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A SU2C Catalyst® Trial of a PD1 Inhibitor With or Without a Vitamin D Analog for the Maintenance of Pancreatic Cancer

NCT03331562

Description:

Chemotherapy regimens for pancreatic cancer can now stabilize a patient's cancer and/or place some patients in remission or partial remission. The challenge now is to find options for maintenance therapies that will improve survival and allow continued benefits with minimal toxicities and inconvenience to the patients. This study will determine the effects of one possible maintenance regimen. The study is being conducted to determine the effects that pembrolizumab with or without the addition of paricalcitol may have on pancreatic cancer. Half of the patients will be randomized to receive pembrolizumab + paricalcitol and half to receive pembrolizumab + placebo.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A SU2C Catalyst® Trial of a PD1 Inhibitor With or Without a Vitamin D Analog for the Maintenance of Pancreatic Cancer
  • Official Title: A SU2C Catalyst ® Randomized Phase II Trial of the PD1 Inhibitor Pembrolizumab With or Without a Vitamin D Receptor Agonist Paricalcitol in Patients With Stage IV Pancreatic Cancer Who Have Been Placed in Best Possible Response

Clinical Trial IDs

  • ORG STUDY ID: TGen 17-001
  • SECONDARY ID: MISP# 56240
  • NCT ID: NCT03331562

Conditions

  • Pancreatic Cancer
  • Pancreas Adenocarcinoma
  • Advanced Pancreatic Cancer
  • Metastatic Pancreatic Cancer
  • Metastatic Pancreatic Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudapembrolizumab & paricalcitol
paricalcitolZemplarpembrolizumab & paricalcitol
placeboplacebo for paricalcitolpembrolizumab & placebo

Purpose

Chemotherapy regimens for pancreatic cancer can now stabilize a patient's cancer and/or place some patients in remission or partial remission. The challenge now is to find options for maintenance therapies that will improve survival and allow continued benefits with minimal toxicities and inconvenience to the patients. This study will determine the effects of one possible maintenance regimen. The study is being conducted to determine the effects that pembrolizumab with or without the addition of paricalcitol may have on pancreatic cancer. Half of the patients will be randomized to receive pembrolizumab + paricalcitol and half to receive pembrolizumab + placebo.

Detailed Description

      Pembrolizumab (also known as Keytruda®), which is approved in the USA and some other
      countries, is available by prescription to treat several different cancers, but has not been
      approved to treat pancreatic cancer. Pembrolizumab helps the body detect and fight cancer by
      making cancer cells more vulnerable to attack by the body's immune system. This medication
      binds to and lessens the action of specific parts of cells in the body's immune system, which
      act to modulate or balance the immune response. By decreasing this modulation of the immune
      response, the body's own system may be better able to fight the cancer. Pembrolizumab is
      known as an immune checkpoint inhibitor.

      It is thought that the effect of pembrolizumab could possibly be strengthened by the addition
      of paricalcitol, which is a form of vitamin D. Paricalcitol may make the cells in the immune
      system more sensitive to the activity of pembrolizumab and could make the local environment
      hostile to the cancer cells. Both activities could be effective against cancer growth.

      Paricalcitol (also known as Zemplar®) is used to treat high levels of parathyroid hormone and
      prevent bone loss in patients with advanced kidney disease. Paricalcitol is not approved by
      the FDA for the treatment of advanced pancreatic cancer.

      The effects of the study drugs will be assessed by repeated radiological imaging (CT scans),
      incidence of adverse reactions, and survival rates.

      Participants will also be asked to provide biological specimens for the study team to measure
      cellular changes. This will include fecal matter (stool), blood, and tumor tissue.

      The Food and Drug Administration (FDA) has determined that this study meets the requirements
      for Investigational New Drug (IND) Exemption.
    

Trial Arms

NameTypeDescriptionInterventions
pembrolizumab & paricalcitolActive Comparatorpembrolizumab 200 mg IV q 3 weeks and paricalcitol 25 mcg IV 3 xs per week
  • Pembrolizumab
  • paricalcitol
pembrolizumab & placeboPlacebo Comparatorpembrolizumab 200 mg IV q 3 weeks & placebo- normal saline IV 3 xs per week
  • Pembrolizumab
  • placebo

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the trial.

          2. Be ≥ 18 years of age on day of signing informed consent.

          3. Histologically or cytologically confirmed pancreatic adenocarcinoma with metastasis,
             who had obtained a best response of at least stable disease (SD) or a partial response
             (PR) for a period of 2 months with no further shrinkage of ≥ 30% on scan on their
             first line of chemotherapy for their advanced metastatic disease. Note: Patients that
             have had prior chemotherapy as adjuvant or neoadjuvant therapy are permitted.

          4. Have a performance status of 0 or 1 on the ECOG performance scale.

          5. Able to submit an archival tumor specimen (primary or metastatic site) and a
             discussion is documented with trial investigator at screening that patient will
             consider providing tissue from a newly obtained core or excisional biopsy of a tumor
             lesion at baseline and a second biopsy 9 weeks after starting trial treatment, unless
             tumor is considered inaccessible or biopsy is otherwise considered not in the patients
             best interest. Participation in this trial is not contingent on patient consenting to
             optional tumor biopsies.

          6. Demonstrate adequate organ function as defined in protocol, AND serum corrected
             calcium value must be ≤ Institutional ULN and ≥ 8.0 mg/dL, and phosphorus levels must
             be ≤ Institutional ULN and ≥ 2.5 mg/dL.

          7. Female participants of childbearing potential should have a negative serum pregnancy
             test within 24 hours prior to receiving first dose of trial medication.

          8. A female participant is eligible to participate if she is not pregnant , not
             breastfeeding, and at least one of the following conditions applies:

               1. Not a woman of childbearing potential (WOCBP) as defined in protocol

                  OR

               2. A WOCBP who agrees to follow the contraceptive guidance in protocol during the
                  treatment period and for at least 120 days after the last dose of trial
                  treatment.

          9. Male participants must agree to use a contraception as detailed in protocol during the
             treatment period and for at least 120 days after the last dose of trial treatment and
             refrain from donating sperm during this period.

        Exclusion Criteria:

          1. Is currently participating and receiving trial therapy or has participated in a trial
             of an investigational agent and received trial therapy or used an investigational
             device within 4 weeks of the first dose of trial treatment.

          2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment. The use of physiologic doses of corticosteroids may be approved after
             consultation with the Sponsor.

          3. Has a known history of active TB (Mycobacterium tuberculosis).

          4. Hypersensitivity to pembrolizumab or paricalcitol or any of its excipients.

          5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle
             1/Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to Cycle1/ Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent(s).

             Note: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may
             qualify for the trial.

             Note: If patient received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting therapy.

          7. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          8. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Patients with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis, which is excluded regardless of clinical stability.

          9. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         10. Has history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis.

         11. Has an active infection requiring systemic therapy.

         12. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the patient's
             participation for the full duration of the trial, or is not in the best interest of
             the patient to participate, in the opinion of the treating investigator.

         13. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

         15. Has a serum vitamin D level of ≥ 50 ng/mL

         16. Currently taking a strong CYP3A inhibitors that cannot be discontinued prior to trial
             enrollment and for the duration of trial. This includes but is not is limited to:
             boceprevir clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole,
             ketoconazole, lopinavir/ritonavir.

         17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         18. Has a known history of or is positive for Hepatitis B (e.g., HBsAg reactive) or
             Hepatitis C (e.g., HCV RNA [qualitative] is detected).

             Note: Without known history testing needs to be performed to determine eligibility.

         19. Current, serious, clinically significant cardiac arrhythmias as determined by the
             investigator, or patient receiving a digitalis derivative.

         20. Has received a live vaccine within 30 days of planned start of trial therapy.

        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
        vaccines, and are not allowed
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percent of patients with radiographic disease progression according to RECIST 1.1 at 6 months from initiation of trial treatment
Time Frame:6 months from trial treatment initiation cycle 1/day 1. Each treatment cycle is 21 days.
Safety Issue:
Description:Difference in progression (by RECIST 1.1) at 6 months between the two treatment arms

Secondary Outcome Measures

Measure:Incidence of treatment-related toxicities as assessed by CTCAE v4.0 from cycle1/day 1 through 30 days after the last dose of trial treatment.
Time Frame:initiation of trial treatment cycle 1/day 1 through 30 days after last dose of trial treatment. Each treatment cycle is 21 days.
Safety Issue:
Description:Incidence of toxicities between two treatment arms
Measure:Difference in overall survival (OS) in patients administered the combination of paricalcitol plus pembrolizumab versus pembrolizumab alone
Time Frame:From date of treatment initiation cycle 1/day 1 until death from any cause, assessed up to 36 months.
Safety Issue:
Description:Overall survival between two treatment arms
Measure:Change in tumor mutational landscape and transcriptional programs using unbiased genome-wide sequencing
Time Frame:Optional tumor biopsy taken at baseline and at 9 +/- 1 week following initiation of treatment
Safety Issue:
Description:Mutational landscapes, transcriptional programs in tumor tissue
Measure:Cellular VDR targets in the immune microenvironment with PD1 blockade
Time Frame:From baseline, at 9 +/- 1 week following initiation of treatment, at the time of confirmed response, and at the time of trial treatment discontinuation for any reason, up to 24 months ( 35 treatment cycles).
Safety Issue:
Description:Identify cellular VDR targets in the immune microenvironment

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Translational Genomics Research Institute

Trial Keywords

  • Pembrolizumab
  • Paricalcitol
  • Pancreatic cancer
  • Metastatic Pancreatic Cancer
  • Vitamin D
  • Immune Checkpoint Inhibitor
  • VDR agonist
  • PD1 Inhibitor

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