Paricalcitol Plus Gemcitabine and Nab-paclitaxel in Metastatic Pancreatic Cancer

Pancreatic cancer is an aggressive disease with treatment options associated with modest
benefit, therefore, new treatment options are needed. Paricalcitol is a man-made form of
vitamin D. It is thought to work by blocking a signal in the cancer tumor cells that leads to
growth and spreading of the tumor. Paricalcitol was approved by the Food and Drug
Administration (FDA) for the prevention and treatment of elevated calcium levels associated
with chronic renal failure. The FDA has not approved paricalcitol as a treatment for
pancreatic cancer. This research study is being performed to evaluate the benefit of
paricalcitol in combination with gemcitabine and nab-paclitaxel for this disease.

The FDA (the U.S. Food and Drug Administration) has approved the combination of gemcitabine
and nab-paclitaxel as a treatment option for this disease.

Treatment will consists of 4 week treatment cycles. Paricalcitol in the oral formulation will
be taken daily, in the intravenous formulation will be administered three times a week.
Nab-paclitaxel and gemcitabine will be administered on days 1,8, and 15.

Subjects continue in the study until disease progression, adverse event/toxicity, death or
either the subject or sponsor discontinues the study.

In this research study, the main objectives include:

- Assess adverse side effects associated with the combination of paricalcitol with
gemcitabine and nab-paclitaxel.

- Evaluate overall survival in patients with pancreatic cancer receiving gemcitabine and
nab-paclitaxel with or without paricalcitol.

Inclusion Criteria:

- 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
5-fluorouracil/leucovorin 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, 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 CT scan, MRI, or calipers by clinical exam. See
Section 11 for the evaluation of measurable disease.

- Age greater than or equal to 18 years.

- Patients must have completed any major surgery or open biopsy ≥4 weeks from start of
treatment.

- ECOG performance status ≤1 (see Appendix A)

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥1,500/mcL

- Platelets ≥100,000/mcL

- Total bilirubin ≤1.5 × institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- Calcium (corrected for albumin) * ≤1 × institutional upper limit of normal

- Creatinine ≤1.5 × institutional upper limit of normal OR

- Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels
above 1.5 × upper limit of normal.

- Corrected Calcium = serum calcium (mg/dL) + 0.8 (4 - serum albumin (g/dL))

- 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

Exclusion Criteria:

- 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. Because the lists of these agents are
constantly changing, it is important to regularly consult a frequently-updated list
such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts
such as the Physicians' Desk Reference may also provide this information. As part of
the enrollment/informed consent procedures, the patient will be counseled on the risk
of interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product. [see Appendix D]

- 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.