Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer
Radiation: Radiation therapy
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
|Official Title:||Phase II Randomized Trial of Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer|
- 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. [ Time Frame: 18 months to patient accrual and 2 years of follow-up after closing accrual. ] [ Designated as safety issue: Yes ]
- Secondary outcome measures include within-arm estimates of time to local progression, time to regional progression, overall survival and toxicity profiles. [ Time Frame: 2 years of follow-up after closing accrual ] [ Designated as safety issue: Yes ]
|Study Start Date:||October 2008|
|Study Completion Date:||September 2014|
|Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
Active Comparator: Arm A
Cetuximab, Pemetrexed and Radiation therapy
Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments.
Other Name: ErbituxDrug: Pemetrexed
Pemetrexed is approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy.
Other Name: AlimtaRadiation: 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
Experimental: Arm B
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab
Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy.
Other Name: Avastin
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00703976
|United States, Pennsylvania|
|University of Pittsburgh Medical Center|
|Pittsburgh, Pennsylvania, United States, 15232|
|Principal Investigator:||Julie E Bauman, MD||University of Pittsburgh|