Clinical Stage I HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage II HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Head and Neck Squamous Cell Carcinoma, 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, Stage IVA Hypopharyngeal Carcinoma AJCC v8, Stage IVA Laryngeal Cancer AJCC v8, Stage IVA Lip and Oral Cavity 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 Lip and Oral Cavity Cancer AJCC v8, Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8
Conditions
Brief summary
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.
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.
Interventions
Undergo blood sample collection
Given IV
Given IV
Undergo CT scan
Undergo IMRT
Undergo MRI
Given IV
Undergo PET scan
Ancillary studies
Sponsors
Study design
Eligibility
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression free survival (PFS) | From randomization until locoregional failure, distant failure, or death due to any cause, up to 8 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | From randomization until death due to any cause, up to 8 years | 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. |
| OS by p16 status | From randomization until death due to any cause, up to 8 years | 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. |
| PFS by p16 status | From randomization until locoregional failure, distant failure, or death due to any cause, up to 8 years | 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. |
| Incidence of adverse events | Up to 24 months from end of radiation therapy (RT) | 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. |
| Incidence of patient reported incidence of adverse events | Up to 12 months from end of RT | Patient responses will be summarized by treatment arm and time point using frequencies and relative frequencies. |
| Time to locoregional failure | From randomization until first evidence of local, regional disease progression or recurrence, or death from study cancer, up to 8 years | 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. |
| Time to distant failure | From randomization until first evidence of distant metastasis, up to 8 years | 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. |
| Time to competing mortality | From randomization until death due to other or unknown causes, up to 8 years | 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. |
| Longitudinal eating/speech profiles | At baseline, end of treatment, 4, 6 and 12 months from end of RT | 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. |
Countries
United States
Contacts
NRG Oncology