Vitamin D Receptor Agonist Paricalcitol plus Gemcitabine and Nab-paclitaxel in Patients with Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:
I. To assess adverse events (per Common Terminology Criteria for Adverse Events [CTCAE] version [v]4.0 criteria) associated with addition of paricalcitol to gemcitabine and nab-paclitaxel. (Safety run-in)
II. To evaluate overall survival (OS) in patients with metastatic pancreatic cancer receiving gemcitabine and nab-paclitaxel with or without paricalcitol. (Phase II)

SECONDARY OBJECTIVE:
I. To evaluate safety, response rate (RR) and progression-free survival (PFS) in patients with metastatic pancreatic cancer receiving gemcitabine and nab-paclitaxel with or without paricalcitol. (Phase II)

EXPLORATORY OBJECTIVES:
I. Pharmacodynamic assessment of VDR binding by the oral and intravenous paricalcitol preparations when given concurrently with gemcitabine and nab-paclitaxel. (Safety run-in)
II. To explore a tumor-derived predictive biomarker for treatment efficacy with gemcitabine, nab-paclitaxel, and paricalcitol. (Phase II)

OUTLINE:
SAFETY RUN-IN PHASE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive nab-paclitaxel intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive a placebo orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive nab-paclitaxel IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive paricalcitol IV once weekly (QW). Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive nab-paclitaxel IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive paricalcitol PO QD on days 1-28. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patient are randomized to 1 of 2 arms.

ARM D: Patients receive nab-paclitaxel IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive a placebo PO QD on days 1-28 or IV QW. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

ARM E: Patients receive nab-paclitaxel IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive paricalcitol PO QD on days 1-28 or IV QW. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 weeks for 52 weeks.

Histologically-confirmed pancreatic adenocarcinoma or poorly differentiated carcinoma that is metastatic to distant sites. Other histologies such as neuroendocrine and acinar cell carcinoma are excluded. Patients with locally advanced, unresectable disease without distant metastases are excluded

No prior chemotherapy for locally advanced or metastatic pancreatic cancer. Patients are eligible if they received adjuvant treatment after surgical resection with single-agent gemcitabine or gemcitabine plus capecitabine or gemcitabine and nab-paclitaxel or 5-fluorouracil/leucovorin or 5-FU/leucovorin plus irinotecan and oxaliplatin that was completed > 12 months before enrollment. Similarly, adjuvant radiation +/- chemosensitization with 5-fluorouracil, capecitabine, or gemcitabine is allowed if completed > 12 months before enrollment

Participants must have measurable disease amendable to biopsy, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam

Age greater than or equal to 18 years

Patients must have completed any major surgery or open biopsy >= 4 weeks from start of treatment

Eastern Cooperative Oncology Group (ECOG) performance status =< 1

Absolute neutrophil count >= 1,500/mcL

Platelets >= 100,000/mcL

Total bilirubin =< 1.5 x institutional upper limit of normal

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal

Calcium (corrected for albumin) * =< 1 x institutional upper limit of normal
* Corrected calcium = serum calcium (mg/dL) + 0.8 (4 – serum albumin [g/dL])

Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above 1.5 x upper limit of normal

Ability to understand and the willingness to sign a written informed consent document

Negative pregnancy testing for women of child bearing age

The effects of paricalcitol, gemcitabine and nab-paclitaxel on the developing human fetus are unknown. For this reason and because vitamin D receptor agonist agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing 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 she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of treatment administration

Prior chemotherapy or any other investigational agents for the treatment of locally advanced or metastatic pancreatic cancer

Concurrent use of any other anti-cancer therapy, including chemotherapy, targeted therapy, immunotherapy, or biological agents

Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events

History of allergic reactions attributed to compounds of similar chemical or biologic composition to paricalcitol, gemcitabine or nab-paclitaxel

Pre-existing hypercalcemia, defined as baseline serum calcium (corrected for albumin) above the institutional upper limit of normal

At the time of trial enrollment, vitamin D containing supplements must be stopped and no vitamin D supplements can be taken while the patient is enrolled to the study due to increased risk for hypercalcemia

At the time of trial enrollment, calcium containing supplements must be stopped and no calcium supplements can be taken while the patient is enrolled to the study due to increased risk for hypercalcemia

History of symptomatic genitourinary stones (e.g. kidney stones) within the past 12 months

History of prior or current synchronous malignancy, except:
* Malignancy that was treated with curative intent and for which there has been no known active disease for > 3 years prior to enrollment
* Curatively treated non-melanoma skin cancer, cervical cancer in situ, or prostatic intraepithelial neoplasia, without evidence of prostate cancer

Pre-existing, clinically significant peripheral neuropathy, defined as CTCAE grade 2 or higher neurosensory or neuromotor toxicity, regardless of etiology

Regular use of thiazide diuretics (e.g. hydrochlorothiazide), which can lead to hypercalcemia. Patients must stop these diuretics prior to initiating treatment. Other anti-hypertensive medications can be substituted, as needed

Participants receiving any medications or substances that are inhibitors or inducers of CYP450 3A enzyme(s) are ineligible

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

Participant must be able to swallow and absorb pills

Pregnant women are excluded from this study because paricalcitol is a vitamin D receptor agonist agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with paricalcitol, breastfeeding should be discontinued if the mother is treated with paricalcitol. These potential risks may also apply to other agents used in this study