Clinical Trials /

Paricalcitol and Hydroxychloroquine in Combination With Gemcitabine and Nab-Paclitaxel for the Treatment of Advanced or Metastatic Pancreatic Cancer

NCT04524702

Description:

This phase II trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in treating patients with pancreatic cancer that has spread to other places in the body (advanced or metastatic). Paricalcitol (a form of vitamin D) works by blocking a signal in the cancer cells that leads to growth and spreading of the tumor. Hydroxychloroquine (an autophagy inhibitor) enhances the activity of standard chemotherapy on cancer cells and prevent them to utilize energy to grow. Chemotherapy drugs, such as gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving paricalcitol and hydroxychloroquine together with standard chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to either paricalcitol or hydroxychloroquine alone.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Paricalcitol and Hydroxychloroquine in Combination With Gemcitabine and Nab-Paclitaxel for the Treatment of Advanced or Metastatic Pancreatic Cancer
  • Official Title: Phase II Trial of Paricalcitol and Hydroxychloroquine (PH) Combination With Gemcitabine and Nab-Paclitaxel in Advanced Pancreatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: STUDY00000996
  • SECONDARY ID: NCI-2020-05417
  • SECONDARY ID: Winship5079-20
  • SECONDARY ID: P30CA138292
  • NCT ID: NCT04524702

Conditions

  • Advanced Pancreatic Adenocarcinoma
  • Metastatic Pancreatic Adenocarcinoma
  • Stage IV Pancreatic Cancer AJCC v8

Interventions

DrugSynonymsArms
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineTreatment (paricalcitol, hydroxychloroquine, chemotherapy)
HydroxychloroquineTreatment (paricalcitol, hydroxychloroquine, chemotherapy)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, Paclitaxel Albumin, paclitaxel albumin-stabilized nanoparticle formulation, Protein-bound PaclitaxelTreatment (paricalcitol, hydroxychloroquine, chemotherapy)
ParicalcitolCompound 49510, ZemplarTreatment (paricalcitol, hydroxychloroquine, chemotherapy)

Purpose

This phase II trial investigates how well paricalcitol and hydroxychloroquine work when combined with gemcitabine and nab-paclitaxel in treating patients with pancreatic cancer that has spread to other places in the body (advanced or metastatic). Paricalcitol (a form of vitamin D) works by blocking a signal in the cancer cells that leads to growth and spreading of the tumor. Hydroxychloroquine (an autophagy inhibitor) enhances the activity of standard chemotherapy on cancer cells and prevent them to utilize energy to grow. Chemotherapy drugs, such as gemcitabine and nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving paricalcitol and hydroxychloroquine together with standard chemotherapy (gemcitabine and nab-paclitaxel) may work better in treating patients with pancreatic cancer compared to either paricalcitol or hydroxychloroquine alone.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (paricalcitol, hydroxychloroquine, chemotherapy)ExperimentalBeginning day -14, patients receive paricalcitol IV three times weekly and hydroxychloroquine PO 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.
  • Gemcitabine
  • Hydroxychloroquine
  • Nab-paclitaxel
  • Paricalcitol

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change from baseline tumor size as measured by cross sectional imaging at 8 weeks.(every 8 weeks)
Time Frame:From date of study entry until date of first documented progression or death from any cause whichever comes first up to 100 months.
Safety Issue:
Description:Assessed per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Tumor measurements will be performed every 8 weeks. Response rate will be estimated, and a 90% exact confidence interval will be reported using the Clopper-Pearson method.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 28 days post treatment from study start
Safety Issue:
Description:Toxicities will be presented as worst toxicity per patient and will be reported as percent toxicity. The number of subjects with skipped doses, dose delays and dose reductions as well as major reasons for dose modifications will be summarized. Adverse events will be classified using MedDRA System Organ Classes and Preferred Terms. Furthermore, serious adverse events (SAEs), adverse events (AEs) with a severity grade of 3 or above using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, AEs deemed related to study drug, AEs leading to discontinuation of study drug, and AEs leading to death will also be summarized in preferred term by system organ class and listed on an individual subject basis.
Measure:Progression-free survival
Time Frame:Up to 3 years from study start
Safety Issue:
Description:Assessed using RECIST 1.1. Will be estimated using the Kaplan-Meier method.
Measure:Overall survival
Time Frame:Up to 3 years from study start
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Last Updated

August 20, 2020