Clinical trial NCT01934335
Conditions: Invasive Breast Cancer
Keywords: breast cancer, TKI, tyrosine kinase inhibitor, vandetanib, Ki-67
Sponsor: Ronald Weigel
Start date: 2013-10-01; Completion date: 2018-12-21
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this project is to examine whether treatment with vandetanib has an effect on the tumor cells in breast cancer by examining tissue markers.

Detailed description:
The purpose of this research study is to test whether vandetanib has an effect on tumor growth markers. Vandetanib is not approved by the FDA for use in treating breast cancer. This study will compare vandetanib to a placebo.

The proposed study is designed to determine the change in Ki-67 expression on paired breast cancer samples obtained before and after treatment with vandetanib. Other tumor markers including RET, TUNEL and phosphorylation specific levels of ERK1/2, AKT and mTOR will also be assessed on the paired samples.

Those who have a core biopsy of the breast which demonstrates invasive breast cancer and requires surgical excision of the lesion will be eligible for inclusion in the study. The tyrosine kinase inhibitor, vandetanib 300 mg, will be given once a day for 7-14 days prior to surgery. Following surgery, tissue markers would be analyzed on each of the paired samples, allowing for rapid assessment of in vivo response to TKI treatment.

Arms: arm 1: Vandetanib, 300 mg, PO, q day for 7-14 days prior to surgery arm 2: Placebo, PO, q day for 7-14 days prior to surgery.
Interventions: intervention 1: Vandetanib intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
A Randomized, Double-Blind, Placebo-Controlled Trial Investigating the 
Effect of Vandetanib on Cellular Markers of Proliferation and Apoptosis in 
Invasive Breast Cancer  
 
 
Principal Investigator 
Ronald J. Weigel, MD, PhD 
EA Crowell Jr Professor and Head 
Department of Surgery 
1509 JCP 
Phone: 319-353-7474 
Fax: 319-356-8378 
ronald-weigel@uiowa.edu 
 
 
 
 
Co-Investigators 
Lillian Erdahl, MD  Department of Surgery 
Sonia Sugg, MD  Department of Surgery 
Ingrid Lizarraga, MD  Department of Surgery 
Mark Karwal, MD  Department of Internal Medicine 
Amani Bashir, MD  Department of Pathology 
 
 
Biostatistician 
Gideon Zamba, Ph.D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Version: 7  Date: 4/5/2017 
 
 


2 
 
 
TABLE OF CONTENTS  
 
 
Page 
1.   Introduction/Background…………...……………………………….….. 
4 
     1.1   Breast Cancer Background………………………………………………….. 
4 
     1.2   Tyrosine Kinase Inhibitor Background……………………………………… 
4 
     1.3   Rationale of Proposed Trial………………………………………………….. 
4 
2.   Study Objectives……………..……………….……….............................. 
6 
3.   On-Study Guidelines………………………………………………..…… 
6 
4.   Eligibility Criteria/Definition………………………………………..….. 
6 
     4.1   Eligibility Criteria………………………………………………………..….. 
6 
        4.1.1.   Inclusion Criteria………………………………………………………. 
6 
        4.1.2   Exclusion Criteria………………………………………………………. 
6 
     4.2   Inclusion of Minorities………………………………………....................... 
7 
     4.3   Sample Size Determination………………………………………………… 
7 
     4.4   Informed Consent…………………………………………………………... 
     4.5   Contacting Subjects for Consent…………………………………………… 
8 
8 
5.   Schedule of Assessments and Procedures…………………….….……. 
8 
6.   Treatment Plan……………………….…………………………..…….. 
9 
7.   Drug Formulation, Availability and Preparation…………………..... 
9 
8.   Ancillary Therapy………………………………..……………….……. 
10 
9.   Criteria for Response………………………………………………..…. 
11 
10.  Removal of Subjects from Protocol Therapy………………...…..….. 
11 
11.  Data Management, Quality Control and Data Security.……………. 
12 
      11.1   Data and Safety Monitoring …………………………………….………. 
12 
      11.2   Adverse Events……………………………………………………….…. 
12 
12.  Statistical Analysis………………………………………..……………. 
17 
13.  References…………………………………………………………….... 
19 
      Appendices……………………………………………………..…..…….      21 
 
 
 
 
 
 
 
 


3 
 
 
Figure 1: Study Design 
 
 
 
Core tissue Biopsy 
Diagnosis of Invasive Breast Carcinoma 
Identify eligible invasive breast cancer at the time of 
clinic visit scheduling 
Pre-op clinic visit, pretreatment labs and EKG, 
informed consent 
Oral Vandetanib, 300 
mg PO daily, for 7-14 
days prior to surgery 
Placebo, PO daily 
for 7-14 days prior 
to surgery 
Surgical Resection 
Paired baseline and endpoint samples for analysis 
Patient given drug or placebo in randomized 
packages according to order of enrollment 
Post-treatment labs and EKG, toxicity 
assessment, drug calendar review and pill count 


4 
 
 
1.0   Introduction 
 
1.1 Breast Cancer Background 
In 2012, an estimated 227,000 women in the US were expected to be diagnosed with invasive breast cancer, 
with breast cancer remaining second only to lung cancer as the most common cause of cancer related death in 
women [1].  Diagnosis is made by core needle biopsy of a palpable mass or abnormality on mammogram.  
Definitive treatment consists of surgical resection with staging of the axilla.  Chemotherapy is reserved for 
advanced cases and can be administered in the adjuvant or neoadjuvant setting.  Patients with estrogen receptor 
positive breast cancer have relatively worse neoadjuvant specific outcomes in terms of clinical and pathologic 
response compared to other types of breast cancer, making this an important group for receptor targeted therapy 
[2]. 
1. 2 Tyrosine Kinase Inhibitor Background 
The receptor tyrosine kinases (RTK) are a family of molecules involved in receiving hormonal and chemokine 
signals and starting signal transduction pathways often involved in growth, cell survival, and proliferation.  
Activating mutations of RTK’s have been identified in a wide variety of cancers including gastrointestinal 
stromal tumors (GIST), chronic myelogenous leukemia (CML) and medullary thyroid cancer (MTC), among 
others.  Tyrosine kinase inhibitor (TKI) therapy has provided promising new targeted treatments for cancers 
driven by RTK activation. 
 
The tyrosine kinase expression profile of breast cancers is a relatively new field.  Since bevacizumab was 
developed, study of tyrosine kinase inhibition has focused on VEGFR antagonism and EGFR. More recently, 
expression of RET has been discovered in breast cancers with an association with estrogen receptor expression 
[3-6].  Mutations of the RET proto-oncogene are well described in MTC and the multiple endocrine neoplasia 
(MEN) 2 syndromes.  Trials have been conducted in breast cancer with multiple TKI’s without significant 
efficacy [7, 8].  However, these trials have focused primarily on ER negative cancers which express low levels 
of RET relative to estrogen receptor positive tumors, and metastatic tumors which are more likely to be ER 
negative.   
 
In vitro, blocking RET activation, either by reducing protein levels, or with pharmacologic inhibition, leads to 
decreased activation of cellular mediators of proliferation and growth including ERK1/2 and AKT [9, 10].  
Further it has been shown that inhibiting RET activation can restore sensitivity to Tamoxifen, prevent 
Tamoxifen resistance, and decrease cell proliferation in an ER and RET expressing breast cancer cell line [6].  
Further, RET expression is a negative prognostic indicator in breast cancer [11].  We hypothesize that 
Vandetanib will be more efficacious in treating RET expressing breast cancers compared to breast cancers 
expressing lower levels of RET.  Although there is a subset of ER-negative RET expressing tumors, most 
expression is associated with ER, making that the most likely phenotype to benefit from RET  antagonist 
therapy.   
 
 
1.3 Rationale of Proposed Trial 
Our unpublished data show that in vitro activation of RET by its ligand, GDNF, leads to phosphorylation of 
ERK1/2 and AKT and leads to an increase in proliferation.  Pharmacologic inhibition with Sunitinib, a small 
molecule tyrosine kinase inhibitor with activity against RET, abrogates GDNF/RET dependent ERK1/2 and 
AKT activation.  Further it results in decreased proliferation, which FACS analysis for Ki-67 and cleaved 
caspase 3 demonstrate is the result of a modest reduction in proliferation and a large induction of apoptosis.  
Oral treatment with Sunitinib reduces human luminal breast cancer tumorigenesis in a xenograft model and 
immunohistochemistry analysis demonstrates a similar effect of a small reduction in Ki-67 positivity with a 
large induction of apoptosis.  Vandetanib, another TKI with higher activity on RET than Sunitinib, similarly 


5 
 
 
reduces tumorigenesis and slows growth of previously formed xenograft tumors.  Additionally, effects on 
proliferation are additive when combined with tamoxifen treatment, with the additional effect of inducing 
apoptosis compared to Tamoxifen treatment alone, indicated a separation of pathways and a role for 
combination therapy.  In fact, treatment with the antiestrogen fulvestrant has been shown enhance Vandetanib 
effects in non-small cell lung cancer indicating a role for TKI and antiestrogen dual treatment to prevent 
pathway cross talk [12].  To corroborate these data in primary tumors we have obtained tissue samples and have 
shown that TKI treatment can decrease activated ERK1/2 in primary breast cancers with an increased effect in 
ER positive tumors.  Our further study will include determining a more specific receptor expression profile that 
will predict TKI responsiveness (Unpublished data). 
 
In the proposed trial women will be offered enrollment after core breast biopsy demonstrates invasive breast 
cancer, for which subsequent surgical resection typically occurs several weeks after the initial biopsy.  Patients 
will be evaluated in the surgery clinic per normal protocol and if eligible and consenting enrolled in this trial.  
They will proceed with the normal course of treatment, with the only modification due to study enrollment 
being randomization to take either Vandetanib, 300 mg by mouth once daily, or placebo for 7 to 14 days prior to 
surgery.  Paired baseline (diagnostic core biopsy) and endpoint tumor samples (surgical resection) will then be 
available for analysis.  Randomization and blinding protocol is described in section 7.0. 
 
Tissue markers would be analyzed on each of these samples allowing for rapid assessment of in vivo response to 
TKI treatment.  In this initial evaluation, tissue levels of RET, Ki-67, TUNEL, phosphorylation specific levels 
of ERK1/2, AKT, and mTOR will be assessed.  This will provide information on the primary endpoint of down 
regulation of Ki-67 expression.  Additionally, proliferation and apoptosis markers were selected to assess the in 
vivo impact of TKI treatment on these carcinogenic mechanisms.  Ki-67, a proliferation gene is weighted 
heavily in the multi-gene assay described by Paik et al which is used with increasing frequency clinically [13].  
TUNEL is an apoptosis marker.  Our pre-clinical studies indicate an effect of tyrosine kinase inhibition on both 
Ki-67 and TUNEL in luminal breast cancer. 
 
Evaluation of paired tumor samples following a brief treatment course has been described in multiple studies 
and is appealing for several reasons.[14-18]  Trials using mortality or disease progression as endpoints often 
require long follow-up, large study enrollment and significant resources.  The proposed design, in contrast, 
permits relatively rapid evaluation of a drug’s in vivo mechanism of action and impact.  Promising agents could 
then be studied in larger, longer term trials.  Paired baseline-to-endpoint samples can also be analyzed for their 
impact on individual patients and smaller subgroups.  Evaluation of these subgroups and comparison with their 
counterparts might provide biochemical clues to support these observations.  Tissue samples may be saved and 
used for subsequent unplanned analysis, should other studies support reevaluation using different markers.  
Finally, patients enrolled in this study would not need additional invasive procedures, as these samples will be 
obtained as part of standard treatment for invasive breast cancer. 
 
The treatment dose will be Vandetanib 300 mg orally, one time each day.  Currently, the FDA has approved 300 
mg orally for treatment of medullary thyroid cancer, which also has been determined to be a safe dose in breast 
cancer [19].  Vandetanib, at this dose, was selected to demonstrate tumor change in the brief interval between 
diagnostic biopsy and surgical resection.  AstraZeneca has agreed to provide Vandetanib and placebo at no cost 
for this trial. 
 
 


6 
 
 
 
2.0   Study Objectives 
2.1 
Determine the change in Ki-67 expression on paired samples obtained before and after 
Vandetanib treatment. 
2.2 
Compare TUNEL levels and phosphorylation specific levels of ERK1/2, AKT, and mTOR levels 
in paired samples obtained before and after Vandetanib treatment. 
2.3 
Evaluate any differences in analyses 2.1 and 2.2 based on level of RET expression as well as 
between ER-positive and ER-negative tumors. 
 
 
3.0    On-Study Guidelines 
This clinical trial can fulfill its objectives only if patients appropriate for the trial are enrolled.  All 
relevant medical and other considerations should be taken into account when deciding whether this 
protocol is appropriate for a particular patient.  Physicians should consider the risks and benefits of any 
therapy and, therefore, only enroll patients for which the agents administered are appropriate.  Although 
they will not be considered as formal eligibility criteria, as part of this decision-making process physicians 
should recognize that the following may increase the risk to the patient entering this protocol: 
3.0.1 A psychiatric condition which would prevent compliance with treatment or informed consent. 
3.0.2 Liver disease, diabetes, pulmonary disease, or infection, which in the opinion of the treating 
physician would make this protocol treatment unreasonably hazardous for the patient. 
3.0.3 Patients with a “currently active” second malignancy other than non-melanoma skin cancers.  
Patients are not considered to have a “currently active” malignancy if they have completed 
therapy and considered by their physician to be at less than 30% risk of relapse within one year. 
3.0.4 Patients who have received any investigational agent within the prior 4 weeks. 
 
4.0  Eligibility Criteria:/Definitions of Disease: 
4.0.1. Patients with core breast biopsy that, on pathology review, demonstrates invasive breast cancer 
and are determined to need surgical excision of the lesion.  All subtypes of invasive breast cancer will be 
enrolled.  Core biopsy specimens of enrolled patients will be stained for RET by immunohistochemistry 
and scored, however, patients will not be excluded according to RET expression. 
 
4.1  Eligibility Criteria: 
4.1.1  Inclusion Criteria  
 Female gender.  There is an incidence of male breast cancer, but it is unclear if the etiology is the same 
and inclusion of males could confound results. 
 Age ≥ 18.  Breast cancer, while not restricted only to adult women, is rare in the younger population. 
 ECOG performance status ≤ 2. 
 Life expectancy of greater than 6 months. 
 Ability and willingness to provide informed consent to participate in this study. 
 
4.1.2  Exclusion Criteria 
 Prolonged QT interval (QTc > 480 milliseconds) on screening EKG or congenital long QT syndrome 
 Any concomitant medications that are known to be associated with Torsades de Pointes or QT 
elongation (see appendix 2). 
 Hypertension not controlled by medical therapy (systolic BP greater than 160 millimeters of mercury 
[mmHg] or diastolic blood pressure great than 100 mmHg). 
 Patients taking metformin or digoxin. 


7 
 
 
 History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular 
tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or 
uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. 
Patients with atrial fibrillation controlled by medication are permitted. 
 Significant cardiac event (e.g., myocardial infarction), superior vena cava syndrome, New York Heart 
Association (NYHA) classification of heart disease ≥2 within 12 weeks, or presence of cardiac disease 
that in the opinion of the Investigator increases the risk of ventricular arrhythmia. 
 Serum calcium or magnesium outside the institutional range of normal. 
 Serum Potassium < 4.0 mmol/L or above 5.0 mmol/L 
 Creatinine clearance < 50 ml/min 
 PT > 12 seconds or PTT > 31 seconds 
 Platelet count of < 100,000 
 Serum bilirubin greater than 1.5 mg/dl 
 Alanine aminotransferase (ALT) > 50 U/L, aspartate aminotransferase (AST) > 65 U/L, or alkaline 
phosphatase (ALP) > 250 U/L 
 Any cytotoxic treatments, such as neoadjuvant chemotherapy, planned before subsequent surgical 
procedure.  
 Previous exposure to Vandetanib 
 Previous enrollment or randomization in this study 
 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and staff at 
UIHC). 
 Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ 
carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin. 
 Patients who have received prior surgical site radiation. 
 Patients on CYP3A4 inhibitors or inducers (see appendix 1). 
 Inability to test core biopsy for study markers 
 Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 2 
weeks prior to randomization according to institutional standards for women of childbearing 
potential.) 
 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, be enrolled or 
receive study medication.  There can be no exceptions to this rule. 
 
Where patients that do not meet the inclusion criteria are enrolled in error or incorrectly started on treatment, or 
where patients subsequently fail to meet the study criteria post initiation, the Investigator should inform the 
Study Physician, Dr. Weigel, immediately. 
 
4.2  Inclusion of Minorities 
Although there is no evidence to suggest that the outcome will differ by ethnicity and there is insufficient power to detect 
small or moderate effects, we will, in a secondary analysis, report the results by ethnicity. 
 
4.3  Sample Size  
This study will aim to accrue a total of 40 subjects with invasive breast cancer into both the placebo and 
treatment arms (80 patients in total).  The diagnosis will be based on histopathological evidence.  The number 
of subjects was chosen based on the estimated ability to provide meaningful information on breast cancer.  For 
discussion of statistics and power analyses, please see Section 12. 
 
 


8 
 
 
 
4.4   Informed Consent 
Signed informed consent for enrollment in this protocol will be obtained from eligible subjects by a member of 
the research team before the start of the study.  Subjects will be fully informed of the purpose and potential risks 
and benefits of participating in the study.  Subjects will have the opportunity to have questions answered to their 
satisfaction before signing the consent.  
 
4.5   Contacting Subjects for Consent 
Patients will be identified for potential study enrollment at the time they are scheduled for a surgery clinic visit 
for a preoperative evaluation for invasive breast cancer.   The study will be reviewed and patients enrolled at the 
time of their preoperative visit.  Some patients will be seen in clinic before they receive the information 
regarding the study.  These patients will be given the opportunity to participate and will have a study related 
discussion at their clinic visit.  All patients seen in breast surgery clinic will be screened by the providing 
surgeon for potential involvement in this study. 
 
5.0 
Schedule of Assessments and Procedures 
 
Baseline (Pre-
operative clinic 
visit)  
Day 
7-14 
 
Post-Treatment 
safety 
assessment visit 
(Day 13 or 14) 
Post-treatment 
sample 
Follow-up 
visit POD 
7-14 
Tests & Observations 
 
 
History 
X 
 
 
 
X 
Age/ECOG PS 
X 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
Pulse, Blood Pressure 
X 
 
X 
 
X 
Weight/Height 
X 
 
 
 
 
Drug Toxicity Evaluation 
 
X 
X 
 
X 
Study Drug Calendar 
 
X 
X 
 
 
EKG 
X 
 
X 
 
 
Pregnancy test within 2weeks of 
treatment (urine or serum) 
X 
 
 
 
 
Laboratory Studies 
 
 
 
 
 
Ca, Mg, K, Cr, PT, PTT, 
Bilirubin, AST, ALT, Alk 
Phos, CBC 
 
X 
 
 
 
 
Ca, Mg, K, platelets 
 
 
X 
 
 
Treatment 
 
 
 
 
 
Placebo/Vandetanib 300 
mg daily 
 
X 
 
 
 
 
 
 
 
 
 
Staging Evaluations 
 
 
 
 
 
Pathologic Tumor Size 
 
 
 
X 
 
Histology 
X 
 
 
X 
 
Tumor markers1 
X 
 
 
X 
 
Elston-Ellis Grade2 
X 
 
 
X 
 
Lymph node status3 
X  
 (CLINICAL) 
 
 
X 
(PATHOLOGIC) 
 
 


9 
 
 
Note: Staging determinants can be obtained on the baseline or post-treatment sample.  They do not need to be 
obtained on both, but should reflect the final conclusions of the pathologist.  
1 Tumor markers are Estrogen Receptor, Progesterone Receptor and Her2/neu.  See Section 9.2. 
2 Eliston-Ellis Grade is a pathological term for tumor aggression. 
3 Lymph node status will be recorded in accordance with preoperative (clinical) and postoperative (pathologic) 
staging. 
 
6.0 
Treatment Plan 
Subjects meeting the eligibility requirements in Section 4.1 and who have given signed informed consent will 
start the treatment dose of Vandetanib 300 mg or placebo orally, daily, starting such time as to allow 7 to14 
doses with the 7th or 14th dose given on the morning of the operation.  Patients will return to clinic the day 
before the scheduled operation or the morning of surgery for repeat laboratory studies and EKG.  Costs of the 
post-treatment labs and EKG will be covered by the PI.  The results will be reviewed and safety to proceed 
documented prior to the operation.  The study calendar (which will be provided at the pretreatment office visit 
to document administration of the study drug and any side effects associated with treatment) will be reviewed, 
pill counts performed, and an adverse events assessment performed at that time.  Any concerns related to 
toxicities and safety to proceed to surgery will be addressed with the attending surgeon at that time.  Common 
induction anesthetics (isoflurane, desflurane and sevoflurane) can cause QTc prolongation.  Any QTc (>440 ms) 
on EKG should be discussed with the attending anesthesiologist prior to induction, and these induction agents 
should not be used if QTc > 480 ms.  A flow chart of the preoperative screening procedure is shown in appendix 
3.  Subjects will be instructed to take their medication at the same time each day.  In general subjects should take 
their dose every day even if it is not at the recommended time.  Specific questions regarding timing and doses can be 
directed to Dr Weigel (319-353-7474, pager 1529).  Patients will be removed from the study for failure to take at 
least 80% of the study doses.  Patients will not be replaced if they are removed from the trial. 
 
Women of Childbearing Potential (WOCBP) must use highly effective methods of birth control (one method or a 
combination of methods that results in a less than 1% failure rate per year) throughout therapy and must maintain 
full contraception for at least 95 days after the last dose of Vandetanib.   
 
7.0 
Drug Formulation, Availability and Preparation 
7.1  
Vandetanib 
Availability 
AstraZeneca Pharmaceuticals Investigational Products will pack, label, and supply the investigational product 
(IP) for this study.  Tablets will be packed into white high-density polythene bottles with child resistant, tamper 
evident closures.  Study drug must be kept out of the reach of children.  Each bottle will contain 100 tablets.  
Patients will be supplied with sufficient amounts of tablets at each dispensing visit plus overage (2 week supply 
with 2 additional doses).  Drug and placebo will be sent to the Investigational Drug Service (IDS) in the 
Department of Pharmaceutical Care at the University of Iowa.  The IDS will perform randomization using 
randomization.com and provide identical packages of drug or placebo for distribution by the pharmacist in the 
cancer center.  Randomization will not be stratified and will be performed in groups of eight patients and for the 
entire cohort.  Packages will be sequentially numbered and distributed as patients are enrolled, such that when a 
patient is enrolled they will be given the lowest numbered package remaining.  Package number and patient 
identification number will be recorded in the study database, and the package key will held by the IDS and 
released to the investigator on completion of the trial. 
 
Vandetanib tablets must be taken whole or dispersed in water, without crushing.  If tablets cannot be taken 
whole, the tablets can be dispersed in a glass containing 60 mL of non-carbonated water and stirred for 
approximately 10 minutes until the tablets are dispersed (will not completely dissolve).  No other liquids should 
be used.  The mixture should be swallowed immediately.  To ensure the full dose is received, the patient should 
refill the glass with an additional half glass of water and mix with any remaining drug and drink it. 


10 
 
 
There are no food restrictions for the administration of Vandetanib tablets.  Vandetanib tablets should be taken 
in the morning at about the same time each day with a glass of water. 
The first dose of Vandetanib tablets will be taken only after all the assessments assigned have been performed.  
Patients should take study drug in the morning.  If a patient inadvertently misses a dose and the next dose is in 
12 hours or more, the patient should take the missed dose immediately and the next dose at the normal time.  If 
it is less than 12 hours before the next dose, the patient should take the next dose at the normal time and the 
missed dose should not be taken.  The missed dose must be documented in the CRF, where appropriate, with a 
comment indicating the patient missed the dose.  The dose of study treatment may be repeated if vomiting 
occurs within 30 minutes of taking the study treatment.  If vomiting occurs after 30 minutes of taking the study 
treatment, the dose will not be repeated. 
 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local regulatory 
guidelines.  The labels will fulfill GMP Annex 13 requirements for labeling. 
Information on the bottle labels for Vandetanib will indicate the study number, contents, caution, and storage 
conditions and will have blank spaces for the patient number, visit number, and dispensing date (to be written in 
by the site personnel at the center at the time of dispensing).  Instruction that study drug should be taken as 
directed will be included on the label.  Patients will be supplied with a study participation card where the dosing 
instruction will be described for a patient by Investigator or delegate.  All study drugs should be kept in a secure 
place under appropriate storage conditions 
 
 
Administration 
Subjects will be asked to take Vandetanib as a single oral daily dose of 300 mg or placebo.  Patients will 
discontinue the drug and be removed from the study for toxicity.  A patient may withdraw from the study at any 
time for any reason without prejudice for future treatment.  Patients will be removed from the study for failure 
to comply with greater than 80% of scheduled doses. 
 
Toxicity 
The major toxicities of Vandetanib are nausea/vomiting/diarrhea, hypertension, thrombocytopenia, prolonged 
QT interval, Torsades de pointes, and ventricular tachycardia.  The patients will be carefully screened for any 
conduction abnormalities, arrhythmia, electrolyte/coagulation/platelet abnormalities, and medications in 
Appendix 2 associated with QT prolongation.  The short duration of treatment, two weeks, should limit toxicity.  
Detailed description of toxicities is provided in sections 11.2.3 and 11.2.4. 
 
 
 
8.0 
Ancillary Therapy 
Because Vandetanib is metabolized by P450 CYP3A4 enzyme, drugs that affect metabolism by this enzyme 
may alter Vandetanib levels and enhance toxicity.  Agents that inhibit CYP3A4 include:  erythromycin, 
cyclosporine, fluconazole, itraconazole, ketoconazole, and grapefruit juice.  For these reasons these drugs and 
foods should be avoided, if at all possible, during the Vandetanib treatment.  See List of CYP3A4 inhibitors in 
Appendix 1.  Vandetanib can also cause prolongation of the QTc and Torsades de Pointes.  Medications that 
cause prolonged QTc are listed in Appendix 2 and should be avoided while on study, and patients will be 
excluded if they take any of the listed medications.  Patients will also be instructed to avoid initiation of any of 
these compounds while on study. Concomitant medications will be reviewed at the time of study entry and at 
the time of scheduled assessments and procedure, to assess use of agents to avoid, but ongoing documentation is 
not required in this study.  
 
9.0 
Criteria for Response 
The primary study end point will be down regulation of proliferative index measured by Ki-67 expression.   


11 
 
 
 
 
9.1 
Ki-67 
Tissue samples from the paired baseline and endpoint samples will be sent to the Histology Research 
Laboratory and percentage of cells expressing K-67 will be determined by immunohistochemical staining.  The 
FFPE tissue blocks from core biopsies performed at other hospitals will be obtained and analysis for study data 
points will be performed and interpreted in the pathology laboratory at UIHC.   
 
9.2. 
Other tumor markers 
ER, PR, and HER2 levels will be assessed per normal procedure by the department of pathology, which is 
standard of care for the diagnosis and treatment of breast cancer.  RET, TUNEL, and phosphorylation specific 
levels of ERK1/2, AKT, and mTOR will also be assessed on the paired samples using immunohistochemical 
staining.  If alternative assays are found to be more effective at evaluating the levels of these markers in the 
paired samples, they could be employed on these tissue samples as well.  All costs of analysis not considered 
standard of care will be covered by the PI.  Laboratory testing will be performed in the department of pathology 
histology lab 5225 RCP.  Cost for assays will be covered by the PI through a HCC MOG grant.  All specimens 
will be processed in the histology lab per standard of care with formalin fixation and paraffin embedding 
followed by routine clinical testing (ER, PR, HER2).   
 
9.3  
Follow-up Post Surgery 
After surgery, the subject will return to clinic for a post-operative visit.  This will involve a final drug toxicity 
evaluation.  This is also the standard of care post-operative follow-up visit.   
 
10.0 
Removal of Subjects from Protocol Therapy 
10.1 
Duration of Treatment 
Subjects will continue vandetanib or placebo up to and including the morning of surgery for a total of 7 to14 
days.  The time frame from preoperative clinic visit until definitive surgery will be a minimum of 2 weeks and 
the maximum of 4 weeks.  Subjects with an adverse reaction of CTCAE grade III or higher will discontinue the 
study drug.  Subjects can voluntarily discontinue the drug at any time during the trial, be removed from the drug 
at the discretion of their treating physician, or be discontinued by the study investigators.  In previous trials with 
vandetanib, surveillance labs and toxicity assessment has been performed at two weeks of treatment, which will 
be done in this trial with the preoperative safety assessment.  Because subjects will have already discontinued 
the study drug at that time it will not be possible to discontinue the study drug early based on that assessment.  
Due to the short duration of treatment in this trial and the low incidence of adverse reactions over that time 
frame in previous phase I and II trials we do not expect a significant number of severe adverse reactions.  
Subjects will be evaluated for study withdrawal if noncompliant with requirement for therapy, or if they are 
experiencing drug related toxicity.  If the date of surgery is unexpectedly changed after initiation of treatment, 
the patient will continue treatment, including the morning of surgery, for not more than 28 total days. 
10.2 
Extraordinary Medical Circumstances:  
If at any time the constraints of this protocol are detrimental to the subject’s health and/or the subject no longer 
wishes to continue protocol therapy, remove the subject from the protocol treatment.  In this event: 
• 
Document the reason(s) for ending treatment on the follow-up form. 
• 
The primary outcomes of response of down regulation of Ki-67 and secondary outcomes of evaluation 
of tumor markers in the baseline and endpoint tissue samples will be analyzed unless the subject withdraws 
consent to do so.   
 
 
 
11.0  Data Management, Quality Control and Data Security  


12 
 
 
Data management for the optimal entry, processing, storage, and retrieval for this protocol’s data will be 
accomplished by the PI.  The data base will be located on a computer or in a locked cabinet in a locked office.  
This computer will be secured, accessible only by the research team.  There will be more than one copy of the 
database.  The second, secured, copy of the protocol data will be stored in a locked room accessible only by the 
research team.  For quality control, auditing, and checking data for integrity, there will be a regular accounting 
date periodically performed. 
 
11.1 
Data and safety monitoring 
1.1.1. Purpose: The Data Safety Monitoring Plan for this study (see Appendix 5) is written to ensure the 
safety of subjects and to verify the validity and integrity of the data. 
1.1.2. Assessment of risk: This investigation involves risk-level 3 out of 4 (see appendix 5) procedures, in a 
population that is at risk of death or severe morbidity because of existing illness or disease. 
1.1.3. DSMC audits: The CRSO will perform biannual audits of the research charts, case report forms and 
the corresponding primary source documents. Safety audits will be conducted to validate eligibility of 
patients accrued to study, check for the presence of informed consent, determine compliance with 
protocol, determine whether AE/SAE are being reported to internal and external regulatory agencies, 
and compare veracity of data in the research record with the primary source documents. As part of the 
ongoing monitoring of this study, the PI will maintain an AE summary table to be reviewed during 
the audits.  
The results of each audit will be reviewed by the DSMC Chair and/or the study monitor. A final 
report for the audit will be sent to the PI, PRMC Chair, and the IRB, along with any resulting 
recommendations or required actions. 
1.1.4. Expedited reports: All expedited adverse event reports will be reviewed by the DSMC. 
1.1.5. Continuing reviews: All DSMC audit reports must be attached to continuing review submissions for 
the IRB approval. 
 
11.2  Adverse Event (AE and Serious Adverse Event [SAE]) 
 
11.2.1 Definitions 
 
An adverse event (AE) is defined in the CTEP, NCI Guidelines [2005] as “any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medical treatment 
or procedure (attribution of unrelated, unlikely, possible, probably or definite).” 
 
A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results 
in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results 
in persistent or significant disability / incapacity, or is a congenital anomaly / birth defect.  Hospitalization for 
planned surgical treatment of breast cancer does not constitute an SAE. 
 
The definition of serious adverse event (experience) also includes important medical event.  Medical and 
scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other 
situations, such as important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes 
listed in the definition above.  These should also usually be considered serious.  Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development of drug dependency or drug abuse. 
 


13 
 
 
The definition of “related” is that there is a reasonable possibility that the drug caused the adverse experience.   
 
Investigators are required by Federal regulations to report serious adverse events as defined in the tables below.  
If a subject has a reportable serious adverse event, the Study Chair and the Institutional Review Board follow 
guidelines of this table.  This study will utilize the Common Toxicity Criteria version 4.0 to determine the 
severity of the reaction for adverse event reporting. 
11.2.2 Assessment of Risk Level 
 
The Data Safety Monitoring Plan (DSMP) can be found in Appendix 5 of this protocol. 
This investigation involves a risk-level 3 procedure, in a population that should not be at any increased risk for 
complications. 
 
11.2.3 Assessing Toxicity: 
 
Toxicity will be graded according to NCI’s Common Toxicity Criteria (CTCAE v4). The investigator will determine 
relationship of toxicity to the investigational drug as unrelated, unlikely related, possibly related, probably related, or 
definitely related using standard criteria for clinical trials.  All grades of toxicity will be noted and reported as directed in 
Table I: Clinical Data Update System (CDUS) Guidelines for Routine Adverse Event Reporting. 
 
Patients who experience a CTCAE (version 4) Grade 3 or 4 toxicity that is considered related to Vandetanib 
will have their study drug stopped.  If a patient discontinues treatment, safety follow-up visits will be performed 
according to the schedule of assessments and procedures.  In addition, a 30 day follow up visit will occur if AEs 
have not resolved by the time of the post op safety visit. SAEs and study drug-related AEs must be followed 
until resolution unless in the Investigator’s opinion, the event is unlikely to resolve due to the patient’s 
underlying condition.  
Cardiac toxicity - QTc prolongation 
Electrocardiograms will be evaluated by suitably qualified personnel for the presence of QTc prolongation or 
other abnormalities, in particular, any changes in the T-wave morphology that would suggest a higher 
likelihood for the development of any arrhythmia.  Any clinically significant abnormal findings or QTc 
prolongations will be recorded as AEs. 
In addition to scheduled ECG, additional ECGs should also be performed in the event of QTc prolongation, 
both during and post the prolongation period. 
 
During the QTc prolongation period: For a single QTc value of >500 ms, Vandetanib must be 
withheld and patients will be removed from the study.  Electrocardiograms will be followed at least 
once per week (done at the same day each week) along with electrolytes, until QTc falls ≤480 ms.   
Gastrointestinal toxicity 
Nausea, vomiting, or both may be controlled with anti-emetic therapy.  The use of somatostatin or a 
somatostatin analogue is allowed to control diarrhea. 
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 CTCAE Grade 3 or 4 diarrhea develops, patients will be removed from the study.  Any electrolyte imbalance 
must be promptly corrected since hypokalemia and hypomagnesaemia are potential risk factors for drug-
induced arrhythmia.  


14 
 
 
Cutaneous toxicity 
It is strongly recommended that all patients follow a program of sun protective measures (wearing additional 
clothing and/or sunscreen) while receiving study treatment and for 3 to 4 weeks after discontinuing study 
treatment.  The aim is to reduce the risk of development of skin rash, or minimize the severity of skin rash, and 
to minimize the requirement for dose reduction of study therapy. 
If a patient develops a skin rash, the 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 or systemic glucocorticoids, either topical or systemic antibiotics, topical or systemic 
antihistamines, and occasionally retinoid creams. 
 
The rash should be graded as soon as possible according to the CTCAE cutaneous toxicity criteria. 
 
If a rash of CTCAE Grade 2 or higher is detected, immediate symptomatic treatment should be 
provided. 
 
If a rash of CTCAE Grade 3 or 4 is detected, patients will be removed from the study  
Hypertension 
Patients who develop CTCAE Grade 3 hypertension may continue on therapy if blood pressure is controlled on 
increased anti-hypertensive medication (to CTCAE Grade 1 or baseline).  If blood pressure cannot be stabilized 
with increased anti-hypertensive medication, patients will be removed from the study. 
Patients with CTCAE Grade 4 hypertension must be removed from the study. 
 
 
11.2.4 Adverse Event Reporting: 
 
Table I: 
Clinical Data Update System (CDUS) Guidelines for Routine Adverse Event Reporting  
Attribution 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Not required 
Not required 
CRSO 
CRSO 
CRSO 
Unlikely 
Not required 
Not required 
CRSO 
CRSO 
CRSO 
Possible 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Probable 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Definite 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
 
Reports are collected by the CRSO or DSMB and communicated to the DSMC 
 
For Hospitalization Only — Any medical event equivalent to CTC Grade 3, 4, 5 which precipitated hospitalization (or prolongation of 
existing hospitalization) must be reported regardless of requirements of Phase of Study, expected or unexpected grade and 
attribution. 
 
 
 
All adverse events related to the experimental procedures will be reported to the Data Safety Monitoring Committee 
(DSMC) via the Clinical Research Safety Officer (CRSO) as well as the appropriate regulatory authority.  Annual 
progress reports will be sent to the CRSO, who will enter this into OnCore and report findings to the DSMC.    Only 


15 
 
 
Grade 4 and 5 events that are unexpected with at least possible attribution to Vandetanib will require an expedited 
report.  The investigator will continue to follow or obtain documentation of the resolution course of such an event.  The 
event may also require reporting to the IRB, as determined by current policies 
(http://research.uiowa.edu/hso/downloads/policies/Guide_Human_Subjects_Research.pdf). 
 
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, of any serious or 
unexpected adverse events that occur in accordance with the reporting obligations of 21 CFR 312.32., and will 
concurrently forward all such reports to AZ.  A copy of the MedWatch/AdEERs report must be faxed to 
AstraZeneca at the time the event is reported to the FDA.  It is the responsibility of the investigator to compile 
all necessary information and ensure that the FDA receives a report according to the FDA reporting requirement 
timelines and to ensure that these reports are also submitted to AstraZeneca at the same time. 
 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs form indicating the 
following: 
 
Investigator Sponsored Study (ISS) 
 
The investigator IND number assigned by the FDA 
 
The investigator’s name and address 
 
The trial name/title and AstraZeneca ISS reference number (#ISS64740032)   
Investigative site must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined by the principal 
investigator. 
 
Send SAE report and accompanying cover page by way of fax to AstraZeneca’s designated fax line: 1-866-984-
7229 
 
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.   
 
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. 
 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the investigational 
product.  All SAEs will be documented.  The investigator is responsible for informing the IRB and/or the 
Regulatory Authority of the SAE as per local requirements. 
Overdose  
If an overdose on an AstraZeneca study drug occurs in the course of the study, then investigators or other site 
personnel inform appropriate AstraZeneca representatives within one day, i.e., immediately but no later than 
the end of the next business day of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all relevant information is 
provided to the AstraZeneca Patient Safety data entry site. 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
Maternal exposure 
 


16 
 
 
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. 
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 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 
The most common side effects seen in patients treated with Vandetanib included the following: 
 
Risks for Vandetanib 
 
Very Common (experienced by more than 10% of patients taking Vandetanib) 
Headache 
Diarrhea 
Nausea/vomiting 
Constipation 
Decreased appetite,  
Rash 
Dry skin 
Hypertension 
Trouble sleeping 
Weakness 
Fatigue 
 
 


17 
 
 
Common (Experienced by 1 – 10% of patients taking Vandetanib) 
QTc prolongation 
Abnormal taste in mouth 
Abdominal pain 
Mouth swelling 
Dry mouth 
Weight loss 
Elevated liver function tests 
Anorexia 
Hypokalemia 
Hypocalcemia 
Dehydration 
Hypomagnesemia 
Skin changes 
Acne 
Hair loss 
Nail disorders 
Mild nose bleed 
Proteinuria 
Kidney stone 
Visual problems 
Depression 
Anxiety 
 
Uncommon (Experienced by fewer than 1% of patients taking vandetanib) 
Heart failure 
Chest pain 
Pancreatitis 
Thrombocytopenia 
Severe skin disorder 
Seizure 
Shortness of breath 
Hypokalemia 
 
 
12.0  Statistical Analysis   
 
In this study, women will be enrolled after core breast biopsy demonstrates invasive breast cancer.  Baseline 
tissue sample will be obtained on study participants, after which, subjects will take Vandetanib or placebo until 
the time of a definitive surgical procedure, at which point the resection specimen will serve as a paired tissue 
sample.  In vivo response Vandetanib will be assessed through analyses of the change in tissue levels of KI67, 
TUNEL, and changes in activation of ERK1/2, AKT, and mTOR and compared to placebo treated patients. All 
data points will be evaluated as paired continuous data points. 
 
Descriptive statistics (means, medians, standard deviations, percentages, and confidence intervals) will be 
reported for all baseline and follow-up variables as well as for their changes over time.  Statistical comparisons 
of the changes will be performed with paired t-test for continuous variables.  Power analysis for comparisons of 


18 
 
 
continuous variables was based on published results for Ki-67 [20]– the only readily available results for the 
proposed treatment and study population.  Based on a published standard deviation of 10%, the planned 
enrollment of 35 subjects will ensure 90% power to detect a decrease of 5% in Ki-67. The power drops to 82% 
if a two-sided alternative is considered. We will enroll 40 patients in each arm to account for non-compliance 
and withdrawal. 
 
With a total of 70 evaluable patients (i.e. 35 in control and 35 in treatment group), we can achieve 70% power 
to detect 6% difference in Ki-67 between the two arms, from the null hypothesis that both arms have equal 
expression of Ki-67. In this case, we operate under the assumption that both arms have similar standard 
deviation of 10%, that the significance level is 5%, and that a two-sided two-sample t-test has been used. The 
power is 80% if a one-sided two-sample t-test is used under the same assumptions.  We will enroll 80 patients 
(40 per arm) to account for potential patient dropouts and ineligibility for analysis due to missed doses. 
 
Power in subgroup comparisons is likely to be low and, thus, the results are most useful for generating 
hypotheses to be tested in future studies.  All statistical tests will be one-sided and assessed for significance at 
the 5% level. 
 
 


19 
 
 
13.0  References 
1. 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10-29. 
2. 
Spanheimer PM, Carr JC, Thomas A, Sugg SL, Scott-Conner CEH, Liao J, Weigel RJ. The Response to 
Neoadjuvant Chemotherapy Predicts Clinical Outcome and Increases Breast Conservation in Advanced Breast 
Cancer. The American Journal of Surgery 2013; In press. 
3. 
Spanheimer PM, Woodfield GW, Cyr AR et al. Expression of the RET Proto-oncogene Is Regulated by 
TFAP2C in Breast Cancer Independent of the Estrogen Receptor. Ann Surg Oncol 2012. 
4. 
Tozlu S, Girault I, Vacher S et al. Identification of novel genes that co-cluster with estrogen receptor 
alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. 
Endocr Relat Cancer 2006; 13: 1109-1120. 
5. 
Kao J, Salari K, Bocanegra M et al. Molecular profiling of breast cancer cell lines defines relevant tumor 
models and provides a resource for cancer gene discovery. PLoS One 2009; 4: e6146. 
6. 
Plaza-Menacho I, Morandi A, Robertson D et al. Targeting the receptor tyrosine kinase RET sensitizes 
breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance. Oncogene 2010; 
29: 4648-4657. 
7. 
Gucalp A, Sparano JA, Caravelli J et al. Phase II trial of saracatinib (AZD0530), an oral SRC-inhibitor 
for the treatment of patients with hormone receptor-negative metastatic breast cancer. Clin Breast Cancer 2011; 
11: 306-311. 
8. 
Boer K, Lang I, Llombart-Cussac A et al. Vandetanib with docetaxel as second-line treatment for 
advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study. Invest New Drugs 
2012; 30: 681-687. 
9. 
Boulay A, Breuleux M, Stephan C et al. The Ret receptor tyrosine kinase pathway functionally interacts 
with the ERalpha pathway in breast cancer. Cancer Res 2008; 68: 3743-3751. 
10. 
Esseghir S, Todd SK, Hunt T et al. A role for glial cell derived neurotrophic factor induced expression 
by inflammatory cytokines and RET/GFR alpha 1 receptor up-regulation in breast cancer. Cancer Res 2007; 67: 
11732-11741. 
11. 
Wang C, Mayer JA, Mazumdar A, Brown PH. The rearranged during transfection/papillary thyroid 
carcinoma tyrosine kinase is an estrogen-dependent gene required for the growth of estrogen receptor positive 
breast cancer cells. Breast Cancer Res Treat 2011. 
12. 
Siegfried JM, Gubish CT, Rothstein ME et al. Combining the multitargeted tyrosine kinase inhibitor 
vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer. J 
Thorac Oncol 2012; 7: 485-495. 
13. 
Paik S, Shak S, Tang G et al. A multigene assay to predict recurrence of tamoxifen-treated, node-
negative breast cancer. N Engl J Med 2004; 351: 2817-2826. 
14. 
Dowsett M, Bundred NJ, Decensi A et al. Effect of raloxifene on breast cancer cell Ki67 and apoptosis: 
a double-blind, placebo-controlled, randomized clinical trial in postmenopausal patients. Cancer Epidemiol 
Biomarkers Prev 2001; 10: 961-966. 
15. 
Dowsett M, Dixon JM, Horgan K et al. Antiproliferative effects of idoxifene in a placebo-controlled trial 
in primary human breast cancer. Clin Cancer Res 2000; 6: 2260-2267. 
16. 
Burcombe R, Wilson GD, Dowsett M et al. Evaluation of Ki-67 proliferation and apoptotic index 
before, during and after neoadjuvant chemotherapy for primary breast cancer. Breast Cancer Res 2006; 8: R31. 
17. 
Mohsin SK, Allred DC, Osborne CK et al. Morphologic and immunophenotypic markers as surrogate 
endpoints of tamoxifen effect for prevention of breast cancer. Breast Cancer Res Treat 2005; 94: 205-211. 
18. 
Arpino G, Ciocca DR, Weiss H et al. Predictive value of apoptosis, proliferation, HER-2, and 
topoisomerase IIalpha for anthracycline chemotherapy in locally advanced breast cancer. Breast Cancer Res 
Treat 2005; 92: 69-75. 
19. 
Miller KD, Trigo JM, Wheeler C et al. A multicenter phase II trial of ZD6474, a vascular endothelial 
growth factor receptor-2 and epidermal growth factor receptor tyrosine kinase inhibitor, in patients with 
previously treated metastatic breast cancer. Clin Cancer Res 2005; 11: 3369-3376. 


20 
 
 
20. 
Garwood ER KA, Baehner FL, Moore DH, Au A, Hylton N, Flowers CI, Garber J, Lesnikoski BA, 
Hwang ES, Olopade O, Port ER, Campbell M, Esserman LJ. . Fluvastatin reduces proliferation and increases 
apoptosis in women with high grade breast cancer. Breast Cancer Res Treat 2010; Jan;119: 137-144. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


21 
 
 
Appendix 1 
List of Drugs with Potential Interactions 
Examples of inducers & inhibitors of isoenzyme CYP3A4 
 
Inducers 
Carbamazepine 
Phenytoin 
Dexamethasone  
Primidone 
Ethosuximide  
Progesterone 
Glucocorticoids  
Rifabutin 
Griseofulvin  
Rifampicin 
Nafcillin  
Rofecoxib 
Nevirapine 
St John’s wort 
Oxcarbazepine  
Sulfadimidine 
Phenobarbital  
Sulfinpyrazone 
Phenylbutazone 
  
  
Troglitazone 
 
 
Inhibitors 
Amiodarone 
Ketoconazole 
Anastrozole 
Metronidazole 
Aprenavir 
Mibefradil 
Azithromycin 
Miconazole 
Bromocriptine 
Nefazodone 
Cannabinoids 
Nelfinavir 
Cimetidine 
Nevirapine 
Cisapride 
Norfloxacin 
Clarithromycin 
Norfluoxetine 
Clotrimazole 
Omeprazole 
Cyclosporine 
Oxiconazole 
Danazol 
Paroxetine 
Delavirdine 
Propoxyphene 
Dexamethasone 
Quinidine 
Diethyldithiocarbamate 
Quinine 
Diltiazem 
Quinupristin and dalfopristin 
Dirithromycin 
Ranitidine 
Disulfiram 
Ritonavir 
Entacapone (high dose) 
Saquinavir 
Erythromycin 
Sertindole 
Ethinyl estradiol 
Sertraline 
Fluconazole 
Telithromycin 
Fluoxetine 
Troglitazone 
Fluvoxamine 
Troleandomycin 
Gestodene 
Valproic acid 
Grapefruit juice 
Verapamil 
lndinavir 
Zafirlukast 
Isoniazid 
Zileuton 
ltraconazole 
 
 
 


22 
 
 
Appendix 2 
List of Drugs with Potential Interactions 
Examples of medications known to prolong the QT interval and/or induce Torsades De Pointes (TDP) 
 
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:  
 
A. 
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 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Amiodarone  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males,TdP risk regarded 
as low 
Arsenic trioxide  
Anti-cancer/Leukemia 
 
Astemizole  
Antihistamine/Allergic rhinitis 
No Longer available in U.S. 
Azithromycin 
Antibiotic/bacterial infection 
 
Bepridil  
Anti-anginal/heart pain 
Females>Males 
Chloroquine 
Anti-malarial/malaria infection 
 
Chlorpromazine  
Anti-psychotic/Anti-emetic/schizophrenia/ 
nausea 
 
Cisapride 
GI stimulant/heartburn 
No longer available in U.S. 
  
Citalopram 
Anti-depressant/depression 
 
Clarithromycin 
Antibiotic/bacterial infection 
 
Disopyramide  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Dofetilide  
Anti-arrhythmic/abnormal heart rhythm 
Females > Males 
Domperidone 
Anti-nausea/nausea 
Not available in U.S. 
Droperidol  
Sedative;Anti-nausea/anesthesia adjunct, 
nausea 
 
Erythromycin  
Antibiotic;GI stimulant/bacterial infection; 
increase GI motility 
Females>Males 
Flecainide 
Anti-arrhythmic/abnormal heart rhythm 
 
Halofantrine  
Anti-malarial/malaria infection 
Females>Males 
Haloperidol  
Anti-psychotic/schizophrenia, agitation 
TdP risk with I.V. or excess dosage 
Ibutilide 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 


23 
 
 
Table 1 
Group 1 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Levomethadyl 
Opiate agonist/pain control, narcotic 
dependence 
Not available in U.S. 
Mesoridazine 
Anti-psychotic/schizophrenia 
 
Methadone 
Opiate agonist/pain control, narcotic 
dependence 
Females>Males 
Moxifloxacin  
Antibiotic/bacterial infection 
 
Pentamidine  
Anti-infective/pneumocystis pneumonia 
Females>Males 
Pimozide 
Anti-psychotic/Tourette's tics 
Females>Males 
Probucol 
Antilipemic/Hypercholesterolemia 
No longer available in U.S. 
Procainamide  
Anti-arrhythmic/abnormal heart rhythm 
 
Quinidine 
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Sotalol  
Anti-arrhythmic/abnormal heart rhythm 
Females>Males 
Sparfloxacin  
Antibiotic/bacterial infection 
No longer available in U.S. 
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 
 
 
 
 
a 
Source: www.QTdrugs.org. Last revised: 17 May 2012 
B. 
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 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Alfuzosin 
Alpha1-blocker/Benign prostatic 
hyperplasia 
 
Amantadine 
Dopaminergic/Anti-viral/Anti-infective/ 
Parkinson's Disease 
 
Artenimol + 
piperaquine 
Anti-malarial/ 
Not available in U.S. 
Atazanavir 
Protease inhibitor/HIV 
 
Chloral hydrate 
Sedative/sedation/ insomnia 
 
Clozapine 
Anti-psychotic/schizophrenia 
 
Dolasetron 
Anti-nausea/nausea, vomiting 
 


24 
 
 
Table 2 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
Dronedarone 
Anti-arrhythmic/Atrial Fibrillation 
 
Eribulin 
Anti-cancer/metastatic breast neoplasias 
 
Escitalopram 
Anti-depressant/Major depression/Anxiety 
disorders 
 
Famotidine 
H2-receptor antagonist/Peptic ulcer/ GERD 
 
Felbamate  
Anti-convulsant/seizure 
 
Fingolimod 
Immunosuppressant/Multiple Sclerosis 
 
Foscarnet  
Anti-viral/HIV infection 
 
Fosphenytoin 
Anti-convulsant/seizure 
 
Gatifloxacin 
Antibiotic/bacterial infection 
Oral/I.V. forms no longer available 
in U.S. and Canada, only 
ophthalmic 
Gemifloxacin 
Antibiotic/bacterial infection 
 
Granisetron 
Anti-nausea/nausea and vomiting 
 
Iloperidone 
Antipsychotic, atypical/Schizophrenia 
 
Indapamide 
Diuretic/stimulate urine & salt loss 
 
Isradipine 
Anti-hypertensive/high blood pressure 
 
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 U.S. 
Sertindole 
Antipsychotic, atypical/Anxiety, 
Schizophrenia 
Not available in U.S. 


25 
 
 
Table 2 
Group 2 Drugsa 
Generic Name 
Class/Clinical Use 
Comments 
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 
 
Voriconazole 
Anti-fungal/anti-fungal 
 
Ziprasidone 
Anti-psychotic/schizophrenia 
 
a 
Source: www.QTdrugs.org. Last revised: 17 May 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


26 
 
 
Appendix 3: Preoperative toxicity visit flowchart 
 
Appendix 3 
Preoperative screening flowchart. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preoperative assessment in the Cancer Center Clinic 
the morning of surgery or day prior to surgery 
Labs, EKG, adverse events assessment, review of  
drug calendar, and pill counts 
Documentation of review of labs, EKG, and  
toxicity by attending surgeon 
No safety concerns 
Concern over abnormal 
labs, EKG, or toxicity 
Transport to OR for 
resection 
Discussion between 
attending surgeon and 
attending anesthesiologist 
Safe to proceed (possibly 
with avoidance of QT 
prolonging medications) 
Not safe to proceed 
Follow applicable 
labs/EKG weekly and 
reschedule resection 
Transport to day of surgery admissions (DOSA) 


27 
 
 
 
Appendix 4 
Randomized, Controlled, Double-Blinded Trial Investigating the Effect of Vandetanib on Cellular 
Markers of Proliferation and Apoptosis in Breast Cancer  
 
Ronald J. Weigel, MD, PhD  
 
INSTRUCTIONS FOR THE PATIENT: This is a monthly calendar on which you are to record which days you 
have taken your Vandetanib. Be sure you have enough calendars to last until your next appointment. If you 
develop any side effects from the pill, mark this on the calendar. 
Bring the unused pills and your calendars with you at your next appointment 
This diary is for your Vandetanib only 
 
If you have any questions contact:_______________________________________ 
Telephone:______________________ 
Your next appointment is:_________________________________ 
 
VANDETANIB DIARY 300 mg daily 
 
Week of 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Week of 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Week of 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Week of 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
Week of 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
Patient’s signature: _________________________________date:_____________ 


28 
 
 
Appendix 5 
Data and Safety Monitoring Plan 
 
 
 
HCCC Clinical Trial Data and Safety Monitoring Plan (DSMP) 
Date: 2/19/2013 
IRB#:  201301763 
Study Title: A Randomized, Double-Blind, Placebo-Controlled Trial Investigating the Effect of Vandetanib on 
Cellular Markers of Proliferation and Apoptosis in Invasive Breast Cancer  
 
 
Principal Investigator:  Ronald J. Weigel, MD, PhD 
 
Co-Investigators:   
Sonia Sugg, MD  Department of Surgery 
Ingrid Lizarraga, MD  Department of Surgery 
Mark Karwal, MD  Department of Internal Medicine 
Amani Bashir, MD  Department of Pathology 
Gideon Zamba, Ph.D  Biostatistician 
 
 
 
 
 
 
 
 
 
 
All investigator-initiated protocols will be subject to ongoing monitoring of accrual, subject eligibility, protocol 
modifications and continuing reviews.  Active studies will be audited for the DSMC by the CRSO, following guidelines 
based on level of risk to subjects.  Audits will be conducted by reviewing subject files provided by clinical research 
coordinators, as well as original source documentation provided by online medical records and research pharmacists.  The 
CRSO will review adverse events, eligibility of subjects, and adherence to the IRB- and PRMC-approved protocol.  
Protocols found to have discrepancies will be require a response from the PI and an action plan for correcting identified 
deficiencies.  The DSMC will provide a schedule of audit and report dates if requested.  Type of Clinical Trial (check 
all that apply): 
__X___ Investigator-initiated (Iowa) 


29 
 
 
_____ Investigator-initiated, multi-center (non-Iowa) 
 
Is this study monitored by an outside DSMB?   Yes_____  No_____ 
_____ Compassionate-use drug protocol 
_____ Pilot study 
_____ Phase I 
_____ Phase I/II 
__X___ Phase II 
_____ Phase III 
_____ Phase IV 
 
Study risk-level (refer to attached risk-level assessment for this study):  
_____ Level 1—low risk of morbidity or death, * <<1% of death or any adverse event  
_____ Level 2—risk of death* <1% or any adverse event 1% – 5%  
__X___ Level 3—risk of death* 1% – 5% or grade 4 – 5 SAE 1% – 5%  
_____ Level 4—risk of death* >5% or grade 4 – 5 SAE >15%  
_____ Drugs being used on a “compassionate” basis  
 
* Risk of death” refers specifically to 100-day treatment-related mortality 


30 
 
 
The following additional documents will be included in the DSMP for this study: 
 
A subject eligibility check-list (inclusion / exclusion criteria), which will be available in OnCore, the HCCC 
CTMS 
 
A list of expected toxicities and stopping rules for suspension of accrual secondary to adverse events and safety 
parameters 
 
A signed and dated statement from the Principal Investigator(s) declaring any conflict of interest (or lack thereof) 
with a description of how a conflict of interest will be monitored to enhance transparency 
 
The Human Subjects application will be obtained from HawkIRB 
 
Future Continuing Review and/or Modification forms will be obtained from HawkIRB 
 
For multi-centered trials, a detailed description of the procedures in place at each center that enable 
communication between participating centers such that the PI is aware of the status of participating subjects 
including the immediate (<24hours – week day) awareness of grade 4 – 5 SAE / death 
 
Risk Level 3  
 
An independent Study Monitor, or the DSMC Chair (or his designee), will review study data (provided by the PI 
and CRSO) and communicate with the PI at least twice yearly.  The proceedings of this meeting will be 
summarized by the CRSO in a brief letter to the PI, a copy of which will be forwarded to the DSMC. 
 
Principal Investigator will provide a QUARTERLY report to the Study Monitor and the CRSO for the DSMC, or 
data may be obtained from OnCore: 
o Quarterly patient accrual data 
 
Copies of all Serious Adverse Events will be reported to the CRSO as per DSMC reporting guidelines. 
 
CRSO will conduct a BIANNUAL audit of at least 25% of the subjects’ research charts, and will report the results 
to the DSMC.  Audits will: 
o Validate eligibility of patients accrued to the study 
o Check for the presence of a signed informed consent 
o Determine compliance with protocol methodology 
o Determine whether SAEs are being reported to internal and external regulatory agencies  
o Compare veracity of data in the research record with the primary source documents 
o Review investigational drug processing and documentation. 
Assess cumulative AE/SAE reports for trends and compare to study stopping rules. 


31 
 
 
Routine Adverse Event Reporting 
 
Routine reporting of adverse events to the DSMC via the CRSO is described in Table 1: 
 
Table I:  Routine Reporting of Adverse Events  
Attribution 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Not required 
Not required 
CRSO 
CRSO 
CRSO 
Unlikely 
Not required 
Not required 
CRSO 
CRSO 
CRSO 
Possible 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Probable 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
Definite 
CRSO 
CRSO 
CRSO 
CRSO 
CRSO 
 
 
 
 


32 
 
 
Eligibility Criteria: 
 
Patient with core biopsy, pathology demonstrating invasive breast cancer, with planned surgical excision 
 Female gender.  There is an incidence of male breast cancer, but it is unclear if the etiology is the same 
and inclusion of males could confound results. 
 Age ≥ 18.  Breast cancer, while not restricted only to adult women, is rare in the younger population. 
 ECOG performance status ≤ 2. 
 Life expectancy of greater than 6 months. 
 Patient able to willingly provide informed consent to participate 
 
4.1.2  Exclusion Criteria 
 Prolonged QT interval (QTc > 480 milliseconds) on screening EKG or congenital long QT syndrome 
 Any concomitant medications that are known to be associated with Torsades de Pointes or QT 
elongation (see appendix 2). 
 Hypertension not controlled by medical therapy (systolic BP greater than 160 mmHg or diastolic blood 
pressure greater than 100 mmHg. 
 Patients taking metformin or digoxin.  History of arrhythmia (multifocal premature ventricular 
contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment 
(CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic 
sustained ventricular tachycardia. Patients with atrial fibrillation controlled by medication are permitted. 
 Significant cardiac event (e.g., myocardial infarction), superior vena cava syndrome, New York Heart 
Association (NYHA) classification of heart disease ≥2 within 12 weeks, or presence of cardiac disease 
that in the opinion of the Investigator increases the risk of ventricular arrhythmia. 
 Serum calcium or magnesium outside the institutional range of normal. 
 Serum Potassium < 4.0 mmol/L or above 5.0 mmol/L 
 Creatinine clearance < 50 ml/min 
 PT > 12 seconds or PTT > 31 seconds 
 Platelet count < 100,000 
 Serum bilirubin greater than 1.5 mg/dl 
 Alanine aminotransferase (ALT) > 50 U/L, aspartate aminotransferase (AST) > 65 U/L, or alkaline 
phosphatase (ALP) > 250 U/LAny cytotoxic treatments, such as neoadjuvant chemotherapy, planned 
before subsequent surgical procedure.  
 Previous exposure to Vandetanib 
 Previous enrollment or randomization in this study. 
 Involvement in the planning and /or conduct of the study (applies to both Astra Zeneca staff and staff at 
UIHC). 
 Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ 
carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin. 
 Patients who have received prior surgical site radiation. 
 Patients on CYP3A4 inhibitors or inducers (see appendix 1). 
 Inability to test core biopsy for study markers 
 Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 2 
weeks prior to randomization according to institutional standards for women of childbearing 
potential.) 
 
 
 
 
 
 


33 
 
 
Toxicities 
Very Common (experienced by more than 10% of patients taking Vandetanib) 
Headache 
Diarrhea 
Nausea/vomiting 
Constipation 
Decreased appetite,  
Rash 
Dry skin 
Hypertension 
Trouble sleeping 
Weakness 
Fatigue 
 
Common (Experienced by 1 – 10% of patients taking Vandetanib) 
QTc prolongation 
Abnormal taste in mouth 
Abdominal pain 
Mouth swelling 
Dry mouth 
Weight loss 
Elevated liver function tests 
Anorexia 
Hypokalemia 
Hypocalcemia 
Dehydration 
Hypomagnesemia 
Skin changes 
Acne 
Hair loss 
Nail disorders 
Mild nose bleed 
Proteinuria 
Kidney stone 
Visual problems 
Depression 
Anxiety 
 
Uncommon (Experienced by fewer than 1% of patients taking vandetanib) 
Heart failure 
Chest pain 
Pancreatitis 
Thrombocytopenia 
Severe skin disorder 
Seizure 
Shortness of breath 
Hypokalemia 


34 
 
 
 
Stopping Rules 
Subjects will continue Vandetanib up to and including the morning of surgery.  The time frame from clinic visit until 
definitive surgery will be a minimum of 2 weeks and the maximum of 4 weeks.  Subjects will be evaluated for study 
withdrawal if noncompliant with requirement for therapy (at least 80% of doses), or if they are experiencing drug related 
toxicity.  Patients may withdraw from the study at any time for any reason without effecting treatment of their breast 
cancer. 
 

ICF_001.pdf: 
FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 1 of 11 
 
INFORMED CONSENT DOCUMENT 
 
Project Title: 
A Randomized, Double-Blind, Placebo Controlled Trial Investigating the Effect of 
Vandetanib on Cellular Markers of Proliferation and Apoptosis in Invasive Breast Cancer 
 
Principal Investigator: 
Ronald J. Weigel, MD, PhD 
 
Research Team Contact: 
Pam Zehr, RN              
 
 
319-353-8914                  
 
 
 
 
 
Michelle Arnold, RN   
Janelle Born, RN 
 
 
 
 
Susan Butcher, RN 
 
 
 
This consent form describes the research study to help you decide if you want to participate.  This form 
provides important information about what you will be asked to do during the study, about the risks and 
benefits of the study, and about your rights as a research subject.   
• If you have any questions about or do not understand something in this form, you should ask 
the research team for more information.   
• You should discuss your participation with anyone you choose such as family or friends.   
• Do not agree to participate in this study unless the research team has answered your 
questions and you decide that you want to be part of this study.  
 
WHAT IS THE PURPOSE OF THIS STUDY? 
 
This is a research study.  We are inviting you to participate in this research study because you have been 
diagnosed with breast cancer. 
 
The purpose of this research study is to test whether a drug called vandetanib has an effect on tumor 
growth markers.  Vandetanib is currently used to treat a specific, rare type of thyroid cancer.  
Vandetanib is considered investigational, which means that it has not been approved by the U.S. Food 
and Drug Administration for use in treating breast cancer.   This study will compare vandetanib to a 
placebo. A placebo is an inactive substance made to look/taste like an active medicine. You will either 
get the study drug, vandetanib or a placebo. The placebo is being used to make sure other factors, such 
as your biopsy, do not affect the marker.    
 
 
HOW MANY PEOPLE WILL PARTICIPATE? 
 
Approximately 100 people will take part in this study conducted by investigators at the University of 
Iowa.  
 
HOW LONG WILL I BE IN THIS STUDY? 
 
  
If you agree to take part in this study, your involvement will last for up to 4 months.  This will include 
the consultation visit, preoperative assessment, breast cancer surgery, and the follow-up clinic visit after 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 2 of 11 
surgery.  The clinic visits will take about 2 hours and the surgery may involve hospitalization.  These 
visits are part of your care for breast cancer and will be necessary regardless of your study 
participation.  Due to study participation, at your preoperative assessment visit, follow up labs and EKG 
will be performed to document any effect of the study drug, which could increase the length of that visit 
by up to an hour.  At that time you will also be asked questions about drug side effects and how often 
you took the study drug.  Taking part in this study will not alter the standard treatment you will receive 
or the timing of your surgery. 
 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
If you are a patient from Mercy Medical Center in Cedar Rapids, some of your tests and procedures will 
be done in Cedar Rapids, and some will be done at University of Iowa Hospitals and Clinics.  The lists 
below tell which tests and procedures will happen in each place.  There is additional information 
following the lists that contain more information about these tests and procedures. 
 
If you are a patient at the University of Iowa Hospitals and Clinics, all of the tests and procedures below 
will be done at the University of Iowa Hospitals and Clinics.   
 
 
If you are a patient from Mercy Medical Center in Cedar Rapids, the following tests and 
procedures will be done in Cedar Rapids: 
 
- Physical exam including vital signs and measurement of your height and weight; 
- Blood tests that are considered standard-of-care 
- Surgery 
- Followup physical exam after surgery including vital signs 
 
You will also sign a release form so that your medical information can be sent to the University of Iowa 
Hospitals and Clinics.   
 
If you are a patient from Mercy Medical Center in Cedar Rapids, the following tests and 
procedures will be done at University of Iowa Hospitals and Clinics: 
 
During the Screening visit: 
- Informed Consent discussion and signing 
- EKG (electrocardiogram – an electrical tracing of your heartbeat) 
- Pregnancy test if you are a woman of child-bearing potential 
- Any blood tests required for the research study that weren’t done in Cedar Rapids as standard-of-care 
- Study drug will be prescribed and dispensed to you 
 
During the visit which occurs the day before surgery: 
- Vital signs will be taken 
- EKG 
- Return of study drug that wasn’t taken 
- Blood tests that are considered research  


FOR IRB USE ONLY 
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APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 3 of 11 
 
 
Additional information regarding the tests and procedures listed above: 
Medical Tests  
The following exam and tests must be done to make sure that you are eligible for this study. None of 
these tests are experimental. They are routine. Depending on when you last had the blood tests, they may 
need to be repeated:  The lab tests are to check your general health prior to surgery.  We will check your 
calcium, magnesium, potassium, creatinine, liver function tests, complete blood count and blood clotting 
studies.  They would be done even if you were not in this study and you or your insurance company will 
be responsible for the payment for these tests.  These blood tests will be repeated after completion of the 
study and the investigators will pay for study related tests. If you are of child-bearing age, we will do a 
pregnancy test. 
 
Study procedures 
We will do a physical exam, record your height and weight, check your blood pressure/pulse, and record 
how well you are doing generally.  Blood will be drawn for lab tests and an EKG will be done to check 
your heart.   
 
If you are able to continue in the study you will be randomized to either receive either study drug or a 
placebo. This means that whichever drug you receive will be determined purely by chance, like flipping 
a coin.  You will have a 50/50 chance of receiving any one of the study drugs.  Neither you nor the 
research team will know which study drug you are receiving, but we will be able to get this information 
quickly if needed to help make the best decisions about your medical care. Regardless of which group 
you are in you will take a pill once a day for 7 to 14 days as described below.  You will be asked to 
record every time you take your medicine on a calendar we provide.  Please also record any symptoms 
you are experiencing.  The dose of vandetanib (300 mg, once per day by mouth) is based on previous 
studies that showed this dosage was generally well-tolerated.   
 
You will take doses of vandetanib or placebo once a day for 7 to 14 days, up to and including the day of 
your breast cancer surgery.  At the time of surgery, we will take a small piece of the cancer tissue and 
send it to our lab.  No additional tissue will be removed because of this study.  We will compare the 
diagnostic biopsy taken to diagnose your cancer and compare it to the resection specimen from your 
operation to learn about whether the vandetanib impacted the cancer. After the study is over, you can 
contact the research coordinator if you would like to know whether you took the vandetanib or the 
placebo. 
 
Tissue Storage for Future Use 
As part of this study, we are obtaining breast cancer tissue from you.    Collection of tissue is standard of 
care at the time of diagnosis and surgical treatment.  We would like to study your tissue in the future, 
after this study is over. 
 
The tests we might want to use to study your tissue may not even exist at this time.  Therefore, we are 
asking for your permission to store your tissue so that we can study them in the future.  These future 
studies may provide additional information that will be helpful in understanding breast cancer, but it is 
unlikely that what we learn from these studies will have a direct benefit to you.  It is possible that your 
tissue might be used to develop products or tests that could be patented and licensed.  There are no plans 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 4 of 11 
to provide financial compensation to you should this occur.   
 
Please place your initials in the blank next to Yes or No for the statement below: 
My tissue may be stored and used in the future for breast cancer research. 
 
_____ Yes 
_____ No 
 
 
If you agree now to future use of your tissue, but decide in the future that you would like to have it 
removed from future research, you should contact Dr Ronald Weigel at 319-353-7474.  However, if 
some research with your tissue has already been completed, the information from that research may still 
be used. 
 
WHAT ARE THE RISKS OF THIS STUDY? 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in this 
study.  
 
The study medication may cause some side effects. Any side effect you experience will be assigned a 
grade 1-4 depending upon how severe it is. The study doctor will grade it based upon criteria that were 
developed by the National Institutes of Health, National Cancer Institute and are called the Common 
Terminology Criteria for Adverse Events. This ensures all study doctors follow the same guideline for 
rating the severity of side effects. If you experience a side effect that is graded severe by the study 
doctor and he/she thinks it is related to the study drug, then the study drug will be stopped and you will 
be removed from the study.  The following side effects were observed in patients receiving 300mg 
Vandetanib alone (with no other treatment).  You may experience none, some, or all of the following: 
Very Common (experienced by more than 10% of patients taking vandetanib) 
• Headache 
• diarrhea 
• nausea 
• vomiting 
• constipation 
• decreased appetite 
• skin rash 
• dry skin 
• elevated blood pressure 
• trouble sleeping 
• weakness  
• fatigue 
 
Patients taking vandetanib may develop a skin rash, which may become severe, but is manageable with 
proper treatment. Vandetanib may also make your skin more sensitive to the sun.  It is recommended 
that you take preventative action to prevent the rash from occurring while receiving study medication 
and for 3 to 4 weeks after stopping medicine by using the following guidelines: 


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IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 5 of 11 
 
• 
Avoiding direct sunlight 
• 
Covering sun exposed skin with clothing (long trousers, long sleeve shirts, and hats) 
• 
Using a sun protection factor (SPF) 45 or higher sun protection cream 
• 
Notifying the study doctor when the first sign of a rash occurs so he/she may take the 
appropriate steps in preventing the rash from becoming severe. 
Common (Experienced by 1 – 10% of patients taking vandetanib) 
• Changes in heart function (called QTc prolongation),  
• abnormal taste in mouth 
• abdominal pain 
• swelling in your mouth 
• dry mouth 
• decrease in thyroid hormone 
• weight loss 
• elevated blood levels of certain proteins produced by the liver 
• anorexia (loss of appetite) 
• low potassium in the blood 
• low calcium in the blood 
• dehydration 
• low magnesium in the blood 
• changes in your skin (sensitivity to the sun, itchy skin, redness) 
• acne 
• hair loss 
• nail disorders 
• mild nose bleeding 
• protein or blood in the urine 
• kidney stone 
• changes in your eyes (vision problems, swollen, dry or irritated eyes) 
• feeling depressed 
• anxiety 
 
The manufacturer of the drug has observed changes in EKGs in some patients being treated with 
vandetanib. These changes in the EKG may be drug-related and usually occur without symptoms; 
accordingly, frequent safety follow-up visits have been built into all studies. Similar changes in the 
EKGs of patients receiving other medications have led to heart rhythm changes, some of which have 
been life threatening. It is estimated that between 0.1 to 1% of patients receiving vandetanib 300 mg 
have developed heart rhythm changes linked to life-threatening arrhythmia called Torsades de Pointes. 
Torsades de Pointes has been associated with sudden death. If any such changes are noted on your 
EKGs, you may need to attend additional visits for further safety assessments.  


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IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 6 of 11 
The risk of developing changes in the EKG and serious heart rhythm changes will be greater if you have 
diarrhea, blood electrolyte imbalance (imbalance of minerals in your blood), vomiting, high fever, 
faintness or dizzy spells, or are unable to maintain a normal diet. You should report any of these 
symptoms to your study doctor immediately. You should review your medications and diet with your 
study doctor at each visit while you are continuing to receive study drug.  
Changes in the heart rhythm may cause rapid or irregular heart beat, dizziness, light-headedness, chest 
discomfort, shortness of breath, or losing consciousness. We will be monitoring your heart function with 
an electrocardiogram. If significant changes occur, we may need to stop therapy. These or other new 
symptoms or possible side effects should be reported immediately to your study doctor. 
Uncommon (Experienced by fewer than 1% of patients taking vandetanib) 
• Certain heart conditions (heart failure – a weakening of the heart’s ability to pump blood, a fast 
heart beat that can be dangerous),  
• chest pain,  
• inflammation in the pancreas,  
• decrease in platelets in the blood which could cause bleeding because platelets help your blood 
clot,  
• small bluish/purple spots on the skin,  
• increase in haemoglobin in the blood, 
• severe skin disorders.  
Some patients have had seizures while taking vandetanib, which can be a result of swelling in the 
brain.  This can be seen on an MRI scan, and is expected to improve after vandetanib has been 
stopped.  If you develop seizures, dizziness, headache, changes in your vision, or confusion, you should 
let your study doctor know as soon as possible. These may be symptoms of reversible posterior 
leukoencephalopathy syndrome (RPLS) which is expected to be uncommon. 
A very small number of patients with lung cancer receiving vandetanib have developed shortness of 
breath and cough because of an inflammation of scar tissue formation in the lungs, although this 
symptom could also be due to the underlying lung cancer. 
 
You should not drink grapefruit juice or eat grapefruit during your participation in this study. It may 
make the amount of vandetanib in your blood increase to a harmful level. 
 
Reproductive risks: Because the drugs in this study can harm an unborn baby, you should not become 
pregnant while on this study. You should not nurse your baby while on this study.  Ask about counseling 
and more information about preventing pregnancy.   
 
 
If you are a woman of child-bearing potential: 
• 
We will ask you to confirm to the best of your knowledge that you are not pregnant now and 
you do not intend to become pregnant during this study 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 7 of 11 
• 
A pregnancy test will be done to confirm that you are not pregnant before you take part in this 
study 
• 
You must avoid becoming pregnant and use a highly effective method of birth control during 
your participation in this study. Acceptable methods of birth control are defined as a barrier 
method in conjunction with a spermicide (i.e., condom with spermicide, diaphragm with 
spermicide), approved contraceptive implants, long-term injectable contraception, intrauterine 
devices, or tubal ligation. The oral contraceptive pill is acceptable, but it must be combined 
with a barrier method in conjunction with a spermicide. You should avoid becoming pregnant 
for 4 months following the last dose of vandetanib. 
If at any time during this study you think you might be pregnant, or later learn that you were pregnant 
during the study, you must contact the study doctor immediately for further instructions about your 
participation in this study and follow-up. You will be asked about the results of the pregnancy/birth and 
may need to have follow up visits. 
 
 
WHAT ARE THE BENEFITS OF THIS STUDY? You will not benefit from being in this study.  
However, we hope that, in the future, other people might benefit from the knowledge that is gained 
about treating breast cancer. 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Before you decide whether or not to be in this study, your doctor will discuss the other options that are 
available to you.  Instead of being in this study, you have the following options:  
* Biopsy and surgery for breast cancer without being in this study. 
* No therapy at this time 
* Treatment with commonly used chemotherapy or experimental chemotherapy. 
 
WILL IT COST ME ANYTHING TO BE IN THISSTUDY? 
You will not have any additional costs for being in this research study. The vandetanib will be paid by 
the study.  You and/or your medical/hospital insurance carrier will remain responsible for your regular 
medical care expenses. 
 
WILL I BE PAID FOR PARTICIPATING? 
 
You will be paid for being in this research study. You will need to provide your social security number 
(SSN) in order for us to pay you. You may choose to participate without being paid if you do not wish to 
provide your social security number (SSN) for this purpose.  You may also need to provide your address 
if a check will be mailed to you. If your social security number is obtained for payment purposes only, it 
will not be retained for research purposes.    
 
 
You will be paid $50 for completing your first study visit (consultation visit), an additional $50 for 
completing your second study visit (pre-operative assessment visit) and an additional $100 on 
completion of your participation in the study (post-operative visit 7-14 days after surgery).  You will 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 8 of 11 
receive payment only for the visits you complete for the research study.     
 
WHO IS FUNDING THIS STUDY? 
 
The National Institutes of Health (NIH) is providing some funding for this research study.  This means 
that the University of Iowa is receiving payments from the NIH to support the activities that are required 
to conduct the study.  No one on the research team will receive a direct payment or increase in salary 
from NIH for conducting this study.  Vandetanib for this study is being provided by the manufacturer, 
AstraZeneca Pharmaceuticals, LP.   
 
 
 
WHAT IF I AM INJURED AS A RESULT OF THIS STUDY? 
 
• If you are injured by or become ill from participating in this study, medical treatment is available 
at the University of Iowa Hospitals and Clinics. 
 
• The sponsor will reimburse your reasonable and necessary medical costs for treatment for a 
research-related illness or injury through the University of Iowa if the injury or illness :  
− is a direct result of the drug being studied or the properly performed study procedures  
− is not a medical condition that you had when you started the study;  
− is not the direct result of a failure to follow the study plan; and 
− is not the direct result of proven negligence of the University of Iowa. 
 
• The sponsor does not plan to provide any other form of compensation to you for any illness or 
injury resulting from this study. 
 
• The University of Iowa does not plan to provide free medical care or payment for treatment of 
any illness or injury resulting from this study unless it is the direct result of proven negligence by 
a University employee.  
 
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will keep your participation in this research study confidential to the extent permitted by law.  
However, it is possible that other people such as those indicated below may become aware of your 
participation in this study and may inspect and copy records pertaining to this research.  Some of these 
records could contain information that personally identifies you.  
* federal government regulatory agencies,  
* The U.S. Food and Drug Administration, AstraZeneca and its related companies located 
throughout the world 
* auditing departments of the University of Iowa, and  
* the University of Iowa Institutional Review Board (a committee that reviews and approves 
research studies)  
To help protect your confidentiality, we will keep paper records of your participation in the study in 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 9 of 11 
coded files, in locked file cabinets, within locked office, and electronic records on password-protected 
computer workstations that only research personnel will have access to. Samples collected will be given 
a unique subject identifier. Only the study staff will know the unique subject identifier. The name that 
belongs to the unique subject identifier will be kept in a locked file or in a computer with a password. 
The results of any research will not be placed in your medical record.  In the event of any report or 
publication from this study, your identity will not be disclosed.  Results will be reported in a 
summarized manner in such a way that you cannot be identified.    
 
The University of Iowa Hospitals and Clinics generally requires that we document in your medical 
record chart that you are participating in this study. The information included in the chart will provide 
contact information for the research team as well as information about the risks associated with this 
study. We will keep this Informed Consent Document in our research files; it will not be placed in your 
medical record chart. 
 
 
WILL MY HEALTH INFORMATION BE USED DURING THIS STUDY? 
 
The Federal Health Insurance Portability and Accountability Act (HIPAA) requires your health care 
provider to obtain your permission for the research team to access or create “protected health 
information” about you for purposes of this research study.  Protected health information is information 
that personally identifies you and relates to your past, present, or future physical or mental health 
condition or care.  We will access or create health information about you, as described in this document, 
for purposes of this research study.  Once your health care provider has disclosed your protected health 
information to us, it may no longer be protected by the Federal HIPAA privacy regulations, but we will 
continue to protect your confidentiality as described under “Confidentiality.” 
 
We may share your health information related to this study with other parties including federal 
government regulatory agencies, the University of Iowa Institutional Review Boards and support staff, 
the U.S. Food and Drug Administration, and UIHC laboratories. 
 
You cannot participate in this study unless you permit us to use your protected health information.  If 
you choose not to allow us to use your protected health information, we will discuss any non-research 
alternatives available to you.  Your decision will not affect your right to medical care that is not 
research-related.  Your signature on this Consent Document authorizes your health care provider to give 
us permission to use or create health information about you. 
 
Although you may not be allowed to see study information until after this study is over, you may be 
given access to your health care records by contacting your health care provider.  Your permission for us 
to access or create protected health information about you for purposes of this study has no expiration 
date.  You may withdraw your permission for us to use your health information for this research study 
by sending a written notice to: 
 
Ronald J. Weigel, MD, PhD 
1509 JCP  
200 Hawkins Dr. 
Iowa City, IA 52242 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 10 of 11 
 
However, we may still use your health information that was collected before withdrawing your 
permission.  Also, if we have sent your health information to a third party, or have removed your 
identifying information, it may not be possible to prevent its future use.  You will receive a copy of this 
signed document. 
 
IS BEING IN THIS STUDY VOLUNTARY? 
 
Taking part in this research study is completely voluntary.  You may choose not to take part at all.  If 
you decide to be in this study, you may stop participating at any time.  If you decide not to be in this 
study, or if you stop participating at any time, you won’t be penalized or lose any benefits for which you 
otherwise qualify. 
 
What if I Decide to Drop Out of the Study? 
 
If you decide to leave the study early, we will ask you to allow us to contact you and follow-up with 
your health one time regarding your reaction to the study drug and your overall health.  Of course, care 
will continue to be available to you in the clinic, and there will be no consequences to you should you 
decide to withdraw from the study. 
  
Will I Receive New Information About the Study while Participating? 
If we obtain any new information during this study that might affect your willingness to continue 
participating in the study, we’ll promptly provide you with that information. 
 
Can Someone Else End my Participation in this Study? 
Under certain circumstances, the researchers might decide to end your participation in this research 
study earlier than planned.  This might happen because, in our judgment, it would not be safe for you to 
continue, or if your condition has become worse. 
 
WHAT IF I HAVE QUESTIONS? 
We encourage you to ask questions.  If you have any questions about the research study itself or 
experience a research-related injury, please contact: Michelle Arnold, RN at 319-356-2778.  If you are 
calling during non-business hours, please call 319-356-1616 and ask the operator to page the surgery 
resident on-call.  Tell the operator you are a research subject in one of Dr. Weigel’s studies.  
 
If you have questions, concerns, or complaints about  your rights as a research subject or about research 
related injury, please contact the Human Subjects Office, 105 Hardin Library for the Health Sciences, 
600 Newton Rd, The University of Iowa, Iowa City, IA  52242-1098, (319) 335-6564, or e-mail 
irb@uiowa.edu.  General information about being a research subject can be found by clicking “Info for 
Public” on the Human Subjects Office web site, http://research.uiowa.edu/hso. To offer input about your 
experiences as a research subject or to speak to someone other than the research staff, call the Human 
Subjects Office at the number above. 
 
 
This Informed Consent Document is not a contract. It is a written explanation of what will happen 
during the study if you decide to participate. You are not waiving any legal rights by signing this 


FOR IRB USE ONLY 
APPROVED BY: IRB-01 
IRB ID #: 201301763 
APPROVAL DATE: 09/04/18 
EXPIRATION DATE: 08/23/19 
 
 
 
Page 11 of 11 
Informed Consent Document. Your signature indicates that this research study has been explained to 
you, that your questions have been answered, and that you agree to take part in this study.  You will 
receive a copy of this form. 
 
 
Subject's Name (printed):  __________________________________________________________ 
 
 
Do not sign this form if today’s date is on or after EXPIRATION DATE: 08/23/19. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Subject)  
 
 
 
 
(Date) 
 
 
 
 
 
Statement of Person Who Obtained Consent 
 
I have discussed the above points with the subject or, where appropriate, with the subject’s legally 
authorized representative.  It is my opinion that the subject understands the risks, benefits, and 
procedures involved with participation in this research study. 
 
 
__________________________________________ 
_______________________________ 
(Signature of Person who Obtained Consent) 
 
(Date)