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A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer

Phase 2
18 Years
Not Enrolling
Head and Neck Cancer, Squamous Cell Carcinoma

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Trial Information

A Phase II Trial of Cetuximab and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer

Approximately 40,000 new cases of head and neck cancer are diagnosed annually in the United
States 1. Squamous cell carcinomas account for more than 90% of head and neck cancer cases.
Patients with squamous cell carcinoma of the head and neck (HNSCC) usually present with
locoregionally advanced disease. Initial presentation with distant metastasis may occur in
about 10% of all patients. However, recurrence of disease either in local or distant sites
after potentially curative treatment with surgery, radiation, and/or chemotherapy occurs in
more than 50% of patients. Therefore, the majority of patients with HNSCC develop recurrent
or metastatic disease during the course of their illness. These patients have a dismal
prognosis with a median survival of 6-9 months 2-4.

Active single agents in head and neck squamous cell carcinoma include methotrexate,
bleomycin, cisplatin, carboplatin, 5-FU, paclitaxel, docetaxel, and CPT-11. A small
randomized study showed that cisplatin monotherapy prolongs survival compared with best
supportive care 5. Response rates for single agents range between 10-40% 2, 4, 6, 7.
Combination chemotherapy with platinum agents, in spite of achieving higher response rates
(about 30% in phase III trials), has not been shown to produce a survival benefit compared
to single agents in randomized comparisons in recurrent/metastatic head and neck cancer 2,

Inclusion Criteria

Eligibility Criteria

Patients must have histologically or cytologically confirmed Squamous Cell Cancer of the
Head and Neck either (a) metastatic (i.e. American Joint Committee on Cancer Staging
System, 6th edition, stage IVC) or (b) recurrent, judged incurable by surgery or

Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >20 mm
with conventional techniques or as >10 mm with CT scan). RECIST criteria will be used (see
section 9).

Therapeutic history in conformance with the following:

No more than one prior adjuvant/neoadjuvant chemotherapy and/or concomitant
chemoradiotherapy regimen that may have included biologic/targeted agent.

No more than one prior regimen (chemotherapy or biologic/targeted) for
recurrent/metastatic disease

ECOG performance status of 0-2 (Karnofsky > 60%; see Appendix A).

Patients must have normal organ and marrow function as defined below:

absolute neutrophil count > 1,000/L platelets > 75,000/L total bilirubin
within normal institutional limits

AST(SGOT)/ALT(SGPT) 5 X institutional upper limit of normal creatinine within
normal institutional limits


creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above
institutional normal

Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
ratio (see Appendix). For UPC ratio > 0.5, 24-hour urine protein should be obtained and
the level should be <1000 mg for patient enrollment.

Note: UPC ratio of spot urine is an estimation of the 24 urine protein excretion - a UPC
ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. UPC ratio is
calculated using on of the following formula:

[urine protein]/[urine creatinine] - if both protein and creatinine are reported in mg/Dl
[(urine protein) x0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L

All patients should have baseline tumor tissue available for EGFR determination
(therapeutic target of cetuximab) and biomarker studies. Patients without available tissue
at baseline may undergo tumor biopsy. Patients who provide consent and have accessible
tumors will have a repeat biopsy 14 days (an interval between 12-16 days is acceptable)
post initiation of therapy. Priority for study entry will be given to patients with easily
accessible tumor and who consent to repeat biopsy. Study entry will not be restricted to
patients who agree to further biopsies. If a patient enrolls on study and later refuses
biopsy (excluding diagnostic), he/she may remain on study.

No prior treatment with cetuximab or bevacizumab or other EGFR or VEGF targeting agents.

Patients should not have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or
mitomycin C) and biologic/targeted agents within 3 weeks. At least 3 months should have
elapsed after prior therapy with monoclonal antibodies.

At least 3 weeks should have elapsed from prior radiotherapy.

Patients must have no history of gross hemoptysis (defined as bright red blood of a ½
teaspoon or more) or coagulopathy. Patients with history of major tumor-related bleeding
that is not controlled despite locoregional treatment or at high risk of recurrent
tumor-related bleeding will be excluded.

Patients should not have a history of thrombosis (e.g. pulmonary embolism or deep venous
thrombosis) and should not be on therapeutic anticoagulation (prophylactic use of warfarin
1 mg per day is allowed) and INR should be less than 1.5 at registration.

Patients with history of hypertension must be well-controlled (≤150/100) on a stable
regimen of anti-hypertensive therapy.

Patients with tumors that invaded major vessels (e.g. the carotid) as shown unequivocally
by imaging studies will be excluded due to the possibility of increased risk for tumor
bleeding with bevacizumab therapy.

No major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment, or anticipation of need for major surgical procedure during the
course of the study. No history of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within 28 days prior to registration. No serious non-healing
wound, ulcer, or bone fracture.

No unstable angina or myocardial infarction within the previous 6 months; no uncontrolled
hypertension; no symptomatic congestive heart failure; no serious cardiac arrhythmia
requiring medication; no clinically significant peripheral vascular disease; no history of
any CNS cerebrovascular ischemia or stroke within the last 6 months; no active serious

No other coexisting medical condition that would preclude full compliance with the study.

Patients may not be receiving any other investigational agents.

Patients with known brain metastases should be excluded from this clinical trial because
of their poor prognosis and because of increased risks with bevacizumab.

Patients should not have a history of prior severe infusion reaction to a monoclonal
antibody. Patients with known hypersensitivity of Chinese hamster ovary cell products or
other recombinant human antibodies.

No history of prior malignancy, with the exception of curatively treated squamous cell or
basal carcinoma of the skin or in situ cervical cancer, unless there is a 3-year
disease-free interval.

Age > 18 years. Because no dosing or adverse event data are currently available on the use
of cetuximab and bevacizumab in patients <18 years of age, children are excluded from
this study but will be eligible for future pediatric single-agent trials, if applicable.

Ability to understand and the willingness to sign a written informed consent document.

Pregnant women are excluded from this study because cetuximab and bevacizumab have the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the mother
with cetuximab and bevacizumab, breastfeeding should be discontinued if the mother is
treated with cetuximab and bevacizumab. The effects of cetuximab and bevacizumab on the
developing human fetus at the recommended therapeutic dose are unknown. For this reason
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control) prior to study entry and for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while in
this study, she should inform her treating physician immediately.

HIV-positive patients receiving combination anti-retroviral therapy are excluded from the
study because of possible drug interactions with cetuximab and bevacizumab. Appropriate
studies will be undertaken in patients receiving combination anti-retroviral therapy when

Inclusion of Women and Minorities

Both men and women and members of all ethnic groups are eligible for this trial. The
proposed study population is illustrated in the table below.

Inclusion of Women in Plan: The gender distribution of our head and neck cancer patients
is detailed in the table below. All efforts are made to recruit women patients with head
and neck cancer to the University of Pittsburgh Medical Center.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

1.1. To determine the objective response rate (primary endpoint) with the combination of cetuximab plus bevacizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma.

Outcome Time Frame:

5 years

Safety Issue:


Principal Investigator

Michael Gibson, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:



United States: Food and Drug Administration

Study ID:




Start Date:

September 2006

Completion Date:

February 2012

Related Keywords:

  • Head and Neck Cancer
  • Squamous Cell Carcinoma
  • head and neck cancer
  • cetuximab
  • bevacizumab
  • squamous cell carcinoma
  • Squamous Cell Carcinoma of the Head and Neck
  • Carcinoma
  • Carcinoma, Squamous Cell
  • Head and Neck Neoplasms



University of Michigan Ann Arbor, Michigan  48109-0624
Case Western Reserve University Cleveland, Ohio  44106
UPMC / UPMC Cancer Centers Pittsburgh, Pennsylvania  15232
University of Texas MD Anderson Houston, Texas  77030