Targeting PD-1 Therapy Resistance With Focused High or High and Low Dose Radiation in SCCHN
Condition: Head and Neck Cancer
MeSH terms: Head and Neck Neoplasms
Intervention: Pembrolizumab; Radiation
Intervention description: Keytruda is designed to restore the natural ability of the immune system to recognize and target cancer cells; Radiation is used to shrink the cancer
Intervention MeSH terms: Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Head and Neck Cancer

Summary:

      This research study is studying immunotherapy in combination with radiation therapy as a
      possible treatment for head & neck cancer that has worsened or spread to another organ or
      part of your body.

      The immunotherapy involved in this study is: MK-3475 (pembrolizumab or KEYTRUDA).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Pathologically confirmed squamous cell carcinoma of the head and neck with evidence of
             metastatic disease considered incurable by local therapies. Patients without
             pathologic or cytologic evidence of metastatic disease should have unequivocal
             evidence of metastasis from physical examination or radiologic evaluation.

          -  Patients must have evidence of radiologic or clinical disease progression during
             previous treatment with systemic PD-1 directed therapy, or have stable disease on
             prior PD-1 therapy (at least 6 doses) and/or have been deemed not to derive clinical
             benefit from PD-1 directed treatment.

          -  Patients must have least 3 measurable non-CNS based lesions that have not previously
             been irradiated. Palliative radiation must be potentially indicated for at least one
             of these lesions.

          -  Patients must agree to undergo a research biopsy, if tumor is accessible, at baseline
             (mandatory) and at the end of cycle 2 of pembrolizumab (optional). .

          -  Prior systemic therapy: Patients must be at least 2 weeks from prior chemotherapy,
             biological agents, immunotherapy or any investigational drug product, with adequate
             recovery of toxicity. For investigational agents, the minimum time from prior therapy
             is 5 half-lives if this is longer than 2 weeks in duration.

          -  Prior radiation therapy: Patients must be at least 2 weeks from prior radiation
             therapy

          -  Concurrent administration of other cancer specific therapy during the course of this
             study is not allowed.

          -  Only patients 18 years and older are eligible. There is no upper age limit but the
             patients must be able to medically tolerate the regimen. Adverse event data are
             currently unavailable on the use immune checkpoint blockade for participants < 18
             years of age, and thus children are excluded from this study.

          -  ECOG performance status <=1 (see Appendix A).

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Female subjects of childbearing potential must have a negative serum pregnancy test at
             screening.

          -  Female and male subjects of childbearing potential must agree to use an adequate
             method of contraception as outlined in section 5.7.1. Contraception is required prior
             to study entry and for the duration of study participation and 4 months after
             completion of pembrolizumab administration.

             --Note: Abstinence is acceptable if this is the usual lifestyle and preferred
             contraception for the subject.

          -  Participants must have normal organ and marrow function as defined below:

               -  leukocytes ≥3,000/mcl

               -  absolute neutrophil count ≥1,500/mcL

               -  platelets ≥100,000/mcL

               -  hemoglobin >= 9 g/dl

               -  total bilirubin ≤1.5 × institutional upper limit of normal (ULN)

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

               -  AST(SGOT)/ALT(SGPT) For patients with documented liver metastases, ≤ 5 ×
                  institutional ULN

               -  creatinine ≤1.5 ×within normal institutional ULN OR

               -  creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
                  above institutional ULN.

               -  International normalized ratio (INR) or Prothrombin Time (PT) <1.5 times the
                  upper limit of normal unless subject is receiving anticoagulant therapy, as long
                  as PT or PTT is within therapeutic range of intended use of anticoagulants.

               -  Activated Partial Thromboplastin Time (aPTT) <1.5 times the upper limit of normal
                  unless subject is receiving anticoagulant therapy, as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants.

          -  Laboratory tests required for eligibility must be completed within 14 days prior study
             entry. Baseline tumor measurements must be documented from tests within 28 days of
             study entry. Other non-laboratory tests must be performed within 28 days of study
             entry.

        Exclusion Criteria:

          -  Metastatic disease impinging on the spinal cord or threatening spinal cord
             compression.

          -  Surgical fixation of bone lesion to be irradiated is required and indicated to provide
             mechanical stability.

          -  Known brain metastases that are untreated, symptomatic, or require therapy to control
             symptoms. Participants with previously diagnosed brain metastases are eligible if they
             have completed treatment at least 2 weeks prior to trial therapy initiation, are
             neurologically stable, and have recovered from the acute effects of radiotherapy or
             surgery. Any corticosteroid use for brain metastases must have been discontinued
             without the subsequent appearance of symptoms for ≥2 weeks before the initiating
             protocol therapy. Treatment for brain metastases may include surgery, whole brain
             radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating
             physician.

          -  Participants who are receiving any other investigational agents.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to pembrolizumab or previous toxicity attributed to pembrolizumab or other
             PD-1 directed therapy that led to drug discontinuation.

          -  Uncontrolled intercurrent illness including but not limited to ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Clinically significant electrocardiogram (ECG) abnormality, including a marked
             Baseline prolonged QT/QTc ([QT interval/corrected QT interval], e.g., a repeated
             demonstration of a QTc interval >500 ms).

          -  Pregnant women are excluded from this study because immunotherapy has the potential
             for teratogenic or abortifacient effects. Because there is an unknown but potential
             risk of adverse events in nursing infants secondary to treatment of the mother with
             immunotherapy, breastfeeding should be discontinued if the mother is treated on this
             protocol.

          -  Individuals with a history of a different malignancy are ineligible except for the
             following circumstances: if they have been disease-free for at least 2 years and are
             deemed by the investigator to be at low risk for recurrence of that malignancy; or if
             diagnosed and treated for cervical cancer in situ or basal cell or squamous cell
             carcinoma of the skin.

          -  HIV-positive individuals on combination antiretroviral therapy are ineligible because
             of the potential for interaction between immunotherapy and these medications.

          -  Has history of (non-infectious) pneumonitis that required steroids, evidence of
             interstitial lung disease or active, non infectious pneumonitis.

          -  Active, suspected or prior documented autoimmune disease that has required systemic
             treatment in the last 2 years with immune modifying agents (e.g. replacement therapy
             such as thyroxine, insulin or physiologic corticosteroids is not an exclusion
             criteria).

          -  The subject is known to be positive for HepBsAg, or HCV RNA.

          -  Lack of availability for follow up assessments.

          -  The investigator's belief that the subject is medically unfit to receive pembrolizumab
             and or unsuitable for any other reason.

          -  Has received a live vaccine within 30 days of planned start of study therapy