PRIMARY OBJECTIVE:
I. To evaluate the anti-tumor activity of the combination of paricalcitol plus
hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment by assessing
the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of the combination of paricalcitol plus
hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment in patients
with advanced pancreatic cancer.
II. To evaluate the anti-tumor activity of the combination of paricalcitol plus
hydroxychloroquine (PH) when added to gemcitabine and nab-paclitaxel treatment by assessing
progression-free survival (PFS) and overall survival (OS).
TERTIARY/EXPLORATORY OBJECTIVES:
I. Evaluate the effects of PH on cancer-associated fibroblasts (CAF) and immune cells using
mass cytometry (CyTOF) to characterize the presence and distribution of these cells.
II. Multiplex immunohistochemistry (IHC) to evaluate these pathways including TGF-beta1,
TGF-beta1 RII, SMAD4, LC3 in addition to markers of fibrosis (collagen) and tumor
(cytokeratin).
OUTLINE:
Beginning day -14, patients receive paricalcitol intravenously (IV) three times weekly and
hydroxychloroquine orally (PO) twice daily (BID). Patients also receive gemcitabine IV over
30 minutes and nab-paclitaxel IV over 30 minutes on days 1, 8, 15. Cycles repeat every 28
days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 28 days and every 12 weeks
thereafter.
Inclusion Criteria:
- Patients must have histologically confirmed advanced or metastatic adenocarcinoma of
the pancreas (stage IV)
- Patients must have measurable disease as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) criteria 1.1 as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded as >= 10 mm (>= 1
cm) on computed tomography (CT) scan, magnetic resonance imaging (MRI)
- Patients may have had prior neoadjuvant or adjuvant treatment for pancreatic cancer.
The last dose of chemotherapy must have been 12 months prior to study entry. No prior
systemic therapy for metastatic disease
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Hemoglobin >= 9.0 g/dl (no transfusions allowed within 7 days of cycle 1 day 1 to meet
entry criteria) (within 28 days of cycle 1 day 1)
- Absolute neutrophil count (ANC) >= 1,500/mcL (after at least 7 days without growth
factor support or transfusion) (within 28 days of cycle 1 day 1)
- Platelets >= 100,000/mcL (no transfusions allowed within 7 days of cycle 1 day 1 to
meet entry criteria) (within 28 days of cycle 1 day 1)
- International normalized ratio (INR) =< 1.5 (within 28 days of cycle 1 day 1)
- Partial thromboplastin time (PTT) < 1.5 x upper limits of normal (ULN) (within 28 days
of cycle 1 day 1)
- Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) (within 28
days of cycle 1 day 1)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 5.0 times the ULN
(within 28 days of cycle 1 day 1)
- Serum creatinine =< 1.5× ULN or creatinine clearance >= 60 mL/min/1.73 m^2 for
patients with creatinine levels > 1.5 x ULN. Creatinine clearance should be calculated
per institutional standard (within 28 days of cycle 1 day 1)
- Calcium (corrected for albumin) =< 1 x institutional upper limit of normal (within 28
days of cycle 1 day 1)
- Patients with prior radiotherapy are acceptable. It must be at least 21 days since
administration of radiation therapy and all signs of toxicity must have abated
- Patient must have a primary or metastatic non-bone site that is amenable to safe
biopsy. Bone only lesions are not suitable for biopsy
- Patients with known G6PD deficiency, severe psoriasis, porphyria, macular degeneration
or severe diabetic retinopathy are ineligible because of the potential for greater
hydroxychloroquine (HCQ) toxicity
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardio- toxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class 2B or better
- The effects of study drugs used in this study on the developing human fetus are
unknown. For this reason, female of child-bearing potential (FCBP) must have a
negative serum or urine pregnancy test prior to starting therapy
- FCBP 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 1 month
after completion of drug administration
- Willingness and ability of the subject to comply with scheduled visits, drug
administration plan, protocol-specified laboratory tests, other study procedures, and
study restrictions
- Evidence of a personally signed informed consent indicating that the subject is aware
of the neoplastic nature of the disease and has been informed of the procedures to be
followed, the experimental nature of the therapy, alternatives, potential risks and
discomforts, potential benefits, and other pertinent aspects of study participation
Exclusion Criteria:
- Prior chemotherapy or any other investigational agents for the treatment of metastatic
pancreatic cancer
- Concurrent use of any other anti-cancer therapy, including chemotherapy, targeted
therapy, immunotherapy, or biological agents
- History of use of HCQ (aminoquinolines) or paricalcitol in the 6 months prior to study
entry
- Pre-existing hypercalcemia, defined as baseline serum calcium (corrected for albumin)
above the institutional upper limit of normal
- After signing consent, vitamin D or calcium containing supplements must be stopped and
no vitamin D or calcium supplements can be taken while the patient is enrolled to the
study due to increased risk for hypercalcemia
- Pre-existing, clinically significant peripheral neuropathy, defined as Common
Terminology Criteria for Adverse Events (CTCAE) grade 2 or higher neurosensory or
neuro-motor toxicity, regardless of etiology
- Participants with uncontrolled 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
- Current use of medications that prolong QT interval unless approved by principal
investigator (PI) or substances that are strong inhibitors or inducers of CYP450 3A
enzyme(s)- unless approved by PI
- 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
- Patients with known G6PD deficiency, severe psoriasis, porphyria, macular degeneration
or severe diabetic retinopathy are ineligible because of the potential for greater HCQ
toxicity
- Pregnant women are excluded from this study because the use of agents 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 study drugs, breastfeeding should be discontinued
- Participant must be able to swallow and absorb pills
