Phase II Randomized Trial of Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer
Overview
- Phase
- Phase 2
- Intervention
- Cetuximab
- Conditions
- Cancer
- Sponsor
- University of Pittsburgh
- Enrollment
- 80
- Locations
- 1
- Primary Endpoint
- 2-year Progression-free Survival (PFS)
- Status
- Completed
- Last Updated
- 9 years ago
Overview
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.
Investigators
Eligibility Criteria
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 study.
- •No prior treatment for head and neck cancer. Limited, organ-preserving surgery is allowed
- •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 normal
- •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
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 effects.
- •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 indicated.
Arms & Interventions
Cetuximab, Pemetrexed and Radiation therapy
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
Intervention: Cetuximab
Cetuximab, Pemetrexed and Radiation therapy
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
Intervention: Pemetrexed
Cetuximab, Pemetrexed and Radiation therapy
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
Intervention: Radiation therapy
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab
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.
Intervention: Bevacizumab
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab
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.
Intervention: Cetuximab
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab
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.
Intervention: Pemetrexed
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab
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.
Intervention: Radiation therapy
Outcomes
Primary Outcomes
2-year Progression-free Survival (PFS)
Time Frame: 18 months to patient accrual and 2 years of follow-up after closing accrual.
Two-year PFS is an estimated percentage of participants without disease progression (locoregional or distant) at two years after the start of study treatment. Progression was defined using Response Evaluation Criteria In Solid Tumors (RECIST v1.0), as: at least a 20% (and at least 5 millimeters) increase in the sum of the diameters of target lesions, or the appearance of one or more new lesions.
Secondary Outcomes
- 2-year Overall Survival (OS)(2 years of follow-up after closing accrual)