Testing the Addition of a New Anti-cancer Drug, M3814 (Peposertib), to the Usual Radiotherapy in Patients With Locally Advanced Pancreatic Cancer

Inclusion Criteria:

• Patients must have pathologically confirmed pancreatic adenocarcinoma. Patients withalternative or mixed histologies (i.e., squamous, neuroendocrine, acinar, colloid)are not eligible

• Received 4-6 months of induction chemotherapy with fluorouracil, irinotecan,leucovorin and oxaliplatin (FOLFIRINOX), fluorouracil, liposomal irinotecan,luecovorin, oxaliplatin (NALIRIFOX), or gemcitabine/Abraxane, as per standard ofcare

• Patients must have locally advanced pancreatic cancer according to NationalComprehensive Cancer Network (NCCN) Guidelines (version 1.2020) on pancreas protocolCT scan performed within 21 days of registration. Locally advanced disease isdefined as any of the following:

• For head or uncinate process tumors:

• Solid tumor contact with superior mesenteric artery > 180 degrees

• Solid tumor contact with the celiac axis > 180 degrees

• Solid tumor contact with the common or proper hepatic arteries > 180degrees or

• For pancreatic body or tail tumors:

• Solid tumor contact of > 180 degrees with the superior mesenteric arteryor celiac axis

• Solid tumor contact with the celiac axis and aortic involvement or

• Unreconstructible superior mesenteric vein or portal vein due to tumorinvolvement or occlusion (can be due to tumor or bland thrombus)

• The determination of locally advanced pancreatic cancer and plan for non-operativetreatment on this clinical trial must be confirmed through local multi-disciplinaryreview

• Measurable disease per response evaluation criteria in solid tumors (RECIST) version (v)1.1

• Age >= 18 years. Because no dosing or adverse event data are currently available onthe use of M3814 (peposertib) in combination with hypofractionated radiation inpatients < 18 years of age, children are excluded from this study, but will beeligible for future pediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 4,000/mcL

• Absolute neutrophil count >= 1.5 x 10^9/L.

• Hemoglobin >= 9 g/dL

• Platelets >= 100 x 10^9/L

• Total bilirubin =< 2.0 x institutional upper limit of normal (ULN)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN

• Creatinine =< 1.5 x institutional ULN

• Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Female patients of childbearing potential must have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required. Female patients of childbearing potential andmale patients must be willing to use an adequate method of contraception for thecourse of the study through 12 weeks after the last dose of study medication.

• Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the patient.

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction. To be eligible for this trial, patients should be American HeartAssociation Stage B (people without current or previous symptoms of heart failurebut with either structural heart disease, increased filling pressures in the heartor other risk factors) or better and New York Heart Association FunctionalClassification II (slight limitation of physical activity, comfortable at rest,ordinary physical activity results in fatigue, palpitation, shortness of breath orchest pain), or better

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally authorized representative (LAR) and/or family member available will also beeligible

Exclusion Criteria:

• Patients who have completed induction chemotherapy less than 2 weeks or more than 8weeks prior to study enrollment

• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia andneuropathy grade =< 2

• Patients who are receiving any other investigational agents

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to M3814 (peposertib)

• Evidence of distant metastatic disease

• More than 1 line of chemotherapy for the treatment of localized pancreatic cancer,unless the change in treatment was made only for toxicity

• Prior abdominal radiation

• Active inflammatory bowel disease or connective tissue disease

• Inability to swallow oral medications or gastrointestinal disease limitingabsorption of oral agents

• History of anaphylactic reaction to iodinated intravenous (IV) contrast required forradiation simulation. Patients with mild reactions may be enrolled, but must receivepremedications for contrast allergy prior to imaging

• Patients who cannot discontinue concomitant medications or herbal supplements thatare strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymesCYP3A4/5, CYP2CP, and CYP2C19. Concomitant use of CYP1A2, CYP2B6, and CYP3A4/5substrates with a narrow therapeutic index are also excluded. Patients may conferwith the study doctor to determine if alternative medications can be used. Thefollowing categories of medications and herbal supplements must be discontinued forat least the specified period of time before the patient can be treated:

• Strong inducers of CYP3A4/5, CYP2C9 and CYP2C19: >= 3 weeks prior to studytreatment

• Strong inhibitors of CYP3A4/5, CYP2C9 and CYP2C19: >= 1 week prior to studytreatment

• Substrates of CYP1A2, CYP2B6, and CYP3A4/5 with a narrow therapeutic index: >= 1 day prior to study treatment

• Because the lists of these agents are constantly changing, it is important toregularly consult a frequently-updated medical reference. As part of theenrollment/informed consent procedures, the patient will be counseled on therisk of interactions with other agents, and what to do if new medications needto be prescribed or if the patient is considering a new over-the-countermedicine or herbal product

• Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patientsmay confer with the study doctor to determine if such medications can bediscontinued. These must be discontinued >= 5 days prior to study treatment.Patients do not need to discontinue calcium carbonate. H2 blockers and antacids areallowed.

• Patients who have received a live attenuated vaccine within 30 days of dosing withM3814 (peposertib)

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because M3814 (peposertib) is aDNA-protein kinase (PK) inhibitor with the potential for teratogenic orabortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with M3814 (peposertib), breastfeeding should be discontinued if the mother is treated withM3814 (peposertib)

• Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment of thisinvestigational regimen