Study of INCB081776 with Radiation Therapy and Other Treatments for Head and Neck Cancer

Inclusion Criteria

• Age ≥ 18 years at the time of signing the informed consent form
• Subjects (or legally acceptable representative if applicable) provides written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
• Must be willing and able to conform to and comply with all protocol requirements, including all scheduled visits, protocol procedures, and the ability to swallow oral capsules
• Histologic or cytologic evidence of head and neck squamous cell carcinoma (HNSCC) that is metastatic or recurrent and therefore considered incurable. Cutaneous skin squamous cell carcinomas located in the head and neck region are eligible after discussion with the sponsor-investigator
• Measurable disease that are considered non-amenable to surgery or other curative treatments or procedures * Note: The preference is for measurable disease to be selected from a site that has not received any prior radiation or locoregional therapy. However, if a tumor lesion is situated in a previously irradiated area, or in an area subjected to other prior locoregional therapy, the lesion should demonstrate disease progression after the prior treatment * Note: The preference is for measurable disease to be other lesions than index tumor B. However, if there are no other sites of disease, then index tumor B can be used as measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Subjects must have known PD-L1 expression status and/or combined proportion score (CPS) score
• Subjects 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 from palliative 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 ** Subjects must be willing to provide at least 2 research biopsies (up to 3 research biopsies) during the conduct of the study ** Note: If a subject is scheduled to have a baseline or on-study tumor biopsy, and the investigator believes that the tumor tissue cannot be obtained safely, then the biopsy may be omitted with approval by the sponsor-investigator. The subject may be replaced in order to enroll sufficient number of subjects for biomarker evaluation ** Note: Care should be taken to biopsy the same lesions for research samples. The preference is for the same lesion to be biopsied at all time points. If a lesion is no longer amenable for a research biopsy (for examples: due to a decrease in size, becomes inaccessible, is not safe/feasible for a biopsy), then an alternative lesion may be utilized with approval by the sponsor-investigator. Index tumor B (lesion to undergo biopsy) must not have received palliative radiation therapy during the study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 within 30 days prior to enrollment
• Willingness to avoid pregnancy or having children based on the criteria below: * Subjects of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 180 days after the last dose of study treatment. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method * Subjects of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on day 1, and must agree to take appropriate precautions to avoid pregnancy from screening through 180 days after the last dose of study treatment. NOTE: Subjects are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months

Exclusion Criteria

• Subjects with thyroid, salivary gland, or nonsquamous histologies are excluded
• Subjects receiving potent inhibitors or inducers of CYP3A4 * A washout period of ≥ 5 half-lives prior to the first dose of INCB081776 is required for enrollment into the study for prior treatment with potent CYP3A4 inhibitors * A washout period of ≥ 14 days prior to the first dose of INCB081776 is required for enrollment into the study for any subject treated with CYP3A4 inducers * A reference of prohibited CYP3A4 inhibitors and inducers and further information is available in the Food and Drug Administration (FDA) Drug Development and Drug Interactions (FDA 2022, https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-tablesubstrates-inhibitors-and-inducers#table3-2)
• Subjects with known retinal or ophthalmologic disorders or conditions. Subjects with macular degeneration, proliferative diabetic retinopathy or diabetic retinopathy with macular edema, retinal vein occlusions, uveitis, central serous retinopathy, leukemic retinopathy, inherited retinal degenerations, known family history of inherited retinal degenerations, and subjects at risk for angle closure glaucoma from pupillary dilation are ineligible. Subjects with other clinically significant abnormalities identified during ophthalmic screening examinations that may confound ocular monitoring are ineligible * Note: Subjects with dry/non-neo-vascular age-related macular degeneration (AMD) are eligible with sponsor-investigator approval, provided no clinically significant retinal pathology is observed at screening that could obscure monitoring for ocular changes on study
• Clinically significant cardiac disease b, including left ventricular ejection fraction (LVEF) < 40%, unstable angina, acute myocardial infarction within 6 months of starting treatment, New York Heart Association class III or IV congestive heart failure, and ventricular arrhythmia requiring therapy by history or medical review
• Untreated brain or central nervous system (CNS) metastases or brain or CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). Subjects who have previously treated and clinically stable brain or CNS metastases and who are off all corticosteroids for ≥ 2 weeks are eligible
• Subjects who have active or inactive autoimmune disease or syndrome either independent of prior therapy or induced by prior immune checkpoint inhibitor therapy (eg, rheumatoid arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic treatment in the past 2 years or who are receiving systemic therapy for an autoimmune or inflammatory disease (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) * Note: Subjects with vitiligo or resolved childhood asthma/atopy, hypothyroidism stable on hormone replacement, controlled asthma, type I diabetes, Graves' disease, or Hashimoto's disease, or with sponsor-investigator approval, will be eligible if they meet all other eligibility criteria
• Subjects with prior grade 3 or higher immune-related adverse events or any ocular toxicity on prior immunotherapy. The following grade 3 or higher adverse events are permitted: * Grade 3 rashes that resolved with topical therapy * Asymptomatic lipase elevations that do not require treatment interruption * Autoimmune conditions allowed per exclusion criterion above
• Platelets < 100 × 10^9/L (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Hemoglobin < 9 g/dL or < 5.6 mmol/L (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Absolute neutrophil count (ANC) < 1.5 × 10^9/L (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≥ 2.5 × upper limit of normal (ULN) (AST and/or ALT ≥ 5 × ULN in participants with liver metastases) (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Alkaline phosphatase ≥ 2.5 × ULN or alkaline phosphatase (≥ 5 x ULN in participants with bone or liver metastases) (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Total bilirubin ≥ 1.2 × ULN, unless direct bilirubin is ≤ ULN (direct bilirubin only needs to be tested if total bilirubin exceeds the ULN) (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Serum creatinine > 1.5 × institutional ULN or creatinine clearance < 50 mL/min for participants with creatinine levels > 1.5 × institutional ULN (if the screening tests were conducted > 7 days before treatment initiation, then the tests must be repeated and eligibility confirmed before study drug administration on cycle 1 day 1)
• Subjects receiving any vitamin K antagonists, including but not limited to acenocoumarol, fluindione, phenprocoumon, and warfarin, are excluded
• Treatment with anticancer medications or investigational drugs within the following intervals before the first administration of study drug: * At least 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Subject must not have had radiation pneumonitis as a result of treatment. A 1-week washout period is permitted for palliative radiation to non-CNS disease with sponsor-investigator approval * At least 28 days for a prior monoclonal antibody used for anticancer therapy. For other agents with long half-lives (eg, > 5 days), enrollment before the fifth half-life requires sponsor-investigator approval * Note: Subjects receiving bisphosphonates and/or denosumab are eligible for enrollment
• Has not recovered to ≤ grade 1 or baseline from toxic effects of prior therapy (including prior immunotherapy) and/or complications from prior surgical intervention before starting study treatment; stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue are allowed
• No use of systemic corticosteroids within 7 days before the first dose of study treatment * Note: The use of inhaled or topical steroids or corticosteroid use for radiographic procedures is permitted * Note: The use of physiologic corticosteroid replacement therapy may be approved after consultation with the sponsor-investigator
• Receipt of a live vaccine within 3 months of the first dose of study treatment
• Active infection requiring systemic therapy. A 28-day washout for systemic antibiotics is required. Probiotic usage while on study and during screening is prohibited
• Subjects with a known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection must be tested. Hepatitis B virus deoxyribonucleic acid (DNA) and HCV ribonucleic acid (RNA) must be undetectable. Subjects cannot be positive for HBV DNA, HCV RNA, hepatitis B surface antigen, or anti-hepatitis B core antibody * Note: Subjects with hepatitis B serology that is hepatitis B surface antigen negative and anti-hepatitis B core antibody positive, with undetectable HBV DNA by polymerase chain reaction, may enroll with sponsor-investigator approval
• Known history of HIV
• Known hypersensitivity or severe reaction to any component of study drugs or formulation components
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data
• Inability of the subject to comprehend the informed consent form (ICF) or unwillingness to sign the ICF
• Subjects with known dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally
• Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious pneumonitis
• History of organ transplant, including allogeneic stem cell transplantation
• Diagnosis of oculocutaneous albinism
• Subjects with known genetic conditions causing pre-disposition to RT toxicity (i.e: Li-Fraumeni, ataxia telangiectasia mutated [ATM] deficiency, active scleroderma, etc.)