Cisplatin, Bevacizumab, and Intensity-Modulated Radiation Therapy in Treating Patients With Stage III or Stage IV Head and Neck Cancer

OBJECTIVES:

Primary

- Determine the 2-year progression-free survival of patients with stage III or IV
squamous cell carcinoma of the head and neck treated with chemoradiotherapy comprising
cisplatin, bevacizumab, and intensity-modulated radiotherapy.

- Determine the safety and tolerability of this regimen in these patients.

Secondary

- Determine the median overall survival of patients treated with this regimen.

OUTLINE:

- Chemoradiotherapy: Patients receive cisplatin IV over 1 hour on days 1, 2, 22, 23, 43,
and 44 and bevacizumab IV over 30-90 minutes on days 1, 22, and 43. Patients also
undergo intensity-modulated radiotherapy on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40,
and 43-47. Treatment continues in the absence of disease progression or unacceptable
toxicity.

Between 3-4 months after completion of chemoradiotherapy, patients undergo evaluation.
Patients with clinical evidence of residual, progressive, or persistent disease may be
eligible to undergo neck surgery at the discretion of their physician.

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

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Inclusion Criteria:

- Stage III/IV HNSCC without distant metastasis, previously untreated. Patients with
stage II squamous cell carcinoma of the hypopharynx will also be eligible.

- Adequate renal function, with serum creatinine ≤ 1.5 mg/dL. Patients with serum
creatinine > 1.5 mg/dL may be eligible if calculated creatinine clearance ≥ 55 ml/min
by Cockcroft and Gault equation (or 24-hour urine collection).

- Age ≥ 18 years

- Karnofsky performance status ≥70%

- Adequate bone marrow function: absolute neutrophil count ≥ 1,500/μl, platelets ≥
100,000/μl, hemoglobin ≥ 9 gm/dl

- Adequate hepatic function: Total bilirubin ≤ 1.5 X UNL (patients with Gilbert's
syndrome as the cause of hyperbilirubinemia may be eligible if total bilirubin ≤ 2.5
X UNL), aspartate aminotransferase (AST) ≤ 2.5 X UNL, alanine aminotransferase (ALT)
≤ 2.5 X UNL, alkaline phosphatase ≤ 2.5 X UNL.

- Men and women of childbearing potential must be willing to consent to using effective
contraception while on treatment and for at least 3 months thereafter.

- Patients must have ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

- Prior chemotherapy or radiation therapy for HNSCC

- Prior treatment with bevacizumab or other agents specifically targeting VEGF

- Other active malignancy, other than indolent malignancies which the investigator
determines are unlikely to interfere with treatment or efficacy analysis. For
example, patients with non-melanoma skin cancer, in situ carcinoma of the cervix, or
prostate cancer within the no current biochemical (PSA) or radiologic evidence of
disease may enroll.

- Patients with nasopharyngeal carcinoma

- Patients who will receive amifostine as part of the radiation treatment plan

- Patients with skin breakdown/ulceration (CTCAE version 3.0, grade 2 or higher).

- Patients with hearing loss requiring hearing aid or intervention (i.e. interfering in
a clinical significant way with activities of daily living).

- Patients with multifocal peripheral sensory alterations or paresthesias (including
tingling) interfering with function, per patient report (example: activities of daily
living).

- History of arterial thromboembolic events, including transient ischemic attack (TIA),
cerebrovascular accident (CVA), unstable angina, or myocardial infarction (MI) within
the last 3 years.

- Urine protein: creatinine (UPC) ratio ≥ 1.0 at screening. A random urine sample is
collected. Total protein (mg/dL) and spot creatinine (mg/dL) are ordered for this
sample. The UPC ratio is calculated from the results of these tests.

- International normalized ratio (INR) > 1.5 or activated partial thromboplastin time
(aPTT) > 1.5 X upper limits of normal (UNL),

- Current use of warfarin, current use of heparin or low-molecular weight heparin,
chronic daily treatment with aspirin (> 325 mg/day) or nonsteroidal antiinflammatory
medications known to inhibit platelet function. Treatment with dipyramidole
(Persantine), ticlopidine (Ticlid), clopidogrel (Plavix) and or cilostazol (Pletal)
is not allowed.

- Patients with gross hemoptysis or hematemesis (defined as bright red blood of 1
teaspoon of more) within 1 month prior to Day 1 protocol treatment will be excluded
from this trial. Patients with incidental blood mixed with phlegm are not excluded.

- Esophageal varices, non-healing ulcer, wound, or bone fracture are exclusion
criteria. However, patients with skin breakdown overlying malignant neck
lymphadenopathy may be eligible, at the discretion of the investigator.

- Anatomic lesion that increases the risk of serious hemorrhage, such as encasement or
invasion of major blood vessels by primary tumor and/or by involved lymph nodes

- Blood pressure of > 150/100 mmHg

- New York Heart Association (NYHA) Grade II or greater congestive heart failure.

- Clinically significant peripheral vascular disease

- History of bleeding diathesis or hemorrhagic disorder, or coagulopathy.

- Major surgical procedure or significant traumatic injury within 28 days prior to
treatment with bevacizumab

- Core biopsy within 15 days prior to treatment with bevacizumab.

- Minor surgical procedures such as fine needle aspirations or placement of
percutaneous gastrostomy tube (PEG) less than 7 days prior to treatment with
bevacizumab

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior enrollment.

- Inability to comply with study and/or follow-up procedures

- Women who are pregnant or lactating