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A Randomized Phase II Trial of Chemoradiotherapy Versus Chemoradiotherapy and Vandetanib for High-Risk Postoperative Advanced Squamous Cell Carcinoma of the Head and Neck

Phase 2
18 Years
Not Enrolling
Head and Neck Cancer

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Trial Information

A Randomized Phase II Trial of Chemoradiotherapy Versus Chemoradiotherapy and Vandetanib for High-Risk Postoperative Advanced Squamous Cell Carcinoma of the Head and Neck



- To screen for an indication that the addition of vandetanib to chemoradiotherapy may
prolong disease-free survival as compared to a combination of chemoradiotherapy in
patients with resected, high-risk stage III or IV head and neck squamous cell


- To determine whether this treatment regimen can be delivered safely and successfully
following surgical resection for advanced head and neck cancer.

- To estimate the locoregional progression, distant metastasis, and overall survival
rates for patients treated with this regimen.

- To examine the distribution of selected biomarkers that may include but are not limited
to EGFR (epidermal growth factor receptor, total and phosphorylated), E-cadherin, pMAPK
(phosphorylated mitogen-activated protein kinase), pAKT, Stat-3 (signal transducer and
activator of transcription 3), Ki-67, COX-2 (cyclooxygenase 2), and cyclin B1
(G2/mitotic-specific cyclin-B1)expression in this group of patients and to explore the
potential correlation between these markers with the ultimate treatment outcome

OUTLINE: This is a multicenter study. Patients are stratified according to Zubrod
performance status (0 vs 1) and primary site of disease (oral cavity/hypopharynx vs larynx
vs oropharynx, HPV+ (human papillomavirus positive) vs oropharynx, HPV- (human
papillomavirus negative)). Patients are randomized to 1 of 2 arms.

- Arm I: Patients undergo radiotherapy 5 times a week for up to 6.5 weeks and receive
cisplatin IV over 1 hour on days 1, 22, and 43 of radiotherapy.

- Arm II: Patients undergo radiotherapy as in arm I and receive cisplatin IV over 1 hour
once a week beginning on day 1 of radiotherapy. Patients also receive oral vandetanib
once daily beginning 14 days prior to the start of radiotherapy.

In both arms, treatment continues for 6 weeks in the absence of disease progression or
unacceptable toxicity.

Tissue samples from all patients are collected and reviewed. Tissue from patients with
oropharyngeal carcinoma is analyzed for human papillomavirus.

After completion of study treatment, patients are followed every 3 months for 2 years, every
6 months for 4 years, and then annually thereafter.

Inclusion Criteria


- Histologically or cytologically confirmed squamous cell carcinoma of the head and
neck, including any of the following subtypes:

- Oral cavity

- Oropharynx

- Larynx

- Hypopharynx

- Stage III or IV disease (no distant metastases)

- No cancer of the lip, nasopharynx, or sinuses

- Must have undergone gross total resection* (with curative intent) within 3-6 weeks of
registration, with pathology demonstrating 1 or more of the following risk factors:

- Histologic extracapsular nodal extension

- Invasive cancer seen on microscopic evaluation of the resection margin, when all
visible tumor has been removed NOTE: *Tonsillar cancer patients who undergo
transoral excision of all gross tumor are eligible if the patient has formal
neck dissection confirming histologic extracapsular nodal extension


Inclusion criteria:

- Zubrod performance status 0-1

- ANC (absolute neutrophil count) ≥ 2,000/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve this level

- Total bilirubin normal

- AST (aspartate aminotransferase) or ALT (alanine amino transferase) ≤ 2 times upper
limit of normal (ULN)

- Alkaline phosphatase ≤ 2.5 times ULN

- Serum creatinine ≤ 1.5 mg/dL

- Creatinine clearance ≥ 60 mL/min

- Glucose ≥ 40 mg/dL AND ≤ 250 mg/dL

- Sodium ≥ 130 mmol/L AND ≤ 155 mmol/L

- Magnesium ≥ 0.9 mg/dL AND ≤ 3 mg/dL (supplementation allowed)

- Potassium ≥ 4 mmol/L AND ≤ 6 mmol/L (supplementation allowed)

- Serum calcium (ionized or adjusted for albumin) ≥ 7 mg/dL AND ≤ 12.5 mg/dL
(supplementation allowed)

- QTc (corrected QT interval) interval ≥ 480 msec must have 2 additional EKGs ≥ 24 hrs
apart and the average QTc from the 3 screening EKGs must be < 480 msec

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for at least 60 days
after completion of study treatment

- May not donate blood during the study or for 3 months after last dose of vandetanib

Exclusion criteria:

- Other simultaneous primary cancer

- Prior invasive malignancy (except nonmelanoma skin cancer) unless disease free for a
minimum of 3 years with the exception of the following:

- Carcinoma in situ of the cervix

- Adequately treated basal cell or squamous cell carcinoma of the skin

- Untreated or treated low-risk prostate cancer (defined as clinical or pathologic
T1c, N0 M0, PSA (prostate-specific antigen) < 10, Gleason < 7, < 50% of the
total cores positive for cancer)

- Severe, active co-morbidity, defined as follows:

- Clinically significant cardiovascular event (e.g., myocardial infarction,
superior vena cava syndrome, or New York Heart Association class II-IV) or
presence of cardiac disease that, in the opinion of the investigator, increases
the risk of ventricular arrhythmia within the past 3 months

- Unstable angina and/or congestive heart failure requiring hospitalization within
the past 3 months

- Transmural myocardial infarction within the past 3 months

- History of arrhythmia (e.g., multifocal premature ventricular contractions,
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial
fibrillation) which is symptomatic or requires treatment (CTCAE [Common
Terminology Criteria for Adverse Events] grade 3), or asymptomatic sustained
ventricular tachycardia

- Patients with atrial fibrillation, controlled on medication, are eligible

- Presence of left bundle branch block

- Previous history of QTc prolongation as a result from other medication that
required discontinuation of that medication

- Congenital long QTc syndrome or first degree relative with unexplained sudden
death under 40 years of age

- QTc with Bazett's correction that is unmeasurable or ≥ 480 msec on screening EKG

- Patients who are receiving a drug that has a risk of QTc prolongation are
not eligible if QTc is ≥ 460 msec

- Hypertension (systolic blood pressure [BP] > 160 mm Hg or diastolic BP > 100 mm
Hg) not controlled by medical therapy

- Diarrhea ≥ grade 1 (increase of < 4 stools per day over baseline or mild
increase in ostomy output compared to baseline)

- Acute bacterial or fungal infection requiring intravenous antibiotics at the
time of registration

- Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within the past 30 days

- Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

- Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC (Center for
Disease Control) definition (no HIV testing is required for study entry)

- Prior allergic reaction to cisplatin or vandetanib or derivatives similar to these


- See Disease Characteristics

- No prior systemic chemotherapy for this disease (prior chemotherapy for a different
cancer allowed)

- No prior radiotherapy to the head and neck area that would result in overlap of
radiotherapy fields

- More than 30 days since prior investigational agents

- More than 3 weeks since prior major surgery and recovered

- More than 2 weeks since prior and no concurrent medications that induce Torsades de

- More than 2 weeks since prior and no concurrent known potent inducers of CYP3A4
(Cytochrome P450 3A4), including rifampicin, phenytoin, carbamazepine, barbiturates,
and Hypericum perforatum (St. John wort)

- No concurrent medication that may cause QTc prolongation

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free Survival

Outcome Description:

This study terminated early with 34 subjects accrued out of 170 planned, therefore no analyses were performed.

Outcome Time Frame:

From randomization to date of failure (local, regional, or distant progression, or death) or last follow-up. Analysis occurs after 78 failures have been reported.

Safety Issue:


Principal Investigator

David Raben, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado, Denver


United States: Food and Drug Administration

Study ID:




Start Date:

November 2008

Completion Date:

August 2011

Related Keywords:

  • Head and Neck Cancer
  • stage III squamous cell carcinoma of the hypopharynx
  • stage IV squamous cell carcinoma of the hypopharynx
  • stage III squamous cell carcinoma of the larynx
  • stage IV squamous cell carcinoma of the larynx
  • stage III verrucous carcinoma of the oral cavity
  • stage IV verrucous carcinoma of the oral cavity
  • stage III squamous cell carcinoma of the oropharynx
  • stage IV squamous cell carcinoma of the oropharynx
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms



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