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 radiationis planned but cisplatin chemotherapy is contraindicated. For the purposes of trial eligibility, anatomic subsites of HNSCC may include thelarynx, oropharynx, hypopharynx, nasopharynx, or unknown primary site presentingwith neck lymph nodal disease. Patients must have a contraindication to cisplatin as defined below. The scores mustbe recorded on a CRF: Age ≥ 70 with moderate to severe comorbidity, defined as having one or more of thefollowing 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 oneor 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 ORmoderate 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) / (SerumCreatinine)) * (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 xULN 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 reasonand because tolinapant as well as other therapeutic agents used in this trial areknown to be teratogenic, females of child-bearing potential (FCBP) must have anegative serum pregnancy test prior to starting therapy.

7. Female patients of childbearing potential and men must agree to use adequatecontraception (at least one highly effective method and one additional method ofbirth control at the same time or complete abstinence) prior to study entry, for theduration of study participation and for at least 6 months following study drugdiscontinuation. Should a woman become pregnant or suspect she is pregnant while sheor her partner is participating in this study, she should inform her treatingphysician immediately. A female of childbearing potential (FCBP) is a sexuallymature 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 naturallypostmenopausal for > 1 year her reproductive status has to be verified by additionallab tests (< 20 estradiol OR estradiol < 40 with FSH > 40 in women not on estrogenreplacement therapy).

8. Willingness and ability of the subject to comply with scheduled visits, drugadministration plan, protocol specified laboratory tests, other study procedures,and study restrictions.

9. Evidence of a personally signed informed consent indicating that the subject isaware of the neoplastic nature of the disease and has been informed of theprocedures to be followed, the experimental nature of the therapy, alternatives,potential risks and discomforts, potential benefits, and other pertinent aspects ofstudy 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 investigationaldevice within 21 days before administration of first dose of study drugs.

3. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to tolinapant.

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements.

5. Significant cardiovascular disease (e.g., myocardial infarction, arterialthromboembolism, cerebrovascular thromboembolism) within 3 months prior to start ofstudy therapy; angina requiring therapy; symptomatic peripheral vascular disease;New York Heart Association Class 3 or 4 congestive heart failure (or ejectionfraction <50%); or uncontrolled Grade ≥3 hypertension (diastolic blood pressure ≥100mmHg 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 seropositiveresults 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 othersubstance abuse that, in the opinion of the investigator, predisposes the subject tohigh 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 3graft-versus-host disease (GVHD) or any clinically significant GVHD requiringsystemic immunosuppression.

15. Systemic corticosteroids >20 mg daily prednisone equivalent (unless patient has beentaking 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.