FOLFIRINOX + Elraglusib + Losartan In Pancreatic Cancer

Inclusion Criteria:

• Histologically confirmed metastatic pancreatic adenocarcinoma without prior therapyfor pancreatic adenocarcinoma.

• Participants must have measurable disease as defined by RECIST 1.1

• Age ≥18 years.

• ECOG performance status ≤1 (Karnofsky ≥ 70%, see Appendix A).

• Participants must have adequate organ and marrow function as defined below:

• Absolute neutrophil count (ANC) ≥ 1,500/mcL

• Platelets ≥ 100,000/mcL

• Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN) if no biliarystenting has been done OR 2.0 x ULN if patient is status post biliary stentingor two downward trending values.

• AST(SGOT)/ALT(SGPT) < 5 x institutional ULN.

• Creatinine ≤ 1.5 mg/dL OR .

• Creatinine clearance ≥ 30 mL/min (as estimated by Cockcroft Gault Equation) (140 - age [yrs]) (body wt [kg]) Creatinine clearance for males = ------------ (72) (serum creatinine [mg/dL])

• Creatinine clearance for females = 0.85 x male value

• Prior treatment with angiotensin receptor blocker (ARB) for hypertension is allowed.If the patient is randomized to a non-losartan containing treatment arm, the patientmust be changed to an antihypertensive medication that is not in the class ofangiotensin receptor blocker (ARB).

• Human immunodeficiency virus (HIV)-infected participants on effectiveanti-retroviral therapy within 6 months are eligible for this trial.

• Participants with evidence of chronic hepatitis B virus (HBV) infection onsuppressive therapy, if indicated.

• Participants with a history of hepatitis C virus (HCV) infection must have beentreated and cured. Participants with HCV infection who are currently on treatmentare eligible even if they do not have an undetectable HCV viral load.

• Participants with treated brain metastases are eligible if follow-up brain imagingafter central nervous system (CNS)-directed therapy shows no evidence ofprogression.

• Participants with new or progressive brain metastases (active brain metastases) orleptomeningeal disease are eligible if the treating physician determines thatimmediate CNS specific treatment is not required and is unlikely to be requiredduring the first cycle of therapy.

• Participants with a prior or concurrent malignancy whose natural history ortreatment does not have the potential to interfere with the safety or efficacyassessment of the investigational regimen are eligible for this trial.

• Participants with known history or current symptoms of cardiac disease, or historyof treatment with cardiotoxic agents, should have a clinical risk assessment ofcardiac function using the New York Heart Association Functional Classification. Tobe eligible for this trial, participants should be class 2B or better.

• The effects of treatment are harmful on the developing human fetus are unknown. Forthis reason, all patients of child-bearing potential must agree to use adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation and 9 months aftercompletion of mFOLFIRINOX administration. Should a woman become pregnant or suspectshe is pregnant while she or her partner is participating in this study, she shouldinform her treating physician immediately.

• Ability to understand and the willingness to sign a written informed consentdocument.

Patients with known history of UGT1A1 gene polymorphism detection are eligible to participate. Sites are required to follow the FDA-approved label guidance for Irinotecan when administrating as part of the FOLFIRINOX regimen.

Exclusion Criteria:

• Any prior chemotherapy, radiation therapy, immunotherapy, biologic ('targeted')therapy or investigational therapy for pancreas adenocarcinoma. No prior adjuvant orneoadjuvant therapy for localized pancreatic adenocarcinoma is allowed.

• Patients with deleterious or suspected deleterious germline or somatic BRCA-mutatedpancreatic cancer.

• Patients with TRK (tropomyosin receptor kinase) fusion-positive cancers.

• Patients with deficient mismatch/microsatellite unstable or high tumor mutationburden cancers.

• Major surgery, excluding laparoscopy, within 4 weeks of the start of studytreatment, without complete recovery

• Participation in any investigational drug study within 4 weeks preceding the startof study treatment.

• Participants who have not recovered from adverse events due to prior anti-cancertherapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia.

• The investigator(s) must state a medical or scientific reason if participants whohave brain metastases will be excluded from the study.

• History of allergic reactions attributed to compounds of similar chemicalcomposition to 9-ING-41, losartan, 5-fluorouracil, irinotecan and oxaliplatin notamenable to institutional chemotherapy desensitization protocol. Prior topicalfluoropyrimidine use is allowed.

• Patients with cardiac ventricular arrhythmias requiring antiarrhythmic therapy, oratrioventricular heart block (due to 5FU administration)

• Known, existing uncontrolled coagulopathy. Concomitant treatment with full dosewarfarin (coumadin) is NOT allowed. Patients may receive low molecular weightheparin (LMWH) (such as enoxaparin and dalteparin) and direct oral anticoagulant (DOAC) for management of deep venous thrombosis (DVT).

• Patients taking strong inhibitors of CYP2C19, CYP3A4, and CYP1A2 or strong inducersof CYP3A4 should only be entered into the study protocol if deemed by theinvestigator to be in their best interest and with study medical coordinatoragreement

• Concomitant use of cimetidine, as it can decrease clearance of 5FU. AnotherH2-blocker or proton pump inhibitor may be substituted before study entry.

• Participants with uncontrolled intercurrent illness.

• Participants with uncontrolled seizures, central nervous system disorders orpsychiatric illness/social situations that would limit compliance with studyrequirements.

• Known history of active TB (Mycobacterium Tuberculosis).

• Has received a live vaccine within 30 days of planned start of study therapy. Note:Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed. COVID non-live vaccines are allowed.