Inclusion Criteria:
* Documented informed consent of the participant and/or legally authorized representative.
* Adult patients lacking capacity to consent may participate if they have a caretaker that could ensure oral medication compliance.
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies.
* If unavailable, exceptions may be granted with study principal investigator (PI) approval.
* Age: ≥ 18 years.
* Eastern Cooperative Oncology Group (ECOG) ≤ 1.
* Subjects must have histologically or cytologically confirmed diagnosis of advanced unresectable pancreatic ductal adenocarcinoma (PDA).
* Measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
* Potential patients must have plans of receiving single agent gemcitabine.
* Fully recovered from the acute toxic effects (except alopecia or neuropathy) to ≤ grade 1 to prior anti-cancer therapy.
* Without bone marrow involvement: Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement.
* Without bone marrow involvement: Platelets ≥ 100,000/mm\^3 NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement.
* Hemoglobin ≥ 9g/dL NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement.
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 x ULN (unless has Gilbert's disease total bilirubin ≤ 3 x ULN)
* Aspartate aminotransferase (AST) ≤ 1.5 x ULN OR if liver metastases ≤ 3 x ULN
* Alanine aminotransferase (ALT) ≤ 1.5 x ULN OR if liver metastases ≤ 2 x ULN
* Creatinine ≤ 1.5 x ULN OR creatinine clearance (Cockcroft Gault) of ≥ 50 mL/min for participants with a creatinine level of \> 1.5 x ULN.
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of gemcitabine therapy for women and at least 3 months after the last dose of gemcitabine therapy for men, and/or undergo drug elimination of leflunomide at end of treatment until leflunomide is undetectable in the plasma.
* Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only).
Exclusion Criteria:
* Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days prior to day 1 of protocol therapy.
* Drugs metabolized by CYP2C8, CYP1A2, BCRP, OATP1B1/B3, and OAT3 transporters within 21 days prior to day 1 of protocol therapy.
* Herbal medications (excluding cannabidiol \[CBD\]).
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent.
* Issues with tolerating oral medication (e.g. inability to swallow pills, malabsorption issues, ongoing nausea or vomiting).
* Positive for tuberculosis or latent tuberculosis (TB).
* Active diarrhea.
* Clinically significant uncontrolled illness.
* Active infection requiring antibiotics.
* Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection. (\*If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable.)
* Diagnosis of Gilbert's disease.
* Prior malignancy other than carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated 5 or more years prior to study entry with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score ≤ 6 = Gleason group 1) localized prostate cancer will be eligible even if diagnosed less than 5 years prior to study entry. Other malignancies with low probability of recurrence may be allowed with PI approval.
* Females only: Pregnant or breastfeeding.
* Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).
