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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

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ClinicalTrials.gov Identifier: NCT03331562
Recruitment Status : Recruiting
First Posted : November 6, 2017
Last Update Posted : September 19, 2018
Sponsor:
Collaborators:
Stand Up To Cancer
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Translational Genomics Research Institute

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Pancreatic Cancer Pancreas Adenocarcinoma Advanced Pancreatic Cancer Metastatic Pancreatic Cancer Metastatic Pancreatic Adenocarcinoma Drug: Pembrolizumab Drug: paricalcitol Drug: placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a double-blind, randomized, placebo-controlled phase II trial with the identity of the treatment unknown to the patients, investigators, and the Sponsor.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Placebo controlled
Primary Purpose: Treatment
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
Actual Study Start Date : December 27, 2017
Estimated Primary Completion Date : May 15, 2019
Estimated Study Completion Date : December 15, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: pembrolizumab & paricalcitol
pembrolizumab 200 mg IV q 3 weeks and paricalcitol 25 mcg IV 3 xs per week
Drug: Pembrolizumab
pembrolizumab solution for infusion
Other Name: Keytruda

Drug: paricalcitol
Paricalcitol solution for injection
Other Name: Zemplar

Placebo Comparator: pembrolizumab & placebo
pembrolizumab 200 mg IV q 3 weeks & placebo- normal saline IV 3 xs per week
Drug: Pembrolizumab
pembrolizumab solution for infusion
Other Name: Keytruda

Drug: placebo
normal saline solution for injection
Other Name: placebo for paricalcitol




Primary Outcome Measures :
  1. 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. ]
    Difference in progression (by RECIST 1.1) at 6 months between the two treatment arms


Secondary Outcome Measures :
  1. 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. ]
    Incidence of toxicities between two treatment arms

  2. 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. ]
    Overall survival between two treatment arms

  3. 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 ]
    Mutational landscapes, transcriptional programs in tumor tissue

  4. 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). ]
    Identify cellular VDR targets in the immune microenvironment


Other Outcome Measures:
  1. Exploratory: Difference in disease progression according to RECIST 1.1 and iRECIST [ Time Frame: tumor assessments performed every 9 +/- 1 week while on treatment, up to 24 months. ]
    Difference in disease progression according to RECIST 1.1 and iRECIST criteria

  2. Exploratory: Utility of a Patient Personalized Clinical Benefit (PPCB) phone based application [ Time Frame: From baseline, patients will complete the PPCB App weekly during trial treatment, and at the time of trial treatment discontinuation for any reason, assessed up to 24 months (35 treatment cycles).Each treatment cycle is 21 days. ]
    Compliance rate responding to a phone - based application for the assessment of patient defined symptoms

  3. Exploratory:Improvement in symptoms as recorded by the Patient Personalized Clinical Benefit (PPCB) with progression at 6 months by RECIST 1.1 [ Time Frame: From baseline, patients will complete the PPCB App weekly during trial treatment, and at the time of trial treatment discontinuation for any reason, assessed up to 24 months (35 treatment cycles). Each treatment cycle is 21 days. ]
    Improvement in symptoms as recorded by the Patient Personalized Clinical Benefit (PPCB)

  4. Changes in tumor and/or tissue texture on imaging in both arms of the trial using quantitative textural analysis (QTA) [ Time Frame: tumor assessments performed every 9 +/- 1 week while on treatment, up to 24 months. ]
    Differences in tumor and/or tissue texture on CT scans between the two treatment arms

  5. Exploratory: Monitor and compare the gut microbial communities in both arms of the trial [ Time Frame: Fecal swab samples collected pre and post dose day 1 of each cycle, up to 35 treatment cycles. Each treatment cycle is 21 days. ]
    Differences in gut microbial communities within and between fecal samples using alpha and beta diversity metrics based on 16S rRNA sequencing



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 ≥ 20% 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 normal (WNL of local lab range) serum correct calcium, and phosphorus levels.
  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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03331562


Contacts
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Contact: Jatan Clark, MBA 602.343.8482 jclark@tgen.org

Locations
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United States, Arizona
HonorHealth Research Institute Recruiting
Scottsdale, Arizona, United States, 85258
Contact: Joyce Schaffer, RN    480-323-1339    clinicaltrials@honorhealth.com   
Principal Investigator: Erkut Borazanci, MD         
Principal Investigator: Gayle Jameson, ACNP-BC AOCN         
United States, California
City of Hope National Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Isma Hafeez    626-218-5013    ihafeez@coh.org   
Principal Investigator: Vincent Chung, MD         
United States, New Jersey
Atlantic Medical Group-Oncology Morristown Medical Center Recruiting
Morristown, New Jersey, United States, 07962
Contact: Nancy Ginder, RN, BSN    973-971-6608      
Principal Investigator: Angela Alistar, MD         
Sponsors and Collaborators
Translational Genomics Research Institute
Stand Up To Cancer
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Daniel D Von Hoff, MD, FACS Translational Genomics Research Institute (TGen) An Affiliate of City of Hope

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Responsible Party: Translational Genomics Research Institute
ClinicalTrials.gov Identifier: NCT03331562     History of Changes
Other Study ID Numbers: TGen 17-001
MISP# 56240 ( Other Identifier: Merck Sharp & Dohme Corp. a Subsidiary of Merck & Co., Inc. )
First Posted: November 6, 2017    Key Record Dates
Last Update Posted: September 19, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Translational Genomics Research Institute:
Pembrolizumab
Paricalcitol
Pancreatic cancer
Metastatic Pancreatic Cancer
Vitamin D
Immune Checkpoint Inhibitor
VDR agonist
PD1 Inhibitor

Additional relevant MeSH terms:
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Adenocarcinoma
Pancreatic Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Digestive System Diseases
Pancreatic Diseases
Endocrine System Diseases
Vitamins
Vitamin D
Ergocalciferols
Vitamin A
Pembrolizumab
Retinol palmitate
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Anticarcinogenic Agents