Pembrolizumab, INCB081776, and Radiation Therapy for Head and Neck Squamous Cell Carcinoma

Inclusion Criteria:

• Participants must have histologic or cytologic evidence of head and neck squamouscell carcinoma (HNSCC) that is metastatic or recurrent and therefore consideredincurable. Cutaneous skin squamous cell carcinomas located in the head and neckregion are eligible after discussion with the Sponsor-Investigator.

• Measurable disease that are considered non-amenable to surgery or other curativetreatments or procedures, with at least 1 target lesion available for evaluation.

• The preference is for measurable disease to be selected from a site that hasnot received any prior radiation or locoregional therapy. However, if a tumorlesion is situated in a previously irradiated area, or in an area subjected toother prior locoregional therapy, the lesion should demonstrate diseaseprogression after the prior treatment.

• Prior cancer treatment must be completed at least 14 days prior to enrollment (forchemotherapy, targeted small molecular therapy, or radiation therapy. Priortreatment with a monoclonal antibody must be completed at least 28 days prior toenrollment. Participants must have recovered from all reversible acute toxic effectsof the regimen (other than alopecia) to ≤ Grade 1 or baseline.

• Participants must have two "index" tumors that meet the following criteria:

• Index tumor A (lesion to receive palliative radiation therapy):

• is deemed by the treating radiation oncologist to potentially benefit frompalliative radiation

• is at least 1 cm in longest dimension for lesions not located in the bone,if radiating bone, presence of a bone lesion is sufficient.

• Index tumor B (lesion to undergo biopsy):

• Is deemed by the treating physician to be amenable to biopsy

• Is at least 1 cm in longest dimension.

• Participants must be willing to provide at least 2 research biopsies (upto 3 research biopsies) during the conduct of the study.

• Note: If a subject is scheduled to have a baseline or on-study tumorbiopsy, and the investigator believes that the tumor tissue cannot beobtained safely, then the biopsy may be omitted with approval by theSponsor-Investigator. The participant may be replaced in order to enrollsufficient number of subjects for biomarker evaluation.

• Note: Care should be taken to biopsy the same lesions for researchsamples. The preference is for the same lesion to be biopsied at all timepoints. If a lesion is no longer amenable for a research biopsy (forexamples: due to a decrease in size, becomes inaccessible, is notsafe/feasible for a biopsy), then an alternative lesion may be utilizedwith approval by the Sponsor-Investigator. Index tumor B (lesion toundergo biopsy) must not have received palliative radiation therapy duringthe study.

• Participants must be willing to provide at least 2 collections of fresh researchbiopsies (up to 3 fresh research biopsies) during the conduct of this study.

• Research biopsy #1 (baseline, mandatory). Archival tissue obtained sincecompletion of last therapy may be used.

• Research biopsy #2 (cycle 1 days 9-14, after treatment with INCB081776 butprior to pembrolizumab, mandatory)

• Research biopsy #3 (cycle 1 day 37-56, after treatment with INCB081776,pembrolizumab and palliative RT). For participants who had baseline archivaltissue collected (no baseline research biopsy was obtained), this fresh corebiopsy is mandatory. For participants who underwent a fresh core researchbiopsy at baseline, this biopsy is optional.

• Note: If a participant is scheduled to have an on-study tumor biopsy, and theinvestigator believes that the tumor tissue cannot be obtained safely, then thebiopsy may be omitted after discussion with the Sponsor-Investigator. Theparticipant may be replaced in order to enroll sufficient number of subjectsfor biomarker evaluation.

• Note: Care should be taken to biopsy the same lesion for the on-treatmentsamples

Exclusion Criteria:

• Subjects with significant intercurrent illnesses per physician discretion.

• Subjects with a diagnosed auto-immune disease requiring systemic treatment withimmunosuppressants.

• Subjects with known genetic conditions causing pre-disposition to RT toxicity (i.e:Li-Fraumeni, ATM deficiency, active scleroderma, etc.).

• Subjects with known retinal or ophthalmologic disorders or conditions. Subjects withmacular degeneration, proliferative diabetic retinopathy or diabetic retinopathywith macular edema, retinal vein occlusions, uveitis, central serous retinopathy,leukemic retinopathy, inherited retinal degenerations, known family history ofinherited retinal degenerations, and subjects at risk for angle closure glaucomafrom pupillary dilation are ineligible. Subjects with other clinically significantabnormalities identified during ophthalmic screening examinations that may confoundocular monitoring are ineligible.