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Adjuvant Cetuximab and Chemoradiotherapy Using Either Cisplatin or Docetaxel in Treating Patients With Resected Stage III or Stage IV Squamous Cell Carcinoma or Lymphoepithelioma of the Head and Neck

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ClinicalTrials.gov Identifier: NCT00084318
Recruitment Status : Completed
First Posted : June 11, 2004
Results First Posted : November 22, 2016
Last Update Posted : December 12, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
NRG Oncology
Information provided by (Responsible Party):
Radiation Therapy Oncology Group

Study Description
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Brief Summary:

RATIONALE: Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Drugs used in chemotherapy, such as cisplatin and docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Cisplatin and docetaxel may make the tumor cells more sensitive to radiation therapy. Combining a monoclonal antibody with chemoradiotherapy and giving them after surgery may kill any remaining tumor cells.

PURPOSE: This randomized phase II trial is studying adjuvant cetuximab given together with chemoradiotherapy using cisplatin to see how well it works compared to adjuvant cetuximab given together with chemoradiotherapy using docetaxel in treating patients with resected stage III or stage IV squamous cell carcinoma (cancer) or lymphoepithelioma of the head and neck.


Condition or disease Intervention/treatment Phase
Head and Neck Cancer Biological: cetuximab Drug: cisplatin Drug: docetaxel Radiation: radiation therapy Phase 2

Detailed Description:

OBJECTIVES:

Primary

  • Compare disease-free survival of patients with resected stage III or IV squamous cell carcinoma or lymphoepithelioma of the head and neck treated with adjuvant cetuximab in combination with chemoradiotherapy comprising docetaxel vs cisplatin.

Secondary

  • Compare the safety and efficacy of these regimens in these patients.
  • Compare locoregional control and overall survival rates in patients treated with these regimens.
  • Correlate epidermal growth factor receptor (total and phosphorylated), pMAPK, pAKT, Stat-3, Ki-67, cyclo-oxygenase-2, and cyclin B1 expression with outcome in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to Zubrod performance status (0 vs 1), risk category (positive margins vs high risk [i.e., ≥ 2 positive nodes or extracapsular nodal extension]) and use of intensity-modulated radiotherapy (no vs yes). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive cetuximab IV over 2 hours on day 1 (week 1). Patients then receive cetuximab IV over 1 hour and cisplatin IV over 1 hour before radiotherapy on days 8, 15, 22, 29, 36, and 43 (weeks 2-7). Patients undergo radiotherapy once daily, 5 days a week, beginning on day 8 for a total of 6 weeks (weeks 2-7).
  • Arm II: Patients receive cetuximab and undergo radiotherapy as in arm I. Patients also receive docetaxel IV over 30 minutes before radiotherapy on days 8, 15, 22, 29, 36, and 43 (weeks 2-7).

Treatment in both arms continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months for 4 years, and then annually thereafter.

PROJECTED ACCRUAL: A total of 230 patients (115 per treatment arm) will be accrued for this study within approximately 29 months.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 238 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Randomized Trial Of Surgery Followed By Chemoradiotherapy Plus Cetuximab For Advanced Squamous Cell Carcinoma Of The Head and Neck
Study Start Date : April 2004
Actual Primary Completion Date : March 2009
Actual Study Completion Date : December 2016

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: RT + cisplatin + cetuximab
Loading dose of cetuximab followed by radiation therapy with weekly cisplatin and cetuximab.
 Biological: cetuximab
400 mg/m^2 intravenously over 120 minutes on day 1 (week 1) followed by 250 mg/m^2 intravenously over 60 minutes in weeks 2 through 7.

Drug: cisplatin
30 mg/m^2 intravenously infused over over 60 minutes in weeks 2 through 7.

Radiation: radiation therapy
60 Gy (2 Gy once a day, 5 times a week)
Experimental: RT + docetaxel + cetuximab
Loading dose of cetuximab followed by radiation therapy (RT) with weekly docetaxel and cetuximab.
 Biological: cetuximab
400 mg/m^2 intravenously over 120 minutes on day 1 (week 1) followed by 250 mg/m^2 intravenously over 60 minutes in weeks 2 through 7.

Drug: docetaxel
15 mg/m^2 intravenously infused over 30 minutes in weeks 2 through 7.

Radiation: radiation therapy
60 Gy (2 Gy once a day, 5 times a week)


Outcome Measures
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Primary Outcome Measures :
  1. Disease-free Survival [ Time Frame: From randomization to 2 years ]
    Two-year rates are shown (Kaplan-Meier estimates). Disease-free survival is defined as the time from randomization to local, regional, or distant progression, second primary, or death (event) or last follow-up (censored). Response criteria as follows: No evidence of disease (NED): All patients must have no measurable tumor following surgery; Local-Regional Relapse: Recurrent cancer in the tumor bed and/or neck not clearly attributable to a second primary neoplasm; biopsy confirmation is necessary; Distant Relapse: Clear evidence of distant metastases (lung, bone, brain, etc.); Biopsy is recommended where possible. A solitary lung mass/nodule is considered a second primary neoplasm unless proven otherwise.


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: From randomization to 2 years ]
    Two-year rates are shown (Kaplan-Meier estimates). Overall survival is defined as the time from randomization to death (event) or last follow-up (censored).

  2. Treatment Tolerance [ Time Frame: From start of treatment to end of treatment (protocol treatment lasts seven weeks). ]
    Tolerability was defined as having received 90% of the radiation dose, 95% of the cetuximab loading dose, and at least 4 weeks of cetuximab and cisplatin or docetaxel at doses 95% of the protocol prescription. The percentage of patients determined to be tolerant of treatment are shown.

  3. Frequency of Toxicity (Grade 5 and Acute Non-hematologic Grade 4) [ Time Frame: From start of treatment to last follow-up. Analysis occurs at the time of the primary analysis. ]
    Each regimen was monitored for excessive acute toxicity (defined as nonhematologic grade 4 toxicity within 90 days of the start of radiation or any grade 5 toxicity). The target rate was based on the observed rate from RTOG-9501/NCT00002670 of 15%. The unacceptable rate was >30%. [RTOG = Radiation Therapy Oncology Group]

  4. Frequency of Other Acute and Late Toxicity [ Time Frame: From start of treatment to last follow-up. Analysis occurs at the time of the primary endpoint analysis. ]
    Maximum grade toxicity that is definitely, probably, or possibly related to protocol treatment.

  5. Local-regional Control [ Time Frame: From randomization to 2 years ]
    Two-year rate is shown (cumulative incidence estimate). Local-regional failure is defined as the time from randomization to local-regional recurrence (event), death (competing risk), or last follow-up (censored).

  6. Correlation of EGFR (Total and Phosphorylated) pMAPK, pAKT, Stat-3, KI-67, COX-2, and Cyclin B1 Expression With Local-regional Control, and Overall and Disease-free Survival [ Time Frame: From randomization to two years ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed squamous cell carcinoma of the head and neck meeting the following criteria:

    • Site of tumor origin in the oral cavity, oropharynx, larynx, or hypopharynx (excluding lip, nasopharynx, or sinuses)

    • Gross total resection must be completed within 7 weeks of randomization, with pathology demonstrating one or more of the following risk factors:

      • Histologic extracapsular nodal extension
      • Histologic involvement of ≥ 2 regional lymph nodes
      • Invasive cancer seen on microscopic evaluation of the resection margin, with no evidence of gross tumor residual.
      • Tonsillar cancer patients who undergo transoral excision of all gross tumor are eligible provided extracapsular nodal extension or involvement of ≥ 2 regional lymph nodes is histologically confirmed
    • American Joint Committee on Cancer (AJCC) pathological stage III or IV
  • No evidence of distant metastases
  • No synchronous or concurrent head and neck primary tumors

PATIENT CHARACTERISTICS:

Age

  • 18 and over

Performance status

  • Zubrod 0-1

Life expectancy

  • Not specified

Hematopoietic

  • Absolute neutrophil count ≥ 2,000/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin > 8.0 g/dL

Hepatic

  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)

  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT), and alkaline phosphatase meeting 1 of the following parameters:

    • Alkaline phosphatase ≤ ULN AND AST or ALT ≤ 5 times ULN
    • Alkaline phosphatase ≤ 2.5 times ULN AND AST or ALT ≤ 1.5 times ULN
    • Alkaline phosphatase ≤ 5 times ULN AND AST or ALT ≤ ULN

Renal

  • Creatinine ≤ 1.5 mg/dL

Cardiovascular

  • No unstable angina
  • No uncontrolled hypertension
  • No myocardial infarction within the past 6 months (unless successfully treated with coronary artery bypass surgery or percutaneous transluminal coronary angioplasty)
  • No uncontrolled arrhythmia
  • No congestive heart failure
  • No more than 2 heart-related hospitalizations within the past year
  • No other active cardiac disease

Pulmonary

  • No more than 2 hospitalizations for chronic obstructive pulmonary disease within the past year

Neurologic

  • No pre-existing peripheral neuropathy ≥ grade 2
  • No uncontrolled seizure disorder
  • No active neurological disease

Other

  • No prior severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80
  • No other invasive malignancy within the past 3 years except nonmelanoma skin cancer
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • No prior anti-epidermal growth factor receptor antibody therapy

Chemotherapy

  • More than 3 years since prior cytotoxic chemotherapy

Endocrine therapy

  • Not specified

Radiotherapy

  • No prior head and neck radiotherapy

Surgery

  • See Disease Characteristics

Other

  • No prior tyrosine kinase inhibitor therapy
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00084318


Locations
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Sponsors and Collaborators
Radiation Therapy Oncology Group
National Cancer Institute (NCI)
NRG Oncology
Investigators
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Principal Investigator: Paul M. Harari, MD University of Wisconsin, Madison
Study Chair: Merrill S. Kies, MD M.D. Anderson Cancer Center
Study Chair: Jeffrey N. Myers, MD, PhD, FACS M.D. Anderson Cancer Center
More Information
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Publications of Results:
Harari PM, Harris J, Kies MS, et al.: Phase II randomized trial of surgery followed by chemoradiation plus cetuximab for high-risk squamous cell carcinoma of the head and neck (RTOG 0234). [Abstract] Int J Radiat Oncol Biol Phys 69 (3 Suppl): A-22, S13, 2007.

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Responsible Party: Radiation Therapy Oncology Group
ClinicalTrials.gov Identifier: NCT00084318    
Obsolete Identifiers: NCT00414674
Other Study ID Numbers: RTOG-0234
CDR0000360850
First Posted: June 11, 2004    Key Record Dates
Results First Posted: November 22, 2016
Last Update Posted: December 12, 2018
Last Verified: December 2016
Keywords provided by Radiation Therapy Oncology Group:
stage III squamous cell carcinoma of the hypopharynx
stage IV squamous cell carcinoma of the hypopharynx
stage III squamous cell carcinoma of the oropharynx
stage IV squamous cell carcinoma of the oropharynx
 stage III squamous cell carcinoma of the larynx
stage IV squamous cell carcinoma of the larynx
stage III lymphoepithelioma of the oropharynx
stage IV lymphoepithelioma of the oropharynx
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Docetaxel
 Cetuximab
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological