Pembrolizumab in Combination With CRT for LA-SCCHN
Condition: Head and Neck Cancer; Squamous Cell Carcinoma; Oral Cavity Cancer; Oropharynx Cancer; Hypopharynx Cancer; Larynx Cancer; Laryngeal Cancer
MeSH terms: Carcinoma; Carcinoma, Squamous Cell; Laryngeal Neoplasms; Mouth Neoplasms; Oropharyngeal Neoplasms
Intervention: pembrolizumab (MK-3475); Cisplatin; Radiation
Intervention description: 200mg IV on days -7(loading dose), 15, 36, 57, 78, 99, 120, 141.; Cisplatin 40 mg/m2 IV on days 1, 8, 15, 22, 29, 36; 70 Gy fractionated over 35 days
Intervention MeSH terms: Cisplatin; Pembrolizumab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 59.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Larynx; Squamous Cell; Oral cavity; Oropharynx; Hypopharynx

Summary:

      This is a single-arm, multi-site, open-label trial of pembrolizumab (MK-3475) used in
      combination with standard, cisplatin-based, definitive chemoradiotherapy (CRT) in patients
      with stage III-IVB squamous cell carcinoma of the head and neck (SCCHN). Approximately 39
      patients with Stage III-IVB SCCHN will be enrolled to evaluate both the safety and efficacy
      of this novel combination. Subjects will not be randomized and will all receive the study
      treatment.

      Treatment will consist of a loading dose of pembrolizumab 200 mg IV given 7 days prior to
      initiation of CRT (day-7). CRT with cisplatin 40 mg/m2 IV weekly and head and neck radiation
      at 70 Gy fractionated at 2 Gy once daily over 35 days, will begin on day 1. CRT will end on
      approximately day 46-50. Pembrolizumab 200 mg IV will continue following CRT in an adjuvant
      fashion starting on day 57 for an additional 5 doses, as tolerated, through day 141. Subjects
      will be evaluated for response following treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have histologically or cytologically-confirmed head and neck squamous cell carcinoma
             of the oral cavity (excluding lip), oropharynx, hypopharynx, or larynx.

          2. Have TNM clinical stage III, IVA, or IVB disease

          3. Be eligible for curative-intent concurrent chemoradiation therapy

          4. Be willing and able to provide written informed consent for the trial.

          5. Be 18 years of age on day of signing informed consent.

          6. Have measurable disease based on RECIST 1.1.

          7. Be willing to provide tissue from a recently obtained core or excisional biopsy of a
             tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days)
             prior to initiation of treatment on Day -7. Subjects for whom newly-obtained samples
             cannot be provided (e.g. inaccessible or subject safety concern) may submit an
             archived specimen only upon agreement from Sanford Research.

          8. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          9. Demonstrate adequate organ function as defined:

             Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9
             g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of
             assessment) Serum creatinine OR Measured or calculated creatinine clearance (GFR can
             also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60
             mL/min for subject with creatinine levels > 1.5 X institutional ULN Serum total
             bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin
             levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with
             liver metastases Albumin >2.5 mg/dL

         10. 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.

         11. 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.

         12. 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.

        Exclusion Criteria:

          1. Patients may not be receiving any other investigational agents, chemotherapy,
             immunotherapy, radiotherapy, or molecular targeted agents within 4 weeks of the start
             of the study treatment.

          2. Prior treatment with radiation to the head and neck

          3. Patients with TNM Stage IVC disease

          4. 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.

          5. Has 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 trial
             treatment.

          6. Has a known history of active TB (Bacillus Tuberculosis)

          7. Hypersensitivity to pembrolizumab or any of its excipients.

          8. 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.

          9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy.

         10. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

         11. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis.

         12. Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         13. Has known history of, or any evidence of active, non-infectious pneumonitis.

         14. Has an active infection requiring systemic therapy.

         15. 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.

         16. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         17. 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 120days after the last dose of trial treatment.

         18. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         19. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         21. Has received a live vaccine within 30 days of planned start of study therapy.