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

• Sponsor: University of Chicago (Other)
• Overall Status: Completed
• CT.gov ID: NCT01414426
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 89
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Lip and Oral Cavity Squamous Cell Carcinoma; Oral Cavity Verrucous Carcinoma; Precancerous Condition	Drug: vandetanib; Other: placebo; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Procedure: biopsy; Other: pharmacological study	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. 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:

1. 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.

2. 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:

1. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Randomized Placebo- Controlled Pilot Study of ZD6474 as a Chemopreventive Agent for Premalignant Lesions of the Head and Neck
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jan 1, 2019
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (chemoprevention) Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.	Drug: vandetanib; Given PO; Other Names: AZD6474 ZD6474 ; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry ; Other: laboratory biomarker analysis; Correlative studies; Procedure: biopsy; Correlative studies; Other Names: biopsies ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies
Placebo Comparator: Arm II (placebo) Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity.	Other: placebo; Given PO; Other Names: PLCB ; Other: immunohistochemistry staining method; Correlative studies; Other Names: immunohistochemistry ; Other: laboratory biomarker analysis; Correlative studies; Procedure: biopsy; Correlative studies; Other Names: biopsies ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. Number of Participants Who Adhered to Treatment [Over 6 months]

   Number of participants who Adhered to Treatment

3. 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

4. Biologic Effect of EGFR and VEGFR2 Inhibition [Baseline and 3 and 6 months]

   Effect of treatment on EGFR and VEGFR2 inhibition

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago	Chicago	Illinois	United States	60637

Sponsors and Collaborators

• University of Chicago
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Tanguy Seiwert, M.D., University of Chicago

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 22, 2019

More Information

Publications

None provided.

• Responsible Party: University of Chicago
• ClinicalTrials.gov Identifier: NCT01414426
• Other Study ID Numbers: 11-0265; NCI-2011-01246
• First Posted: Aug 11, 2011
• Last Update Posted: Jan 14, 2021
• Last Verified: Jan 1, 2021

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Verrucous; Precancerous Conditions; Squamous Cell Carcinoma of Head and Neck

Study Results

Participant Flow

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
Period Title: Overall Study
STARTED	10	10
COMPLETED	9	8
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)	Total
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.1 (10.0)	49.0 (15.0)	54.8 (13.5)
Sex: Female, Male (Count of Participants)
Female	9 90%	4 40%	13 65%
Male	1 10%	6 60%	7 35%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 10%	1 5%
White	9 90%	8 80%	17 85%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 10%	1 10%	2 10%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	20 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The outcome measure microvessel density was not collected on any subjects

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
Measure Participants	0	0

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Adverse events rate shows the total number of subjects with an AE.
Time Frame	Weekly during treatment, up to week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
Measure Participants	10	10
Week 1	3 30%	6 60%
Week 2	4 40%	3 30%
Week 3	0 0%	1 10%
Week 4	2 20%	0 0%
Week 5	5 50%	5 50%
Week 6	0 0%	2 20%
Week 7	0 0%	0 0%
Week 8	0 0%	0 0%
Week 9	7 70%	2 20%
Week 10	0 0%	1 10%
Week 11	0 0%	0 0%
Week 12	0 0%	0 0%
Week 13	3 30%	0 0%
Week 14	0 0%	0 0%
Week 15	0 0%	0 0%
Week 16	0 0%	1 10%
Week 17	2 20%	1 10%
Week 18	0 0%	2 20%
Week 19	0 0%	0 0%
Week 20	0 0%	1 10%
Week 21	1 10%	0 0%
Week 22	0 0%	1 10%
Week 23	2 20%	0 0%
Week 24	0 0%	0 0%
Week 25	2 20%	0 0%

3. Secondary Outcome

Title	Number of Participants Who Adhered to Treatment
Description	Number of participants who Adhered to Treatment
Time Frame	Over 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
Measure Participants	10	10
Number [participants]	4 40%	5 50%

4. Secondary Outcome

Title	Development of Oral and Other Cancers
Description	Number of patients with new cancer
Time Frame	At 6, 9, and 12 months and then ever 6 months for 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
Measure Participants	10	10
6 months	1 10%	0 0%
9 months	0 0%	0 0%
12 months	0 0%	0 0%
18 Months	0 0%	0 0%
24 Months	0 0%	0 0%

5. Secondary Outcome

Title	Biologic Effect of EGFR and VEGFR2 Inhibition
Description	Effect of treatment on EGFR and VEGFR2 inhibition
Time Frame	Baseline and 3 and 6 months

Outcome Measure Data

Analysis Population Description

Outcome measure was not collected.

Arm/Group Title	Arm I (Chemoprevention)	Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies	Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
Measure Participants	0	0

Adverse Events

Time Frame	180 days
Adverse Event Reporting Description	Adverse Events were monitored/assessed without regard to the specific Adverse Event Term
Arm/Group Title	Arm I (Chemoprevention)		Arm II (Placebo)
Arm/Group Description	Patients receive vandetanib PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. vandetanib: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies		Patients receive placebo PO QD for 6 months. Treatment continues in the absence of disease progression or unacceptable toxicity. placebo: Given PO immunohistochemistry staining method: Correlative studies laboratory biomarker analysis: Correlative studies biopsy: Correlative studies pharmacological study: Correlative studies
All Cause Mortality
	Arm I (Chemoprevention)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Arm I (Chemoprevention)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Chemoprevention)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/10 (80%)		6/10 (60%)
Gastrointestinal disorders
Gastrointestinal	6/10 (60%)	8	4/10 (40%)	6
Infections and infestations
Infections	1/10 (10%)	1	1/10 (10%)	1
Metabolism and nutrition disorders
Metabolic	1/10 (10%)	1	0/10 (0%)	0
Musculoskeletal and connective tissue disorders
Muscular	0/10 (0%)	0	2/10 (20%)	3
Nervous system disorders
Nervous System	2/10 (20%)	3	1/10 (10%)	1
Product Issues
General	4/10 (40%)	5	3/10 (30%)	5
Psychiatric disorders
Psychiatric	0/10 (0%)	0	2/10 (20%)	2
Renal and urinary disorders
Renal	1/10 (10%)	1	0/10 (0%)	0
Skin and subcutaneous tissue disorders
Skin	3/10 (30%)	4	3/10 (30%)	5
Vascular disorders
Vascular	2/10 (20%)	4	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.