The Addition of Pembrolizumab to Postoperative Radiotherapy in Cutaneous Squamous Cell Cancer of the Head and Neck

• ClinicalTrials.gov Identifier: NCT03057613
• Recruitment Status: Completed
• First Posted: February 20, 2017
• Results First Posted: October 19, 2020
• Last Update Posted: June 30, 2022
• Sponsor: Case Comprehensive Cancer Center
• Information provided by (Responsible Party): Case Comprehensive Cancer Center

Study Description

Brief Summary:

A small group of skin cancers of the head and neck, called resected cutaneous squamous carcinomas, are more aggressive than most cancers of this type, even after being treated with standard therapy. This trial will use stronger treatment to look at the safety and effectiveness (efficacy) of combining a drug called Pembrolizumab with radiation after a cancer has already been treated to suppress secondary tumor formation in high risk cutaneous squamous cell cancer of the head and neck.

Primary Objective To assess safety by looking at the people with dose limiting responses

Condition or disease	Intervention/treatment	Phase
Squamous Cell Carcinoma of the Head and Neck	Drug: Pembrolizumab; Radiation: IMRT 60-66Gy	Phase 2

Detailed Description:

Primary Objective:

To assess safety and estimate 1-year progression-free survival (PFS) of postoperative radiation therapy (RT) + concurrent and adjuvant Pembrolizumab in high risk resected cutaneous squamous cell cancer of the head and neck (cSCC-HN).

Secondary Objectives

1. To evaluate the relationship of baseline programmed death-ligand 1 (PD-L1) expression by tumor and tumor-infiltrating lymphocytes (TILs) to preliminary efficacy .
2. To phenotype tumor infiltrating lymphocytes and peripheral blood lymphocytes (PBLs), and investigate tumor suppressor populations including Tregs, myeloid-derived suppressor cells (MDSCs) and cluster of differentiation 8 (CD8) suppressor cells and assess ex vivo for effector function by cytokine production and cytotoxicity assays as well as suppressor function in assays with autologous PBLs.
3. To evaluate the tumor microenvironment (TME), and immune markers at the invasive margin of the tumor, including CD8, PD-1, PD-L1, TIM-3, galectin-9 or HMGB-1, BTLA and HVEM, as well as Lag-3, CTLA-4 and others.
4. To evaluate the genomic and/or transcriptomic profile of these tumors using RNA-seq /Whole Transcriptome Shotgun Sequencing

Trial Design:

This is a phase II trial evaluating the addition of concurrent and adjuvant fixed-dose pembrolizumab in combination with standard intensity-modulated radiation therapy (IMRT), in order to establish safety and estimate efficacy of this regimen to be tested in a subsequent randomized registration trial.

Thirty seven patients will be enrolled.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of the Addition of Pembrolizumab to Postoperative Radiotherapy in Resected High Risk Cutaneous Squamous Cell Cancer of the Head and Neck
• Actual Study Start Date: May 10, 2017
• Actual Primary Completion Date: June 26, 2020
• Actual Study Completion Date: September 9, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab + post operative radiotherapy; IMRT 60-66Gy for 6 weeks in combination with Pembrolizumab every 3 weeks for 16 weeks	Drug: Pembrolizumab; 200mg every 3 weeks for 16 weeks given by IV infusion; Radiation: IMRT 60-66Gy; 60-66Gy for 6 weeks

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects With Dose Limiting Toxicities [ Time Frame: Up to 20 weeks post treatment ]
   There will be an initial safety run in cohort consisting of an initial safety run in cohort consisting of eight patients to allow for at least six evaluable patients for dose limiting toxicities (DLTs) by the week 20 visit. If a total of 0-2 of the initial six evaluable patients experience DLTs, the safety run in will have been deemed successful and the 29 remaining planned patients will be accrued. DLT for this study is defined as the occurrence of a severe adverse event (AE) that is at least possibly related to pembrolizumab, and occurs from the initiation of treatment thru 30 days after the final administration of the study treatment
2. Number of Participants With Progression Free Survival [ Time Frame: Up to 1 year after beginning treatment ]
   Progression-free survival (PFS) will be calculated from treatment initiation to disease progression or death from any cause or last follow up

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologic diagnosis of cutaneous squamous cell carcinoma of the head and neck that has been resected with no evidence of gross residual disease (margin positivity is acceptable)

• Patients must have undergone resection of the disease and demonstrate high risk pathologic features including:

  • T4
  • Node positive disease

  • T2/T3N0 disease with any 1 additional feature, including:

    • Recurrent Disease
    • Perineural invasion
    • Lymphovascular space invasion
    • Poorly differentiated histology
    • Positive Margins
    • Satellitosis or in-transit metastases
• Patients are required to have computerized tomography (CT) neck and chest or positron emission tomography/computerized tomography (PET/CT) and have no documented evidence of distant metastases
• Patients must not have a history of the following immunosuppressive conditions:bone marrow transplantation and/or organ transplants and/or chronic rheumatic conditions that require active immunosuppressive therapy. Patients with a history of chronic lymphoid or leukemic malignancies which are not under active therapy (no active therapy within the last 3 months) will be eligible. Patients with chronic lymphoid or leukemic malignancies are eligible with or without active disease as long as they have not had treatment within the past three months.
• Patients may not have had prior therapy with a checkpoint inhibitor (e.g. anti-CTLA-4, anti-PD-1 or anti-PD-L1 therapy)
• Patients may not have had prior radiotherapy (>30Gy) to the area requiring treatment that would result in any overlap of tissue in both fields
• Patients may have received chemotherapy or radiation for a previous, curatively treated malignancy provided at least 2 years have elapsed and there is no current evidence of disease (patients with previous or concurrent additional skin cancers are eligible)
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
• Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

• Patients must have adequate laboratory values

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 9g/dL or ≥5.6mmol/L without transfusion
  • Serum creatinine ≤ 1.5 times upper limit of normal (ULN) or measured creatinine clearance ≥60mL/min for subject with creatinine levels >1.5 times institutional ULN
  • Serum bilirubin ≤ 1.5 times ULN or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
  • Aspartate aminotransferase (AST (SGOT)) and alanine aminotransferase (ALT (SPGT)) ≤ 2.5 times ULN or ≤ 5 times ULN for subjects with liver metastases
  • Albumin ≥ 2.5mg/dL

Exclusion Criteria:

• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a known history of active Bacillus Tuberculosis (TB)
• Hypersensitivity to pembrolizumab.
• Has a history of the following immunosuppressive conditions: bone marrow transplantation, and/or organ transplants and/or chronic rheumatic conditions that require active immunosuppressive therapy. Patients with chronic lymphoid/leukemic malignancies that have undergone treatment in the last 3 months will be ineligible.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e.≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiotherapy within 2 weeks prior to study Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or a separate primary squamous cell carcinoma of the skin or a separate primary squamous cell carcinoma of the skin. Patients with chronic lymphoid or leukemic malignancies are eligible with or without active disease as long as they have not had treatment within the past three months.
• Has metastatic disease.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Is pregnant or breastfeeding, 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 trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA is detected).
• Has received a live vaccine within 30 days of planned start of study therapy.

Contacts and Locations

Locations

United States, Ohio

University Hospitals Cleveland Medical Center, Seidman Cancer Center, Case Comprehensive Cancer Center

Cleveland, Ohio, United States, 44106

Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

Cleveland, Ohio, United States, 44195

Sponsors and Collaborators

Case Comprehensive Cancer Center

Investigators

• Principal Investigator: Shlomo Koyfman, MD; Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center

  Study Documents (Full-Text)

Documents provided by Case Comprehensive Cancer Center:

Study Protocol and Statistical Analysis Plan  [PDF] December 4, 2019

Informed Consent Form  [PDF] January 27, 2020

More Information

• Responsible Party: Case Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT03057613
• Other Study ID Numbers: CASE6316
• First Posted: February 20, 2017
• Results First Posted: October 19, 2020
• Last Update Posted: June 30, 2022
• Last Verified: June 2022

• 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

Keywords provided by Case Comprehensive Cancer Center:

radiation; resected

Additional relevant MeSH terms:

Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Neoplasms, Squamous Cell; Head and Neck Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action