Radiation Therapy With or Without Cetuximab in Treating Patients Who Have Undergone Surgery for Locally Advanced Head and Neck Cancer

• ClinicalTrials.gov Identifier: NCT00956007
• Recruitment Status: Active, not recruiting
• First Posted: August 11, 2009
• Last Update Posted: March 30, 2018
• Sponsor: Radiation Therapy Oncology Group
• Collaborators: National Cancer Institute (NCI); NRG Oncology
• Information provided by (Responsible Party): Radiation Therapy Oncology Group

Tracking Information

• First Submitted Date: August 8, 2009
• First Posted Date: August 11, 2009
• Last Update Posted Date: March 30, 2018
• Actual Study Start Date: November 2009
• Estimated Primary Completion Date: August 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: June 12, 2013): Overall survival [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs after 372 events have been reported. ]
• Original Primary Outcome Measures (submitted: August 8, 2009): Overall survival
• Change History: Complete list of historical versions of study NCT00956007 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 12, 2013)

• Adverse events (dysphagia, xerostomia, and skin toxicity) according to CTCAE, v. 4 and their relationships with patient-reported outcomes at 3, 12, and 24 months [ Time Frame: From start of treatment to 2 years after end of treatment. ]
• Other acute adverse events (≤ 90 days from start of radiotherapy [RT]) according to CTCAE, v. 4 [ Time Frame: From start of treatment to 90 days. ]
• Other late adverse events (> 90 days from start of RT) according to CTCAE, v. 4 [ Time Frame: From 90 days after start of treatment to last follow-up. ]
• Disease-free survival [ Time Frame: From randomization to date of failure (local, regional or distant progression or death) or last follow-up. Analysis occurs at the same time as the primary outcome. ]
• Loco-regional control [ Time Frame: From randomization to date of failure (local or regional progression or distant progression or death) or last follow-up. Analysis occurs at the same time as the primary outcome. ]
• Quality of life as measured by Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) and EuroQol (EQ-5D) at baseline and at 3, 12, and 24 months [ Time Frame: From randomization to 2 years. ]
• Xerostomia as measured by University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) at baseline and at 3, 12, and 24 months [ Time Frame: From randomization to 2 years. ]
• Swallowing as measured by the normalcy of diet subscale of the Performance Status Scale for Head and Neck Cancer (PSS-HN) at baseline and at 3, 12, and 24 months [ Time Frame: From randomization to 2 years. ]
• Skin toxicity as measured by the Dermatology Life Quality Index (DLQI) at baseline and at 3, 12, and 24 months [ Time Frame: From randomization to 2 years. ]

Original Secondary Outcome Measures (submitted: August 8, 2009)

• Adverse events (dysphagia, xerostomia, and skin toxicity) according to CTCAE v3.0 and their relationships with patient-reported outcomes at 3, 12, and 24 months
• Other acute adverse events (≤ 90 days from start of radiotherapy [RT]) according to CTCAE v3.0
• Other late adverse events (> 90 days from start of RT) according to CTCAE v3.0
• Disease-free survival
• Loco-regional control
• Quality of life as measured by Functional Assessment of Cancer Therapy-Head & Neck (FACT-HN) and EuroQol (EQ-5D) at baseline and at 3, 12, and 24 months
• Xerostomia as measured by University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS) at baseline and at 3, 12, and 24 months
• Swallowing as measured by the normalcy of diet subscale of the Performance Status Scale for Head and Neck Cancer (PSS-HN) at baseline and at 3, 12, and 24 months
• Skin toxicity as measured by the Dermatology Life Quality Index (DLQI) at baseline and at 3, 12, and 24 months

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Radiation Therapy With or Without Cetuximab in Treating Patients Who Have Undergone Surgery for Locally Advanced Head and Neck Cancer
• Official Title: A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-Advanced Resected Head and Neck Cancer

Brief Summary

RATIONALE: Giving radiation therapy that uses a 3-dimensional (3-D) image of the tumor to help focus thin beams of radiation directly on the tumor, and giving radiation therapy in higher doses over a shorter period of time, may kill more tumor cells and have fewer side effects. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. It is not yet known whether radiation therapy is more effective when given alone or together with cetuximab in treating patients with head and neck cancer that has been removed by surgery.

PURPOSE: This randomized phase III trial is studying radiation therapy to see how well it works compared with radiation therapy given together with cetuximab in treating patients who have undergone surgery for locally advanced head and neck cancer.

Detailed Description

OBJECTIVES:

Primary

• Determine whether the addition of cetuximab to postoperative intensity-modulated radiotherapy (IMRT) will improve overall survival (OS) in patients with locally advanced squamous cell carcinoma of the head and neck at intermediate risk following surgery.

Secondary

• Assess the impact of the addition of cetuximab to postoperative IMRT on disease-free survival (DFS) of these patients.
• Assess the impact of the addition of cetuximab to postoperative IMRT on acute and late dysphagia, xerostomia, skin toxicity, and other toxicities according to common Toxicity Criteria for Adverse Effects (CTCAE), v. 4 and their relationships with patient-reported outcomes at 3, 12, and 24 months.
• Analyze tumor for epidermal growth factor receptor (EGFR), specifically the extent of EGFR overexpression by immuno-histochemistry (IHC) and FISH analysis, EGFRvIII expression, as well as the association of these assay data with OS and DFS.
• Analyze tumor for human papillomavirus (HPV) infection (as defined by in situ hybridization), specifically, within the cohort of patients with oropharynx cancer, to perform an exploratory analysis of the impact of HPV on DFS and OS of this patient subset.
• Analyze tumor DNA for TP53 mutations as a predictor of response to cetuximab and prognosis.
• Analyze germline DNA of polymorphic variants in EGFR intron repeats as a predictor of response to cetuximab.

Tertiary

• Assess the impact of the addition of cetuximab to postoperative IMRT on loco-regional control.
• Assess the impact of the addition of cetuximab to postoperative IMRT on patient-reported quality of life, swallowing, xerostomia, and skin toxicity based on head and neck specific instruments, including the Performance Status Scale for Head and Neck Cancer (PSS-HN), the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N), the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS), and the Dermatology Life Quality Index (DLQI).
• Assess the impact of the addition of cetuximab to postoperative IMRT on cost-utility analysis using the EuroQol (EQ-5D).
• Evaluate the utility of image-guided radiotherapy (IGRT) as a means of enhancing the efficacy (i.e., loco-regional control) of IMRT while reducing the acute and/or late toxicity (particularly xerostomia) and improving patient-reported outcomes (particularly XeQOLS scores).
• Retrospectively compare the loco-regional control rate in patients treated with IMRT alone (no IGRT or cetuximab) with similar patients treated with external beam radiotherapy alone in the postoperative clinical trial Radiation Therapy Oncology Group (RTOG)-95 01.

OUTLINE: This is a multicenter study. Patients are stratified according to clinical stage (T2-3 vs T4a), EGFR expression (high [≥ 80% of cells staining positive] vs low [< 80% of cells staining positive] vs not evaluable), primary site of disease (oral cavity vs larynx vs oropharynx p16+ vs oropharynx p16- vs oropharynx, p16 not evaluable), and use of image-guided radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo IMRT as in arm I. Patients also receive cetuximab IV over 1-2 hours once weekly beginning at least 5 days prior to the start of IMRT and continuing for 4 weeks after the completion of IMRT (for a total of 11 doses) in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and at 3, 12, and 24 months.

Tissue samples are collected periodically for further laboratory analysis.

After completion of study treatment, patients are followed up at 1 and 3 months, every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Head and Neck Cancer

Intervention

• Biological: cetuximab
  Given IV
• Radiation: intensity-modulated radiation therapy
  Patients undergo radiotherapy.

Study Arms

• Active Comparator: Arm I: Intensity-Modulated Radiotherapy
  Patients undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week for 6 weeks in the absence of disease progression or unacceptable toxicity.
  Intervention: Radiation: intensity-modulated radiation therapy
• Experimental: Arm II: IMRT plus cetuximab
  Patients undergo IMRT as in arm I. Patients also receive cetuximab IV over 1-2 hours once weekly beginning at least 5 days prior to the start of IMRT and continuing for 4 weeks after the completion of IMRT (for a total of 11 doses) in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Biological: cetuximab
  • Radiation: intensity-modulated radiation therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 28, 2018): 703
• Original Estimated Enrollment (submitted: August 8, 2009): 700
• Estimated Study Completion Date: August 2026
• Estimated Primary Completion Date: August 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed squamous cell carcinoma (including variants, such as verrucous carcinoma, spindle cell carcinoma, or carcinoma not otherwise specified) of the head and neck, including the following subtypes:

  • Oral cavity
  • Oropharynx
  • Larynx

• Clinical stage T1, N1-2, M0 OR T2-4a, N0-2, M0 disease based on the following diagnostic workup within the past 8 weeks:

  • General history and physical examination by a Radiation Oncologist and/or Medical Oncologist
  • Chest x-ray or chest CT scan (with or without contrast) or chest CT/PET scan (with or without contrast)

• Must have undergone gross total resection of the primary tumor with curative intent within the past 7 weeks with surgical pathology demonstrating ≥ 1 of the following criteria for "intermediate" risk of recurrence:

  • Perineural invasion
  • Lymphovascular invasion
  • Single lymph node > 3 cm or ≥ 2 lymph nodes (all < 6 cm) (no extracapsular extension)
  • Close margin(s) of resection, defined as cancer extending to within 5 mm of a surgical margin, and/or an initially focally positive margin that is subsequently superseded by intraoperative negative margins (similarly, patients whose tumors had focally positive margins in the main specimen but negative margins from re-excised samples in the region of the positive margin are eligible)
  • Pathologically confirmed T3 or T4a primary tumor
  • T2 oral cavity cancer with > 5 mm depth of invasion
• No positive margin(s) (defined as tumor present at the cut or inked edge of the tumor), nodal extracapsular extension, and/or gross residual disease after surgery

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-1
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention allowed)
• Total bilirubin < 2 times upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 times ULN
• Serum creatinine < 2 times ULN OR creatinine clearance ≥ 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other invasive malignancy within the past 3 years, except for nonmelanomatous skin cancer or previously treated carcinoma in situ of the breast, oral cavity, or cervix
• No simultaneous primary or bilateral tumors

• No severe, active co-morbidity, including any of the following:

  • Unstable angina and/or congestive heart failure requiring hospitalization within the past 6 months
  • Transmural myocardial infarction within the past 6 months
  • Acute bacterial or fungal infection requiring IV antibiotics at the time of study registration
  • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy
  • Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to have required oxygen therapy within the past year
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
  • AIDS based on current Centers for Disease Control (CDC) definition

  • Grade 3-4 electrolyte abnormalities according to CTCAE, v. 4, including any of the following:

    • Serum calcium (ionized or adjusted for albumin) < 7 mg/dL or > 12.5 mg/dL*
    • Glucose < 40 mg/dL or > 250 mg/dL
    • Magnesium < 0.9 mg/dL or > 3 mg/dL*
    • Potassium < 3.0 mmol/L or > 6 mmol/L*
    • Sodium < 130 mmol/L or > 155 mmol/L* NOTE: *Despite intervention to normalize levels.
• No prior allergic reaction to cetuximab

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior systemic chemotherapy or anti-epidermal growth factor (EGF) therapy for this cancer

  • Prior chemotherapy or anti-EGF therapy for a different cancer allowed
• No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields
• No concurrent amifostine as a radioprotector
• No concurrent granulocyte colony-stimulating factor or erythropoietin

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, China, Saudi Arabia, United States
• Removed Location Countries: Hong Kong

Administrative Information

• NCT Number: NCT00956007
• Other Study ID Numbers: RTOG 0920; CDR0000651536; NCI-2011-00878 ( Registry Identifier: CTRP (Clinical Trials Reporting Program )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Radiation Therapy Oncology Group
• Study Sponsor: Radiation Therapy Oncology Group

Collaborators

• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Study Chair: Mitchell Machtay, MD; University Hospitals Seidman Cancer Center

• PRS Account: Radiation Therapy Oncology Group
• Verification Date: March 2018