Testing the Addition of an Investigational Drug, Xevinapant, to Usual Radiation Therapy Plus Cisplatin/Carboplatin for Patients With Head and Neck Cancer

Inclusion Criteria:

* Patient must be ≥ 18 years of age
* Patient must have stage III or IVA or IVB HPV-negative squamous cell carcinoma of the head and neck (HNSCC) by American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition criteria
* Patient must have undergone gross total surgical resection of high-risk oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to randomization
* Patient must have evidence of high-risk features on final postoperative pathology including positive margins (R1) and/or extranodal extension. Patients with gross residual disease are not eligible
* Patient must have tumor origin site in the oral cavity, oropharynx, larynx, or hypopharynx
* Patient must have received no prior treatment for HNSCC with the exception of curative intent surgical resection
* Patient must have imaging consisting of CT of the head, neck and chest within 10 weeks prior to randomization to confirm there is no evidence of disease
* Patient must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
* Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used

  * All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy
  * A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
* Patient must not expect to conceive or father children by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and continue contraception measures for 6 months after the last dose of cisplatin or carboplatin and for 3 months after the last dose of xevinapant. Patient must not breast-feed while on protocol treatment and for one month after the last dose of any protocol treatment. Patient must not donate sperm while on protocol treatment
* Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
* White blood cell (WBC) ≥ 3,000/mcL (obtained ≤ 14 days prior to protocol randomization)
* Absolute neutrophil count (ANC) ≥ 1,500/mcL (obtained ≤ 14 days prior to protocol randomization)
* Platelets ≥ 100,000/mcL (obtained ≤ 14 days prior to protocol randomization)
* Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (obtained ≤ 14 days prior to protocol randomization)
* Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3.0 × institutional ULN (obtained ≤ 14 days prior to protocol randomization)
* Creatinine clearance ≥ 60 mL/min (estimated using Cockcroft-Gault method or measured) (obtained ≤ 14 days prior to protocol randomization)
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial. Patients with HIV must have viral load monitored as clinically indicated
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C) are not eligible
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. Patients with non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C) are not eligible
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
* Patient must not have had a live-attenuated vaccine within 30 days prior to randomization
* Patient must not have a known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal surgery that may limit oral absorption
* Patient must not have taken any agents on the prohibited medication list within 14 days prior to randomization or require any of these agents for ongoing treatment while on protocol treatment
* Patient must not have active, uncontrolled inflammatory disease (including rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, severe extensive psoriasis, and other autoimmune diseases) requiring ongoing treatment with anti-tumor necrosis factor (TNF) medication
* Patient must have had a pre-surgical or other baseline electrocardiogram (EKG) report within 6 months prior to randomization indicating a corrected QT (QTc) using Fridericia's formula (QTcF) interval \< 450 ms for males and \< 470 ms for females
* Patient must not be on any concomitant medication known to prolong the QTcF interval that cannot be discontinued or replaced by safe alternative medication within 7 days prior to randomization
* Patient must not have a known allergy to xevinapant, cisplatin, carboplatin, other platinum-based agent or any excipient known to be present in any of these products