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

Study Overview
=================
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.

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.

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

Conditions
-----------------
Pancreatic Cancer, Pancreas Adenocarcinoma, Advanced Pancreatic Cancer, Metastatic Pancreatic Cancer, Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Drug: paricalcitol
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Be willing and able to provide written informed consent for the trial. Be ≥ 18 years of age on day of signing informed consent. 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. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale. 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. Demonstrate adequate organ function as defined in protocol, AND serum corrected calcium value must be ≤ Institutional Upper Limit of Normal (ULN) and ≥ 8.0 mg/dL, and phosphorus levels must be ≤ Institutional ULN and ≥ 2.5 mg/dL. Female participants of childbearing potential should have a negative serum pregnancy test within 24 hours prior to receiving first dose of trial medication. A female participant is eligible to participate if she is not pregnant , not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in protocol OR 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. 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: 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. 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. Has a known history of active TB (Mycobacterium tuberculosis). Hypersensitivity to pembrolizumab or paricalcitol or any of its excipients. 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. 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. 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. 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. 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. Has history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has an active infection requiring systemic therapy. 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. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has a serum vitamin D level of ≥ 50 ng/mL Currently taking a strong cytochrome P450 3A (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. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Has a known history of or is positive for Hepatitis B (e.g., HBsAg reactive) or Hepatitis C virus (e.g., HCV RNA [qualitative] is detected). Note: Without known history testing needs to be performed to determine eligibility. Current, serious, clinically significant cardiac arrhythmias as determined by the investigator, or patient receiving a digitalis derivative. 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: pembrolizumab & paricalcitol<br>pembrolizumab 200 mg IV q 3 weeks and paricalcitol 25 mcg IV 3 xs per week | Drug: Pembrolizumab<br>* pembrolizumab solution for infusion<br>* Other names: Keytruda;Drug: paricalcitol<br>* Paricalcitol solution for injection<br>* Other names: Zemplar;|
| Placebo Comparator: pembrolizumab & placebo<br>pembrolizumab 200 mg IV q 3 weeks & placebo- normal saline IV 3 xs per week | Drug: Pembrolizumab<br>* pembrolizumab solution for infusion<br>* Other names: Keytruda;Drug: placebo<br>* normal saline solution for injection<br>* Other names: placebo for paricalcitol;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression- Free Survival at 6 Months From Initiation of Trial Treatment | Progression Free Survival (PFS) defined per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) survival in the absence of death or progressive disease which is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). | 6 months from trial treatment initiation cycle 1/day 1. Each treatment cycle is 21 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | All adverse events occurring on or after Cycle 1/day 1through 30 days after the last dose of trial treatment will be summarized by body systems and per grade according to NCI-CTCAE Version 4. | initiation of trial treatment cycle 1/day 1 through 30 days after last dose of trial treatment. Each treatment cycle is 21 days. | 
| Difference in Overall Survival (OS) in Patients Administered the Combination of Paricalcitol Plus Pembrolizumab Versus Pembrolizumab Alone | Duration of survival will be defined as the time from initial treatment (cycle1/day1) until death. Overall survival will be estimated for each arm using a Kaplan-Meier estimate. | From date of treatment initiation cycle 1/day 1 until death from any cause, assessed up to 24 months ( the end of the study). | 
| Change in Tumor Mutational Landscape and Transcriptional Programs Using Unbiased Genome-wide Sequencing | Mutational landscapes, transcriptional programs in tumor tissue | Optional tumor biopsy taken at baseline and at 9 +/- 1 week following initiation of treatment | 
| Cellular VDR Targets in the Immune Microenvironment With PD1 Blockade | Identify cellular VDR targets in the immune microenvironment | 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). | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
VDR agonist, Pembrolizumab, Paricalcitol, Pancreatic cancer, Metastatic Pancreatic Cancer, Vitamin D Receptor (VDR), Immune Checkpoint Inhibitor, PD1 Inhibitor