Bevacizumab and Erlotinib in Treating Patients With Recurrent or Metastatic Head and Neck Cancer

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose and dose-limiting toxicity of bevacizumab when
administered with erlotinib in patients with recurrent or metastatic head and neck cancer.

II. Determine the objective response rate and stable disease/absence of early progression in
patients treated with this regimen.

OUTLINE: This is a dose-escalation study of bevacizumab followed by a randomized, multicenter
study.

Phase I: Patients receive bevacizumab IV over 30-90 minutes on day 1 and oral erlotinib on
days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.

Cohorts of 3-6 patients receive escalating doses of bevacizumab until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.

Phase II: Course 1 is 28 days in length. All subsequent courses are 21 days.

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

Arm I: Patients receive bevacizumab IV over 30-90 minutes on day 15 and oral erlotinib on
days 1-28.

Arm II: Patients receive bevacizumab IV over 30-90 minutes on day 1 and oral erlotinib on
days 1-28.

All subsequent courses: All patients receive bevacizumab as in arm II and oral erlotinib on
days 1-21.

Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Histologically or cytologically confirmed squamous cell cancer of the head and neck

- Recurrent or metastatic disease

- Determined to be incurable by surgery or radiotherapy

- Measurable disease

- No tumor involvement encasing or too close in proximity to a major artery or vein

- No known brain metastases

- No prior or concurrent CNS disease

- No primary brain tumor

- Performance status - ECOG 0-2

- Performance status - Karnofsky 60-100%

- More than 12 weeks

- No history of bleeding diathesis

- WBC at least 3,000/mm^3

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- INR less than 1.5

- Bilirubin normal

- AST and ALT no greater than 2.5 times upper limit of normal

- Creatinine normal

- Creatinine clearance at least 60 mL/min

- No significant renal impairment

- 24-hour urinary protein less than 0.5 g required if more than trace proteinuria at
baseline

- No uncontrolled hypertension

- No symptomatic congestive heart failure

- No serious cardiac arrhythmia requiring medication

- No deep venous thrombosis

- No prior stroke

- No New York Heart Association class II-IV heart disease

- No grade II-IV peripheral vascular disease within the past year

- No arterial thromboembolic event within the past 6 months, including any of the
following:

- Unstable angina pectoris

- Myocardial infarction

- Transient ischemic attack

- Cerebrovascular accident

- No clinically significant peripheral artery disease

- No significant ophthalmologic abnormalities* including any of the following:

- Severe dry eye syndrome

- Keratoconjunctivitis sicca

- Sjögren's syndrome

- Severe exposure keratopathy

- Disorders that might increase the risk for epithelium-related complications
(e.g., bullous keratopathy, aniridia, severe chemical burns, neutrophilic
keratitis)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No prior allergic reactions to compounds of similar chemical or biologic composition
to bevacizumab or other study agents

- No known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies

- No significant traumatic injury within the past 28 days

- No other concurrent uncontrolled illness

- No psychiatric illness or social situation that would preclude study compliance

- No ongoing or active infection requiring parenteral antibiotics

- No serious non-healing wound ulcer or bone fracture

- No seizures not controlled by standard medical therapy

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

- More than 4 weeks since prior radiotherapy

- More than 4 weeks since prior major surgery

- More than 4 weeks since prior open biopsy

- Recovered from prior therapy

- No more than 1 prior regimen for recurrent disease

- No prior epidermal growth factor receptor (EGFR)-based therapy for recurrent disease

- No prior vascular EGFR-based therapy for recurrent disease

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent chronic use of aspirin (325 mg/day or more) or other nonsteroidal
anti-inflammatory drugs

- No concurrent warfarin or heparin, including low-molecular weight heparin

- No other concurrent or recent (within 1 month) thrombolytic agents or full-dose
anticoagulants (except to maintain patency of preexisting, permanent indwelling IV
catheters)