Testing the Addition of Chemotherapy or Chemo-Immunotherapy to the Usual Surgery for Advanced Head and Neck Cancer

June 17, 2026 updated by: National Cancer Institute (NCI)

A Phase II Randomized Trial of Neoadjuvant Chemotherapy or Chemo-Immunotherapy in Patients With Recurrent/Persistent PD-L1 Enriched Squamous Cell Carcinoma of the Head and Neck Undergoing Salvage Surgery (NEOPOLIS)

This phase II trial tests the addition of chemotherapy, with carboplatin and paclitaxel, or chemo-immunotherapy, with carboplatin, paclitaxel and cemiplimab to standard salvage surgery followed by post operative radiation therapy and cisplatin for high risk patients, for the treatment of patients with PD-L1 positive head and neck squamous cell carcinoma that has come back and spread to nearby tissue or lymph nodes after a period of improvement (locally recurrent) or is persistent. 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. Immunotherapy with monoclonal antibodies, such as cemiplimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Salvage surgery is surgery that takes place to remove tumor tissue after a failure of other treatment. High risk patients also receive radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Adding chemotherapy or chemo-immunotherapy to standard salvage surgery may kill more tumor cells than salvage surgery alone in patients with PD-L1 positive locally recurrent or persistent head and neck squamous cell carcinoma.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVE:

I. To assess and compare investigator-assessed event-free survival (EFS) of patients treated with chemotherapy (carboplatin + paclitaxel) or chemo-immunotherapy (carboplatin + paclitaxel + cemiplimab [REGN2810]) prior to salvage surgery (SS) versus patients undergoing standard of care SS.

SECONDARY OBJECTIVES:

I. To assess and compare disease-free survival (DFS). II. To assess and compare overall survival (OS). III. To assess and compare distant metastasis (DM). IV. To assess and compare acute and late toxicity (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0), and surgical complications.

V. To assess radiographic response (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) to neoadjuvant therapy in the experimental arms.

VI. To assess pathologic response in the experimental arms.

EXPLORATORY OBJECTIVES:

I. To assess and compare clinical outcomes (EFS, DFS, OS, DM, and response) within the PD-L1 subgroups (combined positive score < 20 versus ≥ 20).

II. To determine the impact of surgical quality benchmarks (margin assessment, cervical lymph node harvest collected per central surgery review) and oncologic outcomes.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM 1: Patients undergo standard of care salvage surgery. Starting within 8 weeks of surgery, patients with high risk features also undergo radiation therapy daily for 5 treatments per week for 6 weeks and receive cisplatin intravenously (IV) once per week for 6 weeks during radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, positron emission tomography (PET) scan and optionally undergo blood sample collection throughout the study.

ARM 2: Patients receive paclitaxel IV and carboplatin IV on day 1 of each cycle. Cycles repeat every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. 6-10 weeks after cycle 1 day 1 patients undergo standard of care salvage surgery. Starting within 8 weeks of surgery, patients with high risk features also undergo radiation therapy daily for 5 treatments per week for 6 weeks and receive cisplatin IV once per week for 6 weeks during radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan and optionally undergo blood sample collection throughout the study.

ARM 3: Patients receive paclitaxel IV, carboplatin IV and cemiplimab IV, over 30 minutes, on day 1 of each cycle. Cycles repeat every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. 6-10 weeks after cycle 1 day 1 patients undergo standard of care salvage surgery. Starting within 8 weeks of surgery, patients with high risk features also undergo radiation therapy daily for 5 treatments per week for 6 weeks and receive cisplatin IV once per week for 6 weeks during radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan and optionally undergo blood sample collection throughout the study.

After completion of study treatment, patients are followed up at 12 weeks or at the end of post operative radiation, then every 3 months for 2 years, every 6 months for years 3 and 4 and annually thereafter.

Study Type

Interventional

Enrollment (Estimated)

180

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Arizona
      • Tucson, Arizona, United States, 85719
        • Recruiting
        • Banner University Medical Center - Tucson
        • Principal Investigator:
          • Ricklie A. Julian
        • Contact:
      • Tucson, Arizona, United States, 85719
        • Recruiting
        • University of Arizona Cancer Center-North Campus
        • Principal Investigator:
          • Ricklie A. Julian
        • Contact:
    • California
      • Los Angeles, California, United States, 90033
        • Recruiting
        • USC / Norris Comprehensive Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 323-865-0451
        • Principal Investigator:
          • Jacob S. Thomas
      • Sacramento, California, United States, 95816
    • Georgia
      • Atlanta, Georgia, United States, 30308
        • Recruiting
        • Emory University Hospital Midtown
        • Principal Investigator:
          • Jennifer Gross
        • Contact:
          • Site Public Contact
          • Phone Number: 888-946-7447
      • Atlanta, Georgia, United States, 30308
        • Recruiting
        • Emory Proton Therapy Center
        • Principal Investigator:
          • Jennifer Gross
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Recruiting
        • Rush MD Anderson Cancer Center
        • Principal Investigator:
          • Michael J. Jelinek
        • Contact:
      • Lisle, Illinois, United States, 60532
        • Recruiting
        • Rush MD Anderson Cancer Center at Rush Lisle
        • Principal Investigator:
          • Michael J. Jelinek
        • Contact:
      • Shiloh, Illinois, United States, 62269
        • Recruiting
        • Memorial Hospital East
        • Contact:
        • Principal Investigator:
          • Brendan J. Knapp
    • Iowa
      • Ankeny, Iowa, United States, 50023
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Ankeny Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Clive, Iowa, United States, 50325
        • Recruiting
        • UI Health Care Mission Cancer and Blood - West Des Moines Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Council Bluffs, Iowa, United States, 51503
        • Suspended
        • Methodist Jennie Edmundson Hospital
      • Des Moines, Iowa, United States, 50314
        • Recruiting
        • Broadlawns Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 515-282-2200
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50314
        • Recruiting
        • Mercy Medical Center - Des Moines
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Richard L. Deming
      • Des Moines, Iowa, United States, 50309
        • Recruiting
        • Iowa Methodist Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-6727
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50309
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Des Moines Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Des Moines, Iowa, United States, 50314
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Laurel Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
      • Waukee, Iowa, United States, 50263
        • Recruiting
        • UI Health Care Mission Cancer and Blood - Waukee Clinic
        • Contact:
          • Site Public Contact
          • Phone Number: 515-241-3305
        • Principal Investigator:
          • Seema Harichand-Herdt
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Recruiting
        • University of Kansas Cancer Center
        • Contact:
        • Principal Investigator:
          • Omar A. Karadaghy
      • Overland Park, Kansas, United States, 66210
        • Recruiting
        • University of Kansas Cancer Center-Overland Park
        • Contact:
        • Principal Investigator:
          • Omar A. Karadaghy
      • Westwood, Kansas, United States, 66205
        • Recruiting
        • University of Kansas Hospital-Westwood Cancer Center
        • Contact:
        • Principal Investigator:
          • Omar A. Karadaghy
    • Louisiana
      • Baton Rouge, Louisiana, United States, 70805
        • Recruiting
        • LSU Health Baton Rouge-North Clinic
        • Contact:
        • Principal Investigator:
          • Sagar G. Kansara
      • Baton Rouge, Louisiana, United States, 70808
        • Recruiting
        • Our Lady of the Lake Physician Group
        • Contact:
        • Principal Investigator:
          • Sagar G. Kansara
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • Recruiting
        • University of Michigan Rogel Cancer Center
        • Principal Investigator:
          • Paul L. Swiecicki
        • Contact:
      • Brighton, Michigan, United States, 48116
        • Recruiting
        • University of Michigan - Brighton Center for Specialty Care
        • Contact:
          • Site Public Contact
          • Phone Number: 800-865-1125
        • Principal Investigator:
          • Paul L. Swiecicki
      • Detroit, Michigan, United States, 48202
        • Recruiting
        • Henry Ford Hospital
        • Contact:
        • Principal Investigator:
          • Samantha H. Tam
    • Missouri
      • City of Saint Peters, Missouri, United States, 63376
        • Recruiting
        • Siteman Cancer Center at Saint Peters Hospital
        • Contact:
        • Principal Investigator:
          • Brendan J. Knapp
      • Creve Coeur, Missouri, United States, 63141
        • Recruiting
        • Siteman Cancer Center at West County Hospital
        • Contact:
        • Principal Investigator:
          • Brendan J. Knapp
      • Kansas City, Missouri, United States, 64154
        • Recruiting
        • University of Kansas Cancer Center - North
        • Contact:
        • Principal Investigator:
          • Omar A. Karadaghy
      • Kansas City, Missouri, United States, 64116
        • Recruiting
        • University of Kansas Cancer Center - Briarcliff
        • Principal Investigator:
          • Omar A. Karadaghy
        • Contact:
          • Site Public Contact
          • Phone Number: 913-588-3671
      • Lee's Summit, Missouri, United States, 64064
        • Recruiting
        • University of Kansas Cancer Center - Lee's Summit
        • Contact:
        • Principal Investigator:
          • Omar A. Karadaghy
      • St Louis, Missouri, United States, 63110
        • Recruiting
        • Washington University School of Medicine
        • Contact:
        • Principal Investigator:
          • Brendan J. Knapp
      • St Louis, Missouri, United States, 63129
        • Recruiting
        • Siteman Cancer Center-South County
        • Contact:
        • Principal Investigator:
          • Brendan J. Knapp
      • St Louis, Missouri, United States, 63136
        • Recruiting
        • Siteman Cancer Center at Christian Hospital
        • Contact:
        • Principal Investigator:
          • Brendan J. Knapp
    • Nebraska
      • Omaha, Nebraska, United States, 68114
        • Recruiting
        • Nebraska Cancer Specialists/Oncology Hematology West PC - MECC
        • Contact:
          • Site Public Contact
          • Phone Number: 402-334-4773
        • Principal Investigator:
          • Yungpo B. Su
      • Omaha, Nebraska, United States, 68114
        • Recruiting
        • Nebraska Methodist Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 402-354-5144
        • Principal Investigator:
          • Yungpo B. Su
    • New Jersey
      • Jersey City, New Jersey, United States, 07302
        • Recruiting
        • Jersey City Medical Center
        • Principal Investigator:
          • Dylan F. Roden
        • Contact:
      • New Brunswick, New Jersey, United States, 08903
        • Recruiting
        • Rutgers Cancer Institute of New Jersey
        • Principal Investigator:
          • Dylan F. Roden
        • Contact:
          • Site Public Contact
          • Phone Number: 732-235-7356
      • Newark, New Jersey, United States, 07101
        • Recruiting
        • Rutgers New Jersey Medical School
        • Principal Investigator:
          • Dylan F. Roden
        • Contact:
          • Site Public Contact
          • Phone Number: 732-235-7356
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Recruiting
        • UNC Lineberger Comprehensive Cancer Center
        • Contact:
        • Principal Investigator:
          • Mihir R. Patel
    • Ohio
      • Sylvania, Ohio, United States, 43560
        • Recruiting
        • ProMedica Flower Hospital
        • Contact:
        • Principal Investigator:
          • Chang Xia
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Recruiting
        • University of Oklahoma Health Sciences Center
        • Contact:
        • Principal Investigator:
          • Christina Henson
    • Oregon
      • Clackamas, Oregon, United States, 97015
        • Recruiting
        • Clackamas Radiation Oncology Center
        • Principal Investigator:
          • Dan S. Zuckerman
        • Contact:
      • Gresham, Oregon, United States, 97030
        • Recruiting
        • Legacy Mount Hood Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 503-413-2150
        • Principal Investigator:
          • Andrew Y. Kee
      • Newberg, Oregon, United States, 97132
        • Recruiting
        • Providence Newberg Medical Center
        • Principal Investigator:
          • Dan S. Zuckerman
        • Contact:
      • Oregon City, Oregon, United States, 97045
        • Recruiting
        • Providence Willamette Falls Medical Center
        • Principal Investigator:
          • Dan S. Zuckerman
        • Contact:
      • Portland, Oregon, United States, 97213
        • Recruiting
        • Providence Portland Medical Center
        • Principal Investigator:
          • Dan S. Zuckerman
        • Contact:
      • Portland, Oregon, United States, 97225
        • Recruiting
        • Providence Saint Vincent Medical Center
        • Principal Investigator:
          • Dan S. Zuckerman
        • Contact:
      • Portland, Oregon, United States, 97210
        • Recruiting
        • Legacy Good Samaritan Hospital and Medical Center
        • Contact:
          • Site Public Contact
          • Phone Number: 800-220-4937
          • Email: cancer@lhs.org
        • Principal Investigator:
          • Andrew Y. Kee
      • Tualatin, Oregon, United States, 97062
        • Recruiting
        • Legacy Meridian Park Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 503-413-1742
        • Principal Investigator:
          • Andrew Y. Kee
    • Pennsylvania
      • Erie, Pennsylvania, United States, 16505
        • Recruiting
        • UPMC Hillman Cancer Center Erie
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Farrell, Pennsylvania, United States, 16121
        • Recruiting
        • UPMC Cancer Center at UPMC Horizon
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Indiana, Pennsylvania, United States, 15701
        • Recruiting
        • IRMC Cancer Center
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Johnstown, Pennsylvania, United States, 15901
        • Recruiting
        • UPMC-Johnstown/John P. Murtha Regional Cancer Center
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
          • Site Public Contact
          • Phone Number: 814-534-4724
      • Monroeville, Pennsylvania, United States, 15146
        • Recruiting
        • UPMC Hillman Cancer Center - Monroeville
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Monroeville, Pennsylvania, United States, 15146
        • Recruiting
        • UPMC Cancer Center - Monroeville
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Philadelphia, Pennsylvania, United States, 19107
        • Recruiting
        • Thomas Jefferson University Hospital
        • Contact:
        • Principal Investigator:
          • Jennifer M. Johnson
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • University of Pittsburgh Cancer Institute (UPCI)
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
          • Site Public Contact
          • Phone Number: 412-647-8073
      • Pittsburgh, Pennsylvania, United States, 15215
        • Recruiting
        • UPMC-Saint Margaret
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
          • Site Public Contact
          • Phone Number: 412-784-4900
      • Pittsburgh, Pennsylvania, United States, 15243
        • Recruiting
        • UPMC-Saint Clair Hospital Cancer Center
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
          • Site Public Contact
          • Phone Number: 412-502-3920
      • Pittsburgh, Pennsylvania, United States, 15232
        • Recruiting
        • UPMC-Shadyside Hospital
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
          • Site Public Contact
          • Phone Number: 412-621-2334
      • Seneca, Pennsylvania, United States, 16346
        • Recruiting
        • UPMC Cancer Center at UPMC Northwest
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
          • Site Public Contact
          • Phone Number: 814-676-7900
      • Washington, Pennsylvania, United States, 15301
        • Recruiting
        • UPMC Cancer Center-Washington
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Washington, Pennsylvania, United States, 15301
        • Recruiting
        • UPMC Washington Hospital Radiation Oncology
        • Principal Investigator:
          • Steven B. Chinn
        • Contact:
      • Willow Grove, Pennsylvania, United States, 19090
        • Recruiting
        • Asplundh Cancer Pavilion
        • Contact:
        • Principal Investigator:
          • Jennifer M. Johnson
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Recruiting
        • Medical University of South Carolina
        • Contact:
        • Principal Investigator:
          • Alexandra E. Kejner
    • Tennessee
      • Nashville, Tennessee, United States, 37232
        • Recruiting
        • Vanderbilt University/Ingram Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 800-811-8480
        • Principal Investigator:
          • Jennifer H. Choe
    • Washington
      • Vancouver, Washington, United States, 98686
        • Recruiting
        • Legacy Salmon Creek Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 503-413-2150
        • Principal Investigator:
          • Andrew Y. Kee
      • Vancouver, Washington, United States, 98684
        • Recruiting
        • Legacy Cancer Institute Medical Oncology and Day Treatment
        • Contact:
        • Principal Investigator:
          • Andrew Y. Kee
    • Wisconsin
      • Johnson Creek, Wisconsin, United States, 53038
        • Recruiting
        • University of Wisconsin Carbone Cancer Center - Johnson Creek
        • Principal Investigator:
          • Justine Yang-Bruce
        • Contact:
      • Madison, Wisconsin, United States, 53792
        • Recruiting
        • University of Wisconsin Carbone Cancer Center - University Hospital
        • Principal Investigator:
          • Justine Yang-Bruce
        • Contact:
      • Madison, Wisconsin, United States, 53718
        • Recruiting
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
        • Principal Investigator:
          • Justine Yang-Bruce
        • Contact:
      • Menomonee Falls, Wisconsin, United States, 53051
        • Recruiting
        • Froedtert Menomonee Falls Hospital
        • Contact:
          • Site Public Contact
          • Phone Number: 262-257-5100
        • Principal Investigator:
          • Jennifer D. Bruening
      • Milwaukee, Wisconsin, United States, 53226
        • Recruiting
        • Medical College of Wisconsin
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-3666
        • Principal Investigator:
          • Jennifer D. Bruening
      • New Berlin, Wisconsin, United States, 53151
        • Recruiting
        • Froedtert and MCW Moorland Reserve Health Center
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-0505
        • Principal Investigator:
          • Jennifer D. Bruening
      • Oak Creek, Wisconsin, United States, 53154
        • Recruiting
        • Drexel Town Square Health Center
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-0505
        • Principal Investigator:
          • Jennifer D. Bruening
      • West Bend, Wisconsin, United States, 53095
        • Recruiting
        • Froedtert West Bend Hospital/Kraemer Cancer Center
        • Contact:
          • Site Public Contact
          • Phone Number: 414-805-0505
        • Principal Investigator:
          • Jennifer D. Bruening

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Pathologically (histologically or cytologically) proven diagnosis of locally recurrent or persistent squamous cell carcinoma of head and neck (SCCHN) arising within the oral cavity, oropharynx, larynx, or hypopharynx
  • PD-L1 combined positive score (CPS) ≥ 1 using a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory
  • Verify insurance (or other payment) coverage for neoadjuvant chemotherapy
  • Measurable disease as defined by RECIST 1.1

  • Patients must have locally recurrent or persistent SCCHN arising within the oral cavity, oropharynx, larynx, or hypopharynx (American Joint Committee on Cancer [AJCC] Cancer Staging Manual, 8th Edition) AND are deemed candidates for salvage surgery:

    • P16 positive oropharynx patients with T2, T3, T4, N0, N1, N2 and all other patients with T2, T3, T4a, N0, N1, N2a, N2b, N2c, N3a are eligible.
    • Patients must be deemed surgically resectable without gross residual disease.
    • For patients with oral cavity SCCHN, only those with recurrent or persistent disease after prior surgery are eligible.
    • Patients who are candidates for salvage laryngectomy to treat recurrent laryngeal cancer and who are having salvage surgery for curative intent are eligible.
    • Patients with resectable lymph node-only recurrence are eligible.
    • No major vascular involvement (> 180° involvement of the common carotid or internal carotid artery), jugular foramen involvement, or prevertebral, paraspinous muscle involvement precluding a curative resection
  • No evidence of distant metastatic disease

  • The following minimum diagnostic workup is required:

    • General history and physical examination.
    • Diagnostic-quality neck CT and PET/CT of neck (PET with attenuation-correction CT of neck, chest, and abdomen)
  • Age ≥ 18
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
  • Negative urine or serum pregnancy test (in persons of childbearing potential) within 30 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
  • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
  • Platelets ≥ 100,000 cells/mm^3
  • Hemoglobin ≥ 8.0 g/dL (Note: The use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dL is acceptable)
  • Adequate renal function defined as creatinine clearance (CrCL) > 50 mL/min by the Cockcroft-Gault formula
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (Not applicable to patients with known Gilbert's syndrome)
  • Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN

  • Only patients who received prior radiation therapy in the definitive or post-operative setting (limited to one course) are eligible.

    • Prior radiation therapy must have been completed at least 6 months prior to registration with the majority of the index persistent/recurrent cancer volume (> 50%) irradiated to ≥ 40 Gy at the time
  • Prior systemic therapy including immunotherapy with anti-PD1 or anti-PDL1 within the definitive setting (neo-adjuvant, or adjuvant) is permitted and must have been completed at least 4 months prior to registration
  • Prior systemic therapy including immunotherapy for treatment of recurrent or metastatic SCCHN is not permitted
  • No investigational anti-cancer agents received within 4 weeks prior to registration
  • No New York Heart Association Functional Classification III or IV (Note: 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)
  • No active infection requiring IV antibiotics, IV antiviral, or IV antifungal treatments
  • No peripheral neuropathy grade 3 or 4
  • No history of interstitial lung disease
  • No active, noninfectious pneumonitis requiring immunosuppressive therapy
  • No history of a solid organ transplant (other than corneal transplant)

  • No active autoimmune disease that has required systemic treatment in the past 2 years (i.e., use of disease-modifying agents, corticosteroids [> 10 mg prednisone/day or equivalent] or immunosuppressive drugs)

    • NOTE: Patients meeting the following criteria are not considered immunosuppressed and are eligible to enroll:

      • Patients who require a brief course of steroids (e.g., prophylaxis for imaging assessments due to hypersensitivity to contrast agents) are not excluded
      • Patients with type I diabetes mellitus, and endocrinopathies (including hypothyroidism due to autoimmune thyroiditis) only requiring hormone replacement, or skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
      • Physiologic replacement doses ≤ 10 mg prednisone/day or equivalent are allowed. Inhaled or topical steroids are permitted
  • No history of allergic reaction to the study agent, compounds of similar chemical or biologic composition to the study agent, and immune checkpoint inhibitors (or any of its excipients)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm 1 (Salvage surgery)
Patients undergo standard of care salvage surgery. Starting within 8 weeks of surgery, patients with high risk features also undergo radiation therapy daily for 5 treatments per week for 6 weeks and receive cisplatin IV once per week for 6 weeks during radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan and optionally undergo blood sample collection throughout the study.
Drug: Cisplatin
Given IV
Other Names:
  • CDDP
  • Cis-diamminedichloridoplatinum
  • Cismaplat
  • Cisplatinum
  • Neoplatin
  • Platinol
  • Abiplatin
  • Blastolem
  • Briplatin
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cisplatina
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
Procedure: Biospecimen Collection
Undergo blood sample collection
Other Names:
  • Biological Sample Collection
  • Biospecimen Collected
  • Specimen Collection
  • Sample Collection
Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Energy Type
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
Procedure: Salvage Surgery
Undergo standard of care salvage surgery
Other Names:
  • Rescue Surgery
  • Salvage Resection
  • Salvage Surgical Resection
  • Surgical Salvage
Experimental: Arm 2 (Chemotherapy, salvage surgery)
Patients receive paclitaxel IV and carboplatin IV on day 1 of each cycle. Cycles repeat every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. 6-10 weeks after cycle 1 day 1 patients undergo standard of care salvage surgery. Starting within 8 weeks of surgery, patients with high risk features also undergo radiation therapy daily for 5 treatments per week for 6 weeks and receive cisplatin IV once per week for 6 weeks during radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan and optionally undergo blood sample collection throughout the study.
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
Drug: Cisplatin
Given IV
Other Names:
  • CDDP
  • Cis-diamminedichloridoplatinum
  • Cismaplat
  • Cisplatinum
  • Neoplatin
  • Platinol
  • Abiplatin
  • Blastolem
  • Briplatin
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cisplatina
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
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
  • Sample Collection
Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Energy Type
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
Procedure: Salvage Surgery
Undergo standard of care salvage surgery
Other Names:
  • Rescue Surgery
  • Salvage Resection
  • Salvage Surgical Resection
  • Surgical Salvage
Experimental: Arm 3 (Chemo-immunotherapy, salvage surgery)
Patients receive paclitaxel IV, carboplatin IV and cemiplimab IV, over 30 minutes, on day 1 of each cycle. Cycles repeat every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. 6-10 weeks after cycle 1 day 1 patients undergo standard of care salvage surgery. Starting within 8 weeks of surgery, patients with high risk features also undergo radiation therapy daily for 5 treatments per week for 6 weeks and receive cisplatin IV once per week for 6 weeks during radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, PET scan and optionally undergo blood sample collection throughout the study.
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
Drug: Cisplatin
Given IV
Other Names:
  • CDDP
  • Cis-diamminedichloridoplatinum
  • Cismaplat
  • Cisplatinum
  • Neoplatin
  • Platinol
  • Abiplatin
  • Blastolem
  • Briplatin
  • Cis-diammine-dichloroplatinum
  • Cis-diamminedichloro Platinum (II)
  • Cis-diamminedichloroplatinum
  • Cis-dichloroammine Platinum (II)
  • Cis-platinous Diamine Dichloride
  • Cis-platinum
  • Cis-platinum II
  • Cis-platinum II Diamine Dichloride
  • Cisplatina
  • Cisplatyl
  • Citoplatino
  • Citosin
  • Cysplatyna
  • DDP
  • Lederplatin
  • Metaplatin
  • Peyrone's Chloride
  • Peyrone's Salt
  • Placis
  • Plastistil
  • Platamine
  • Platiblastin
  • Platiblastin-S
  • Platinex
  • Platinol- AQ
  • Platinol-AQ
  • Platinol-AQ VHA Plus
  • Platinoxan
  • Platinum
  • Platinum Diamminodichloride
  • Platiran
  • Platistin
  • Platosin
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
  • Sample Collection
Radiation: Radiation Therapy
Undergo radiation therapy
Other Names:
  • Cancer Radiotherapy
  • ENERGY_TYPE
  • Irradiate
  • Irradiated
  • Irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • Radiotherapy
  • RT
  • Therapy, Radiation
  • Energy Type
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: Cemiplimab
Given IV
Other Names:
  • REGN2810
  • Cemiplimab RWLC
  • Cemiplimab-rwlc
  • Libtayo
  • REGN 2810
  • REGN-2810
Procedure: Salvage Surgery
Undergo standard of care salvage surgery
Other Names:
  • Rescue Surgery
  • Salvage Resection
  • Salvage Surgical Resection
  • Surgical Salvage

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Event free survival (EFS)
Time Frame: From randomization to disease progression or treatment-related toxicities that precludes surgery, disease progression in the absence of surgery, disease recurrence after surgery, or death due to any cause, up to 7 years
Will be summarized by treatment arm using standard Kaplan-Meier methods, reporting the estimated 2-year EFS rate with corresponding 95% confidence intervals.
From randomization to disease progression or treatment-related toxicities that precludes surgery, disease progression in the absence of surgery, disease recurrence after surgery, or death due to any cause, up to 7 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease free survival (DFS)
Time Frame: From randomization until disease recurrence, death due to any cause, up to 7 years
Will be summarized by treatment arm using standard Kaplan-Meier methods, where estimates of the 2-year DFS will be obtained with 95% confidence intervals. Comparisons between the experimental arms and the control arm will be made using the stratified log-rank test.
From randomization until disease recurrence, death due to any cause, up to 7 years
Overall survival (OS)
Time Frame: From randomization until death due to any cause, up to 7 years
Will be summarized by treatment arm using standard Kaplan-Meier methods, where estimates of the 2-year OS will be obtained with 95% confidence intervals. Comparisons between the experimental arms and the control arm will be made using the stratified log-rank test.
From randomization until death due to any cause, up to 7 years
Time to distant metastasis
Time Frame: From randomization until detection of distant metastases or death, up to 7 years
The cumulative incidence method will be used to estimate the incidence of distant metastases; where estimates of the 2-year distant metastasis rates will be obtained with 95% confidence intervals. Comparisons between the experimental arms and the control arm will be made using the stratified Gray's test.
From randomization until detection of distant metastases or death, up to 7 years
Surgical complications
Time Frame: Up to 7 years
Will be assessed using the Comprehensive Complication Index. Surgical complications will be summarized by treatment arm using frequencies and relative frequencies; where the overall complication rate will be estimated by treatment arm using 95% confidence intervals obtained by the Clopper-Pearson method. Comparisons between the experimental arms and the control arm will be made using the Cochran-Mantel-Haenszel test.
Up to 7 years
Incidence of acute adverse events
Time Frame: Up to 30 days from the last treatment
Assessed by Common Terminology Critiera for Adverse Events (CTCAE) version (v) 5.0. The overall (highest grade) acute toxicities will be summarized by treatment arm using frequencies and relative frequencies.
Up to 30 days from the last treatment
Incidence of late adverse events
Time Frame: From day 31 to 180 days from the last treatment
Assessed by CTCAE v 5.0. The overall (highest grade) late toxicities will be summarized by treatment arm using frequencies and relative frequencies.
From day 31 to 180 days from the last treatment
Radiographic response (Arm 2 and 3)
Time Frame: Up to 7 years
Response will be assessed using Response Evaluation Criteria in Solid Tumors 1.1. Best response will be summarized by treatment arm using frequencies and relative frequencies; where the complete (CR) and objective response rates (CR + partial response) will be estimated using 95% confidence intervals obtained by the Clopper-Pearson method.
Up to 7 years
Major pathological response (mPR) (Arm 2 and 3)
Time Frame: Up to 7 years
mPR will be summarized by treatment arm using frequencies and relative frequencies; where the mPR rates will be estimated using 95% confidence intervals obtained by the Clopper-Pearson method.
Up to 7 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Nabil F Saba, NRG Oncology

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 24, 2026

Primary Completion (Estimated)

February 1, 2033

Study Completion (Estimated)

February 1, 2033

Study Registration Dates

First Submitted

September 26, 2025

First Submitted That Met QC Criteria

September 26, 2025

First Posted (Actual)

September 29, 2025

Study Record Updates

Last Update Posted (Actual)

June 18, 2026

Last Update Submitted That Met QC Criteria

June 17, 2026

Last Verified

April 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2025-06920 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
  • U10CA180868 (U.S. NIH Grant/Contract)
  • NRG-HN015 (Other Identifier: CTEP)

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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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