A Phase III Randomized Trial of MK-3475 (Pembrolizumab) versus Standard Treatment in Subjects with Recurrent or Metastatic Head and Neck Cancer

Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.;2. Be > 18 years of age on day of signing informed consent.;3. Have histologically or cytologically-confirmed R/M HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies. Subjects may not have any other primary tumor site (e.g. nasopharynx).;4. Prior platinum failure as defined by either:;a. Disease progression after treatment with a platinum-containing regimen for recurrent/metastatic disease ;Note: Disease progression may occur at any time during or after a platinum-containing regimen (e.g. carboplatin or cisplatin) which was administered in either 1L or 2L in the recurrent/metastatic setting.
OR
b. Recurrence/progression within 6 months of prior multimodal therapy using platinum (e.g. locally advanced setting);5. Have results from local testing of HPV positivity for oropharyngeal cancer defined as p16 IHC testing using CINtec® p16 Histology assay and a 70% cutoff point.;Note: HPV stratification in this trial will be performed using local testing of HPV status in patients with oropharynx cancer. Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing by p16 IHC as by convention assumed to be HPV negative.;6. Have provided tissue for PD-L1 biomarker analysis from a newly obtained core or excisional biopsy - and received the PD-L1 results * (PD-L1 analysis will be blinded to both site and sponsor). Repeat samples may be required if adequate tissue is not provided or for indeterminate results. ;Note: Patients for whom newly obtained samples cannot be obtained (e.g. inaccessible or patient safety concern) may submit an archived specimen only upon agreement from the Sponsor.;Note: If emerging data indicate a high concordance in PD-L1 expression scores between newly obtained and archival samples, archived samples may be acceptable.;7. Have radiographically measurable disease based on RECIST 1.1 as determined by the site. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.;8. Have a performance status of 0 or 1 on the ECOG Performance Scale, as assessed within 10 days of treatment initiation.;9. Demonstrate adequate organ function as defined in Table 1 of the protocol, all screening labs should be performed within 10 days of treatment initiation. ;10. Female subjects of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a serum test is not appropriate.;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 (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Note: For UK subjects:
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 doseof study medication (and specifically through 180 days after the last dose of docetaxel or methotrexate) (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Note: The Summary of Country-Specific Revisions is provided in Appendix 12.9.
Note: Abstinence is acceptable if this is the usual lifestyle, established and/or preferred contraception for the subject. ;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.

1. Has disease that is suitable for local therapy administered with curative intent.;2. Had progressive disease within three months of completion of curatively intended treatment for locoregionally advanced or metastatic HNSCC.
Note: This exclusion criterion is only applicable for subjects who have not had treatment in the metastatic/recurrent setting.;3. Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks prior to the first dose of trial treatment.;4. Was previously treated with 3 or more systemic regimens given for recurrent and/or metastatic disease.;5. Patients previously treated or resistant to one of the 3 standard of care agents in this trial (i.e. docetaxel, methotrexate, or cetuximab) may not receive the same agent if randomized to the standard treatment arm (see Section 5.2 for details). ;6. 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. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor. ;7. 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.;8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 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.;Note: Subjects with * Grade 2 neuropathy or * Grade 2 alopecia are an exception to this criterion and may qualify for the study.;Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. ;9. Has a diagnosed and/or treated additional malignancy within 5 years
prior to randomization with the exception of curatively treated basal cell
carcinoma of the skin, squamous cell carcinoma of the skin and/or
curatively resected in situ cervical and/or breast cancers.;10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.;11. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren*s syndrome will not be excluded from the study.;12. Has active, non-infectious pneumonitis; ;13. Has an active infection requiring systemic therapy.;14. 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. ;15. Has a known psychiatric or substance abuse disorders that would interfere with co- operation with the requirements of the trial.;16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.;17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.;18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).;;19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).;20. Has received a live vaccine within 30 days of planned start of study therapy.