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pembrolizumab 200 mg IV q 3 weeks and paricalcitol 25 mcg IV 3 xs per week

pembrolizumab 200 mg IV q 3 weeks \& placebo- normal saline IV 3 xs per week

paricalcitol

placebo

Daniel D Von Hoff, MD, FACS

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.

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.

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.

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

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

Difference in disease progression according to RECIST 1.1 and iRECIST criteria

Patient compliance rate of completing the PPCB application was calculated by the total percentage of completed questionnaires over expected questionnaires across all participants.

Improvement in symptoms as recorded by the Patient Personalized Clinical Benefit (PPCB)

Differences in tumor and/or tissue texture on CT scans between the two treatment arms

Differences in gut microbial communities within and between fecal samples using alpha and beta diversity metrics based on 16S rRNA sequencing

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).

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.

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.

Mutational landscapes, transcriptional programs in tumor tissue

Identify cellular VDR targets in the immune microenvironment

Stand Up To Cancer

Merck Sharp & Dohme LLC

Translational Genomics Research Institute

Participants with multiple events for a given AE term were counted only once for each AE term. If the same AE term was reported more than once for a participant, only the AE term with the highest grade was included.

pembrolizumab 200 mg IV q 3 weeks and paricalcitol 25 mcg IV 3 xs per week

Pembrolizumab: pembrolizumab solution for infusion

paricalcitol: Paricalcitol solution for injection

Pembrolizumab & Paricalcitol

pembrolizumab 200 mg IV q 3 weeks \& placebo- normal saline IV 3 xs per week

Pembrolizumab: pembrolizumab solution for infusion

placebo: normal saline solution for injection

Pembrolizumab & Placebo

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

ECOG 0

ECOG 1

Eastern Cooperative Oncology Group (ECOG performance) status scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.

ECOG 0=Fully active, able to carry on all pre-disease performance without restriction

ECOG=1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work.

ECOG Performance Status

Due to lack of grant funding, the other exploratory objectives to assess the changes in tumor and/or tissue texture on imaging, and to monitor and compare gut microbial communities in both arms, have not yet been able to be accomplished. The Investigators are looking for some way to fund the exploratory objectives in the future.

Derek Cridebring, PhD. Director, Molecular Medicine Division

All patients that receive trial treatment will be included in the analysis. Excludes 3 participants in the pembrolizumab + paricalcitol group: 1 participant that died due to other cause before 6 months, 2 participants who withdrew from study treatment before 6 months.

Progression- Free Survival at 6 Months From Initiation of Trial Treatment

Abdominal bloating

Abdominal pain

ALT increase

Alkaline phosphatase increase

Anemia

Arthralgia

AST increase

Creatinine increase

Hypertension

Hypophysitis

Nausea

Pruritis

Uticaria

Vomiting

All patients who received any amount of trial treatment were included in the analysis. The reported AEs are those noted as possibly or definitely related to study agents.

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.

Difference in Overall Survival (OS) in Patients Administered the Combination of Paricalcitol Plus Pembrolizumab Versus Pembrolizumab Alone

Data could not be analyzed due to lack of funding for the project.

Change in Tumor Mutational Landscape and Transcriptional Programs Using Unbiased Genome-wide Sequencing

Due to lack of funding, this analysis could not be performed.

Cellular VDR Targets in the Immune Microenvironment With PD1 Blockade

This planned analysis was not performed, as we were not able to obtain confirmation of disease progression by iRECIST for a majority of the patients.

Exploratory: Difference in Disease Progression According to RECIST 1.1 and iRECIST

Compliance rate for all participants treated in the Pembrolizumab \& Paricalcitol arm

Compliance rate for all participants treated in the Pembrolizumab \& Placebo Arm

All patients were included in the analysis.

Exploratory: Utility of a Patient Personalized Clinical Benefit (PPCB) Phone Based Application

Improvement in symptoms

Worsening in symptoms

No change in symptoms

All participants that completed the questionnaires in Pembrolizumab \& Paricalcitol arm

All participants who completed questionnaire in Pembrolizumab \& Placebo Arm

Exploratory:Improvement in Symptoms as Recorded by the Patient Personalized Clinical Benefit (PPCB) With Progression at 6 Months by RECIST 1.1

Due to lack of funding analysis could be be completed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A SU2C Catalyst® Trial of a PD1 Inhibitor With or Without a Vitamin D Analog for the Maintenance of Pancreatic Cancer	NCT03331562	Pancreatic Canc... Pancreas Adenoc... Advanced Pancre... Metastatic Panc... Metastatic Panc...	Pembrolizumab paricalcitol placebo	18 Years -	Translational Genomics Research Institute
A SU2C Catalyst® Trial of a PD1 Inhibitor With or Without a Vitamin D Analog for the Maintenance of Pancreatic Cancer	NCT03331562	Pancreatic Canc... Pancreas Adenoc... Advanced Pancre... Metastatic Panc... Metastatic Panc...	Pembrolizumab paricalcitol placebo	18 Years -	Translational Genomics Research Institute

Spots Global Cancer Trial Database for vitamin d receptor (vdr)