Tolinapant and Radiation for Cisplatin-Ineligible, Previously Untreated, Locally Advanced Head and Neck Cancer

Inclusion Criteria: 1. Male or Female. 2. Age ≥18 years. 3. ECOG performance status ≤1 (see Appendix A). 4. Patients with histologically or cytologically confirmed diagnosis of HNSCC, previously untreated and locally advanced, for whom definitive or adjuvant radiation is planned but cisplatin chemotherapy is contraindicated. For the purposes of trial eligibility, anatomic subsites of HNSCC may include the larynx, oropharynx, hypopharynx, nasopharynx, or unknown primary site presenting with neck lymph nodal disease. Patients must have a contraindication to cisplatin as defined below. The scores must be recorded on a CRF: Age ≥ 70 with moderate to severe comorbidity, defined as having one or more of the following conditions within 30 days prior to registration: * Modified Charlson Comorbidity Index ≥ 1 * ACE-27 Index ≥ 1 * G-8 score ≤ 14 * CARG Toxicity Score ≥ 30% * CIRS-G Score ≥ 4 -OR- Age ≥ 18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following criterion within 30 days prior to registration: * Pre-existing peripheral neuropathy grade ≥ 1; * History of hearing loss, defined as either an existing need of a hearing aid OR moderate hearing loss as defined by the American Speech and Hearing Association (pretreatment audiogram showing 40-55 db HL hearing loss) * Creatinine clearance (CrCl) must be \> 30 and \< 50 mL/min. For this calculation, use the Cockroft-Gault formula: CrCl = 0.85 (if female)\* ((140-Age) / (Serum Creatinine)) \* (Weight in kg / 72). 5. Acceptable organ function, as evidenced by the following laboratory data: * Absolute neutrophil count \[ANC\] ≥ 1,500 cells/l; hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/l. * Serum creatinine ≤ 1.5 mg/dl, or calculated creatinine clearance ≥ 60 ml/min. * Bilirubin ≤ upper limit normal \[ULN\], alanine aminotransferase \[ALT\] ≤ 1.5 x ULN and/or aspartate aminotransferase \[AST\] ≤ 1.5 x ULN, alkaline phosphatase ≤ 2.5 x ULN. * Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 x ULN. * Activated partial thromboplastin (aPTT) time ≤ 1.5 x ULN. Amylase and lipase ≤ ULN. 6. The effects of tolinapant on the developing human fetus are unknown. For this reason and because tolinapant as well as other therapeutic agents used in this trial are known to be teratogenic, females of child-bearing potential (FCBP) must have a negative serum pregnancy test prior to starting therapy. 7. Female patients of childbearing potential and men must agree to use adequate contraception (at least one highly effective method and one additional method of birth control at the same time or complete abstinence) prior to study entry, for the duration of study participation and for at least 6 months following study drug discontinuation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (if age \> 55 years); if the female subject is \< 55 years and she has been naturally postmenopausal for \> 1 year her reproductive status has to be verified by additional lab tests (\< 20 estradiol OR estradiol \< 40 with FSH \> 40 in women not on estrogen replacement therapy). 8. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol specified laboratory tests, other study procedures, and study restrictions. 9. Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential risks and discomforts, potential benefits, and other pertinent aspects of study participation. Exclusion Criteria: 1. Patients who have had prior radiotherapy to the head and neck region 2. Patients who are receiving any other investigational agents or an investigational device within 21 days before administration of first dose of study drugs. 3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to tolinapant. 4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 5. Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 3 months prior to start of study therapy; angina requiring therapy; symptomatic peripheral vascular disease; New York Heart Association Class 3 or 4 congestive heart failure (or ejection fraction \<50%); or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100 mmHg or systolic blood pressure ≥160 mmHg) despite antihypertensive therapy. 6. Contraindications to radiotherapy (e.g. uncontrolled connective tissue disorder). 7. Women who are pregnant or breast feeding. 8. Vulnerable populations including prisoners and adults who are unable to consent. 9. Known history of human immunodeficiency virus (HIV) infection, or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. 10. Grade 3 or greater neuropathy. 11. Known distant metastases (i.e., outside of the neck). 12. Known significant mental illness or other conditions such as active alcohol or other substance abuse that, in the opinion of the investigator, predisposes the subject to high risk of noncompliance with the protocol treatment or assessments. 13. Concurrent second malignancy requiring active therapy. 14. Patients with a history of allogenic transplant must not have ≥Grade 3 graft-versus-host disease (GVHD) or any clinically significant GVHD requiring systemic immunosuppression. 15. Systemic corticosteroids \>20 mg daily prednisone equivalent (unless patient has been taking a continuous dose for \>3 weeks prior to study entry). 16. Medications known to cause QT prolongation including some antipsychotics (chlorpromazine, haloperidol, droperidol, quetiapine, olanzapine, amisulpride, thioridazine), antiarrhythmics (quinidine, procainamide, disopyramide, flecanide, encainide, sotalol, amiodarone), antidipressants (amitriptyline, doxepin, imipramine, nortriptyline, desipramine), mianserin, citalopram, escitalopram, venlafaxine, bupropion, moclobemide), and antihistamines (diphenhydramine, astemizole, loratadine, terfenadine), macrolide antibiotics (erythromycin, clarithromycin), and antimalarials (chloroquine, hydroxychloroquine, quinine), unless the use of these drugs cannot be avoided.