Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer - Full Text View

Sponsors and Collaborators:	University of Pittsburgh Eli Lilly and Company Genentech
Information provided by:	University of Pittsburgh
ClinicalTrials.gov Identifier:	NCT00703976

Purpose

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 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.

Condition	Intervention	Phase
Cancer	Drug: Bevacizumab Drug: Cetuximab Drug: Pemetrexed Radiation: Radiation therapy	Phase II

MedlinePlus related topics: Cancer Head and Neck Cancer

Drug Information available for: Pemetrexed disodium Pemetrexed Bevacizumab Cetuximab

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Diagnostic, Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study
Official Title:	Phase II Randomized Trial of Radiation, Cetuximab and Pemetrexed With or Without Bevacizumab in Locally Advanced Head and Neck Cancer

Further study details as provided by University of Pittsburgh:

Primary Outcome Measures:

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 accruall ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

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 ]

Estimated Enrollment:	80
Study Start Date:	October 2008
Estimated Study Completion Date:	August 2012
Estimated Primary Completion Date:	August 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm A: Active Comparator Cetuximab, Pemetrexed and Radiation therapy	Drug: Cetuximab Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments. Drug: Pemetrexed Pemetrexed is approved by the Food and Drug Administration (FDA) for head and neck cancer when used in combination with radiation therapy. Radiation: 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 B: Experimental Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab	Drug: Bevacizumab Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy.

Arms

Assigned Interventions

Arm A: Active Comparator

Cetuximab, Pemetrexed and Radiation therapy

Drug: Cetuximab

Cetuximab is approved by the FDA for head and neck cancers in patients who have failed other chemotherapy treatments.

Drug: Pemetrexed

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

Radiation: 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 B: Experimental

Cetuximab, Pemetrexed, Radiation Therapy plus Bevacizumab

Drug: Bevacizumab

Bevacizumab is approved by the Food and Drug Administration (FDA) for colorectal cancer and non-small cell lung cancer in combination of chemotherapy.

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, after a loading dose of 400mg/m2 one week prior starting radiation, and pemetrexed 500mg/m2 every 21 days. In arm B, patients will be treated with the same regimen with the addition of bevacizumab 15mg/kg every 21 days. After the completion of the combination treatment, if there is no progression, bevacizumab 15mg/kg every 3 weeks will be administered alone in arm B. Bevacizumab maintenance will continue for 24 weeks post radiation therapy completion (8 additional cycles of bevacizumab) unless disease progression or intolerable toxicity (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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

All patients must have pathologically confirmed AJCC 6th edition 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. 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
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
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
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) < 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. No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days 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
Patients must be agreeable to submit archival tumor samples, unstained slides or blocks, for correlative studies

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00703976

Contacts

Contact: Athanassios Argiris, MD	412-648 6575	argirisae@upmc.edu
Contact: Rita Johnson, RN	412-647-8571	johnsonr1@upmc.edu

Locations

United States, Pennsylvania
University of Pittsburgh Medical Center	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Athanassios Argiris, MD 412-648-6575 argirisae@upmc.edu
Contact: Rita Johnson, RN 412-647-8571 johnsonr1@upmc.edu
Principal Investigator: Athanassios Argiris, MD
Sub-Investigator: Jennifer R Grandis, MD
Sub-Investigator: Marjorie Romkes,, Ph.D.
Sub-Investigator: Gauri Kiefer, MD
Sub-Investigator: Jennifer Osborn, MD
Sub-Investigator: Samuel Jacobs, MD
Sub-Investigator: Ronald Stoller, MD
Sub-Investigator: Martin Earle, MD
Sub-Investigator: Andrew Laman, MD
Sub-Investigator: Raja Seethala, MD
Sub-Investigator: Hyoung Kim, MD
Sub-Investigator: Kevin Kane, MD
Sub-Investigator: Louis Pietragallo, MD
Sub-Investigator: Robert Volkin, MD
Sub-Investigator: Richard Pinkerton, MD
Sub-Investigator: Stewart Lancaster, MD
Sub-Investigator: William Ferri, MD
Sub-Investigator: Theodore Crandall, MD
Sub-Investigator: Robert Gluckman, MD
Sub-Investigator: Kiran Rajasenan, MD
Sub-Investigator: Sheryl Simon, MD
Sub-Investigator: Eric Safayan, MD
Sub-Investigator: Rashid Awan, MD
Sub-Investigator: William R Wynert, MD
Sub-Investigator: Michael Voloshin, MD
Sub-Investigator: Peter Ellis, MD
Sub-Investigator: Bernard Zidar, MD
Sub-Investigator: Mark S Georgiadis, MD
Sub-Investigator: Terry Evans, MD
Sub-Investigator: Franklin Viverette, MD
Sub-Investigator: Matthew Sulecki, MD
Sub-Investigator: Jin Lee, MD
Sub-Investigator: Edward P Balaban, DO, FACP
Sub-Investigator: Alfred P Doyle, MD
Sub-Investigator: Michael M Sherry, MD
Sub-Investigator: Marmee Maylone, CRNP
Sub-Investigator: Eugene Myers, MD
Sub-Investigator: Robert Ferris, MD
Sub-Investigator: Jonas Johnson, MD
Sub-Investigator: Carl Snyderman, MD
Sub-Investigator: Richardo Carrau, MD
Sub-Investigator: David Friedland, MD
Sub-Investigator: Barry Lembersky, MD
Sub-Investigator: Stanley M Marks, MD
Sub-Investigator: Jeffrey E Shogan, MD
Sub-Investigator: Dennis Meisner, MD
Sub-Investigator: Christopher Lindberg, PA-C
Sub-Investigator: Steven Burton, MD
Sub-Investigator: Melvin Deutsch, MD
Sub-Investigator: Dwight Heron, MD
Sub-Investigator: Ryan Smith, MD
Sub-Investigator: Robert Piroli, MD
Sub-Investigator: Douglas Kondziolka, MD
Sub-Investigator: Wayne Pfrimmer, MD
Sub-Investigator: Alexis Megadulis, MD
Sub-Investigator: Patrick Kane, MD
Sub-Investigator: Joel Greenberger, MD
Sub-Investigator: John C Flickinger, MD
Sub-Investigator: Mohammad Rahman, MD
Sub-Investigator: Susan Rakfal, MD
Sub-Investigator: Sanjeev Bahri, MD
Sub-Investigator: Kiran Mehta, MD
Sub-Investigator: Alex Chen, MD
Sub-Investigator: Kristina Gerszten, MD
Sub-Investigator: Sushil Beriwal, MD
Sub-Investigator: Richard Antemann, MD
Sub-Investigator: David Stefanik, MD
Sub-Investigator: Robert Werner, MD
Sub-Investigator: Harry Katz, MD
Sub-Investigator: Rita Johnson, RN
Sub-Investigator: Maury Rosenstein, MD
Sub-Investigator: Prahba Bansal, MD
Sub-Investigator: Michael Gibson, MD

Sponsors and Collaborators

University of Pittsburgh

Eli Lilly and Company

Genentech

Investigators

Principal Investigator:

Athanassios Argiris, MD

University of Pittsburgh

More Information

Responsible Party:	University of Pittsburgh Medical Center ( Athanassios Argiris,MD, FACP )
Study ID Numbers:	UPCI 07-021
Study First Received:	June 20, 2008
Last Updated:	November 18, 2008
ClinicalTrials.gov Identifier:	NCT00703976
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Pittsburgh:

head and neck cancers

Study placed in the following topic categories:

Folic Acid
Pemetrexed
Head and Neck Neoplasms
Cetuximab
Bevacizumab

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Growth Substances
Physiological Effects of Drugs
Enzyme Inhibitors
Folic Acid Antagonists

Angiogenesis Inhibitors
Pharmacologic Actions
Neoplasms
Neoplasms by Site
Therapeutic Uses
Growth Inhibitors
Angiogenesis Modulating Agents

ClinicalTrials.gov processed this record on January 15, 2009