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RECRUITING Phase 3 ClinicalTrials.gov

Testing the Addition of Anti-Cancer Drug, Cetuximab, to Standard of Care Treatment (Pembrolizumab) for Returning or Spreading Head and Neck Cancer After Previous Treatment

Sponsor: National Cancer Institute (NCI) • ClinicalTrials.gov ID: NCT06589804

Registry updated: 2026-10-19
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Description

This phase III trial compares the effect of adding cetuximab to pembrolizumab versus pembrolizumab alone in treating patients with head and neck squamous cell carcinoma (HNSCC) that has come back after a period of improvement (recurrent) and/or that has spread from where it first started (primary site) to other places in the body (metastatic). Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of tumor cells. This may help keep tumor cells from growing. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving cetuximab and pembrolizumab together may be more effective at treating patients with recurrent and/or metastatic HNSCC than pembrolizumab alone.

Interventions

  • Biospecimen Collection (Procedure)
    Undergo blood sample collection
  • Cetuximab (Biological)
    Given IV
  • Computed Tomography (Procedure)
    Undergo CT or PET/CT
  • Magnetic Resonance Imaging (Procedure)
    Undergo MRI
  • Pembrolizumab (Biological)
    Given IV
  • Positron Emission Tomography (Procedure)
    Undergo PET/CT

Eligibility criteria

Inclusion Criteria: * Histologically confirmed diagnosis head and neck squamous cell carcinomas (HNSCC). * Previously untreated for recurrent and/or metastatic disease incurable by local therapies. * Primary tumor location of oral cavity, oropharynx, larynx, or hypopharynx. * Note: Other primary tumor sites of HNSCC, including nasopharynx primary tumor are not eligible. Unknown primary tumors may be eligible and can be enrolled at the discretion of the treatment team with approval by the study chair. * Measurable disease. * Must have platinum-refractory disease defined as disease progression during or ≤ 29 weeks after completion of definitive therapy (chemoradiation therapy) or adjuvant (post-operative) therapy. * Patient must have a combined positive score PD-L1 positive (CPS \>/= 1) tumor. * Any radiation therapy must be completed \>= 10 days prior to registration. * Patients should not have received any prior treatment in the recurrent or metastatic setting. * Prior therapy with neoadjuvant or induction anti PD-1/PD-L1 monoclonal antibody or cetuximab in the curative setting is allowed if last treatment dose was \>= 26 weeks prior to registration without evidence of disease progression during that treatment period. * Patient has not received a live vaccine within 30 days prior to registration. * Patient does not have a history of any contraindication or has a severe hypersensitivity to any component of pembrolizumab or cetuximab (≥ grade 3). * Patient has not received chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to registration. * Patient with oropharyngeal cancer only must have negative results from testing of human papillomavirus (HPV) status defined as p16 immunohistochemistry (IHC) and/or HPV in situ hybridization (ISH). * Note: A Clinical Laboratory Improvement Act (CLIA) certified circulating tumor HPV deoxyribonucleic acid (ctHPVDNA) assay can be used if tissue sample is not available. * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Absolute neutrophil count (ANC) ≥ 1,500/mm\^3. * Platelet count ≥ 100,000/mm\^3. * Hemoglobin (Hgb) ≥ 9 g/dL (if \< 9 g/dL, then transfusions are acceptable to increase hemoglobin above 9 g/dL). * Creatinine ≤ 1.5 x upper limit of normal (ULN) OR calculated (calc.) creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula for participant with creatinine levels \> 1.5 x institutional ULN. * Total bilirubin ≤ 1.5 x ULN OR direct bilirubin \< ULN for participant with total bilirubin \> 1.5 x institutional ULN. * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) ≤ 3.0 x ULN unless liver metastases are present in which case \< 5.0 x ULN. * Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. * Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required. * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen should be included. * For treated/stable brain metastases: Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. * Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy. * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial. * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. * Patients does not have a history of active myocarditis. * Patients does not have a history of any form of pneumonitis or diffuse idiopathic or immune mediated interstitial pulmonary disease. * Patient does not have a history of solid organ transplantation.

Conditions

Metastatic Head and Neck Squamous Cell Carcinoma Metastatic Hypopharyngeal Squamous Cell Carcinoma Metastatic Laryngeal Squamous Cell Carcinoma Metastatic Oral Cavity Squamous Cell Carcinoma Metastatic Oropharyngeal Squamous Cell Carcinoma Recurrent Head and Neck Squamous Cell Carcinoma Recurrent Hypopharyngeal Squamous Cell Carcinoma Recurrent Laryngeal Squamous Cell Carcinoma Recurrent Neck Squamous Cell Carcinoma of Unknown Primary Recurrent Oral Cavity Squamous Cell Carcinoma Recurrent Oropharyngeal Squamous Cell Carcinoma Refractory Head and Neck Squamous Cell Carcinoma Refractory Hypopharyngeal Squamous Cell Carcinoma Refractory Laryngeal Squamous Cell Carcinoma Refractory Oral Cavity Squamous Cell Carcinoma Refractory Oropharyngeal Squamous Cell Carcinoma Stage IV Head and Neck Cutaneous Squamous Cell Carcinoma AJCC v8 Stage IV Hypopharyngeal Carcinoma AJCC v8 Stage IV Laryngeal Cancer AJCC v8 Stage IV Lip and Oral Cavity Cancer AJCC v8 Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8

Locations

  • University of Arkansas for Medical Sciences — Little Rock, Arkansas, United States
  • Fremont - Rideout Cancer Center — Marysville, California, United States
  • VA Palo Alto Health Care System — Palo Alto, California, United States
  • UCHealth Memorial Hospital Central — Colorado Springs, Colorado, United States
  • Memorial Hospital North — Colorado Springs, Colorado, United States
  • Poudre Valley Hospital — Fort Collins, Colorado, United States
  • Cancer Care and Hematology-Fort Collins — Fort Collins, Colorado, United States
  • Lutheran Hospital - Cancer Centers of Colorado — Golden, Colorado, United States
  • UCHealth Greeley Hospital — Greeley, Colorado, United States
  • Medical Center of the Rockies — Loveland, Colorado, United States
  • Mount Sinai Comprehensive Cancer Center at Aventura — Aventura, Florida, United States
  • Mount Sinai Medical Center — Miami Beach, Florida, United States
  • Saint Alphonsus Cancer Care Center-Boise — Boise, Idaho, United States
  • Saint Alphonsus Cancer Care Center-Caldwell — Caldwell, Idaho, United States
  • Kootenai Health - Coeur d'Alene — Coeur d'Alene, Idaho, United States
  • Saint Alphonsus Cancer Care Center-Nampa — Nampa, Idaho, United States
  • Kootenai Clinic Cancer Services - Post Falls — Post Falls, Idaho, United States
  • Kootenai Clinic Cancer Services - Sandpoint — Sandpoint, Idaho, United States
  • Advocate Good Shepherd Hospital — Barrington, Illinois, United States
  • University of Chicago Comprehensive Cancer Center — Chicago, Illinois, United States
  • Advocate Illinois Masonic Medical Center — Chicago, Illinois, United States
  • AMG Crystal Lake - Oncology — Crystal Lake, Illinois, United States
  • Carle at The Riverfront — Danville, Illinois, United States
  • Cancer Care Specialists of Illinois - Decatur — Decatur, Illinois, United States
  • Decatur Memorial Hospital — Decatur, Illinois, United States
  • Advocate Good Samaritan Hospital — Downers Grove, Illinois, United States
  • Carle Physician Group-Effingham — Effingham, Illinois, United States
  • Crossroads Cancer Center — Effingham, Illinois, United States
  • Advocate Sherman Hospital — Elgin, Illinois, United States
  • Advocate South Suburban Hospital — Hazel Crest, Illinois, United States
  • AMG Libertyville - Oncology — Libertyville, Illinois, United States
  • Condell Memorial Hospital — Libertyville, Illinois, United States
  • Illinois CancerCare-Macomb — Macomb, Illinois, United States
  • Carle Physician Group-Mattoon/Charleston — Mattoon, Illinois, United States
  • UC Comprehensive Cancer Center at Silver Cross — New Lenox, Illinois, United States
  • Carle BroMenn Medical Center — Normal, Illinois, United States
  • Carle Cancer Institute Normal — Normal, Illinois, United States
  • Cancer Care Center of O'Fallon — O'Fallon, Illinois, United States
  • Advocate Christ Medical Center — Oak Lawn, Illinois, United States
  • Advocate Outpatient Center - Oak Lawn — Oak Lawn, Illinois, United States
  • University of Chicago Medicine-Orland Park — Orland Park, Illinois, United States
  • Advocate High Tech Medical Park — Palos Heights, Illinois, United States
  • Advocate Lutheran General Hospital — Park Ridge, Illinois, United States
  • Illinois CancerCare-Peoria — Peoria, Illinois, United States
  • UW Health Carbone Cancer Center Rockford — Rockford, Illinois, United States
  • Memorial Hospital East — Shiloh, Illinois, United States
  • Southern Illinois University School of Medicine — Springfield, Illinois, United States
  • Springfield Clinic — Springfield, Illinois, United States
  • Springfield Memorial Hospital — Springfield, Illinois, United States
  • Carle Cancer Center — Urbana, Illinois, United States
  • UChicago Medicine Northwest Indiana — Crown Point, Indiana, United States
  • Mary Greeley Medical Center — Ames, Iowa, United States
  • McFarland Clinic - Ames — Ames, Iowa, United States
  • McFarland Clinic - Boone — Boone, Iowa, United States
  • Mercy Hospital — Cedar Rapids, Iowa, United States
  • Oncology Associates at Mercy Medical Center — Cedar Rapids, Iowa, United States
  • McFarland Clinic - Trinity Cancer Center — Fort Dodge, Iowa, United States
  • McFarland Clinic - Jefferson — Jefferson, Iowa, United States
  • McFarland Clinic - Marshalltown — Marshalltown, Iowa, United States
  • HaysMed — Hays, Kansas, United States
  • University of Kansas Cancer Center — Kansas City, Kansas, United States
  • Lawrence Memorial Hospital — Lawrence, Kansas, United States
  • The University of Kansas Cancer Center - Olathe — Olathe, Kansas, United States
  • University of Kansas Cancer Center-Overland Park — Overland Park, Kansas, United States
  • University of Kansas Hospital-Indian Creek Campus — Overland Park, Kansas, United States
  • Salina Regional Health Center — Salina, Kansas, United States
  • University of Kansas Health System Saint Francis Campus — Topeka, Kansas, United States
  • University of Kansas Hospital-Westwood Cancer Center — Westwood, Kansas, United States
  • University of Maryland/Greenebaum Cancer Center — Baltimore, Maryland, United States
  • Boston Medical Center — Boston, Massachusetts, United States
  • Trinity Health Saint Joseph Mercy Hospital Ann Arbor — Ann Arbor, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology - Brighton — Brighton, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology - Canton — Canton, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital — Chelsea, Michigan, United States
  • Cancer Hematology Centers - Flint — Flint, Michigan, United States
  • Genesee Hematology Oncology PC — Flint, Michigan, United States
  • Genesys Hurley Cancer Institute — Flint, Michigan, United States
  • Hurley Medical Center — Flint, Michigan, United States
  • University of Michigan Health - Sparrow Lansing — Lansing, Michigan, United States
  • Trinity Health Saint Mary Mercy Livonia Hospital — Livonia, Michigan, United States
  • Trinity Health Saint Joseph Mercy Oakland Hospital — Pontiac, Michigan, United States
  • Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus — Ypsilanti, Michigan, United States
  • Sanford Joe Lueken Cancer Center — Bemidji, Minnesota, United States
  • Minnesota Oncology - Burnsville — Burnsville, Minnesota, United States
  • Mercy Hospital — Coon Rapids, Minnesota, United States
  • Fairview Southdale Hospital — Edina, Minnesota, United States
  • Saint John's Hospital - Healtheast — Maplewood, Minnesota, United States
  • Abbott-Northwestern Hospital — Minneapolis, Minnesota, United States
  • Hennepin County Medical Center — Minneapolis, Minnesota, United States
  • Park Nicollet Clinic - Saint Louis Park — Saint Louis Park, Minnesota, United States
  • Regions Hospital — Saint Paul, Minnesota, United States
  • United Hospital — Saint Paul, Minnesota, United States
  • Saint Francis Medical Center — Cape Girardeau, Missouri, United States
  • Siteman Cancer Center at Saint Peters Hospital — City of Saint Peters, Missouri, United States
  • Siteman Cancer Center at West County Hospital — Creve Coeur, Missouri, United States
  • University Health Truman Medical Center — Kansas City, Missouri, United States
  • University of Kansas Cancer Center - Briarcliff — Kansas City, Missouri, United States
  • University of Kansas Cancer Center - North — Kansas City, Missouri, United States
  • University of Kansas Cancer Center - Lee's Summit — Lee's Summit, Missouri, United States
  • Liberty Hospital — Liberty, Missouri, United States
  • Lake Regional Hospital — Osage Beach, Missouri, United States
  • Washington University School of Medicine — St Louis, Missouri, United States
  • Mercy Hospital South — St Louis, Missouri, United States
  • Siteman Cancer Center-South County — St Louis, Missouri, United States
  • Siteman Cancer Center at Christian Hospital — St Louis, Missouri, United States
  • Community Hospital of Anaconda — Anaconda, Montana, United States
  • Billings Clinic Cancer Center — Billings, Montana, United States
  • Bozeman Health Deaconess Hospital — Bozeman, Montana, United States
  • Benefis Sletten Cancer Institute — Great Falls, Montana, United States
  • Logan Health Medical Center — Kalispell, Montana, United States
  • Community Medical Center — Missoula, Montana, United States
  • Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center — Lebanon, New Hampshire, United States
  • Memorial Sloan Kettering Basking Ridge — Basking Ridge, New Jersey, United States
  • Jefferson Cherry Hill Hospital — Cherry Hill, New Jersey, United States
  • Memorial Sloan Kettering Monmouth — Middletown, New Jersey, United States
  • Memorial Sloan Kettering Bergen — Montvale, New Jersey, United States
  • Sidney Kimmel Cancer Center Washington Township — Sewell, New Jersey, United States
  • Memorial Sloan Kettering Commack — Commack, New York, United States
  • Glens Falls Hospital — Glens Falls, New York, United States
  • Memorial Sloan Kettering Westchester — Harrison, New York, United States
  • Memorial Sloan Kettering Cancer Center — New York, New York, United States
  • State University of New York Upstate Medical University — Syracuse, New York, United States
  • SUNY Upstate Medical Center-Community Campus — Syracuse, New York, United States
  • Memorial Sloan Kettering Nassau — Uniondale, New York, United States
  • Upstate Cancer Center at Verona — Verona, New York, United States
  • UNC Lineberger Comprehensive Cancer Center — Chapel Hill, North Carolina, United States
  • Margaret R Pardee Memorial Hospital — Hendersonville, North Carolina, United States
  • FirstHealth of the Carolinas-Moore Regional Hospital — Pinehurst, North Carolina, United States
  • Sanford Bismarck Medical Center — Bismarck, North Dakota, United States
  • Sanford Broadway Medical Center — Fargo, North Dakota, United States
  • Sanford Roger Maris Cancer Center — Fargo, North Dakota, United States
  • Miami Valley Hospital South — Centerville, Ohio, United States
  • Miami Valley Hospital — Dayton, Ohio, United States
  • Miami Valley Hospital North — Dayton, Ohio, United States
  • Atrium Medical Center-Middletown Regional Hospital — Franklin, Ohio, United States
  • Miami Valley Cancer Care and Infusion — Greenville, Ohio, United States
  • ProMedica Flower Hospital — Sylvania, Ohio, United States
  • Upper Valley Medical Center — Troy, Ohio, United States
  • Cancer Centers of Southwest Oklahoma Research — Lawton, Oklahoma, United States
  • University of Oklahoma Health Sciences Center — Oklahoma City, Oklahoma, United States
  • Saint Alphonsus Cancer Care Center-Ontario — Ontario, Oregon, United States
  • Providence Willamette Falls Medical Center — Oregon City, Oregon, United States
  • Providence Portland Medical Center — Portland, Oregon, United States
  • Providence Saint Vincent Medical Center — Portland, Oregon, United States
  • Lehigh Valley Hospital-Cedar Crest — Allentown, Pennsylvania, United States
  • Lehigh Valley Hospital - Muhlenberg — Bethlehem, Pennsylvania, United States
  • Carlisle Regional Cancer Center — Carlisle, Pennsylvania, United States
  • Pocono Medical Center — East Stroudsburg, Pennsylvania, United States
  • UPMC Hillman Cancer Center Erie — Erie, Pennsylvania, United States
  • UPMC Cancer Centers - Arnold Palmer Pavilion — Greensburg, Pennsylvania, United States
  • UPMC Pinnacle Cancer Center/Community Osteopathic Campus — Harrisburg, Pennsylvania, United States
  • IRMC Cancer Center — Indiana, Pennsylvania, United States
  • UPMC-Johnstown/John P. Murtha Regional Cancer Center — Johnstown, Pennsylvania, United States
  • UPMC Hillman Cancer Center at Rocco And Nancy Ortenzio Cancer Pavilion — Mechanicsburg, Pennsylvania, United States
  • UPMC Hillman Cancer Center - Monroeville — Monroeville, Pennsylvania, United States
  • Jefferson Torresdale Hospital — Philadelphia, Pennsylvania, United States
  • UPMC-Saint Margaret — Pittsburgh, Pennsylvania, United States
  • UPMC Hillman Cancer Center — Pittsburgh, Pennsylvania, United States
  • UPMC-Passavant Hospital — Pittsburgh, Pennsylvania, United States
  • UPMC-Saint Clair Hospital Cancer Center — Pittsburgh, Pennsylvania, United States
  • UPMC Cancer Center at UPMC Northwest — Seneca, Pennsylvania, United States
  • UPMC Cancer Center-Uniontown — Uniontown, Pennsylvania, United States
  • UPMC Cancer Center-Washington — Washington, Pennsylvania, United States
  • Medical University of South Carolina — Charleston, South Carolina, United States
  • Avera Cancer Institute - Mitchell — Mitchell, South Dakota, United States
  • Avera Cancer Institute at Pierre — Pierre, South Dakota, United States
  • Sanford Cancer Center Oncology Clinic — Sioux Falls, South Dakota, United States
  • Avera Cancer Institute — Sioux Falls, South Dakota, United States
  • Sanford USD Medical Center - Sioux Falls — Sioux Falls, South Dakota, United States
  • Avera Cancer Institute at Yankton — Yankton, South Dakota, United States
  • Dartmouth Cancer Center - North — Saint Johnsbury, Vermont, United States
  • VCU Massey Cancer Center at Stony Point — Richmond, Virginia, United States
  • VCU Massey Comprehensive Cancer Center — Richmond, Virginia, United States
  • Vandalia Health/CAMC Institute for Academic Medicine — Charleston, West Virginia, United States
  • Aurora Cancer Care-Southern Lakes VLCC — Burlington, Wisconsin, United States
  • Aurora Saint Luke's South Shore — Cudahy, Wisconsin, United States
  • Marshfield Medical Center-EC Cancer Center — Eau Claire, Wisconsin, United States
  • Aurora Health Care Germantown Health Center — Germantown, Wisconsin, United States
  • Aurora Cancer Care-Grafton — Grafton, Wisconsin, United States
  • Aurora BayCare Medical Center — Green Bay, Wisconsin, United States
  • Aurora Cancer Care-Kenosha South — Kenosha, Wisconsin, United States
  • Gundersen Lutheran Medical Center — La Crosse, Wisconsin, United States
  • Aurora Bay Area Medical Group-Marinette — Marinette, Wisconsin, United States
  • Marshfield Medical Center-Marshfield — Marshfield, Wisconsin, United States
  • Aurora Cancer Care-Milwaukee — Milwaukee, Wisconsin, United States
  • Aurora Saint Luke's Medical Center — Milwaukee, Wisconsin, United States
  • Aurora Sinai Medical Center — Milwaukee, Wisconsin, United States
  • ProHealth D N Greenwald Center — Mukwonago, Wisconsin, United States
  • ProHealth Oconomowoc Memorial Hospital — Oconomowoc, Wisconsin, United States
  • Vince Lombardi Cancer Clinic - Oshkosh — Oshkosh, Wisconsin, United States
  • Aurora Cancer Care-Racine — Racine, Wisconsin, United States
  • Vince Lombardi Cancer Clinic-Sheboygan — Sheboygan, Wisconsin, United States
  • Marshfield Medical Center-River Region at Stevens Point — Stevens Point, Wisconsin, United States
  • Aurora Medical Center in Summit — Summit, Wisconsin, United States
  • Vince Lombardi Cancer Clinic-Two Rivers — Two Rivers, Wisconsin, United States
  • ProHealth Waukesha Memorial Hospital — Waukesha, Wisconsin, United States
  • UW Cancer Center at ProHealth Care — Waukesha, Wisconsin, United States
  • Aurora Cancer Care-Milwaukee West — Wauwatosa, Wisconsin, United States
  • Aurora West Allis Medical Center — West Allis, Wisconsin, United States
  • Marshfield Medical Center - Weston — Weston, Wisconsin, United States
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Official Source

Data sourced from ClinicalTrials.gov, a service of the U.S. National Institutes of Health.

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