Summary

This phase I trial tests the safety and side effects of a tolinapant given together with radiation therapy in treating patients with head and neck cancer for which the patient has not received treatment in the past (previously untreated), has spread to nearby tissue or lymph nodes (locally advanced) and cannot receive cisplatin (cisplatin-ineligible). Tolinapant may stop the growth of cancer cells by blocking XIAP and cIAP1, proteins needed for cancer cell survival. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving tolinapant and radiation therapy may kill more tumor cells.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of tolinapant in combination with radiation in patients with head and neck squamous cell carcinoma (HNSCC).

SECONDARY OBJECTIVE:
I. To evaluate the anti-tumor activity of the combination of tolinapant + radiation by assessing locoregional control (LRC) and overall survival (OS).

TERTIARY/EXPLORATORY OBJECTIVES:
I. To assess the effects of the combination of tolinapant + radiation on immune cells in blood and tumor.
II. To assess the association between immune responses and FADD expression in tumors.

OUTLINE:
Patients undergo standard of care radiation therapy for a total of 35 fractions over 7 weeks and receive tolinapant orally (PO) daily for 7 days during weeks 1, 3, 5, and 7 of radiation therapy in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) or positron emission tomography (PET) during screening and follow-up. Additionally, patients undergo blood sample collection and tissue biopsy during screening on the trial.

After completion of study treatment, patients are followed up 1, 3, 6, 12, and 24 months.

Eligibility

1. Male or female
2. Age >= 18 years
3. Eastern Cooperative Oncology Group (ECOG) performance status =< 1
4. Patients with histologically or cytologically confirmed diagnosis of HNSCC, previously untreated and locally advanced, for whom definitive or adjuvant (post-surgical) radiation is planned but cisplatin chemotherapy is contraindicated. For the purposes of trial eligibility, anatomic subsites of HNSCC may include the oral cavity, 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 case report form (CRF). Age >= 70 with moderate to severe comorbidity, defined as having one or more of the following conditions within 30 days prior to registration (can use comogram.org to calculate): * Modified Charlson Comorbidity Index >= 1 * Adult Comorbidity Evaluation-27 (ACE-27) Index >= 1 * Geriatric Screening Tool (G-8) score =< 14 * Cancer and Aging Research Group (CARG) Toxicity Score >= 30% * Cumulative Illness Rating Scale for Geriatrics (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 (calculated using Cockcroft-Gault formula)
5. Absolute neutrophil count (ANC) >= 1,500 cells/ul
6. Hemoglobin >= 9 g/dl
7. Platelets >= 100,000/ul
8. Serum creatinine =< 1.5 mg/dl, or calculated creatinine clearance >= 60 ml/min (unless qualified for trial on the basis of creatinine clearance as listed above)
9. Bilirubin =< upper limit normal (ULN)
10. Alanine aminotransferase (ALT) =< 1.5 x ULN and/or aspartate aminotransferase (AST) =< 1.5 x ULN
11. Alkaline phosphatase =< 2.5 x ULN
12. Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN
13. Activated partial thromboplastin (aPTT) time =< 1.5 x ULN
14. Amylase and lipase =< ULN
15. 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
16. 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 follicle stimulating hormone [FSH] > 40 in women not on estrogen replacement therapy)
17. Willingness and ability of the subject to comply with scheduled visits, drug administration plan, protocol-specified laboratory tests, other study procedures, and study restrictions
18. 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