clinically indicated 
 
 
X 
MRI brain¢ 
Cycle 1 then annually or 
as clinically indicated 
 
 
 
Bone scan@ 
Cycle 1 then annually or 
as clinically indicated 
 
 
X 
MRI of the knee to assess 
the volume of the growth 
plate£ 
Cycle 1, 3, 5, 7, 9, 13, 
19, 25, etc. until closed 
 
 
 
 

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OBSERVATION 
Prior to Cycle†% 
During Cycle 1 
only 
During Cycle 2 
Post 
Study 
% After cycle 3, evaluations can be done at NIH as travel permits and if possible at home  
†  All pre-treatment labs must be completed within 72 hours of starting vandetanib for cycle 1  
§  Day 7 ± (2 days)  
+ Mid-cycle = day 14 (± 3 days)  
&  If total bilirubin elevated, check direct bilirubin  
* Urine/serum pregnancy test in females of childbearing potential  
^ On day 28 ± 5 of cycle 2 obtain samples pre-dose and then 1, 2, 4, 6, 8, 10, and 24 h post 
dose.  A single trough sample should be obtained on day 1 of cycles 2 and 3. Only patients who 
have their dose escalated to 150 mg/m2/d after cycle 2 trough should have samples obtained on 
day 1 of cycles 4 & 5. 
¢ On treatment MRI brain scans will be performed only if the baseline scan was positive and 
then as clinically indicated. Neck MRI is optional if disease can be adequately followed on CT.  
@ If baseline bone scan is positive then subsequent bone scans will be obtained. 
£ On treatment MRIs will be performed only if the growth plates were open on the baseline 
MRI and can be discontinued after growth plates are fused.  
++ Every other visit – when staging is not done – patients may be seen by their local physician 
to have these studies completed. Records are to be sent to the NIH. Once the patient has 
completed Cycle 13, the visit schedule may be broadened to allow a +/- 4 week window. 
Patients may be seen by their local physician in order to complete the necessary 
requirements for the study, including history and physical examinations, blood pressure 
monitoring, performance status, urinalysis and routine laboratory tests (blood counts and 
chemistries), when they are not seen by a study investigator.  Whenever possible, restaging 
studies and biomarkers should be performed at the NIH. 
3.6.1 GENERAL 
x BLOOD PRESSURE: Should be monitored and recorded prior to the first dose of vandetanib, 
on day 1, and then on day 2, day 3, day 7 (± 2 days) and weekly with physical exams during 
cycle 1.  In addition, blood pressure should be monitored and recorded at least every 2 
weeks during cycle 2, and then prior to each cycle on cycles 3 through 9, then every 3 
cycles (+/- 28 days) (13, 16, 19, 22, etc).  See Section 6.1 for management of elevated 
diastolic BP. 
x PHYSICAL EXAMINATION: A physical examination should be performed weekly during 
cycle 1. Then prior to and at the midpoint (day 14 ± 3 days) during cycle 2. Then prior to 
each cycle for cycles 3 through 9, then every 3 cycles (+/- 28 days) (13, 16, 19, 22, etc). 
x HEIGHT, WEIGHT, AND BSA: Recorded prior to each treatment cycle for cycles 1 through 
9, then prior to cycle 13, and then every 6 cycles (19, 25, etc). 

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x PERFORMANCE STATUS: Record any changes to performance status prior to each treatment 
cycle for cycles 1 through 3, and then prior to cycles 5, 7, 9, and 13, and then every 6 cycles 
(19, 25, etc) (Appendix 1: Performance Status Scales/Scores). 
3.6.2 LABORATORY 
x HEMATOLOGY: Complete blood count, differential and platelet count weekly (more 
frequent monitoring may be performed if the ANC <1,000/μL or platelet count 
<50,000/μL) for cycle 1, and then prior to and mid cycle for cycle 2. Then prior to each 
treatment cycle for cycles 3 through 9, then every 3 cycles (13, 16, 19, 22, etc). PT and 
PTT are monitored prior to each cycle for cycles 1 through 3, and then prior to cycles 5, 7, 
9, and 13, and then every 6 cycles (19, 25 etc). 
x CHEMISTRIES: Weekly BUN, creatinine, electrolytes (including Ca, Mg, PO4), LDH, AST, 
ALT, alkaline phosphatase, bilirubin (total and direct if total is elevated), calcium, 
magnesium, phosphorus, glucose, and uric acid during cycle 1, then prior to and midcycle 
(day 14 ± 3) for cycle 2. And then prior to each cycle for cycles 3 through 9, then every 3 
cycles (13, 16, 19, 22, etc), and at off study evaluation.  GGT, total protein and albumin 
are monitored prior to cycles 1 through 9 then every 3 cycles (13, 16, 19, 22, etc).  
x THYROID STIMULATING HORMONE (TSH) AND FREE THYROXINE (T4), FREE T3: Prior to 
every cycle on cycles 1-3, then prior to cycle 5, 7, 9, then every 3 cycles (13, 16, 19, 22, 
etc). 
x BIOMARKERS: Serum CTN and CEA prior to cycles 1, 3, 5, 7, 9, and 13, and then every 6 
cycles (19, 25, etc).  Serum calcitonin should be drawn after a 12 hour fast and sent to the 
lab immediately at room temperature.  
x URINALYSIS: Perform prior to every treatment cycle for cycles 1 through 9, then every 3 
cycles (13, 16, 19, 22, etc). 
x SERUM/URINE PREGNANCY TEST:  Prior to every cycle in females with child bearing 
potential for cycles 1 through 9, then cycle 13, and every 6 cycles (19, 25, etc). 
x Plasma Metanephrines and nor-Metanephrines and Vitamin D 25-OH: Prior to cycle 1 and 
then every year (at NIH). 
3.6.3 ECG WITH CALCULATION OF QTC 
Prior to cycle 1 and on days 3 and 7 and then weekly during cycle 1.  Then prior to all 
subsequent cycles for cycles 2 through 9, then every 3 cycles (13, 16, 19, 22, etc).  See Section 
6.2 for management of QTc prolongation.  Use Bazett’s correction (QTc = QT/RR0.5). 
3.6.4 TUMOR MEASUREMENTS AND RADIOGRAPHIC EVALUATION 
x The longest diameter of palpable tumors should be measured prior to each treatment cycle. 
x CT scans of the neck, chest and abdomen prior to cycles 1, 3, 5, 7, 9, and 13, and then 
every 6th cycle (19, 25, 31, etc).  For patients who demonstrate a PR or CR, the response 
should be confirmed by repeating the scans after the next cycle. 
x MRI of the brain (if positive at baseline) annually or as clinically indicated.  MRI of the 
neck (optional if disease can be adequately followed by CT) prior to cycles 1, and then as 
clinically indicated. 

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x 
99mTc-Bone scan (if positive at baseline) prior to cycles 1 then annually or as clinically 
indicated. 
x MRI of the knee to assess the volume of growth plates only in patients with open growth 
plates on the pretreatment MRI.  Scans will be performed prior to cycles 1, 3, 5, 7, 9, 13 
and then every 6th cycle (19, 25, 31, etc), until growth plates are fused. 
4 
CONCOMITANT MEDICATIONS/MEASURES   
4.1.1 OTHER ANTI-CANCER AGENTS 
Patients may not receive other forms of cancer chemotherapy, radiation therapy, immunotherapy 
or investigational agents while enrolled on this trial and receiving vandetanib. 
4.1.2 COMPLEMENTARY AND ALTERNATIVE THERAPIES 
All complementary or alternative therapies including herbal preparations, vitamins, and 
supplements should be discussed with the PI or an Associate Investigator.  All agents will be 
recorded on the electronic case report forms. 
4.1.3 THYROID REPLACEMENT THERAPY 
Patients who are receiving thyroid replacement therapy at the time of enrollment onto the study 
should be maintained on thyroid replacement therapy.  The dose should be adjusted to maintain 
the TSH within the normal range.  Patients who have an elevated TSH at enrollment and who are 
not on thyroid replacement therapy should be started on replacement therapy and maintained on 
a dose that suppresses TSH into the normal range. 
4.1.4 ANTI-HYPERTENSIVE THERAPY 
Please refer to Section 6.1.2 for information on the use of enalapril for the management of 
vandetanib-related hypertension. 
4.1.5 AGENTS THAT PROLONG THE QTC  
Please refer to Appendix 4: Medications Known to Prolong the QT Interval or Induce Torsades 
de Pointes prior to starting any new supportive care drug to ensure that it does not cause 
prolongation of the QTc. Agents in Group 1 cannot be administered concurrently with 
vandetanib. Participants requiring one of these agents should be removed from the treatment with 
vandetanib. 
Drugs in Group 2 of Appendix 4: Medications Known to Prolong the QT Interval or Induce 
Torsades de Pointes are allowed during the study, at the discretion of the Investigator, if 
considered absolutely necessary (no alternative is available). In such cases, the patient must be 
closely monitored, including regular checks of QTc and electrolytes. 
5 
Criteria for Removal from Protocol Therapy and Off Study Criteria 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days following the last dose of study therapy. 
5.1.1 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY 
x Toxicity: Patients who develop a vandetanib-related DLT (Section 3.1.4) that does not 
recover to grade ≤1 in ≤14 days will discontinue protocol therapy.  See Sections 6.1 to 6.3 

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for criteria on discontinuation of vandetanib for hypertension, QTc prolongation, and skin 
toxicity. 
x Concurrent use of agents that prolong the QTc:  Vandetanib use must be discontinued 
if one of the QTc prolonging agents in Group 1 of Appendix 4: Medications Known 
to Prolong the QT Interval or Induce Torsades de Pointes is started. 
x Progressive Disease: Patients with clinical or radiographic evidence of progressive disease 
will discontinue vandetanib (see Section 7.2). If possible, tumor progression should be 
documented radiographically. Patients with progression of both CTN and CEA, should 
have a radiological evaluation to determine whether there is measurable evidence of tumor 
progression by RECIST. 
Patients participating on the dose escalation portion of the trial will receive a lower dose (100 
mg/m2/d) for the first 2 28-day treatment cycles.  Those who are eligible for dose escalation may 
continue on treatment at the 150 mg/m2/d dose level starting on cycle 3 and beyond as long as 
the sum of the longest diameters of target lesions has not increased by more than 40% compared 
to baseline and no new lesions have appeared, in order to ensure that these patients have an 
opportunity to receive the equivalent to the adult recommended dose (150 mg/m2/d) of 
vandetanib. 
x Other Medical Reason:  
o The development of a concurrent serious medical condition that might 
preclude or contraindicate the further administration of vandetanib. 
o It is deemed in the best interest of the patient. In this instance the Principal 
Investigator should be notified and the reasons for discontinuation of 
vandetanib should be noted in the patient's medical record.  
o Serious protocol violation, such as non-compliance, as determined by the 
Principal Investigator. 
5.1.2 OFFSTUDY CRITERIA 
x Patient or guardian withdrawal of consent.  Reasons must be noted on the patient's 
medical record.  
x Lost to follow up. 
[Overall survival is an endpoint on this trial.  Patients will remain on this trial to be monitored for 
this endpoint.] 
The NCI Central Registration Office should be notified when a participant is taken off study. 
5.1.3 OFF PROTOCOL THERAPY AND OFF-STUDY PROCEDURE 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 

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5.2 
Post-Treatment Evaluations 
5.2.1 FOLLOW-UP EVALUATIONS 
Once a patient develops progressive disease, annual contact with the patient or health care 
provider will be attempted to obtain survival data. 
5.2.2 OFF-STUDY VISIT 
The following tests or procedures should be performed, if possible, immediately prior to the time 
a patient comes off study regardless of the reason, unless the test or procedures have been 
performed within the past two weeks. 
x Physical examination 
x Performance status 
x Assessment of clinical toxicity/adverse events 
x Complete blood count with differential and platelet count 
x Electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, uric acid, ALT, total 
and direct bilirubin, alkaline phosphatase, and albumin. 
x Serum CTN and CEA drawn after a 12 hour fast and sent to the lab at room temperature. 
x Radiographic evaluation of measurable or evaluable disease. 
6 
SUPPORTIVE CARE ISSUES 
As of Amendment J: All patients remaining on trial in long term therapy will be monitored and 
managed according to Appendix 5: As of Amendment J: Care, Monitoring and Management of 
all Patients Remaining on Study on Long Term Vandetanib Therapy. 
6.1 
Management of Hypertension (HTN) 
6.1.1 HTN MANAGEMENT ALGORITHM 
If the diastolic BP is found to be elevated above the 95th percentile for age and gender 
(Appendix 2: Normal Blood Pressure Range for Children) at any point during treatment, the 
measurement should be repeated twice more with an appropriate size cuff.  The diastolic BP will 
be considered to be elevated if at least 2 of the 3 diastolic BP measurements exceed the 95th 
percentile. 
 

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x Refer to Appendix 2: Normal Blood Pressure Range for Children for age and gender 
normal blood pressure ranges in children and adolescents. 
x Arm 1 of algorithm: If diastolic blood pressure ≤95% for age and gender, continue 
vandetanib at the same dose or dose escalate (Section 3.1.2)  
x Arm 2 of algorithm:  If diastolic blood pressure ≤10 mm Hg above the ULN for age and 
gender, continue vandetanib at the same dose and recheck the DBP within 72 h. 
o If the DBP is ≤95% for age and gender on recheck, continue vandetanib at 
the same dose or dose escalate (Section 3.1.2). 
o If the DBP remains above the ULN for age and gender on recheck, then start 
antihypertensive therapy (Section 6.1.2) and follow Arm 3 of the algorithm 
from the point that anti-hypertensive therapy is started. 
x Arm 3 of algorithm: If diastolic blood pressure is 11 to 25 mm Hg above the 95% for 
age on ≥2 of 3 measurements, start single agent anti-hypertension therapy (see Section 
6.1.2), continue vandetanib at the same dose, and monitor blood pressure at least every 3 
days. 
o If the diastolic blood pressure drops to ≤95% for age within 14 days, 
continue vandetanib at the same dose and continue concurrent single agent 
anti-hypertensive therapy. 
o If the diastolic blood pressure remains elevated ≤25 mm Hg above the 95% 
for age for more than 14 days after the institution of single agent anti-

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hypertensive therapy, hold vandetanib, monitor blood pressure at least every 
3 days, and follow Arm 4 of the algorithm from the point that vandetanib is 
held.  The antihypertensive therapy should be continued until the DBP <10 
mm Hg above the ULN for age and gender.   
 If the diastolic blood pressure drops to ≤95% for age within 14 days and the 
antihypertensive therapy can be discontinued, restart vandetanib at a reduced 
dose (Section 3.3.1). 
 If the diastolic blood pressure remains >95% for age for more than 14 days, 
discontinue vandetanib (Section 5). 
o If the diastolic blood pressure increases to >25 mm Hg above the 95% for 
age despite anti-hypertensive therapy or the participant develops grade 4 
hypertension (CTCAE v.3), hold vandetanib, but continue the anti-
hypertensive agent until the diastolic blood pressure is <10 mm Hg above 
the 95% for age on 2 measurements at least 3 days apart.  Monitor the 
blood pressure at least every 3 days and follow Arm 4 of the algorithm 
from the point that vandetanib is held. 
 If the diastolic blood pressure is ≤95% for age within 14 days off 
of anti-hypertensive therapy, restart vandetanib at a reduced dose 
(Section 3.3.1). 
 If the diastolic blood pressure is >95% for age for more than 14 
days, discontinue vandetanib (Section 5) 
x Arm 4 of algorithm: If diastolic blood pressure is >25 mm Hg above the 95% for age or 
the participant develops grade 4 hypertension (CTCAE v.3), hold vandetanib and monitor 
blood pressure at least every 3 days.  Anti-hypertensive therapy can be used until the 
diastolic blood pressure is <10 mm Hg above the 95% for age on 2 measurements at least 
3 days apart. 
o If the diastolic blood pressure drops to ≤95% for age within 14 days off of 
anti-hypertensive therapy, restart vandetanib at a reduced dose (Section 
3.3.1). 
o If the diastolic blood pressure is >95% for age for >14 days, discontinue 
vandetanib (Section 5) 
x The cycle duration remains 28 consecutive days in patients who have dose interruptions. 
6.1.2 SINGLE AGENT ANTI-HYPERTENSIVE THERAPY 
x Participants with a persistently (>72 h) elevated DBP that is ≤10 mm Hg 
above the 95% for gender and age (ULN, Appendix 2: Normal Blood 
Pressure Range for Children) or with ≥2 of 3 DBP measurements on a single 
day that are 11-25 mm Hg above the ULN should be started on enalapril at a 
dose of 2.5 mg PO once daily for children weighing <50 kg and 5.0 mg PO 
once daily for children weighing ≥50 kg.40 
x Blood pressure should be monitored 4 hours after the first dose (day 1), 24 
hours after the first dose, and then every 48 hours until the DBP is ≤ULN x 2 
measurements. 
x If the DBP remains elevated at ≤25 mm Hg above the ULN after 7 days of 
enalapril, the dose of enalapril can be doubled, if the participant has not 
experienced enalapril-related toxicity at the starting dose. 

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x If the DBP remains elevated at ≤25 mm Hg above the ULN after 14 days of 
enalapril, then the vandetanib should be held (see Section 6.1.1). 
x If the DBP increases to >25 mm Hg above the ULN on ≥2 of 3 measurements 
at any time during enalapril treatment or the participant develops grade 4 
hypertension at any time, then the vandetanib should be held. 
Antihypertensive therapy should be continued until the DBP is <10 mm Hg 
above the 95% for age and gender on 2 measurements at least 3 days apart 
(see Section 6.1.1). 
6.2 
Management of QTc Prolongation 
If a QTc value is ≥550 msec OR the QTc increases by ≥100 msec from baseline, vandetanib 
must be held and an ECG repeated at least twice weekly until the QTc interval is ≤480 msec. 
After resolution of the QTc prolongation to ≤480 msec, vandetanib may be restarted at a reduced 
dose (see Section 3.3) after discussion with the protocol PI. Once the vandetanib is restarted at a 
lower dose, ECGs should be performed weekly for the first 8 weeks and then every 4 weeks 
thereafter. If the QTc does not return to ≤480 msec in ≤14 days, vandetanib should be 
discontinued. 
If a QTc value is ≥500 msec but <550 msec, OR the QTc increases by ≥60 msec but <100 msec 
from baseline and the QTc is ≥480 msec, then a repeat ECG should be performed within 48 
hours to confirm the QTc prolongation. Vandetanib should continue to be taken until the second 
ECG is performed. Then: 
x If the repeat QTc meets the criteria above again, vandetanib should be held and an ECG 
repeated at least twice a week until the QTc is ≤480 msec. After resolution of the QTc 
prolongation to ≤480 msec, vandetanib may be restarted at a reduced dose (Section 3.3) 
after discussion with the protocol PI. Once the vandetanib is restarted at a lower dose, 
ECGs should be performed weekly for the first 8 weeks and then every 4 weeks 
thereafter. If the QTc does not return to ≤480 msec in ≤14 days, vandetanib will be 
discontinued.  
x If the repeat QTc does not meet the criteria above, vandetanib should be continued and 
ECG monitoring should be performed as outlined in Section 3.6. 
6.3 
Management of Skin Toxicity 
Vandetanib must be held when any CTCAE grade 3 or 4 vandetanib-related skin toxicity occurs.  
For grade 3 or 4 allergic skin reactions, vandetanib should be discontinued.  For non-allergic 
reactions, treatment may be resumed at a lower dose (Section 3.3) if the toxicity recovers to 
grade ≤1 or baseline within 14 days of discontinuing the drug. If the skin toxicity does not 
resolve to grade ≤1 or baseline in ≤14 days, vandetanib should be discontinued. 
Agents that can be used to manage skin rashes include mild to moderate strength steroid creams, 
topical or systemic antibiotics, topical or systemic antihistamines, and occasionally retinoid 
creams. If a patient develops a skin rash, the following actions are recommended for the 
management of this toxicity: 
x For a grade ≥2 vandetanib-related rash, symptomatic treatment with topical creams or 
systemic anti-histamines should be provided. 
x For grade ≥3 vandetanib-related rash (non-allergic), vandetanib should be held until 
recovery to grade ≤1. After recovery, vandetanib may be restarted at a reduced dose 

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(Section 3.3) after discussion with the protocol PI. If the rash does not resolve to grade ≤1 
in ≤14 days OR the rash is an allergic rash, vandetanib will be discontinued. 
6.4 
Management of Gastrointestinal Toxicity 
Electrolytes should be closely monitored in the event of persistent vomiting or diarrhea. 
Vandetanib should be held in patients who develop electrolyte abnormalities from vomiting or 
diarrhea until the electrolyte abnormalities are corrected because of the risk of QTc prolongation 
and subsequent arrhythmias. 
6.4.1 NAUSEA OR VOMITING 
Nausea and vomiting may be controlled with antiemetic therapy. There is a risk that the use of 
5HT-3 antagonists may prolong QTc interval; therefore, these agents are prohibited. The dose of 
vandetanib may be repeated once if emesis occurs within 15 minutes of taking the dose.  
6.4.2 VANDETANIB-RELATED DIARRHEA 
Diarrhea that occurs after initiation of vandetanib is likely to be treatment-related and should be 
treated symptomatically to avoid dose modification or interruption. Diarrhea due to vandetanib 
has been successfully managed in adults with anti-diarrheal agents such as loperamide.  Because 
diarrhea may be a component of MTC with elevated CTN, no dose modifications will be made 
for pre-existing cases of diarrhea. If grade 3 diarrhea that cannot be controlled by symptomatic 
treatments within 48 h or grade 4 diarrhea develops, or diarrhea worsens by one grade level 
(grade 3 to grade 4) while on vandetanib and is not alleviated by symptomatic treatment within 
48 h, vandetanib should be held until diarrhea resolves to grade ≤1 or baseline. Once the diarrhea 
resolves, vandetanib may restarted at a reduced dose (Section 3.3). Dose reduction should only 
occur if the investigator believes the diarrhea is related to vandetanib. 
6.5 
Management of MTC-Related Diarrhea 
Patients who are receiving symptomatic treatment for diarrhea at study entry can continue the 
treatment while on study.  If CTN levels are elevated at study entry in these patients and the 
levels drop by >50% on vandetanib therapy, an attempt should be made to taper or discontinue 
the symptomatic anti-diarrheal therapy. 
Adults with MTC and CTN-related diarrhea had improvement in diarrhea on vandetanib, so 
symptomatic treatment for MTC-related diarrhea should not be started after study entry for at 
least 2 weeks to determine whether vandetanib can alleviate the diarrhea. 
Patients should not be treated with short- or long-acting octreotide while on study because it may 
have an independent therapeutic effect on the biomarker endpoints (CTN and CEA). 
7 
DATA COLLECTION AND EVALUATION 
7.1 
Data Collection 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) 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 

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45 
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 breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified. 
Clinical data will be shared with AstraZeneca as outlined in the CTA. 
As of Amendment J: For all patients remaining on study on long term therapy after > 2 years of 
treatment with vandetanib, only Unanticipated Events and response data will be captured in 
C3D.  In addition, safety evaluations required for continued treatment with vandetanib will be 
collected, but not entered into C3D. 
7.1.1 SOURCE DOCUMENTS 
Source documents are defined as original documents, data and records.  This may include 
hospital records, clinical and office charts, laboratory data/information, or evaluation checklists, 
pharmacy dispensing and other records, recorded data from automated instruments, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays. In the case of foreign language 
documents received from LMD or health care institutions, a certified NIH Translation Office 
translation may be accepted as a source document (but is not required). 
 The investigator will permit trial-related monitoring, audits, IRB review, and regulatory 
inspection(s), providing direct access to source documents. 
7.1.2 CASE REPORT FORMS 
Data may be entered from the source documents directly into eCRFs in C3D for each patient 
enrolled in this study.   
As of Amendment J: For all patients remaining on study on long term therapy after > 2 years of 
treatment with vandetanib only SAEs and response data will be captured in C3D. 
The principal investigator or research nurse will review the eCRFs for completeness and 
accuracy. Independent audits may also be conducted by NCI personnel to ensure completeness 
and accuracy of data in C3D.  
In addition to the eCRFs the following forms will be completed: 
x Eligibility checklist prior to enrollment (FAXed to the Central Registration Office). 
x PK worksheets (Appendix 3: Pharmacokinetic Worksheet for Vandetanib) at the end of 
cycle 1. 
7.1.3 DATA QUALITY ASSURANCE 
The CRAs will monitor each patient’s data set throughout the study.  Source document review 
will be made against entries on the eCRF and a quality assurance check will be performed to 
ensure that the investigator is complying with the protocol and regulations.  In addition, after 
eCRFs are completed by the CRA, review of the data will be conducted by a research nurse or 
physician at the NCI POB. 
All data are coordinated through: 

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46 
Claudia Derse-Anthony, R.N. 
10 Center Drive, Room 1C244 
Bethesda, MD 20982 
Office Phone: (240) 760-6102  
7.2 
Genomic Data Sharing Plan 
There is no GDS plan for this protocol. Patients on this study are co-enrolled in protocol 12-C-
0178, Longitudinal Assessment and Natural History Study of Children and Young Adults with 
MEN2A or MEN2B with or without Medullary Thyroid Carcinoma, where genomic data sharing 
and analysis are conducted.  
7.3 
Response Criteria 
7.3.1 RECIST 
Baseline documentation of “Target” and “Non-Target” lesions 
x 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.  
x 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.  
x All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline. 
x 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).  
x 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. 
x All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
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 

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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 
Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
Incomplete Response/ Stable 
Disease (SD): 
Persistence of one or more non-target lesion(s) or 
maintenance of tumor marker level above the normal 
limits 
Progressive Disease (PD): 
Appearance of one or more new lesions or unequivocal 
progression of existing non-target lesions. 
Although a clear progression of “non-target” lesions 
only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time 
by the review panel (or Principal Investigator). 
Confirmation of Response 
x The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed.  In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
x To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed no less than 4 weeks after the criteria for response 
are first met. Longer intervals as determined by the study protocol may also be appropriate.  
x In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum 8 weeks from study entry. 
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 

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48 
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 
Best Response for this Category 
Also Requires: 
CR 
CR 
No 
CR 
>4 wks. confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
>4 wks. confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once >4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
Duration of Response 
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. 
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. 
To be considered clinically relevant, the duration of stable 
disease must be ≥8 weeks. 

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Progression-Free Survival (PFS) 
PFS is defined as the duration of time from start of treatment to time of progression. 
7.3.2 BIOMARKER RESPONSE CRITERIA 
See Section 3.6 for calcitonin (CTN) and CEA sampling time points. Only patients with average 
pretreatment CTN and CEA levels that are >2 times the ULN are evaluable for response. 
Response criteria for CEA and CTN are: 
x Complete Response (CR): Normalization (≤ULN) of CEA or CTN level following 
treatment, confirmed with a repeat CEA/CTN level at least 4 weeks apart. 
x Partial Response (PR): A ≥50% decrease in the CEA or CTN level relative to the 
baseline level, confirmed with a repeat CEA/CTN level at least 4 weeks apart.  
x Progression (P): A ≥50% increase in the CEA or CTN relative to the prior value on 2 
consecutive measurements at least 4 weeks apart (e.g., if the last prior CTN value was 
1,000 pg/ml, consecutive values of 1,500 pg/ml and then 2,250 pg/ml at least 4 weeks 
later would represent progression).  The patient must have been taking vandetanib for 4 
weeks prior to the first measurements and must have continued to take the drug through 
the time that the second measurement was drawn. 
x Stable (S): <50% increase or decrease in CTN or CEA level relative to the baseline level. 
To be assigned a status of biomarker PR or CR, changes in serum tumor biomarker level must be 
confirmed by repeat measurement, which should be performed ≥4 weeks after the criteria for PR 
or CR are first met. 
For stable disease, follow-up CEA/CTN levels must have met the stable disease criteria at least 
once after study entry at a minimum interval defined as 12 weeks. 
Each patient’s best CEA response and best CTN response will be calculated from the average 
(of 2) baseline measurement and lowest measurement during treatment (confirmed by a second 
measurement ≥4 weeks later). Responders are those subjects with a best biomarker response of 
CR or PR. 
7.4 
Toxicity Criteria 
This study will utilize the Cancer Therapy Evaluation Program Common Terminology Criteria 
for Adverse Events (CTCAE-3) for toxicity and Adverse Event grading and reporting. A copy of 
the CTCAE-3 can be downloaded from the CTEP website 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_30). 
8 
Statistical Considerations 
8.1.1 PATIENT ACCRUAL 
Patients of both genders, from all racial and ethnic groups are eligible for this trial if they meet 
the eligibility criteria outlined in Section 2.1.  There is no clinical information that suggests 
differences in vandetanib metabolism, disposition or MTC response among racial or ethnic 
groups or between the genders, indicating that results of the trial will be applicable to all groups.  
This phase II trial of vandetanib will be conducted in children and adolescents (5-18 year olds) 
with hereditary MTC, which is a very rare condition. A similar trial has been conducted in adults 
with MTC. Efforts will be made to extend the accrual to a representative group from this 
population, but with a rare disease and with a planned accrual of 21 patients, a balance must be 

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struck between completing the trial in a timely fashion on the one hand and the need to explore 
gender, racial, and ethnic aspects of clinical research on the other. If differences in outcome that 
correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional 
studies may be performed to investigate those differences more fully.  We anticipate that accrual 
to this trial can be completed in 2 to 3 years. 
8.1.2 STATISTICS AND FEASIBILITY 
The primary objective of this trial is to determine whether the RET inhibitor, vandetanib, which 
is active against hereditary MTC in adults, has equivalent anti-tumor activity in children and 
adolescents with hereditary MTC.  The primary endpoint is objective response (CR or PR) 
measured with RECIST (see Section 7.3.1). Because the agent is already known to be active in 
hereditary MTC, the trial will follow a single stage design (no early analysis for futility). The 
response rate in adults is 5/18 (28%; lower one-sided 95% CI bound = 10%).  This trial is 
designed to determine whether the response rate in children and adolescents with hereditary 
MTC exceeds 10% and may be consistent with a response rate as high as 30%.  With a planned 
sample size of 21 evaluable patients (see Section 3.1.6), using a one-sided 0.1 alpha level exact 
binomial test, the trial would have 80% power to rule out a 10% response rate in favor of a 30% 
response rate.  In practice, 5 responses in 21 patients would marginally rule out 10% as a 
response rate, and also may be consistent with a response rate of approximately 40%. 
Biomarker (CTN and CEA) and clinical response rate will be reported with their associated exact 
95% CIs.  Only a subset of enrolled subjects will be evaluable for biomarker response or clinical 
response as defined in Sections 7.3.1 and 7.3.2.  The mean pretreatment CTN and CEA levels 
and mean nadir CTN and CEA levels across all patients enrolled on the trial will be calculated.  
There are no phase I data for vandetanib in children. Therefore, the safety and tolerability of 
doses that are equivalent to the recommended doses in adults will be assessed initially in 
adolescents (13-18 yo) and then in children (5-12 yo).  This will be done using an intra-patient 
dose escalation design, which will ensure that all patients receive the dose equivalent to the one 
used in the adult phase II trial (if that dose is tolerable in children), and therefore ensure that all 
patients are evaluable for the phase II component of this trial.  The design of the limited dose 
escalation portion of this trial is described in detail in Section 3.1.2. Because of the rare nature of 
this disease, the patients in the dose escalation phase are included in the 21 evaluable patients 
who are to be enrolled to evaluate response.  Patients who are enrolled on the dose escalation 
portion of the trial and who do not complete the first 2 cycles for reasons other than a 
vandetanib-related DLT can be replaced on the intra-patient dose escalation portion of the trial, 
but they will remain potentially evaluable for the phase II portion of the trial. 
The pharmacokinetics of vandetanib will be studied in children and adolescents with hereditary 
MTC at steady state (end of cycle 2) after at least 42 days of continuous dosing.  At steady state, 
the AUC for the dosing interval (0 to 24 h) is equivalent to the AUC0-∞ after a single dose.  
Pharmacokinetic parameters to be derived include the AUC0-24h, the peak and trough plasma 
concentrations, the time to peak concentration, and the CL/F.  The relationship of CL/F to age 
and gender will be assessed as will the relationship of AUC0-24 to pharmacodynamic outcomes 
(toxicity, response). 
Evaluations of other objectives will be done in an exploratory fashion: 

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x To determine the progression-free survival and overall survival in children and 
adolescents with hereditary MTC treated with vandetanib. Kaplan Meier curves will 
be constructed, and descriptively reported, including appropriate confidence intervals. 
x To assess the expression of RET, EGFR, VEGFR, and somatostatin receptor by 
immunohistochemistry (IHC) in archival tissue blocks from children and adolescents 
enrolled on this protocol.  IHC data will be scored and the findings will be reported 
descriptively. In those patients who have pre-treatment (diagnostic or research) 
samples, the difference in the scored values will be compared by a marginal 
homogeneity test or McNemar’s test for paired categorical data, depending on the 
availability of data. 
x To assess gene expression by microarray prior to and during treatment with 
vandetanib, appropriate data will be collected and analyzed by individuals with 
experience doing this evaluation. This will be considered an exploratory analysis. 
x To perform RET gene mutational analysis in tumor and peripheral blood 
mononuclear cells prior to treatment and in tumor at the time of disease progression 
on treatment with vandetanib. Any novel gene mutations identified will be reported 
and, if possible, evaluated with respect to an association with disease progression 
using exploratory techniques. Kaplan-Meier analysis or other methods to relate 
genotype to clinical endpoints will be used in an exploratory fashion. 
x To perform comparative genomic hybridization on tumor tissue DNA to globally 
screen for gains/losses of DNA.  This will be considered an exploratory analysis. 
x To study the effects of vandetanib on proliferation of pediatric MTC cell lines 
established from patients with clinically sensitive and resistant tumors and to study 
the drug’s effects on RET activation and signaling pathways in the drug exposed cell 
lines.  Standard cell survival analyses will be used to quantify the effect of various 
drug concentrations on cell proliferation compared to an untreated control.  The effect 
of the drug on signaling pathways will be correlated to the IC50 of vandetanib in each 
cell line.  This will also be considered an exploratory analysis. 
Stopping Rule:  If one grade ≥3 adverse event that is related to a core needle biopsy to obtain a 
research specimen occurs in a patient on this trial, then no further biopsies will be performed to 
obtain research samples. 
8.2 
Data Safety and Monitoring Plan 
Vandetanib has been approved by the US Food and Drug Administration (FDA) for treatment of 
MTC and currently has a well established toxicity profile.  Therefore, only unexpected ≥ grade 2 
adverse events at least possibly related to study drug or any ≥ grade 3 or adverse events  
observed in patients enrolled on the trial will be recorded by the Principal and Associate 
Investigators, and attribution of these events to vandetanib will be determined at the end of each 
treatment cycle in each subject.  The clinical research team (PI, adjunct PI, research nurses, data 
managers) will meet on a regular basis when patients are being actively treated on the trial to 
discuss each patient in detail and ensure that all events are graded appropriately, and that the 
attribution to study drug is correct.  Decisions about dose level (escalation) and enrollment will 
be made based on the toxicity data from prior patients. 
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 

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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 or 
as needed, 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. 
This trial will not require monitoring by a DSMB. 
8.3 
Sample Storage, Tracking and Disposition 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without IRB notification and an executed MTA. 
Research specimen collection, labeling, and initial processing is outlined in Sections 3.4 and 3.5.  
Specimens will initially be stored in monitored freezers (-70°C or -20°C) or refrigerators (4°C) 
in the Pharmacology & Experimental Therapeutics Section (PETS) Laboratory, POB, NCI on 1 
West (CRC). Samples will be tracked using the PETS pharmacokinetics FileMaker database.  
Samples will be identified using a unique patient number (study number).  Specimens will be 
distributed to the following labs for assay: 
x Plasma samples for pharmacokinetic analysis of vandetanib and its metabolites will 
be shipped in batches to AstraZeneca for analysis by HPLC-MS/MS.  The PI will 
instruct AZ to destroy the residual samples after all pharmacokinetic samples have 
been assayed and the analysis of the PK data has been completed. 
x Slides from archival tissues blocks will be requested from each patient’s referring 
medical team.  These slides will be transferred to Dr. Maria Merino-Neumann in the 
Laboratory of Pathology for immunohistochemical staining (RET, VEGFR, EGFR, 
somatostatin receptor).  Stained slides, which will be labeled with the patients study 
number, will be stored in the Lab of Pathology until the trial is completed.  If 
unstained slides are available after planned studies are completed, these may be used 
for future research after getting an exemption form OHSR or approval from the IRB. 
x Cell lines generated from biopsy or surgical specimens will be maintained in vitro in 
tissue culture indefinitely. 
x Snap frozen biopsy specimens and a blood specimen will be transferred to Dr. Paul 
Meltzer’s lab for gene expression and RET mutation analysis.  These specimens will 
be labeled with the patient’s study number.  Dr. Meltzer will retain residual 
specimens, which may be used for future research after getting an exemption form 
OHSR or approval from the IRB. 
The study will remain open and status of the trial (and specimens) will be reported to the NCI 
IRB until all samples have been analyzed, reported, destroyed, stripped of all identifiers and 
unlinked from the protocol database, or transferred to another protocol. Unintentional loss or 
destruction of any samples will be reported to the NCI IRB as part of annual continuing reviews.  

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Any use of samples not outlined in Section 3.4 or 3.5 will require an exemption from OHSR or 
prospective NCI IRB review and approval. 
9 
COLLABORATIVE AGREEMENTS 
9.1 
Clinical Trial Agreement (00720-07) 
A Clinical Trial Agreement (CTA) has been established between the CCR and AstraZeneca. 
10 HUMAN SUBJECTS PROTECTION 
10.1 Rationale for Subject Selection 
Subject accrual in regard to gender, and racial and ethnic groups is described in Section 8.1.1.  
The study population is limited to patients 18 years and younger because there is a separate 
phase II trial of vandetanib in adults with hereditary MTC. There is a younger age limit of 5 
years because it is very unlikely that patients younger than 5 years with MEN 2A or 2B will have 
recurrent or refractory MTC. 
10.2 Participation of Children 
This trial is designed to determine whether the response rate of hereditary MTC to vandetanib in 
children and adolescents is equivalent to the response rate in adults with the same condition. 
There is currently no experience with vandetanib in children, so the tolerability of the adult 
equivalent doses in children, the toxicity spectrum in children and the pharmacokinetics in 
children are also being studied. Therefore, children and adolescents will be enrolled onto this 
research trial. This trial will be conducted by pediatric oncologists who have extensive 
experience in performing investigational drug trials in children.  Patients enrolled at the POB, 
NCI will be cared for in the POB outpatient clinic or day hospital. When patients require hospital 
admission, they will be cared for on the 1NW Pediatric Unit by the POB staff. 
10.3 Participation of Subjects Unable to Give Consent 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 10.5), all subjects ≥ age 18 will be offered the opportunity to fill 
in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated 
or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become 
incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in MAS Policy 87-4 for appointing a surrogate decision maker for adult subjects who 
are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 
10.4 Risks and Benefits 
The primary risk to patients participating in this research study is from toxicity of vandetanib. In 
adults, vandetanib has been relatively well tolerated.  The most common adverse events have 
been rash, diarrhea and asymptomatic QTc prolongation, which are reversible and generally can 

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be alleviated by dose reduction. Because the drug has not been previously administered to 
pediatric patients, the protocol provides for detailed and careful monitoring of all patients to 
assess for toxicity.  The starting dose is based on the results of previous adult phase I trials of 
vandetanib and planned dose escalation will not exceed the dosing range which demonstrated 
clinical benefit and which was well tolerated in adults.  Toxicity data from the first dose level 
will be collected and reviewed in real time to ensure that there were no severe (dose-limiting) 
toxicities prior to escalating to the second dose level (intra-patient dose escalation on cycle 3); 
and adolescents (13-18 yo) will be studied before introducing the drug to children (5-12 yo). The 
benefits of this molecularly-targeted agent in hereditary MTC have been demonstrated in adults.  
The objective response rate (PRs) by RECIST is approximately 30% and the majority of patients 
have substantial reductions in serum calcitonin levels, which is felt to contribute to MTC-related 
diarrhea. 
The protocol incorporates percutaneous core needle biopsies of superficial tumors with minimal 
risk to surrounding vital structures in order to obtain tumor specimens for research purposes in 
participants over the age of 12 years who meet the eligibility criteria in Section 2.1.3.  These 
research specimens would be used to assess the effect of vandetanib (in vivo) on gene expression 
in tumors that partially respond to the agent and, more importantly, to assess the mutational 
status of the RET gene mutations in the tumor (compared to germ line mutations) at the onset of 
treatment and at the time of progressive disease.  Pediatric MTC tumor cell lines will also be 
established to study the effects of vandetanib on the tumor in vitro.  New mutations that account 
for drug resistance provide valuable information for the development of new agents to 
circumvent drug resistance.  These types of studies have been critical to understanding and 
overcoming resistance to imatinib, another RTK inhibitor.41,42  There would be no immediate 
direct benefit to the subject who undergoes a biopsy on this trial.  The most likely site for 
biopsies would be superficial lymph nodes in the neck.  In a small series (n=15) describing the 
use of ultrasound-guided cutting needle biopsy (16 or 18 gauge) in pediatric neck masses, 100% 
of the biopsy attempts yielded a tissue core from the target organ, including 12 lymph node 
masses.43  Thirteen of these 15 patients had the biopsy successfully performed under local 
anesthesia (topical anesthetic cream and local injection of local anesthetic).  There were no 
complications from the biopsies, but potential risks from the procedure include infection, local 
spread of tumor, pain, bleeding, and damage to structures in proximity to the biopsy site. 
10.5 Risks/Benefits Analysis 
Children and adolescents will be entered on this trial. A primary risk to patients participating in 
this research study is from toxicity of vandetanib, an investigational agent. In adult patients, 
doses of up to 300 mg daily (approximately equivalent to 150 mg/m2/d) have been well tolerated.  
The pediatric starting dose on this trial is 100 mg/m2/d, which is 40% below the adult 
recommended dose and the dose will be escalated 150 mg/m2/d on cycle 3 only in patients who 
have demonstrated that they can tolerate the 100 mg/m2/d dose in the initial dose escalation 
portion of the trial. The primary objective of this trial is to determine the activity of vandetanib in 
children and adolescents with hereditary MTC, and thus all patients entered will be treated with 
therapeutic intent and response to the therapy will be closely monitored.  The potential benefits 
from this therapy are disease stabilization or shrinkage and a reduction in symptoms caused by 
the MTC, such as diarrhea.  Therefore, the phase I/II component of this protocol involves greater 
than minimal risk to children, but presents the prospect for direct benefit to individual child-
subjects (Category 2). 

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The biopsies being performed to obtain tumor samples for research purposes will not provide 
immediate direct benefit to the participants but will potentially provide value data regarding the 
mechanisms of resistance to vandetanib.  The identification of a new somatic RET mutation in a 
tumor from a single patient would be significant if the mutation results in drug resistance.  The 
four categories of research in minor subjects that can be approved by an IRB are listed below and 
on the OHSR website at http://ohsr.od.nih.gov/irb/Attachments/5-12_Children.htm 
Category 1: Research that does not involve greater than minimal risk to children. 
Category 2: Research involving greater than minimal risk but presenting the prospect of direct 
benefit to the individual child-subject. 
Category 3: Research involving greater than minimal risk and no prospect of benefit to the 
individual child-subject. In order to approve research in this category, an IRB must determine 
that the risk of the research represents no more than a minor increase over minimal risk; that the 
intervention or procedure presents experiences to the child-subjects that are reasonably 
commensurate with those inherent in their actual, or expected medical, dental, psychological, 
social, or educational situations; and the intervention or procedure is likely to yield generalizable 
knowledge about the subject's disorder or condition which is of vital importance for 
understanding or amelioration of the disorder or condition. 
Category 4: Research not otherwise approvable under one of the above categories but the IRB 
determines that the study presents a reasonable opportunity to further the understanding, 
prevention, or alleviation of a serious problem affecting the health or welfare of children. In 
these cases the IRB will forward the research for review by the Deputy Director for Intramural 
Research (DDIR). If he/she agrees, the study will be forwarded to the Secretary of HHS who 
may approve the research after consultation with a panel of experts. The panel must determine 
that the research presents a reasonable opportunity to further the understanding, prevention, or 
alleviation of a serious problem affecting the health or welfare of children, and that the research 
will be conducted in accordance with sound ethical principles. 
Category 3 allows for research that has no prospect of direct benefit to the individual child-
subject if the IRB determines that the risk of the research (tumor biopsy) represents no more than 
a minor increase over minimal risk.  The description of this category suggests that the IRB 
determine that the risk or “experience” of the procedure is “reasonably commensurate with those 
inherent in their actual or expected medical, dental, psychological, social, or educational 
situations”.  The statement raises the concept of relative risk – indicating that what is acceptable 
(a minor increment over minimal risk) is in part determined by the subjects prior life experiences 
and that in a child with cancer who has undergone surgery, frequent blood draws, chemotherapy, 
or radiation, the proposed biopsy of a superficial tumor lesion may be commensurate with their 
life experiences and be considered a minor increase over minimal risk.  If the IRB determines 
that the risk of the biopsies is greater than a minor increment over minimal risk (Category 4), the 
research is still approval but must be reviewed and approved by the NIH DDIR and then sent to 
the Secretary of DHHS for an ad hoc committee review. 
A stopping rule has been included to discontinue performing biopsies for research samples if a 
single grade ≥3 adverse event related to the biopsy procedure occurs on this trial. 

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10.6 Consent and Assent Process and Documentation 
Effective with amendment J, the protocol was closed to accrual. The information below 
regarding two consents is no longer applicable, but is being retained for historical purposes. 
Because not all patients enrolled on this trial will be eligible to have a biopsy to obtain a research 
specimen, we have written 2 consents for this trial – one of the treatment portion and one for the 
biopsy to obtain a tumor specimen for research purposes.  We have also written an assent form 
for the biopsy.  The treatment consent will explain the investigational nature and research 
objectives of this trial, the procedures (other than the biopsy) and treatment involved and the 
attendant risks and discomforts and benefits, and potential alternative therapies.  These issues 
will also be carefully explained to the patient's parents or guardian (or the patient if he/she is 18 
years old), and a signature will be obtained on the informed consent document prior to entry onto 
the study. Where deemed appropriate by the clinician and the child's parents or guardian, the 
child will also be included in all discussions about the trial and verbal assent will be obtained for 
participation in the treatment portion of the trial. The parent or guardian will sign the designated 
line on the informed consent attesting to the fact that the child has given verbal assent.  Senior 
investigators from the Pharmacology & Experimental Therapeutics Section of the POB will lead 
this discussion.  For those patients with a superficial tumor that can be safely biopsied, the 
investigator will also explain the purpose, risks, and lack of direct benefit from participating in 
the series of biopsies, and the optional nature of the procedure will be explained (i.e., refusing 
participation will not impact on their eligibility to participate in the treatment component of the 
trial).  A signature will be obtained on a separate written consent and assent forms prior to 
performing the biopsies. The investigators are requesting a waiver from the IRB to allow only 
one parent to sign the treatment informed consent form to enter a child on the protocol.  Because 
many patients must travel to the NIH from long distances at substantial expense, requiring both 
parents to be present for the consent process could be a financial hardship for many families.  
The parent who signs the consent for a minor must be a legally recognized parent or guardian. 
Both parents must consent to the biopsy for research purposes, unless there is only one legal 
guardian. If one of the parents did not accompany the child to the NIH, then consent will be 
obtained by phone. The biopsy consent form will be sent (FAX, e-mail or overnight shipping) to 
the parent who is not present prior to the telephone discussion. The child and the parent who 
came with the child to the NIH will be included on the call. The parent present at the NIH will 
sign for the absent parent if that parent agrees to the biopsy after the telephone conference call. A 
witness at the NIH will also be included on the call and sign the consent as a witness. 
10.6.1 CONSENT FOR MINORS WHEN THEY REACH THE AGE OF MAJORITY  
When a pediatric subject reaches age 18, continued participation will require consenting of the 
now adult with the standard protocol consent document to ensure legally effective informed 
consent has been obtained. We are requesting waiver of informed consent for those individuals 
who have been lost to follow-up or who, prior to the approval of Amendment L, have been taken 
off study before reaching the age of majority. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d): 
(1) The research involves no more than minimal risk to the subjects. 
a. Analysis of samples and data from this study involves no additional risks to 
subjects. 

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(2) The waiver or alteration will not adversely affect the rights and welfare of the 
subjects. 
a. Retention of these samples or data does not affect the welfare of subjects.  
(3) The research could not practicably be carried out without the waiver or alteration. 
a. Considering the length of time between a minor’s enrollment and their age of 
majority, it is possible that more than a few subjects may be lost to follow 
up.  A significant reduction in the number of samples analyzed could impact 
the quality of the research.  
(4) Whenever appropriate, the subjects will be provided with additional pertinent 
information after participation. 
a. We only plan to request a waiver of consent for those subjects who have been 
lost to follow-up or who, prior to the approval of Amendment L, have been 
taken off study before reaching the age of majority. 
11 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
All data collection and reporting will be coordinated through: 
Claudia Derse-Anthony, R.N. 
10 Center Drive, Room 1C244 
Bethesda, MD 20982 
Office Phone: (240) 760-6102  
Email: derseanthonycp@mail.nih.gov 
 
This trial of the investigational agent, vandetanib, will be performed under an investigator IND 
held by the study PI, Dr. Brigitte Widemann.  The Investigator IND is cross-filed on the IND 
held by the drug manufacturer, AstraZeneca.  AstraZeneca will supply vandetanib for this trial.  
The Study PI and IND holder for this trial is responsible for reporting directly to FDA any 
adverse experiences that are associated with the use of vandetanib and that are both serious and 
unexpected (see definitions below) in an expedited fashion (see Section 11.3) and for filing 
annual reports on the progress of the trial to the FDA (see Section 11.3).  The study PI will 
simultaneously provide AstraZeneca with a copy of all submissions (IND Safety Reports and 
Annual Reports) to the FDA.  Expedited reporting of deaths on study and adverse events to the 
NCI IRB is described in Section 11.2. 
11.1 Definitions 
11.1.1 ADVERSE EVENT 
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 unless otherwise noted above in 
Section 7.1. 

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All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until return to baseline or stabilization of event. Serious adverse 
events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of at least possibly related to the agent/intervention 
should be recorded and reported as per sections 11.2, 11.3, 11.4.   
As of Amendment J: For all patients remaining on study on long term therapy after > 2 years of 
treatment with vandetanib only unanticipated problems will be collected and documented. 
11.1.2 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. 
11.1.3 UNEXPECTED ADVERSE REACTION 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure, package insert, 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 or package insert 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. 
11.1.4 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. 
11.1.5 SERIOUS ADVERSE EVENT:  
Any 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: 
x Death, 
x A life-threatening adverse drug experience 
x Inpatient hospitalization or prolongation of existing hospitalization 
x Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x A congenital anomaly/birth defect.  
x 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. 
11.1.6 DISABILITY:  
A substantial disruption of a person’s ability to conduct normal life functions. 

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11.1.7 LIFE-THREATENING ADVERSE DRUG EXPERIENCE:   
Any adverse drug experience that places the patient or subject, in the view of the investigator, 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. 
11.1.8 PROTOCOL DEVIATION (NIH DEFINITION) 
Any change, divergence, or departure from the IRB-approved research protocol. 
11.1.9 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. 
11.1.10UNANTICIPATED PROBLEM 
Any incident, experience, or outcome that: 
x  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 
x Is related or possibly related to participation in the research; AND 
x 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. 
11.2 NCI-IRB and Clinical Director Reporting 
11.2.1 NCI-IRB AND NCI CD EXPEDITED REPORTING OF UNANTICIPATED PROBLEMS, AND 
DEATHS 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations, except as noted above 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
11.2.2 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: 
x All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  

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x All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research; 
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
11.2.3 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. 
11.3 IND Sponsor Reporting Criteria 
An investigator must immediately report to the sponsor, using the mandatory MedWatch form 
3500a or equivalent, any serious adverse event, whether or not considered drug related, including 
those listed in the protocol or investigator brochure and must include an assessment of whether 
there is a reasonable possibility that the drug caused the event.  
x All Grade 5 (fatal) events (except death due to progressive disease) must be reported via 
email within 24 hours.  A complete report must be submitted within one business day.  
x All other serious adverse events including deaths due to progressive disease must be 
reported within one business day 
Study endpoints that are serious adverse events (e.g. all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between 
the drug and the event (e.g. death from anaphylaxis).  In that case, the investigator must 
immediately report the death to the sponsor. 
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov  
and to the CCR PI and study coordinator. 
11.3.1 REPORTING PREGNANCY 
11.3.1.1 Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately and the pregnancy reported to the Sponsor. The potential risk of 
exposure of the fetus to the investigational agent(s) or chemotherapy agents (s) should be 
documented in box B5 of the MedWatch form “Describe Event or Problem”. 
Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study 
risk intrauterine exposure of the fetus to agents which may be teratogenic, the CCR is requesting 
that pregnancy should be reported in an expedited manner as Grade 3 “Pregnancy, puerperium 
and perinatal conditions - Other (pregnancy)” under the Pregnancy, puerperium and 
perinatal conditions SOC.  
Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented. 

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If any pregnancy occurs in the course of the study, then the investigator should inform the 
Sponsor within 1 day, i.e., immediately, but no later than 24 hours of when he or she becomes 
aware of it. 
The designated Sponsor representative will work with the investigator to ensure that all relevant 
information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days 
for all other pregnancies. 
The same timelines apply when outcome information is available. 
11.3.1.2 Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 3 
months after the last dose of Vandetanib. 
Pregnancy of the patient’s partner is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 3 months after the last 
dose should, if possible, be followed up and documented. 
11.4 Safety Reporting Criteria to the Pharmaceutical Collaborators 
All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov.  
The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described 
below. 
The Sponsor will notify AstraZeneca (SAE Fax line, 302-886-1528 or email: 
AEMailboxClinicalTrialTCS@astrazeneca.com) in a written IND Safety Report (MedWatch, 
Form 3500A) of any adverse experience associated with the use of vandetanib that is both 
serious and unexpected as soon as possible and in no event later than 15 calendar days after 
initial receipt of the information. 
The Sponsor will also notify AstraZeneca by email: 
AEMailboxClinicalTrialTCS@astrazeneca.com ) of any unexpected fatal or life-threatening 
experience associated with the use of vandetanib as soon as possible but in no event later than 7 
calendar days of initial receipt of the information. A Fax cover page should accompany the 
MedWatch form that is sent to AstraZeneca indicating the following: 
x Vandetanib Investigator Sponsored Study (ISS) 
x The investigator IND number assigned by the FDA 
x The investigator’s name and address 
x The trial name/title and AstraZeneca reference number 
The Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
Any event or hospitalization that is unequivocally due to progression of disease, as determined 
by the PI, will not be reported as an SAE, however should be communicated to AstraZeneca. 
Serious adverse events that do not require expedited reporting to the FDA will be reported to 
AstraZeneca quarterly in the form of a spreadsheet generated from the CCR C3D Oracle Clinical 
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62 
For the purposes of this study any detrimental change in a patient’s condition from the time 
written informed consent is given until 28 days after the last dose of study treatment should be 
considered an AE. 
All dose-limiting toxicities (see Section 3.1.4) that are possibly, probably, or definitely related to 
vandetanib and all serious adverse drug experiences (see Section 11.1), including oncology 
related events that meet the criteria for a serious adverse drug experience, whether related to 
vandetanib or not, will be reported to Dr. Brigitte Widemann by telephone within 24 hours of 
being made aware of the event:  
Brigitte Widemann, M.D. 
Pediatric Oncology Branch 
National Cancer Institute 
10 Center Drive, MSC 1104 
Bldg. 10 CRC, Rm. 1-3750 
Bethesda, MD 20814-1104  
Phone: 240-760-6203 
E-mail:  widemanb@mail.nih.gov 
12  PHARMACEUTICAL INFORMATION 
12.1 Vandetanib (IND #77570) 
12.1.1 CHEMICAL INFORMATION 
Chemical name (IUPAC): 
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-
piperidinyl)methoxy]-4-quinazolinamine 
Other Names:  ZD6474, vandetanib, ZACTIMA 
Chemical Structure: 
 
Molecular Formula:  C22H24BrFN4O2 
Molecular Weight:  475.36 
12.1.2 MECHANISM OF ACTION 
Vandetanib is a potent inhibitor of the tyrosine kinase activity of kinase insert domain-containing 
receptor (KDR), an endothelial cell receptor for vascular endothelial growth factor (VEGF), and 
also possesses activity against epidermal growth factor receptor (EGFR).  Vandetanib is being 
developed clinically for its antiangiogenic properties, but it also inhibits the enzymatic activity of 
RET-derived oncoproteins with an IC50 of 100 nM.  RET inhibition is the basis for the use of 
vandetanib in MTC. 
N
N
N
O
O
CH3
N
Br
F
H
CH3

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12.1.3 SOURCE 
This trial of vandetanib for children and adolescents with MTC is being performed under an 
Investigator IND to be held by the protocol PI.  The vandetanib for the trial was being supplied 
to the NCI by AstraZeneca. Effective 2016, Genzyme is supplying vandetanib for the study. 
12.1.4 FORMULATION AND PREPARATION 
The 50 and 100 mg tablets contain vandetanib, calcium hydrogen phosphate, microcrystalline 
cellulose, crospovidone, povidone, and magnesium stearate with a film coating containing 
methylhydroxypropylcellulose, polyethylene glycol 300 and titanium dioxide. 
The oral solution will be used as needed until supplies are exhausted.  The oral solution comes as 
15 mL of 10 mg/mL vandetanib in 25 mL oral solution bottles. 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. 
12.1.5 STABILITY AND STORAGE 
The tablets and bottles should be stored at room temperature in the original pack until use. 
Documentation indicating Vandetanib was destroyed will be sent to AstraZeneca. 
12.1.6 ADMINISTRATION PROCEDURES 
Vandetanib is administered orally, once daily continuously.  A cycle of vandetanib is defined as 
28 consecutive days starting with the first day of treatment (day 1). The dose of vandetanib is 
determined from the patient’s body surface area using the dosing nomogram (Section 3.2). 
Treatment will be administered in an outpatient setting. Tablets and oral solution can be 
combined to accurately dose patients (e.g., a dose of 75 mg could be one 50 mg tablet plus 2.5 
ml of the 10 mg/ml oral solution). 
12.1.7 DISPENSING VANDETANIB 
Vandetanib will be dispensed by the CC Pharmacy and documented according to CC Pharmacy 
SOP for drug accountability.  Vandetanib will be dispensed every 6 cycles to patients who meet 
criteria for continued therapy according to Appendix 5: As of Amendment J: Care, Monitoring 
and Management of all Patients Remaining on Study on Long Term Vandetanib Therapy.   
12.1.8 TOXICITY 
Adverse events (>0.1%) by system organ class and preferred term in vandetanib emerging safety 
profile 
Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1839) 
Cardiovascular 
N (%) 
ECG QT prolongation 
127(6.9) 
Myocardial infarction 
11 (0.6) 

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Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1839) 
Angina pectoris 
10 (0.5) 
Nervous System 
 
Headache 
228 (12.4) 
Dysgeusia 
61 (3.3) 
Cerebrovascular accident 
5 (0.3) 
Gastrointestinal 
 
Diarrhea 
931 (50.6) 
Nausea 
480 (26.1) 
Vomiting 
256 (13.9) 
Constipation 
230 (12.5) 
Abdominal pain 
119 (6.5) 
Stomatitis 
92 (5.0) 
Dry mouth 
85 (4.6) 
Pancreatitis 
3 (0.2) 
Endocrine disorders 
 
Hypothyroidism 
23 (1.3) 
Blood and lymphatic system  
 
Thrombocytopenia 
15 (0.8) 
Investigations 
 
Weight loss 
141 (7.7) 
Elevated liver function tests 
34-42 (1.8 – 2.3) 
Metabolic and nutritional disorders 
 

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Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1839) 
Decreased appetite 
253 (13.8) 
Anorexia 
182 (9.9) 
Hypokalemia 
81 (4.4) 
Hypocalcemia 
67 (3.6) 
Dehydration 
49 (2.7) 
Hypomagnesemia 
23 (1.3) 
Hypophosphatemia 
4 (0.2) 
Skin/appendages 
 
Rash (variety of terms)# 
46% 
Renal 
 
Hematuria 
5% 
Proteinuria 
1% 
Respiratory 
 
Interstitial lung disease (including 
pneumonitis)§ 
5% 
Pulmonary embolism 
2% 
Vascular 
 
Arterial ischemic events¶ 
2% 
Venous thromboembolism 
1% 
General 
 
Asthenia 
8% 
Fatigue 
40% 
Psychiatric disorders£ 
 

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Event by system organ class 
Percentage of patients from patients 
receiving vandetanib 300 mg 
monotherapy (N=1839) 
Anxiety 
12% 
Depression 
11% 
Insomnia 
11% 
* 
The values reflect the frequency of events as a reported adverse event and do not include 
out-of-range laboratory values or abnormal vital signs. The events of hypophosphatemia and 
ecchymosis occurred in phase I studies, but did not occur in study 6474IL/0003; the frequency 
has therefore been set as <1%. The events of interstitial lung disease/pneumonitis, pulmonary 
embolism and venous thromboembolism occurred in study 6474IL/0003, but these events are 
heavily confounded by advanced cancer, previous radiation and chemotherapy, and disease 
progression. 
† 
CIOMS Council for International Organization for Medical Sciences (subset of World 
Health Organization). 
# 
Acneiform rash, pruritus, macular or macupapular rash (generalized or localized), 
localized and generalized erythema, photosensitivity reaction, sweating.  On occasion (especially 
when given with chemotherapy) these have progressed to more serious conditions to include 
exfoliative dermatitis, skin desquamation, erythroderma, toxicoderma, toxic epidermal 
necrolysis, erythema multiforme 
§ 
Preliminary data from the Phase III program suggest that the incidence of interstitial lung 
disease may be higher in Japan (≈ 10%) than in rest of world (≈ 1%). 
¶ 
Includes myocardial infarction/stroke/peripheral arterial ischemia 
£ 
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). 
In addition to the above toxicity profile, we have also observed cramping abdominal pain 
associated with drug-related diarrhea and hypothyroidism manifested as an increase in TSH 
requiring an increase in the dose of thyroid hormone replacement. 
12.2 Enalapril 
12.2.1 CHEMICAL INFORMATION 
Chemical name (IUPAC): 
1-[2-(1-ethoxycarbonyl-3-phenyl-propyl) aminopropanoyl] 
pyrrolidine-2-carboxylic acid 
Other Names:  Enalapril maleate 
Molecular Formula:  C20H28N2O5 
Molecular Weight:  376.45 

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12.2.2 MECHANISM OF ACTION 
Enalapril is an anti-hypertensive agent that inhibits angiotensin converting enzyme (ACE). 
12.2.3 SOURCE 
Enalapril maleate tablets are available as a generic from commercial sources.  Enalapril is on the 
NIH Pharmacy formulary. 
12.2.4 FORMULATION AND PREPARATION 
Enalapril maleate is available in 2.5, 5, and 20 mg tablets.  Enalaprilat (Vasotec) is also available 
as an IV formulation  
12.2.5 STABILITY AND STORAGE 
Refer to the product label. 
12.2.6 ADMINISTRATION PROCEDURES 
Enalapril tablets will be administered once daily in the morning at a dose of 2.5 mg in children 
weighing <50 kg and a dose of 5 mg for children who weigh ≥50 kg. 
12.2.7 TOXICITY 
In a study of 110 children between the ages of 6 and 16 years treat with enalapril at one of 3 dose 
levels (low dose = 0.625 mg if <50 kg or 1.25 mg if ≥50 kg; middle dose = 2.5 mg if <50 kg or 5 
mg if ≥50 kg; or high dose = 20 mg if <50 kg or 40 mg if ≥50 kg), 14 adverse events that were 
believed to be possibly, probably, or definitely drug related were reported in 12 patients. 
Dizziness was the most common adverse event, occurring in 4 patients (3 in the high-dose group 
and 1 in the middle-dose group). Two patients complained of headaches. The following adverse 
experiences were recorded in 1 patient each: chest pain, increased blood pressure, hypotension, 
diarrhea, cough, dyspnea, pruritis, rash, and blurred vision. In the low-, middle-, and high-dose 
groups, 2, 4, and 6 patients reported adverse events. A total of 3 patients reported cough, but 
none were discontinued from the study and only one episode was considered drug related. None 
of the patients experienced renal failure, angioedema, or hyperkalemia. No serious laboratory 
abnormalities were observed. Five adverse events that were believed to be possibly, probably, or 
definitely related to the study drug were reported in 3 patients. The adverse events were slight 
increases in BUN, creatinine, and serum uric acid and decreased hemoglobin and hematocrit. In 
the aggregate, there were no differences in mean pre- and post-dose hemoglobin, serum sodium, 
potassium, creatinine, AST, or ALT. 

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68 
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Quayle FJ, Moley JF. Medullary thyroid carcinoma: including MEN 2A and MEN 2B 
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Peczkowska M, Januszewicz A. Multiple endocrine neoplasia type 2. Fam Cancer 
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Skinner MA, DeBenedetti MK, Moley JF, Norton JA, Wells SA, Jr. Medullary thyroid 
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Skinner MA, Moley JA, Dilley WG, Owzar K, Debenedetti MK, Wells SA, Jr. 
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Danko ME, Skinner MA. Surgical intervention in children with multiple endocrine 
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nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary 
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Cohen R, Campos JM, Salaun C, et al. Preoperative calcitonin levels are predictive of 
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d'Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab 2000;85:919-22. 
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Hirsch PF, Baruch H. Is calcitonin an important physiological substance? Endocrine 
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Findlay DM, Sexton PM. Calcitonin. Growth Factors 2004;22:217-24. 
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Reasbeck PG, Burns SM, Shulkes A. Calcitonin gene-related peptide: enteric and 
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Chiefari E, Russo D, Giuffrida D, et al. Analysis of RET proto-oncogene abnormalities in 
patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma. J Endocrinol 
Invest 1998;21:358-64. 
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Gujral TS, Singh VK, Jia Z, Mulligan LM. Molecular mechanisms of RET receptor-
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Carlomagno F, Vitagliano D, Guida T, et al. ZD6474, an orally available inhibitor of 
KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 
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30. 
Wedge SR, Ogilvie DJ, Dukes M, et al. ZD6474 inhibits vascular endothelial growth 
factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 
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31. 
Vidal M, Wells S, Ryan A, Cagan R. ZD6474 suppresses oncogenic RET isoforms in a 
Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid 
carcinoma. Cancer Res 2005;65:3538-41. 
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Herbst RS, Heymach JV, O'Reilly MS, Onn A, Ryan AJ. Vandetanib (ZD6474): an orally 
available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor 
growth and angiogenesis. Expert Opin Investig Drugs 2007;16:239-49. 
33. 
Ryan AJ, Wedge SR. ZD6474--a novel inhibitor of VEGFR and EGFR tyrosine kinase 
activity. Br J Cancer 2005;92 Suppl 1:S6-13. 
34. 
Checkley D, Tessier JJ, Kendrew J, Waterton JC, Wedge SR. Use of dynamic contrast-
enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 
prostate tumours. Br J Cancer 2003;89:1889-95. 
35. 
Holden SN, Eckhardt SG, Basser R, et al. Clinical evaluation of ZD6474, an orally active 
inhibitor of VEGF and EGF receptor signaling, in patients with solid, malignant tumors. Ann 
Oncol 2005;16:1391-7. 
36. 
Tamura T, Minami H, Yamada Y, et al. A phase I dose-escalation study of ZD6474 in 
Japanese patients with solid, malignant tumors. J Thoracic Oncol 2006;1:1002-9. 
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Natale RB, Bodkin D, Govindan R, et al. ZD6474 versus gefitinib in patients with 
advanced NSCLC: Final results from a two-part, double-blind, randomized phase II trial. Proc 
Am Soc Clin Oncol 2006;24:7000 (Abstr). 
38. 
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study conduct efficiency. J Clin Oncol 2005;23:8431-41. 
39. 
Smith RP, Kennedy S, Robertson J, Sandall D, Oliver R. The effect of food on the intra-
subject variability of the pharmacokinetics of ZD6474, a novel antiangiogenic agent, in healthy 
subjects. Proc Am Soc Clin Oncol 2005;23:3167. 
40. 
Wells T, Frame V, Soffer B, et al. A double-blind, placebo-controlled, dose-response 
study of the effectiveness and safety of enalapril for children with hypertension. J Clin 
Pharmacol 2002;42:870-80. 
41. 
Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance 
in gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764-74. 
42. 
Mauro MJ. Defining and managing imatinib resistance. Hematology Am Soc Hematol 
Educ Program 2006:219-25. 
43. 
Bain G, Bearcroft PW, Berman LH, Grant JW. The use of ultrasound-guided cutting-
needle biopsy in paediatric neck masses. Eur Radiol 2000;10:512-5. 
 
 
 

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71 
14 Appendix 1: Performance Status Scales/Scores 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
Karnofsky 
Lansky 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no evidence of 
disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, minor 
signs or symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on normal 
activity or do active work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional assistance, but is 
able to care for most of his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance and 
frequent medical care. 
50 
Gets dressed, but lies around much of 
the day; no active play, able to 
participate in all quiet play and 
activities. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
20 
Very sick, hospitalization indicated.  
Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes progressing 
rapidly. 
10 
No play; does not get out of bed. 
Patients >10 years old : use Karnofsky performance criteria 
Patients ≤ 10 years old: use Lansky performance criteria 

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15 Appendix 2: Normal Blood Pressure Range for Children 
Diastolic blood pressure levels for BOYS aged 1-18 years   
 
1 
2 
3 
4 
Age 
(years) 
ULN* DBP 
mmHg 
DBP ≤10 
mmHg above 
ULN 
10<DBP ≤25 
mmHg above 
ULN 
DBP>25 
mmHg 
above ULN 
1 
58 
59-68 
69-83 
84 
2 
62 
63-72 
73-87 
88 
3 
66 
67-76 
77-91 
92 
4 
69 
70-79 
80-94 
95 
5 
71 
72-81 
82-96 
97 
6 
73 
74-83 
84-98 
99 
7 
74 
75-84 
85-99 
100 
8 
75 
76-85 
86-100 
101 
9 
77 
78-87 
88-102 
103 
10 
78 
79-88 
89-103 
104 
11 
79 
80-89 
90-104 
105 
12 
80 
81-90 
91-105 
106 
13 
82 
83-92 
93-107 
108 
14 
83 
84-93 
94-108 
109 
15 
83 
84-93 
94108 
109 
16 
84 
85-94 
95-109 
110 
17 
84 
85-94 
95-109 
110 
18 
84 
85-94 
95-109 
110 
* ≤95th percentile for age and 50% height percentile 
Diastolic blood pressure levels for GIRLS aged 1-18 years  

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1 
2 
3 
4 
Age 
(years) 
ULN* DBP 
mmHg  
DBP ≤10 
mmHg above 
ULN 
10<DBP ≤25 
mmHg above 
ULN 
DBP>25 
mmHg 
above ULN 
1 
57 
58-67 
68-82 
83 
2 
61 
62-71 
72-86 
87 
3 
65 
66-75 
76-90 
91 
4 
68 
69-78 
79-93 
94 
5 
71 
72-81 
82-96 
97 
6 
74 
75-84 
85-99 
100 
7 
76 
77-86 
87-101 
102 
8 
77 
78-87 
88-102 
103 
9 
79 
80-89 
90-104 
105 
10 
80 
81-90 
91-105 
106 
11 
80 
81-90 
91-105 
106 
12 
81 
82-91 
92-106 
107 
13 
82 
83-92 
93-107 
108 
14 
82 
83-92 
93-107 
108 
15 
83 
84-93 
94-108 
109 
16 
85 
86-95 
96-110 
111 
17 
87 
88-97 
98-112 
113 
18 
87 
88-97 
98-112 
113 
* ≤95th percentile for age and 50% height percentile 
These Charts list DBP levels within the ULN (1), within 10 mmHg above the ULN (2), within 
11-25 mmHg above the ULN (3), and >25 mmHg above the ULN (4).  
Instructions for using this BP Chart: 
1. Measure the patient’s blood pressure using an appropriate size cuff. 

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74 
2. Select appropriate chart for a female or male patient. 
3. Using the “age” row determine if the DBP is within the ULN (1) or elevated (2, 3, 4).  
4. See Section 3.1.4 for definition of dose limiting hypertension. 
5. See Section 6.1 for management of vandetanib related hypertension. 
 
 

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16 Appendix 3: Pharmacokinetic Worksheet for Vandetanib 
Patient Study ID 
#: 
 
Weight 
(kg): 
 
Height (cm): 
 
BSA (m2): 
 
Dose level (mg/m2): 
 
Actual 
Dose 
(mg):  
 
Date: 
 
Time dose  taken: 
 
Cycle/Day: 
 
 
Sample 
# 
Cycl
e 
Day Hour 
Target Date & 
Time  
Actual 
Time 
Obtained 
Pre 
1 
0 
Pre dose #1 
 
 
1 
1 
2 
24* 
 
 
 
 
 
 
 
 
2 
2 
1 
24* 
 
 
 
 
 
 
 
 
3 
2 
28 
Pre dose 
 
 
4 
2 
28 
1  
 
 
5 
2 
28 
2  
 
 
6 
2 
28 
4 
 
 
7 
2 
28 
6 
 
 
8 
2 
28 
8 
 
 
9 
2 
28 
10 to 12 
 
 
10 
3 
1 
24* 
 
 

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76 
 
 
 
 
 
 
11 
4§ 
1 
24* 
 
 
 
 
 
 
 
 
12 
5§ 
1 
24* 
 
 
* 
Draw hr 24 sample prior to administering the next days dose. 
§ 
Only in patients who have their dose escalated to 150 mg/m2/d after cycle 2. 
Blood samples of approximately 2 ml will be collected by venipuncture or from an indwelling 
venous central or peripheral line (after discarding appropriate waste) into a lithium heparin 
Vacutainer tube (green top).  Following blood collection, the tubes should be inverted several times 
to ensure mixing with the anticoagulant.  The tubes should be placed on crushed ice, and samples 
centrifuged for 10 minutes at approximately 1000 x g at room temperature within 30 minutes after 
collection.  The plasma samples will be transferred using plastic pipettes into screw-capped 
polypropylene tubes labeled with vandetanib study number, the patient ID number, date, study 
day, collection time, and sample #.  The plasma samples will be frozen within 1 hours after 
collection and will remain frozen at < -20°C until shipped. 
Plasma samples can be stored frozen at -20qC or -70qC for a period of up to 6 months after 
which time they should be shipped to BASi (see details below). They should be packed securely 
to avoid breakage during transit and with enough dry ice to prevent thawing for at least 72 hours. 
A sample itinerary detailing sample numbers and identification should be sent with each 
shipment and BASi should be contacted by fax or email prior to each sample shipment.  Samples 
should be shipped to avoid arrival at the laboratory during weekends and public holidays and 
should be sent to the following address. 
Jason Plassard 
Bioanalytical Systems Inc. (BASi) 
2701 Kent Avenue  
West Lafayette 
IN 47906-1350  
Phone:  765.497.5853 
Fax:  765.497.5863 
Email:  japlassard@bioanalytical.com  

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17 Appendix 4: Medications Known to Prolong the QT Interval or Induce Torsades de 
Pointes 
It has been recognized for a number of years that certain 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 or have a risk of inducing Torsade de Pointes (TdP) are listed 
below, divided into two groups based on their known or perceived risk of causing TdP. 
Group 1. 
Drugs that are generally accepted as having a risk of causing Torsades de Pointes 
Concomitant use of these drugs is not allowed during the study or within 2 weeks of enrollment 
(at least four weeks for levomethadyl). These drugs should also be avoided for up to 4 weeks 
following discontinuation of vandetanib: 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
Amiodarone 
Anti-arrhythmic (heart rhythm) 
F>M, TdP Cases in 
Literature 
Arsenic trioxide 
Anti-cancer (leukemia) 
TdP Cases in Literature 
Astemizole 
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 (anesthesia 
adjunct) 
TdP Cases in Literature 
Erythromycin 
Antibiotic/GI stimulant 
(infection/GI motility) 
F>M 
Halofantrine 
Anti-malarial (malaria infection) 
F>M 

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Haloperidol 
Anti-psychotic (schizophrenia, 
agitation) 
 
Ibutilide 
Anti-arrhythmic (heart rhythm) 
F>M 
Levomethadyl 
Opiate agonist (narcotic 
dependence) 
 
Mesoridazine 
Anti-psychotic (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. 
Thioridazine 
Anti-psychotic (schizophrenia) 
 
Vandetanib (*Does not 
apply in this study) 
Anti-cancer (thyroid cancer) 
“Zactima®” is the proposed 
brand name 
Group 2. 
Drugs that may be associated with Torsades de Pointes but lack substantial 
evidence of causing Torsades de Pointes. 
These drugs will be allowed during the study, at the discretion of the Investigator, if considered 
absolutely necessary (no alternative is available). In such cases, the patient must be closely 
monitored, including regular checks of QTc and electrolytes. 

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Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Alfuzocin 
Alpha 1-blocker (Benign prostatic 
hyperplasia) 
 
Amantadine 
Dopaminergic/Anti-
viral/Antiinfective (Parkinson’s 
disease) 
 
Atazanavir 
Protease inhibitor (HIV) 
 
Azithromycin 
Antibiotic (bacterial infection) 
 
Chloral hydrate 
Sedative (sedation/insomnia) 
 
Clozapine 
Anti-psychotic (schizophrenia) 
 
Dolasetron 
Anti-nausea (nausea and vomiting) 
 
Dronedarone 
Anti-arrhythmic (atrial fibrillation) 
 
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) 
 

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Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
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 
diarrhea) 
 
Ofloxacin 
Antibiotic (bacterial infection) 
 
Ondansetron 
Anti-emetic (nausea &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 

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Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Tamoxifen 
Anti-cancer (breast cancer) 
 
Telithromycin 
Antibiotic (bacterial infection) 
 
Tizanidine 
Muscle relaxant 
 
Vardenafil 
Phosphodiesterase inhibitor 
(vasodilator) 
 
Venlafaxine 
Antidepressant (depression) 
 
Voriconazole 
Anti-fungal (fungal infection) 
 
Ziprasidone 
Anti-psychotic (schizophrenia) 
 
Updated 19 August 2011 

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18 Appendix 5: As of Amendment J: Care, Monitoring and Management of all Patients Remaining on Study on Long Term 
Vandetanib Therapy 
 
Introduction:  As of Amendment J, the requirements for the care, monitoring and management of all patients remaining on the trial on 
long term treatment with vandetanib will be consistent with the package insert Medication Guide recommendations.  Evaluations may 
be performed by local medical doctor (LMD) or health care institution that will provide status updates to the NCI. At least annually, 
safety and response evaluations will be performed at NCI.  LMDs will be requested to complete evaluations (as per attached letter) 
and notify the NCI study team of patient status.  Source documents will be sent to the NIH and once the status is verified by the NCI 
study team, vandetanib will be ordered from the NIH CC Pharmacy (See Drug Ordering Below).   
DRUG ADMINISTRATION: 
Vandetanib is administered orally, once daily on a continuous dosing schedule. A cycle of vandetanib is defined as 28 consecutive 
days starting with the first day of treatment (day 1). The dose of vandetanib is determined from the patient’s body surface area using 
the dosing nomogram below. The BSA should be recalculated at least annually (at least every 12 cycles, or with a major change in 
height or weight). 
Vandetanib is supplied as either a 10 mg/ml suspension or 50 and 100 mg tablets.  Vandetanib should be stored at room temperature in 
the original pack until use. 
Vandetanib should be taken once daily at the same time of day, irrespective of meals.  If liquid suspension or 50 mg tablets are not 
available, an every other day dosing schedule can be used to achieve the correct dose, but is not preferred.  See package insert for 
directions regarding missed doses. 
Supportive care and concomitant medications may be administered as clinically indicated and as according to the Vandetanib package 
insert (Appendix 6: Vandetanib Package Insert). 
 
Dose 
Level 
[mg/m2] 
 
 
 
 
 
 
 
100 
BSA 
[m2] 
0.50-
0.62 
0.63-
0.87 
0.88-
1.12 
1.13-
1.37 
1.38-
1.75 
>1.75- 
200 

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83 
Dose 
[mg] 
50 
75 
100 
125 
150 
100 
(tablets 
only) 
BSA 
[m2] 
Dose 
[mg] 
0.50-
0.74 
50 
 
0.75-
1.24 
100 
 
1.25-
1.75 
150 
>1.75 
200 
150 
BSA 
[m2] 
Dose 
[mg] 
0.50-
0.83 
100 
 
084-1.16 
150 
1.17-
1.50 
200 
1.51-
1.83 
250 
>1.83 
300 
 
EVALUATIONS: 
Quarterly evaluations should be performed by LMD or health care institution that has agreed to supply the information to the NCI (see 
attached letter) 
1. Every 3 cycles (± 30 days) 
x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, other evaluations as clinically 
indicated 
x Obtain 12-lead electrocardiogram and evaluate QTc 
x Evaluate for unanticipated problems (UPs); if clinical evaluations are performed by the LMD as clinically indicated, study staff 
will contact the patient via phone to ascertain UPs since last contact. 
2. Every 6 cycles (± 30 days) 
x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, Serum CTN and CEA, other 
evaluations as clinically indicated 
x Obtain 12-lead electrocardiogram and evaluate QTc 
x Evaluate for UPs; clinical evaluations are performed by the LMD as clinically indicated, study staff will contact the patient via 
phone to ascertain UPs since last contact. 
x Pregnancy test prior to imaging tests in women of child-bearing potential 
x Radiographic evaluation of disease 
3. Every 12 cycles (must be performed at NIH) (± 30 days) 

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84 
x History and Physical Exam with height and weight (BSA),  
x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, Serum CTN and CEA, other 
evaluations as clinically indicated 
x Obtain 12-lead electrocardiogram and evaluate QTc 
x Evaluate for UPs 
x Pregnancy test prior to imaging tests in women of child-bearing potential 
x Radiographic evaluation of disease 
 
DOSE MODIFICATIONS: 
Study drug dose reductions will be allowed and are to be made based on discussions between the subject, the subject’s LMD 
and the study investigator. Physicians (LMDs and investigators) should fully document the findings of these calls/visits in the 
subject’s medical records. Dose modifications and delays may be made according to the package insert (See Appendix 6: 
Vandetanib Package Insert) and good clinical practice.   
 
DATA COLLECTION AND DOCUMENTATION: 
As of approval of Amendment J for all subjects remaining on trial and receiving long term therapy, only SAEs and response 
data will be captured in C3D.  All evaluations and physician visits should be documented in the patient’s medical record. 
 
PHARMACY DISPENSING OF VANDETANIB: 
Patients returning to NIH for follow up visits will be dispensed vandetanib from the Clinical Center (CC) Pharmacy.  At the time of 
the NIH visit, patients should return any unused drug supplies, which will be discarded in CC Pharmacy as medical waste. 
Patients who are evaluated by their LMD / health care institution will be contacted by phone by the study team and evaluated for UPs 
and drug accountability (doses left).  Once the study team determines the patient is eligible to continue therapy (information received 
from LMD), a CRIS order will be submitted for a 6 cycle supply of study drug to be shipped to the patient via priority mail, when 
feasible.  Subjects should be directed not to finish the study drug from the previous visit.  Instead, when the new drug supply arrives, 
the patient should be directed to hold all unused drug and bottles and to bring them to the study site at the next scheduled visit.  Non-
compliance by the patient in returning study drug back to the site can result in the patient being terminated from the study. 

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Version Date: 06/27/2017 
 
 
85 
Public Health Service 
National Institutes of Health 
Memorandum 
 
[Recipient Name] 
[Title] 
[Company Name] 
[Street Address] 
[City, ST  ZIP Code] 
 
Dear Health Care Provider/ insert MD name, 
 
Your patient __<name>____ is enrolled on a research protocol at the National Institutes of Health Pediatric Oncology Branch (“A 
phase I/II Trial of Vandetanib (ZD6474, ZACTIMA) in Children and Adolescents with Hereditary Medullary Thyroid Carcinoma”).  
Your patient has been receiving vandetanib as part of this study for over two years.  As part of our research, we ask for your 
participation in monitoring and evaluating _<name>____ every three cycles (each cycle is 28 days), and as clinically needed. 
Vandetanib is approved by the FDA for treatment of medullary thyroid carcinoma in adults, but has not been approved in children.  
We have an agreement with AstraZeneca, the drug manufacturer, to supply vandetanib on this study for your patient.  As part of our 
agreement, the following evaluations must be performed and the results sent to the NIH: 
1. Every 3 cycles, please perform the following tests: 
x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests; correct electrolyte abnormalities 
as needed. Other evaluations performed as clinically indicated. 
x Obtain 12-lead electrocardiogram and evaluate QTc 
x Evaluate for serious adverse events (SAEs) 
x Fax or e-mail the test results and any follow up to: 
Claudia Derse-Anthony, R.N. 
10 Center Drive, Room 1C244 
Bethesda, MD 20982 
Office Phone: (240) 760-6102  

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86 
Email: derseanthonycp@mail.nih.gov 
2. Every 6 cycles 
x Monitor laboratory values: serum potassium, calcium, magnesium, and thyroid function tests, Serum CTN and CEA; correct 
electrolyte abnormalities as needed.  Other evaluations performed as clinically indicated. 
x Obtain 12-lead electrocardiogram and evaluate QTc 
x Evaluate for serious adverse events (SAEs)  
x Radiographic evaluation of disease (if indicated, perform pregnancy evaluation prior to scans) 
x Fax or e-mail the test results and any follow up to: 
Claudia Derse-Anthony, R.N. 
10 Center Drive, Room 1C244 
Bethesda, MD 20982 
Office Phone: (240) 760-6102  
Email: derseanthonycp@mail.nih.govIf your patient experiences any toxicities related to the vandetanib that meet the criteria in the 
attached package insert for dose modification, please contact Dr. Brigitte Widemann at 240-760-6203 or widemanb@mail.nih.gov to 
discuss any dose modifications to the vandetanib daily dose. 
We will have your patient return annually to the NIH for evaluation.  After we receive your evaluation results, we will contact your 
patient and if the patient does not have unacceptable toxicity or progression of disease, we will have a 6- cycle supply of vandetanib 
shipped directly to your patient.   
We thank you for your participation.  If you have any questions at all, please do not hesitate to contact Dr. Brigitte Widemann at 240-
760-6203 or widemanb@mail.nih.gov. 
 
Best regards, 
 
 
Brigitte Widemann, M.D.  
Head, Pharmacology and Experimental Therapeutics Section, POB, CCR, NCI, NIH 
10 Center Drive, MSC 1104 
Bldg. 10 CRC, Rm. 1-3750 
Bethesda, MD 20814-1104  

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19 Appendix 6: Vandetanib Package Insert 
 

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