Xevinapant in Combination with Radiation and Concurrent Carboplatin and Paclitaxel for Treating Patients with Locoregionally Advanced Head and Neck Cancer Who Cannot Take Cisplatin

Inclusion Criteria

• Pathologically proven diagnosis of HNSCC of the oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, or sinuses * Patients with oropharynx cancer need p16 determination by immunohistochemistry (where positive is defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells) * Oral cavity, larynx, hypopharynx, or p16-negative oropharynx cancer must be stages T1-2N1-3 or T3-4N0-3 (American Joint Committee on Cancer [AJCC] 8th edition). Sinus primary must be T4bN0-3 not amenable to surgical resection * P16-positive oropharynx cancer patients, stages T1-2N1-3 or T3-4N0-3 (AJCC 8th edition staging)
• The patient has unresected, measurable disease as defined by the presence of at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Age ≥ 18 years of age
• Patients must have a contraindication to cisplatin as defined in the following points: Comogram * 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 ** Adult Comorbidity Evaluation-27 (ACE-27) Index ≥ 1 ** Omega (ω) score < 0.80 ** Geriatric 8 (G-8) score ≤ 14 ** Cancer and Aging Research Group (CARG) toxicity score ≥ 30% ** Cumulative Illness Rating Scale-Geriatric (CIRS-G) score ≥ 4 —OR— * Age < 70 with severe comorbidity, defined as having two or more of the following conditions within 30 days prior to registration: ** Modified Charlson Comorbidity Index ≥ 1 ** ACE-27 Index ≥ 1 ** ω score < 0.80 ** 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 criteria within 30 days prior to registration: ** Pre-existing peripheral neuropathy grade ≥ 2 ** Creatinine clearance (CrCl) must be > 30 and < 60 mL/min (For this calculation, use the Cockroft-Gault formula) ** History of hearing loss, defined as either: *** Existing need of a hearing aid OR *** ≥ 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated. Of note, a baseline hearing test is only required if no other criteria for inclusion criteria #4 are met
• Zubrod Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• White blood cell (WBC) >= 2000 cells/mm3
• Absolute neutrophil count (ANC) >= 1,500 cells/mm3
• Platelets >= 100,000 cells/mm3
• Hemoglobin >= 9.0 g/dL
• Creatinine clearance (CrCl) > 30 mL/min
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert Syndrome who can have total bilirubin < 3.0 mg/dL)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
• For women of childbearing potential (e.g. uterus present and menstruating), a negative serum pregnancy test within 14 days prior to registration. A woman of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL * The effects of xevinapant on the developing human fetus are unknown. For this reason and because IAP agents as well as other therapeutic agents used in this study are known to be teratogenic, women of childbearing potential and non-sterilized men treated or enrolled on this study must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from informed consent form (ICF) signature to 6 months after completing chemotherapy treatment or 3 months after last dose of xevinapant, whichever is the latest. 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
• The patient must provide study-specific informed consent prior to study entry
• Patients with a history of hepatitis B or C infection are eligible if they have an undetectable viral load
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Definitive clinical or radiologic evidence of distant (beyond cervical lymph node and neck tissue) metastatic disease
• Carcinoma of the neck of unknown primary site of origin
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable if not within < 3 years
• Severe, active co-morbidity defined as follows: * History of bone marrow transplant and organ transplant, including allogeneic stem cell transplantation * Unstable angina requiring hospitalization in the last 6 months * New York Heart Association Functional Classification III/IV * Myocardial infarction within the last 6 months * Persistent grade 3-4 electrolyte abnormalities that cannot be reversed despite as indicated by repeat testing * Ongoing active infection associated with symptoms and/or requires antibiotic therapy at the time of initiation of treatment
• Pregnancy and nursing females, if applicable * Pregnant women are excluded from this study because xevinapant is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with xevinapant, breastfeeding should be discontinued if the mother is treated with xevinapant. These potential risks also apply to other agents used in this study including carboplatin and paclitaxel
• Receipt of live vaccinations within 28 days prior to registration
• Patients who are receiving any other investigational agents
• Patients with a “currently active” second malignancy other than non-melanoma skin cancers. Patients are not considered to have a “currently active” malignancy if they have completed therapy and are free of disease for ≥ 3 years
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to xevinapant, carboplatin, or paclitaxel
• 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
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with xevinapant. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• 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
• Any concomitant medication known to prolong the QT interval that cannot be discontinued or replaced by safe alternative medication within 7 days prior to start of treatment
• Symptomatic pulmonary disease requiring continuous or intermittent oxygen supply
• Active alcohol or any other drug abuse, including but not limited to cannabis and cannabidiol (CBD) use
• Non-compensated or symptomatic liver cirrhosis (Child-Pugh score: B or C)
• Known gastrointestinal disorder with clinically established malabsorption syndrome and major gastrointestinal surgery that may limit oral absorption
• Active gastrointestinal bleeding, or any other uncontrolled bleeding requiring more than 2 red blood cell transfusions or 4 units of packed red blood cells within 4 weeks prior to randomization