Testing the Addition of M3814 (Peposertib) to Radiation Therapy for Patients With Advanced Head and Neck Cancer Who Cannot Take Cisplatin

Inclusion Criteria:

• Pathologically (histologically) proven diagnosis of HNSCC of the oral cavity,oropharynx, larynx, or hypopharynx prior to registration;

• Patients with oropharynx cancer need p16 determination by immunohistochemistry (where positive is defined as greater than 70% strong nuclear or nuclear andcytoplasmic staining of tumor cells), Note: Institutions must screen patientsusing a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.A rigorous laboratory accreditation process similar to the United States (U.S.)CLIA certification, such as the provincial accreditation status offered by theOntario Laboratory Accreditation (OLA) Program in Canada, the College ofAmerican Pathologists (CAP), or an equivalent accreditation in other countries,is acceptable. The p16 results must be reported on the pathology report beingsubmitted;

• Oral cavity, larynx, hypopharynx, or p16-negative oropharynx cancer must bestages T1-2N2-3 or T3N1-3 or T4N0-3 (American Joint Committee on Cancer [AJCC]version 8);

• p16-positive oropharynx cancer patients, stages T4N0-3 or T1-3N2-3 (AJCCversion 8);

• The patient has measurable disease as defined by the presence of at least onemeasurable lesion per RECIST 1.1;

• Please note: A histological or pathological specimen from cervical lymph nodeswith well-defined primary site documented clinically or radiologically isacceptable

• Clinical stage noted above should be based upon following diagnostic workup:

• History/physical examination within 30 days prior to registration;

• Examination by radiation oncologist or medical oncologist or otolaryngology (ENT) or head & neck surgeon 30 days prior to registration, including fiberoptic exam with laryngopharyngoscopy;

• Diagnostic quality computed tomography (CT) or magnetic resonance imaging (MRI)of neck, with contrast, within 30 days prior to registration. FludeoxyglucoseF-18 (18F-FDG) whole body positron emission tomography (PET)-CT scan within 42days of registration is strongly recommended but does not replace the CT or MRIstudy. Note: If CT component of the PET/CT is of diagnostic quality then PET/CTcan be used for eligibility, however the PET/CT scan must be done within 30days prior to registration

• Diagnostic quality, cross sectional imaging of the thorax within 42 days priorto registration; 18-F-FDG-PET/CT or conventional CT are acceptable

• Age >= 18 years

• Patients must have a contraindication to cisplatin as defined in the followingbullet points. Sites must complete the online tool at comogram.org prior toregistration to determine if the patient is eligible. The scores must be recorded ona case report form (CRF). (Refer to data submission table on the NRG-HN008 protocolpage on the NRG website);

• Age >= 70 with moderate to severe comorbidity, defined as having one or more ofthe following conditions within 30 days prior to registration;

• Modified Charlson Comorbidity Index >= 1

• Adult Comorbidity Evaluation (ACE)-27 Index >= 1

• Omega score < 0.80

• 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 < 70 with severe comorbidity, defined as having two or more of thefollowing conditions within 30 days prior to registration;

• Modified Charlson Comorbidity Index >= 1

• ACE-27 Index >= 1

• Omega 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, definedas one or more of the following criterion within 30 days prior to registration:

• Pre-existing peripheral neuropathy grade >= 1;

• Creatinine clearance (CrCl) must be > 30 and < 60 mL/min

• For this calculation, use the Cockcroft-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 pretreatmenthearing test as clinically indicated

• Zubrod Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 within 30days prior to registration

• Whole blood cell (WBC) >= 2000 cells/mm^3 (within 30 days prior to registration)

• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (within 30 days prior toregistration)

• Platelets >= 100,000 cells/mm^3 (within 30 days prior to registration)

• Hemoglobin >= 9.0 g/dL (within 30 days prior to registration); Note: The use oftransfusion is acceptable

• Creatinine clearance (CrCl) > 30 mL/min (within 30 days prior to registration)

• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbertsyndrome who can have total bilirubin < 3.0 mg/dL) (within 30 days prior toregistration)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 30 days prior to registration)

• For women of child bearing potential (e.g. uterus present and menstruating), anegative serum pregnancy test within 14 days prior to registration. Women ofchildbearing potential (WOCBP) is defined as any female who has experienced menarcheand who has not undergone surgical sterilization (hysterectomy or bilateraloophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12months of amenorrhea in a woman over 45 in the absence of other biological orphysiological causes. In addition, women under the age of 55 must have a documentedserum follicle stimulating hormone (FSH) level less than 40 mIU/mL

• The patient must provide study-specific informed consent prior to study entry

• Known human immunodeficiency virus (HIV) infected patients on effectiveanti-retroviral therapy with undetectable viral load within 6 months and CD4 T cellcount >= 200 are eligible for this trial. Testing is not required for entry intoprotocol

• Patients with a history of hepatitis B or C infection are eligible if they have anundetectable viral load

• Willing to use highly effective contraceptives for males and females of childbearingpotential during therapy and for 12 weeks after the last dose of M3814 (peposertib);this inclusion is necessary because the treatment in this study may be significantlyteratogenic

• Patients must be able to swallow whole tablets

Exclusion Criteria:

• Definitive clinical or radiologic evidence of distant (beyond cervical lymph nodeand neck tissue) metastatic disease

• Carcinoma of the neck of unknown primary site origin

• Patients with oral cavity cancer are excluded from participation if the patient ismedically operable and the resection of the primary tumor is considered technicallyfeasible by an oral or head and neck cancer surgical subspecialist

• Gross total excision of both primary and nodal disease; this includes tonsillectomy,local excision of primary site, and nodal excision that removes all clinically andradiographically evident disease

• Note: Patients with RECIST, version (v.) 1.1 evaluable remaining cancer eitherin the neck or primary site remain eligible

• Prior invasive malignancy (except non-melanomatous skin cancer carcinoma, in situ ofthe breast, oral cavity, or cervix, low or very low-risk prostate cancer) unlessdisease free for a minimum of 3 years

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for adifferent cancer is allowable if not within =< 3 years

• Prior radiotherapy to the region of the study cancer that would result in overlap ofradiation therapy fields

• Severe, active co-morbidity defined as follows:

• History of bone marrow transplant and organ transplant, including allogenicstem cell transplantation;

• Unstable angina requiring hospitalization in the last 6 months;

• New York Heart Association Functional classification III/IV (Note: Patientswith known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association FunctionalClassification.);

• Myocardial infarction within the last 6 months;

• Persistent grade 3-4 (Common Terminology Criteria for Adverse Events [CTCAE]version 5.0) electrolyte abnormalities that cannot be reversed despite asindicated by repeat testing;

• Ongoing active infection that is associated with symptoms and/or requiresantibiotic therapy at the time of registration (excluding asymptomaticbacteriuria, genital herpes, oral herpes, thrush, bacterial vaginosis, vaginalcandidiasis, topical antifungals)

• Pregnancy and nursing females, if applicable

• Concomitant use of proton pump inhibitors (or unable to stop 5 days prior totreatment)

• Receipt of live vaccinations within 28 days prior to registration

• Patients unable to discontinue medications or substances that are:

• Strong inhibitors, inducers or sensitive substrates of CYP3A4/5, CYP2C19, orCYP2C9 prior to study treatment;

• Substrates of CYP1A2, CYP2B6, or CYP3A4/5 with a narrow therapeutic prior tostudy treatment;

• Note: Opioids are allowed, with the exception of methadone

• Fridericia's correction formula (QTcF) > 450 ms for males and > 470 ms for females