Cisplatin, Intensity-Modulated Radiation Therapy, and Pembrolizumab in Treating Patients With Stage III-IV Head and Neck Squamous Cell Carcinoma

June 9, 2022 updated by: National Cancer Institute (NCI)

A Phase I and Expansion Cohort Study of Adjuvant Cisplatin, Intensity-Modulated Radiotherapy, and MK-3475 (Pembrolizumab) in High-Risk Head and Neck Squamous Cell Carcinoma (HNSCC)

This phase I trial studies the side effects and best dose of pembrolizumab when given together with cisplatin and intensity-modulated radiation therapy, in treating patients with stage III-IV squamous cell carcinoma of the head and neck. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Intensity-modulated radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab with cisplatin and intensity-modulated radiation therapy may work better in treating patients with squamous cell carcinoma of the head and neck.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) for the combination of MK-3475 (pembrolizumab) and standard, adjuvant cisplatin-radiotherapy in patients with high-risk, human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), based upon dose-limiting toxicity (DLT).

SECONDARY OBJECTIVES:

I. To describe 1-year disease-free survival (DFS), overall survival (OS), local-regional failure (LRF), and rate of distant metastases following treatment with adjuvant cisplatin-radiotherapy and MK-3475 (pembrolizumab).

II. To describe the toxicity of the combination of cisplatin-radiotherapy and MK-3475 (pembrolizumab) according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4, including immune-related adverse events (AEs).

III. To describe the relationship between baseline programmed cell death 1 ligand 1 (PD-L1) expression 1-year disease-free survival (DFS).

IV. To describe baseline immune-inflammatory biomarkers in both tumor and tumor-infiltrating lymphocytes (TILs), and correlate them with 1-year DFS.

V. To describe baseline and change in expression of peripheral immune-inflammatory biomarkers, including a panel of candidate tumor antigen (TA)-specific memory T cells, and correlate with 1-year DFS.

OUTLINE:

Patients receive cisplatin intravenously (IV) over 1-2 hours once weekly for weeks 1-6 and pembrolizumab IV over 30 minutes every 3 weeks in weeks 9, 12, 15, 18, and 21. Patients also undergo intensity-modulated radiation therapy (IMRT) in weeks 1-6. Patients may also receive pembrolizumab IV over 30 minutes in weeks 3, 6, 24, and 27.

After completion of study treatment, patients are followed up at months 6, 9, 12, 15, 18, 21, 24, 30, and 36.

Study Type

Interventional

Enrollment (Actual)

37

Phase

  • Phase 1

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
        • Banner University Medical Center - Tucson
    • California
      • La Jolla, California, United States, 92093
        • UC San Diego Moores Cancer Center
      • Los Angeles, California, United States, 90048
        • Cedars Sinai Medical Center
      • Sacramento, California, United States, 95816
        • Sutter Medical Center Sacramento
    • Colorado
      • Aurora, Colorado, United States, 80045
        • University of Colorado Hospital
      • Colorado Springs, Colorado, United States, 80907
        • Penrose-Saint Francis Healthcare
      • Fort Collins, Colorado, United States, 80524
        • Poudre Valley Hospital
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Yale University
    • Delaware
      • Newark, Delaware, United States, 19713
        • Helen F Graham Cancer Center
      • Newark, Delaware, United States, 19718
        • Christiana Care Health System-Christiana Hospital
    • Florida
      • Coral Gables, Florida, United States, 33146
        • UM Sylvester Comprehensive Cancer Center at Coral Gables
      • Deerfield Beach, Florida, United States, 33442
        • UM Sylvester Comprehensive Cancer Center at Deerfield Beach
      • Gainesville, Florida, United States, 32610
        • University of Florida Health Science Center - Gainesville
      • Miami, Florida, United States, 33136
        • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Georgia
      • Atlanta, Georgia, United States, 30308
        • Emory University Hospital Midtown
      • Atlanta, Georgia, United States, 30322
        • Emory University Hospital/Winship Cancer Institute
      • Atlanta, Georgia, United States, 30303
        • Grady Health System
    • Illinois
      • Aurora, Illinois, United States, 60504
        • Rush - Copley Medical Center
      • Chicago, Illinois, United States, 60611
        • Northwestern University
      • Chicago, Illinois, United States, 60612
        • Rush University Medical Center
      • Decatur, Illinois, United States, 62526
        • Decatur Memorial Hospital
      • Peoria, Illinois, United States, 61636
        • Methodist Medical Center of Illinois
      • Peoria, Illinois, United States, 61637
        • OSF Saint Francis Medical Center
      • Urbana, Illinois, United States, 61801
        • Carle Cancer Center
    • Indiana
      • Indianapolis, Indiana, United States, 46237
        • Franciscan Health Indianapolis
    • Iowa
      • Des Moines, Iowa, United States, 50309
        • Iowa Methodist Medical Center
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • University of Kansas Cancer Center
      • Overland Park, Kansas, United States, 66210
        • University of Kansas Cancer Center-Overland Park
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • The James Graham Brown Cancer Center at University of Louisville
    • Louisiana
      • New Orleans, Louisiana, United States, 70121
        • Ochsner Medical Center Jefferson
    • Michigan
      • Brownstown, Michigan, United States, 48183
        • Henry Ford Cancer Institute-Downriver
      • Clinton Township, Michigan, United States, 48038
        • Henry Ford Macomb Hospital-Clinton Township
      • Detroit, Michigan, United States, 48202
        • Henry Ford Hospital
    • Minnesota
      • Bemidji, Minnesota, United States, 56601
        • Sanford Joe Lueken Cancer Center
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic in Rochester
    • Missouri
      • Kansas City, Missouri, United States, 64154
        • University of Kansas Cancer Center - North
      • Kansas City, Missouri, United States, 64131
        • The University of Kansas Cancer Center-South
      • Lee's Summit, Missouri, United States, 64064
        • University of Kansas Cancer Center - Lee's Summit
    • Nebraska
      • Omaha, Nebraska, United States, 68114
        • Nebraska Methodist Hospital
    • New Hampshire
      • Lebanon, New Hampshire, United States, 03756
        • Dartmouth Hitchcock Medical Center
    • New Mexico
      • Albuquerque, New Mexico, United States, 87102
        • University of New Mexico Cancer Center
    • New York
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center - Moses Campus
    • North Dakota
      • Bismarck, North Dakota, United States, 58501
        • Sanford Bismarck Medical Center
      • Fargo, North Dakota, United States, 58122
        • Sanford Roger Maris Cancer Center
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic Foundation
      • Cleveland, Ohio, United States, 44111
        • Cleveland Clinic Cancer Center/Fairview Hospital
      • Columbus, Ohio, United States, 43210
        • Ohio State University Comprehensive Cancer Center
      • Independence, Ohio, United States, 44131
        • Cleveland Clinic Cancer Center Independence
      • Mansfield, Ohio, United States, 44906
        • Cleveland Clinic Cancer Center Mansfield
      • Mayfield Heights, Ohio, United States, 44124
        • Hillcrest Hospital Cancer Center
      • Mentor, Ohio, United States, 44060
        • UH Seidman Cancer Center at Lake Health Mentor Campus
      • Sandusky, Ohio, United States, 44870
        • North Coast Cancer Care
      • Strongsville, Ohio, United States, 44136
        • Cleveland Clinic Cancer Center Strongsville
      • Wooster, Ohio, United States, 44691
        • Cleveland Clinic Wooster Family Health and Surgery Center
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • University of Oklahoma Health Sciences Center
    • Oregon
      • Clackamas, Oregon, United States, 97015
        • Clackamas Radiation Oncology Center
      • Portland, Oregon, United States, 97213
        • Providence Portland Medical Center
    • Pennsylvania
      • Bethlehem, Pennsylvania, United States, 18015
        • Saint Luke's University Hospital-Bethlehem Campus
      • Chadds Ford, Pennsylvania, United States, 19317
        • Christiana Care Health System-Concord Health Center
      • Hershey, Pennsylvania, United States, 17033-0850
        • Penn State Milton S Hershey Medical Center
      • Philadelphia, Pennsylvania, United States, 19111
        • Fox Chase Cancer Center
      • Pittsburgh, Pennsylvania, United States, 15232
        • UPMC-Shadyside Hospital
    • South Dakota
      • Sioux Falls, South Dakota, United States, 57117-5134
        • Sanford USD Medical Center - Sioux Falls
    • Texas
      • Dallas, Texas, United States, 75390
        • UT Southwestern/Simmons Cancer Center-Dallas
      • San Antonio, Texas, United States, 78229
        • University of Texas Health Science Center at San Antonio
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • Huntsman Cancer Institute/University of Utah
    • Washington
      • Bellingham, Washington, United States, 98225
        • PeaceHealth Saint Joseph Medical Center
      • Seattle, Washington, United States, 98195
        • University of Washington Medical Center - Montlake

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

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • STEP 1 (REGISTRATION)
  • Pathologically (histologically or cytologically) proven diagnosis of head and neck squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips), oropharynx (p16 negative), hypopharynx or larynx
  • Patients must have undergone gross total surgical resection of high-risk oral cavity, oropharynx (p16 negative), larynx, or hypopharynx squamous cell carcinoma (SCC) within 63 days prior to registration; note: patients may have a biopsy under general anesthesia in an operating room followed by definitive ablative cancer surgery representing gross total resection; the gross total resection has to be done within 63 days prior to registration; if, however, patients have ablative resection but demonstrate rapid gross recurrence or are determined to have gross persisting disease requiring re-resection to achieve gross total resection, then the patient is not eligible

  • Patients must have at least one of the following high risk pathologic features:

    • Extracapsular nodal extension
    • Invasive cancer at the primary tumor resection margin (tumor on ink); Note: Patients who have a positive margin and undergo re-resection with final negative margin are eligible only if they can be enrolled within 63 days of initial gross total resection AND extracapsular nodal extension was also present; patients who have a positive margin and undergo re-resection with final negative margin and do not have extracapsular nodal extension, are NOT eligible

  • Pathologic stage III or IV HNSCC, including no distant metastases, based on the following minimum diagnostic workup:

    • General history/physical examination by a radiation oncologist and/or medical oncologist within 84 days prior to registration
    • Examination by an ear nose and throat (ENT) or head & neck surgeon prior to surgery; a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure), if appropriate, is recommended but not required; intra-operative examination is acceptable documentation
    • Pre-op Imaging of the head and neck: a neck computerized tomography (CT) (with contrast) or CT/positron emission tomography (PET) (with contrast) and/or an magnetic resonance imaging (MRI) of the neck (T1 with gadolinium and T2) within 84 days prior to surgery; note: this imaging data (diagnostic pre-operative scan showing gross disease) is to be submitted in Digital Imaging and Communications in Medicine (DICOM) format via transfer of images and data (TRIAD); the report is to be uploaded into Rave
    • Chest imaging with either a CT scan (with or without contrast) or CT/PET (with or without contrast) that includes the chest within 120 days prior to registration; Note: if the CT/PET with or without contrast is done within 84 days prior to surgery, it fulfills the chest imaging requirement
  • For patients with oropharyngeal cancer only: the institution will do p16 testing, and if p16 is negative, this tissue must be submitted for central review for confirmation before Step 2 registration; note: if the institution finds that the patient is p16 positive, the patient is excluded from this trial on the basis of distinct biology, prognosis, and low- or intermediate-risk rather than high-risk status
  • Zubrod performance status of 0-1 within 28 days prior to registration
  • Absolute neutrophil count (ANC): >= 1,500 /mm^3
  • Platelets: >= 100,000 / 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)
  • Creatinine clearance (CrCl) >= 50 ml/min within 14 days prior to registration as determined by 24-hour collection or estimated by Cockcroft-Gault formula
  • Serum total bilirubin: =< 1.5 X ULN OR
  • Direct bilirubin: =< ULN for patients with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN
  • International normalized ratio (INR) or prothrombin time (PT): =< 1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated Partial Thromboplastin Time (aPTT): =< 1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • The following assessments are required within 14 days prior to registration: sodium (Na), potassium (K), chlorine (Cl), glucose, calcium (Ca), magnesium (Mg), and albumin; note: patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g., magnesium oxide) at the investigator's discretion
  • For women of childbearing potential, a negative serum pregnancy test within 14 days of registration
  • Female patients of childbearing potential and men receiving MK-3475 (pembrolizumab) who are sexually active with women of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of MK-3475 (pembrolizumab); note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient
  • Patients with feeding tubes are eligible for the study
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry, including consent for mandatory tumor tissue, serum, and blood submission for immune correlatives (all patients) and p16 analysis (oropharyngeal cases only)
  • STEP 2 (REGISTRATION)
  • For patients with oropharyngeal cancer only: p16 negative, confirmed by central pathology review

Exclusion Criteria:

  • Definitive clinical or radiologic evidence of metastatic disease
  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma in situ of the breast, oral cavity, or cervix) are permitted even if diagnosed and treated < 3 years ago
  • Patients with simultaneous primaries or bilateral tumors are excluded, with the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0 differentiated thyroid carcinoma, who are eligible
  • Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer; note: prior cytotoxic chemotherapy or biologic/targeted therapy for a different cancer is allowable; however, a prior anti-programmed cell death (PD)-1, anti-PD-L1, or anti-programmed cell death 1 ligand 2 (PD-L2) agent is not permitted
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields

  • Severe, active co-morbidity defined as follows:

    • Unstable angina and/or congestive heart failure requiring hospitalization within 6 months prior to registration
    • Transmural myocardial infarction within 6 months prior to registration
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; Note: if the infection resolves and the patient is on oral (p.o.) and still within, the required registration timeframe, then the patient is eligible
    • Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
    • Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to registration
    • History of (non-infectious) pneumonitis that required steroids or current pneumonitis
    • Acquired immune deficiency syndrome (AIDS) based upon current Center for Disease Control and Prevention (CDC) definition; note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the cisplatin and IMRT involved in this protocol may be significantly immunosuppressive; patients with known HIV, CD4 counts >= 250/uL, and undetectable viral loads who are stable on an antiretroviral regimen may be included
    • A diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of the MK-3475 (pembrolizumab)
    • Known history of active TB (Bacillus tuberculosis)
    • Known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis c virus [HCV] ribonucleic acid [RNA] [qualitative] is detected); Note: patients who have been curatively treated for hepatitis C and have no detectable viral load are eligible
    • Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Grade 3-4 electrolyte abnormalities (CTCAE, v. 4):
  • Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5 mg/dl (> 3.1 mmol/L) despite intervention to normalize levels
  • Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14mmol/L)
  • Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention to normalize levels
  • Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels
  • Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels
  • Patients who are pregnant, nursing, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of MK-3475 (pembrolizumab)
  • Hypersensitivity to MK-3475 (pembrolizumab) or any of its excipients;
  • Patients who have received a live vaccine within 30 days of planned start of study therapy; Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • Patients for whom it is not in the best interest to participate in the study, in the opinion of the treating investigator

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: NA
  • Interventional Model: SINGLE_GROUP
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Treatment (cisplatin, pembrolizumab, IMRT)
Patients receive cisplatin IV over 1-2 hours once weekly for weeks 1-6 and pembrolizumab IV over 30 minutes every 3 weeks in weeks 9, 12, 15, 18, and 21. Patients also undergo IMRT in weeks 1-6. Patients may also receive pembrolizumab IV over 30 minutes in weeks 3, 6, 24, and 27.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Cisplatin
Given IV
Biological: Pembrolizumab
Given IV
Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose limiting toxicities in patients with high-risk head and neck squamous cell carcinoma treated with adjuvant cisplatin, intensity-modulated radiation therapy, and pembrolizumab
Time Frame: Up to 4 weeks post intensity-modulated radiation therapy
Will be summarized using proportions for binary outcome per cohort.
Up to 4 weeks post intensity-modulated radiation therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Disease free survival
Time Frame: Up to 1 year
Descriptive statistics for disease free survival will be estimated using the Kaplan-Meier method.
Up to 1 year
Overall survival
Time Frame: Up to 1 year
Descriptive statistics for overall survival will be estimated using the Kaplan-Meier method
Up to 1 year
Local-regional failure
Time Frame: Up to 1 year
Descriptive statistics for rates local-regional failure will be estimated using the cumulative incidence method.
Up to 1 year
Distant metastases
Time Frame: Up to 1 year
Descriptive statistics for distant metastasis will be estimated using the cumulative incidence method.
Up to 1 year
Incidence of acute toxicities by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame: Up to 1 year
Adverse events will be estimated using a binomial distribution along with their associated 95% confidence intervals.
Up to 1 year
Incidence of late toxicities by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame: Up to 1 year
Adverse events will be estimated using a binomial distribution along with their associated 95% confidence intervals.
Up to 1 year
Levels of PDL1
Time Frame: Up to 1 year
Will be assessed in tumor tissue by light microscopy.
Up to 1 year
Immune-inflammatory biomarkers
Time Frame: Up to 1 year
Will be correlated in both tumor and tumor infiltrating lymphocytes
Up to 1 year
Change in expression of peripheral immune-inflammatory biomarkers
Time Frame: Up to 1 year
Change in expression will be assessed.
Up to 1 year

Collaborators and Investigators

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

Sponsor

National Cancer Institute (NCI)

Collaborators

NRG Oncology

Investigators

  • Principal Investigator: Julie E Bauman, 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)

November 28, 2016

Primary Completion (ACTUAL)

December 3, 2018

Study Completion (ACTUAL)

May 20, 2022

Study Registration Dates

First Submitted

May 16, 2016

First Submitted That Met QC Criteria

May 16, 2016

First Posted (ESTIMATE)

May 18, 2016

Study Record Updates

Last Update Posted (ACTUAL)

June 10, 2022

Last Update Submitted That Met QC Criteria

June 9, 2022

Last Verified

June 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2016-00667 (REGISTRY: CTRP (Clinical Trial Reporting Program))
  • U10CA180868 (U.S. NIH Grant/Contract)
  • NRG-HN003 (OTHER: CTEP)

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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