NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer

This phase II trial evaluates whether early switching from modified fluorouracil/irinotecan/leucovorin/oxaliplatin (mFOLFIRINOX) chemotherapy regimen to a combination of gemcitabine and nab-paclitaxel (GA) before surgery is effective in treating patients with pancreatic cancer that can be surgically removed (resectable or borderline resectable), or that has spread to nearby tissue or lymph nodes and cannot be removed by surgery (locally-advanced unresectable). Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, oxaliplatin, gemcitabine, and nab-paclitaxel work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. The study will also evaluate the drug losartan in combination with mFOLFIRINOX or GA.

PRIMARY OBJECTIVE:

I. To determine the rate of margin-negative (R0) resection in participants with resectable or borderline resectable pancreatic cancer (BRPC) following treatment using NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX alone, or switch to GA).

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

II. To determine the PFS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy, plus preoperative radiation therapy (RT).

III. To determine the disease-free survival (DFS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

IV. To determine the DFS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

V. To determine the overall survival (OS) of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy.

VI. To determine the OS for the subset of resectable or BRPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

VII. To assess the surgical complications of resectable or BRPC participants that undergo surgical resection.

VIII. To assess 30-day post-operative mortality of participants with resectable or BRPC that undergo surgical resection.

IX. To assess safety of NeoOPTIMIZE adaptive therapy (all participants).

EXPLORATORY OBJECTIVES:

I. To monitor changes in CA19-9 levels (all participants). II. To determine the rate of margin-negative (R0) resection in patients with locally advanced pancreatic cancer (LAPC), following treatment using NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX alone, or switch to GA).

III. To determine the PFS of LAPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

IV. To determine the PFS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative radiation therapy (RT).

V. To determine the disease-free survival (DFS) of LAPC participants that received NeoOPTIMIZE adaptive therapy (i.e., FOLFIRINOX, or switch to GA).

VI. To determine the DFS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

VII. To determine the OS of LAPC participants that received NeoOPTIMIZE adaptive therapy.

VIII. To determine the OS for the subset of LAPC participants that received NeoOPTIMIZE adaptive therapy plus preoperative RT.

IX. To assess the surgical complications of LAPC participants that undergo surgical resection.

X. To assess 30-day post-operative mortality of LAPC participants who undergo surgical resection.

OUTLINE:

mFOLFIRINOX REGIMEN: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1. Patients also receive fluorouracil IV over 46 hours starting on day 1. Treatment with mFOLFIRINOX repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo disease restaging (re-stage I). Patients with radiographic response and no disease progression receive mFOLFIRINOX for an additional 2 months (approximately 4 cycles). Patients then undergo second re-staging (re-stage II).

GA REGIMEN: After re-stage I, patients with disease progression or toxicity to mFOLFIRINOX (per assessment of the treating physician) switch to receive the GA regimen comprising gemcitabine hydrochloride IV over 30-60 minutes and nab-paclitaxel IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo second re-staging (re-stage II). Patients may be switched to GA regimen from FOLFIRINOX regimen prior to re-stage I (per assessment of the treating physician).

LOSARTAN: Starting cycle 1 day 1, patients also receive losartan potassium orally (PO) once daily (QD) until completion of RT in the absence of disease progression or unacceptable toxicity.

RT/SURGERY: Patients with no vascular tumor involvement at re-stage II, undergo surgery 1-4 after completion of chemotherapy. Patients with resolution of tumor contact with pancreatic vasculature at re-stage II, undergo short-course RT to receive a total of 10 fractions over 5 days weekly (Monday-Friday). Patients with tumor vessel involvement that is persistent at re-stage II, undergo long-course RT to receive a total of 15-25 fractions over 5 days weekly (Monday-Friday), and receive capecitabine PO twice daily (BID) on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks after completion RT.

Patients undergo diagnostic imaging as clinically indicated throughout the trial. Patients also undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up as clinically indicated and following institutional standards, and then every 3 months for 6 months, and then every 6 months for up to 2 years.

Eligibility Criteria:
Inclusion Criteria:

* Ability to understand and the willingness to sign a written informed consent document
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
* Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study entry

  * If a biopsy (e.g., endoscopic ultrasound \[EUS\]-guided fine needle aspiration \[FNA\]) is planned per standard of care, the participant may be asked to consent to the additional collection of tumor tissue for research
* No evidence of metastatic disease as determined by chest computed tomography (CT) scan, abdomen/pelvis computed tomography (CT) scan (or magnetic resonance imaging \[MRI\] with gadolinium and/or manganese) within the 45-day window of study entry or prior to the one cycle of standard of care (SOC) administered before study entry, which is consistent with the standard of care

  * Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, baseline radiographic imaging performed per institutional guidelines prior to SOC chemotherapy treatment may be used per investigator discretion to fulfill baseline radiographic imaging criteria even if performed \> 45 days prior to official study entry.
* Diagnostic staging laparoscopy is not required for study eligibility

  * If staging laparoscopy is planned per standard of care, the participant may be asked to consent to the collection of tumor tissue for research
* At time of screening, per National Comprehensive Cancer Network (NCCN) criteria, must have either:

  * Resectable pancreatic ductal adenocarcinoma (PDAC), defined as no arterial tumor contact (celiac axis \[CA\], superior mesenteric artery \[SMA\], or common hepatic artery \[CHA\]), or
  * Node positive disease as defined by CT, MRI, or EUS imaging, or
  * Borderline resectable PDAC, defined as:

    * For tumors of the head or uncinate process:

      * Solid tumor contact with the superior mesenteric vein (SMV) or portal vein of \> 180 degrees with contour irregularity of the vein or thrombosis of the vein, but with suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction
      * Solid tumor contact with the inferior vena cava
      * Solid tumor contact with the common hepatic artery without extension to the celiac axis or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction
      * Solid tumor contact with the SMA =\< 180 degrees
      * Solid tumor contact with variable anatomy (e.g., accessory right hepatic artery, replaced right hepatic artery, replaced common hepatic artery, and the origin of replaced or accessory artery), and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning
    * For tumors of the body/tail:

      * Solid tumor contact with the celiac axis of =\< 180 degrees
      * Solid tumor contact with the celiac axis \>180 degrees without involvement of the aorta and with an intact and uninvolved gastroduodenal artery, thereby permitting a modified Appleby procedure (although some members of the consensus committee preferred this criterion to be in the unresectable category)
  * Locally-advanced, unresectable disease as defined by NCCN guidelines as follows:

    * Tumors of the head with SMA \>= 180 degrees, or any celiac abutment, unreconstractable SMV or portal occlusion, or aortic invasion or encasement
    * Tumors of the body with SMA or celiac encasement 180 degrees, unreconstractable SMV or portal occlusion, or aortic invasion
    * Tumors of the tail with SMA or celiac encasement \>= 180 degrees
    * Irrespective of location, all tumors with evidence of nodal metastasis outside of the resection field that are considered unresectable
* Must be deemed fit to undergo planned curative resection as determined by institutional standards
* No history of previous chemotherapy for pancreatic cancer. At the discretion of the principal investigator (PI), patient that have received no more than 1 month of systemic chemotherapy (e.g., mFOLFIRINOX), per standard of care, for the treatment of their PDAC may be eligible to participate
* For participants who will get INV losartan, baseline systolic blood pressure (BP) \> 100 mm Hg taken as the average of 3 blood pressure readings
* Hemoglobin \> 9 g/dL with no blood transfusion within 28 days of starting treatment (prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  * Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed \> 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
* Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L (\> 1000 cells/mm\^3) (prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  * Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed \> 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
  * May be waived on a case-by-case basis for patient populations recognized to have normal baseline values below this level
* Platelet count \>= 100 x 10\^9/L (\> 100,000 per mm\^3) (at time of registration and within 4 weeks prior to initiating study therapy)
* Creatinine =\< 1.5 mg/dL OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 30 mL/min/1.73 m\^2 for participants with creatinine levels \> 1.5 x institutional upper limit of normal (ULN) prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  * Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed \> 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
  * Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis
* Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN); or =\< 2 x ULN or 2 down-trending values for individuals who have undergone biliary stenting prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  * Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed \> 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x ULN, OR two consecutive down-trending values for individuals who have undergone biliary stenting prior to the one month of standard of care chemotherapy allowed by the protocol or within 4 weeks of screening)

  * Note: On a case by case basis, for participants who enroll on trial after having received up to 1 month of standard of care chemotherapy per Investigator discretion, labs prior to initiation of SOC chemotherapy treatment may be used per Investigator discretion to fulfill screening lab requirements even if performed \> 4 weeks prior to official study entry and/or there are more recent labs available from during chemotherapy treatment
* Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to initiating study therapy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Female participants of childbearing potential agree to use adequate methods of contraception starting with the first dose of study therapy through 30 days after the last dose of study therapy

  * Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year without an alternative medical cause
* Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 30 days after the last dose of study therapy
* Male patients must use a condom during treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male participant should also use a highly effective form of contraception if they are of childbearing potential
* Participants currently receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) will remain eligible for study participation. In such cases, losartan will not be assigned as part of the study intervention. These participants will continue to receive their ACE inhibitor or ARB per standard-of-care. The ACE inhibitor or ARB type should be recorded as a concomitant medication (including dose and frequency)

Exclusion Criteria:

* History of previous chemotherapy (other than no more than one cycle of standard systemic chemotherapy), targeted/biologic therapy, or radiation therapy for the treatment of their PDAC
* Evidence of metastasis to distant organs (liver, peritoneum, lung, others)
* Any other active malignancy or prior history of malignancy with less than a 90% cure rate in the judgement of the investigators
* Medical co-morbidities that are deemed to make risk of surgery unacceptably high as determined by institutional standards
* Personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Patients with cardiovascular conditions that are well-controlled in the clinical judgement of the treating oncologist are eligible to participate
* Recent major surgery (excluding laparoscopy) within 4 weeks prior to starting study treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be recovered from effects of surgery
* Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy \[hormone replacement therapy is acceptable\]), not otherwise allowed in this study. Note: participation in other trials for supportive cancer care (e.g., cancer-related cachexia) interventions is permitted per PI discretion.
* Participants with a history of hypersensitivity reactions to study agents or their excipients. In cases of losartan hypersensitivity, losartan will be omitted and patient may still be eligible to participate
* Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 30 days after the last dose of trial therapy
* Psychiatric illness/social situations, or any condition that, in the opinion of the investigator, would: interfere with evaluation of study treatment or interpretation of participant safety or study results, or substantially increase risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent
* Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements