Clinical trial NCT01414426
Conditions: Lip and Oral Cavity Squamous Cell Carcinoma Oral Cavity Verrucous Carcinoma Precancerous Condition
Sponsor: University of Chicago
Start date: 2012-01-01; Completion date: 2019-06-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well vandetanib works in preventing head and neck cancer in patients with precancerous head and neck lesions. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of vandetanib may keep cancer from forming in patients with premalignant lesions

Detailed description:
PRIMARY OBJECTIVE:

I. Determine the effect of ZD6474 (vandetanib) compared to placebo on microvessel density (MVD) from baseline to 3 months in patients at risk for oral squamous cell carcinoma (OSCC) with preneoplastic lesions.

SECONDARY OBJECTIVES:

I. Change in MVD over 6 months. II. Change in putative targets of ZD6474: tissues will be analyzed by immunohistochemistry (IHC) for phosphorylated epidermal growth factor receptor (pEGFR), EGFR, phosphorylated-vascular endothelial growth factor receptor 2 (pVEGFR2), VEGFR2.

III. Change in proliferative index as measured by Ki-67 IHC. IV. Safety, tolerability, and adherence to ZD6474 for 6 months in patients at risk for OSCC.

TERTIARY OBJECTIVES:

I. Compare OSCC incidence in both study arms (ZD6474 and placebo).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive vandetanib orally (PO) once daily (QD) for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 9 and 12 months and then every 6 months for 2 years.

Arms: arm 1: Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: vandetanib intervention 2: placebo intervention 3: immunohistochemistry staining method intervention 4: laboratory biomarker analysis intervention 5: biopsy intervention 6: pharmacological study
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies intervention 5: Correlative studies intervention 6: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
Vandetanib (ZACTIMA™; ZD6474) 
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Drug 
Vandetanib (ZACTIMA™; ZD6474) 
AZ Reference No. 
 
Version No. 
FINAL Version:  03 February 2011 
Revision 1: 09 March 2011 (FDA Comments) 
Revision 2: 14 March 2011 (FDA Comments) 
 
 
Randomized Placebo-Controlled Pilot Study of ZD6474 as a Chemopreventive Agent for 
Premalignant Lesions of the Head and Neck 
 
 
 
 
Coordinating Site: 
The University of Chicago 
 
Principal Investigator:        AlexanderPearson,MD 
                                                University of Chicago 
5841 S. Maryland Ave, MC 2115 
Chicago, IL 60637 
Phone: (773) 834-1604 
Fax: (773) 702-9268  
apearson@medicine.bsd.uchicago.edu 
 
 
Co-Investigators:  
Mark Lingen, MD 
Everett Vokes, MD  
Louis Portugal, MD 
Elizabeth Blair, MD  
 
Participating Site(s): 
 
The University of Texas MD Anderson Cancer Center 
1515 Holcombe Blvd 
Houston, TX 77030 
Site Principal Investigator: 
William N. William, Jr, MD 


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PROTOCOL SYNOPSIS 
 
Randomized Placebo-Controlled Phase II Study of ZD6474 as a Chemopreventive Agent 
for Premalignant Lesions of the Head and Neck 
 
 
Study Centre(s) and Number of Subjects Planned 
University of Chicago 
University of Texas MD Anderson Cancer Center 
 
Study period 
Phase of development 
Estimated   date  of  first  subject 
enrolled 
October 2011 
Phase 0 
Estimated   date   of   last   subject 
completed 
October 2013 
 
Objectives 
To  assess   the  change   in  microvessel   density   (MVD)   from  baseline   to  3  months   in 
preneoplastic lesions from patients treated with ZD6474 compared to placebo 
 
Study Design 
Randomized, double-blind, placebo controlled 
 
Target Subject Population 
Only subjects felt to be at high risk for oral squamous cell carcinoma (OSCC) will be enrolled 
to maximize risk/benefit ratio.  Subjects will be required to have an area of dysplasia on prior 
biopsy or a history of OSCC. 
 
Investigational Product, Dosage and Mode of Administration 
ZD6474 (vandetanib), 100 mg, oral 
 
Comparator, Dosage and Mode of Administration 
Placebo 
 
Duration of Treatment 
6 months 
 
Safety 
Adverse events will be monitored and reported as detailed in the protocol.   Data and Safety 
Monitoring meetings will be held weekly.   Adherence will be monitored by pill counts and 
diaries.  Toxicity and adherence will be reported as secondary endpoints. 
 
Statistical Methods 
The primary endpoint of this study is the comparison between treatment groups of the within- 
patient  change  in  MVD  score  from  baseline  to  3-months  following  treatment  initiation 


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(ΔMVD).  The primary analysis upon which the sample size calculations are based is the 
comparison  of  ΔMVD  between  treatment  arms  using  a  two-sample  t-test  with  unequal 
variances.  A Wilcoxon ranksum test may be used if the normality assumption is not satisfied. 
Alternatively, ΔMVD may be transformed (e.g. log-transformation) to satisfy the normality 
assumption.    Additional  analyses  of  the  primary  endpoint  will  include  linear  regression 
models with treatment effect and other prognostic factors as covariates. 


 
 
 
 
 
Vandetanib (ZACTIMA™; ZD6474) 
 
 
 
TABLE OF CONTENTS  
PAGE 
PROTOCOL SYNOPSIS.......................................................................................................2 
TABLE OF CONTENTS .......................................................................................................4 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................6 
 
1. 
INTRODUCTION..................................................................................................7 
1.1 
Background ..............................................................................................................8 
 
2. 
STUDY OBJECTIVES........................................................................................16 
2.1 
Primary Objective ..................................................................................................16 
2.2 
Secondary Objectives.............................................................................................16 
2.3 
Exploratory Objectives ..........................................................................................16 
 
3. 
STUDY PLAN AND PROCEDURES ................................................................16 
3.1 
Overall Study Design .............................................................................................16 
3.2 
Study Plan ..............................................................................................................17 
3.3 
Selection of Study Population ................................................................................20 
3.4 
Registration Procedures .........................................................................................22 
3.5 
Precautions for Treatment ......................................................................................23 
3.6 
Guidance on the Management of Toxicity............................................................24 
3.7 
Discontinuation of Subjects from Treatment or Assessment .................................27 
3.8 
Treatments..............................................................................................................28 
3.9 
Drug Supply Information .......................................................................................28 
3.10 
Safety Measurements and Variables ......................................................................30 
 
4. 
PHARMACOKINETICS & PHARMACODYNAMICS   ...............................36 
4.1 
Pharmacodynamics ................................................................................................36 
4.2 
Electrocardiogram (ECG) Assessments for Study Plan.........................................38 
4.3 
Imaging ..................................................................................................................38 
4.4 
Response Data........................................................................................................38 
 
5. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE.......................................................................................................................38 
5.1 
Statistical Evaluation – General Aspects ...............................................................38 
5.2 
Description of Outcome Variables in Relation to Objectives and 
Hypotheses .............................................................................................................39 
5.3 
Description of Analysis Sets ..................................................................................39 
5.4 
Method of Statistical Analysis ...............................................................................39 
5.5 
Determination of Sample Size ...............................................................................40 
5.6 
Interim Analyses ....................................................................................................42 
5.7 
Data and Safety Monitoring Board ........................................................................42 
5.8 
Study management .................................................................................................42 
 
 
 
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6. 
ETHICS.................................................................................................................43 
6.1 
Ethics Review ........................................................................................................43 
6.2 
Ethical Conduct of the Study .................................................................................44 
6.3 
Written Informed Consent .....................................................................................44 
6.4 
Subject Data Protection..........................................................................................44 
 
7. 
EMERGENCY PROCEDURES.........................................................................44 
7.1 
Procedures in Case of Pregnancy...........................................................................44 
 
8. 
REFERENCES.....................................................................................................46 
 
LIST OF APPENDICES 
 
APPENDIX A- Medications Known To Prolong the QT Interval and/or Induce Torsades 
De Pointes (TdP) 
APPENDIX B - Drug Administration Diary 
APPENDIX C – New York Heart Association (NYHA) Cardiac Classification 
 
APPENDIX D – Non-Serious Adverse Event Reporting Template 
 
APPENDIX E – Instructions for Dispersing Vandetanib Tablets 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation or special term 
Explanation 
OSCC 
Oral Squamous Cell Carcinoma 
VEGF(R) 
Vascular 
Endothelial 
Growth 
Factor 
(Receptor) 
EGFR 
Epidermal Growth Factor Receptor 
MVD 
Microvessel Density 


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1. 
INTRODUCTION 
 
Despite  advances  in  diagnosis  and  treatment,  improved  long-term  survival  for  oral 
squamous  cell  carcinoma  (OSCC)  patients  has  remained  modest  (1,  2).    Several  factors 
contribute to this relatively poor outcome.   First, OSCC is often diagnosed at an advanced 
stage.    Second,  as a result  of “field  cancerization”,  the development  of multiple  primary 
tumors has a major impact on survival.  For patients with early stage disease, second primary 
tumors  are their most common  cause of treatment  failure and death  (1, 2).   Therefore,  to 
improve outcomes, a comprehensive treatment plan must include effective chemoprevention 
strategies. 
Chemoprevention can be defined as the use of natural or synthetic agents to reverse or halt 
the progression of premalignant lesions.   Chemopreventive  agents are currently being tested 
for their efficacy in preclinical and clinical settings for many malignancies including OSCC 
(3,  4).    However,  initial  promising  results  for  OSCC  chemoprevention  have  not  been 
consistently reproduced and toxicity has often been significant.   The issue of toxicity is 
particularly important in chemoprevention as prolonged therapy in the absence of a known 
diagnosis of OSCC may be required. 
 
Angiogenesis is an essential phenotype in both physiologic and pathologic settings (5). 
Because of its critical role in cancer biology, the inhibition of angiogenesis  is an attractive 
target for therapy.   The induction of the angiogenic phenotype in OSCC is mediated by the 
direct and indirect production of various factors capable of inducing blood vessel growth (6). 
Among these, the vascular endothelial growth factor (VEGF) family is thought to play an 
important role.  The biological effects of the VEGF ligands are mediated through their binding 
to members of the vascular endothelial growth factor receptor family (VEGFR-1, VEGFR-2, 
VEGFR-3).  This interaction leads to autophosphorylation of specific tyrosine residues and 
subsequent downstream activation of intracellular signaling pathways, such as the mitogen- 
activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. 
Importantly, the induction of angiogenesis is one of the first recognizable phenotypic changes 
observed in both experimental models as well as in human OSCC (7-10), suggesting that 
inhibitors of angiogenesis may also hold promise in the field of chemoprevention. 
 
The development, growth and survival of OSCC are also highly dependent upon the 
Epidermal Growth Factor Receptor (EGFR) signaling pathway.  EGFR is a transmembrane 
glycoprotein that is a member of the ErbB/HER receptor tyrosine kinase family.  Upon ligand 
binding, EGFR signaling is mediated by the MAPK and PI3K/Akt pathways.   Increased 
expression  of EGFR and its ligand transforming  growth  factor-α  (TGF-α)  are observed  in 
most OSCC and premalignant oral lesions, and this expression correlates with poor prognosis 
(11). In addition, members of the EGFR pathway contribute to the induction of angiogenesis. 
For example, the expression of TGF-α or EGFR causes increased expression of VEGF (12, 
13).   Because of its importance  in epithelial malignancies,  there is considerable  interest in 
targeting the EGFR pathway for chemoprevention. 
 
ZD6474 (vandetanib,  ZACTIMA)  is an orally available tyrosine kinase inhibitor (TKI) 
with activity against multiple signal transduction  pathways including VEGFR-2  and EGFR 
(14-16).     In  preclinical   studies,  ZD6474   was  a  potent  inhibitor  of  angiogenesis   and 


 
 
 
 
 
Vandetanib (ZACTIMA™; ZD6474) 
 
 
 
proliferation  of a number of different tumor cell types (17).   Further, it is currently under 
active investigation in clinical trials for the treatment of various malignant neoplasms  (17). 
Using the 4-Nitroquinoline 1-Oxide (4-NQO) mouse model, we have demonstrated that ABT- 
510 (a global inhibitor of angiogenesis) and ZD6474 (a dual tyrosine kinase inhibitor (TKI) 
against EGFR and VEGFR-2) significantly decreased the incidence of dysplasia and OSCC 
(18, 19).  These data support the hypothesis that agents with anti-angiogenic activity may hold 
promise as chemopreventive agents for OSCC. 
 
1.1           Background 
 
Using the 4-NQO model, we found that ABT-510 (a global inhibitor of angiogenesis) and 
ZD6474 (a dual TKI against EGFR and VEGFR-2) significantly decreased the incidence of 
dysplasia  and  OSCC  (18, 19).   In the ZD6474  study,  mice  were  administered  4-NQO  (100 
µg/ml) in their drinking water for a period of 8 weeks, returned to normal water, and then 
randomized  to  observation  or  daily  oral  gavage  of  ZD6474  (25  mg/Kg/day)  for  24  weeks. 
During the 24-week chemoprevention regimen, no significant differences in food and fluid 
consumption or activity were observed between the groups.   At the completion of the 32 week 
study, 71% of the control mice and 12% of the ZD6474-treated mice harbored OSCC (p<0.001) 
(Table 1).  Similarly, the proportion of mice with dysplasia or OSCC was significantly different 
between the two groups.   In the control group, 96% of the animals demonstrated dysplasia or 
OSCC, while 28% ZD6474 treatment group had dysplasia or OSCC (p<0.001).  In total, this 
represented a 71% decrease in OSCC or Dysplasia and an 83% decrease in OSCC.   ZD6474 
inhibits tumor cell proliferation and angiogenesis via its dual activity against EGFR and VEGFR- 
2 (14-16).   We performed IHC for Ki67 and CD31 as surrogate markers for proliferation and 
microvessel density (MVD).   Overall, the proliferative index (PI) for ZD6474-treated  animals 
was significantly lower when compared to the control mice (Table 2).  The control group had a 
PI of 46 + 10, while the ZD6474 treatment group had a PI of 29 + 10 (p<0.001).  Overall, there 
was a significant  decrease  in MVD in the ZD6474-treated  mice compared  to controls.   The 
control group had a MVD score of 265 + 60, while the ZD6474 treatment group had a MVD 
score of 106 + 73 (p<0.001). 
 
 
 
 
 
 
 
 
 
 
Table 1. Incidence of dysplasia and OSCC in control and 
ZD6474 treated mice. 
 
 
 
 
 
 
 
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Table 2. ZD6474 inhibits proliferation, 
microvessel density and 
phosphorylation  of EGFR and 
 
 
Vandetanib  (ZD6474)  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).   VEGF is a humoral mediator of endothelial  cell proliferation,  and is one of the 
primary  growth  factors  responsible  for  the  initiation  of  new  blood  vessel  growth.    This 
process, termed angiogenesis, is essential for the growth and dissemination of tumors.  By 
specifically targeting angiogenesis, it is hoped that the growth of tumors will be controlled, 
with relative sparing of normal tissues. 
 
Vandetanib has shown excellent inhibition of tumor cell growth in a broad range of 
pre-clinical models, including lung cancer xenografts (Calu-6 and A549).   Regression of 
established tumors (PC-9 lung cancer and PC-3 prostate cancer) in animals was observed 
following oral administration.   Vandetanib was considered to have an acceptable pre-clinical 
toxicology profile for the proposed therapeutic indication.  Vandetanib also inhibits epidermal 
growth factor (EGF) stimulated cell proliferation, though at a concentration (the molar 
concentration  of  a  compound  required  to  produce  50%  inhibition  of  a  biological  effect; 
IC50=170 nM) approximately 3-fold higher than that required for the inhibition of VEGF- 
stimulated cell proliferation (60 nM). 
 
Vandetanib has demonstrated inhibition of both vascular endothelial growth factor 
receptor (VEGFR) and EGFR tyrosine kinases in vitro, and pre-clinical models have shown 
activity against non-small cell lung cancer (NSCLC) xenografts.  AstraZeneca has conducted 
clinical studies in patients with NSCLC.  In the Japanese Phase I study (TVE-15-11), 4 of 9 
patients with NSCLC had confirmed partial responses (PRs).   Subsequently,  2 randomized 
Phase II studies (6474IL/0003 and 6474IL/0006) were performed in patients with NSCLC 
refractory to first-line therapy.  Vandetanib demonstrated an advantage in progression-free 
survival  (PFS)  compared  with  gefitinib  in  study  6474IL/0003,  and  in  combination  with 
docetaxel compared with docetaxel alone in study 6474IL/0006.  The results of these Phase II 
studies led to the designs of 4 Phase III studies.  Two studies investigated vandetanib in 
combination  with  chemotherapy  (study  D4200C00032  with  docetaxel  and  study 
D4200C00036  with  pemetrexed),  and  2  studies  investigated  vandetanib  as  monotherapy 
 
 
 
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Vandetanib (ZACTIMA™; ZD6474) 
 
 
 
(study D4200C00057 compared to erlotinib and study D4200C00044 compared to best 
supportive care in patients who have previously received an EGFR inhibitor).   In the 2 
combination studies, the addition of vandetanib to docetaxel provided a statistically significant 
advantage in PFS compared to docetaxel alone; in the smaller study with pemetrexed, there 
was a positive trend for PFS in favor of the addition of vandetanib.  Study D4200C00057 did 
not meet the goal of demonstrating superiority in PFS compared to erlotinib, but the efficacy 
of the 2 drugs was equivalent.  Study D4200C00044 was still ongoing at the time of edition 11 
of  the  Investigator’s   Brochure  (IB).     The  most  common  side  effects  associated  with 
vandetanib are rash and diarrhea.  In addition to the studies of vandetanib in NSCLC, several 
other Phase I and II studies are ongoing in other tumors, and a Phase III study in patients with 
medullary thyroid cancer is also ongoing. a 
 
a Vandetanib, ZD6474, Investigator’s Brochure, Edition Number 10, March 2009 
 
Summary of Adverse Events (AE) in Vandetanib (ZD6474) Phase I and Phase II Studies 
The events below are discussed regardless of causality to vandetanib.   Some of these events 
may reflect symptoms of cancer, effects of chemotherapy or radiation, or concomitant medical 
illness.   Events that are thought likely to be causally related to vandetanib are listed in the 
Emerging Safety Profile section below. 
 
Skin and Subcutaneous Tissue Disorders 
The events, organized by MedDRA preferred term, that were categorized under this system 
organ class include rash, acne, maculo-papular rash, dry skin, night sweats, pruritus, acneform 
dermatitis, exfoliative dermatitis, contusion, rash photosensitivity, photosensitivity reaction, 
desquamation,   erythema,  erythematous   rash,  macular  rash,  pruritic  rash,  pustular  rash, 
follicular  rash,  skin  eruption,  hyperhidrosis,  nail  discoloration,  skin  ulcer,  urticaria  and 
alopoecia. 
 
Most  of  these  skin  disorders  happened  in  the  first  4  weeks  of  treatment   and  were 
CTC/CTCAE grade 1-2.  There was a tendency for dose-dependent increase in incidence of 
drug-related  adverse events.   At least 2 distinct types of rash related to vandetanib therapy 
have been described, namely, a macular erythema in some patients and a follicular (acneform) 
rash in others.  Also, photosensitive rash has been reported in some of these patients.  When 
vandetanib was combined with pemetrexed, 10 patients developed skin rash; 7 of the events 
were considered  to be vandetanib-related.    None of the cases was reported  to be CTCAE 
Grade 3 or higher.  The majority of the events developed within the first 6 weeks of treatment 
and some of them within the first week of vandetanib exposure. 
 
Gastrointestinal System 
Events included diarrhea, nausea, vomiting, constipation,  abdominal pain, upper abdominal 
pain, abdominal discomfort, abdominal distention, flatulence, dry mouth, dry lip, mouth 
ulceration, dyspepsia, dysphagia, gastroesophageal, stomatitis, aphthous stomatitis, acquired 
esophageal stenosis, and gingival bleeding.  Most of these adverse events were CTC/CTCAE 
grade 1 or 2 and did not need interruption of study treatment.   Routine anti-diarrheal agents 
are also recommended.   Abdominal pain has been seen in Phase I, but was not common in 
Phase II studies. 
 
 
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General Disorders and Administration Site Conditions 
Fatigue, pyrexia and peripheral  edema were observed, as were asthenia, rigors, chest pain, 
chest  tightness,  mucosal  inflammation,  abnormal  gait,  and lethargy.   Most of the adverse 
events were CTC/CTCAE grade 1-2; grade 3 was rare. 
 
Vascular Disorders 
Hypertension is considered to be a class effect for VEGF pathway inhibitors, and was a DLT 
for studies 6474IL/0001 and TVE-15-11.   Pulmonary thrombosis and deep vein thrombosis 
have been observed so far.  One instance of pulmonary hemorrhage after cavitation was also 
observed  in a study of vandetanib  combined  with docetaxel  (6474IL/0006.)    It is unclear 
whether deep vein thrombosis and pulmonary hemorrhage may be related to vandetanib or 
reflect the underlying cancer or co-morbid conditions. 
 
Respiratory System 
Cough and dyspnea were common adverse events, but are common symptoms of lung cancer. 
Other reported adverse events included pharyngolaryngeal pain, epistaxis, dysphonia, hiccups, 
respiratory alkalosis, rhinorrhea, pulmonary embolism, and pulmonary artery thrombosis. 
 
Other adverse events 
Other commonly reported AEs included nervous system disorders (lethargy, neuropathy 
peripheral,  headache and dysaesthesia),  blood and lymphatic system disorders (neutropenia 
and thrombocytopenia) and metabolism and nutrition disorders (hypokalaemia). 
 
QT/ QTc Prolongationa 
Phase I studies 
Prolongation  of  the  ECG  corrected  QT  interval  was  initially  observed  in  Phase  I and  II 
studies, and no patients experienced  symptoms definitely related to QTc prolongation.   On 
rare  occasions,  patients  with  QTc  prolongation   have  experienced   cardiac  arrhythmias; 
however, all patients had confounding factors that were much more likely to be the cause. 
 
Phase II studies 
Prolongation of the QTc interval, using Bazett's correction, was seen in Phase II studies.  No 
significant changes in heart rate were observed across any of the doses studied.   No patient 
developed symptomatic ventricular arrhythmias, although 1 patient with pneumonia and QTc 
greater than 600 ms was noted to have a non-sustained run of ventricular tachycardia while in 
a monitored hospital setting (see below).  Using extensive ECG monitoring to assess the QTc 
prolongation  more  closely,  at a dose of 300  mg/day,  QTc  prolongation  resulting  in dose 
reduction  has  been  seen  in  approximately  5%  of  patients,  and  at  a  dose  of  100  mg  in 
combination with chemotherapy in <2% of patients. 
 
Phase III studies 
In the Phase III studies, the incidence of prolongation of the ECG QTc interval was seen in 
1.9% of patients treated with vandetanib 100 mg plus docetaxel and in 0.4% of patients treated 
with  vandetanib  100  mg  plus  pemetrexed.     No  patients  receiving  vandetanib  100  mg 
experienced  torsade  de pointes  or other  arrhythmia  attributed  to prolongation  of the QTc 
interval.   In study D4200C00057, 5% of patients receiving vandetanib 300 mg experienced 
 
 
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prolongation  of the QTc interval,  and there was 1 case or reversible,  non-fatal  torsade de 
pointes.     The  QTc  prolongation  was  managed  by  dose  interruption  followed  by  dose 
reduction.   A non-linear relationship between QTc and vandetanib plasma concentration has 
been determined using pharmacokinetic/pharmacodynamic  modeling. 
 
a   Above  Summary  of  Adverse  Events  taken  from  Vandetanib,  ZD6474,  Investigator’s 
Brochure, Edition Number 10, March 2009. 
 
Emerging Safety Profilea 
Vandetanib produces repolarization  abnormalities  in human myocardium that are consistent 
with blockade of the IKR (potassium) channel.  The most consistent electrophysiologic effects 
are a change in T-wave morphology (flattening, broadening or notching) and prolongation of 
the QT interval, both of which occur more commonly as the dose is increased.   Vandetanib 
can cause rash, diarrhea and hypertension, all of which appear to be dose-related and are likely 
to be related to the pharmacologic activity of vandetanib. 
 
The drug-related AEs seen with vandetanib monotherapy are also expected to occur in 
combination with chemotherapy.   All drug-related AEs expected to occur in association with 
the concomitant chemotherapeutic agent(s) (as defined and listed in the package insert[s]) will 
be expected to occur when used in combination with vandetanib.   The relevant product 
information for the concomitant chemotherapy should be used to determine these expected, 
drug-related AEs. 
 
Reported adverse events that may be related to vandetanib are listed below by body system: 
 
Cardiovascular 
Abnormal ECG (with or without QT prolongation; i.e. either T-wave or ST-segment changes 
consistent with repolarization abnormalities), torsade-de-pointes and ventricular tachycardia 
(both at 300 mg daily dose) and hypertension. 
 
Cardiac failure (300 mg daily dose) (See Appendix C for the New York Heart Association 
(NYHA) Cardiac Classifications.) 
 
Central Nervous System –headache, Reversible Posterior Leukoencephalopathy  Syndrome 
(RPLS) 
 
Digestive – constipation, diarrhea, nausea, vomiting 
 
Hematologic and Lymphatic – ecchymosis and thrombocytopenia 
 
Investigations – elevated liver function tests (generally CTC/CTCAE grade 1-2, weight loss 
 
Metabolic  and  nutritional  –  dehydration,  hypokalemia,  hypomagnesemia, 
hypophosphatemia 
 
 
 
 
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Skin and Appendages – acneform 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 
 
Respiratory  – interstitial lung disease (ILD).   A very small number of patients with lung 
cancer   receiving   vandetanib   have   developed   shortness   of   breath   and   cough   due   to 
inflammation  or  scar  tissue  formation  in  the  lungs  (although  this  could  be  due  to  the 
underlying lung cancer) 
 
Renal – proteinuria, hematuria 
 
Vascular – Arterial ischaemic events (including myocardial infarction, stroke, peripheral 
ischaemia) 
 
Psychiatric - Mood disorders (anxiety, depression, insomnia).  It is possible that these events 
are not direct effects of vandetanib, but rather are secondary to symptoms of cancer or to other 
effects of vandetanib (rash, etc.). 
 
General – asthenia, fatigue 
 
a  Above text taken from Vandetanib, ZD6474, Investigator’s Brochure, Edition Number 10, 
March 2009. 
 
For additional  details  on vandetanib,  please  refer to the current  Vandetanib  Investigator’s 
Brochure. 
 
Rationale 
Our data support the hypothesis that agents with anti-angiogenic activity may hold promise in 
chemoprevention.  Therefore, we will conduct a double-blind, placebo-controlled, randomized 
phase II trial that will assess the pharmacodynamic  effects of ZD6474 in high-risk patients. 
The primary endpoint will examine the ability of ZD6474 to inhibit angiogenesis, as measured 
by MVD.  Secondary endpoints will include inhibition of proliferation, modulation of EGFR 
and VEGFR2 phosphorylation, tolerability and feasibility of administration, and development 
of OSCC.  We hypothesize that ZD6474 will inhibit angiogenesis in preneoplastic tissues 
compared to placebo.   These results will serve as proof of principle to implement larger 
prospective chemoprevention trials of anti-angiogenic or anti-EGFR inhibitors in high-risk 
patients. 
 
Study Design: This will be a randomized, double-blinded, placebo controlled study with a 
primary endpoint of reducing MVD in preneoplastic lesions at 3 months compared to baseline. 
We will administer ZD6474 or placebo for 6 months and monitor subjects for up to 3 years. 
Biopsies will be obtained at baseline, 3 months, and 6 months from the same area of known 
dysplasia  and banked in the Biobanking  and Pathology Core.   A placebo  control group is 
 
 
 
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necessary due to the lack of validated historic controls in this population and ethical because 
standard of care in these patients would be active surveillance. 
 
Proposed study population: Only subjects felt to be at high risk for OSCC will be enrolled to 
maximize risk/benefit ratio.   Subjects will be required to have an area of dysplasia on prior 
biopsy or a history of OSCC. Using these criteria, subjects would be expected to have a 
significant cumulative lifetime risk of developing OSCC of ~50%.   Other eligibility criteria 
are will include normal organ function, QTc interval < 450ms, performance status > 70% on 
the Karnofsky scale, and age > 18 years. 
 
Choice  of  primary  endpoint:  Despite  extensive  studies  to  identify  patients  at  risk  for 
developing OSCC, there are no established chemopreventive agents.   Prior Phase III studies 
have  been  negative  due  to  a  lack  of  efficacy,  inadequate  understanding  of  molecular 
mechanisms underlying the intervention, or tolerability of the agent for long periods of time. 
Therefore, with preclinical and safety data strongly supporting the rationale for administering 
ZD6474 as a chemopreventative agent, this study will assess two critical limitations of prior 
approaches.    The  primary  endpoint  reflects  an  effect  of  ZD6474  on  microvessel  density 
(MVD)  in  preneoplastic  lesions  which  correlated  strongly  with  OSCC  inhibition  in  the 
preclinical model and serves as a surrogate for the latter.  We will also assess tolerability and 
feasibility of administering ZD6474 for 6 months (see below).  The results of this trial would 
inform the planning of larger studies of this approach in preventing OSCC. 
 
Secondary Endpoints: The trial will examine endpoints related to putative targets of ZD6474, 
safety and tolerability, and OSCC development.   To assess the biologic effect of EGFR and 
VEGFR2  inhibition,  tissues  will  be  analyzed  by  IHC  for  pEGFR,  EGFR,  pVEGFR2, 
VEGFR2, and Ki-67.   We hypothesize that biopsies from ZD6474 patients will exhibit 
significantly lower expression of pEGFR and VEGFR2 and proliferation indices. 
 
A critical parameter of successful chemoprevention efforts is adherence and safety. 
Ideally, an agent would be easily administered for a duration that will affect the natural history 
of the disorder and be well tolerated.  ZD6474 is an orally available, well-tolerated drug with 
demonstrated  anti-angiogenic  and  EGFR  inhibitory  properties  that  has  been  administered 
safely  to  patients  for  prolonged  periods.    ZD6474  has  been  studied  in  37  clinical  trials 
involving over 2000 subjects.   The agent is administered once daily with predictable 
pharmacokinetics and without significant food-drug or drug-drug interactions.  In general, the 
agent  has  been  well  tolerated  even  for  long-term  administration  with  the  most  common 
adverse events being rash, nausea, diarrhea, fatigue, and hypertension.  Reversible and dose 
related QT prolongation has been observed with ZD6474.   At 300 mg daily, dose reduction 
has been required in approximately 15% of subjects for QTc prolongation.   Deep venous 
thrombosis has been observed with ZD6474 but these events are rare (1% incidence) and it is 
unclear whether they are causally related to the agent.  Recently a placebo controlled, phase 3, 
2:1 randomized study administering ZD6474 in patients with medullary thyroid cancer was 
reported.  The primary endpoint of progression-free survival significantly favored ZD6474 
(Hazard ratio = 0.46 (0.31–0.69), p<0.0001).  Among the 231 subjects enrolled to receive 
ZD6474, median duration of therapy was 90 weeks with only 12% of subjects discontinuing 
therapy due to an adverse event.   The most common grade 3 or greater adverse events and 
 
 
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their frequency were diarrhea (11%), hypertension (9%), and QT prolongation (8%).  Thus, in 
large  randomized  trials,  ZD6474  can  be  safely  and  feasibly  administered  for  prolonged 
periods. 
 
Adherence in both arms will be monitored by self-administered patient diaries. 
Remaining pill counts will be performed to determine reliability of self-reporting.   Subjects 
will be seen upon starting therapy, at weeks 1, 2, 4, 5, 8, 9, 13, 17, 21, 25; months 6, 9, and 
12; and at least every 6 months for 2 years.  Subjects will be followed and monitored for oral 
and other cancers.   We expect that ZD6474 treated patients will have a lower incidence of 
OSCC.  However, the study is clearly underpowered to demonstrate a statistically significant 
difference between groups. 
 
Study Feasibility: The Head and Neck Cancer Program at the University of Chicago has a 
strong record of multi-disciplinary care with expertise in all aspects of the disease including 
head and neck cancer surgery, radiation therapy, medical oncology, and oral pathology.   In 
2009 the program registered over 800 unique patient visits and performed approximately 300 
new patient  consults.   A High  Risk Clinic  to specifically  deal with  the needs  of patients 
without  active  disease  but who  are at increased  risk to develop  HNSCC  is available  and 
overseen by Dr. Elizabeth Blair.  These patients often have a personal or strong family history 
of HNSCC,  engaged  in behavior  associated  with developing  OSCC  (e.g. tobacco  use), or 
harbor  a pre-neoplastic  lesion.   The clinic  will serve  as the setting  to screen  prospective 
patients,  obtain  tissue,  and perform  the clinical  study.   We recognized  the importance  of 
OSCC chemoprevention  and have participated  in three such studies that are either already 
closed or are anticipated to complete accrual prior to the initiation of this proposed trial. 
 
Dr. Lingen is a Board Certified Oral & Maxillofacial Pathologist.  His outreach service 
receives biopsies from dentists throughout  Illinois and Northwestern  Indiana.   Drs. Dennis 
Solt and Reza Mostofi are oral pathologists with outreach services in Chicago.  The 3 services 
have a combined total of ~10,000 cases/year, and approximately ~100 dysplasia cases.  All 3 
biopsy services have contributed patients for the EPOC prevention trial currently underway 
with the MD Anderson.  Therefore, the involvement of these biopsy services will be important 
for the accrual of subjects for the proposed study. 
 
In order to achieve the target sample size, accrual for this trial must be 2 patients per month. 
 
Rationale for Collection of Blood Samples for Biomarker Analysis 
There are currently no known markers that are predictive of response or resistance to VEGF 
signaling inhibitors including vandetanib.  By collecting and storing serial samples of plasma 
and serum for the first months of treatment with vandetanib it will be possible to explore 
relationship between changes in biomarkers and response and to explore the mechanisms 
underlying the biological response and resistance to VEGF signaling inhibitors.   It is likely 
that additional information and assays for biomarkers that are important for the response to 
vandetanib will become available in the future.  It is, therefore, important to be able to store 
samples in order to retain the possibility of investigating biomarker changes in the context of 
vandetanib treatment in the future. 
 
 
 
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2. 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
Determine the effect of ZD6474 compared to placebo on MVD from baseline to 3 months in 
patients at risk for OSCC with preneoplastic lesions. 
 
2.2 
Secondary Objectives 
 
 Change in MVD over 6 months 
 
 Change in putative targets of ZD6474 
o tissues  will  be  analyzed  by  immunohistochemistry  (IHC)  for  pEGFR,  EGFR, 
pVEGFR2, VEGFR2 
 
 Change in proliferative index  as measured by Ki-67 IHC 
 
 Safety,  tolerability,  and adherence  to ZD6474  for 6 months  in patients  at risk for 
OSCC 
 
2.3 
Exploratory Objectives 
 
 Compare OSCC incidence in both study arms (ZD6474 and placebo) 
 
3. 
STUDY PLAN AND PROCEDURES 
 
3.1 
Overall Study Design 
 
 Placebo-controlled, double-blind study of single agent ZD6474 
 
 A  total  of  54  patients  will  be  enrolled  to  allow  for  20%  loss-to-follow  up  and 
unevaluable samples 
 
 Subjects will be randomized 1:1, ZD6474 vs. placebo without stratification 
 
 Primary variable  will be change in within-patient  MVD scores from baseline  to 3- 
months of treatment (ΔMVD) will be compared between the treatment arms using a 
two-sample t-test with unequal variance. 
 
 Subjects will be required to have an area of dysplasia on prior biopsy or a history of 
OSCC 
 
 ZD6474, 100 mg, or placebo will be administered PO daily for 6 months.   Subjects 
will be followed for a minimum of 3 years. 
 
 
 
 
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1:1
RANDOMIZE 
 
 
 
 Data and safety monitoring will be conducted through the University of Chicago, Head 
and Neck Cancer program on a weekly basis 
 
 There are no planned interim analyses 
 
3.2 
Study Plan 
 
 
 
SCREENING 
High-risk for OSCC 
Normal organ function 
QTc < 450 ms 
Karnofsky PS ≥ 70% 
18 years or older 
ZD6474 100mg QD 
 
Duration of therapy: 6 months 
Biopsy at baseline, 3 months, 6 months 
 
 
Placebo 


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Study Plan 
 
Screen 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4c 
Subsequent 
Visits† 
Week 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
13 
Informed consent 
X 
Medical history 
X 
Inclusion/ Exclusion 
X 
Physical examination 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Electrocardiogram 
Xa 
Xb 
Xb 
Xb 
Xb 
Xb 
Hematology/ 
clinical chemistry ^ 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
Pregnancy teste 
X 
X 
X 
X 
Xe 
Performance Status@ 
X 
X 
X 
X 
X 
Randomization 
X§ 
Study medication 
dispensingd 
X 
X 
Tolerability/ 
AE reporting 
X 
X 
X 
X 
X 
X 
X 
Assessment of 
Concomitant 
Medication 
X 
X 
X 
X 
X 
Lesion measurement* 
X 
X 
X 
X 
X 
Tissue Sample# 
X 
X 
X 
(only month 
6) 
 
a:   12-lead ECG must be performed at screening (within 7 days before first dose.) The screening QTc 
must be < 450 msec. Up to 3 ECGs may be obtained at screening, and the mean QTc value used to 
determine eligibility. 
b:   On day 1/visit 1, 12-lead ECGs are to be performed pre-dose. Baseline QTc will be determined by 
the average of no less than 3 consecutive ECGs (within 5-10 minutes of one another) on day 1.  If 
the screening QTc is obtained with 3 consecutive ECGs within 3 days before day 1, then the 
screening QTc will be considered to be the baseline, and repeat ECGs will not be necessary on day 
1. When possible, ECGs should be performed at the same time throughout the study (performed 4- 
8 hours after the patient takes their oral medication ECGs must be done at weeks 1, 2, 5, 9, 13, 
17, 21 and 25; at discontinuation; and as clinically indicated. In addition, upon occurrence of 
electrolyte disturbance or severe diarrhea, close monitoring of ECGs is recommended. 
c:   Study assessments repeated every 4 weeks until month 6. 
d:   100 – Vandetanib 100mg on Cycle 1 and 4.to be dispensed. 
e:   For women of child-bearing potential only.  Negative pregnancy test required at baseline; every 
28-30 days while receiving the study medication and for 2 months after the last dose. 
^ CBC, complete metabolic profile, magnesium 
@ Karnofsky Performance Status 
* Only in subjects with visible lesions 
# Tissue collection will consist of serum and biopsy of previous area of dysplasia (see Section 4) . At 
screen, DNA from peripheral blood and plasma will also be obtained as part of tissue collection (see 
Scetion 4). Collection should occur on Cycle 4, Day 1 and Cycle 6, day 28. 


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†Every 6 months for a total of  3 years from the start of therapy. 
§Randomization can occur at any time after the subject is deemed eligible and screening procedures 
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3.3 
Selection of Study Population 
 
3.3.1 
Study Selection Record 
 
A record of patients who were considered for enrollment, but were never enrolled, along with 
the reasons for not enrolling will be kept. 
 
3.3.2 
Inclusion Criteria 
 
1. Histological/cytological confirmation of oral cavity dysplasia or prior history of OSCC 
 
2. Provision of informed consent 
 
3. Age ≥18 years 
 
4. Females of child bearing age must have a negative serum pregnancy test within 7 days of 
first dose of study drug. 
 
5. Patients must not have been taking steroids or are on a stable dose of steroids for at least 14 
days before enrolment 
 
6. Patients must have a Karnofsky Performance Score of 70% or above 
 
3.3.3 
Exclusion Criteria 
 
Any of the following is regarded as a criterion for exclusion from the study: 
 
1. 
History of malignancy within the last 2 years other than squamous cell carcinoma of the 
head and neck (SCCHN) and superficial  non-melanoma  skin cancer.   Patients with a 
history of SCCHN must be free of active carcinoma. 
 
2. 
Currently receiving treatment for any malignancy. 
 
3. 
Laboratory results: 
 Serum bilirubin  >1.5x the upper limit of reference range (ULRR) 
 Creatinine clearance < 30 mL/minute (calculated by Cockcroft-Gault formula.) 
 Potassium, <4.0 mmol/L despite supplementation; or above the CTCAE grade 1 upper 
limit. 
 Magnesium  below the normal range despite supplementation,  or above the CTCAE 
grade 1 upper limit. 
 Serum calcium  above the CTCAE  grade 1 upper limit.   In cases where the serum 
calcium  is below the normal  range, 2 options  would be available:   1) the calcium 
adjusted for albumin is to be obtained and substituted for the measured serum value. 
Exclusion  is to then be based on the adjusted for albumin values falling below the 
normal limit.  2) Determine the ionized calcium levels.  If these ionized calcium levels 
are out of normal range despite supplementation, then the patient must be excluded. 
 
 
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 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5  ULRR 
or alkaline phosphatase (ALP) >2.5 x ULRR. 
 
4. 
Evidence of severe or uncontrolled systemic disease or any concurrent condition which 
in the Investigator’s opinion makes it undesirable for the patient to participate in the trial 
or which would jeopardize compliance with the protocol. 
 
5. 
Clinically  significant  cardiovascular  event  (e.g.  myocardial  infarction,  superior  vena 
cava syndrome  (SVC),  New York Heart  Association  (NYHA)  classification  of heart 
disease  >2 within 3 months  before entry; or presence  of cardiac  disease  that, in the 
opinion of the Investigator, increases the risk of ventricular arrhythmia. 
 
6. 
History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, 
trigeminy,  ventricular  tachycardia,  or uncontrolled  atrial fibrillation),  which  is 
symptomatic   or  requires  treatment  (CTCAE  grade  3)  or  asymptomatic   sustained 
ventricular tachycardia.  Atrial fibrillation, controlled on medication is not excluded. 
 
7. 
QTc   prolongation   with   other   medications   that   required   discontinuation   of   that 
medication. 
 
8. 
Congenital  long  QT  syndrome  or 1st  degree  relative  with  unexplained  sudden  death 
under 40 years of age. 
 
9. 
Presence of left bundle branch block (LBBB.) 
 
10.    QTc with Bazett’s  correction  that is unmeasurable  or 450  msec on screening ECG. 
(Note: If a subject has a QTc interval 450  msec on screening ECG, the screen ECG 
may  be  repeated  twice  [at  least  24  hours  apart].    The  average  QTc  from  the  three 
screening ECGs must be <450 msec in order for the subject to be eligible for the study.) 
 
11.    Any concurrent medication with a known risk of inducing Torsades de Pointes, that in 
the investigator’s opinion cannot be discontinued. 
 
12.    Concomitant  medications  that  are  potent  inducers  (rifampicin,  rifabutin,  phenytoin, 
carbamazepine, phenobarbital and St. John’s Wort) of CYP3A4 function. 
 
13. 
Hypertension  not controlled by medical therapy (systolic blood pressure greater than 
160 mm Hg or diastolic blood pressure greater than 100 mm Hg). 
 
14.    Currently active diarrhea that may affect the ability of the patient to absorb the ZD6474 
or tolerate diarrhea. 
 
15.    Women who are currently pregnant or breast-feeding. 
 
 
 
 
 
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16.    Receipt  of  any  investigational  agents  within  30  days  prior  to  commencing  study 
treatment. 
 
17.    Previous enrollment or randomization of treatment in the present study. 
 
18.    Major surgery within 4 weeks or incompletely healed surgical incision before starting 
study therapy. 
 
19.    Involvement in the planning and conduct of the study (applies to both AstraZeneca staff 
and staff at the study site). 
 
3.3.4 
Restrictions 
 
1. Patients who are blood donors should not donate blood during the trial and for 3 months 
following their last dose of trial treatment. 
 
2. Due to the experimental nature of vandetanib, female patients must be one year post- 
menopausal, surgically sterile, or using an acceptable method of contraception during and 
continued after the last dose of study medication (oral contraceptives, barrier methods in 
conjunction with spermicide, approved contraceptive implant, long-term injectable 
contraception, intrauterine device or tubal ligation).  Contraceptive use will continue for at 
least two months, five half-lives, after the last dose of study medication.   All women of 
child-bearing  potential  will require a pregnancy  test every 28-30 days while taking the 
study medication  and  for  at least  2 months  after  the last dose.   If a subject  becomes 
pregnant while taking vandetanib, the study medication must be permanently discontinued. 
 
3.4 
Registration Procedures 
 
3.4.1 
Guidelines for Lead Institution 
 
All  patients  should  be  registered  by  the  responsible  Clinical  Research  Associate  and/or Research Nurse in the eVelos Database 
prior the start of study.  All selection criteria listed in Section  3.3 should be confirmed prior to registration. 
 
3.4.2        Guidelines for Participating Sites 


 
 
 
 
 
 
Eligible participants  will be entered on study centrally at the University of Chicago by 
the  Lead  Clinical  Research  Associate.    All  sites  should  c onfirm  all  selection  criteria 
listed in Section  3.3 and then complete the Subject Registration Form and call the 
lead site at (773) 702-0712 or email Shane Small   at Ssmall@medicine  .bsd.uchicago.edu 
with the following information prior to start of study. 
 
 
 
 
 
 
 Provider of information 
 Study # and Institution 
 Treating Physician 
 Patient name/initials and hospital ID number 
 
 
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 Patient's zip code of residence 
 Date of signed informed consent 
 Gender 
 Date of birth of patient 
 Diagnosis and date of initial diagnosis 
 Anticipated start date 
 All source docs used to confirm eligibility (labs, physical exam, etc.). 
 Consent and Inclusion and Exclusion checklist 
 
A confirmation of registration and randomization assignment will be issued by the lead site 
upon receipt of the completed registration form. 
 
Affiliate patients eligibility must be confirmed with the Leading Institution 
(University of Chicago) prior to the starting the study. 
 
3.5           Precautions for Treatment 
 
Vandetanib should not be administered to pregnant women.  A negative pregnancy test should 
be confirmed before start of administration of vandetanib and prior to the start of each cycle. 
 
The exposure to vandetanib is unchanged whether given in the fasted state or with food and 
thus a restriction on dosing with food is not required. 
 
Exposure to vandetanib is increased with renal impairment thus caution must be adopted if 
being  given  to  such  patients,  especially  those  with  severe  renal  impairment  where  the 
exposure could potentially double. 
 
There is no known  antidote  for vandetanib,  and treatment  of AEs  associated  with  its use 
should be for the underlying adverse symptoms. 
 
If a patient develops torsades de pointes or ventricular tachycardia, vandetanib therapy must 
be stopped.  Vandetanib may be resumed at a lower dose when the arrythmia has resolved and 
the ECG QT interval has returned to normal, if clinically appropriate. 
 
Reversible  posterior  leukoencephalopathy  syndrome,  a syndrome  of subcortical  vasogenic 
edema diagnosed on magnetic resonance imaging of the brain, has been diagnosed in a patient 
receiving vandetanib.   This syndrome should be considered in any patient presenting with 
seizures,  headache,  visual  disturbances,  confusion  or  altered  mental  function  and 
hypertension, as the syndrome is expected to be reversible if vandetanib is stopped. 
 
There is no specific treatment for an overdose of vandetanib.  In clinical trials, single doses of 
1200 mg have been given to healthy volunteers with minimal symptoms.   Chronic dosing of 
600 mg has resulted in diarrhea and other AEs.  In case of overdose, vandetanib therapy may 
be interrupted, and any adverse reactions treated symptomatically. 


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3.6           Guidance on the Management of Toxicity 
 
In all cases where the dose of study treatment has been reduced/modified or the patient 
withdrawn due to unusual or unusually severe toxicity considered related to study treatment, 
the investigator must contact and inform the AstraZeneca study physician. 
 
All patients  who  experience  any NCI CTCAE  grade 3 or 4, including  QTc  changes  (see 
below), skin, gastrointestinal and other adverse events must be permanently discontinued from 
study treatment and monitored until resolution or return to baseline. 
 
For guidance on the management of QTc prolongation, see Figure 1 below.  Also see 
Appendix A - Medications Known to Prolong the QT Interval and/or Induce Torsades De 
Pointes (TDP). 
 
For all other toxicities, the dose of study treatment will be withheld for up to 3 weeks until the 
toxicity has resolved to CTCAE grade 0 or baseline.  Study treatment may then be restarted at 
a reduced dose (see Table 3 below).  Patients will be withdrawn from the study if toxicity does 
not resolve to  CTCAE grade 0 or baseline within 3 weeks.  If grade 1 or 2 toxicity recurs 
after dose reduction, the patient must be permanently discontinued from study treatment. 
 
A guideline for dose reduction is shown in the table below. 
 
Table 3 Dose Reduction 
Original dose 
Reduced 
dose 
Vandetanib dispensed for 
reduced dose 
Tablets per daily dose 
100 mg 
100 mg 
every 
other day 
1 every other day 
 
3.6.1 
QTc Prolongation 
 
Patients will have ECGs performed to monitor QTc interval (using Bazett’s correction) as 
outlined in the study plan. 
 
QTc prolongation is defined as: 
 Two consecutive  QTc measurements, within 48 hours of one another,  where either of 
the following criteria are met for both QTc values (the second being the mean of 3 
consecutive ECGs): 
 A QTc interval  450 msec  OR 
 An increase of > 60 msec from baseline QTc. 


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Figure 1 
Flowchart detailing management of QTc prolongation 
 
 
QTc   501 msec OR  in baseline of > 60 msec 
Yes 
Discontinue study drug.  Admit and follow for resolution 
of QTc prolongation. 
 
 
No 
 
 
QTc  450 msec and < 501 msec 
No 
Continue study drug 
 
 
Yes 
 
Continue study drug. Repeat 
ECG in triplicate within 48 
hours 
Repeat ECG 
QTc  450 msec and < 501 msec 
 
No 
Yes 
 
Continue double- 
blind study drug 
Hold study drug until resolution of QTc 
prolongation (until CTCAE grade 0 or 
baseline). 
 
Management of Patients with QTc Prolongation 
For a single QTc value of > 450 msec but < 500 msec, vandetanib may be continued but a 
repeat  ECG  (in  triplicate)  must  be  obtained  within  48  hours.    If  QTc  prolongation  is 
confirmed, vandetanib must be held.   ECGs and electrolytes  should be followed 3 times a 
week until QTc falls below 450 msec or baseline whichever is higher.  Vandetanib treatment 
may be resumed at a lower dose after the QTc recovers to < 450 msec or baseline whichever is 
higher. 
 
If the patient does not meet the criteria for QTc prolongation  at the repeat ECG, then the 
patient should continue treatment and resume the ECG schedule as outlined in the Study Plan. 
 
Patients experiencing NCI CTCAE grade 3 or 4 QTc prolongation, i.e. QTc ≥ 501 msec or > 
60 ms change from baseline and Torsades de pointes or polymorphic ventricular tachycardia 
or  signs/symptoms  of  serious  arrhythmia  must  discontinue  treatment  AND  admitted  to 
hospital for monitoring until resolution or return to baseline. 
 
3.6.2        Management of Skin Toxicity 
 
It is strongly recommended  that all patients  follow a program  of sun protective  measures 
while receiving study therapy and for 3-4 weeks after discontinuing study therapy.  The aim is 
to reduce the risk of development of skin rash, minimize the severity of skin rash, and to 
minimize the requirement for dose reduction of study therapy. 


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If a patient develops a skin rash, the following actions are recommended to the Investigator 
for the management of this reaction: 
 
 A variety of agents can be used to manage skin rashes.  These include mild to moderate 
strength steroid creams, topical or systemic antibiotics, topical or systemic 
antihistamines, and occasionally retinoid creams. 
 
 The rash should be graded/assessed by a physician as soon as possible according to the 
CTCAE cutaneous toxicity criteria and documented accordingly 
 
 If a rash of CTCAE grade 2 is detected, immediate symptomatic treatment should be 
provided. 
 
 If a rash of CTCAE grade 3 or higher is detected, vandetanib should be discontinued. 
 
If severe cutaneous toxicity recurs at reduced dose of vandetanib, the patient will permanently 
discontinue study treatment of vandetanib.  If vandetanib must be withheld for >3 weeks due 
to cutaneous toxicity, the patient will be discontinued. 
 
3.6.3        Management of Gastrointestinal (GI) Toxicity 
 
Nausea, vomiting, or both may be controlled with antiemetic therapy.   In subjects who have 
emesis and are unable to retain vandetanib/ placebo, every attempt should be made to obtain 
control of nausea and vomiting.  The dose of vandetanib/ placebo may be repeated if emesis 
occurs within 30 minutes of taking the tablet.   Diarrhea should be treated with standard 
medications  to  avoid  dose  modification  or  interruption,  if  possible.     Electrolyte 
supplementation with regular laboratory monitoring should be used, when appropriate, to 
maintain electrolytes within normal limits and prevent an increased risk of QTc prolongation. 
If grade 1 or 2 diarrhea develops, vandetanib should be withheld until diarrhea resolves to 
grade  0  or  baseline.    Patients  who  are  clinically  unstable  because  of  diarrhea  or  other 
intercurrent medical illness must be admitted and evaluated using telemetry, until clinically 
stable.  Upon recovery, treatment may resume at a permanently reduced dose (refer to section 
3.3.5.)  If vandetanib must be withheld for more than 3 weeks for resolution of diarrhea, the 
patient will not restart treatment with study medication.  If grade 1 or 2 diarrhea recurs after 
this dose reduction, the patient must permanently discontinue study treatment. 
 
3.6.4        Other Toxicity 
 
If any other CTCAE grade 3 or 4 toxicity that is not outlined in Sections 3.3.6.1 to 3.3.6.3 
develops and is attributable to vandetanib, vandetanib should be permanently discontinued. 
 
If study treatment must be interrupted for more than 3 weeks to allow for toxicity to resolve, 
the patient’s vandetanib will be discontinued. 


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Table 4 
Summary of Guidance on the Management of Toxicity for Vandetanib 
 
Toxicity 
Vandetanib 
QTc  value  501   msec  or 
prolonged   60   msec  from 
baseline 
Discontinue vandetanib AND admit to hospital for monitoring 
until resolution or return to baseline. 
Grade 3 or 4 cutaneous 
Discontinue vandetanib and monitor until resolution or return 
to baseline. 
Other grade 3 or 4 toxicity 
related to vandetanib 
Discontinue vandetanib and monitor until resolution or return 
to baseline. 
 
3.7 
Discontinuation of Subjects from Treatment or Assessment 
 
3.7.1 
Criteria for Discontinuation 
 
Subjects should be discontinued from study for the following reasons: 
• 
Completion of protocol intervention and required follow-up 
• 
Diagnosis of cancer 
• 
Disease  progression  requiring  alternative  therapy  in  the  opinion  of  the  Principal 
Investigator 
• 
Adverse event/serious adverse event including grade 1 toxicity that is unacceptable to 
the patient or physician 
• 
Repeated grade 1 or 2 toxicities or grade 3 or 4 toxicity that is believed to be possibly, 
probably or definitely related to study medication 
• 
Pregnancy 
• 
Allergic reaction to the study medication 
• 
Inability or unwillingness to adhere to protocol procedures and instructions 
• 
Medical contraindication 
• 
Withdrawal of informed consent 
• 
Patients who require medication that may prolong the QT interval while on study that 
the investigator’s  opinion  cannot be discontinued,  should  be discontinued  from the 
study.  Refer to Appendix A for a list of medications known to induce Torsades de 
Pointes. 
 
3.7.2 
Procedures for Discontinuation 
 
If a subject discontinues study, reason for discontinuation must be documented and attempts 
to retrieve all study drug should be undertaken.  If possible, subjects should be assessed within 
30 days of study discontinuation.   If a subject discontinues drug, attempts should be made to 
follow outcome for at least 2 years after discontinuation as outlined in Study Plan. 


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3.8 
Treatments 
 
3.8.1 
Investigational Products 
 
3.8.1.1 
Identity of Investigational Product and Comparators 
 
Subjects  will be randomized  to receive  ZD6474  (vandetanib,)  versus  placebo  for up to 6 
months. 
 
3.8.1.2 
Doses and Treatment Regimens 
 
ZD6474 100 mg QD PO 
Matching placebo will be supplied by AstraZeneca 
 
If  subject(s)  cannot  swallow  tablets,  see  Appendix  E  for  Instructions   for  Dispersing 
Vandetanib Tablets. 
 
Missed or Forgotten Doses 
If the subject inadvertently does not take the dose in the morning, he or she may take that 
day’s dose any time up to 10 pm that same day.   However, if a subject misses taking their 
scheduled dose and is unable to take the missed dose on the same day, he or she must take the 
next scheduled dose and the missed dose will not be made up.  The dose of study medication 
may be repeated if vomiting occurs within 30 minutes of taking the study treatment. 
 
3.8.1.3     Labeling 
 
Labeling of the investigational product will be performed in accordance with Good 
Manufacturing Practices (GMP.)  AstraZeneca, or a company acting on their behalf, will pack 
tablets into high-density polyethylene (HDPE) bottles with child-resistant tamper-evident 
closures.   Each bottle will be labeled with the statement: "Caution: New Drug - Limited by 
Federal (or USA) Law to Investigational Use".  Instructions stating that the tablets are to be 
taken orally “as directed  by your doctor” will be included.   Information  on the label will 
indicate the identity and quantity of tablets and storage conditions.   Additional subject 
information will be identified as dictated by the protocol; it may be necessary for information 
to be recorded on the label by the investigator at the time the bottle is dispensed. 
 
3.9           Drug Supply Information 
 
3.9.1        Storage 
 
All  investigational  products  must  be  kept  in  a  secure  place  under  appropriate  storage 
conditions.  Descriptions of the appropriate storage and shipment conditions are specified on 
the investigational product label and investigator brochure.   The stored study drug supplies 
must be accessible to authorized staff only.  The storage area must also have adequate control 
of temperature in order to maintain stability and potency of study drug supplies.  The tablets 


 
 
 
 
 
Vandetanib (ZACTIMA™; ZD6474) 
 
 
 
should be stored in the original pack until use.  For further information, investigators should 
refer to the investigational product label. 
 
3.9.2 
Accountability 
 
All subjects will maintain a drug diary documenting drug administration and adverse events 
(Appendix B).  At each visit, subjects will return any unused drug and pill counts will be    
performed to account for drug administration. 
 
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of the study drug.  All study drug must be accounted for, including study 
drug accidentally or deliberately destroyed.  All discrepancies between amounts of study drug 
dispensed and amounts returned must be documented.   Under no circumstances will the 
investigator allow the investigational drug to be used other than as directed by the protocol 
without prior AstraZeneca approval.   If appropriate, drug storage, drug dispensing, and drug 
accountability may be delegated to the pharmacy section of the investigative site. 
 
3.9.3        Mechanism of Drug Destruction 
 
At the conclusion of the study, unused containers of the investigational drug are inventoried 
and prepared for return to the sponsor or destroyed in accordance with the requirements of the 
sponsor or the manufacturer or the state board of pharmacy.  All documentation regarding 
receipt, storage, dispensing, and return of used containers must be complete and accurate. 
 
** Unused expiring drug ** 
The expiration date of the drug should be noted, and the drug should be returned, disposed of, 
or destroyed in accordance with the approved protocol when the drug expires.   An ongoing 
audit of drug expiration will be performed as the medication is received and as the medication 
is dispensed.  In addition, a random audit of medication supplies and expiration dates will be 
performed  weekly  on  10  active  protocols.     Documentation   indicating  study  drug  was 
destroyed will be sent to AstraZeneca. 
 
3.9.4        Blinding and Procedures for Unblinding the Study 
 
Methods for ensuring blinding 
A  secure  online  registration  interface  has  been  developed  to  register  patients,  and  it  is 
integrated with the randomization component.   This type of an interface has been used 
successfully in other Head and Neck cancer clinical trials at the University of Chicago (e.g. 
DeCIDE).   At the time of patient registration  an electronic notification  will be sent to the 
study pharmacist.   To randomize the patient, the pharmacist will securely login into the 
registration system, which will provide the randomized treatment assignment.   Only the 
pharmacist will have access to the treatment assignment to maintain the blinding. 
 
Methods for unblinding the study 
In the event of an emergency,  Dr. Jonas De Souza   at the University of Chicago shall be 
contacted at the 24-hour pager number:  (773) 702-4400, which will be printed on the study 
 
 
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medication  label.   Remember,  this is only in the event of an emergency.   The protocol 
number, the patient study ID number, and the patient’s initials (e.g., “FL”) or name will be 
required to unblind the patient.  Once Dr. De Souza  concurs that unblinding is appropriate, he 
will ascertain  the treatment  assigned  to that patient by securely logging  into a designated 
website,  and  inform  the  caller  of  the  patient’s  treatment.    If  a  patient  is  emergently 
unblinded, he/she is considered to be off treatment, but should continue to be followed 
for outcome evaluations. 
 
3.9.5        Pre-Study, Concomitant and Post-Study Treatment(s) 
 
Concomitant use of any therapy during study must be documented and should be approved by 
the treating physician prior to initiation.  Concomitant use of the known potent inducers of 
CYP3A4:   rifampicin, phenytoin, carbamazepine, barbiturates and St. John's Wort are not 
allowed within 2 weeks of study or during the study.  Until the effect of CYP3A4 inducers in 
the  exposure  to  vandetanib  in  humans  has  been  assessed,  the  co-administration  of  such 
inducers with vandetanib is not allowed.  However, it has been shown that CYP3A4 inhibitors 
have little effect on the exposure to vandetanib in humans, and therefore these can be co- 
administered with vandetanib. 
 
A potent CYP3A4 inducer has been shown to reduce the exposure to vandetanib by 40% thus 
the co-administration of such inducers with vandetanib is not allowed.  A potent CYP3A4 
inhibitor has been shown have little effect on the exposure to vandetanib and therefore these 
can be co-administered with vandetanib. 
 
In vitro data has shown vandetanib inhibits CYP2D6 and CYP2C8.  Based on the maximum 
steady state total plasma concentrations observed in patients the I/Ki ratio for both these is less 
than 0.10, and a SimCYP simulation for the potential inhibition of CYP2D6 (lower IC50 and 
Ki), concluded there would be little effect on CYP2D6 substrates.  Thus substrates of both 
CYP2D6 and CYP2C8 may be co-administered with vandetanib. 
 
Patients   who  require  medication   that  may  prolong  the  QT  interval   while  on  study: 
antiarrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, 
sotalol, dofetilide) and other drugs that may prolong the QT interval (including but not limited 
to cloroquine, clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, 
and pimozide), that the investigator’s opinion cannot be discontinued, should be discontinued 
from the study.  Refer to Appendix A for a list of medications known to induce Torsades de 
Pointes. 
 
3.10         Safety Measurements and Variables 
 
3.10.1      Adverse Events 
 
3.10.1.1   Definitions 
 
 
 
 
 
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The  definitions  of  Adverse  Events  (AEs)  and  Serious  Adverse  Events  (SAEs)  are  given 
below.  It is of the utmost importance that all staff involved in the study be familiar with the 
content of this section.  The Principal Investigator is responsible for ensuring this. 
 
Adverse Event 
An Adverse Event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product.   An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 
tachycardia,  enlarged  liver)  or  the  abnormal  results  of  an  investigation  (e.g.,  laboratory 
findings, ECG).  In clinical studies, an AE can include an undesirable medical condition 
occurring at any time, including run-in or washout periods, even if no study treatment has 
been administered. 
 
Any detrimental change in a patient’s condition subsequent to them entering the study and 
during the follow-up period should be considered an AE.  When there is a deterioration in the 
condition for which the study treatment is being used, there may be uncertainty as to whether 
this is lack of efficacy or an AE.  In such cases, unless the reporting physician considers that 
study treatment contributed to the deterioration or local regulations state to the contrary, the 
deterioration should be considered a lack of efficacy.  Signs and symptoms of disease 
progression are therefore not considered AEs. 
 
The development of a new cancer should be regarded as an AE.  New cancers are those that 
are not the primary reason for administration of study treatment and have been identified after 
inclusion of the patient into the clinical study. 
 
Serious Adverse Event 
A Serious Adverse Event (SAE) is an AE occurring during any study phase (e.g., run-in, 
treatment, washout, follow-up), and at any dose of the investigational product, comparator or 
placebo, that fulfills one or more of the following criteria: 
- 
Results in death 
- 
Is immediately life-threatening 
- 
Requires inpatient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant disability or incapacity 
- 
Is a congenital abnormality or birth defect 
- 
Is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above. 
 
Any event or hospitalization that is unequivocally due to progression of disease, as 
determined by the investigator, must not be reported as an SAE, however should be 
communicated to AstraZeneca 
 
The  causality  of  SAEs  (their  relationship  to  all study  treatment)  will  be  assessed  by the 
investigator(s) and communicated to AstraZeneca. 
 
 
 
 
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Serious and Unexpected Suspected Adverse Reaction (SUSAR) 
 
A serious adverse event is considered to be a suspected adverse reaction if there evidence to 
suggest a causal relationship to the adverse event.  This may include a single occurrence of an 
event strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more 
occurrence of an event otherwise uncommon is the study population, or an aggregate analysis 
of specific events occurring at greater frequency than expected from historical controls, or 
occurs at a greater frequency in the investigational versus the placebo arm of the study. 
 
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
consent, investigator brochure, FDA-approved package insert, or elsewhere in the current IND 
application.  This includes adverse events listed in the protocol, consent or IND as occurring 
within the class of drugs or otherwise expected from the drug’s pharmacological  properties 
but which have not been previously observed with this investigational agent. 
 
ALL SUSARS occurring on this clinical trial must be reported to the FDA.   Refer to 
Section 3.10.1.6 for reporting guidelines. 
 
 
 
 
3.10.1.2   Reporting of Adverse Events 
 
Adverse events will be recorded at each study visit, graded using Common Toxicity Criteria 
Version 4.0, and assigned an attribution to study drug from 1-5 (not related, unlikely related, 
possibly related, probably related, definitely related).  Adverse event onset, resolution, action 
taken, and whether it constitutes a serious adverse event will be recorded. 
 
Pregnancy should be excluded before randomization.  Should a pregnancy occur during study 
participation,  it must  be reported  in accordance  with  the procedures  described  in Section 
7.1,  Procedures in Case of Pregnancy.  Pregnancy in itself is not regarded as an AE unless 
there is a suspicion that an investigational product may have interfered with the effectiveness 
of a contraceptive medication 
 
All non-serious adverse events will be reported to AstraZeneca at the conclusion of the study. 
 
3.10.1.3   Reporting of Serious Adverse Events 
 
 
 
 
The principal investigator and other designated site personnel are responsible for informing 
the University of Chicago  Comprehensive  Cancer Center (UCCCC) Cancer Clinical Trials 
Office (CCTO)  of any serious  and unexpected  adverse events.   AstraZeneca  must also be 
notified of all such adverse events.  Events that qualify as a SUSAR or other reportable events 
be reported  to  the FDA.   Refer  to  Section  3.10.1.6  for details  of FDA  reporting 
requirements. 
 
Guidelines for reporting to each of these groups are provided below. 
 
3.10.1.4   University of Chicago Comprehensive Cancer Center 
 
 
 
 
 
 
 
 
 
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Events Occurring at the University of Chicago: 
 
All serious adverse events (as defined in Section 3.10.1. )  and protocol deviations must  
be  reported  to  the  University  of  Chicago  Comprehensive  Cancer  Center  (UCCCC) 
Cancer Clinical Trials Office (CCTO) using the eVelos database.   The Research  Nurse  or 
other designated individual should report the SAE/deviation to the UCCCC Quality Assurance 
(QA) Coordinator  by the end of the business day when s/he becomes aware of the event. 
Events occurring after business hours should be reported to the CCTO by 12pm (noon) the 
next business day.  Each event report must indicate where the event meets the University of 
Chicago Institutional Review Board’s (UCIRB) Unanticipated Problem reporting criteria. 
 
Events Occurring at Participating Site(s) 
For  serious  and  unexpected  adverse  events  occurring  at  a  participating  site  it  is  the 
responsibility of the research nurse, study coordinator, or other designated individual at the 
site where the event occurs to notify the UCCCC of the adverse event.   Events should be 
reported to the UCCCC QA Coordinator be email:  QACCTO@bsd.uchicago.edu  or by fax at 
(773) 834-5800. 
 
For unexpected  and serious suspected  adverse reactions  which FDA require reporting as a 
single  occurrence,  Form  3500a  (MedWatch)  must  be  completed  by  the  designated  site 
personnel and returned to the UCCCC QA Coordinator according to the timeframes in Section 
3.10.1.6. 
 
 
3.10.1.5   Institutional Review Board 
 
Events meeting current IRB reporting criteria must be submitted by the principal investigator 
via   the IRB’s electronic submission system   within   the  IRB’s   designated   reporting 
timeframes.  Details of the IRB’s current reporting policy and timelines can be found on their 
website at: http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html. 
 
The responsible research nurse or other designated individual are responsible for entering the 
appropriate information into the IRB’s electronic submission system and forwarding the 
completed submission to the principal investigator for reporting to the IRB. 
 
Events occurring at a participating site should be reported to the local IRB of record according 
to their policies and procedures and may be reported to the University of Chicago IRB if they 
meet current reporting criteria. 
 
3.10.1.6   FDA 
 
This study will be conducted under an IND held by Jonas De Souza   at the University of 
Chicago. 
 
Per  21  CFR  312.32,  the  sponsor-investigator   is  required  to  notify  the  FDA  and  all 
participating investigators of potential serious risks within 15 calendar days.  Unexpected fatal 
or life-threatening adverse events must be reported to the FDA by the sponsor-investigator via 
phone or fax within 7 calendar days. 
 
 
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Current  FDA  regulations  require  that  all  SUSARs  (see  definition  in  Section  3.10.1.1) 
occurring on this trial, other findings that suggest a significant risk to humans exposed to the 
investigational  drug  (e.g.  information  from  pooled  analysis  of  multiple  studies),  and  any 
clinically significant increase in the rate of an expected serious adverse reaction be reported as 
an IND Safety Report.  Refer to Table A below for guidelines for reporting these events to the 
FDA. 
 
In order to meet these requirements, the sponsor-investigator will review all reported serious 
adverse  events  as  they  occur  and  will  conduct  a  literature  search  to  seek  new  safety 
information  and  review  and  analyze  all safety  information  from  this clinical  trial  at least 
annually and more frequently as appropriate. 
 
Table A: FDA Reporting Requirements 
 
 
Report Type 
Method of Report 
Responsible 
Party 
Timeline1 
Fatal/Life-Threatening Event 
 
Yes 
No 
 
 
Individual Report 
Form 3500A (MedWatch)7 
RN/CRA 
4 calendar days5 
10 calendar days5 
 
 
 
Other Findings that 
3 
6 
6 
Suggest Significant Risk2 
Narrative 
PI 
4 calendar day 
10 calendar days 
 
 
Clinically Significant 
Increased Frequency of 
Suspected Adverse 
Reactions4 
 
 
Narrative 
PI 
4 calendar days6 
10 calendar days6 
 
1:   Report Due to CCTO IND Coordinator according to the specified timeline regardless of whether or not all information 
regarding the event is available.  If applicable, a follow-up report should be provided to the IND Coordinator once additional 
information on the event is available. 
2:   An IND Protocol Amendment is also required to describe any changes to the protocol, consent, or overall conduct of the 
study made as a result of this information.  All revised documents should be made available to the CCTO IND Coordinator at 
the time of IRB submission. 
3:   Copy of relevant publication(s) should be included if applicable. 
4:   Details of individual cases should be included as appropriate 
5:   From date event was reported to the sponsor-investigator 
6:   After information is received by the investigator and determined to meet reporting criteria 
7:   Copy should be maintained in the subject research chart and master IND file in the CCTO. 
 
All  other  events  (e.g.  protocol  deviations   or  other  safety  concerns)  not  meeting  the 
requirements for IND Safety Reporting (per 21 CFR 312.32) but which require reporting to 
 
 
 
 
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the  IRB  as  an  Unanticipated  Problem  will  be  reported  to  the  FDA  as  an  informational 
amendment or with the annual report as appropriate. 
 
3.10.1.7   Participating Sites 
 
It is the responsibility of the designated Regulatory Manager on behalf of the sponsor- 
investigator to notify all participating sites of all unexpected and serious suspected adverse 
reactions that occur on this clinical trial and which are reported to the FDA as an IND Safety 
Report (21 CFR 312.32).   A copy of the completed Form 3500A (MedWatch) and/or IND 
Safety Report Narrative will be provided to the responsible Regulatory Manager by the IND 
Coordinator for distribution to all participating sites. 
 
3.10.1.8   AstraZeneca 
 
All serious and unexpected adverse events must also be reported to AstraZeneca.  It is the 
responsibility of the research nurse or other designated member of the research team at the site 
where the event occurred to report these events to AZ. 
 
Reports should be submitted to by fax to AstraZeneca’s  designated fax line: (800) 972-4533, 
Attention Oncology ISS Safety Representative.* 
 
A  cover   page   with   the   following   information   should   accompany   the   completed 
MedWatch form: 
 
 Vandetanib Investigator Sponsored Study (ISS) 
 The investigator IND number assigned by the FDA 
 The investigator’s name and address 
 The trial name/title and AstraZeneca reference number 
 
* It must be indicated, 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. 
 
If a non-serious AE becomes serious, this and other relevant follow-up information must also 
be provided to AstraZeneca and the FDA. 
 
Serious adverse events that do not require expedited reporting to the FDA need to be reported 
to AstraZeneca  preferably using the MedDRA coding language for serious adverse events. 
This information should be reported on a monthly basis and under no circumstance less 
frequently than quarterly 
 
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of 
the  randomization  code/  code-break  information  or  unblind  those  SAEs  which  require 
expedited reporting. 
 
 
 
 
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All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product.  All SAEs will be documented. 
 
Non-serious adverse events and SAEs will be collected from the time consent is given, 
throughout the treatment period and up to and including the 30 day follow-up period.  (See 
Appendix D for the Non-Serious Adverse Event Reporting Template.)  After withdrawal from 
treatment, subjects must be followed-up for all existing and new AEs for 30 calendar days 
after the last dose of trial drug and/or until event resolution.   All new AEs occurring during 
that  period  must  be  recorded  (if  SAEs,  then  they  must  be  reported  to  the  FDA  and 
AstraZeneca).   All study-related toxicities/ SAEs must be followed until resolution, unless in 
the Investigator’s opinion, the condition is unlikely to resolve due to the patient’s underlying 
disease. 
 
4.              PHARMACOKINETICS & PHARMACODYNAMICS 
 
4.1            Pharmacodynamics 
 
Biopsy: 
A biopsy will be performed prior to starting therapy (baseline), 3 months, and 6 months.  The 
primary endpoint of the study will be to assess the change in MVD from baseline to 3 months 
in subjects receiving ZD6474 versus placebo.  Therefore, biopsy is mandatory for all subjects. 
Tissue should be obtained in the area of prior or current dysplasia or cancer.  Anatomic biopsy 
location must be documented textually and diagrammatically to insure that the same area is 
biopsied at each time point.  Biopsies will consist of either a 5 mm or an 8 mm punch biopsy 
of the oral mucosa.  Tissue specimens will be bisected, with half of the specimen immediately 
embedded in OCT and frozen at -80 C with the other half placed in 10% buffered formalin, 
processed and embedded in paraffin. 
 
Immunohistochemistry: 
For detection of CD34, antigen retrieval will be achieved by using DAKO Proteinase K (Cat # 
S3004) treatment for 15 minutes at room temperature.  Endogenous peroxidase activity will be 
quenched with 1% hydrogen/methanol.   The primary antibody for CD34 (Vector, Catalog # 
VP-C345) will be applied at 1: 50 dilution for a one hour incubation at room temperature, 
followed 
by anti-rabbit 
polymer 
labeled 
HRP 
bound 
secondary 
reagent 
(DAKO 
Envision+System-HRP). 
 
For detection of phosphorylated EGFR (pEGFR) and phosphorylated VEGFR-2 (pVEGFR-2), 
antigen retrieval will be achieved using Immuno/DNA retriever with citrate (BioSB, 
SantaBarbara,  CA Catalog # BSB0021).   Endogenous peroxidase activity will be quenched 
with Mouse/Rabbit ImmunoDetector Peroxidase Block Kit.  Sections will be incubated using 
primary  antibody  to  pVEGFR-2  1:300  (Abcam,  Cambridge,  MA;  Catalog  #  ab38464)  or 
pEGFR   1:250   (Cell  signaling,   Danvers,   MA  Catalog   #4407)   for  one  hour  at  room 
temperature.   Antibody binding will be visualized by using Mouse/Rabbit ImmunoDetector 
HRP/DAB Detection System (BioSBSanta Barbara, CA Catalog # BAB0003). 
 
 
 
 
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For detection of Ki-67, antigen retrieval will be achieved using 10mM TrisBase, 1mM EDTA 
pH 9.0.  Endogenous peroxidase activity was quenched with 1% hydrogen peroxide/Methanol. 
The primary antibody for Ki67 (NeoMarkers,  Fremont, CA; Catalog # RM-1906), sections 
will be incubated at a 1:300 dilution at room temperature for one hour followed by anti-rabbit 
polymer labeled HRP bound secondary reagent (Envision+system-HRP). 
 
All immunohistochemistry stains will be developed with DAB chromogen and counterstained 
with hematoxylin.   Corresponding negative control experiments were performed by omitting 
the incubation step with the primary antibody. 
 
Scoring of immunohistochemical staining will be performed using the Automated Cellular 
Imaging System (Aperio Image Analysis Workstation).  Stained sections will be scanned and 
acquired using an Aperio imaging/microscopy system.   Proliferation will be measured by 
calculating the average labeling percentage of the epithelial compartment for Ki67 for each 
specimen.    For determination  of microvessel  density  (MVD),  the total  number  of CD34- 
stained clusters or single cells, with or without a lumen, was quantified for each specimen. 
For pVEGFR-2 and pEGFR quantification was, an index of staining will be calculated and 
expressed as the percentage of staining multiplied by staining intensity after subtracting the 
index staining of corresponding negative controls. 
 
DNA from peripheral blood: 
A 10 ml purple-top (EDTA-containing) vacutainer will be used to draw blood at baseline. The 
site coordinator or designee at each site will separate plasma from buffy coat by centrifugation 
at 3500 rpm at 4°C for 15 minutes. Plasma will be aliquoted into 2 ml cyrovials and stored at - 
80°C for future biomarker studies. The buffy coat of cells will be transferred to a separate 
tube, to which 5 mL of PBS will be added and mixed with the buffy coat. The buffy coat tube 
+ PBS will be centrifuged for 5 min at 3000 RPM, the supernatant will be removed and the 
cell pellet will be stored at -80 for LOH and other biomarker analysis. 
 
Serum: 
Serum samples will be collected prior to therapy on all patients and at 3 and 6 months in two 
7-10 cc SST tubes.   Blood  in the serum collection  tube should be allowed  to clot for 60 
minutes and then centrifuged to separate serum.   Serum should be stored in 2 mL cryovial 
tubes  (Nalgene  Cat#  5000-0020)  in  410uL  aliquots.     Samples  should  be  labeled  with 
institution, protocol number, patient initials, patient registration number, and the date and time 
of draw.  Serum samples should be stored at -80°C. 
 
Saliva collection, stabilization and processing 
Unstimulated saliva samples will be procured from subjects prior to starting therapy, at 3 and 
6 months.   Subjects will be asked to refrain from eating, drinking, smoking, or oral hygiene 
procedures for at least one hour prior to the collection.  Saliva samples will be centrifuged at 
2,600  x  g  for  15  min  at  4°C.    The  supernatant  will  be  removed  from  the  pellet  and 
immediately mixed with SUPERase•In (Ambion Inc., TX) or with a cocktail of protease 
inhibitors (Roche, USA). 
 
Sample shipping and Storage: 
 
 
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All the tissue samples will be packaged and transported by carrier service in batched samples 
following  the government  regulation  42 CFR Part  72  – “Interstate  Shipment  of Etiologic 
Agents,” which describes the requirements for the proper packaging and shipping of infectious 
substances and other biomedical material. All the samples will be packaged and delivered in 
such a way that the contents will not leak and will arrive in good condition. The tissue will be 
transported  in  the  packages  with  the  biohazard  label  on  the  front  to  the  Human  Tissue 
Resource  Center  at  the  University  of  Chicago  (address  below).  Paraffin-embedded  tissue 
blocks should be shipped at ambient temperature. All institutional requirements for safety and 
confidentiality will be met during specimen transmittance. 
 
Human Tissue Resource Center (HTRC) 
University of Chicago 
5835 S. Cottage Grove, Room Room P-616A 
Chicago, IL 60637 
Phone: 773-834-8391 
Fax: 773-834-8740 
e-mail: tissuebank@bsd.uchicago.edu 
 
4.2           Electrocardiogram (ECG) Assessments for Study Plan 
 
• 
Baseline QTc (Bazett’s) will be determined by the average of no less than three (3) 
consecutive ECGs (within 5-10 minutes of one another.) 
 
ECGs will be repeated at weeks 1, 2, 5, 9, 13, 17, 21 and 25; at discontinuation; and as 
clinically indicated (ECGs to be consistent with the chemotherapy schedule, where 
relevant.)  In addition, upon occurrence of electrolyte disturbances or severe diarrhea, 
close monitoring of ECGs is recommended. 
 
• 
If QTc prolongation occurs at one of the usual assessment times, or at any other time, 
the QTc  will  be re-evaluated  with  no  less  than  3 consecutive  ECGs  (within  5-10 
minutes)  of one another,  as per baseline  (Refer  to Section  3.3.6.1,  “QTc 
Prolongation.”) 
 
4.3           Imaging 
 
Not applicable to study.  Imaging should be performed as clinically indicated. 
 
4.4           Response Data 
 
Visible  lesions  will  be measured  at  each  visit  and  change  in  size  or  appearance  will  be 
documented. 
 
5.             STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
 
5.1           Statistical Evaluation – General Aspects 
 
 
 
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This  is  a randomized,  double-blind,  placebo-controlled  study  with  a primary  endpoint  of 
reducing  microvessel  density  (MVD)  in  preneoplastic  lesions  at  3  months  compared  to 
baseline.  A placebo control group is necessary due to the lack of validated historic controls in 
this population and is ethical since the standard of care for these patients would be active 
surveillance.  Patients eligible to participate in this trial will be at high risk of developing oral 
cancer, but will be free of disease when enrolled on the study.  Thus, commonly used clinical 
trial endpoints such as response rate or progression-free  survival are not applicable to this 
patient population.  Time to disease recurrence could be used as the primary endpoint, but due 
to the incidence of cancer development even among the high-risk patients, this endpoint will 
require too large a sample size to be feasible at this point. 
 
Eligible patients will be randomized to ZD6474 (treatment) or placebo (control) arms for 6 
months  and  monitored  for  up  to  3  years.  Tissue  biopsies  from  the  same  area  of  known 
dysplasia will be obtained at baseline, 3 months, and 6 months, and will be banked by the 
Biobanking and Pathology Core.  Statistical analyses will be performed using SAS or Stata 
statistical software.  Analyses will be performed by the study statistician, Dr. Kocherginsky. 
 
5.2           Description of Outcome Variables in Relation to Objectives and Hypotheses 
 
Despite extensive studies to identify patients at risk for developing OSCC, there are no 
established chemopreventive agents.  Prior Phase III studies have been negative due to a lack 
of efficacy, inadequate understanding of molecular mechanisms underlying the intervention, 
or lack of tolerability of the agent for long periods of time.  Therefore, with preclinical and 
safety  data  strongly  supporting  the  rationale  for  administering  ZD6474  as  a 
chemopreventative agent, this study will address these critical limitations of prior approaches. 
The primary endpoint  was chosen  to reflect  the effect of ZD6474  on microvessel  density 
(MVD)  in  preneoplastic  lesions  which  correlated  strongly  with  OSCC  inhibition  in  the 
preclinical model and serves as a surrogate for the latter.   Secondary endpoints will include 
feasibility, safety and tolerability of ZD6474, development  of OSCC, as well as molecular 
studies of putative targets of ZD6474. 
 
5.3           Description of Analysis Sets 
 
Full  Analysis  Set  (intention-to-treat  population):  The  full  analysis  set  is  the  primary 
analysis population and will consist of all randomized patients. 
 
Safety  Set:  The  safety  set  will  consist  of  all  randomized  patients  who  received  trial 
medication at least once.  This set will be used for safety analyses. 
 
5.4           Method of Statistical Analysis 
 
Primary Endpoint:  The primary endpoint of this study is the comparison between treatment 
groups  of  the  within-patient  change  in  MVD  score  from  baseline  to  3-months  following 
treatment initiation (ΔMVD).  The primary analysis upon which the sample size calculations 
are based is the comparison of ΔMVD between treatment arms using a two-sample t-test with 
unequal variances.  A Wilcoxon ranksum test may be used if the normality assumption is not 
 
 
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satisfied.  Alternatively, ΔMVD may be transformed (e.g. log-transformation) to satisfy the 
normality  assumption.    Additional  analyses  of  the  primary  endpoint  will  include  linear 
regression models with treatment effect and other prognostic factors as covariates.  Model 
selection will follow strategies described in Harrell (2001). 
 
Secondary Endpoints: ZD6474 has been studied in 37 clinical trials involving over 2000 
subjects.  In general, the agent has been well tolerated even for long-term administration with 
the most  common  adverse  events  being  rash,  nausea,  diarrhea,  fatigue,  and  hypertension. 
Adverse events data will be collected, and event rates will be summarized using frequency 
tables.   Event rates will be compared  between  treatment  arms using a Chi-squared  test or 
Fisher’s exact test. 
 
Adherence to treatment will be monitored by self-administered patient diaries.  Remaining pill 
counts will be performed at each visit, and pill counts will be compared with those reported on 
patient diaries to determine the reliability of self-reporting.  Adherence rates will be defined as 
the number of doses administered divided by the total number of doses that was prescribed, 
and will be summarized for each 3-month period.   Agreement between pill counts and self- 
reported doses administered will be analyzed using the kappa coefficient and Bland-Altman 
plots. 
 
Subjects will be monitored for the development of oral and other cancers.  We expect that 
ZD6474 treated patients will have a lower incidence of OSCC.  Time to cancer development 
will  be summarized  using  the method  of Kaplan  and  Meier  for  each  treatment  arm,  and 
compared between arms using the logrank test.  In addition, yearly incidence rates will be 
reported.  However, the study is clearly underpowered to demonstrate a statistically significant 
difference between groups with respect to time-to-event or incidence rates due to the low 
expected overall number of cancer cases. 
 
To assess the biologic effect of EGFR and VEGFR2 inhibition, tissues will be analyzed by 
IHC for pEGFR, EGFR, pVEGFR2, VEGFR2, and Ki-67.  We hypothesize that biopsies from 
ZD6474 patients will exhibit significantly lower expression of pEGFR and VEGFR2 and 
proliferation indices.  Expression levels will be measured on a continuous scale, and within- 
patient changes in expression will be compared between treatment arms using a t-test or 
Wilcoxon ranksum test as appropriate. 
 
5.5           Determination of Sample Size 
 
Changes in within-patient MVD scores from baseline to 3-months of treatment (ΔMVD) will 
be compared between the treatment arms using a two-sample t-test with unequal variance.  We 
assume that baseline mean and variance will be similar to what is reported in Li et al (29) who 
examined MVD in 52 samples with mild, moderate and severe dysplasia.  To calculate sample 
size we make the following assumptions: 
 
• 
baseline average MVD = 30.1 (the weighted average of all dysplastic samples in Li et 
al); 


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Rho Placebo 
SDΔ 
ZD6474 
SDΔ 
N 
(per arm) 
0.25 15.5 
13.1 
31 
0.50 12.7 
10.9 
22 
0.75 9.0 
8.0 
12 
 
 
 
• 
coefficient of variation CV = 40%, both at baseline and at 3 months (CV in Li et al 
ranged from 30%-56% across dysplastic groups; Michailidou et al (30) report CV = 
28% in leukoplakia with dysplasia); 
• 
10% increase in MVD in the placebo arm, which corresponds to a difference between 
mild vs. moderate or moderate vs. severe dysplasia in Li et al.(29); 
• 
25% decrease in MVD in the ZD6474 arm, which corresponds to a difference between 
moderate dysplasia vs. normal epithelia in Li et al(29).   Similarly,  MVD was 35% 
lower  in  normal  mucosa  than  in  leukoplakia   with  dysplasia  tissue  samples  in 
Michailidou et al.(30); 
• 
within-patient correlation between baseline and 3-month MVD ranging between 0.25- 
0.75. 
 
Based on these assumptions, expected baseline MVD is 30.1±12.1, and 3-month MVD will be 
33.2±13.3 and 22.6± 9.0 in the placebo and ZD6474 arms, respectively.  This corresponds to 
an average change ΔMVD of 3 and -7.5 in each treatment arm. 
 
Table 5 lists the sample sizes required to attain 80% power with two-sided α=0.05 to detect 
differences in ΔMVD for various levels of within-patient correlation.  Assuming a moderately 
high within-patient  correlation ρ=0.50, 22 patients per arm will be required.   A total of 54 
patients will be enrolled to allow for 20% loss-to-follow up and unevaluable samples.  These 
calculations are somewhat conservative because much larger change in MVD (40% decrease) 
was observed in ZD6474-treated mice in the 4NQO mouse model.   Also, a somewhat 
conservatively high CV=40% is assumed. 
 
Table 5. Calculation of number of patients 
required per arm of the clinical trial. 
 
 
 
 
Study Feasibility: The Head and Neck Cancer Program at the University of Chicago has a 
strong record of multi-disciplinary care and expertise in all aspects of the disease.  In 2009 the 
program  registered  over  800  unique  patient  visits  and  performed  approximately  300  new 
patient consults.   A High Risk Clinic to specifically deal with the needs of patients without 
active disease but who are at increased risk to develop HNSCC is available and overseen by 
Dr. Elizabeth Blair.  These patients often have a personal or strong family history of HNSCC, 
engaged in behavior associated with developing OSCC (e.g. tobacco use), or harbor a pre- 
neoplastic lesion.   The clinic will serve as the setting to screen prospective patients, obtain 
tissue, and perform the clinical study.   The Head and Neck Cancer Program has recognized 
the importance of OSCC chemoprevention and participated in three such studies that are either 
already closed or are anticipated to complete accrual prior to the initiation of this proposed 
trial. 
 
Dr.  Lingen  is  a Board  Certified  Oral  &  Maxillofacial  Pathologist.    His  outreach  service 
receives biopsies from dentists throughout  Illinois and Northwestern  Indiana.   Drs. Dennis 


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Solt and Reza Mostofi are oral pathologists with outreach services in Chicago.  The 3 services 
have a combined total of ~10,000 cases/year, and approximately ~100 dysplasia cases.  All 3 
biopsy services have contributed patients for the EPOC prevention trial currently underway 
with the MD Anderson.  Therefore, the involvement of these biopsy services will be important 
for the accrual of subjects for the proposed study.  In order to achieve the target sample size, 
accrual for this trial must be 2 patients per month.  ZD6474 and placebo will be supplied by 
AstraZeneca.   The study will be conducted under an IND held by the protocol principal 
investigator, Dr. Jonas De Souza   . 
 
5.6           Interim Analyses 
 
Not applicable. 
 
5.7           Data and Safety Monitoring Board 
 
Subject enrollment, clinical response, and toxicity will be reviewed on a weekly basis during 
the  Head  and  Neck  Cancer  Data  and  Safety  Meeting.    Since  the  study  is  blinded,  an 
independent  Data and Safety Monitoring Board (DSMB) will be convened annually.   This 
board will consist of a medical oncologist and statistician who are independent of the study. 
DSMB minutes will be reported to the principal investigator, FDA, IRB, and AstraZeneca. 
The protocol will be reviewed annually by the Institutional Review Board and the Scientific 
and Accrual Committee at the University of Chicago.  An annual report to the FDA for IND 
renewal will be submitted. 
 
5.8           Study management 
 
5.8.1        Training of site personnel 
 
A data manager and research nurse will be assigned to the study.   All study procedures and 
data collection parameters will be reviewed with them.  A study database will be established 
in The University of Texas M.D. Anderson Cancer Center DMI Portal with web-based case 
report forms (CRF).  All study personnel will be required to complete and document clinical 
research training as mandated by each institution. 
 
5.8.2        Source data 
 
All data will be stored electronically in the secure The University of Texas M.D. Anderson 
Cancer Center DMI Portal.. A designated data manager will extract and enter data from source 
documents.   Data elements will include, but not be limited to, age; sex; performance status; 
prior history and therapy for cancer or preneoplasia; tobacco use and other risk factor history; 
concomitant medications; adverse events; lesion location and response; drug administration; 
date and nature of progression; incident cancers; and date and cause of death. 
 
5.8.3        Multi-center Guidelines 


 
 
 
 
 
Vandetanib (ZACTIMA™; ZD6474) 
 
 
 
5.8.3.1 
Study Documents 
 
Each participating site is responsible for submitting copies of all relevant regulatory 
documentation to the lead site.  The required documents include, but are not limited to the 
following: local IRB approvals (i.e., protocol, consent form, amendments, patient brochures 
and recruitment material, etc.) and summary of unanticipated problems or protocol deviations. 
The Coordinating Center will provide each participating site with a comprehensive list of the 
necessary documents.  It is the responsibility of the participating sites to maintain copies of all 
documentation submitted to the Coordinating Center. 
 
A completed FDA Form 1572 and investigator CVs must be received by the lead site prior to 
start of enrollment at the participating site. 
 
5.8.3.2     Data Submission Instructions for Participating Site(s) 
Investigators must record the information required by the protocol. Electronic Case Report 
Forms (CRF) will be made available for all data elements required by the study. 
 
5.8.4        Study timetable and end of study 
 
The end of the entire study is defined as “the last visit of the last subject undergoing  the 
study”.  The study is expected to start in Spring 2011 and to be completed by Spring 2013. 
AstraZeneca may terminate the study prematurely if concerns for safety arise within this study 
or in any other study involving vandetanib. 
 
6.             ETHICS 
 
6.1           Ethics Review 
 
The final study protocol, including the final version of the written Informed Consent Form, 
must be approved or given a favorable opinion in writing by an IRB. 
 
The principal investigator is responsible for informing the IRB of any amendments to the 
protocol  in  accordance  with  local  requirements.    In  addition,  the  IRB  must  approve  all 
advertising used to recruit subjects for the study.   The protocol must be re-approved by the 
IRB annually, as local regulations require. 
 
Progress  reports  and  notifications  of  serious,  unexpected  adverse  drug  reactions  will  be 
provided to the IRB according to local regulations and guidelines. 
 
The principal investigator is also responsible for providing the IRB with reports of any serious 
adverse drug reactions from any other study conducted with the investigational product. 
AstraZeneca will provide this information to the principal investigator. 
 
Any changes to the protocol will be made in the form of an amendment and must be approved 
by the IRB of each participating institution prior to implementation. 
 
 
 
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The Protocol Chair (or his/her designee) is responsible for the coordination and development 
of all protocol amendments, and will disseminate this information to the participating site(s). 
Documentation of local IRB approval must be received by the lead site within 90 days of 
distribution. 
 
6.2           Ethical Conduct of the Study 
 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration  of  Helsinki  and  are  consistent  with  ICH/Good  Clinical  Practice,  applicable 
regulatory requirements. 
 
6.3           Written Informed Consent 
 
Provision of written Informed Consent must be obtained prior to any study-related procedures. 
The principal  investigator  will ensure that the subject  is given  full and adequate  oral and 
written information about the nature, purpose, possible risk and benefit of the study.  Subjects 
must also be notified that they are free to discontinue from the study at any time.  The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. 
 
Where genetic analyses are included, special account of these will be made in the consent 
form, as it is recognized that special provisions need to be made to retain confidentiality of 
medical information.  These factors have been taken into account in the design of the consent 
form.   Consent  forms specific  for the collection  of genotyping  samples  will be used;  the 
format depends on the design of the study. 
 
The subject’s signed and dated informed consent(s) must be obtained before conducting any 
procedure  specifically  for the study.   The principal  investigator(s)  must store the original, 
signed  written  Informed  Consent  Form(s.)    A  copy  of  signed  written  Informed  Consent 
Form(s) must be given to the subject. 
 
If modifications are made according to local requirements, the new version has to be approved 
by AstraZeneca. 
 
6.4           Subject Data Protection 
 
In accordance with the Health Information Portability and Accountability Act (HIPAA), the 
written Informed Consent Form must include a subject authorization to release medical 
information to AstraZeneca and/or allow AstraZeneca, a regulatory authority, or Institutional 
Review  Board  access  to  subject’s  medical  information  that  includes  all  hospital  records 
relevant to the study, including subjects’ medical history. 
 
7.             EMERGENCY PROCEDURES 
 
7.1           Procedures in Case of Pregnancy 
 
 
 
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Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational   product   under  study  may  have  interfered   with  the  effectiveness   of  a 
contraceptive  medication.     However,  the outcome  of all pregnancies  (spontaneous 
miscarriage, elective termination, normal birth or congenital abnormality) must be followed 
up and documented even if the subject was discontinued from the study.   Should pregnancy 
occur during a female subject’s trial participation, the female subject will immediately be 
discontinued from the trial and followed-up per protocol. 
 
All reports  of congenital  abnormalities/birth  defects  are SAEs.   Spontaneous  miscarriages 
should  also  be  reported  and  handled  as  SAEs.    Elective  abortions  without  complications 
should not be handled as AEs.  All outcomes of pregnancy must be followed-up, documented 
and reported to AstraZeneca.  The site will complete and forward to AstraZeneca their site- 
specific pregnancy form.  The following information must be reported to AstraZeneca: 
 
• 
DOB, Occupation 
• 
Relevant medical history (pregnancy risk factors, smoking alcohol, etc.) 
• 
Relevant family history 
• 
Previous pregnancies (overall number, deliveries, spontaneous miscarriage, etc) 
• 
Current pregnancy (LMP, expected delivery date, any amniocentesis, chorionic villus 
sampling, in-vitro fertilization) 
• 
Concomitant  medications  taken  during  pregnancy  (name,  total  daily  dose,  therapy 
duration, indication) 
• 
Outcome  of  pregnancy  (i.e.,  full-term,  premature  birth,  spontaneous  miscarriage, 
elective termination.   If premature birth, specify gestational age in weeks.  If elective 
abortion, specify if any medical reason.) 
• 
Details   of  birth  (i.e.,  DOB,  weight,   sex,  healthy  baby,  sick  baby,   congenital 
anomaly/birth defect, still birth, multiple births, sickness manifestations, etc.) 
• 
Any complications, infections, illness during pregnancy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.             REFERENCES 
 
1.        Lippman SM, Hong WK. Second malignant tumors in head and neck squamous cell 
carcinoma: the overshadowing threat for patients with early-stage disease. Int J Radiat Oncol 
Biol Phys. 1989;17:691-4. 
2.         Rennemo E, Zatterstrom U, Boysen M. Impact of second primary tumors on survival 
in head and neck cancer: an analysis of 2,063 cases. Laryngoscope. 2008;118:1350-6. 
3.         Kelloff GJ, Lippman SM, Dannenberg  AJ, Sigman CC, Pearce HL, Reid BJ, et al. 
Progress in chemoprevention drug development: the promise of molecular biomarkers for 
prevention of intraepithelial neoplasia and cancer--a plan to move forward. Clin Cancer Res. 
2006;12:3661-97. 
4.         Wrangle JM, Khuri FR. Chemoprevention of squamous cell carcinoma of the head and 
neck. Curr Opin Oncol. 2007;19:180-7. 
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Appendix A 
Medications Known To Induce Torsades De Pointes (TDP) 
 
 
MEDICATIONS KNOWN TO PROLONG THE QT INTERVAL AND/OR 
INDUCE TORSADES DE POINTES (TDP) 
 
Appendix A updated 19 August 2011 
 
It has been recognized for a number of years that certain prescription medications can prolong 
the QT/QTc interval and cause a form of acquired Long QT syndrome, known as drug 
induced LQTS.  The drugs that prolong the QT interval and/or have a risk of inducing 
Torsades de Pointes (TdP) are listed below.  We have divided these into two groups based on 
their known or perceived risk of causing TdP: 
 
Group 1. Drugs that are generally accepted by authorities to have a risk of causing 
Torsades de Pointes 
 
Concomitant use of these drugs is not allowed during the study or within 2 weeks of 
randomization (at least four weeks for levomethadyl).  These drugs should also be avoided for 
up to 4 weeks following discontinuation of study treatment: 
 
Table 1 
Group 1 Drugs 
 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
 
Amiodarone 
Anti-arrhythmic / abnormal 
heart rhythm 
Arsenic trioxide 
Anti-cancer / Leukemia 
 
TdP risk regarded as low 
 
Astemizole 
Antihistamine / Allergic rhinitis 
No Longer available in U.S. 
Bepridil 
Anti-anginal / heart pain 
Chloroquine 
Anti-malarial / malaria infection 
Chlorpromazine 
Anti-psychotic/ Anti-emetic / 
schizophrenia/ nausea 
Cisapride 
GI stimulant / heartburn 
Restricted availability 
Clarithromycin 
Antibiotic / bacterial infection 
 
Disopyramide 
Anti-arrhythmic / abnormal 
heart rhythm 
Dofetilide 
Anti-arrhythmic / abnormal 
heart rhythm 
Domperidone 
Anti-nausea / nausea 
Not available in the U.S. 
Droperidol 
Sedative; Anti-nausea / 
anesthesia adjunct, nausea 


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Table 1 
Group 1 Drugs 
 
Drug (Generic Names) 
Drug Class (Clinical Usage) 
Comments 
Erythromycin 
Antibiotic; GI stimulant / 
bacterial infection; increase GI 
motility 
Halofantrine 
Anti-malarial / malaria infection 
Haloperidol 
Anti-psychotic / schizophrenia, 
agitation 
When given intravenously or at 
higher-than- recommended 
doses, risk of sudden death, QT 
prolongation and torsades 
increases. 
Ibutilide 
Anti-arrhythmic / abnormal 
heart rhythm 
Levomethadyl 
Opiate agonist / pain control, 
narcotic dependence 
Mesoridazine 
Anti-psychotic / schizophrenia 
Methadone 
Opiate agonist / pain control, 
narcotic dependence 
Moxifloxacin 
Antibiotic / bacterial infection 
Pentamidine 
Anti-infective / pneumocystis 
pneumonia 
Pimozide 
Anti-psychotic / Tourette's tics 
Probucol 
Antilipemic / 
Hypercholesterolemia 
No longer available in U.S. 
Procainamide 
Anti-arrhythmic / abnormal 
heart rhythm 
Quinidine 
Anti-arrhythmic / abnormal 
heart rhythm 
Sotalol 
Anti-arrhythmic / abnormal 
heart rhythm 
Sparfloxacin 
Antibiotic / bacterial infection 
Terfenadine 
Antihistamine / Allergic rhinitis 
No longer available in U.S. 
Thioridazine 
Anti-psychotic / schizophrenia 
Vandetanib (*Does not apply to 
this study) 
Anti-cancer / Thyroid cancer 
"Zactima®" is the proposed 
brand name 
Source: www.QTdrugs.org 


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Group 2. Drugs that in some reports may be associated with Torsades de Pointes but at 
this time lack substantial evidence of causing Torsades de Pointes. 
Concomitant use of these drugs is not allowed within 2 weeks of randomization or during the 
study.  These drugs will be allowed during the study, at the discretion of the Investigator, if 
considered absolutely necessary.  In such cases, the patient must be closely monitored, 
including regular checks of QTc and electrolytes (reference section 5.6.2 of the protocol). 
 
Table 2 
Group 2 Drugs 
 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Alfuzosin 
Alpha1-blocker / Benign 
prostatic hyperplasia 
Amantadine 
Dopaminergic/Anti-viral / Anti- 
infective/ Parkinson's Disease 
Atazanavir 
Protease inhibitor / HIV 
Azithromycin 
Antibiotic / bacterial infection 
Chloral hydrate 
Sedative / sedation/ insomnia 
Clozapine 
Anti-psychotic / schizophrenia 
Dolasetron 
Anti-nausea / nausea, vomiting 
Dronedarone 
Anti-arrhythmic / Atrial 
Fibrillation 
Escitalopram 
Anti-depressant / Major 
depression/ Anxiety disorders 
Famotidine 
H2-receptor antagonist / Peptic 
ulcer/ GERD 
Felbamate 
Anti-convulsant / seizure 
Flecainide 
Anti-arrhythmic / abnormal 
heart rhythm 
Foscarnet 
Anti-viral / HIV infection 
Fosphenytoin 
Anti-convulsant / seizure 
Gatifloxacin 
Antibiotic / bacterial infection 
Gemifloxacin 
Antibiotic / bacterial infection 
Granisetron 
Anti-nausea / nausea and 
vomiting 
Indapamide 
Diuretic / stimulate urine & salt 
loss 
Isradipine 
Anti-hypertensive / high blood 
pressure 


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Table 2 
Group 2 Drugs 
 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Lapatinib 
Anti-cancer / breast cancer, 
metastatic 
Levofloxacin 
Antibiotic / bacterial infection 
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 and 
vomiting 
Oxytocin 
Oxytocic / Labor stimulation 
Paliperidone 
Antipsychotic, atypical / 
Schizophrenia 
Perflutren lipid microspheres 
Imaging contrast agent / 
Echocardiography 
Quetiapine 
Anti-psychotic / schizophrenia 
Ranolazine 
Anti-anginal / chronic angina 
Risperidone 
Anti-psychotic / schizophrenia 
Roxithromycin* 
Antibiotic / bacterial infection 
*not available in the United 
States 
Sertindole 
Antipsychotic, atypical / 
Anxiety, Schizophrenia 
Sunitinib 
Anti-cancer / RCC, GIST 
Tacrolimus 
Immunosuppressant / Immune 
suppression 
Tamoxifen 
Anti-cancer / breast cancer 
Telithromycin 
Antibiotic / bacterial infection 
Tizanidine 
Muscle relaxant / 
Vardenafil 
phosphodiesterase inhibitor / 
vasodilator 
Venlafaxine 
Anti-depressant / depression 


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Table 2 
Group 2 Drugs 
 
Drug (Brand Names) 
Drug Class (Clinical Usage) 
Comments 
Voriconazole 
Anti-fungal / anti-fungal 
Ziprasidone 
Anti-psychotic (schizophrenia) 
Source: www.QTdrugs.org 
 
 
Appendix B. Drug Administration Diary 
 
Site Number 
Subject Number 
Subject Initials 
Cycle 
 
 
Subject Drug Diary 
Bring your diary and study drug bottles (containing unused drug and empty bottles) to EACH appointment 
with the research nurse. 
 
Please complete the diary every day.  Write the date and time of each dose of drug you take.  If you did not 
take your daily dose, or did not take your full dose, please write down the actual amount taken.  If you 
experience any health/medical complaints, please record this information. 
 
Day 
Date 
time of dose 
# of Tablets 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
11 


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12 
13 
14 
15 
16 
Day 
17 
Date 
time of dose 
# of Tablets 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
 
Health / Medical Complaints 
 
Please describe what you experienced 
 
Date 
started 
 
Dated 
stopped 


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Other Medication 
Record only medication (prescription and/or over-the counter, including herbal medications and vitamins) 
taken other than study drug. 
Name of Medication 
Why did you take the medication? 
Date started 
Dated 
stopped 


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Appendix C 
 
New York Heart Association (NYHA) Cardiac Classification 
 
The NYHA classification system relates symptoms to everyday activities and the patient’s quality of life. 
Class 
Symptoms 
Class I (Mild) 
No limitation of physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity.  Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or dyspnea. 
Class III (Moderate) 
Marked limitation of physical activity.  Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity is undertaken, discomfort is increased. 


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Appendix D 
 
Non-Serious Adverse Event Reporting Template 


 
 
 
 
Vandetanib (ZACTIMA™; ZD6474) 
 
 
 
Patient 
Identifier 
Adverse Event 
Term 
CTC 
Grade 
Treatment (if 
required) 
Causality 
(Y or N) 
Event Became 
Serious (Y or N) 
Withdrawn 
from Study 
(Y or N) 
Additional Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix E 
 
Instructions for Dispersing Vandetanib Tablets 
 
Do not crush tablets.  Drop the number of vandetanib tablets required for a single dose into an 
appropriate container (ideally glass to help confirm removal of all the dispersed material) 
containing approximately 2 ounces (or 50 mL) of water (either drinking water, sterile water 
for injection, or purified water) at room temperature.  Stir the liquid occasionally to ensure 
complete break-up of the tablets.  When the tablets have broken up into a fine dispersion 
(approximately 10 to 15 minutes) it can be administered to the patient.  Administration to the 
patient should occur immediately after dispersion is complete whenever possible. 
 
To ensure delivery of the whole dose, rinse the container with a similar amount of water to 
ensure removal of any material adhering to the walls of the container and administer the 
additional water to the patient. 
 
Glass Contamination 
As long as the glassware is cleaned thoroughly after use, using standard washing detergent or 
in a dishwasher then the risk of glass contamination is minimal.   As an extra precaution, it 
could be suggested that the patient dedicates one glass for preparation of the oral dispersion, 
which is not used by other members of the household. 
 
Spillage 
If the oral dispersion is spilled, it should be cleaned up using plenty of water and the area 
washed with water until no residual drug remains.  If the dispersion is spilled on the skin, the 
skin should be washed with plenty of clean water.   If there is any contact with eyes, they 
should be irrigated with plenty of clean water for at least 10 minutes. 
 
Stability Summary 
Experimentation has shown that vandetanib tablets will break up into a fine dispersion within 
10 to 15 minutes when they are dropped whole into water (either drinking water, sterile water 
for injection, or purified water) at room temperature.   The dispersion should be administered 
to the patient immediately if possible.  In the event of a delay in administration, the dispersion 
is chemically stable up to 4 hours after preparation. 
 
The  data  confirms  that  aqueous  dispersal  of  vandetanib  (as  described  above)  has  no 
detrimental  effects  on  the  release  of  the  active  pharmaceutical  ingredient  (API)  when 
compared to administration of the intact tablet and that a delay of up to 4 hours between 
preparation of the dispersion and administration will not have any detrimental effect on the 
assay and degradation products or the release of API in the dispersed tablet. 
 
Effect of Variation in pH and Temperature of Water for Dispersion 
The temperature and pH of the water used to prepare the dispersed tablet may vary in the 
clinic.  The effect of pH of the water used for dispersion was evaluated over the range pH 5 – 
8.  Over this range, the pH of the water used for dispersing the tablets has no significant effect 
on the dispersion times. 


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The temperature range defined in the USP for controlled room temperature excursions that are 
experienced in hospitals is 15 °C to 30 °C.  Over this range, the temperature of the water does 
have an effect on tablet dispersion times with the tablets taking longer to disperse at lower 
temperatures.  All tablets tested dispersed within 10 minutes. 
 
Compatibility With Delivery Devices 
The dispersed tablet may be administered by nasogastric tube or gastrostomy tube.  To ensure 
that the dose is not affected by the method of delivery, the vandetanib content and degradation 
products were determined after the dispersion had been passed through the delivery tube.  See 
Table1  for details of the feeding tubes tested. 
 
 
 
 
 
 
 
Table 1 
Feeding tube equipment tested 
Tube 
No 
Feeding 
tube type 
Product details 
Product 
Code 
Lot No 
1 
Nasogastric 
Flocare  nasointestinal  feeding  tube   from 
Nutricia (CH10). (PD Ref. P/4163/07) 
35231 
200509353 
2 
Gastrostomy 
Flocare PEG set from Nutricia (CH14).  (PD 
Ref. P/4163/08) 
35428 
200506132 
3 
Nasogastric 
CORFLO 
Controller 
PILL-NG 
enteral 
feeding tube from Viasys (10FR).  (PD Ref. 
P/4163/011) 
20-2551 
18864 
 
No significant difference was observed between the delivered dose obtained for the feeding 
tubes and the content of vandetanib in the control sample, indicating that the patient should 
receive the full dose when the dispersed tablet is administered using a feeding tube. 
 
For  the  assay  and  degradation  products  results,  no  significant  difference  was  observed 
between  the  results  obtained  for  the  feeding  tubes  and  those  obtained  for  intact  tablets 
indicating that there are no compatibility issues with any of the tubes. 
 
The  administration  method  and  any  change  in  that  method  must  be  recorded  on  the 
appropriate CRF.