Clinical trial NCT06589804: 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
Official title: Randomized Phase III Trial of Pembrolizumab vs. Pembrolizumab/Cetuximab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma With Platinum Refractory Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2024-09-19
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: PRIMARY OBJECTIVE:

I. To assess whether the combination of cetuximab and pembrolizumab (arm 2) compared to pembrolizumab alone (arm 1) results in improved overall survival (OS) in subjects with platinum refractory HNSCC.

SECONDARY OBJECTIVES:

I. To compare pembrolizumab + cetuximab (arm 2) versus (vs.) pembrolizumab alone (arm 1) with respect to objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

II. To compare pembrolizumab + cetuximab (arm 2) vs. pembrolizumab alone (arm 1) with respect to progression free survival (PFS) per RECIST 1.1.

III. To evaluate pembrolizumab + cetuximab (arm 2) vs. pembrolizumab alone (arm 1) with respect to duration of response (DOR) per RECIST 1.1.

IV. To assess the safety and tolerability of pembrolizumab + cetuximab (arm 2) vs. pembrolizumab alone (arm 1).

V. To assess the patient-reported toxicity using Patient Reported Outcomes version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) of pembrolizumab + cetuximab (arm 2) vs. pembrolizumab alone (arm 1).

EXPLORATORY OBJECTIVES:

I. To identify specific mutational changes that may be indicative of clinical response to pembrolizumab + cetuximab and pembrolizumab alone.

II. To evaluate circulating tumor-derived deoxyribonucleic acid (ctDNA) kinetics over the course of treatment in response to pembrolizumab + cetuximab and pembrolizumab alone.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive pembrolizumab intravenously (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 computed tomography (CT), positron emission tomography (PET)/CT or magnetic resonance imaging (MRI) throughout the trial and optionally undergo blood sample collection on study and at disease progression or end of treatment.

ARM 2: Patients 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.

After completion of study treatment, patients are followed up within 4 weeks and then every 3 and/or 6 months for up to 5 years.

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 ≤ 6 months 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 anti PD-1/PD-L1 monoclonal antibody or cetuximab in the curative setting is allowed if last treatment dose was \>= 6 months 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.

Primary outcomes:
measure: Overall survival
timeFrame: Time from randomization to death from any cause, assessed up to 5 years
Secondary outcomes:
measure: Confirmed response rate
timeFrame: Up to 5 years
measure: Duration of response
timeFrame: From the date at which the patient's earliest best objective status is first noted to be either a complete response (CR) or partial response (PR) to the earliest date progression is documented, assessed up to 5 years
measure: Progression free survival
timeFrame: Time from randomization to the first of either disease progression or death from any cause, assessed up to 5 years
measure: Incidence of adverse events
timeFrame: Up to 5 years
measure: Patient-reported toxicity
timeFrame: Up to 5 years
Other outcomes:
measure: Estimates of median OS by sex
timeFrame: Up to 5 years
measure: Estimates of median OS by race
timeFrame: Up to 5 years
measure: Estimates of median OS by ethnicity
timeFrame: Up to 5 years
Locations:
city: Marysville
country: United States
facility: Fremont - Rideout Cancer Center
state: California
city: Golden
country: United States
facility: Lutheran Hospital - Cancer Centers of Colorado
state: Colorado
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Caldwell
country: United States
facility: Saint Alphonsus Cancer Care Center-Caldwell
state: Idaho
city: Coeur d'Alene
country: United States
facility: Kootenai Health - Coeur d'Alene
state: Idaho
city: Nampa
country: United States
facility: Saint Alphonsus Cancer Care Center-Nampa
state: Idaho
city: Post Falls
country: United States
facility: Kootenai Clinic Cancer Services - Post Falls
state: Idaho
city: Sandpoint
country: United States
facility: Kootenai Clinic Cancer Services - Sandpoint
state: Idaho
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Decatur
country: United States
facility: Cancer Care Specialists of Illinois - Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: New Lenox
country: United States
facility: UC Comprehensive Cancer Center at Silver Cross
state: Illinois
city: O'Fallon
country: United States
facility: Cancer Care Center of O'Fallon
state: Illinois
city: Orland Park
country: United States
facility: University of Chicago Medicine-Orland Park
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Rockford
country: United States
facility: UW Health Carbone Cancer Center Rockford
state: Illinois
city: Shiloh
country: United States
facility: Memorial Hospital East
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Springfield
country: United States
facility: Springfield Clinic
state: Illinois
city: Springfield
country: United States
facility: Springfield Memorial Hospital
state: Illinois
city: Crown Point
country: United States
facility: UChicago Medicine Northwest Indiana
state: Indiana
city: Ames
country: United States
facility: Mary Greeley Medical Center
state: Iowa
city: Ames
country: United States
facility: McFarland Clinic - Ames
state: Iowa
city: Boone
country: United States
facility: McFarland Clinic - Boone
state: Iowa
city: Cedar Rapids
country: United States
facility: Mercy Hospital
state: Iowa
city: Cedar Rapids
country: United States
facility: Oncology Associates at Mercy Medical Center
state: Iowa
city: Fort Dodge
country: United States
facility: McFarland Clinic - Trinity Cancer Center
state: Iowa
city: Jefferson
country: United States
facility: McFarland Clinic - Jefferson
state: Iowa
city: Marshalltown
country: United States
facility: McFarland Clinic - Marshalltown
state: Iowa
city: Hays
country: United States
facility: HaysMed
state: Kansas
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Olathe
country: United States
facility: The University of Kansas Cancer Center - Olathe
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Hospital-Indian Creek Campus
state: Kansas
city: Salina
country: United States
facility: Salina Regional Health Center
state: Kansas
city: Topeka
country: United States
facility: University of Kansas Health System Saint Francis Campus
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Ann Arbor
country: United States
facility: Trinity Health Saint Joseph Mercy Hospital Ann Arbor
state: Michigan
city: Brighton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Brighton
state: Michigan
city: Canton
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Canton
state: Michigan
city: Chelsea
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
state: Michigan
city: Flint
country: United States
facility: Cancer Hematology Centers - Flint
state: Michigan
city: Flint
country: United States
facility: Genesee Hematology Oncology PC
state: Michigan
city: Flint
country: United States
facility: Genesys Hurley Cancer Institute
state: Michigan
city: Flint
country: United States
facility: Hurley Medical Center
state: Michigan
city: Livonia
country: United States
facility: Trinity Health Saint Mary Mercy Livonia Hospital
state: Michigan
city: Ypsilanti
country: United States
facility: Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
state: Michigan
city: Bemidji
country: United States
facility: Sanford Joe Lueken Cancer Center
state: Minnesota
city: Cape Girardeau
country: United States
facility: Saint Francis Medical Center
state: Missouri
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Kansas City
country: United States
facility: University Health Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: University of Kansas Cancer Center - North
state: Missouri
city: Lee's Summit
country: United States
facility: University of Kansas Cancer Center - Lee's Summit
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Anaconda
country: United States
facility: Community Hospital of Anaconda
state: Montana
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Health Deaconess Hospital
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Missoula
country: United States
facility: Community Medical Center
state: Montana
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center-Community Campus
state: New York
city: Verona
country: United States
facility: Upstate Cancer Center at Verona
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Hendersonville
country: United States
facility: Margaret R Pardee Memorial Hospital
state: North Carolina
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Broadway Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Lawton
country: United States
facility: Cancer Centers of Southwest Oklahoma Research
state: Oklahoma
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Ontario
country: United States
facility: Saint Alphonsus Cancer Care Center-Ontario
state: Oregon
city: Oregon City
country: United States
facility: Providence Willamette Falls Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital-Cedar Crest
state: Pennsylvania
city: Bethlehem
country: United States
facility: Lehigh Valley Hospital - Muhlenberg
state: Pennsylvania
city: East Stroudsburg
country: United States
facility: Pocono Medical Center
state: Pennsylvania
city: Mitchell
country: United States
facility: Avera Cancer Institute - Mitchell
state: South Dakota
city: Pierre
country: United States
facility: Avera Cancer Institute at Pierre
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford Cancer Center Oncology Clinic
state: South Dakota
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Yankton
country: United States
facility: Avera Cancer Institute at Yankton
state: South Dakota
city: Richmond
country: United States
facility: VCU Massey Cancer Center at Stony Point
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University/Massey Cancer Center
state: Virginia
city: Charleston
country: United States
facility: West Virginia University Charleston Division
state: West Virginia
city: La Crosse
country: United States
facility: Gundersen Lutheran Medical Center
state: Wisconsin
city: Mukwonago
country: United States
facility: ProHealth D N Greenwald Center
state: Wisconsin
city: Oconomowoc
country: United States
facility: ProHealth Oconomowoc Memorial Hospital
state: Wisconsin
city: Waukesha
country: United States
facility: ProHealth Waukesha Memorial Hospital
state: Wisconsin
city: Waukesha
country: United States
facility: UW Cancer Center at ProHealth Care
state: Wisconsin
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Siddharth Sheth
role: PRINCIPAL_INVESTIGATOR
References: