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.
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.
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.
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.
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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.
18 months to patient accrual and 2 years of follow-up after closing accrual.
Julie E Bauman, MD
University of Pittsburgh
United States: Institutional Review Board
|University of Pittsburgh Medical Center||Pittsburgh, Pennsylvania 15213|