Conditions: Cancer
Keywords: head and neck cancers
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 80
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the effects (good and bad) of chemoradiotherapy with or without Bevacizumab (Avastin). Chemoradiotherapy is the combination of chemotherapy (the drugs pemetrexed and cetuximab) and radiation. Pemetrexed is not approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy. Cetuximab is also approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments. Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy. In this study, the use of bevacizumab is investigational.

Detailed description:
Background

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.

Arms:
arm 1: Cetuximab, Pemetrexed and Radiation therapy Cetuximab: Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments.

Pemetrexed: Pemetrexed is approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy.

Radiation therapy: Radiation therapy standard fractionation 2 Gy/day without planned interruptions beginning on day 1 (Monday or Tuesday preferred). Radiation will be given 5 days/week, Monday through Friday, for 7 consecutive weeks arm 2: Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab Cetuximab: Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments.

Pemetrexed: Pemetrexed is approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy.

Radiation therapy: Radiation therapy standard fractionation 2 Gy/day without planned interruptions beginning on day 1 (Monday or Tuesday preferred). Radiation will be given 5 days/week, Monday through Friday, for 7 consecutive weeks Bevacizumab: Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy.

Interventions: intervention 1: Bevacizumab intervention 2: Cetuximab intervention 3: Pemetrexed intervention 4: Radiation therapy
Intervention descriptions: intervention 1: Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy. intervention 2: Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments. intervention 3: Pemetrexed is approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy. intervention 4: Radiation therapy standard fractionation 2 Gy/day without planned interruptions beginning on day 1 (Monday or Tuesday preferred). Radiation will be given 5 days/week, Monday through Friday, for 7 consecutive weeks

Protocol document: