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
Randomized Phase III Trial of Pembrolizumab vs. Pembrolizumab/Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma With Platinum Refractory Disease
3 other identifiers
interventional
158
1 country
177
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_3
Started Mar 2025
Longer than P75 for phase_3
177 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 6, 2024
CompletedFirst Posted
Study publicly available on registry
September 19, 2024
CompletedStudy Start
First participant enrolled
March 27, 2025
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 30, 2029
ExpectedStudy Completion
Last participant's last visit for all outcomes
November 30, 2029
June 11, 2026
March 1, 2026
4.7 years
September 6, 2024
June 10, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
Overall survival (OS)
Will be estimated using the Kaplan-Meier method. Will be based on the stratified log-rank test that will compare the distributions across the treatment arms. Univariable and multivariable Cox models stratified by the stratification factors used in the randomization will be assessed as well, where the multivariable Cox model will also adjust for other key baseline factors of interest. Hazard ratios and 95% confidence intervals, along with likelihood ratio p-values will be reported from these Cox models.
Time from randomization to death from any cause, assessed up to 5 years
Secondary Outcomes (5)
Confirmed response rate
Up to 5 years
Duration of response
From the date at which the patient's earliest best objective status is first noted to be either a complete response or partial response to the earliest date progression is documented, assessed up to 5 years
Progression free survival
Time from randomization to the first of either disease progression or death from any cause, assessed up to 5 years
Incidence of adverse events
Up to 5 years
Patient-reported toxicity
Up to 5 years
Other Outcomes (3)
Estimates of median OS by sex
Up to 5 years
Estimates of median OS by race
Up to 5 years
Estimates of median OS by ethnicity
Up to 5 years
Study Arms (2)
Arm 1 (pembrolizumab)
ACTIVE COMPARATORPatients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT or MRI throughout the trial and optionally undergo blood sample collection on study and at disease progression or end of treatment.
Arm 2 (cetuximab, pembrolizumab)
EXPERIMENTALPatients receive cetuximab IV over 120 minutes on day -14 prior to cycle 1 and then on days 1, 15 and 29 of each cycle and pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 42 days for up to 18 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT or MRI throughout the trial and optionally undergo blood sample collection on study and at disease progression or end of treatment.
Interventions
Given IV
Undergo CT or PET/CT
Undergo blood sample collection
Given IV
Undergo MRI
Undergo PET/CT
Eligibility Criteria
You may qualify if:
- 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.
- +20 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (177)
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72205, United States
Fremont - Rideout Cancer Center
Marysville, California, 95901, United States
VA Palo Alto Health Care System
Palo Alto, California, 94304, United States
UCHealth Memorial Hospital Central
Colorado Springs, Colorado, 80909, United States
Memorial Hospital North
Colorado Springs, Colorado, 80920, United States
Poudre Valley Hospital
Fort Collins, Colorado, 80524, United States
Cancer Care and Hematology-Fort Collins
Fort Collins, Colorado, 80528, United States
Lutheran Hospital - Cancer Centers of Colorado
Golden, Colorado, 80401, United States
UCHealth Greeley Hospital
Greeley, Colorado, 80631, United States
Medical Center of the Rockies
Loveland, Colorado, 80538, United States
Mount Sinai Medical Center
Miami Beach, Florida, 33140, United States
Saint Alphonsus Cancer Care Center-Boise
Boise, Idaho, 83706, United States
Saint Alphonsus Cancer Care Center-Caldwell
Caldwell, Idaho, 83605, United States
Kootenai Health - Coeur d'Alene
Coeur d'Alene, Idaho, 83814, United States
Saint Alphonsus Cancer Care Center-Nampa
Nampa, Idaho, 83687, United States
Kootenai Clinic Cancer Services - Post Falls
Post Falls, Idaho, 83854, United States
Kootenai Clinic Cancer Services - Sandpoint
Sandpoint, Idaho, 83864, United States
Advocate Good Shepherd Hospital
Barrington, Illinois, 60010, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, 60637, United States
Advocate Illinois Masonic Medical Center
Chicago, Illinois, 60657, United States
AMG Crystal Lake - Oncology
Crystal Lake, Illinois, 60014, United States
Cancer Care Specialists of Illinois - Decatur
Decatur, Illinois, 62526, United States
Decatur Memorial Hospital
Decatur, Illinois, 62526, United States
Advocate Good Samaritan Hospital
Downers Grove, Illinois, 60515, United States
Crossroads Cancer Center
Effingham, Illinois, 62401, United States
Advocate Sherman Hospital
Elgin, Illinois, 60123, United States
Advocate South Suburban Hospital
Hazel Crest, Illinois, 60429, United States
AMG Libertyville - Oncology
Libertyville, Illinois, 60048, United States
Condell Memorial Hospital
Libertyville, Illinois, 60048, United States
Illinois CancerCare-Macomb
Macomb, Illinois, 61455, United States
UC Comprehensive Cancer Center at Silver Cross
New Lenox, Illinois, 60451, United States
Cancer Care Center of O'Fallon
O'Fallon, Illinois, 62269, United States
Advocate Christ Medical Center
Oak Lawn, Illinois, 60453-2699, United States
Advocate Outpatient Center - Oak Lawn
Oak Lawn, Illinois, 60453, United States
University of Chicago Medicine-Orland Park
Orland Park, Illinois, 60462, United States
Advocate High Tech Medical Park
Palos Heights, Illinois, 60463, United States
Advocate Lutheran General Hospital
Park Ridge, Illinois, 60068, United States
Illinois CancerCare-Peoria
Peoria, Illinois, 61615, United States
UW Health Carbone Cancer Center Rockford
Rockford, Illinois, 61114, United States
Memorial Hospital East
Shiloh, Illinois, 62269, United States
Southern Illinois University School of Medicine
Springfield, Illinois, 62702, United States
Springfield Clinic
Springfield, Illinois, 62702, United States
Springfield Memorial Hospital
Springfield, Illinois, 62781, United States
UChicago Medicine Northwest Indiana
Crown Point, Indiana, 46307, United States
Mary Greeley Medical Center
Ames, Iowa, 50010, United States
McFarland Clinic - Ames
Ames, Iowa, 50010, United States
McFarland Clinic - Boone
Boone, Iowa, 50036, United States
Mercy Hospital
Cedar Rapids, Iowa, 52403, United States
Oncology Associates at Mercy Medical Center
Cedar Rapids, Iowa, 52403, United States
McFarland Clinic - Trinity Cancer Center
Fort Dodge, Iowa, 50501, United States
McFarland Clinic - Jefferson
Jefferson, Iowa, 50129, United States
McFarland Clinic - Marshalltown
Marshalltown, Iowa, 50158, United States
HaysMed
Hays, Kansas, 67601, United States
University of Kansas Cancer Center
Kansas City, Kansas, 66160, United States
Lawrence Memorial Hospital
Lawrence, Kansas, 66044, United States
The University of Kansas Cancer Center - Olathe
Olathe, Kansas, 66061, United States
University of Kansas Cancer Center-Overland Park
Overland Park, Kansas, 66210, United States
University of Kansas Hospital-Indian Creek Campus
Overland Park, Kansas, 66211, United States
Salina Regional Health Center
Salina, Kansas, 67401, United States
University of Kansas Health System Saint Francis Campus
Topeka, Kansas, 66606, United States
University of Kansas Hospital-Westwood Cancer Center
Westwood, Kansas, 66205, United States
University of Maryland/Greenebaum Cancer Center
Baltimore, Maryland, 21201, United States
Boston Medical Center
Boston, Massachusetts, 02118, United States
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
Ann Arbor, Michigan, 48106, United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
Brighton, Michigan, 48114, United States
Trinity Health IHA Medical Group Hematology Oncology - Canton
Canton, Michigan, 48188, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
Chelsea, Michigan, 48118, United States
Cancer Hematology Centers - Flint
Flint, Michigan, 48503, United States
Genesee Hematology Oncology PC
Flint, Michigan, 48503, United States
Genesys Hurley Cancer Institute
Flint, Michigan, 48503, United States
Hurley Medical Center
Flint, Michigan, 48503, United States
University of Michigan Health - Sparrow Lansing
Lansing, Michigan, 48912, United States
Trinity Health Saint Mary Mercy Livonia Hospital
Livonia, Michigan, 48154, United States
Trinity Health Saint Joseph Mercy Oakland Hospital
Pontiac, Michigan, 48341, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
Ypsilanti, Michigan, 48197, United States
Sanford Joe Lueken Cancer Center
Bemidji, Minnesota, 56601, United States
Minnesota Oncology - Burnsville
Burnsville, Minnesota, 55337, United States
Mercy Hospital
Coon Rapids, Minnesota, 55433, United States
Fairview Southdale Hospital
Edina, Minnesota, 55435, United States
Saint John's Hospital - Healtheast
Maplewood, Minnesota, 55109, United States
Abbott-Northwestern Hospital
Minneapolis, Minnesota, 55407, United States
Hennepin County Medical Center
Minneapolis, Minnesota, 55415, United States
Park Nicollet Clinic - Saint Louis Park
Saint Louis Park, Minnesota, 55416, United States
Regions Hospital
Saint Paul, Minnesota, 55101, United States
United Hospital
Saint Paul, Minnesota, 55102, United States
Saint Francis Medical Center
Cape Girardeau, Missouri, 63703, United States
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141, United States
University Health Truman Medical Center
Kansas City, Missouri, 64108, United States
University of Kansas Cancer Center - Briarcliff
Kansas City, Missouri, 64116, United States
University of Kansas Cancer Center - North
Kansas City, Missouri, 64154, United States
University of Kansas Cancer Center - Lee's Summit
Lee's Summit, Missouri, 64064, United States
Lake Regional Hospital
Osage Beach, Missouri, 65065, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Mercy Hospital South
St Louis, Missouri, 63128, United States
Siteman Cancer Center-South County
St Louis, Missouri, 63129, United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136, United States
Community Hospital of Anaconda
Anaconda, Montana, 59711, United States
Billings Clinic Cancer Center
Billings, Montana, 59101, United States
Bozeman Health Deaconess Hospital
Bozeman, Montana, 59715, United States
Benefis Sletten Cancer Institute
Great Falls, Montana, 59405, United States
Logan Health Medical Center
Kalispell, Montana, 59901, United States
Community Medical Center
Missoula, Montana, 59804, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Lebanon, New Hampshire, 03756, United States
Memorial Sloan Kettering Basking Ridge
Basking Ridge, New Jersey, 07920, United States
Jefferson Cherry Hill Hospital
Cherry Hill, New Jersey, 08002, United States
Memorial Sloan Kettering Monmouth
Middletown, New Jersey, 07748, United States
Memorial Sloan Kettering Bergen
Montvale, New Jersey, 07645, United States
Sidney Kimmel Cancer Center Washington Township
Sewell, New Jersey, 08080, United States
Memorial Sloan Kettering Commack
Commack, New York, 11725, United States
Glens Falls Hospital
Glens Falls, New York, 12801, United States
Memorial Sloan Kettering Westchester
Harrison, New York, 10604, United States
Memorial Sloan Kettering Cancer Center
New York, New York, 10065, United States
State University of New York Upstate Medical University
Syracuse, New York, 13210, United States
SUNY Upstate Medical Center-Community Campus
Syracuse, New York, 13215, United States
Memorial Sloan Kettering Nassau
Uniondale, New York, 11553, United States
Upstate Cancer Center at Verona
Verona, New York, 13478, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, 27599, United States
Margaret R Pardee Memorial Hospital
Hendersonville, North Carolina, 28791, United States
FirstHealth of the Carolinas-Moore Regional Hospital
Pinehurst, North Carolina, 28374, United States
Sanford Bismarck Medical Center
Bismarck, North Dakota, 58501, United States
Sanford Broadway Medical Center
Fargo, North Dakota, 58122, United States
Sanford Roger Maris Cancer Center
Fargo, North Dakota, 58122, United States
Miami Valley Hospital South
Centerville, Ohio, 45459, United States
Miami Valley Hospital
Dayton, Ohio, 45409, United States
Miami Valley Hospital North
Dayton, Ohio, 45415, United States
Atrium Medical Center-Middletown Regional Hospital
Franklin, Ohio, 45005-1066, United States
Miami Valley Cancer Care and Infusion
Greenville, Ohio, 45331, United States
ProMedica Flower Hospital
Sylvania, Ohio, 43560, United States
Upper Valley Medical Center
Troy, Ohio, 45373, United States
Cancer Centers of Southwest Oklahoma Research
Lawton, Oklahoma, 73505, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, 73104, United States
Saint Alphonsus Cancer Care Center-Ontario
Ontario, Oregon, 97914, United States
Providence Willamette Falls Medical Center
Oregon City, Oregon, 97045, United States
Providence Portland Medical Center
Portland, Oregon, 97213, United States
Providence Saint Vincent Medical Center
Portland, Oregon, 97225, United States
Lehigh Valley Hospital-Cedar Crest
Allentown, Pennsylvania, 18103, United States
Lehigh Valley Hospital - Muhlenberg
Bethlehem, Pennsylvania, 18017, United States
Pocono Medical Center
East Stroudsburg, Pennsylvania, 18301, United States
Jefferson Torresdale Hospital
Philadelphia, Pennsylvania, 19114, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
Avera Cancer Institute - Mitchell
Mitchell, South Dakota, 57301, United States
Avera Cancer Institute at Pierre
Pierre, South Dakota, 57501, United States
Sanford Cancer Center Oncology Clinic
Sioux Falls, South Dakota, 57104, United States
Avera Cancer Institute
Sioux Falls, South Dakota, 57105, United States
Sanford USD Medical Center - Sioux Falls
Sioux Falls, South Dakota, 57117-5134, United States
Avera Cancer Institute at Yankton
Yankton, South Dakota, 57078, United States
Dartmouth Cancer Center - North
Saint Johnsbury, Vermont, 05819, United States
VCU Massey Cancer Center at Stony Point
Richmond, Virginia, 23235, United States
VCU Massey Comprehensive Cancer Center
Richmond, Virginia, 23298, United States
West Virginia University Charleston Division
Charleston, West Virginia, 25304, United States
Aurora Cancer Care-Southern Lakes VLCC
Burlington, Wisconsin, 53105, United States
Aurora Saint Luke's South Shore
Cudahy, Wisconsin, 53110, United States
Marshfield Medical Center-EC Cancer Center
Eau Claire, Wisconsin, 54701, United States
Aurora Health Care Germantown Health Center
Germantown, Wisconsin, 53022, United States
Aurora Cancer Care-Grafton
Grafton, Wisconsin, 53024, United States
Aurora BayCare Medical Center
Green Bay, Wisconsin, 54311, United States
Aurora Cancer Care-Kenosha South
Kenosha, Wisconsin, 53142, United States
Gundersen Lutheran Medical Center
La Crosse, Wisconsin, 54601, United States
Aurora Bay Area Medical Group-Marinette
Marinette, Wisconsin, 54143, United States
Marshfield Medical Center-Marshfield
Marshfield, Wisconsin, 54449, United States
Aurora Cancer Care-Milwaukee
Milwaukee, Wisconsin, 53209, United States
Aurora Saint Luke's Medical Center
Milwaukee, Wisconsin, 53215, United States
Aurora Sinai Medical Center
Milwaukee, Wisconsin, 53233, United States
ProHealth D N Greenwald Center
Mukwonago, Wisconsin, 53149, United States
ProHealth Oconomowoc Memorial Hospital
Oconomowoc, Wisconsin, 53066, United States
Vince Lombardi Cancer Clinic - Oshkosh
Oshkosh, Wisconsin, 54904, United States
Aurora Cancer Care-Racine
Racine, Wisconsin, 53406, United States
Vince Lombardi Cancer Clinic-Sheboygan
Sheboygan, Wisconsin, 53081, United States
Marshfield Medical Center-River Region at Stevens Point
Stevens Point, Wisconsin, 54482, United States
Aurora Medical Center in Summit
Summit, Wisconsin, 53066, United States
Vince Lombardi Cancer Clinic-Two Rivers
Two Rivers, Wisconsin, 54241, United States
ProHealth Waukesha Memorial Hospital
Waukesha, Wisconsin, 53188, United States
UW Cancer Center at ProHealth Care
Waukesha, Wisconsin, 53188, United States
Aurora Cancer Care-Milwaukee West
Wauwatosa, Wisconsin, 53226, United States
Aurora West Allis Medical Center
West Allis, Wisconsin, 53227, United States
Marshfield Medical Center - Weston
Weston, Wisconsin, 54476, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Siddharth Sheth
Alliance for Clinical Trials in Oncology
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 6, 2024
First Posted
September 19, 2024
Study Start
March 27, 2025
Primary Completion (Estimated)
November 30, 2029
Study Completion (Estimated)
November 30, 2029
Last Updated
June 11, 2026
Record last verified: 2026-03
Data Sharing
- IPD Sharing
- Will share
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.