Comparing Radiation Plus Cetuximab to Radiation Plus Chemotherapy in People With Head and Neck Cancer Who Cannot Receive Cisplatin

Radiotherapy With Concurrent Cetuximab vs. Carboplatin and Paclitaxel in Patients With Stage III-IVB Head and Neck Cancer With a Contraindication to Cisplatin: A Pragmatic Phase III Randomized Trial

This phase III trial compares cetuxumab to chemotherapy, carboplatin and paclitaxel, with intensity modulated radiation therapy for the treatment of patients with head and neck cancer who are unable to receive cisplatin. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Intensity modulated radiation therapy is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. It is not yet know if cetxiumab or chemotherapy, with intensity modulated radiation therapy works best for the treatment of patients with head and neck cancer who are unable to receive cisplatin.

Study Overview

• Status: Not yet recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma; Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8; Stage III Hypopharyngeal Carcinoma AJCC v8; Stage III Laryngeal Cancer AJCC v8; Stage III Lip and Oral Cavity Cancer AJCC v8; Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8; Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8; Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8; Stage IVA Lip and Oral Cavity Cancer AJCC v8; Stage IVA Hypopharyngeal Carcinoma AJCC v8; Stage IVA Laryngeal Cancer AJCC v8; Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8; Stage IVB Hypopharyngeal Carcinoma AJCC v8; Stage IVB Laryngeal Cancer AJCC v8; Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8; Stage IVB Lip and Oral Cavity Cancer AJCC v8
• Intervention / Treatment: Drug: Carboplatin; Procedure: Magnetic Resonance Imaging; Drug: Paclitaxel; Procedure: Biospecimen Collection; Other: Survey Administration; Radiation: Intensity-Modulated Radiation Therapy; Procedure: Positron Emission Tomography; Procedure: Computed Tomography; Biological: Cetuximab

Detailed Description

PRIMARY OBJECTIVE:

I. To determine whether radiation therapy (RT) and concurrent carboplatin and paclitaxel (RT + carboplatin and paclitaxel [CP]) improves progression-free survival (PFS) compared to RT with concurrent cetuximab (RT + cetuximab [Cetux]) in patients with locoregionally advanced head and neck cancer (HNC) who have a contraindication to cisplatin.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) between RT+CP versus (vs.) RT + Cetux. II. To compare PFS and OS by study arm within p16-negative and p16-positive subgroups.

III. To compare safety and toxicity of RT+CP vs. RT + Cetux. IV. To compare patterns of failure (locoregional and distant) and competing causes of death of RT+CP vs. RT + Cetux.

V. To compare changes in diet, eating, and speech behaviors between RT+CP vs. RT + Cetux.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients undergo intensity modulated radiation therapy (IMRT) 5 days per week for 35 treatments. Starting within 7 days prior to radiation, patients receive a loading dose of cetuximab intravenously (IV) and then concurrently with radiation on day 1 of each cycle. Cycles repeat every 7 days for 7 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan on study and blood sample collection throughout the study. Patients may undergo PET scan or magnetic resonance imaging (MRI) during screening.

ARM 2: Patients undergo IMRT 5 days per week for 35 treatments. Starting on day 1 of radiation, patients receive concurrent carboplatin IV and paclitaxel on day 1 of each cycle. Cycles repeat every 7 days for 7 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan on study and blood sample collection throughout the study. Patients may undergo PET scan or MRI during screening.

After completion of study treatment, patients are followed up at 30 days and then 4, 6, 12, 18, 24, 30 and 36 months then annually thereafter.

• Study Type: Interventional
• Enrollment (Estimated): 454
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, or oral cavity
• Local evaluation of p16 status is required for all oropharynx patients prior to registration
• Local evaluation of p16 status is recommended for non-oropharynx patients prior to registration

• Locoregionally advanced head and neck squamous cell carcinoma (HNSCC) defined as:

  • Non-oropharynx and p16-negative oropharynx cancer: American Joint Commission on Cancer (AJCC) 8th edition stage III-IVB

    • Laryngeal, Hypopharyngeal, Oral Cavity, and p16-Negative Oropharyngeal Primaries:

      • AJCC 8th Edition TNM: T3-4b N0 M0 AJCC 8th Edition Stage: III-IVB
      • AJCC 8th Edition TNM: T1-4b N1-3 M0 AJCC 8th Edition Stage: III-IVB

  • p16-positive oropharynx cancer: AJCC 8th edition stage III and selected stage I-II based on smoking status in pack-years

    • Eligible p16-Positive Oropharyngeal Primaries

      • AJCC 8th Edition TNM: T1-2 N1 M0 AJCC 8th Edition Stage: I Pack-Years: > 10
      • AJCC 8th Edition TNM: T1-2 N2 M0 AJCC 8th Edition Stage: II Pack-Years: any
      • AJCC 8th Edition TNM: T3 N0-1 M0 AJCC 8th Edition Stage: II Pack-Years: > 10
      • AJCC 8th Edition TNM: T3 N2 M0 AJCC 8th Edition Stage: II Pack-Years: any
      • AJCC 8th Edition TNM: T1-3 N3 M0 AJCC 8th Edition Stage: III Pack-Years: any

      • AJCC 8th Edition TNM: T4 N0-3 M0 AJCC 8th Edition Stage: III Pack-Years: any

        • Note: Number of pack-years = [Frequency of smoking (number of cigarettes per day) × duration of cigarette smoking (years)] / 20
        • Note: Cigar and pipe tobacco consumption is not included in calculating the lifetime pack-years. Marijuana consumption is likewise not considered in this calculation. There is also no clear scientific evidence regarding the role of chewing tobacco-containing products in oropharyngeal cancer, although this is possibly more concerning given the proximity of the oral cavity and oropharynx. In any case, investigators should not count use of non-cigarette tobacco products in the pack-years calculation

• The following are required prior to registration:

  • Imaging of the head and neck with a neck CT or MRI (with contrast, unless contraindicated) or PET/CT which includes diagnostic-quality CT of the neck (with contrast, unless contraindicated)
  • Chest imaging: Chest CT (with contrast, unless contraindicated) or PET/CT
• Age ≥ 18
• Complete the online tool at www.nrgoncology.org prior to registration and record the (modified) Charleston Comorbidity Index (CCI), Head and Neck Cancer Intergroup (HNCIG) omega, and G-8 scores on the registration form in Oncology Patient Enrollment Network (OPEN)

• Patients must have a contraindication to cisplatin as defined in the following bullet points:

  • Absolute or relative contraindication to cisplatin, defined as ONE OR MORE of the following prior to registration:

    • Creatinine clearance (CrCl) < 60 mL/min by the Cockroft-Gault formula
    • Pre-existing peripheral (sensory or motor) neuropathy grade ≥ 2 (per Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0)

    • History of hearing loss, defined as either:

      • Existing need of a hearing aid OR
      • ≥ 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated OR
  • age ≥ 70 with Head and Neck Cancer Intergroup (HNCIG) omega score < 0.80 prior to registration OR

  • Age < 70 with ALL of the following conditions prior to registration (see Appendix II for calculation instructions):

    • HNCIG omega score < 0.80
    • (Modified) Charlson Comorbidity Index (CCI) ≥ 1
    • G-8 score ≤ 14
• Not pregnant and not nursing
• Participants must be able to safely receive the radiation and drug regimens per current Food and Drug Administration (FDA)-approved package insert(s), treating investigator's discretion, and institutional guidelines
• No prior systemic therapy for the study cancer; note that prior systemic therapy for a different cancer is allowable
• No prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
• No prior surgery for the study cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (IMRT, cetuximab); Patients undergo IMRT 5 days per week for 35 treatments. Starting within 7 days prior to radiation, patients receive a loading dose of cetuximab IV and then concurrently with radiation on day 1 of each cycle. Cycles repeat every 7 days for 7 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan on study and blood sample collection throughout the study. Patients may undergo PET scan or MRI during screening.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Other: Survey Administration; Ancillary studies; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Radiation, Intensity-Modulated Radiotherapy; Intensity modulated radiation therapy (procedure); Procedure: Positron Emission Tomography; Undergo PET scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type; Biological: Cetuximab; Given IV; Other Names: C225; Erbitux; IMC-C225; Cetuximab Biosimilar CDP-1; Cetuximab Biosimilar CMAB009; Cetuximab Biosimilar KL 140; Chimeric Anti-EGFR Monoclonal Antibody; Chimeric MoAb C225; Chimeric Monoclonal Antibody C225; C-225; C 225
Active Comparator: Arm 2 (IMRT, carboplatin, paclitaxel); Patients undergo IMRT 5 days per week for 35 treatments. Starting on day 1 of radiation, patients receive concurrent carboplatin IV and paclitaxel on day 1 of each cycle. Cycles repeat every 7 days for 7 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan on study and blood sample collection throughout the study. Patients may undergo PET scan or MRI during screening.	Drug: Carboplatin; Given IV; Other Names: Blastocarb; Carboplat; Carboplatin Hexal; Carboplatino; Carboplatinum; Carbosin; Carbosol; Carbotec; CBDCA; Displata; Ercar; JM-8; Nealorin; Novoplatinum; Paraplatin; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo; JM8; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Drug: Paclitaxel; Given IV; Other Names: Taxol; Anzatax; Asotax; Bristaxol; Praxel; Taxol Konzentrat; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Other: Survey Administration; Ancillary studies; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Radiation, Intensity-Modulated Radiotherapy; Intensity modulated radiation therapy (procedure); Procedure: Positron Emission Tomography; Undergo PET scan; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; PT; Positron emission tomography (procedure); Procedure: Computed Tomography; Undergo CT scan; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Diagnostic CAT Scan; Diagnostic CAT Scan Service Type

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	The PFS rates for each treatment arm will be estimated in the overall sample and within each p16 subgroup using the Kaplan-Meier method. Estimates of the median PFS and 2-year PFS rates will be obtained with 90% confidence intervals. The comparison of PFS distributions between each treatment arm will be performed using a one-sided stratified log-rank test (stratified by the randomization stratification factors). As additional analysis of treatment effect, multivariable analysis will be performed using a Cox proportional hazards model, where the stratification factors, and relevant patient and tumor characteristics are included (as measured by the model's Bayesian Information Criterion [BIC]). Hazard ratios and their respective 90% confidence intervals will be provided.	From randomization until locoregional failure, distant failure, or death due to any cause, up to 8 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Will be summarized by treatment arm using standard Kaplan-Meier methods, where estimates of the median and 2-year OS will be obtained with 90% confidence intervals. The OS will be compared using a one-sided stratified log-rank test, stratified by the randomization strata.	From randomization until death due to any cause, up to 8 years
OS by p16 status	Assessments within p16 subgroups is to compare treatment arms within potentially clinically relevant subgroups. Within p16-negative and p16-positive subgroups, the OS will be summarized by study arm using standard Kaplan-Meier methods. The median OS and 2-year OS rates will be reported with 90% confidence intervals. Comparisons will be made using one-sided stratified log-rank tests. Multivariate Cox regression models will also be considered, where relevant covariates are selected based on the model's BIC.	From randomization until death due to any cause, up to 8 years
PFS by p16 status	PFS assessments within p16 subgroups is to compare treatment arms within potentially clinically relevant subgroups. Within p16-negative and p16-positive subgroups, the PFS will be summarized by study arm using standard Kaplan-Meier methods. The median PFS and 2-year PFS rates will be reported with 90% confidence intervals. Comparisons will be made using one-sided stratified log-rank tests. Multivariate Cox regression models will also be considered, where relevant covariates are selected based on the model's BIC. No adjustments will be made for multiplicity.	From randomization until locoregional failure, distant failure, or death due to any cause, up to 8 years
Incidence of adverse events	Adverse event grades will be assessed by Common Terminology Criteria for Adverse Events version 5.0. The overall (highest grade) adverse events will be summarized by treatment arm using frequencies and relative frequencies.	Up to 24 months from end of radiation therapy (RT)
Incidence of patient reported incidence of adverse events	Patient responses will be summarized by treatment arm and time point using frequencies and relative frequencies.	Up to 12 months from end of RT
Time to locoregional failure	Will compare patterns of failure and competing causes of death between treatment arms. The number and type of failures will be summarized by treatment arm using frequencies and relative frequencies. The time to failure will be summarized by treatment arm using the cumulative incidence method, where estimates of the 2-year failure rates will be obtained with 90% confidence intervals. Comparisons between treatment arms will be made using the stratified Gray's test.	From randomization until first evidence of local, regional disease progression or recurrence, or death from study cancer, up to 8 years
Time to distant failure	Will compare patterns of failure and competing causes of death between treatment arms. The number and type of failures will be summarized by treatment arm using frequencies and relative frequencies. The time to failure will be summarized by treatment arm using the cumulative incidence method, where estimates of the 2-year failure rates will be obtained with 90% confidence intervals. Comparisons between treatment arms will be made using the stratified Gray's test.	From randomization until first evidence of distant metastasis, up to 8 years
Time to competing mortality	Will compare patterns of failure and competing causes of death between treatment arms. The number and type of failures will be summarized by treatment arm using frequencies and relative frequencies. The time to failure will be summarized by treatment arm using the cumulative incidence method, where estimates of the 2-year failure rates will be obtained with 90% confidence intervals. Comparisons between treatment arms will be made using the stratified Gray's test.	From randomization until death due to other or unknown causes, up to 8 years
Longitudinal eating/speech profiles	Assessed via the Performance Status Scale for Head and Neck Cancer. The mean score change (relative to end of radiation treatment) for each of these subscales between arms will be compared at 12 months post-RT using a two-sample independent t-test with a two-sided significance level of 0.05. A Wilcoxon test will be used if normality assumption does not hold. Temporal trends and differences between arms at other time points will be assessed using mixed models with the following covariates: time, treatment arm and its interaction.	At baseline, end of treatment, 4, 6 and 12 months from end of RT

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary outcome treatment effect by sex	Estimates of treatment effect and the corresponding 95% confidence intervals will be provided.	Up to 8 years
Primary treatment outcome by race	Estimates of treatment effect and the corresponding 95% confidence intervals will be provided.	Up to 8 years
Primary treatment outcome by ethnicity	Estimates of treatment effect and the corresponding 95% confidence intervals will be provided.	Up to 8 years

Collaborators and Investigators

• Sponsor: NRG Oncology
• Investigators: Principal Investigator: Loren K Mell, NRG Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): January 6, 2027
• Primary Completion (Estimated): November 30, 2035
• Study Completion (Estimated): November 30, 2035

Study Registration Dates

• First Submitted: February 24, 2026
• First Submitted That Met QC Criteria: February 24, 2026
• First Posted (Actual): March 2, 2026

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mouth Diseases; Stomatognathic Diseases; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Otorhinolaryngologic Diseases; Pharyngeal Neoplasms; Otorhinolaryngologic Neoplasms; Pharyngeal Diseases; Carcinoma, Squamous Cell; Laryngeal Diseases; Squamous Cell Carcinoma of Head and Neck; Carcinoma; Laryngeal Neoplasms; Mouth Neoplasms; Oropharyngeal Neoplasms; Hypopharyngeal Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Investigative Techniques; Therapeutics; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Coordination Complexes; Taxoids; Cyclodecanes; Diterpenes; Health Care Economics and Organizations; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Economics; Cetuximab; Carboplatin; Paclitaxel; Specimen Handling; Magnetic Resonance Spectroscopy; Radiotherapy, Intensity-Modulated; (225)Ac-DOTA-c(RGDyK); Taxes
• Other Study ID Numbers: NRG-HN016 (Other Identifier: CTEP); U10CA180868 (U.S. NIH Grant/Contract); NCI-2026-00811 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No