FOLFIRINOX + Elraglusib + Losartan In Pancreatic Cancer

Inclusion Criteria:

* Histologically confirmed metastatic pancreatic adenocarcinoma without prior therapy for 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 biliary stenting has been done OR 2.0 x ULN if patient is status post biliary stenting or 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 patient must be changed to an antihypertensive medication that is not in the class of angiotensin receptor blocker (ARB).
* Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy within 6 months are eligible for this trial.
* Participants with evidence of chronic hepatitis B virus (HBV) infection on suppressive therapy, if indicated.
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with HCV infection who are currently on treatment are eligible even if they do not have an undetectable HCV viral load.
* Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.
* Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* The effects of treatment are harmful on the developing human fetus are unknown. For this reason, all patients of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and 9 months after completion of mFOLFIRINOX administration. 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.
* Ability to understand and the willingness to sign a written informed consent document.

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 or neoadjuvant therapy for localized pancreatic adenocarcinoma is allowed.
* Patients with deleterious or suspected deleterious germline or somatic BRCA-mutated pancreatic cancer.
* Patients with TRK (tropomyosin receptor kinase) fusion-positive cancers.
* Patients with deficient mismatch/microsatellite unstable or high tumor mutation burden cancers.
* Major surgery, excluding laparoscopy, within 4 weeks of the start of study treatment, without complete recovery
* Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
* Participants 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.
* The investigator(s) must state a medical or scientific reason if participants who have brain metastases will be excluded from the study.
* History of allergic reactions attributed to compounds of similar chemical composition to 9-ING-41, losartan, 5-fluorouracil, irinotecan and oxaliplatin not amenable to institutional chemotherapy desensitization protocol. Prior topical fluoropyrimidine use is allowed.
* Patients with cardiac ventricular arrhythmias requiring antiarrhythmic therapy, or atrioventricular heart block (due to 5FU administration)
* Known, existing uncontrolled coagulopathy. Concomitant treatment with full dose warfarin (coumadin) is NOT allowed. Patients may receive low molecular weight heparin (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 inducers of CYP3A4 should only be entered into the study protocol if deemed by the investigator to be in their best interest and with study medical coordinator agreement
* Concomitant use of cimetidine, as it can decrease clearance of 5FU. Another H2-blocker or proton pump inhibitor may be substituted before study entry.
* Participants with uncontrolled intercurrent illness.
* Participants with uncontrolled seizures, central nervous system disorders or psychiatric illness/social situations that would limit compliance with study requirements.
* 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 and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. COVID non-live vaccines are allowed.