Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer

Phase 2

Completed

Conditions: Cancer

Interventions: Drug: Cetuximab
Drug: Bevacizumab
Drug: Pemetrexed
Radiation: Radiation therapy

Registration Number: NCT00703976

Lead Sponsor: University of Pittsburgh

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 80

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
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 pathologist.

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cetuximab, Pemetrexed and Radiation therapy	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
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab	Radiation therapy	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.
Cetuximab, Pemetrexed and Radiation therapy	Pemetrexed	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
Cetuximab, Pemetrexed and Radiation therapy	Cetuximab	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
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab	Cetuximab	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.
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab	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.
Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab	Pemetrexed	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.

Primary Outcome Measures

Name	Time	Method
2-year Progression-free Survival (PFS)	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 Outcome Measures

Name	Time	Method
2-year Overall Survival (OS)	2 years of follow-up after closing accrual	Two-year OS is an estimated percentage of participants still living at two years after the start of study treatment.