Given the efficacy of nanoliposomal irinotecan as a second-line regimen in pancreatic ductal adenocarcinoma (PDAC), together with the favorable toxicity profile of paricalcitol and its interplay with irinotecan metabolism, the investigators propose a second-line pilot study in advanced PDAC that will enroll patients who have progressed on a gemcitabine-based regimen.

Inclusion Criteria:

• Histologically or cytologically confirmed pancreatic adenocarcinoma.

• Must have progressed on or become intolerant to gemcitabine-containing therapy in the advanced setting (not resectable). This is intended to be a second-line trial.

• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.

• At least 18 years of age.

• Life expectancy > 3 months.

• ECOG performance status ≤ 1

• Normal bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin ≤ 1.5 x ULN
  • Serum albumin > 3g/dL
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN unless there are liver metastases, in which case AST and ALT ≤ 5.0 x IULN
  • Creatinine ≤ 1.5 x IULN OR GFR > 50 mL/min
  • Corrected calcium < 10.3 mg/dL
  • Phosphorus ≤ 4.5 mg/dL

• Patients will require a 2-week washout period from previous gemcitabine-based systemic therapy, a 2-week washout period from previous radiation therapy, and a 4-week washout period from major surgery prior to the first planned dose of study treatment.

• Prior clinically significant treatment-related toxicity must recover to grade 1 or less prior to the first planned dose of study treatment.

• Women of childbearing potential and men 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• More than one prior systemic treatment in the advanced setting. Disease recurrence within 6 months of adjuvant therapy is considered one line of systemic treatment.
• Patients with active renal, ureteral, or bladder stones on the screening imaging.
• Current use of or anticipated need for alternative, holistic, naturopathic, or botanical formulations used for the purpose of cancer treatment.
• A history of other malignancy within 2 years previous, with the exception of those basal cell or squamous cell carcinoma of the skin which were treated with local resection only, or carcinoma in situ of the cervix.
• Currently receiving any other investigational agents.
• Patients who received FOLFIRINOX or FOLFIRI in the neoadjuvant or adjuvant setting who experienced disease recurrence within 6 months will be excluded (patients who received 5-FU or capecitabine as a radiosensitizer are permitted to enroll.)
• Patients with known active/ progressive brain metastases or leptomeningeal involvement will be excluded due to their poor prognosis. Patients with treated/stable brain metastases, defined as patients who have received prior therapy for their brain metastases and whose CNS disease is radiographically stable at study entry, are eligible.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to paricalcitol, liposomal irinotecan, 5-FU, LV, or other agents used in the study.
• Clinically significant ascites that requires therapeutic paracentesis or significant pleural effusion that requires therapeutic thoracentesis.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 7 days of study entry.
• Known HIV-positivity not on anti-retroviral therapy, or with CD4+ T cell count < 200/ul (patients with known HIV currently on anti-retroviral therapy with CD4+ T cell count > 200/ul will be included).

Plan for sharing IPD to be determined.

Time frame for accessing IPD to be determined.

Access criteria for sharing IPD to be determined.