Vandetanib in Preventing Head and Neck Cancer in Patients With Precancerous Head and Neck Lesions

Phase 2

Completed

Conditions: Precancerous Condition
Lip and Oral Cavity Squamous Cell Carcinoma
Oral Cavity Verrucous Carcinoma

Interventions: Other: placebo
Drug: vandetanib
Other: immunohistochemistry staining method
Other: laboratory biomarker analysis
Procedure: biopsy
Other: pharmacological study

Registration Number: NCT01414426

Lead Sponsor: University of Chicago

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

Detailed Description: PRIMARY OBJECTIVE:

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

SECONDARY OBJECTIVES:

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

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

TERTIARY OBJECTIVES:

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

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

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

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

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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 excluded
QTc prolongation with other medications that required discontinuation of that medication
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) function
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 treatment
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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm II (placebo)	placebo	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm I (chemoprevention)	immunohistochemistry staining method	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm I (chemoprevention)	laboratory biomarker analysis	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm I (chemoprevention)	biopsy	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm I (chemoprevention)	pharmacological study	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	laboratory biomarker analysis	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	immunohistochemistry staining method	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm I (chemoprevention)	vandetanib	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	biopsy	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.
Arm II (placebo)	pharmacological study	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Comparison Between Treatment Groups of the Within-patient Change in MVD Score Following Treatment Initiation	Baseline to 3 months	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events	Weekly during treatment, up to week 24	Adverse events rate shows the total number of subjects with an AE.
Number of Participants Who Adhered to Treatment	Over 6 months	Number of participants who Adhered to Treatment
Development of Oral and Other Cancers	At 6, 9, and 12 months and then ever 6 months for 2 years	Number of patients with new cancer
Biologic Effect of EGFR and VEGFR2 Inhibition	Baseline and 3 and 6 months	Effect of treatment on EGFR and VEGFR2 inhibition