A Randomized Phase III study of pembrolizumab given concomitantly with chemoradiation and as maintenance therapy versus chemoradiation alone in subjects with locally advanced head and neck squamous cell carcinoma (KEYNOTE-412)

1. Have a pathologically proven new diagnosis of squamous cell carcinoma of:
a. Oropharyngeal p16 positive
b. Oropharyngeal p16 negative
c. Larynx/hypopharynx/oral cavity (independent of p16)
2. 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.
3. Have results from (local) testing of HPV status for oropharyngeal cancer. If
HPV status was previously tested using the method as prescribed by protocol, no
additional testing is required.
4. Have provided adequate tissue in terms of quality and quantity for PD-L1
biomarker analysis from a core or excisional biopsy. If an excisional or
incisional biopsy has been performed, subjects remain eligible for the study
provided the residual disease meets the staging criteria required for the trial
(e.g., excisional biopsy of a lymph node with residual T4 primary). Prior
surgical debulking, including tonsillectomy, for the head and neck cancer under
study is not allowed.
5. Be >=18 years of age on day of signing informed consent.
6. Have evaluable tumor burden (measurable and/or non-measurable tumor lesions)
assessed by CT scan or MRI, based on RECIST version 1.1.
7. Be eligible for definitive CRT and not considered for primary surgery based
on investigator decision.
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of
0 or 1 performed within 10 days of treatment initiation.
9. Female subjects of childbearing potential must have a negative urine or
serum pregnancy test within 72 hours prior to receiving the first dose of trial
treatment. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an
adequate method of contraception as outlined in the protocol, for the course of
the study through 180 days after the last dose of study medication.
11. Male subjects of childbearing potential must agree to use an adequate
method of contraception as outlined in the protocol, starting with the first
dose of study therapy through 180 days after the last dose of study therapy.
12. Demonstrate adequate organ function as defined in the protocol. All
screening labs should be performed within 10 days prior to treatment initiation
and assessed prior to randomizing the subject.

1. Has current participation or treatment with an investigational agent or use
of an investigational device within 4 weeks of the first dose of trial
treatment.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent
or with an agent directed to another co-inhibitory T-cell receptor or has
previously participated in Merck MK-3475 clinical trials.
3. Has received a live vaccine within 30 days prior to the first dose of study
treatment.
4. Has cancer outside of the oropharynx, larynx, and hypopharynx or oral
cavity, such as nasopharyngeal, sinus, other para-nasal, or other unknown
primary HNC.
5. Has had prior systemic therapy, targeted therapy, radiotherapy treatment or
radical surgery for head and neck cancer under study.
6. Has Grade >=2 audiometric hearing loss. Audiometric abnormalities without
corresponding clinical symptoms of Grade >=2 hearing loss will not be grounds
for exclusion.
7. Has Grade >=2 neuropathy.
8. Has Grade 3-4 bleeding due to the underlying malignancy.
9. If subject has received major surgery, and the subject has not recovered
adequately form the toxicity and/or complications from the intervention prior
to starting trial treatment.
10. Has known active Hepatitis B or C.
11. Has known history of Human Immunodeficiency Virus (HIV) (HIV-1/2
antibodies).
12. 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. Corticosteroid use as pre-medication for
allergic reactions (e.g. IV contrast), or as a prophylactic management of
adverse events related to the chemotherapies specified in the protocol is
allowed. A short course of steroids may be used as concomitant medication for
either treatment of an adverse event or medical condition with Sponsor approval.
The use of physiologic doses of corticosteroids may be approved after
consultation with the Sponsor.
13. Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.
14. Has an 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.
15. Has history of a diagnosed and/or treated hematologic or primary solid
tumor malignancy, unless in remission for at least 5 years prior to
randomization. A T1-2 prostatic cancer Gleason score <=6, superficial bladder
cancer, non melanomatous skin cancer or carcinoma in situ of the cervix is
eligible. Other exceptions may be considered with Sponsor consultation.
16. Has known active central nervous system (CNS) metastases and/or
carcinomatous meningitis.
17. Has had previous allogeneic tissue/solid organ transplant.
18. Has active infection requiring systemic therapy.
19. Has a history of severe hypersensitivity reaction (e.g., generalized
rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to
pembrolizumab, cisplatin or radiotherapy or their analogs.
20. Is a female subject who is pregnant or breast feeding or a male expecting
to conceive or father children within the projected treatment phase of the
trial, starting with the screening visit through 180 days after the last dose
of trial treatment.
21. Have severe comorbidities that, in the opinion of the Investigator, might
hamper participation in the study and/or the treatment administration.
22. 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.
23. Has known psychiatric or substance abuse disorders that would interfere
with cooperation with the requirements of the trial.