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Randomized Placebo- Controlled Pilot Study of ZD6474 as a Chemopreventive Agent for Premalignant Lesions of the Head and Neck

Phase 2
18 Years
Open (Enrolling)
Lip and Oral Cavity Squamous Cell Carcinoma, Oral Cavity Verrucous Carcinoma, Precancerous Condition

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Trial Information

Randomized Placebo- Controlled Pilot Study of ZD6474 as a Chemopreventive Agent for Premalignant Lesions of the Head and Neck


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


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

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


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

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

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

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

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

Inclusion Criteria:

- Histological/cytological confirmation of oral cavity dysplasia and one of three
additional criteria:

- Prior history of OSCC

- Loss of heterozygosity (LOH) at 3p or 9p

- Expression by immunohistochemistry (IHC) of budding uninhibited by benzimidazoles 3
(BUB3)/sex determining region Y (SOX4)

- Provision of informed consent

- Females of child bearing age must have a negative serum pregnancy test within 7 days
of first dose of study drug

- Patients must not have been taking steroids or are on a stable dose of steroids for
at least 14 days before enrollment

- Patients must have a Karnofsky Performance Score of 70% or above

Exclusion Criteria:

- History of malignancy within the last 5 years other than squamous cell carcinoma of
the head and neck (SCCHN) and superficial non-melanoma skin cancer; patients with a
history of SCCHN must be free of active carcinoma

- Currently receiving treatment for any malignancy

- Serum bilirubin > 1.5x the upper limit of reference range (ULRR)

- Creatinine clearance =< 30 mL/minute (calculated by Cockcroft-Gault formula)

- Potassium, < 4.0 mmol/L despite supplementation; or above the Common Terminology
Criteria for Adverse Events (CTCAE) grade 1 upper limit

- Magnesium below the normal range despite supplementation, or above the CTCAE grade 1
upper limit

- Serum calcium above the CTCAE grade 1 upper limit; in cases where the serum calcium
is below the normal range, 2 options would be available: 1) the calcium adjusted for
albumin is to be obtained and substituted for the measured serum value; exclusion is
to then be based on the adjusted for albumin values falling below the normal limit;
2) Determine the ionized calcium levels; if these ionized calcium levels are out of
normal range despite supplementation, then the patient must be excluded

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × ULRR

- Alkaline phosphatase (ALP) > 2.5 x ULRR

- Evidence of severe or uncontrolled systemic disease or any concurrent condition which
in the Investigator's opinion makes it undesirable for the patient to participate in
the trial or which would jeopardize compliance with the protocol

- Clinically significant cardiovascular event (e.g. myocardial infarction, superior
vena cava syndrome [SVC], New York Heart Association [NYHA] classification of heart
disease > 2 within 3 months before entry; or presence of cardiac disease that, in the
opinion of the Investigator, increases the risk of ventricular arrhythmia

- History of arrhythmia (multifocal premature ventricular contractions (PVCs),
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation),
which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained
ventricular tachycardia; atrial fibrillation, controlled on medication is not

- QTc prolongation with other medications that required discontinuation of that

- Congenital long QT syndrome or 1st degree relative with unexplained sudden death
under 40 years of age

- Presence of left bundle branch block (LBBB)

- QTc with Bazett's correction that is unmeasurable or ≥450 msec on screening
electrocardiogram (ECG); (Note: If a subject has a QTc interval >= 450 msec on
screening ECG, the screen ECG may be repeated twice [at least 24 hours apart]; the
average QTc from the three screening ECGs must be < 450 msec in order for the subject
to be eligible for the study)

- Any concurrent medication with a known risk of inducing Torsades de Pointes, that in
the investigator's opinion cannot be discontinued

- Concomitant medications that are potent inducers (rifampicin, rifabutin, phenytoin,
carbamazepine, phenobarbital and St. John's Wort) of Cytochrome P450 3A4 (CYP3A4)

- Hypertension not controlled by medical therapy (systolic blood pressure greater than
160 mm mercury (Hg) or diastolic blood pressure greater than 100 mm Hg)

- Currently active diarrhea that may affect the ability of the patient to absorb the
ZD6474 or tolerate diarrhea

- Women who are currently pregnant or breast-feeding

- Receipt of any investigational agents within 30 days prior to commencing study

- Previous enrollment or randomization of treatment in the present study

- Major surgery within 4 weeks or incompletely healed surgical incision before starting
study therapy

- Involvement in the planning and conduct of the study (applies to both Astra Zeneca
staff and staff at the study site)

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Outcome Measure:

Comparison between treatment groups of the within-patient change in MVD score following treatment initiation

Outcome Description:

A Wilcoxon ranksum test may be used if the normality assumption is not satisfied. Alternatively, change in MVD may be transformed (e.g. log-transformation) to satisfy the normality assumption. Additional analyses will include linear regression models with treatment effect and other prognostic factors as covariates.

Outcome Time Frame:

Baseline to 3 months

Safety Issue:


Principal Investigator

Ezra Cohen

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago


United States: Food and Drug Administration

Study ID:




Start Date:

January 2012

Completion Date:

January 2014

Related Keywords:

  • Lip and Oral Cavity Squamous Cell Carcinoma
  • Oral Cavity Verrucous Carcinoma
  • Precancerous Condition
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms
  • Precancerous Conditions
  • Carcinoma, Verrucous



University of ChicagoChicago, Illinois  60637