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Phase II Randomized Trial of Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer

Phase 2
18 Years
Open (Enrolling)

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Trial Information

Phase II Randomized Trial of Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer


Patients with squamous cell carcinoma of the head and neck (HNSCC) are increasingly treated
with primary chemoradiotherapy. The incorporation of novel targeted therapies to
chemoradiotherapy is of major interest since it may potentially improve efficacy without
significantly increasing toxicity. Radiation and cetuximab, a chimeric anti-epidermal growth
factor receptor monoclonal antibody, has emerged as a standard non-surgical therapy for
stage III/IV HNSCC. Bevacizumab, an anti-vascular endothelial growth factor antibody is
currently being investigated in HNSCC with promising results. A phase II study investigating
the combination of pemetrexed and bevacizumab in recurrent or metastatic HNSCC is currently
ongoing at our institution with encouraging results (UPCI# 05-002). In addition, we are
completing a phase I trial of radiation, cetuximab plus pemetrexed (UPCI #05-005).
Pemetrexed was dose escalated in successive cohorts of patients on 3 dose levels: starting
dose level (0) 350 mg/m2, dose level (-1) 200 mg/m2, dose level (+1) 500 mg/m2. Currently
three patients have been treated at dose level +1 (pemetrexed 500 mg/m2) which will be the
pemetrexed dose in this study. No dose limiting toxicities (DLTs) have been observed at
this dose level, which was the maximum tolerated dose (MTD) for the combination regimen in
previously non-irradiated patients.

Specific aims

To evaluate the progression-free survival at 2 years (primary endpoint), locoregional and
distant disease-free survival, overall survival, toxicities and quality of life with the
combination of radiation, cetuximab and pemetrexed with or without bevacizumab in patients
with locally advanced HNSCC. Also, we plan to collect tumor tissue from previous diagnostic
procedures and baseline blood specimens for future correlative studies.

Subject population

We will enroll patients with previously untreated stage III/IV squamous cell carcinoma or
undifferentiated carcinoma of the head and neck (except nasopharynx and unknown primary).
Patients should not have active bleeding due to HNSCC or history of persistent bleeding due
to HNSCC that required major intervention (surgery or embolization) to be controlled. Please
see section 3 for detailed eligibility criteria.

Treatment plan

Patients will be randomized in two arms. In arm A, patients will be treated with radiation
2Gy/day for 7 weeks to a total of 70 Gy, cetuximab 250mg/m2 weekly during radiation, after a
loading dose of 400mg/m2 one week prior starting radiation, and pemetrexed 500mg/m2 every 21
days for 3 cycles. In arm B, patients will be treated with the same regimen with the
addition of bevacizumab 15mg/kg every 21 days for 3 cycles (see section 5 for detailed
treatment plan and dose modifications).

Statistical design and sample size

Phase II, randomized, multi-center study with progression-free survival at 2 years as the
primary endpoint. The historical control is a 2-year progression-free survival of 46% with
radiation plus cetuximab alone. We assume a 2 year progression free survival of 64% (40%
relative improvement in progression-free survival over historical control) as worthy of
further testing. We will require 40 evaluable patients per arm for a total of 80 patients.
Alpha = 0.1, beta = 0.1; all tests one-tailed.

Inclusion Criteria:

- All patients must have pathologically confirmed AJCC 6th edition (see Appendix) stage
III or IV (M0) squamous cell carcinoma or undifferentiated or poorly differentiated
carcinoma of the oropharynx, larynx, or hypopharynx with no evidence of distant
metastasis. Biopsy sampling of primary tumor with pathology report documentation of
confirmed diagnostic tissue type is required. Patients should be evaluated by a
Radiation Oncologist, Medical Oncologist and Otolaryngologist prior to enrolling on

- No prior treatment for head and neck cancer. Limited, organ-preserving surgery is

- ECOG performance status 0-1

- Unidimensionally measurable disease is not required. However, patients should
require treatment with full dose radiotherapy (not postoperative)

- Age greater or equal to 18 years

- Absolute neutrophil count greater or equal to 1500/µl, Platelet count greater or
equal to 100,000/µl

- Creatinine clearance 45 ml/min or higher calculated using the Cockcroft-Gault formula

- Total bilirubin within normal limits and AST/ALT less than 3 times the upper limit of

- Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC)
ratio. For UPC ratio >0.5, 24-hour urine protein should be obtained and the level
must be <1000mg for patients to be eligible

- Informed consent must be obtained from all patients prior to beginning therapy.
Patients should have the ability to understand and the willingness to sign a written
informed consent document

- Patients should be willing and able to take folic acid and vitamin B12
supplementation and should interrupt aspirin or other non-steroidal anti-inflammatory
agents for a 5-day period

- The use of anti-platelet agents(e.g. dipyridamole (Persatine), ticlopidine (Ticlid),
clopidogrel (Plavix)) is allowed only if patient is not receiving aspirin or NSAID's
known to inhibit platelet function.

- Patients who meet the following criteria will be excluded due to the possibility of
increased risk for tumor bleeding with bevacizumab therapy:

- active bleeding due to head and neck cancer of more than ½ teaspoon of bright
red blood per episode or history of persistent bleeding due to SCCHN that
required major intervention (surgery or embolization) to be controlled.

- history of gross hemoptysis (bright red blood of .05 teaspoon or more per
episode of coughing) less than or equal to 3 months prior to enrollment

- history of coagulopathy or hemorrhagic disorders

- Patients should not be on therapeutic anticoagulation (prophylactic use of warfarin 1
mg per day is allowed) and INR should be < 1.5 at registration.

- Patients with a prior history of squamous cell or basal carcinoma of the skin or in
situ cervical cancer must have been curatively treated. Patients with a history of
other prior malignancy must have been treated with curative intent and must have
remained disease-free for 5 years post diagnosis

- Patients with history of hypertension must be well-controlled upon study entry
(≤150/90) on a stable regimen of anti-hypertensive therapy. Patients should not have
any prior history of hypertensive crisis or hypertensive encephalopathy.

- 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. Prior surgical therapy will consist only of
incisional or excisional biopsy and organ sparing procedures such as debulking of
airway compromising tumors or neck dissection in a patient with an existing primary
tumor. Any non-biopsy procedure must have taken place >4 weeks but <3 months of
initiating protocol treatment. No history of abdominal fistula, gastrointestinal
perforation, or intra-abdominal abscess within 6 months prior to registration. No
serious non-healing wound, ulcer, or bone fracture.

- No unstable angina or myocardial infarction within the previous 6 months; no
symptomatic congestive heart failure; no serious cardiac arrhythmia requiring
medication; no clinically significant peripheral vascular disease; no history of
aortic dissection; no history of any CNS cerebrovascular ischemia or stroke within
the last 6 months; no active serious infection. All patients will have a baseline
EKG. If abnormalities consistent with active coronary artery disease are detected,
the patient will be referred to a cardiologist for appropriate evaluation and
management prior to treatment on study

- For patients who have baseline clinically significant pleural or peritoneal effusions
(on the basis of symptoms or clinical examination) before initiation of protocol
therapy, consideration should be given to draining the effusion prior to starting
therapy due the potential of increased toxicity with pemetrexed in that setting

- Submission of archival tumor samples, unstained slides or blocks, for correlative
studies is strongly encouraged, but not required for subject participation if tissue
is not readily available or quantity is not sufficient for release per submitting

Exclusion Criteria:

- Patients who are receiving any other investigational agents.

- Ineligible will be patients with uncontrolled intercurrent illness including, but not
limited to,ongoing or active infection or psychiatric illness/social situations that
would limit compliance with study requirements.

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

- Women must not be pregnant or breast feeding because chemotherapy may be harmful to
the fetus or the nursing infant. Pregnant women are excluded from this study because
chemotherapy and/or bevacizumab have the potential for teratogenic or abortifacient

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

Type of Study:


Study Design:

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

Outcome Measure:

Each treatment arm will be evaluated on the basis of the primary endpoint - estimated progression-free survival,to be defined as the time from initiation of treatment to the first documented progressive disease.

Outcome Time Frame:

18 months to patient accrual and 2 years of follow-up after closing accrual.

Safety Issue:


Principal Investigator

Julie E Bauman, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Pittsburgh


United States: Institutional Review Board

Study ID:

UPCI 07-021



Start Date:

October 2008

Completion Date:

December 2013

Related Keywords:

  • Cancer
  • head and neck cancers
  • Head and Neck Neoplasms



University of Pittsburgh Medical Center Pittsburgh, Pennsylvania  15213