Clinical trial NCT03331562
Conditions: Pancreatic Cancer Pancreas Adenocarcinoma Advanced Pancreatic Cancer Metastatic Pancreatic Cancer Metastatic Pancreatic Adenocarcinoma
Keywords: Pembrolizumab Paricalcitol Pancreatic cancer Metastatic Pancreatic Cancer Vitamin D Receptor (VDR) Immune Checkpoint Inhibitor VDR agonist PD1 Inhibitor
Sponsor: Translational Genomics Research Institute
Start date: 2017-12-27; Completion date: 2020-07-10
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: pembrolizumab 200 mg IV q 3 weeks and paricalcitol 25 mcg IV 3 xs per week arm 2: pembrolizumab 200 mg IV q 3 weeks \& placebo- normal saline IV 3 xs per week
Interventions: intervention 1: Pembrolizumab intervention 2: paricalcitol intervention 3: placebo
Intervention descriptions: intervention 1: pembrolizumab solution for infusion intervention 2: Paricalcitol solution for injection intervention 3: normal saline solution for injection

Protocol documents:
Prot_000.pdf: 






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INVESTIGATOR PROTOCOL AGREEMENT 
Protocol #TGen 17-001 MISP # 56240 
 
Title: A SU2C Catalyst® Randomized Phase II Trial of the PD1 Inhibitor Pembrolizumab (Keytruda®) 
with vitamin D receptor agonist Paricalcitol (Zemplar®) in Patients with Stage IV Pancreatic Cancer 
Who Have Been Placed in Best Possible Response (with no further improvement in their tumor)   
 
Version 10.0  Aug 29, 2019 
 
I confirm that my staff and I have carefully read and understand this protocol. I/we agree to 
comply with the procedures and terms of the clinical trial specified herein. In particular, I/we 
have agreed to: 
 
• 
Abide by all obligations stated on the Form FDA 1572 and on other document(s) required by 
local regulatory authority. 
• 
Comply with Good Clinical Practice (GCP) and all applicable regulatory requirements. 
• 
Maintain confidentiality and assure security of TGen and SU2C confidential documents. 
• 
Obtain Institutional Review Board (IRB) approval of the protocol, any amendment to the 
protocol, and periodic re-approval as required, and to keep the IRB informed of any adverse 
events and periodically report the status of the trial to the IRB. 
• 
Not implement any deviations from or changes to the protocol without agreement from the 
Sponsor and prior review and written approval from the IRB, except where necessary to 
eliminate an immediate hazard to the patients or for administrative aspects of the trial (where 
permitted by all applicable regulatory requirements). 
• 
Assure that each patient enrolled into the trial has read, understands, and has signed the 
informed consent. 
• 
Ensure that I and all persons assisting me with the trial are adequately informed and trained 
about the trial treatment and of their trial-related duties and functions as described in the 
protocol. 
• 
Make prompt reports of serious adverse events (SAEs) and deaths (within 1 business day of 
learning) to the Sponsor. 
• 
Assure access by the Sponsor, the assigned CRO 
), and/or FDA to original source 
documents. 
• 
Prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the investigation on each individual treated in the 
investigation. 
• 
Arrange for the transfer of appropriate data from case histories to case report forms for the 
collection and transmission of data to the Sponsor. 
• 
Retain records and documents related to this trial for at least 3 years after the completion of 
the trial as confirmed by the sponsor. 
• 
Cooperate fully with any trial-related GCP audit as performed by the assurance group 
specified by the Sponsor, SU2C, or 
. 
Abide by the stipulations in the Confidentiality and Financial Disclosure sections and the 
manuscript preparation/authorship guidelines established at the outset of the trial. 
 
 
Investigator’s Printed Name: _________________________________________ 
 
Investigator’ Signature: ____________________________ Date: ____________ 




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Section 1.4 
Pembrolizumab 
(Keytruda®) 
Deleted the following bullets: 
• 
Metastatic NSCLC whose tumors have 
high PD-L1 expression [(Tumor 
Proportion Score (TPS) ≥50%)] as 
determined by an FDA-approved test, 
with no EGFR or ALK genomic tumor 
aberrations, and no prior systemic 
chemotherapy treatment for metastatic 
NSCLC. 
 
• 
Patients with metastatic NSCLC in 
combination with chemotherapy. 
 
• 
Metastatic NSCLC whose tumors express 
PD-L1 (TPS ≥1%) as determined by an 
FDA-approved test, with disease 
progression on or after platinum-
containing chemotherapy.  
 
 
Added the additional bullets: 
• 
As adjuvant treatment of patients with 
melanoma with involvement of lymph 
node(s) following complete resection 
 
• 
In combination with pemetrexed and 
platinum 
chemotherapy, 
as 
first-line 
treatment of patients with metastatic non-
squamous NSCLC, with no EGFR or 
anaplastic 
lymphoma 
kinase 
(ALK) 
genomic tumor aberrations 
 
• 
In combination with carboplatin and either 
paclitaxel or paclitaxel protein-bound, as 
first-line 
treatment 
of 
patients 
with 
metastatic squamous NSCLC 
 
• 
As a single agent for the first-line 
treatment of patients with Stage III 
NSCLC, who are not candidates for 
surgical 
resection 
or 
definitive 
chemoradiation, or metastatic NSCLC, 
and whose tumors express PD-L1 (TPS 
≥1%) as determined by an FDA-approved 
test, with no EGFR or ALK genomic tumor 
aberrations. 
 
• 
As a single agent for the treatment of 
patients with metastatic NSCLC whose 
tumors express PD-L1 (TPS ≥1%) as 
determined by an FDA-approved test, 
with disease progression on or after 
platinum-containing 
chemotherapy. 
Patients with EGFR or ALK genomic 
tumor aberrations should have disease 
Revision to include the update to 
the approved indications for 
Pembrolizumab in the US as per 
the updated Investigator 
Brochure Version 17 dated 26 
Jul 2019 and Risk Language 
dated 29 Jul 2019 provided by 
Merck. 


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progression on FDA-approved therapy for 
these 
aberrations 
prior 
to 
receiving 
KEYTRUDA®.  
 
• 
Adult and pediatric patients with refractory 
primary 
mediastinal 
large 
B-cell 
lymphoma 
(PMBCL), 
or 
who 
have 
relapsed after 2 or more prior lines of 
therapy 
 
• 
Patients with recurrent locally advanced 
or metastatic gastric or gastroesophageal 
junction (GEJ) adenocarcinoma whose 
tumors express PD-L1 (CPS ≥1) as 
determined by an FDA-approved test, 
with disease progression on or after two 
or more prior lines of therapy including 
fluoropyrimidine- and platinum-containing 
chemotherapy 
and 
if 
appropriate, 
HER2/neu-targeted therapy. 
 
• 
Patients with recurrent or metastatic 
cervical cancer with disease progression 
on or after chemotherapy whose tumors 
express PD-L1 (CPS ≥1) as determined 
by an FDA-approved test. 
 
• 
Patients with hepatocellular carcinoma 
(HCC) who have been previously treated 
with sorafenib. 
 
• 
Adult and pediatric patients with recurrent 
locally advanced or metastatic Merkel cell 
carcinoma (MCC). 
 
• 
In combination with axitinib, for the first-
line treatment of patients with advanced 
renal cell carcinoma (RCC). 
 
 
Revised 
the 
following 
bullets 
(additions 
underlined: 
• Patients 
with 
locally 
advanced 
or 
metastatic urothelial carcinoma (UC) who 
are not eligible for cisplatin-containing 
chemotherapy 
and 
whose 
tumors 
express PD-L1 (combined positive score 
(CPS) ≥10) as determined by an FDA-
approved test, or in patients who are not 
eligible for any platinum containing 
chemotherapy 
regardless 
of 
PD-L1 
status. 
 
• 
Patients 
with 
locally 
advanced 
or 
metastatic 
UC 
who 
have 
disease 


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progression during or following platinum-
containing chemotherapy or within 12 
months 
of 
neoadjuvant 
or 
adjuvant 
treatment 
with 
platinum-containing 
chemotherapy.  
 
Table 7. Screen – 
Treatment Period 
Schedule  
 
Added the following text: 
Optional  
 
Added the following row to the table: 
Tumor Tissue Collection [Tumor tissue collection 
for those that consent to this optional collection 
and undergo a routine care biopsy 
of their tumor during their participation in the 
study] q 
 
Added Footnotes:  
p. All patients are required to provide archival 
tumor specimen from either a primary or 
metastatic site.  (Refer to 4.1.1 and 6.1.2.8) 
 
q. For only those patients that consent to the 
optional tissue collection.  (Refer to 6.1.2.8). 
 
r. For only those patients consenting to the 
optional tumor biopsy, a baseline tumor biopsy will 
be collected and used for profiling. If possible 
(patient condition permitting) this will be repeated 
after 9 ± 1 weeks on trial treatment, or at the time 
of disease progression. (Refer to 6.1.2.8). 
 
Revision to distinguish the 
Optional tumor biopsy. 
 
Revision to include the additional 
optional tissue collection as part 
of a routine care biopsy if 
performed during the patient’s 
participation in the study.  
 
 
Revision to provide clarification 
for the required archival tissue 
and the optional tissue 
collection. 
 
 
Revision to include that the 
optional biopsy is to be collected 
at 9 weeks or at the time of 
disease progression.   
Table 8. Post 
Treatment Period  
(EOT- Follow-Up) 
Schedule 
Added the following row to the table: 
Optional -Tumor Tissue Collection 
[Tumor tissue collection for those that consent to 
this optional collection and undergo a routine care 
biopsy 
of their tumor during their participation in the 
study] j 
 
Added Footnotes:  
j. For only those patients that consent to the 
optional tissue collection.  (Refer to 6.1.2.8). 
 
Revision to include the additional 
optional tissue collection as part 
of a routine care biopsy if 
performed during the patient’s 
participation in the study.  
 
Section 6.1.2.7 
Blood Collection 
Replaced the previous text: 
flow cytometry based immune profiling 
 
With the following text: 
existing technologies, such as flow cytometry, 
CyTOF, single-cell RNA-Seq, and single cell 
ATAC-Seq, as well as various new technologies 
as they become available. 
 
Revised to specify the types of 
technologies to be used for 
analysis and allow for the use of 
additional technologies as they 
become available.  


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Section 6.1.2.8 
Tumor Tissue 
Collection 
Replaced the previous text: 
block  with specimen 
 
Added the following text: 
Archival tissue will be analyzed in a similar 
manner as described below for formalin fixed 
paraffin embedded (FFPE) biopsy samples. 
Specific details for archival tissue processing and 
distribution will be provided to the investigative 
sites in the Trial Laboratory Manual. Sites will be 
asked to indicate whether blocks will be available 
for additional sectioning at a later point in time if 
additional tissue is needed.  
 
Patients will be provided with the following two 
additional options to provide fresh tumor tissue for 
the analysis as described below. 
 
 
Revised the following text (additions 
underlined). 
Patients will be provided the option to consent to 
provide fresh tissue samples from a newly 
obtained core or excisional biopsy of a tumor 
lesion if performed recently (within 30 days prior 
to Cycle 1/Day 1) and during their participation in 
the study should they be scheduled for a biopsy 
as part of their routine care during their 
participation in the study through the follow-up 
period.  
 
Additionally, patients will also be provided with the 
option to consent to undergo a biopsy of a tumor 
lesion at baseline, at the completion of 3 cycles of 
treatment (9 weeks after starting trial treatment), 
or at the time of disease progression if prior to 
week 9, unless tumor is considered inaccessible 
or biopsy is otherwise considered not in the 
patients best interest.  Participation in this trial is 
therefore not contingent on the patient consenting 
to optional tumor biopsies for fresh tissue. 
 
For patients consenting to the optional tumor 
biopsy, a baseline tumor biopsy will be collected 
and used for profiling. If possible (patient condition 
permitting) this will be repeated after 9 ± 1 weeks 
on trial treatment, or at the time of disease 
progression.   
 
 
Two passes will be split evenly and processed for 
formalin-fixed paraffin (FFP) and optimal cutting 
temperature (OCT) embedding and samples will 
be centrally analyzed using existing technologies, 
such as immunohistochemistry, 
immunofluorescence, and RNA-in situ 
Revision to specify archival 
specimen will be collected, as 
these may be submitted by the 
site either as a block or slides 
per the sites policy. 
 
 
Revision to specify the planned 
analysis for the archival 
specimen. 
 
 
 
 
Revision to include the additional 
optional tissue collection as part 
of a routine care biopsy if 
performed during the patient’s 
participation in the study.  
 
 
 
Revision to include that the 
optional biopsy is to be collected 
at 9 weeks or at the time of 
disease progression.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revisions to include 
specifications on the planned 
analysis based on existing 
technologies as well as other 
various new technologies as 


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hybridization, as well as various new technologies 
as they become available to evaluate the 
following: 
• 
Stromal/extracellular matrix content (e.g. 
collagen and hyaluronic acid) 
 
• 
Quantity and quality of vascularization 
(e.g. CD31) 
 
• 
Expression of pembrolizumab related 
targets (e.g. PD-1 and PD-L1) 
 
• 
Presence/ distribution, and activation of 
key immune cell populations (e.g. cytotoxic T 
Cells, TAMs, MDSCs, and Tregs) 
 
• 
Presence, distribution, and activation of 
other stromal cell populations, including 
fibroblasts (e.g. αSMA). 
 
Two passes will be immediately frozen in 
Bambanker™ freezing media for the following 
central analysis: 
 
• 
Genomic analysis of T-cell receptor 
clonality by sequencing (a measure of 
intratumoral T cell response) 
 
Bulk and single-cell analysis of mutational profiles, 
transcriptional profiles, and epigenetic states 
within tumors, including analysis of sorted tumor 
cell nuclei. 
 
In the event that biopsy tissue becomes limiting 
for certain analyses, snap frozen and 
Bambanker™ frozen tissue may be used 
interchangeably where technically feasible. 
 
they become available. 
Section 6.1.4 
Patient 
Personalized 
Clinical Benefit 
(PPCB) 
 
 
 
 
 
Revised the following text (additions 
underlined): 
 
In the event that a patient does not have the type 
of mobile device required to access the APP, or 
the patient chooses not to complete the PPCB via 
the APP, the patient will be provided a paper 
questionnaire to complete.  The site will record the 
reason the patient is not utilizing the APP in the 
source documents.  Refer to Appendix 6 for more 
details on the PPCB App. 
 
Revisions to account for the 
various scenarios that a patient 
may not use the PPCB APP and 
the reason for  not using the 
APP to be collected.  


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Section 6.1.7.1 
Screening Period 
Added the following: 
 
17. For those patients consenting to the optional 
fresh tissue collection: Obtain fresh tissue from a 
newly obtained core or excisional biopsy if 
performed within the last 30 days prior to first 
dose of trial medication (C1/D1).  Refer to Section 
6.1.2.8. 
 
Revised the previous text to include the 
following additions underlined:  
18. For those patients consenting to the optional 
baseline biopsy: Fresh tissue is to be obtained up 
to 3 weeks (21 days) prior to first dose of trial 
medication (C1/D1). Refer to Section 6.1.2.8. 
 
Added the following: 
 
19.Obtain archival tumor specimen for all patients 
- as required for eligibility. Refer to Section 
6.1.2.8. 
 
Refer to Section 6.1.2.7. 
 
Refer to Section 6.1.6. 
 
Revision to include the additional 
optional tissue collection as part 
of a routine care biopsy if 
performed during the patient’s 
participation in the study.  
 
 
 
 
 
 
 
 
 
 
 
Revision to include the steps 
pertaining to the required 
archival tissue specimen.  
 
Revision to include reference to 
other sections of the protocol 
pertaining to Blood and Tumor 
Tissue Collection. 
 
 




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Glossary of Abbreviations 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
AST 
Aspartate Aminotransferase 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA-125 
Cancer antigen 125 
CA19-9 
Carbohydrate antigen 19-9  
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
cHL 
Classical Hodgkin’s Lymphoma 
CMH 
Cochran-Mantel-Hanzel 
CNS 
Central Nervous System 
CPS 
Combined Positive Score 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTC 
Circulating Tumor Cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trial Facilitation Group  
DSMP 
Data Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECI 
Event of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
ERC 
Ethical Review Committee 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed Paraffin-Embedded 
FU 
Follow-Up 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction 
GvHD 
Graft versus Host Disease 
HBsAg 
Hepatitis B Surface Antigen 
HCC 
Hepatocellular Carcinoma   
HCV RNA 
Hepatitis C Virus RNA 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HRT 
Hormonal Replacement Therapy 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
INR 
International Normalized Ratio 


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irAEs 
Immune-Related Adverse Events 
iRECIST 
Immune-related Response Evaluation Criteria in Solid Tumors 
IRB 
Institutional Review Board 
IV 
Intravenous 
mAb 
Monoclonal Antibody 
MCC 
Merkel Cell Carcinoma 
MDSC 
Myeloid-Derived Suppressor Cells 
MRI 
Magnetic Resonance Imaging 
MSI-H 
Microsatellite Instability-High 
Nab 
Nanoparticle albumin bound 
NCI 
National Cancer Institute 
NIH 
National Institutes for Health 
NSCLC 
Non-Small Cell Lung Cancer 
OCT 
Optimal Cutting Temperature  
OS 
Overall Survival 
OTC 
Over-the-Counter 
PBMC 
Peripheral Blood Mononuclear Cells 
PBPK 
Physiologically-based Pharmacokinetic 
PDA 
Pancreatic Ductal Adenocarcinoma 
PHI 
Protected Health Information 
PK 
Pharmacokinetic 
PMBCL 
Primary mediastinal large B-cell lymphoma 
PPCB 
Patient Personalized Clinical Benefit 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QTA 
Quantitative Textural Analysis 
RCC 
Renal Cell Carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SJS 
Stevens-Johnson Syndrome 
SU2C 
Stand Up to Cancer 
T3 
Triiodothyronine 
T4 
Thyroxine 
TAM 
Tumor Associated Macrophages 
TB 
Mycobacterium tuberculosis 
TEN 
Toxic Epidermal Necrolysis 
TGen 
Translation Genomic Research Institute 
TKI 
Tyrosine Kinase Inhibitor 
TMDD 
Target-Mediated Drug Disposition 
TPS 
Tumor Proportion Score 
Tregs 
Tregulatory Cells 
TSH 
Thyroid-Stimulating Hormone 
UC 
Urothelial Carcinoma 
ULN 
Upper Limit of Normal 
VDR 
Vitamin D Receptor 
WOCBP 
Women of Childbearing Potential 






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application 
 
3. Assess the association between improvement in symptoms as recorded by the Patient 
Personalized Clinical Benefit (PPCB) with progression at 6 months by RECIST 1.1  
 
4. Assess any changes in tumor and/or tissue texture on imaging in both arms of the trial 
 
5. To monitor and compare the gut microbial communities in both arms of the trial. 
 
Trial Design: Randomized Double Blind, Placebo Controlled 
 
No. Patients: Total of 24, 12 randomized to each treatment arm 
 
Name, dose of drugs:  
• 
Pembrolizumab (Keytruda®) 200 mg administered as an intravenous infusion over 30 
minutes every 3 weeks. 
 
• 
Paricalcitol (Zemplar®) 25 mcg administered intravenously 3 times per week (given on 
days 1, 3, 5, 8, 10, 12, 15, 17, 19 ± 1 day of each 21 day cycle) and prior to each 
pembrolizumab infusion. 
 
• 
Placebo- equivalent volume administered intravenously, 3 times per week and prior to 
each pembrolizumab infusion. 
 
Treatment Arms: 
Arm1: pembrolizumab + paricalcitol 
Arm 2: pembrolizumab + placebo (saline solution) 
 
Patient Population: Patients with stage IV pancreatic cancer who have been put in best 
response, defined as: Must have obtained a best response of at least stable disease (SD) or 
partial response (PR) for a period of 2 months with no further shrinkage of ≥ 30% on scan. 
 
Endpoints: 
Primary: The percent of patients with radiographic disease progression according to RECIST 
1.1 at 6 months. 
 
Secondary:  
• 
Incidence of toxicities 
 
• 
Overall survival 
 
• 
Mutational landscape 
 
• 
Transcriptional programs 
 
• 
Cellular (immunity) VDR targets in the immune microenvironment 
 
Exploratory: 
• 
Difference in disease progression according to RECIST 1.1 and iRECIST (Appendix 5) 
criteria 
 
• 
Compliance rate responding to a phone - based application for the assessment of patient 


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defined symptoms  
 
• 
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  
 
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 Table 2, 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 (see Section 4.7.2), not 
breastfeeding, and at least one of the following conditions applies:  
 
a.) Not a woman of childbearing potential (WOCBP) as defined in Section 
4.7.2.  
OR 
 
b.) A WOCBP who agrees to follow the contraceptive guidance in Section 
4.7.2 during the treatment period and for at least 180 days after the last 
dose of trial treatment.  
 
9. Male participants must agree to use contraception as detailed in Section 4.7.2 of this 
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. 
 


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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 
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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. 
  
Statistical Methods: The primary endpoint for this clinical trial is the percent of patients with 
radiographic disease progression according to RECIST 1.1 at 6 months.  Without maintenance 
therapy, 92% of patients are expected to progress by 6 months.  Therefore, we assume 1/12 
(0.083) pembrolizumab + placebo arm show no progression versus 7/12 pembrolizumab + 
paricalcitol.  This gives 90% statistical power with one side alpha = (0.05). 
  
Statistical analysis will compare the proportion progression free at 6 months using a one-sided 
test comparing binomial proportions (equivalent to a Pearson’s chi-square test).   The incidence 
of toxicities will be tabulated.  Overall survival will be estimated for each arm using a Kaplan-
Meier estimate.  Statistical comparison of overall survival will be performed using a log-rank test 
with estimation of the hazards ratio using a Cox proportional hazards model. 
 


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TABLE OF CONTENTS 
1.0 BACKGROUND AND RATIONALE ............................................................................... 24 
1.1 Overview ................................................................................................................................ 24 
1.2 A major developing problem in the care of patients with advanced pancreatic cancer ............ 24 
1.3 Rationale - The reasoning behind a maintenance regimen ..................................................... 25 
1.4 Pembrolizumab (Keytruda®) ................................................................................................... 26 
1.5 Paricalcitol (Zemplar®) ............................................................................................................ 29 
1.6 Trial Dose Rationale and Sequence ....................................................................................... 30 
1.6.1 Pembrolizumab Dose ...................................................................................................... 30 
1.6.2 Paricalcitol Dose ............................................................................................................. 31 
2.0 HYPOTHESIS ................................................................................................................ 32 
3.0 OBJECTIVES ................................................................................................................ 32 
3.1 Primary Objective ................................................................................................................... 32 
3.2 Secondary Objectives ............................................................................................................. 32 
3.3 Exploratory Objectives ............................................................................................................ 32 
3.4 Primary Endpoints .................................................................................................................. 33 
3.5 Secondary Endpoints ............................................................................................................. 33 
3.6 Exploratory Endpoints ............................................................................................................ 33 
4.0 METHODS ..................................................................................................................... 33 
4.1 Eligibility ................................................................................................................................. 33 
4.1.1 Inclusion Criteria ............................................................................................................. 34 
4.1.2 Exclusion Criteria ............................................................................................................ 35 
4.2 Trial Treatments ..................................................................................................................... 37 
4.2.1 Dose Selection/Modification ............................................................................................ 37 
4.2.2 Paricalcitol (Zemplar®) and Placebo ................................................................................ 38 
4.2.3 Pembrolizumab (Keytruda®) ............................................................................................ 38 
4.2.4 Dose Modification (Escalation/Titration/Other) of Pembrolizumab (Keytruda®) in cases of 
Toxicity ............................................................................................................................ 39 
4.2.5 Dose Interruption of Paricalcitol in Cases of Toxicity ....................................................... 44 
4.2.6 Timing of Dose Administration ......................................................................................... 44 
4.2.7 Trial Blinding/Masking ..................................................................................................... 45 
4.3 Randomization or Treatment Allocation .................................................................................. 45 
4.4 Stratification ............................................................................................................................ 45 
4.5 Concomitant Medications/Vaccinations (allowed & prohibited) ............................................... 45 
4.5.1 Acceptable Concomitant Medications .............................................................................. 45 
4.5.2 Prohibited Concomitant Medications ............................................................................... 46 
4.6 Rescue Medications & Supportive Care ................................................................................. 47 
4.6.1 Rescue Medication and Supportive Care Guidelines ....................................................... 47 
4.6.2 Treatment of Patients with Hypercalcemia ...................................................................... 47 
4.7 Diet/Activity/Other Considerations .......................................................................................... 47 
4.7.1 Diet ................................................................................................................................. 47 
4.7.2 Contraception .................................................................................................................. 47 
4.7.3 Use in Pregnancy ............................................................................................................ 50 
4.7.4 Use in Nursing Women ................................................................................................... 50 
4.8 Patient Withdrawal/Discontinuation Criteria ............................................................................ 50 
4.9 Patient Replacement Strategy ................................................................................................ 51 
4.10 Clinical Criteria for Early Trial Termination by the Sponsor .................................................... 51 
5.0 Trial Schedule ................................................................................................................ 52 


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6.0 TRIAL PROCEDURES .................................................................................................. 56 
6.1 Trial Procedures ..................................................................................................................... 56 
6.1.1 Administrative Procedures ............................................................................................... 56 
6.1.2 Clinical Procedures/Assessments ................................................................................... 58 
6.1.3 Laboratory Procedures/Assessments .............................................................................. 62 
6.1.4 Patient Personalized Clinical Benefit (PPCB) .................................................................. 63 
6.1.5 Quantitative Textural Analysis (QTA) ............................................................................... 63 
6.1.6 16S Gut Microbiome rRNA Analysis ................................................................................ 64 
6.1.7 Visit Requirements .......................................................................................................... 65 
6.2 Assessing and Recording Adverse Events ............................................................................. 71 
6.2.1 Definition of an Overdose for This Protocol and Reporting to the Sponsor ...................... 71 
6.2.2 Reporting of Pregnancy and Lactation to the Sponsor ..................................................... 72 
6.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck ............................ 72 
6.2.4 Evaluating Adverse Events .............................................................................................. 74 
6.2.5 Investigator Responsibility for Reporting Adverse Events ................................................ 76 
7.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ......... 77 
7.1 Packaging and Labeling Information ....................................................................................... 77 
7.2 Storage and Handling Requirements ...................................................................................... 77 
7.3 Returns and Reconciliation ..................................................................................................... 78 
8.0 STATISTICAL CONSIDERATIONS ............................................................................... 78 
8.1 Trial Design ............................................................................................................................ 78 
8.2 Sample Size Considerations ................................................................................................... 78 
8.3 Statistical Analysis Plan .......................................................................................................... 79 
8.3.1 Analysis of the Conduct of the Trial ................................................................................. 79 
8.3.2 Analysis of Patient Characteristics .................................................................................. 79 
8.3.3 Analysis of Pembrolizumab and Paricalcitol Administration ............................................. 79 
8.3.4 Analysis of Primary Endpoint - Disease progression at 6 months .................................... 79 
8.3.5 Analysis of Secondary Endpoints .................................................................................... 79 
8.3.6 Analysis of Exploratory Endpoints ................................................................................... 80 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS ....................................................... 81 
9.1 Institutional Review Board/Ethics Committee Approval ........................................................... 81 
9.2 Investigators protocol agreement ............................................................................................ 81 
9.3 Remaining Samples ............................................................................................................... 81 
9.4 Confidentiality ......................................................................................................................... 82 
9.5 Publication .............................................................................................................................. 82 
9.6 Compliance with Financial Disclosure Requirements .............................................................. 82 
9.7 Compliance with Trial Registration and Results Posting Requirements .................................. 82 
9.8 Quality Management System .................................................................................................. 82 
9.8.1 Data Monitoring Plan ....................................................................................................... 82 
9.8.2 Data Safety Monitoring .................................................................................................... 83 
9.9 Data Management .................................................................................................................. 83 
9.9.1 Case Report Forms ......................................................................................................... 83 
9.9.2 Source Documents .......................................................................................................... 84 
REFERENCES ..................................................................................................................... 85 
APPENDICES ...................................................................................................................... 87 
Appendix 1 - Pembolizumab (Keytruda®) Package Insert .................................................... 88 
Appendix 2 - Paricalcitol (Zemplar®) Package Insert ............................................................ 89 
Appendix 3 - NCI CTCAE version 4.0 ................................................................................... 90 


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Appendix 4 - ECOG Performance Status ............................................................................. 91 
Appendix 5 - Protocol Criteria for Measurement of Trial Endpoint RECIST 1.1 and iRECIST
 ............................................................................................................................. 92 
Appendix 6 - Patient Personalized Clinical Benefit APP ..................................................... 100 
Appendix 7 - Quantitative Textural Analysis ....................................................................... 105 
Appendix 8 - 16S Gut Microbiome rRNA Analysis .............................................................. 110 
Appendix 9 - Fecal Swab Sample Collection Instructions (To be included in Fecal Swab 
Collection kit) ...................................................................................................... 112 
 
 
TABLES 
Table 1.  Immune Checkpoint Inhibitors in PDA ................................................................... 25 
Table 2.  Adequate Organ Function Laboratory Values ........................................................ 34 
Table 3.  Trial Treatments .................................................................................................... 37 
Table 4. Dose Modification and Management Guidelines for Drug-Related Adverse Events 40 
Table 5. Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines ... 43 
Table 6. Highly Effective Contraceptive Methods That Have Low User Dependency........... 49 
Table 7. Screen – Treatment Period Schedule ..................................................................... 53 
Table 8. Post-Treatment Period  (EOT– Follow-Up) Schedule ............................................. 55 
Table 9. Laboratory Tests – performed locally...................................................................... 62 
Table 10. Pembrolizumab Descriptions ................................................................................ 77 


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1.0 BACKGROUND AND RATIONALE 
1.1 Overview 
Pancreatic cancer continues to be a very lethal disease.  It was estimated that in 2016, 
53,070 Americans would be diagnosed with pancreatic ductal adenocarcinoma (PDA), and 
41,780 would die from the disease.  This makes pancreatic cancer the third leading cause of 
death from cancer in the US.1   
 
Furthermore it is projected that by 2030, PDA will be the second leading cause of death from 
cancer in the US. Worldwide, PDA is the twelfth most common cancer, accounting for an 
estimate of > 300,000 deaths a year. 2 
 
Detection of pancreatic cancer has been notoriously very late in the disease and therefore 
the 5-year survival rate is only 8%. Right now, the only potential cure for pancreatic cancer is 
surgical resection (if the disease is caught early).  However only about 20% of PDA patients 
are eligible for potentially curable resection and unfortunately most (> 80%) have 
reoccurrence of their cancer within 2 years of resection, and those reoccurrences are almost 
universally fatal. 3,4 
 
But there is some hope. Recently there are regimens that actually improve survival for 
patients with advanced stage IV PDA.  Conroy and colleagues have developed the Folfirinox 
regimen, which in a large randomized trial improved survival over gemcitabine as a single 
agent.5 Von Hoff and colleagues developed the nanoparticle albumin (nab) associated 
paclitaxel plus gemcitabine regimen which improved survival over single agent gemcitabine 
again in a single randomized trial.6 Even more recently Jameson and colleagues have 
presented a combined regimen of nab-paclitaxel + gemcitabine + cisplatin in a small 24 
patient phase Ib/II trial that gave a response rate of 71% with 2 patients having complete 
response and a median survival of 16+ months.7 
 
1.2 A major developing problem in the care of patients with advanced pancreatic cancer 
With the greater chance of getting patients with advanced pancreatic cancer into remission, 
there is a new challenge - keeping the patient in partial or complete remission.  The rough 
parts of trying to keep patients in remission include: 
 
• Cumulative toxicities of the treatment regimens keeping one from continuing the 
chemotherapeutic regimen. 
 
• Patients get to a maximum amount of tumor shrinkage but that shrinkage often stops 
after a partial response is reached, e.g. we can see it is likely the patient is no longer 
benefitting from that regimen or we can see resistance developing. 
 
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There are multiple possible reasons postulated for the real inactivity of the immune-oncology 
agents (besides the fact that the patients had very advanced pancreatic cancer).  These 
include: 
 
a) The PDA microenvironment could limit efficacy because it is a very desmoplastic 
tumor (a physical barrier to therapeutics, driven by tissue resident stellate cells) which 
reduce intratumor vasculature and delivery of drugs and immune-oncology blockade 
agents. This desmoplastic reaction has been documented in both the primary 
pancreatic lesions and in metastatic sites.13  
 
b) The PDA microenvironment is an immunosuppressive cancer cell friendly 
environment with abundant tumor associated macrophages (TAMs), myeloid-derived 
suppressor cells (MDSCs) and Tregulatory cells (Tregs). This microenvironment 
excludes T effector cells which inhibits the patient’s antitumor immune response.  
Therefore the tumor microenvironment is a site of immune privilege for pancreatic 
cancer cells. 
 
A recent very remarkable finding is that vitamin D receptor (VDR) agonists will sensitize both 
primary and metastatic pancreatic cancer lesions to PD-1 blockade (in addition to, on its 
own) making the tumor microenvironment more hostile to the pancreatic cancer cell and 
more vulnerable to the patient’s own immune system.  Sherman and colleagues 
 
 noted that VDR agonists, particularly those that are synthetic and which cannot 
be degraded by up-regulated CYP24A1 in the cancer, can reduce tumor fibrosis, can permit 
drug delivery and can reduce an immunosuppressive environment.14 Very important is a pilot 
pre-op SU2C supported clinical trial of nab-paclitaxel plus gemcitabine with the addition of 
paricalcitol where there were remarkable decreases in extracellular matrix collagen, 
incredible increases in tumor vascularity, and an enhanced infiltration of CD3 cells.  This 
really set up the question as to whether or not the VDR agonist paricalcitol could improve the 
activity of an immune checkpoint inhibitor - pembrolizumab. 
 
However we need to have a clinical situation which gives the optimal opportunity for an 
immune checkpoint inhibitor with or without paricalcitol to work for patients and we think 
examining the agent in a randomized fashion in a maintenance design is the way to do just 
that. 
 
1.4 Pembrolizumab (Keytruda®) 
Refer to the Pembrolizumab Investigator Brochure for complete information on preclinical 
and clinical data and Appendix 1 – Package Insert for Pembrolizumab for complete safety 
and dosing information. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  Keytruda® (pembrolizumab) has been approved in the United 
Stated for the treatment of patients with: 
 
• Unresectable or metastatic melanoma 


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• As adjuvant treatment of patients with melanoma with involvement of lymph node(s) 
following complete resection 
 
• In combination with pemetrexed and platinum chemotherapy, as first-line treatment of 
patients with metastatic non-squamous NSCLC, with no EGFR or anaplastic 
lymphoma kinase (ALK) genomic tumor aberrations 
 
• In combination with carboplatin and either paclitaxel or paclitaxel protein-bound, as 
first-line treatment of patients with metastatic squamous NSCLC 
 
• As a single agent for the first-line treatment of patients with Stage III NSCLC, who are 
not candidates for surgical resection or definitive chemoradiation, or metastatic 
NSCLC, and whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-
approved test, with no EGFR or ALK genomic tumor aberrations. 
 
• As a single agent for the treatment of patients with metastatic NSCLC whose tumors 
express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease 
progression on or after platinum-containing chemotherapy. Patients with EGFR or 
ALK genomic tumor aberrations should have disease progression on FDA-approved 
therapy for these aberrations prior to receiving KEYTRUDA®.  
 
• Recurrent or metastatic HNSCC with disease progression on or after platinum-
containing chemotherapy. 
 
• Adult and pediatric patients with refractory classical Hodgkin’s Lymphoma (cHL) or 
who have relapsed after 3 or more prior lines of therapy. 
 
• Adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma 
(PMBCL), or who have relapsed after 2 or more prior lines of therapy 
 
• Adult and pediatric patients with unresectable or metastatic, microsatellite instability-
high (MSI-H) or mismatch repair deficient  
 
o solid tumors that have progressed following prior treatment and who have no 
satisfactory alternative treatment options, or 
 
o colorectal 
cancer 
that 
has 
progressed 
following 
treatment 
with 
a 
fluoropyrimidine, oxaliplatin, and irinotecan. 
 
• Patients with locally advanced or metastatic urothelial carcinoma (UC) who are not 
eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 
(combined positive score (CPS) ≥10) as determined by an FDA-approved test, or in 
patients who are not eligible for any platinum containing chemotherapy regardless of 
PD-L1 status. 
 
• Patients with locally advanced or metastatic UC who have disease progression during 
or following platinum-containing chemotherapy or within 12 months of neoadjuvant or 
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• Patients with recurrent locally advanced or metastatic gastric or gastroesophageal 
junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as 
determined by an FDA-approved test, with disease progression on or after two or 
more prior lines of therapy including fluoropyrimidine- and platinum-containing 
chemotherapy and if appropriate, HER2/neu-targeted therapy. 
 
• Patients with recurrent or metastatic cervical cancer with disease progression on or 
after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an 
FDA-approved test. 
 
• Patients with hepatocellular carcinoma (HCC) who have been previously treated with 
sorafenib. 
 
• Adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell 
carcinoma (MCC). 
 
• In combination with axitinib, for the first-line treatment of patients with advanced renal 
cell carcinoma (RCC). 
 
The most common side effects of treatment with pembrolizumab include decreased appetite, 
fatigue, pruritis, rash, diarrhea, nausea, vomiting, constipation, dyspnea, cough, pyrexia, 
arthralgia, asthenia, headache, back pain, anemia, and peripheral edema.  
 
Most frequently reported serious adverse events related to pembrolizumab include immune-
mediated pneumonitis, colitis, diarrhea, pyrexia, autoimmune hepatitis, pneumonia, adrenal 
insufficiency, hyponatremia, dyspnea, hyperthyroidism, and nausea.  
 
Less common risks associated with treatment with pembrolizumab are as follows: 
 
• Symptoms of pneumonitis e.g. shortness of breath, chest pain, new or worsened 
cough. 
 
• Symptoms of colitis e.g. diarrhea, abnormal stool, severe abdominal pain. 
 
• Symptoms of hepatitis e.g. jaundice, nausea, vomiting, appetite loss, right abdominal 
pain, more frequent bleeding or bruising, dark urine. 
 
• Symptoms of endocrinopathies, including hypophysitis (including hypopituitarism and 
secondary adrenal insufficiency), thyroid disorders (hypo or hyperthyroidism and 
thyroiditis), Type 1 diabetes mellitus, rapid heart rate, change in weight, increased 
sweating, hunger and/or thirst, frequent urination, hair loss, feeling cold, constipation, 
deeper voice, muscle aches, unusual and persistent headache, dizziness or fainting. 
 
• Symptoms of nephritis or kidney failure e.g. change in amount or color or urine. 
 
• Symptoms 
of 
Guillain-Barre 
syndrome, 
pancreatitis, 
myasthenic 
syndrome, 
encephalitis, uveitis, sarcoidosis, and myocarditis (some fatal). 


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• Symptoms of solid organ transplant rejection, and graft versus host disease (GvHD) in 
patients who had an allogeneic stem cell transplant after treatment with 
pembrolizumab. 
 
• Symptoms of other organ issues e.g. rash, changes in eyesight, severe or persistent 
muscle or joint pain, severe muscle weakness, myositis, severe skin reactions, and 
anemia.  Rarely, severe skin reactions have included cases of Stevens-Johnson 
syndrome (SJS) and toxic epidermal necrolysis (TEN) some with fatal outcome.   
 
• Symptoms of infusion reactions which may be life-threatening e.g. chills, shaking, 
shortness of breath, wheezing, itching, rash, flushing, dizziness, fever or feelings of 
passing out. 
 
Patients with the following may be at particular risk: 
 
• Immune system disorders e.g. Crohn’s, ulcerative colitis, lupus. 
 
• Organ transplant – solid organ transplant rejection in donor recipients has been 
reported.  Consider the benefit of treatment with pembrolizumab versus the risk of 
possible organ rejection in the patients. 
 
• Lung or breathing conditions e.g. interstitial lung disease. 
 
• Liver problems e.g. hepatitis. 
 
The effects of pembrolizumab on unborn fetus and possible transmission through breast milk 
have not been established. Patients on pembrolizumab should not become pregnant or 
breast-feed. It is recommended that patients should use adequate birth control and abstain 
from breast-feeding until at least 4 months after dosing with this product. 
 
1.5 Paricalcitol (Zemplar®) 
Refer to Appendix 2- Package Insert for Paricalcitol for complete information. 
 
Paricalcitol is a vitamin D analog used for the prevention and treatment of secondary 
hyperparathyroidism. Excessive amounts of vitamin D compounds including paricalcitol can 
cause over suppression of the parathyroid hormone, hypercalcemia, hypercalciuria, 
hyperphosphatemia and adynamic bone disease.  
 
Paricalcitol should not be given to patients with evidence of vitamin D toxicity, 
hypercalcemia, or hypersensitivity to any ingredient in this product. 
 
The most common side effects of treatment with paricalcitol are diarrhea, nasopharyngitis, 
dizziness, vomiting, hypertension, hypersensitivity, nausea and edema. 
 
Taste perversion, such as metallic taste, and allergic reactions, such as rash, urticaria and 
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Risks associated with treatment with paricalcitol include: Symptoms of elevated calcium 
levels e.g. feeling tired, difficulty in thinking clearly, loss of appetite, nausea, vomiting, 
constipation, increased thirst, increased urination and weight loss. Prescription based doses 
of vitamin D should be withheld during treatment with paricalcitol. 
 
The effects of paricalcitol on unborn fetus and possible transmission through breast milk 
have not been fully established. Patients on paricalcitol should avoid pregnancy and should 
not breast feed. 
 
1.6 Trial Dose Rationale and Sequence 
1.6.1 Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based 
on the totality of data generated in the Keytruda® development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by: 
 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 
 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were 
enrolled with melanoma and non-small cell lung cancer (NSCLC), covering different disease 
settings (treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different 
treatment settings (monotherapy and in combination with chemotherapy).  Five studies 
compared 2 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, 
KN002, KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B3, KN001 Cohort F2 and KN006).  All of these studies demonstrated flat 
dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5 fold difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W 
provided similar responses to the highest doses studied.  Subsequently, flat dose-exposure-
response relationships were also observed in other tumor types including head and neck 
cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type.  These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
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Q3W.  Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression.  This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor. 
 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap in 
the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols. 
 
1.6.2 Paricalcitol Dose 
The dose for paricalcitol is 25 mcg IV (or equivalent volume for placebo) three times per 
week given on days 1, 3, 5, 8, 10, 12, 15, 17, 19 (+/-1 day allowed for dosing per 21 day 
cycle) and prior to pembrolizumab. This dosing schedule has been evaluated in a pilot SU2C 
protocol (in 24 patients) in which patients were administered 25 mcg of paricalcitol 
intravenously weekly X 3 (with nab-paclitaxel + gemcitabine) the paricalcitol was well 
tolerated, with only report of a renal calculus in one elderly patient .17 
 
 
 


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2.0 HYPOTHESIS 
The combination regimen of paricalcitol plus pembrolizumab can give benefit for 
maintenance of remission for patients with advanced pancreatic cancer (over 
pembrolizumab alone). 
3.0 OBJECTIVES 
3.1 Primary Objective 
To estimate the percentage of patients with radiographic disease progression according to 
RECIST1.1 at 6 months when maintained on a combination regimen of paricalcitol plus 
pembrolizumab versus pembrolizumab alone. 
 
3.2 Secondary Objectives 
1. Evaluate the toxicity of the combination of paricalcitol plus pembrolizumab versus 
pembrolizumab alone. 
 
2. Evaluate the difference in overall survival (OS) in patients administered the 
combination of paricalcitol plus pembrolizumab versus pembrolizumab alone. 
 
3. Define the impact of the combination of paricalcitol and pembrolizumab on tumor 
mutational landscape and transcriptional programs. 
 
4. Identify cellular VDR targets in the immune microenvironment with PD1 blockade. 
 
3.3 Exploratory Objectives 
1. Evaluate the difference in disease progression according to RECIST 1.1 vs 
iRECIST (Appendix 5) criteria. 
 
2. Assess the utility of a Patient Personalized Clinical Benefit (PPCB) phone based 
application.    
 
3. Assess the association between improvement in symptoms as recorded by the 
Patient Personalized Clinical Benefit (PPCB) with progression at 6 months by 
RECIST 1.1. 
 
4. To assess any changes in tumor and/or tissue texture on imaging in both arms of 
the trial. 
 
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3.4 Primary Endpoints 
The percent of patients with radiographic disease progression according to RECIST 1.1 at 6 
months. 
 
3.5 Secondary Endpoints 
• Incidence of toxicities 
 
• Overall survival 
 
• Mutational landscapes 
 
• Transcriptional programs 
 
• Cellular (immunity) VDR targets in the immune microenvironment 
 
3.6 Exploratory Endpoints 
• Difference in disease progression according to RECIST 1.1 and iRECIST  
(Appendix 5) criteria 
 
• Compliance rate responding to a phone - based application for the assessment of 
patient defined symptoms  
 
• Improvement in symptoms as recorded by the Patient Personalized Clinical 
Benefit (PPCB)  
 
• Differences in tumor and/or tissue texture on CT scan 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  
 
4.0 METHODS  
4.1 Eligibility 
Twenty-four eligible patients will be recruited from up to 7 centers. Patients with stage IV 
pancreatic cancer who had been placed in best possible response with first line 
chemotherapy for their advanced metastatic disease as defined by at least stable disease 
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on scan.  The best response on prior therapy will need to be evaluated and documented by 
treating investigator at time of determining eligibility for this trial. 
 
4.1.1 Inclusion Criteria 
Patients must meet the following criteria in order to be eligible for participation in the trial: 
 
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 below in Table 2. AND serum 
corrected calcium value must be ≤ Institutional ULN and ≥ 8.0mg/dL, and phosphorus 
levels must be ≤ Institutional ULN  and ≥ 2.5 mg/dL. 
 
Table 2.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
  
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
  
Creatinine OR 
Measured or calculatedb creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
  
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
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AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
  
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use 
of anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell 
(pRBC) transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory 
value requirements should be adapted according to local regulations and guidelines for the 
administration of specific chemotherapies. 
 
 
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 (see Section 4.7.2 
not breastfeeding, and at least one of the following conditions applies:  
 
a.) Not a woman of childbearing potential (WOCBP) as defined in Section 4.7.2.  
 
OR 
 
b.) A WOCBP who agrees to follow the contraceptive guidance in Section 4.7.2 
during the treatment period and for at least 180 days after the last dose of trial 
treatment.  
 
9. Male participants must agree to use contraception as detailed in Section 4.7.2 of this 
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. 
 
 
4.1.2 Exclusion Criteria 
 
Patients meeting the following criteria will NOT be eligible to participate in this trial:  
 
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. 
 
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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 Cycle 1/ Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
 
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. 
 


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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 inhibitor 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 (Cycle 1 
/Day 1). 
 
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. 
4.2 Trial Treatments 
The treatments to be used in this trial are outlined below in Table 3. 
 
Table 3.  Trial Treatments 
Drug 
Dose/ 
Potency 
Dose 
Frequency Route 
Regimen/ 
Treatment Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion Day 1 of each 3 
week cycle 
Experimental 
Paricalcitol (or 
placebo) 
25 mcg 
3 X Week 
IV 
3 times per week 
(Day 1*,3 ,5, 8 10, 
12, 15, 17 and 19 
(+/-1 day) per 21 
day cycle 
Experimental 
* paricalcitol will be injected >30 mins prior to the pembrolizumab infusion  
 
4.2.1 Dose Selection/Modification 
The rationale for selection of doses to be used in this trial is provided in Section 1.  
 
On Day 1 of each three - week cycle, patients will receive 25 mcg of paricalcitol or placebo 
intravenously followed ≥ 30 minutes later by 200 mg of pembrolizumab infused over 30 


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minutes.  Patients will then receive 25 mcg of paricalcitol or placebo intravenously on days  
3, 5, 8, 10, 12, 15, 17, 19 (± 1 day) of each 21 day cycle. 
 
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. 
 
4.2.2 Paricalcitol (Zemplar®) and Placebo 
Dosage Form: Paricalcitol is available as a sterile, clear, colorless aqueous solution for 
injection, in concentrations of 2mcg/mL and 5mcg/mL.   Each site will be using their local 
pharmacy supply of paricalcitol and will use the necessary volume for the given 
concentration and per the product labeling instructions (Appendix 2) to administer a total 
dose of 25mcg.  Patients will receive either paricalcitol or the equivalent volume of placebo 
(saline solution) intravenously at each dosing point.  
 
The doses will be prepared in an aseptic manner and documented by the unblinded 
Pharmacist just prior to dosing. Documentation relating to this preparation will be available 
for independent monitoring and verification.  
 
Further details of preparation are provided in the Pharmacy manual. 
 
There must be ≥ 30 minutes in between the completion of the paricalcitol injection and 
the start of the pembrolizumab infusion. 
 
Note: The same IV line may be used to administer both the paricalcitol and the 
pembrolizumab.  However there must be at least 30 minutes in between the completion of 
the paricalcitol injection and the start of the pembrolizumab infusion.  Sites should use 
normal saline to keep line open for this period in between paricalcitol injection and 
subsequent pembrolizumab infusion. 
 
 
 
4.2.3 Pembrolizumab (Keytruda®) 
Dosage Form: Pembrolizumab Solution for Infusion, 100 mg/ 4 mL vial to be stored under 
refrigerated conditions (2 – 8 °C (36 °F to 46 °F)) and protected from light in the original 
container and outer box. 
 
Pembrolizumab Solution for Infusion is a sterile, non-pyrogenic aqueous solution supplied in 
single-use Type I glass vial containing 100 mg/4 mL of pembrolizumab. The product is 
preservative-free solution which is essentially free of extraneous particulates. 
 
Preparation and Storage for Intravenous Infusion: 
 
Specific instructions on the aseptic technique used to prepare the intravenous solution will 
be provided in a Pharmacy manual.  
 
In summary the process will involve: 
 


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• Two vials of pembrolizumab solution will be used for each infusion. Each vial is 
100mg/4 mL. 
 
• Infusion solutions will be prepared in 0.9% Sodium Chloride Injection, USP (normal 
saline). Pembrolizumab SHOULD NOT BE MIXED WITH OTHER DILUENTS. 
 
• The diluted solution will be mixed by gentle inversion, should not contain visible 
particulate matter or discoloration and should not be frozen. 
 
• When removed from refrigeration the vials of solution and/or the prepared infusion 
may be stored at room temperature for a cumulative total of 6 hours only. This time 
includes the time of the infusion. 
 
• The prepared infusion IV bags may be stored under refrigeration at 2 °C to 8 °C (36 
°F to 46 °F) for up to 24 hours. If refrigerated, allow the IV bags to come to room 
temperature prior to use and the infusion should be completed within 6 hours. 
 
• Specific materials for infusion bags and infusion sets are approved for administration 
of pembrolizumab. A list of approved materials is provided in the Pharmacy manual. 
 
• There must be 30 minutes in between the completion of the paricalcitol 
injection and the start of the pembrolizumab infusion. 
 
• The solution is slowly infused over a period of 30 minutes through an approved IV line 
with no other drugs co-administered through the same line.  
 
The infusions will be prepared and documented by the unblinded pharmacist just prior to 
dosing. Documentation relating to this preparation will be available for independent 
monitoring and verification. 
 
4.2.4 Dose Modification (Escalation/Titration/Other) of Pembrolizumab (Keytruda®) in cases 
of Toxicity 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 4. 
 
 




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AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5-1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
• Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable 
Grade 3 or 4 
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
  
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemi
a associated 
with evidence 
of β-cell 
failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
• Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
  
• Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated.  
 
• Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1 
Hyperthyroidism 
Grade 2 
Continue 
• Treat with non-
selective beta-
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate 
• Monitor for signs and symptoms 
of thyroid disorders. 
 
Grade 3 or 4 
Withhold 
or 
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue 
• Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyronine) per 
standard of care 
• Monitor for signs and symptoms 
of thyroid disorders. 
 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(prednisone 
1-2 mg/kg or 
equivalent) 
followed by 
taper. 
• Monitor changes of renal 
function. 
 
Grade 3 or 4 
Permanently 
discontinue 


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Myocarditis 
Grade 1 or 2 
 
Withhold 
• Based on 
severity of AE 
administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Grade 3 or 4 
 
Permanently 
discontinue 
All Other irAEs 
Intolerable/ 
persistent 
Grade 2 
Withhold 
• Based on 
severity of AE 
administer 
corticosteroids 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
 
Grade 3 
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Guillain-Barré 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue 
1.Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
 
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 5. Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines 
NCI CTCAE Grade 
 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (eg, from 100 mL/hr to 
50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment 
Participant may be 
premedicated 1.5 h 
(±30 minutes) prior to infusion 
of pembrolizumab with: 
• 
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine). 
• 
Acetaminophen 
500-1000 mg PO (or 
equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include 
but is not limited to: 
• 
Epinephrine** 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDs 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
 


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4.2.4.1 Other allowed dose interruption for pembrolizumab 
 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record.  
 
4.2.5 Dose Interruption of Paricalcitol in Cases of Toxicity 
In the event there is an AE that is attributable to paricalcitol, the paricalcitol would be held 
until the AE resolves. The management of patients with clinically significant hypercalcemia 
should follow guidelines as detailed in Section 4.6.2 
 
4.2.6 Timing of Dose Administration 
Trial treatment with paricalcitol followed by pembrolizumab should be administered on Day 1 
of each cycle after all procedures/assessments have been completed as detailed on the Trial 
Schedule (Section 5).  Following the initial dose (cycle1 day1), pembrolizumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
Paricalcitol 25mcg IV (or equivalent volume for placebo) will be administered intravenously 
three times per week given on day 1 prior to pembrolizumab, and on days 3, 5, 8, 10, 12, 15, 
17, and 19 (+/-1 day allowed for dosing per 21 day cycle). Site should make every effort to 
standardize the time and day of administration of paricalcitol. 
 
There must be at least 30 minutes in between the completion of the paricalcitol injection and 
the start of the pembrolizumab infusion. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks on 
C1/Day1 of each 21 week cycle.  Sites should make every effort to target infusion timing to 
be as close to 30 minutes as possible.  However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes: -5 min/+10 min). 
 
Note: The same IV line may be used to administer both the paricalcitol and the 
pembrolizumab.   However there must be at least 30 minutes in between the completion of 
the paricalcitol injection and the start of the pembrolizumab infusion. 
 
The Pharmacy Manual contains specific instructions for the preparation and administration of 
the pembrolizumab infusion fluid and paricalcitol IV doses. 
 


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4.2.7 Trial Blinding/Masking 
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.  Only the site pharmacist 
and unblinded monitor will be aware of the assigned treatment arm. 
 
4.3 Randomization or Treatment Allocation 
Randomization will be in a 1:1 ratio to pembrolizumab + paricalcitol or pembrolizumab + 
placebo.  Randomization will be performed by the trial biostatistician or designee using a 
computer-generated algorithm with a block size of 4.  The RAND function in MySQL is used 
to generate a random number, with a value based on the computer clock used as seed.  The 
program randomly assigns participants to one of the two treatments with the pre-selected 
block size.  After study initiation, the randomization sequence will be provided to the 
unblinded central monitor.  After consent and confirmation of eligibility, the site study 
coordinator will notify the site pharmacist and the unblinded monitor.  The unblinded monitor 
will provide the next randomized treatment from the sequence to the site pharmacist.  The 
unblinded monitor also will notify the trial biostatistician.  The trial biostatistician or designee 
will be available to assist with identifying the next randomized treatment if the unblinded 
central monitor is not available. 
 
4.4 Stratification 
No stratification will be performed. 
 
4.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial treatment or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Sponsor. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient's primary physician.  
 
4.5.1 Acceptable Concomitant Medications 
All concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), multivitamins, nutritional and/or herbal supplements, 
and IV medications and fluids.  If changes occur during the trial period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF. 
 
All concomitant medications received within 30 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
reported for SAEs and ECIs as defined in Section 6.2. 
 


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4.5.2 Prohibited Concomitant Medications 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial.  For specific therapies there is a washout window prior to 
cycle1/day1, indicated below and per eligibility criteria in Section 4.1. 
 
• Antineoplastic systemic chemotherapy or biological therapy.  Prior anti-cancer 
monoclonal antibody (mAb) must be > 4 weeks prior to Cycle 1/Day 1. 
 
• Immunotherapy  
 
• Chemotherapy targeted small molecule therapy, or radiation therapy within 2 weeks 
prior to Cycle 1/Day 1. 
 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
 
• Investigational agents within 4 weeks prior to Cycle 1/Day 1 
 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 
• Systemic glucocorticoids in doses of ≥ 10 mg/day prednisone or equivalent for any 
purpose other than to modulate symptoms from an event of clinical interest of 
suspected immunologic etiology. The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor.  
 
• Strong inhibitors of CYP3A, digitalis or its compounds, aluminum containing 
preparations should not be used during the trial due to their potential to interact with 
paricalcitol. 
 
• Phosphate or vitamin-D related compounds should not be taken concomitantly with 
paricalcitol.  Patients will be asked to report vitamin and nutritional supplement use at 
baseline and throughout the trial.   
 
Patients who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Patients may receive other medications (not listed here as prohibited) that the investigator 
deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
 
There are no prohibited therapies during the Post-Treatment Survival Follow-up Phase of the 
trial. 
 


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4.6 Rescue Medications & Supportive Care 
4.6.1 Rescue Medication and Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by 
the treating investigator.  Suggested supportive care measures for the management of AEs 
with potential immunologic etiology are outlined along with the dose modification guidelines 
in Section 4.2.4, Table 4.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  
For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care.  The 
treatment guidelines are intended to be applied when the investigator determines the events 
to be related to pembrolizumab.  
 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance.  Refer to Table 4 in Section 
4.2.4 for guidelines regarding dose modification and supportive care.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event.  
 
For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines the events 
to be related to pembrolizumab.  
 
4.6.2 Treatment of Patients with Hypercalcemia 
Treatment of patients with clinically significant hypercalcemia consists of immediate dose 
interruption of paricalcitol therapy and includes a low calcium diet, withdrawal of calcium 
supplements, patient mobilization, attention to fluid and electrolyte imbalances, assessment 
of electrocardiographic abnormalities (critical in patients receiving digitalis), and 
hemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted. Serum 
calcium levels should be monitored frequently until normal calcemia ensues. 
 
4.7 Diet/Activity/Other Considerations 
4.7.1 Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
4.7.2 Contraception 
Pembrolizumab or paricalcitol may have adverse effects on a fetus in utero.  Furthermore, it 
is not known if pembrolizumab has transient adverse effects on the composition of sperm.   
 


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Woman of Childbearing Potential (WOCBP) 
 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
 
Women in the following categories are not considered WOCBP: 
 
• Premenarchal 
 
• Premenopausal female with 1 of the following: 
 
o Documented hysterectomy 
 
o Documented bilateral salpingectomy 
 
o Documented bilateral oophorectomy 
 
Note:  Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history 
interview. 
 
• Postmenopausal female 
 
o A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause. 
 
 A high follicle stimulating hormone (FSH) level in the 
postmenopausal 
range 
may 
be 
used 
to 
confirm 
a 
postmenopausal 
state 
in 
women 
not 
using 
hormonal 
contraception or hormonal replacement therapy (HRT). However, 
in the absence of 12 months of amenorrhea, confirmation with 
two FSH measurements in the postmenopausal range is 
required. 
 
o Females on HRT and whose menopausal status is in doubt will be 
required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment. 
 
Contraception Requirements 
 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol - defined timeframe in section 5.0: 


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• Be abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 
 
• Use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 6 when having penile-vaginal 
intercourse with a woman of childbearing potential who is not currently 
pregnant. 
 
o Note: Men with a pregnant or breastfeeding partner must agree to 
remain abstinent from penile vaginal intercourse or use a male condom 
during each episode of penile penetration. 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 6 during the protocol-defined time frame in Section 5.0.  
 
Table 6. Highly Effective Contraceptive Methods That Have Low User Dependency 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
• 
Progestogen- only contraceptive implant a, b 
• 
Intrauterine hormone-releasing system (IUS) b 
• 
Intrauterine device (IUD) 
• 
Bilateral tubal occlusion 
 
• 
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be 
used. 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit 
ovulation. 
 


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b) If hormonal contraception efficacy is potentially decreased due to interaction with 
study treatment, condoms must be used in addition to the hormonal 
contraception during the treatment period and for at least 6 months  after the last 
dose of study treatment.  
 
Pregnancy Testing 
WOCBP should only be included after a negative serum pregnancy test and in accordance 
with local requirements.  When applicable this test should be repeated a maximum of 24-
hours before the first dose of trial treatment. 
 
Following initiation of treatment additional pregnancy testing will be performed prior to day 1 
of each cycle during the treatment period and at 30 days after the last dose of study 
treatment and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 
4.7.3 Use in Pregnancy 
If a patient inadvertently becomes pregnant while on trial treatment, the patient will 
immediately be removed from the trial.  The site will contact the patient at least monthly and 
document the patient’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor without delay and within 24 hours. 
The Sponsor will report to Merck within 24 hours (working days) if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).   
 
The trial investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male patient 
impregnates his female partner, the trial personnel at the site must be informed immediately 
and the pregnancy reported to the Sponsor.  The Sponsor will report to Merck and follow the 
pregnancy as described above and in Section 6.2.2. 
 
4.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab or paricalcitol is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, patients who are breast-feeding are not eligible for enrollment. 
 
4.8 Patient Withdrawal/Discontinuation Criteria 
Patients may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a patient may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding assessments to be done at an End of Treatment (EOT) visit at time of 
discontinuation or withdrawal are provided in Section 6.1.7.3. 
 


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A patient must be discontinued from the trial for any of the following reasons: 
 
• The patient or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 
• Confirmed disease progression 
 
• Unacceptable adverse experiences as described in Section 4.2.4 
 
• Inter-current illness that prevents further administration of treatment 
 
• Investigator’s decision to withdraw the patient 
 
• The patient has a confirmed positive serum pregnancy test 
 
• Noncompliance with trial treatment or procedure requirements 
 
• The patient is lost to follow-up 
 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 cycles of 
trial treatment whichever is later. 24 months of trial medication is calculated from the 
date of first dose.  
 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 5 (Trial Schedule) 
and Section 6.1.7 (Visit Requirements).  After the end of treatment, each patient will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 6.2.3.1).  Patients who 
discontinue for reasons other than progressive disease will have post-treatment follow-up  
every 90 days for disease status until disease progression, initiating a non-study cancer 
treatment, withdrawing consent or becoming lost to follow-up, or the end of the trial, 
whichever occurs first. 
 
4.9 Patient Replacement Strategy  
Patients who are randomized to the trial but who then do not go on to initiate trial treatment, 
for any reason, will be replaced.  The reason for not initiating treatment will be documented 
by the investigator.  Patients who initiate trial treatment and discontinue from the trial for any 
reason will not be replaced. Patients who discontinue treatment without progression will be 
followed to determine their disease status every 90 days by phone until the trial ends. 
 
4.10 Clinical Criteria for Early Trial Termination by the Sponsor 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete 


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2. Poor adherence to protocol and regulatory requirements 
 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to patients 
 
4. Plans to modify or discontinue the development of the trial treatment 
 
In the event of Merck’s decision to no longer supply pembrolizumab, ample notification will 
be provided so that appropriate adjustments to patient treatment can be made. 
 
 
5.0 Trial Schedule 
The trial will consist of the following three periods:   
 
Screening (SCN) Period: The screening period will take place only after informed consent 
is obtained and within the 21 days prior to C1/D1.  The screening visit may be counted as 
the baseline visit if completed within 7 days of initial dosing on C1/D1.  
 
Treatment Period: Patients will be treated at 21 ± 3 day intervals.  Patient must begin cycle 
1 within 21 days of signing the IRB approved informed consent document and after the 
screening assessments have been performed and reports have been reviewed to confirm 
eligibility. The patient will continue on maintenance therapy until there is evidence of clear-
cut tumor progression, has treatment ending toxicities, or withdraws from treatment (refer to 
section 4.8).  Table 7 below summarizes the Screen-Treatment Period Schedule.  
 
Post Treatment Period: Patients will return to the investigative site for an End of Treatment 
(EOT) visit within 5 days after the last dose of trial treatment or before the initiation of a new 
anti-cancer treatment, whichever comes first (refer to Section 6.1.7.3).  An additional  
mandatory Safety Follow- up visit should be conducted approximately 30 days after the last 
dose of trial treatment and before initiation of a new anti-cancer treatment, whichever comes 
first (6.1.7.4).  WOCBP will be required to have a pregnancy test at this visit.  
 
After the 30 day-FU visit, patients will then move into the Survival Phase and be contacted 
by telephone every 90 days thereafter until death, withdrawal of consent, or the end of the 
trial, whichever occurs first.  The protocol approved contraceptive guidance (Section 4.7.2) 
must be followed for at least 120 days (for males) and 180 days (for WOCBP) after the last 
dose of trial treatment. Table 8 below summarizes the Post Treatment Period Schedule.  




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Footnotes for Table 7. Screen – Trial Treatment Period Schedule 
 
a. Written IRB-approved informed consent must be obtained prior to any screening assessments being performed. 
 
b. Documented medical history to include, demographics, concurrent baseline conditions (using NCI-CTCAE V4. Appendix 3), prior cancer 
treatment and surgeries.  
 
c. For the time that the consent form is signed until treatment allocation/randomization, any events of clinical interest (ECI, refer to 6.2.3.2), 
serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study 
(reference Section 6.2.3.3 for additional details) that occurs to any patient must be reported within 24 hours to the Sponsor.  AEs will continue to 
be assessed and reported throughout the trial treatment period, for 30 days following the EOT and again at 90 days for serious adverse events 
(refer to Section 6.2 for complete details). 
 
d. Complete physical exam at screening including height and weight, directed physical exam with weight for day 1, 8, 15 of each cycle and at the 
EOT. 
 
e. Vital signs to include: Blood pressure, pulse, respiratory rate, and temperature. 
 
f. ECOG Performance Status must be 0 or 1 to be eligible for entry to the trial. 
 
g. Negative serum pregnancy test is required for women of child-bearing potential (WOCBP) within 24 hours of start of trial medication. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when pregnancy is otherwise suspected. Participants 
must agree to use a contraception as detailed in Section 4.7.2  
 
h. Refer to Table 9 for details of required labs to be included.  Adequate organ function must be demonstrated in accordance with protocol criteria 
within 10 days of start of trial medication as defined in Table 2. 
 
i. TSH, T3, Free T4, and PTH (not required at C1/Day 1 if completed at SCN within 21 days). Results must be reviewed prior to treatment 
initiation. Repeated every other cycle throughout treatment period (i.e. prior to Cycle 3, 5, 7, etc.). 
 
j. CT/MRI scan to document disease status at baseline to include chest abdomen and pelvis and other regions as clinically indicated.  Brain scan 
is required to rule out brain metastases if clinically indicated. The same radiographic procedures used to document disease status at baseline 
must be used throughout the trial. If a CT scan was taken within 28 days prior to first dose, a new scan is not necessary. However, if a new scan 
is to be done, it should be performed within 10 ± 2 days prior to starting trial medication. Tumor assessments will be conducted using CT or MRI, 
approximately every 9 ± 1 weeks until trial discontinuation or disease progression, whichever is later. All sites of disease must be followed using 
the same baseline assessment method.  The investigator will complete tumor measurements and response evaluation per  RECIST 1,1 and 
iRECIST.  The central radiologist will also perform an independent read of each scan.  (Refer to section 6.1.2.6) 
 
k. CA19-9 (or CEA or CA-125 if not expressers of CA19-9) assessments will be taken at baseline and approximately every 21 days during the trial 
treatment period. All CA19-9 assessments must be assayed by the same laboratory for each patient. The Investigator is encouraged to obtain 
radiological assessments and CA19-9 values earlier if there is a strong clinical suspicion of disease progression, in order to confirm or refute the 
clinical impression. 
 
l. Site will provide to patient the Fecal Swab sample collection kits and instructions to collect two samples at home per each treatment cycle as 
follows:  Pre-Dose Sample 1. within 72 hours prior to scheduled Day 1 of each treatment cycle and Post Dose Sample 2. between 24 - 72 hours 
after Day 1 study treatment.  Refer to Section 6.1.6 for complete details. 
 
m. Patient will return Fecal samples to clinic during scheduled apt, must be within 72 hours of fecal sample collection. 
 
n. Required only if not performed within the 3 months prior to informed consent. 
 
o. Screening clinical evaluations and laboratory assessments may be used as the Cycle 1/ Day 1 evaluations if they are completed within 7 days 
prior to trial treatment administration. 
 
p. All patients are required to provide archival tumor specimen from either a primary or metastatic site .  (Refer to 4.1.1 and 6.1.2.8) 
 
q. For only those patients that consent to the optional tissue collection.  (Refer to 6.1.2.8). 
 
r. For only those patients consenting to the optional tumor biopsy, a baseline tumor biopsy will be collected and used for profiling. If possible 
(patient condition permitting) this will be repeated after 9 ± 1 weeks on trial treatment, or at the time of disease progression. (Refer to 6.1.2.8). 
 
 


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Table 8. Post-Treatment Period  (EOT– Follow-Up) Schedule 
Post-Treatment Period 
EOT 
30 days 
from 
EOT 
 Every 90 days post 
EOT 
Scheduling Window (Days) 
At time 
of 
disconti
nuation   
(within 5 
days of 
last 
dose) 
30 ± 5 
days 
from 
EOT 
90 ± 5 days from EOT 
then every 90 ± 15 
days i 
Post-trial anticancer treatment status 
X 
X 
X 
Disease/Survival Status a 
X 
X 
X 
Concomitant Medication Review 
X  
X 
X  
Assess & Report Adverse Events b 
X 
X 
X 
Directed Physical Examination  
X 
 
 
Patient Personalized Clinical Benefit App 
X 
 
 
Vital Signs and Weight c 
X 
 
 
ECG 
X 
 
 
ECOG (see appendix 4) 
X 
 
 
Serumβ HCG Pregnancy Test for WOCBP  
X 
X 
 
CBC with Differential 
X 
 
 
Comprehensive Serum Chemistry Panel 
X 
 
 
Urinalysis 
X 
 
 
T3, FT4 and TSH 
X 
 
 
Tumor Imaging d 
X 
 
 
CA19-9 e 
X 
 
 
Central Lab Samples (Blood and Fecal 
Swabf) 
X 
Xf 
 
Review contraception use as required by 
protocol Section 4.7.2 (where applicable) g 
X 
X 
X 
Optional -Tumor Tissue Collection 
[Tumor tissue collection for those that consent to this optional 
collection and undergo a routine care biopsy 
of their tumor during their participation in the study] j 
Contact Information Review h 
X 
X 
X 
Footnotes for Table 8. Post –Treatment Period 
a. Post-treatment follow-up for disease status until documented disease progression, initiating a non-trial cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression each pt will be followed by 
telephone for survival status. 
b. Assess and record any new or ongoing AEs at time of EOT. Following the EOT, each patient will be followed for 30 days, 
for adverse event monitoring.  Serious adverse events and Events of Clinical Interest (ECI) will be collected for 90 days after 
the end of treatment as described in Section 6.2.3.1. 
c. Vital signs to include: Blood pressure, pulse, respiratory rate, and temperature. 
d. Tumor assessments will be conducted using CT or MRI at trial discontinuation or disease progression, whichever is later.  
All sites of disease must be followed using the same baseline assessment method.  
e. CA19-9 assessments will be taken at baseline and approximately every 3 weeks during the trial treatment period and at 
the end of treatment visit. All CA19-9 assessments are to be assayed by the same laboratory for each patient. The 
Investigator is encouraged to obtain radiological assessments and CA19-9 values earlier if there is a strong clinical suspicion 
of disease progression, in order to confirm or refute the clinical impression. 
f. Site to provide patient with Fecal Swab sample collection kit and instructions to collect sample at home within the 72 hours 
prior to the scheduled 30-day follow-up visit. Patient will return fecal sample to clinic during the scheduled visit, or make 


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arrangements to drop sample off within 72 hours of collection. 
g. Adequate contraception as defined by the protocol should be used throughout the trial and for at least 120 days for males 
w/WOCBP sexual partner and 180 days for WOCBP from the last dose of trial treatment. Refer to Section 4.7.2. for complete 
details. 
h. Site to confirm contact information for patient and a designated family member and remind patient of FU telephone contact 
that will be conducted every 90 days for survival status 
i. During the  Survival Follow-up Phase the patient should be contacted by telephone 90 ± 5 days from EOT and every 90 ± 
15 days after that until death, withdrawal of consent, or the end of the trial, whichever occurs first. 
j. For only those patients that consent to the optional tissue collection.  (Refer to 6.1.2.8). 
 
6.0 TRIAL PROCEDURES 
6.1 Trial Procedures 
Individual trial procedures (Administrative, Clinical, and Laboratory) are described in detail 
below. The specific visit requirements are detailed in Section 6.1.7.   It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
 
Furthermore, additional evaluations/ testing may be deemed necessary by the Sponsor for 
reasons related to patient safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the patient.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
6.1.1 Administrative Procedures 
6.1.1.1 Informed Consent 
 
The Investigator or qualified designee must obtain documented consent from each potential 
patient prior to participating in a clinical trial. 
 
6.1.1.1.1 General Informed Consent 
 
Consent must be documented by the patient’s dated signature.  A copy of the signed and 
dated consent form should be given to the patient before participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any 
written 
information 
provided 
to 
the 
patient 
must 
receive 
the 
IRB/ERC’s 
approval/favorable opinion in advance of use.  The patient or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the patient’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the patient’s dated signature or 
by the patient’s legally acceptable representative’s dated signature. 
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
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6.1.1.2 Inclusion/Exclusion Criteria 
 
All inclusion and exclusion criteria will be reviewed and documented by the investigator or 
qualified designee to ensure that the patient qualifies for the trial.  
 
6.1.1.3 Medical History 
 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the patient has enrolled in this trial will be recorded separately and not listed as 
medical history.   
 
6.1.1.4 Prior and Concomitant Medications Review 
6.1.1.4.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the patient 
within the 30 days before starting the trial.  Treatment for the disease for which the patient 
has enrolled in this trial will be recorded separately and not listed as a prior medication.  
 
6.1.1.4.2 Concomitant Medications 
 
The investigator or qualified designee will record medications including prescription, over-
the-counter (OTC), multivitamins, nutritional and/or herbal supplements, IV medications and 
fluids, if any, taken by the patient during the trial.  All medications related to reportable SAEs 
and Events of Clinical Interest (ECIs) should be recorded as defined in Section 6.2. 
 
6.1.1.5 Disease Details and Treatments 
6.1.1.5.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
 
6.1.1.5.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.  The investigator will assess and provide as 
part of the baseline eCRF data, the Best Response on the last treatment prior to enrollment 
in this trial. 
 
6.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
 


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The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a patient initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the EOT visit must occur before the first dose of 
the new therapy.  Once new anti-cancer therapy has been initiated the patient will move into 
survival follow-up.  
 
6.1.1.6 Assignment of Screening Number 
 
A patient will be assigned a screening number once they provide written informed consented 
for the trial.  This screening number will be site specific and maintained on a Screening log in 
the Investigator Site File. 
 
6.1.1.7 Assignment of Randomization Number 
 
Eligible patients will be assigned a randomization number that will serve as the patient’s 
number throughout the trial.  This randomization number will be maintained on a 
Randomization log in the Investigator Site File.  
 
 
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
 
The investigator or qualified designee will assess each patient to evaluate for potential new 
or worsening AEs as specified in the Trial Schedule Section 5.0 (during the trial treatment 
period, for 30 days following end of treatment and again at 90 days for serious adverse 
events and more frequently if clinically indicated.  Adverse experiences will be graded and 
recorded throughout the trial and during the follow-up period according to NCI CTCAE 
Version 4.0 Toxicities will be characterized in terms regarding seriousness, causality, toxicity 
grading, and action taken with regard to trial treatment.  
 
Please refer to section 6.2 for detailed information regarding the assessment and recording 
of AEs.   
 
6.1.2.2 Full Physical Exam 
 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  
 
6.1.2.3 Directed Physical Exam 
 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration on days 1, 8, and 15 of each cycle, and at treatment discontinuation. 
 


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6.1.2.4 Vital Signs 
 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Schedule (Section 5.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
 
6.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (Appendix 4) at screening, 
prior to the administration of trial treatment, on days 1, 8, and 15 of each cycle, and at 
discontinuation of trial treatment as specified in the Trial Schedule.   
 
6.1.2.6 Tumor Imaging and Assessment of Disease  
 
The patient’s pancreatic cancer will be evaluated by the investigator based on tumor 
assessments using RECIST 1.1 and iRECIST criteria (Appendix 5).  
 
Tumor assessments for evaluation of response will be conducted using CT or MRI, 
approximately every 9 ± 1 weeks until trial discontinuation or disease progression, whichever 
is later. All sites of disease must be followed using the same baseline assessment method. 
 
CT is the preferred imaging modality for this study. I.V. contrast should be administered, 
unless medically contraindicated. 
 
If CT with I.V. contrast is contraindicated, the alternative is to acquire a CT of the chest 
without contrast and MRI of the abdomen and pelvis with gadolinium contrast.  
 
Other protocols, such as non-contrast CT of chest abdomen pelvis, should not be performed. 
For CT scans oral contrast should be administered in addition to IV contrast. Radiolucent 
agents (e.g., water) are generally preferred over radiopaque agents (e.g., iodine and barium-
based agents). 
 
All target lesions will be measured by consistent imaging techniques for each patient 
throughout the trial. Suitable imaging techniques include CT-scan, or MRI. The same 
technique should be used for each evaluation in an individual patient. Copies of the scans 
must be available for review. 
 
In addition, a central radiologist, blinded to the treatment assignment, will perform an 
independent read of each scan, assessing tumor response using RECIST 1.1 and iRECIST 
criteria (Appendix 5). 
 
In the event that PD by RECIST 1.1 or iUPD is determined, a repeat scan must be 
performed within 4 - 6 weeks to confirm PD.  Trial treatment may be continued during this 
time (past the initial PD assessment) but only if patient is clinically stable as defined by: 
 
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• No clinically relevant increase in disease related symptoms 
 
• No requirement for intensified management of disease related symptoms (analgesics, 
radiation, palliative care) 
 
If the investigator assesses a patient to have PD (defined by RECIST 1.1), the central 
radiologist will review the scan to confirm the PD, prior to the discontinuation of trial 
treatment.  
 
CA19-9 assessments (or CEA or CA-125 for not expressers of CA19-9) will be taken at 
baseline and approximately every 21 days during the trial treatment period. All CA19-9 
assessments must be assayed by the same laboratory for each patient.  Disease 
progression will not be determined by CA19-9, however increases in CA19-9 may warrant 
the investigator to obtain radiographic assessments.  
 
Note: In order to more precisely determine time to progression, the investigator is 
encouraged to obtain radiological assessments and CA19-9 values earlier if there is a strong 
clinical suspicion of disease progression. In order to either confirm or refute the clinical 
impression. 
 
6.1.2.7 Blood Collection 
 
Each patient will have two - 10 mL vials of blood collected at the following timepoints: 
baseline, 9 ± 1 weeks on trial treatment, at time of confirmed response (if applicable) and at 
the EOT. Blood samples will be processed for serum and for peripheral blood mononuclear 
cells (PBMCs). Viable PBMCs will be stored in Bambanker™ freezing media for later 
analysis of circulating immune cells by existing technologies, such as flow cytometry, 
CyTOF, single-cell RNA-Seq, and single cell ATAC-Seq, as well as various new 
technologies as they become available. Serum will be snap frozen and used to evaluate the 
impact of therapies on circulating cytokine levels (e.g. IL6) by ELISA and multiplex cytokine 
assays. 
 
Blood samples will be sent and centrally analyzed by 
 and the 
. 
 
Specific details for blood sample collection and handling will be provided to the investigative 
sites in the Trial Laboratory Manual. 
 
6.1.2.8 Tumor Tissue Collection 
 
All patients will be required to provide an archival tissue specimen. Archival tissue will be 
analyzed in a similar manner as described below for formalin fixed paraffin embedded 
(FFPE) biopsy samples. Specific details for archival tissue processing and distribution will be 
provided to the investigative sites in the Trial Laboratory Manual. Sites will be asked to 
indicate whether blocks will be available for additional sectioning at a later point in time if 
additional tissue is needed.  


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Patients will be provided with the following two additional options to provide fresh tumor 
tissue for the analysis as described below. 
 
Patients will be provided the option to consent to provide fresh tissue samples from a newly 
obtained core or excisional biopsy of a tumor lesion if performed recently (within 30 days 
prior to Cycle 1/Day 1) and during their participation in the study should they be scheduled 
for a biopsy as part of their routine care during their participation in the study through the 
follow-up period.  
 
Additionally, patients will also be provided with the option to consent to undergo a biopsy of a 
tumor lesion at baseline, at the completion of 3 cycles of treatment (9 weeks after starting 
trial treatment), or at the time of disease progression if prior to week 9, unless tumor is 
considered inaccessible or biopsy is otherwise considered not in the patients best interest.  
Participation in this trial is therefore not contingent on the patient consenting to optional 
tumor biopsies for fresh tissue. 
 
For patients consenting to the optional tumor biopsy, a baseline tumor biopsy will be 
collected and used for profiling. If possible (patient condition permitting) this will be 
repeated after 9 ± 1 weeks on trial treatment, or at the time of disease progression.  Each 
tumor biopsy will consist of approximately 5 passes, refer to Trial Laboratory Manual for 
more details. The site  is asked to provide an image (CT image) of needle orientation.   
Alternatively, if the biopsy is performed under ultrasound guidance, the site is asked to 
provide details on which lesion and where that lesion is located on a diagnostic CT or MRI 
(i.e. CT series and slice number). This de-identified image will be sent to 
 
 (refer to protocol section 6.1.5).  
 
Tissue samples will be sent and centrally analyzed by 
 and the 
. 
 
Two passes will be split evenly and processed for formalin-fixed paraffin (FFP) and optimal 
cutting temperature (OCT) embedding and samples will be centrally analyzed using existing 
technologies, such as immunohistochemistry, immunofluorescence, and RNA-in situ 
hybridization, as well as various new technologies as they become available to evaluate the 
following: 
 
• Stromal/extracellular matrix content (e.g. collagen and hyaluronic acid) 
 
• Quantity and quality of vascularization (e.g. CD31) 
 
• Expression of pembrolizumab related targets (e.g. PD-1 and PD-L1) 
 
• Presence/ distribution, and activation of key immune cell populations (e.g. cytotoxic T 
Cells, TAMs, MDSCs, and Tregs) 
 
• Presence, distribution, and activation of other stromal cell populations, including 
fibroblasts (e.g. αSMA) 


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One pass will be immediately snap frozen for the following central analysis  
 
• Analysis of bulk tumor RNA for VDR expression and VDR targets (e.g. CYP24A1) 
 
• Analysis of bulk tumor RNA for Expression of VDR regulated inflammatory gene (e.g. 
IL6, CXCL1, CSF2, CXCLR) 
 
Two passes will be immediately frozen in Bambanker™ freezing media for the following 
central analysis: 
 
• Genomic analysis of T-cell receptor clonality by sequencing (a measure of 
intratumoral T cell response) 
 
Bulk and single-cell analysis of mutational profiles, transcriptional profiles, and 
epigenetic states within tumors, including analysis of sorted tumor cell nuclei. 
 
In the event that biopsy tissue becomes limiting for certain analyses, snap frozen and 
Bambanker™ frozen tissue may be used interchangeably where technically feasible. 
  
Specific details for tumor tissue collection and handling will be provided to the 
investigative sites in the Trial Laboratory Manual. 
 
6.1.3 Laboratory Procedures/Assessments 
Safety laboratory tests for hematology, chemistry, and urinalysis (as detailed in Table 9) will 
be performed by the local laboratory for each investigational site at screening, baseline and 
throughout the trial treatment period.  Serum vitamin D levels will be performed at screening. 
HBsAg and HCV RNA (qualitative) will be performed at screening if not performed within the 
last 3 months.  Thyroid and Parathyroid function (T3, FT4 TSH, and PTH) will be performed 
as part of screening and every other cycle during the trial treatment period.  
 
Table 9. Laboratory Tests – performed locally 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) 
Platelet count 
Alanine 
aminotransferase (ALT) 
Protein 
aPTT 
WBC (total and 
differential) 
Aspartate 
aminotransferase (AST) 
Specific gravity  
Thyroid stimulating 
hormone (TSH) 
Red Blood Cell 
Count 
Lactate dehydrogenase 
(LDH) 
Microscopic exam (If 
abnormal results are 
noted) 
Total triiodothyronine (T3) 
Absolute Neutrophil 
Count 
Carbon Dioxide ‡ 
Free thyroxine (T4) 
Absolute 
Lymphocyte Count 
  (CO2 or bicarbonate) 
 
PTH (parathyroid 
hormone) 
 
Uric Acid 
 
Serum vitamin D (25-


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Hematology 
Chemistry 
Urinalysis 
Other 
hyroxy vitamin D) 
 
Calcium 
 
HBsAG 
 
Chloride 
 
HCV RNA qualitative 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Creatinine 
 
 
† Perform on women of childbearing potential (WOCBP) only.  
‡  If considered standard of care in your region. 
 
 
6.1.4 Patient Personalized Clinical Benefit (PPCB)  
The exploratory objective to assess Patient Personalized Clinical Benefit (PPCB) will be 
evaluated based on the improvement in disease-related symptoms.  The specific disease-
related symptoms that are most bothersome for the individual patient will be identified at 
baseline and followed throughout the trial. Patients will use a trial-specific phone-based 
application to record the status of their three most bothersome disease-related symptoms at 
baseline, weekly during the treatment period, and at the EOT visit.  The patient will be 
provided instructions and download and complete the app during the baseline C1/Day 1 visit. 
The patient will enter their responses directly into the APP via their mobile device using an 
assigned patient ID and therefore no protected health information (PHI) will be recorded. In 
the event that a patient does not have the type of mobile device required to access the APP, 
or the patient chooses not to complete the PPCB via the APP, the patient will be provided a 
paper questionnaire to complete.  The site will record the reason the patient is not utilizing 
the APP in the source documents.  Refer to Appendix 6 for more details on the PPCB App. 
 
6.1.5 Quantitative Textural Analysis (QTA) 
Quantitative Textural Analysis (QTA) will be used to explore differences in tumor and tissue 
texture between the two treatment arms of this trial using baseline, on treatment, and post 
treatment CT scans. Such information may provide a basis for establishing a complementary 
diagnostic biomarker that could 1) predict disease stability in the maintenance environment 
2) provide an imaging signature that is associated with immune infiltrative activity, 3) allow a 
non-invasive method for detecting tumor and tissue texture changes related to vitamin D 
(paricalcitol) exposure and 4) identify other correlations of imaging to tumor biology, 
response to treatment, and laboratory assessments. 
 
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Sites will be provided instructions for sending de-identified CT scans 
 
 for analysis. Images will be reviewed to ensure 
appropriate series, images and anatomic coverage is available and that all PHI has been 
removed. Only query-free studies will be forwarded for analysis. Query-free scans will be 
loaded onto 
 QTA analysis platform for textural analysis.  Refer to 
Appendix 7 for specific information on the planned QTA analysis to be performed.  
 
6.1.6 16S Gut Microbiome rRNA Analysis 
The exploratory objective to monitor and compare the gut microbial communities will be 
evaluated using patient collected fecal samples.  The differences in gut microbial 
communities within and between fecal samples will be compared using alpha and beta 
diversity metrics based on 16S rRNA sequencing. The DNA extraction and sequencing 
analysis will be performed at 
.  Refer to Appendix 8 for more 
specific information on the planned analysis to be performed.  Specific details for sample 
handling and shipping will be provided to the investigative sites in the Trial Laboratory 
Manual. 
 
Fecal samples are relatively easy to collect and non-invasive. They provide an indication of 
the gut microbiome which may be an indicator of general health, impact drug availability, and 
indicate the presence of communities associated with inflammation, digestive inefficiencies, 
and pathogens. Monitoring the gut microbiome may allow us to predict the risk of possible 
side effects of pembrolizumab (colitis and decreased appetite) and paricalcitol (decreased 
appetite).   
 
Fecal samples will be collected by the patient at home during trial participation.  Patients will 
be asked to collect two samples per treatment cycle.  One fecal swab sample is to be 
collected within the 72 hours prior to Day 1 of each treatment cycle, and a second fecal swab 
sample within 24-72 hours after treatment on Day 1.  The patient will also be asked to collect 
one final sample approximately 30 days following treatment discontinuation.  Patients will be 
provided with collection instructions (refer to Appendix 9), collection container, sterile 
CultureSwabs in individual pre-labeled containers, and a biospecimen bag. Patients will 
collect fecal material in a collection container, and then transfer a pea size amount of fecal 
matter using the provided CultureSwabs, into the original pre-labeled fecal swab collection 
container, and place in the provided biospecimen bag. The patient will be asked to store the 
fecal samples in the freezer and deliver to the research site within 72 hours of collection (this 
will correspond with the patients’ return to clinic - so it is not anticipated that additional clinic 
visits should be required).  
 
6.1.6.1 Withdrawal/Discontinuation 
 
When a patient discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the EOT visit should be performed at the time of discontinuation.  Any adverse 
events which are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements outlined in Section 6.2 - Assessing and Recording 
Adverse Events.   
 


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6.1.6.2 Blinding/Unblinding 
 
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.  Only the site pharmacist 
and unblinded trial monitor will be aware of the assigned treatment arm.  
 
Investigators will be able to unblind in emergency situations when the identity of the 
treatment must be known in order to provide appropriate treatment.  The sponsor must be 
contacted (if possible) prior to the treating investigator unblinding a patient.    
 
Additionally, at the time of disease progression the treating investigator may request the 
unblinded treatment assignment for the patient.  This will be provided by the unblinded trial 
monitor to the treating Investigator for the purposes of considering future treatment options.   
The remainder of the trial team will not have access to this unblinded treatment assignment.  
  
Once a patient is unblinded he/she will not be allowed to continue on trial medication and will 
be considered an early withdrawal and will need to complete the required EOT procedures 
and necessary follow-up per section 6.1.5.3. 
 
6.1.7 Visit Requirements 
Visit requirements are outlined in Section 5.0 - Trial Schedule.  Specific procedure-related 
details are provided above in Section 6.1 - Trial Procedures. 
 
6.1.7.1 Screening Period 
 
Screening of potential patients will be performed only after informed consent is obtained and 
within 21 days prior to first dose of trial medication (unless otherwise noted below).  All 
necessary laboratory values and assessment reports must be available and reviewed prior to 
cycle1/ day 1.  
 
 The following will be completed as part of the screening visit: 
 
1. Written informed consent   
 
2. Medical history including concurrent baseline conditions (using NCI CTCAE version 
4.0; Appendix 3), prior cancer therapy (including documentation of prior surgery, 
adjuvant or neoadjuvant chemotherapy and radiotherapy) 
 
3. Complete physical examination including height (cm) and weight (kg) 
 
4. ECOG Performance Status (see Appendix 4) 
 
5. Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
6. Computed tomography (CT) / magnetic resonance imaging (MRI) scan to document 
disease status (including chest, abdomen, pelvis, and other regions as clinically 
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indicated only). If a CT scan was taken within 28 days prior to first dose, a new scan 
is not necessary. However, if a new scan is to be done, it should be performed within 
10 ± 2 days prior to starting trial medication. Obtain De-identified Dicomm encoded 
CT scan for central lab (Appendix 7). 
 
7. Electrocardiogram (ECG) 
 
8. PT/INR and aPTT 
 
9. Complete blood count (CBC) with differential and platelet count 
 
10. Comprehensive serum chemistries (refer to Table 9) 
 
11. TSH, T3, Free T4, and PTH 
 
12. Serum vitamin D level 
 
13. HBsAg and HCV RNA (qualitative) if not performed in the last 3 months 
 
14. Urinalysis (refer to Table 9) 
 
15. Serum β-HCG pregnancy test for women of child-bearing potential (refer to Section 
4.7.2 for more details) 
 
16. Concomitant medication notation (to include all medications taken within 30 days prior 
to enrollment) 
 
17. For those patients consenting to the optional fresh tissue collection: Obtain fresh 
tissue from a newly obtained core or excisional biopsy if performed within the last 30 
days prior to first dose of trial medication (C1/D1).  Refer to Section 6.1.2.8. 
 
18. For those patients consenting to the optional baseline biopsy: Fresh tissue is to be 
obtained up to 3 weeks (21 days) prior to first dose of trial medication (C1/D1). Refer 
to Section 6.1.2.8. 
 
19. Obtain archival tumor specimen for all patients - as required for eligibility. Refer to 
Section 6.1.2.8. 
 
20. Central Lab Blood Sample 2 X 10 mL vials . Refer to Section 6.1.2.7. 
 
21. Provide Fecal Swab collection kit and review instructions with patient for return of 
sample on Cycle 1/Day 1. Refer to Section 6.1.6. 
 
22. Investigator or qualified designee to review and record the patient’s three most 
bothersome disease-related symptoms (as determined by the patient) to be followed 
during treatment period, via the Patient Personalized Clinical Benefit (PPCB) App – 
Refer to Appendix 6. 
 


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6.1.7.2 Treatment Period 
 
Patients will be treated at 21 ± 3 day intervals.  Patient must begin cycle 1 within 21 days of 
signing the IRB approved informed consent document and after the screening assessments 
have been performed and reports have been reviewed to confirm eligibility. Screening 
clinical evaluations and laboratory assessments may be used as the Cycle 1/ Day 1 
evaluations if they are completed within 7 days prior to trial treatment administration. 
 
Treatment will be administered by qualified and trained site personnel in a hospital, clinic, or 
other outpatient setting appropriate for chemotherapeutic infusions.  
 
For subsequent cycles, all assessments must be conducted prior to treatment administration 
and within 72 hours (except those noted), or if medical or scheduling conditions require a 
delay.   
 
Day 1 of each cycle  
 
• Inclusion/exclusion review (Cycle 1 only) 
 
• Directed physical exam 
 
• Vital signs 
 
• Measurement of weight (kg) and BSA calculation prior to dosing (After Cycle 1, the 
BSA only needs to be changed if there has been a change > 10% in body weight from 
Cycle 1 /Day 1 
 
• ECOG Performance Status  (Appendix 4) 
 
• Hematology: CBC with differential and platelet count.  Results must be reviewed prior 
to treatment initiation to ensure patient still meets inclusion criteria. 
 
• Serum chemistries (refer to Table 9). Results must be reviewed prior to treatment 
initiation to ensure patient still meets inclusion criteria. 
 
• CA19-9 (C1/D1) 
 
Every other cycle only: TSH, T3, Free T4, and PTH (not required at C1/Day 1 if 
completed within 21 days). Results must be reviewed prior to treatment initiation. To 
be repeated every other cycle, i.e. prior to cycle 3, 5, 7, 9, etc. 
 
• Urinalysis 
 
• Serum β-HCG pregnancy test. Results must be reviewed prior to treatment initiation 
confirming a negative serum β-HCG for women of child-bearing potential and 
documentation of the patients confirmation of preferred acceptable method of 
contraception per Section 4.7.2 starting from the day of trial treatment initiation (refer 
to Section 4.7.2 for more details). 


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• AEs using the NCI CTCAE V4.0 (Appendix 3) 
 
• Concomitant medication notation of all medications taken within the 30 days prior to 
C1/D1 
 
• Provide Fecal Swab collection kit and review instructions (Appendix 9) with patient for 
return of sample on Day 3 
 
• Patient to complete the Patient Personalized Clinical Benefit (PPCB) App (Appendix 
6) 
 
• Paricalcitol administration 
 
• Pembrolizumab administration 
 
Day 3, 5 , 8 ,10 ,12, 15, 17, and 19  (± 1 day)  of each cycle  
 
• Vital signs 
 
• AEs using the NCI CTCAE (Appendix 3) 
 
• Concomitant medication notation 
 
• Day 8 and 15 of each cycle only: Directed physical exam, including weight  
 
• Day 8 and 15 of each cycle only: ECOG Performance Status   
 
• Day 8 and 15 of each cycle only: Hematology: CBC with differential and platelet 
count - results must be reviewed prior to paricalcitol administration  
 
• Day 8 and 15 of each cycle only: Serum chemistries (refer to Table 9) - results must 
be reviewed prior to paricalcitol administration  
 
• Day 8 and 15 of each cycle only: Patient to complete the Patient Personalized 
Clinical Benefit (PPCB) App (Appendix 6) 
 
• Day 19 Only: Provide Fecal Swab collection kit and review instructions with patient 
for return of sample on Day 1 on next treatment cycle 
 
• Paricalcitol administration 
 
 
Week 9 (+/- 1 week) 
 
• Optional repeat biopsy refer to Section 6.1.2.8 
 
• Central Lab Blood Sample, 2 X 10 mL vials refer to Section 6.1.2.7 


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End of 3 treatment cycles (every 9 ± 1 weeks) until disease progression or end of trial, 
whichever comes first 
 
• CT/MRI scan to evaluate disease status (using same imaging method as Baseline).  
Obtain De-identified dicomm encoded CT scan for central lab (Appendix 7). 
 
Note: In order to more precisely determine time to progression, the investigator is 
encouraged to obtain radiological assessments and CA19-9 values earlier if there is a strong 
clinical suspicion of disease progression. In order to either confirm or refute the clinical 
impression. 
 
6.1.7.3 End of Treatment (EOT) 
 
The patient will continue on maintenance therapy until there is evidence of clear-cut tumor 
progression, has treatment ending toxicities, or withdraws from treatment (refer to section 
4.8). The following assessments will be performed within 5 days after completing the last 
dose of trial medication or before the initiation of a new anti-cancer treatment, whichever 
comes first: 
 
• Directed physical exam 
 
• ECOG Performance Status (see Appendix 4) 
 
• Vital signs 
 
• ECG 
 
• Hematology: CBC with differential and platelet count 
 
• Serum chemistries 
 
• TSH, T3, T4 
 
• CA19-9 (or CEA or CA-125 if not expressers of CA19-9) 
 
• Urinalysis 
 
• Serum β-HCG pregnancy test (for WOCBP) 
 
• Central lab blood sample, 2 X10 mL vials  
 
• Concomitant medication  
 
• Patient to complete the PPCB App (Appendix 6) 
 


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• Provide Fecal Swab collection kit and review instructions(Appendix 9) with patient for 
return of sample within 72 hours of collection (coordinate with 30 day Safety Follow-
Up visit)  
 
• CT/MRI scan to evaluate disease status (using same imaging method as Baseline). 
Obtain De-identified dicomm encoded CT scan for central lab (Appendix 7). 
 
• AEs using the NCI CTCAE Version 4.0 (see Appendix 3) 
 
• Review contraception use as required by protocol Section 4.7.2 (where applicable) 
 
• Confirm contact information for patient and a designated family member and remind 
patient of FU telephone contact that will be conducted every 90 days for survival 
status following the 30 - day follow-up visit. 
 
6.1.7.4 Follow-up Period 
 
30-day Follow-up Visit 
 
The mandatory Safety Follow- up visit should be conducted approximately 30  (± 5 days) 
after the last dose of trial treatment and before initiation of a new anti-cancer treatment, 
whichever comes first.   
 
The following assessments will be performed: 
 
• Serum β-HCG pregnancy test (for WOCBP) 
 
• AEs using the NCI CTCAE Version 4.0 (see Appendix 3) 
 
• Review contraception use as required by protocol Section 4.7.2 (where applicable) 
 
• Confirm contact information for patient and a designated family member and remind 
patient of FU telephone contact that will be conducted every 90 days for survival 
status. 
 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Patients with an AE 
of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-cancer therapy, whichever occurs first.  
  
SAEs that occur within 90 days of the end of trial treatment or before initiation of a new anti-
cancer treatment should also be followed and recorded.   
 
Survival Follow-up Phase 
Once a patient experiences confirmed disease progression or starts a new anti-cancer 
therapy, the patient moves into the Survival Follow-up Phase and should be contacted by 
telephone 90 (± 5 days) from EOT and every 90 ± 15 days after that until death, withdrawal 
of consent, or the end of the trial, whichever occurs first.  
 


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6.2 Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product or 
protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the pembrolizumab and /or paricalcitol, is also an adverse event. 
 
Adverse events may occur during the course of the use of pembrolizumab and/or paricalcitol 
in clinical trials, or as prescribed in clinical practice, from overdose (whether accidental or 
intentional), from abuse and from withdrawal. 
 
Progression of the cancer under study (pancreatic cancer) is not considered an adverse 
event.  
 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the patient to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
6.2.3.1. The investigator will make every attempt to follow all patients with non-serious 
adverse events for outcome. 
 
6.2.1 Definition of an Overdose for This Protocol and Reporting to the Sponsor 
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥ 5 times the indicated dose). 
 
No specific information is available on the treatment of overdose of pembrolizumab.  In the 
event of overdose, the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
In the event that an inadvertent overdose of pembrolizumab occurs during the trial this 
should be immediately reported to the Sponsor. Any untoward events occurring as a result of 
the overdose should be reported within 24 hours to the Sponsor as SAE or ECI per the 
guidance under section 6.2.3.1 
 
 


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6.2.2 Reporting of Pregnancy and Lactation to the Sponsor 
Female patients that are pregnant or breastfeeding, or expecting to conceive within the 
projected duration of the trial, starting with the screening visit through 120 days after the last 
dose of trial treatment are excluded from participating in the trial.  However in the unlikely 
event that pregnancy or lactation occurs during the course of the patient’s participation in the 
trial the following section describes the required reporting of these events. 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a patient 
(spontaneously reported to them) that occurs during the trial. 
 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the patient to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
 
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of trial medication or 30 days following cessation of 
trial treatment if the patient initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor.  The Sponsor will report within 
24 hours (working days) to Merck Global Safety.  
 
6.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
6.2.3.1 Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
pembrolizumab and/or paricalcitol that results in any of the following: 
 
• Death; 
 
• A life threatening adverse drug experience; 
 
• Persistent or significant disability/incapacity; 
 
• Inpatient hospitalization or prolongation of an existing hospitalization; 
 
• Congenital anomaly/birth defect; 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious drug adverse experience when, based upon 


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appropriate medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
 
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Sponsor and Merck 
in the same timeframe as SAEs to meet certain local requirements. Therefore, these 
events are considered serious by Merck for collection purposes. 
 
• Is a new cancer (that is not a condition of the trial); 
 
• Is associated with an overdose. 
 
Refer to Section 6.2.4 for additional details regarding each of the above criteria. 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study 
(reference Section 6.2.3.3 for additional details) that occurs to any patient must be reported 
within 24 hours to the Sponsor.  The Sponsor will report within 24 hours (working days) to 
Merck Global Safety if it causes the patient to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the patient 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 6.2.3.3 for additional details), whether or not related 
to the trial treatment, must be reported within 24 hours to the Sponsor.  The Sponsor will 
report within 24 hours (working days) to Merck Global Safety. 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to pembrolizumab that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor.  The Sponsor will then report 
to Merck Global Safety. 
 
All patients with serious adverse events must be followed up for outcome. 
 
6.2.3.2 Events of Clinical Interest (ECI) 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 24 hours to the Sponsor and the Sponsor will 
report within 24 hours (working days) to Merck Global Safety.  
 
Events of clinical interest for this trial include: 
 


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1. An overdose of pembrolizumab, as defined in Pharmacy manual and Section 6.2.1 - 
Definition of an Overdose for This Protocol and Reporting of Overdose, that is not 
associated with clinical symptoms or abnormal laboratory results.  
 
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing. * 
 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any patient must be 
reported within 24 hours to the Sponsor and the Sponsor will report within 24 hours (working 
days) to Merck Global Safety if it causes the patient to be excluded from the trial, or is the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the patient 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to pembrolizumab, must be reported within 24 hours to the Sponsor 
and the Sponsor will report within 24 hours  (working days) to Merck Global Safety. 
 
 
6.2.4 Evaluating Adverse Events 
AE Grade 
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0.  A copy of the CTCAE 
Version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
website 
at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
Any adverse event which changes CTCAE grade over the course of a given episode will 
have each change of grade recorded on the adverse event case report forms/worksheets. 
 
When specific adverse events are not listed in the CTCAE they will be graded by the 
investigator according to the following grades and definitions, consistent with the CTCAE 
Version 4.0. 
 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). Instrumental ADL refer to 


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preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care 
ADL. Self care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden 
 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
• Grade 5: Death related to AE. 
 
Duration 
 
The investigator will record the start and stop dates of the adverse event.  If less than1 day, 
this will be indicated in the appropriate length of time in units. 
 
Action Taken 
 
Did the adverse event cause the trial treatment to be discontinued? 
 
Relationship 
 
All adverse events regardless of CTCAE grade must also be evaluated for relationship (in 
regards to trial treatment/ trial interventions).  
 
The determination of the likelihood that trial treatment caused the adverse event will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame.  
 
The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the trial treatment and the adverse event 
based upon the available information. 
 
The following components are to be used to assess the relationship between trial treatment 
and the AE; the greater the correlation with the components and their respective elements 
(in number and/or intensity), the more likely the trial treatment caused the adverse event 
(AE): 
 
Exposure: Is there evidence that the patient was actually exposed to trial treatment such as: 
reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
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Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors? 
 
Dechallenge: Was trial treatment discontinued or dose/exposure/frequency reduced? 
 
If yes, did the AE resolve or improve?  If yes, this is a positive dechallenge. 
 
If no, this is a negative dechallenge. 
 
 
Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the trial treatment; or (3) 
the trial is a single-dose drug trial); or (4) trial treatment is/are only used one time. 
 
Rechallenge: Was the patient re-exposed to trial treatment in this trial? 
 
If yes, did the AE recur or worsen?  
 
If yes, this is a positive rechallenge.  
 
If no, this is a negative rechallenge. 
 
Note: If a rechallenge is planned for an adverse event which was serious and which 
may have been caused by either of the trial treatments, or if re-exposure to trial 
treatment poses additional potential significant risk to the patient, then the rechallenge 
must be approved in advance by the Sponsor as per dose modification guidelines in the 
protocol. 
 
Consistency with Trial Treatment Profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding trial treatment or drug class 
pharmacology or toxicology? 
 
 
Relationship 
Attribution 
Description 
Unrelated to the trial 
treatment/intervention 
Unrelated 
The AE is clearly NOT related to the trial 
treatment/intervention 
Unlikely 
The AE is doubtfully related to the trial 
treatment/intervention 
Related to the trial 
treatment/intervention 
Possible 
The AE may be related to trial 
treatment/intervention 
Definite 
The AE is clearly related to trial 
treatment/intervention 
 
6.2.5 Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 


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7.0 LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.   
 
For the purposes of this trial the investigational products refer to both paricalcitol (or placebo) 
and pembrolizumab.    
 
Paricalcitol will not be provided directly to the site as part of this trial but will be obtained 
directly from the treating investigator’s designated pharmacy supply. Therefore the labeling, 
storage and, handling, of paricalcitol will follow the dispensing pharmacy’s own standard 
operating procedures.   
 
Pembrolizumab will be provided by Merck in temperature-controlled shipments directly to the 
site Pharmacy as summarized in Table 10 below.  The details for the labeling, storage, 
handling, and disposal of pembrolizumab provided for use in this trial are therefore detailed 
below. 
 
Table 10. Pembrolizumab Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100mg/4 mL 
Solution for Injection 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
 
7.1 Packaging and Labeling Information 
Pembrolizumab will be provided by Merck and will not be distinguished from the commercial 
product.  Therefore, Investigator sites will be required to confirm prior to site initiation and 
pembrolizumab shipment, their specific plans for maintaining the trial supplied 
pembrolizumab separate from the pharmacy supply and how this will be distinguished for 
other pharmacy staff on site. 
 
7.2 Storage and Handling Requirements 
Pembrolizumab must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
 
The investigator or authorized person at the trial site must maintain records of receipt and 
ongoing inventory of clinical trial supply of pembrolizumab at the site including the 
dispensing and administration of the pembrolizumab vials used for each patient.   
 
Clinical trial supplies of pembrolizumab may not be used for any purpose other than that 
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7.3 Returns and Reconciliation 
Upon completion or termination of the trial, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
8.0 STATISTICAL CONSIDERATIONS 
8.1 Trial Design 
This is a randomized, double blind, placebo-controlled clinical trial.   Eligible patients will be 
randomized in a 1:1 ratio to one of two treatment arms: pembrolizumab + paricalcitol or 
pembrolizumab + placebo. 
 
Trial treatment will be administered every three weeks per the schedule as described in 4.2.  
The percent of patients with disease progression at six months will be the primary endpoint.  
Secondary endpoints will include: incidence of toxicities, overall survival, mutational 
landscape, transcriptional programs and cellular (immunity) VDR targets in the immune 
microenvironment. 
 
8.2 Sample Size Considerations 
The primary endpoint is the percentage of patients progressing at 6 months.  Based on a 
contemporary control of no maintenance after best response to prior chemotherapy8, the 
control arm with pembrolizumab alone is expected to have only 8% of patients with no 
progression at 6 months. To be of clinical interest, at least 58% of patients must be 
progression-free at 6 months on the pembrolizumab plus paricalcitol arm. A sample size of 
12 patients per arm will provide 90% statistical power to detect this difference assuming a 
one-sided alpha level of 0.05.  A one-sided test was selected as we are only interested in the 
combination if it decreases the percentage of patients progressing at 6 months.  This sample 
size estimate was obtained using binomial enumeration of all possible outcomes to compare 
two independent binomial proportions (Pearson’s chi-squared test) using PASS 15.18  A 
statistical concern is that the Pearson chi-squared test does not guarantee the alpha level.  
We confirmed that we have adequate statistical power using the Miettinen & Nurminen 19 
exact likelihood score method (89% power) using Pass 15. 
 
 
 
 
 


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8.3 Statistical Analysis Plan 
8.3.1 Analysis of the Conduct of the Trial 
Enrollment, major protocol violations, and discontinuations for the trial will be summarized 
using a CONSORT diagram. 
 
8.3.2 Analysis of Patient Characteristics 
Demographic and baseline characteristics, such as age, race, BSA, duration of pancreatic 
cancer, site(s) of metastatic disease, prior cancer treatment, and baseline ECOG 
performance status will be summarized using means (± standard error) or medians (range) 
for continuous variables and proportions for categorical variables. 
 
8.3.3 Analysis of Pembrolizumab and Paricalcitol Administration 
Pembrolizumab + Paricalcitol (or placebo) dose administration will be listed and dose 
modifications will be flagged.  Mean and standard deviations will be used to summarize the 
average dose received.   
 
8.3.4 Analysis of Primary Endpoint - Disease progression at 6 months 
All patients that receive trial treatment will be included in the analysis to determine the 
percentage of patients progressing by RECIST 1.1 criteria at 6 months when maintained on 
a combination regimen of paricalcitol plus pembrolizumab versus pembrolizumab alone.  The 
6-month time-point will be defined as 6 months (180 days) from the initial treatment (cycle 
1/day 1).  Statistical analysis will compare the proportion progression free at 6 months using 
a one-sided test of binomial proportions (equivalent to a Pearson’s chi-squared test).  If the 
assumptions of the Pearson's chi-squared test are not met, we will analyze the data using 
Barnard's exact unconditional test of equality, as implemented in StatXact.20 
 
8.3.5 Analysis of Secondary Endpoints 
8.3.5.1 Analysis of Toxicities 
 
All adverse events occurring on or after Cycle 1/day 1 will be summarized by body systems 
and per grade according to NCI-CTCAE Version 4.  Additionally, all serious adverse events 
and events of clinical interest (ECI) as defined in section 6.2.3.2 will be listed separately and 
tabulated.  All patients who receive any amount of trial treatment will be included in the 
analysis. 
 
8.3.5.2 Comparison of Overall Survival 
 
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.  Statistical 
comparison of overall survival between the two treatment arms will be performed using a log-
rank test, with estimation of the hazards ratio using a Cox proportional hazards model.   
 
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The change in the biomarkers in the pre- versus 6-week biopsies will be estimated for each 
patient.  A two-sample t test will be used to compare the continuous changes between the 
two treatment arms, assuming that the differences are normally distributed.  If they are non-
normal, a Wilcoxon Rank Sum Test will be used.   A sensitivity analysis will use a linear 
regression model to compare the two treatment arms, adjusted for the baseline level. 
 
8.3.5.3 Analysis of Cellular VDR targets with PD1 Blockade 
 
Analysis of the specified cellular VDR targets will be assessed using the change in the pre- 
versus 9-week biopsies.  A two-sample t test or Wilcoxon Rank Sum Test, and a sensitivity 
analysis using linear regression will be performed as outlined previously. 
  
8.3.6 Analysis of Exploratory Endpoints 
8.3.6.1 Comparison of RECIST 1.1 and iRECIST criteria 
 
Given that pembrolizumab is an immunotherapy agent, disease progression will be defined 
by RECIST and iRECIST criteria (Appendix 5).  Comparison of the proportion progression-
free at 6 months using iRECIST will be performed using the same method as for the primary 
endpoint of RECIST 1.1.  Additionally, McNemar’s Test will be used to estimate the 
concordance between the two outcome measures. 
 
8.3.6.2 Compliance to Use of a Phone-Based Application for Assessing Patient Defined 
Symptoms 
 
The planned statistical analysis is included in Appendix 6. 
 
8.3.6.3 Patient Personalized Clinical Benefit 
 
The symptoms identified by each patient and the change across time will be evaluated 
graphically.  The most severe ranking across the three items will be compared at baseline 
and the EOT visits to determine whether each patient’s symptoms have improved across 
time.  The relationship between progression at 6 months by RECIST 1.1 versus the change 
in rankings from baseline to EOT will be assessed using a Wilcoxon Rank Sum test. 
 
8.3.6.4 Quantitative Textural Analysis (QTA) 
 
The planned analysis for QTA is included in Appendix 7. 
 
8.3.6.5 16S Gut Microbiome rRNA Analysis 
 
The planned analysis for 16S Gut Microbiome is included in Appendix 8. 
 


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9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 Institutional Review Board/Ethics Committee Approval 
Before trial initiation, this protocol and informed consent form will be submitted for review 
and approval to the IRBs charged with oversight for the clinical sites. In addition, any form of 
proposed advertising and advertising text for patient recruitment must be reviewed and 
approved by the Sponsor prior to submission to the IRB. The Investigator will forward to the 
Sponsor a copy of the IRB’s approval of this protocol, any amendments, informed consent 
form, and any modifications to the informed consent, based on the FDA regulations set forth 
in 21 CRF 56 of the Code of Federal Regulations. 
 
In addition, the Investigator will be responsible for forwarding to the Sponsor a description of 
the IRB members (including profession and affiliation) or a United States (US) Department of 
Health and Human Services (DHHS) General Assurance number and expiration date. If 
neither of these is available, the chairperson must submit a statement indicating that the 
members of the board responsible for the review meet the FDA and other appropriate 
regulatory requirements. In addition, the labeling for all approved trial medications should be 
submitted to the IRB for information purposes. 
 
Clinical supplies will not be shipped to the clinical site until IRB approval is obtained for the 
protocol.  Any existing amendments, informed consent, and photocopies of the approved 
documents must be received by the Sponsor prior to drug shipment. 
 
9.2 Investigators protocol agreement 
The Investigator must sign the Investigator’s Protocol Agreement. The original must be kept 
on file by the Sponsor and the Investigator must retain a copy. The completed Investigator’s 
Protocol Agreement signifies agreement to comply with all procedures outlined by this 
protocol by the Investigator. An Investigator’s Protocol Agreement must be signed if and 
when a protocol amendment is issued.  
 
9.3 Remaining Samples 
Any samples remaining after the trial specified analyses is completed will be transferred to 
and stored at TGen if the patient consented for use of their remaining samples for future 
research purposes at TGen's discretion. This includes the original specimen collected from 
the patient [blood, tumor tissue, or fecal swabs]) as well as derivatives created from the 
original specimen (DNA, RNA, blocks or slides). Documentation of the transfer of all 
specimens will be recorded on the Sample Destruction/Return Request Form- refer to Trial 
Laboratory Manual.  
 
If a patient has not consented for their remaining samples to be used for future research 
purposes, remaining samples and derivatives will be destroyed and documented on the 
Sample Destruction/Return Request Form- refer to Trial Laboratory Manual. 
 


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9.4 Confidentiality 
The Investigator and any other personnel involved in this trial shall not disclose, or use for 
any purposes (other than for the performance of this trial any data, records, or other 
information (hereinafter collectively “information”) disclosed to the Investigator or other trial 
personnel. Such information shall remain the confidential and proprietary property of the 
TGen and SU2C, and shall be disclosed only to the Investigator or other designated trial 
personnel. 
 
Patient confidentiality will be ensured by using assigned site-specific Screening and 
Randomization numbers (refer to Section 6.1) throughout the trial. 
 
9.5 Publication  
As a general rule, no trial results should be published without prior approval of the Sponsor. 
The rights of the investigator and the Sponsor with regard to publication of the results of this 
trial are described in the investigator contract. 
 
9.6 Compliance with Financial Disclosure Requirements 
All Investigators will be required to submit written financial disclosures to the Sponsor prior to 
participating in this clinical trial and any changes in disclosures during the course of the trial 
as per 21 CFR part 54.  
 
9.7 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are patient to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow patients to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.   
   
9.8 Quality Management System 
9.8.1 Data Monitoring Plan 
Data monitoring procedures will be carried out by 
 for all participating 
sites, and will be performed on a regular basis to comply with Good Clinical Practice 
guidelines. 
 
Review of the case report forms, cross-reference with source documents (including radiology 
review), review of trial related regulatory documents and logs (e.g. enrollment, trial site staff), 
would be monitored on an ongoing basis during monitoring sessions. The monitor will ensure 
that the investigation is conducted according to protocol design and regulatory requirements. 
 


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At the conclusion of the monitoring visit, the monitor will meet with the site staff to discuss 
and request specific corrections to the case report forms, and/or request clarification, and/or 
additional source documentation. The site Clinical Research Coordinator responsible for the 
trial will be provided with a copy of the written monitoring notes for resolution of the findings. 
 
The monitor will complete a written monitoring report and provide to the Sponsor and 
.  The report will include a summary of what the site monitor reviewed and the site 
monitor’s statements concerning the significant findings/facts, deviations and deficiencies, 
conclusions, actions taken or to be taken, and/or actions recommended to ensure 
compliance.  The site Principal Investigator will be expected to submit any Corrective Action 
Plans, in writing, to the Sponsor. A copy of the monitoring forms, final monitoring reports, 
and Corrective Action Plan will be kept in the site monitor’s trial file follow up at the next 
monitoring session. 
 
For drug accountability an independent unblinded monitor will be assigned to monitor the 
Pharmacy file containing all information on preparation and dispensing of trial medication.  
Monitoring will occur on an ongoing basis to determine that the medication is being prepared 
and dispensed in accordance with the protocol design.  
 
A blinded report documenting the visit and any findings will be written and provided to the 
Sponsor. 
 
9.8.2 Data Safety Monitoring  
A trial specific Data Safety Monitoring Plan (DSMP) will be implemented for this trial. The 
Trial Principal Investigators and an independent Medical Monitor will review the safety and 
progress of the trial on a regular interval and provide documentation of their review and any 
recommendations that will then be shared with the trial team.   
 
The trial progress reports will be prepared by 
 in aggregate and provide blinded trial 
data pertaining to: patient recruitment, retention/attrition, data collection status, and adverse 
events.  The progress reports will not provide data on the primary or secondary endpoints of 
the trial as there is no interim analysis planned for this trial.   
 
In additional a separate unblinded trial report will be generated by the unblinded trial monitor 
and provided only to the independent medical monitor to review.   
 
An annual trial progress report will be generated by 
 and sent to the Independent 
Monitor, Consulting Investigator, funding organization (SU2C), and each site Principal 
Investigator for submission to their governing IRB.  
 
9.9 Data Management 
9.9.1 Case Report Forms 
All the clinical data will be captured by the site on electronic case report forms (eCRFs).   
The eCRFs will be used for all consented patients. The investigator and trained trial 
personnel will enter and edit the data via a secure network, with secure identification and 


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password requirement.  A complete electronic audit trial will be maintained.  The investigator 
will be required to provide approval of all data to confirm accuracy.   Copies of the eCRFs 
will be provided to the investigator at the conclusion of the trial.    
 
9.9.2 Source Documents 
Source documents serve as the evidence of the existence of the patient and the data 
collected for this trial.  Source documents will be the responsibility of the Investigator and will 
be filed at the site and available as needed by the Sponsor, 
, or assigned clinical 
monitor. 
 
Data captured on the eCRF is to be transcribed from source document and must be 
consistent with any discrepancies explained and documented. 


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19. Miettinen, O.S. and Nurminen, M. 1985. 'Comparative analysis of two rates.' Statistics 
in Medicine 4: 213-226. 
 
20. StatXact® 11, Cytel Corporation 
 


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APPENDICES 
 
 


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Appendix 1 - Pembolizumab (Keytruda®) Package Insert  
 
The pembrolizumab (Keytruda®) package insert can be accessed at the following link:  
https://www.accessdata.fda.gov/drugsatfda docs/label/2016/125514s012lbl.pdf 
 
 
 


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Appendix 2 - Paricalcitol (Zemplar®) Package Insert 
 
The paricalcitol (Zemplar®) injection package insert can be accessed at the following link: 
https://www.accessdata.fda.gov/drugsatfda docs/label/2004/20819se5-014 zemplar lbl.pdf 
 


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Appendix 3 - NCI CTCAE version 4.0 
 
The CTCAE Version 4.0 can be accessed and downloaded from the CTEP website at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
 
 




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Appendix 5 - Protocol Criteria for Measurement of Trial Endpoint 
RECIST 1.1 and iRECIST 
 
1. 
Definitions 
 
1.1. Evaluable for adverse events. All patients will be evaluable for adverse event evaluation 
from the time of their first treatment. 
 
1.2. Evaluable for response. All patients who have received at least one cycle of therapy 
and have their disease re-evaluated will be considered evaluable for response 
(exceptions will be those who exhibit objective disease progression prior to the end of 
cycle 1 who will also be considered evaluable). Patients on therapy for at least this 
period and who meet the other listed criteria will have their response classified 
according to the definitions set out below. 
 
Response and progression will be evaluated in this study using the revised international 
criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) 
committee as well as the modified iRECIST guidelines. Investigators should note the 
different requirements for confirmatory scans as well as follow up for the two criteria. 
 
See section 6.1.2.6 for criteria for continuing treatment past RECIST 1.1 disease 
progression. 
 
2. 
RECIST 1.1 Response and Evaluation Endpoints 
 
2.1. Measurable Disease. Measurable tumour lesions (nodal, subcutaneous, lung 
parenchyma, solid organ metastases) are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm with 
chest x-ray and as ≥10 mm with CT scan or clinical examination. Bone lesions are 
considered measurable only if assessed by CT scan and have an identifiable soft tissue 
component that meets these requirements (soft tissue component ≥10 mm by CT 
scan). Malignant lymph nodes must be ≥15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumour 
measurements must be recorded in millimetres (or decimal fractions of centimetres). 
Previously irradiated lesions are not considered measurable unless progression has 
been documented in the lesion. 
 
2.2. Non-measurable Disease. All other lesions (or sites of disease), including small lesions 
are considered non- measurable disease. Bone lesions without a measurable soft 
tissue component, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of 
lung or skin and abdominal masses followed by clinical examination are all non-
measurable. Lesions in previously irradiated areas are non-measurable, unless 
progression has been demonstrated. 
 


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2.3. Target Lesions. When more than one measurable tumour lesion is present at baseline 
all lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the basis of 
their size (lesions with the longest diameter), be representative of all involved organs, 
but in addition should be those that lend themselves to reproducible repeated 
measurements. Note that pathological nodes must meet the criterion of a short axis of 
≥15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis ≥10 mm but <15 mm) 
should be considered non-target lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed (see 8.2.4). At 
baseline, the sum of the target lesions (longest diameter of tumour lesions plus short 
axis of lymph nodes: overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for 
each assessment, even if very small. If extremely small and faint lesions cannot be 
accurately measured but are deemed to be present, a default value of 5 mm may be 
used. If lesions are too small to measure and indeed are believed  to be absent, a 
default value of 0 mm may be used. 
 
2.4. Non-target Lesions. All non-measurable lesions (or sites of disease) plus any 
measurable lesions over and above those listed as target lesions are considered non-
target lesions. Measurements are not required but these lesions should be noted at 
baseline and should be followed as “present” or “absent”. 
 
2.5. Response. 
 
All patients will have their BEST RESPONSE from the start of study treatment until the 
end of treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and 
normalization of tumour markers. Pathological lymph nodes must have short axis 
measures <10 mm (Note: continue to record the measurement even if <10 mm and 
considered CR). Residual lesions (other than nodes <10 mm) thought to be non-
malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases4 before CR can be accepted. 
Confirmation of response is only required in non-randomised studies. 
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest 
diameter for tumour lesions and short axis measure for nodes) of target lesions, taking 
as reference the baseline sum of diameters. Non target lesions must be non-PD. 
Confirmation of response is only required in non-randomised studies. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of 
measured lesions taking as references the smallest sum of diameters recorded on 
study (including baseline) AND an absolute increase of ≥5 mm. Appearance of new 




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of RECIST 1.1 in many respects but have been adapted to account for instances where 
an increase in tumour burden, or the appearance of new lesions, does not reflect true 
tumour progression. 
 
Key differences are described below. All responses defined using iRECIST criteria are 
designated with a prefix. iRECIST time-point and best overall responses will be 
recorded separately. 
 
3.1. Confirming Progression 
 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the 
terms iUPD (unconfirmed progression) and iCPD (confirmed progression). Confirmatory 
scans should be performed at least 4 weeks, but no longer than 8 weeks after iUPD. 
 
iCPD is confirmed if further increase in tumour burden, compared to the last 
assessment, is seen as evidenced by one or more of the following: 
• Continued increase in tumour burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
o Continued unequivocal progression in non-target disease with an increase in 
tumour burden 
o Increase in size of previously identified new lesion (s) (an increase of at least 5 
mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions. 
• RECIST 1.1  criteria  are  met  in  lesions  types  (target  or  non-target  or  new  
lesions)  where progression was not previously identified, including the 
appearance of additional new lesions. 
 
If iUPD is not confirmed at the next assessment, then the appropriate response will be 
assigned (iUPD if the criteria are still met, but no worsening, or iSD, iPR or iCR if those 
criteria are met compared to baseline). As can be seen in table 2, the prior 
documentation of iUPD does not preclude assigning iCR, iPR, or iSD in subsequent 
time-point assessments or as best overall response (BOR) providing that iCPD is not 
documented at the next assessment after iUPD. 
 
3.2. New lesions 
 
New lesions should be assessed and measured as they appear using RECIST 1.1 
criteria (maximum of 5 lesions, no more than 2 per site, at least 10 mm in long axis (or 
15 mm in short axis for nodal lesions), and recorded as New Lesions-Target (NLT) and 
New Lesion-Non-Target (NLNT) to allow clear differentiation from baseline target and 
non-target lesions. 
 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). 
However, the measurements of target lesions should NOT be included in the sum of 
measures of original target lesions identified at baseline. Rather, these measurements 
will be collected on a separate table in the case record form. 
 


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PD is confirmed in the New Lesion category if the next imaging assessment, conducted 
at least 4 weeks (but not more than 8 weeks) after iUPD confirms further progression 
from iUPD with either an increase of at least 5 mm in the absolute value of the sum of 
NLT OR an increase (but not necessarily unequivocal increase) in the size of NLNT 
lesions OR the appearance of additional new lesions. 


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Table S2: Time-point (TP) iResponse 
Target 
Lesions* 
Non-Target 
Lesions* 
New 
Lesions* 
Time Point Response 
No 
prior 
iUPD** 
Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD 
with 
no 
change 
OR 
decrease 
from last 
TP 
iUPD 
with 
no 
change
 
O
R decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified and 
increase in size (≥5 mm in SOM for NLT or any increase for 
NLNT) or number. If no change in NLs (size or number) 
from last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in further 
increase in size of NT disease (need not meet RECIST 1.1 
criteria for unequivocal PD) 
iUPD 
Non-iCR/Non- 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
o further increase in SOM of at least 5 mm, otherwise 
remains iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
o  previously identified T lesion iUPD SOM ≥5 mm and / or 
o NT lesion iUPD (prior assessment - need not be 
unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further 
increase in: 
o  previously identified T lesion iUPD ≥5 mm and / or 
o previously identified NT lesion iUPD (need not be 
unequivocal) and /or 
o  size or number of new lesions previously identified 
Non- 
iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
o  increase in size or number of new lesions previously 
identified 
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD 
would be the same. ** in any lesion category. *** previously identified in assessment immediately prior to this 
TP. 


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All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
 
 Table S3:iRECIST Best Overall Response (iBOR) 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR,
 
iPR
, iUPD, NE 
iCR, iPR, iUPD, NE iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, NE iCR 
iCR, iPR, iSD, iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, NE, iCPD iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
1. Table assumes a randomised study where confirmation of CR or PR is not required. 
2. NE = not evaluable that cycle. 
3. Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
4. For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each 
TPR but is not shown in the table for ease of presentation. 
 
5. 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
 
Response duration will be measured from the time measurement criteria for CR/PR or 
iCR/iPR (whichever is first recorded) are first met until the first date that recurrent or 
progressive disease is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline). 
 
Stable disease duration will be measured from the time of start of treatment until the 
criteria for progression are met, taking as reference the smallest sum on study 
(including baseline). 
 
6. Methods of Measurement 
 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up. 
Assessments should be identified on a calendar schedule and should not be affected 
by delays in therapy. While on study, all lesions recorded at baseline should have their 
actual measurements recorded at each subsequent evaluation, even when very small 
(e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned. For lesions which fragment/split add together the longest diameters of the 
fragmented portions; for lesions which coalesce, measure the maximal longest 
diameter for the “merged lesion”. 
 
6.1. Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥10 mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by colour photography including a ruler to estimate the size 
of the lesion is recommended. If feasible, imaging is preferred. 


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6.2. Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions. However, lesions ≥20 mm on chest X-ray may be considered measurable 
if they are clearly defined and surrounded by aerated lung. 
 
6.3. CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable 
lesion should be twice the slice thickness. MRI is also acceptable in certain situations 
(e.g. for body scans). Other specialized imaging or other techniques may also be 
appropriate for individual case.4 For example, while PET scans are not considered 
adequate to measure lesions, PET-CT scans may be used providing that the measures 
are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
 
6.4. Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. If new lesions are identified by ultrasound in the 
course of the study, confirmation by CT is advised. 
 
6.5. Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
 
6.6. Tumour Markers. Tumour markers alone cannot be used to assess objective tumour 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. 
 
6.7. Cytology, Histology. These techniques can be used to differentiate between PR and CR 
in rare cases if required by protocol (for example, residual lesions in tumour types such 
as germ cell tumours, where known residual benign tumours can remain). When 
effusions are known to be a potential adverse effect of treatment (e.g. with certain 
taxane compounds or angiogenesis inhibitors), the cytological confirmation of the 
neoplastic origin of any effusion that appears or worsens during treatment when the 
measurable tumour has met criteria for response or stable disease is advised to 
differentiate between response or stable disease and progressive disease. 


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Appendix 6 - Patient Personalized Clinical Benefit APP 
 
BACKGROUND AND SIGNIFICANCE  
Standard paper based questionnaires are typically filled out only during office visits and the 
questions are predefined by the study or clinic. This reduces the number of data points that 
are collected during a study and relies heavily on a patient’s ability to recall specifics from 
days to weeks prior to the questions being asked. In addition, many of the questions may be 
irrelevant to that specific patient. Paper based questionnaires also require a patient or 
healthcare provider to fill out the forms with identifiable information so the data can be 
correlated to that patient. The healthcare provider is then required to enter the data into an 
electronic database after completion, which provides for more chance of error. 
 
The Patient Personalized Clinical Benefit (PPCB) App not only simplifies data entry, by 
alleviating the need to enter a patient’s name or other info, but also limits questions to the 
three main symptoms bothering each individual patient. In addition, data is automatically 
uploaded to an electronic database, removing the need for a healthcare provider to input 
data. This can significantly reduce costs associated with collecting and analyzing data, as 
well as decrease the chance for error. These questions will be asked once a week (patients 
will have a reminder setup via the app as to increase adherence) for the entire study duration 
or until the patient elects to stop taking the questionnaire.   
 
INSTRUCTIONS 
The patient will be provided the following instructions for downloading the app. 
 
Patient Instructions for Downloading the PPCB Phone App 
 
iPhone Users 
1. Go to the App Store on your iPhone or iPad and search for [insert APP name]: 
2. Tap the app. 
3. Tap GET on the right side of the screen, then tap Install. 
4. If asked, enter your password. You can also use Touch ID for app purchases. 
5. The app then downloads to your device. 
6. Find the app once it has downloaded and tap on the app icon to open the app 
7. Enter the assigned UserID that your study team has provided to you. 
8.  Then tap START QUESTIONNAIRE  
 
Android Users 
1. Go to the Play Store on your Android device and search for [insert APP name]: 
2. Tap the app. 
3. Tap INSTALL,  read access needs and tap ACCEPT. 
4. The app then downloads to your device. 
5. Click OPEN, or find the app on your device and tap on the app icon to open the app 
6. Enter the assigned UserID that your study team has provided to you. 
7. Then tap START QUESTIONNAIRE  
 
 
 


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QUESTIONNAIRE 
The 3-item phone-based app uses a Likert scale for the patient to rate general symptoms 
The app will be accessed and completed weekly to assess self-defined symptoms in cancer 
patients.  In the event that a patient does not have the type of mobile device required to 
access the APP, the patient will be provided the paper version of the questionnaire (printed 
in color as per screen shots) to complete.  Examples of both the PCBB APP- screen shot 
and the hard copy PPCB Questionnaire are included below. 
 
PPCB App Screen Shot 
 


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Personalized Patient Clinical Benefit Questionnaire- Hard Copy 
Instructions for Site: Complete the three patient reported symptoms in provided form and 
print in color for the patient to complete. 
 
 
 
COMPLIANCE 
The compliance rate will be estimated as the number of days in which a report was 
completed, out of the total number of days in which a report was expected. Usability metrics 
will include the average duration for each daily assessment. These data may be compared to 
other lab values or treatment information collected while on study. The results of this 
questionnaire will not affect the patient’s current treatment. 
 
SECURITY 
Data security and integrity is maintained through multi-layered encryption of the 
communication pathways and tokens using leading industry standards. Communication 
between the mobile device and the backend service utilizes a Restful interface using HTTPS 
encryption and authentication tokens. Additionally, no communication to the backend can be 
achieved without the clientID, which is unique to each user. Data collected from the 
application is stored within a secured database on the backend. No encryption is performed 
on data at rest currently, however, this can be enabled as needed. Please note, that even 
though multiple protocols are being employed to secure the communication pathways, no 


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personal user information is stored in the database. There is no name, email or any other 
information that is stored in the database that could be used to identify the individual utilizing 
the application. 
 
ACCESS AND SUPPORT 
The link to the app in the Android "Play Store" or Apple "App Store" can be provided via 
email or directly searched for using the app name. Initial usability support would be provided 
by the app support staff. An email distribution list will be set up for any support issues. Any 
technical issues would be emailed to that distribution list with an expected turnaround time of 
<24 hrs. 
 
When the app is run on either Android or iOS platforms, the only identifiable information that 
is sent and used to identify the end user is the initial “ID” that is entered to start the app. The 
user’s IP address, phone model, or phone number are not collected by the app. 
 
DATA ANALYSIS  
Frequency distributions and descriptive statistics will be computed on all variables.  Any 
continuous variable with a markedly non-normal distribution will be transformed to more 
closely approximate a normal distribution. 
 
The compliance rate to weekly reporting will be computed as the number of assessments 
completed divided by the number of expected assessments.  Number of questions 
completed, duration of each reporting session, and time of day of each reporting session will 
be analyzed using descriptive statistics.  Statistical analysis will employ both daily scores for 
individual items as well as summary measures (e.g., mean scores computed per item per 
patient over each 8 week period in which at least 4 surveys are completed).  Patient weekly 
and monthly scores for individual items will be graphically displayed longitudinally using 
stream plots and mean plots.  Mean scores with standard deviations will be computed at 
each time point (weekly as well as monthly).  Mean scores for each individual item over time 
(weekly and monthly) will be modeled using a generalized linear mixed model with a 
covariate for time (weeks or months since registration) and a random intercept term per 
patient.  Correlations between items will be assessed using Pearson correlations at fixed 
time points.  The threshold for feasibility is estimated at 70%.  Finally, coordinator feedback 
will be collected via interviews and qualitatively analyzed. 
 
  
REFERENCES 
Basch E, Deal AM, Kris MG, Scher HI, Hudis CA, Sabbatini P, Rogak L, Bennett AV, Dueck 
AC, Atkinson TM, Chou JF, Dulko D, Sit L, Barz A, Novotny P, Fruscione M, Sloan JA, 
Schrag D. Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer 
Treatment: A Randomized Controlled Trial. J Clin Oncol. 2016 Feb 20;34(6):557-65. doi: 
10.1200/JCO.2015.63.0830. Epub 2015 Dec 7. Erratum in: J Clin Oncol. 2016 Jun 
20;34(18):2198. PubMed PMID: 26644527; PubMed Central PMCID: PMC4872028. 
 
Center for Medical Technology Policy.  Recommendations for incorporating patient-reported 
outcomes (PRO’s) into clinical comparative effectiveness research (CER) in adult oncology.  
http://www.cmtpnet.org/docs/resources/PRO_EGD.pdf.  Accessed July 5, 2016. 
 


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Eckhardt, G.S.; De Porre, P; Smith, D; Maurel, J.; Steward, W.P.; Bouche, O; Van de Velde, 
H.; Michiels, B; Bugat, R. Patient-Reported Outcomes as a Component of the Primary 
Endpoint in a Double-Blind, Placebo-Controlled Trial in Advanced Pancreatic Cancer.  J. 
Pain 
and 
Symptom 
Management. 
2009 
Feb. 
37;(2) 
135-143. 
doi.org/10.1016/j.jpainsymman.2008.02.007 
 
Movsas B, Hunt D, Watkins-Bruner D, Lee WR, Tharpe H, Goldstein D, Moore J, Dayes IS, 
Parise S, Sandler H. Can electronic web-based technology improve quality of life data 
collection? Analysis of Radiation Therapy Oncology Group 0828. Pract Radiat Oncol. 2014 
May-Jun;4(3):187-91. doi: 10.1016/j.prro.2013.07.014.  
 
Epub 2013 Sep 16. PubMed PMID: 24766686; PubMed Central PMCID: PMC4007315. 
 
Reeve, B., Mitchell, S., Dueck, A., Basch, E.,Cella, D., Reilly, C., Minasian,L., Denicoff, A., 
O’Mara, A., Fisch, M., Chauhan, C., Aaronson, N., Coens, C., & Bruner, D. (2014). 
Recommended Patient-Reported Core Set of Symptoms to Measure in Adult Cancer 
Treatment Trials.  Journal of the National Cancer Institute, 106, 7, DOI:10.1093/jnci/dju129.  
First published online July 8, 2014. 
 
 
 
 
 
 
 


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Appendix 7 - Quantitative Textural Analysis  
 
A Quantitative Radiomics Approach 
 
Recent data acquisition and analytical advances have expanded the traditional role of 
medical imaging beyond subjective/qualitative arenas.  Radiomics refers to the 
comprehensive analyses of tumor phenotypes based on quantifiable image features (1). 
Quantitative CT-based tumor and tissue texture analysis (QTA) provides comprehensive, 3-
dimensional and temporal analyses of tumor heterogeneity (1).   This approach represents 
an emerging technology that can conceivably monitor tumor development, progression, 
immune cell activity and response to treatment.  Tumor heterogeneity on cross-sectional 
imaging is manifested by histopathological differences in cell density, necrosis, and 
hemorrhage (2,3). Image texture analyses assess tumor heterogeneity in accordance to the 
distribution and relationship of pixel or voxel-gray levels in the image (4).  Findings from 
several studies have suggested that imaging texture reflects tumor-host interactive status 
within the tumor microenvironment (5,6).  CT tumor texture analysis has shown promise in 
predicting pathologic features, overall survival, and response to therapy in NSCLC (1,7-9), 
colorectal cancers (3,5), esophageal cancer (10), head and neck cancers (11) and 
metastatic renal cell cancer (13). For, example, Aerts  have examined 440 quantitative 
features that define tumor image intensity, shape and texture extracted from CT scans of 
1,019 patients with NSCLC or head and neck cancers and has shown an association 
between tumor patterns and outcomes through unsupervised clustering analyses of 
Radiomic expression patterns and demonstrated associations with primary tumor stage (T 
stage), overall stage, and histology in 422 Stage I/II NSCLC patients (1).  Using a prognostic 
signature that comprised the top features of tumor image intensity, shape, texture, and 
multiscale wavelet findings, QTA were better than tumor volume and TNM staging in survival 
prediction by Kaplan Meier analyses.   Features describing heterogeneity in the primary 
tumor were associated with worse survival, whereas patients with more compact/spherical 
tumors had better survival probability. In separate studies, we have shown prognostic QTA 
signature that differentiated K-ras mutant NSCLC tumors from pan-wild type NSCLCs (9). 
We have recently demonstrated that using QTA, a specific imaging QTA signature of 
kurtosis and entropy is associated with interchromosomal aberrations in mPDA as 
determined by NGS and that these imaging features are associated with PFS and OS (12). 
Furthermore, preliminary work from our core lab by QTA analysis from the standard of care 
baseline CT scans from 28 subjects with metastatic solid tumors treated with PD-1 therapy 
demonstrated a distinct texture signature that distinguished which tumors were going to 
respond to PD-1 therapy. Finally, an analysis of the texture of tissue and tumors from 
subjects treated with paracalcitol showed a distinct texture pattern in the liver and pancreas 
of mPDA subjects on both the pre treatment and early post treatment scans leading to 
texture differences that may be distinctive based on vitamin D levels measured in patient 
serum. These encouraging results provide the rationale for using QTA to explore differences 
in tumor and tissue texture between the two arms of this study using baseline to and post 
treatment scans. Such information would be informative and provide a basis for establishing 
a complementary diagnostic biomarker that could 1) predict disease stability in the 
maintenance environment 2) provide an imaging signature that is associated with immune 
infiltrative activity, 3) allow a non invasive method for detecting tumor and tissue texture 
changes related to vitamin D exposure and 4) identify other correlations of imaging to tumor 
biology, response, laboratory assessments. 
 


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In order to perform Quantitative Textural Analysis (QTA) the following steps are required- 
De-identified dicomm encoded CT scans will be sent to 
 
 for analysis. Images will be reviewed to ensure appropriate series, 
images and anatomic coverage is available and that all PHI has been removed. Only query 
free studies will be forwarded for analysis. Query-free scans will be loaded onto 
 
 QTA analysis platform for textural analysis. Standard reconstructed algorithm 
generated image series will be evaluated for presence or absence of evaluable tumor, i.e. 
tumor >10mm containing clearly defined tumor margins on at least two consecutive slices. 
Polygon ROI tools will be selected and an ROI will be posited around the mid-slice section of 
the tumor lesion or tissue of interest such as the liver, pancreas, lung, and muscle.  
 
QTA will be applied to regions of interest which uses an image filtration-histogram technique 
whereby the filtration technique applies a Laplacian of Gaussian band-pass filter enhanced 
algorithm leading to extracted features of different sizes based on the spatial scale filter 
(SSF) value varying from fine-texture (SSF2, 2 mm in radius), medium texture (SSF3, 3 mm 
in radius), and coarse-texture (SSF4, 4 mm in radius). This is followed by quantification of 
tumor texture from the filtered histogram based texture maps producing the following 
quantitative parameters  
a) Mean (a measure of average brightness within the ROI) 
b) Kurtosis (K, a measure of peakedness and tailedness)  
c) Skewness (S, a measure of asymmetry of the histogram) 
d) Standard-deviation (SD, a measure of variation or dispersion that exists from the 
mean) 
e) Mean Positive Pixel (MPP, a measure of pixels that contain non-fat/air densities) 
f) Entropy (a measure of orderliness based upon co-occurrence matrix principles) 
 
A Sample Output from QTA Analysis of Lung Metastasis Lesions is shown below 


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The resulting Signature Readout file will be forwarded to IE’s data management site and 
entered into a secure database for marker analysis. Additional IE published Radiomics 
features may be extracted on the imaging slice (e.g. DVP signs, feature convergence, AB 
index, etc) as appropriate for tumor size, location and pattern features. Clinical team will 
supply IE with appropriate data to perform bioinformatics linkage with clinical and genomic 
data for surrogate marker testing. IE Data Management Team will perform full QC on 
entered data and manage query resolution process.  The expected statistical analysis of the 
data will involve a non-parametric Mann Whitney test used to assess the ability of the QTA, 
clinical, and patient characteristics to differentiate between early disease relapses, 
immunoinfiltration, vitamin D levels, molecular characterization and relapse risk. We 
anticipate using a recursive-type decision tree (or similar) approach to determine whether 
the differentiation between these outcomes could be improved by sequential application of 
QTA parameters. The QTA parameter that most accurately identifies the selected 
dependent variable will be used in the entire patient cohort as the first node, thereby 
generating two branches. The abilities of additional QTA parameters to identify outcomes 
will then be separately tested for each branch, adding further nodes to the tree. The 
diagnostic threshold values for the QTA parameters used at each node will be optimized 
using Receiver Operator Characteristic (ROC) analysis to maximize diagnostic accuracy. 
QTA parameters will be applied in order of overall accuracy for determination between early 
disease relapses, immunoinfiltration, molecular characterization and relapse risk. If two 
modalities have the same accuracy, the modality with the highest sensitivity will be applied 
first. No further node will be added to a branch if the misclassification rate in that branch is 
less than 15%. The final decision tree will be applied to the whole cohort to determine the 


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overall sensitivity, specificity, and accuracy. Since this is an exploratory study, General 
mixed linear modeling and/or computer simulation analysis will be sought to link early 
disease relapses, immunoinfiltration, vitamin D levels, molecular characterization and 
relapse risk with QTA results. In our prior work a Monte Carlo analysis using 1,000 iterations 
of the decision tree was used to assess the impact of uncertainty in the sensitivity and 
specificity for each QTA parameter (expressed as their 95% confidence intervals [CI]) on the 
overall diagnostic performance of the decision tree. For early disease relapses and relapse 
risk, univariate Kaplan-Meier survival (KM) analysis will assess the relationship between the 
above. An iterative procedure will also be applied to identify the optimal cut off for each 
marker that provides the best separation of the population into ‘good’ and ‘poor’ prognosis 
groups (indicated by the best p-value from log-rank test). Due to small numbers, we might 
need to censor reporting results for significant features yielding less than 10 patients per 
group for comparison to avoid overstating significant results. Additionally, we will focus on 
analysis for SSF0 through 4, because we believe that there will be a small numbers of cases 
having QTA measures for SSF 5 mm in radius and above in cases of tumors that are 
approximately 1 cm. Multivariate Cox regression will be used to determine which significant 
univariate parameters along with their interactions are independent predictors of recurrence, 
metastasis and relapse, along with the hazard ratio (HR) and the CI. A two-tailed P value of 
less than 0.05 will be considered to indicate a significant difference. 
 
Cited References  
1. Aerts HJ, Velazquez ER, Leijenaar RT, Parmar C, Grossmann P, Carvalho S, et al. Decoding tumour 
phenotype by noninvasive imaging using a quantitative radiomics approach. Nature communications. 
2014;5:4006. PubMed PMID: 24892406. Pubmed Central PMCID: 4059926 
 
2. Ng F, Kozarski R, Ganeshan B, Goh V. Assessment of tumor heterogeneity by CT texture analysis: can 
the largest cross-sectional area be used as an alternative to whole tumor analysis? European journal of 
radiology. 2013 Feb;82(2):342-8. PubMed PMID: 23194641. 
 
3. Ng F, Ganeshan B, Kozarski R, Miles KA, Goh V. Assessment of primary colorectal cancer 
heterogeneity by using whole-tumor texture analysis: contrast-enhanced CT texture as a biomarker of 
5-year survival. Radiology. 2013 Jan;266(1):177-84. PubMed PMID: 23151829. 
 
4. Ganeshan B, Miles KA. Quantifying tumour heterogeneity with CT. Cancer imaging : the official 
publication of the International Cancer Imaging Society. 2013;13:140-9. PubMed PMID: 23545171. 
Pubmed Central PMCID: 3613789. 
 
5. Lubner MG, Stabo N, Lubner SJ, Del Rio AM, Song C, Halberg RB, et al. CT textural analysis of 
hepatic metastatic colorectal cancer: pre-treatment tumor heterogeneity correlates with pathology and 
clinical outcomes. Abdominal imaging. 2015 Oct;40(7):2331-7. PubMed PMID: 25968046. 
 
6. Miles KA, Ganeshan B, Hayball MP. CT texture analysis using the filtration-histogram method: what do 
the measurements mean? Cancer imaging : the official publication of the International Cancer Imaging 
Society. 2013;13(3):400-6. PubMed PMID: 24061266. Pubmed Central PMCID: 3781643. 
 
7. Ganeshan B, Goh V, Mandeville HC, Ng QS, Hoskin PJ, Miles KA. Non-small cell lung cancer: 
histopathologic correlates for texture parameters at CT. Radiology. 2013 Jan;266(1):326-36. PubMed 
PMID: 23169792. 
 
8. Yamamoto S, Korn RL, Oklu R, Migdal C, Gotway MB, Weiss GJ, et al. ALK molecular phenotype in 
non-small cell lung cancer: CT radiogenomic characterization. Radiology. 2014 Aug;272(2):568-76. 
PubMed PMID: 24885982. 
 


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9. Weiss GJ, Ganeshan B, Miles KA, Campbell DH, Cheung PY, Frank S, et al. Noninvasive image 
texture analysis differentiates K-ras mutation from pan-wildtype NSCLC and is prognostic. PloS one. 
2014;9(7):e100244. PubMed PMID: 24987838. Pubmed Central PMCID: 4079229. 
 
10. Yip C, Landau D, Kozarski R, Ganeshan B, Thomas R, Michaelidou A, et al. Primary esophageal 
cancer: heterogeneity as potential prognostic biomarker in patients treated with definitive 
chemotherapy and radiation therapy. Radiology. 2014 Jan;270(1):141-8. PubMed PMID: 23985274. 
 
11. Zhang H, Graham CM, Elci O, Griswold ME, Zhang X, Khan MA, et al. Locally advanced squamous cell 
carcinoma of the head and neck: CT texture and histogram analysis allow independent prediction of 
overall survival in patients treated with induction chemotherapy. Radiology. 2013 Dec;269(3):801-9. 
PubMed PMID: 23912620. 
 
12. Campbell D, Barrett M, Ramanathan R, Von Hoff D, Korn R.  Quantitative Textural Analysis (QTA) in 
CT imaging: Identifying markers for genetic instability and overall survival in cohort of previously treated 
metastatic pancreatic cancer (mPC) Cancer Res October 1 2014 (74) (19 
Supplement) 1885; DOI:10.1158/1538-7445.AM2014-1885  
 
13. Goh V, Ganeshan B, Nathan P, Juttla JK, Vinayan A, Miles KA. Assessment of response to tyrosine 
kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. Radiology. 2011 
Oct;261(1):165-71. PubMed PMID: 21813743 
 
 
 
 
 
 
 
 
 
 


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Appendix 8 - 16S Gut Microbiome rRNA Analysis 
 
The bacterial communities living in and on our bodies interact with our epithelial cells and 
can influence adaptive immunity, metabolic functions, and inflammation at a local and 
systemic level. The gut microbiota has been particularly well-studied and regulates the 
barrier functions of the gut epithelium, prevents pathogen or pathobiont overgrowth, 
facilitates metabolism of dietary fibers, and regulates metabolism. The gut microbiota may 
also influence the initiation, progression, and treatment of cancer. Monitoring the microbiota 
in patients may enhance our ability to predict the likelihood of a positive patient response to 
therapy as well as indicators of adverse treatment effects and sensitive metrics of general 
patient health. Given the possibility of altering the microbiome of a patient, future research is 
likely to include manipulating microbiotic communities to maximize the effectiveness of other 
therapies. 
 
Fecal samples are relatively easy to collect and non-invasive. They provide an indication of 
the gut microbiome which may be an indicator of general health, impact drug availability, and 
indicate the presence of communities associated with inflammation, digestive inefficiencies, 
and pathogens. Monitoring the gut microbiome may allow us to predict the risk of possible 
side effects of pembrolizumab (colitis and decreased appetite) and paricalcitol (decreased 
appetite).   
 
Sample processing. Quantitative TaqMan PCR assay will be used that targets Variable 
Regions 3 and 4 of the 16S rRNA sequence. This assay will provide a rough estimation of 
the overall bacterial load per sample. It is important to recognize that different species have 
different copy numbers of the rrs gene that encodes the 16S rRNA, however this assay will 
still provide a rough estimation of bacterial load for inter-sample comparisons. For whole 
community surveys, 515F/806R 16S rRNA primers will be used to amplify Variable Regions 
4 and 5. This primer pair achieves nearly universal coverage across bacteria and archaea7. 
These amplicons will be sequenced using the Illumina MiSeq, NextSeq, or HiSeq next 
generation sequencing platforms. For the purposes of this work, the throughput, cost, and 
depth of coverage provided by the Illumina MiSeq currently make this sequencing platform 
better suited than other technologies. Moreover, the read lengths of up ~300bp allows 
approximately genus, and sometimes even species-level discrimination of taxa. 
 
Sequence Analyses. The microbial communities will be compared using phylogenetic beta 
diversity metrics based on 16S rRNA reads. The 515F/806R 16S rRNA primers will amplify a 
292bp region containing variable regions 4 and 5. Sequences will be processed using the 
open source Quantitative Insights Into Microbial Ecology 2 (QIIME2) software package to 
demultiplex, quality filter, and cluster sequences into operational taxonomic units (OTUs). 
Taxonomy will be assigned to OTUs by classification against the Greengenes database 
using the RDP Classifier (unless a better approach is available at the time of analysis). 
These data will be used to understand the differences in taxonomic composition. 
 
Measuring diversity within and between samples. Beta diversity is a measure of the relative 
similarity of samples (i.e., the between-sample diversity), while alpha diversity is a measure 
of the diversity within a sample. Thus beta diversity will provide an estimate on how different 


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microbial communities are, while alpha diversity provides information on the richness or 
evenness of a single community. Both alpha and beta diversity measures can be qualitative, 
considering only presence/absence of taxonomic groups in a community, or quantitative, 
considering the abundance of taxonomic groups. Qualitative measurement of beta diversity, 
for example, may be simply the fraction of shared taxa, but differences may be overlooked if 
the same set of taxa are present but in different abundances. However, quantitative diversity 
metrics may be misleading as community profiling based on amplicon sequence data is not 
necessarily quantitatively accurate. Additionally, diversity metrics are either taxon-based or 
phylogenetic-based. Taxon-based diversity considers all taxa to be equally related, ignoring 
the likelihood that closely related taxa are phenotypically similar. Phylogenetic diversity 
accounts for the evolutionary relationships between taxa, and has been shown to improve 
the resolution of differences between microbial communities.  
 
 


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Appendix 9 - Fecal Swab Sample Collection Instructions (To be 
included in Fecal Swab Collection kit) 
 
You have been provided a Fecal Swab Collection kit. 
The collection kit includes the following items: 
 
1. 
Disposable Gloves 
2. 
A stool collection bowl (toilet hat), as pictured below.  
3. 
A bio-specimen bag  
 
4. 
A pre-labeled CultureSwab tube, as pictured below. The tube has already been 
labeled with your assigned subject ID.  Please DO NOT write your name on the label. 
 
 
 
In order to ensure the best results, please follow the instructions below.  
 
You will need to collect two different stool samples during each treatment cycle: 
 
1. The first stool sample is to be collected up to 72 hours before your study treatment 
on day 1 of each treatment cycle.  
 
2. The second stool sample is to be collected from your first or second bowel movement 
within 24-72 hours after receiving your study treatment on day 1 of each treatment 
cycle. 
 
A final stool sample will be collected approximately 30 days after your last dose of study 
treatment.  
 


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To Collect a Stool Specimen: 
 
1. Raise the toilet seat and place the stool collection container (toilet hat) on the back of 
toilet bowl. Place the toilet seat down.  
2. Pass stool into the stool collection container. Do not urinate into the container.  
3. Put the provided disposable gloves on before collecting the stool sample.  Use the 
provided CultureSwab to remove a portion of the stool, as follows: 
a. Remove the CultureSwab tube from the plastic bag. 
b. Remove the sterile swab from the tube while handling only the cap and not 
touching the swab or shaft. 
c. Wipe the sterile swab across the stool to collect a pea size amount of stool on 
the tip of the swab. Do not touch the swab on the sides of the collection bowl or 
on any other surface.  
d. Carefully re-insert the swab with the fecal sample back into the CultureSwab 
tube and close with the cap. 
4. Write the date and time of collection on the label that is affixed to the tube.  
DO NOT write your name on the tube. 
5. Dump the remaining stool in the toilet and flush. The stool collection bowl and the 
disposable gloves may be disposed in the regular trash. Wash your hands thoroughly 
with soap and water. 
6. Store the CultureSwab tube in the bio-specimen bag in the FREEZER. 
7. Return the sample to the study team within 24-72 hours of collection. This should 
correspond with your next study visit. Sample can be transported in the car without 
need for ice packs, if the car is air-conditioned. If the car is not air-conditioned please 
transport the specimen on ice to keep cool. 
 
IMPORTANT: If for some reason you cannot make your scheduled appointment within 72 
hours of the fecal collection, please contact your study site at (site to specify contact tel 
number) to make arrangements for return of the sample. 
 
If you have any questions please call (site to specify contact tel number) 
 
Thank you for your participation! 
 

SAP_001.pdf: 
 
1 
Statistical Analysis Plan (SAP) – Clinical Endpoints 
 
A SU2C CATALYST® RANDOMIZED PHASE II TRIAL OF THE PD1 INHIBITOR 
PEMBROLIZUMAB (KEYTRUDA®) WITH OR WITHOUT A VITAMIN D RECEPTOR 
AGONIST PARICALCITOL (ZEMPLAR®) IN PATIENTS WITH STAGE IV 
PANCREATIC CANCER WHO HAVE BEEN PLACED IN BEST POSSIBLE 
RESPONSE (WITH NO FURTHER IMPROVEMENT IN THEIR TUMOR) 
 
Clinicaltrials.gov: NCT03331562 
 
July 10, 2020 
 
 
1 
INTRODUCTION   
 
The 5-year survival rate for pancreatic ductal adenocarcinoma (PDA) is only 8%, as 
detection is usually very late in the disease, most patients are not eligible for potentially 
curable resection, and those with resection usually experience fatal reoccurrence within 
2 years. There are some new treatments that improve survival for patients with stage IV 
PDA, but keeping patients in partial or complete remission is a major challenge. A 
maintenance regimen based on a vitamin D receptor (VDR) agonist, paricalcitol, could 
improve the activity of an immune checkpoint inhibitor, pembrolizumab. The 
combination regimen of paricalcitol + pembrolizumab is hypothesized to give benefit for 
maintenance of remission for patients with advanced pancreatic cancer (over 
pembrolizumab alone). 
 
 
2 
DATA SOURCE 
 
Datasets will come from the phase II clinical trial titled: A SU2C Catalyst® Randomized 
Phase II Trial of the PD1 Inhibitor Pembrolizumab (Keytruda®) with vitamin D receptor 
agonist Paricalcitol (Zemplar®) in Patients with Stage IV Pancreatic Cancer Who Have 
Been Placed in Best Possible Response (with no further improvement in their tumor). 
 
 
3  
ANALYSIS OBJECTIVES 
 
The primary objective is to determine whether combined paricalcitol + pembrolizumab 
reduces disease progression compared to pembrolizumab alone among patients with 
stage IV pancreatic cancer who have been put in best response. 
 
The primary endpoint is the percent of patients with radiographic disease progression 
according to RECIST 1.1 at 6 months. 
 
Secondary objectives include: 


 
2 
(1) Evaluate the toxicity of the combination of paricalcitol + pembrolizumab versus 
pembrolizumab alone. 
(2) Evaluate the difference in overall survival in patients administered the 
combination of paricalcitol + pembrolizumab versus pembrolizumab alone. 
 
Exploratory objectives include: 
(1) Evaluate the difference in disease progression according to iRECIST vs. RECIST 
1.1 criteria. 
 
 
4 
ANALYSIS SETS/ POPULATIONS/ SUBGROUPS 
 
This trial will have 24 patients randomized to paricalcitol + pembrolizumab (n=12) or 
pembrolizumab alone (n=12). No stratification will be performed. 
 
 
5 
ENDPOINTS AND COVARIATES 
 
Primary endpoint: Percent of patients with radiographic disease progression according 
to RECIST 1.1 at 6 months, defined as 180 days from initial treatment (C1/D1).  
 
Secondary endpoints: 
(1) Incidence of toxicities 
From initial treatment to end-of-treatment 
(2) Overall survival 
Time from initial treatment to death 
 
Exploratory endpoints: 
(1) Disease progression according to RECIST 1.1 versus iRECIST criteria 
Percent of patients with radiographic disease progression at 6 months 
 
 
6 
HANDLING OF MISSING VALUES AND OTHER DATA CONVENTIONS 
 
Patients with missing values at a particular time point will be unevaluable at that time 
point. Missing data will not be imputed. 
 
 
7 
STATISTICAL METHODOLOGY   
7.1 
STATISTICAL PROCEDURES 
 
Primary outcome: Progression-free survival 
The proportion of patients in each arm who are progression-free at 6-months will 
be compared using a one-sided test of binomial proportions (equivalent to a Pearson’s 
chi-squared test). If the assumptions of the Pearson’s chi-squared test are not met, 
Barnard’s exact unconditional test of equality will be used, as implemented in StatXact.  


 
3 
Patients unevaluable for progression at 6-months due to a non-progression related 
event will be excluded from analysis.   
Statistical comparison of progression-free survival between the two treatment 
arms will be performed using a log-rank test, with estimation of the hazards ratio using a 
Cox proportional hazards model.  A sensitivity analysis will include patients with an 
outcome of death due to another cause (other than progressive disease), which will be 
considered a competing event for progression.  Analysis will be performed using the 
Fine and Gray (1999) approach. 
 
Secondary outcome 1: Toxicity 
All adverse events (AE) occurring on or after C1/D1 will be summarized by body 
systems and per grade according to NCI-CTCAE Version 4. Additionally, all serious 
adverse events (SAE) and events of clinical interest (ECI) will be listed separately and 
tabulated. ECIs for this trial include an overdose of pembrolizumab and an elevated 
AST or ALT lab value, as defined in section 6.2.3.2 of the protocol. All patients who 
receive any amount of trial treatment will be included in the analysis. The proportion of 
patients in each arm with toxicity will be compared using a chi-squared test or Barnard’s 
exact unconditional test of equality as outlined above. 
 
Secondary outcome 2: Overall survival 
Overall survival will be calculated for each arm using a Kaplan-Meier estimate. 
Statistical comparison of overall survival between the two treatment arms will be 
performed using a log-rank test, with estimation of the hazards ratio using a Cox 
proportional hazards model.  Patients with an outcome of death due to another cause 
(other than progressive disease) will be considered a competing event for death.  
Analysis will be performed using the Fine and Gray (1999) approach. 
 
Exploratory outcome 1: RECIST 1.1 versus iRECIST 
Comparison of the proportion of patients who are progression-free at 6 months 
using iRECIST will be performed using the same method as for the primary endpoint of 
RECIST 1.1. McNemar’s test will be used to estimate the concordance between 
RECIST 1.1 and iRECIST. 
 
 
 


 
4 
 
7.2 
MEASURES TO ADJUST FOR MULTIPLICITY, CONFOUNDERS, 
HETEROGENEITY, ETC.  
 
Since all primary and secondary endpoints are pre-specified, there will be no 
adjustment for multiple comparisons. In the context of a randomized clinical trial, the two 
treatment arms are expected to be balanced with regard to potential confounders, 
therefore, adjustment is generally not necessary. 
 
 
References: 
 
Fine, J. P., and R. J. Gray. 1999. A proportional hazards model for the subdistribution of 
a competing risk. Journal of the American Statistical Association 94: 496–509. 
 
 


 
5 
Proposed Tables 
 
Table 1. Characteristics of patients at baseline 
Characteristic 
Pembrolizumab  
 
n = x 
Pembrolizumab 
+ Paricalcitol  
n = x 
Total 
 
n = x 
Age, y 
 
 
 
Median 
 
 
 
Range 
 
 
 
Sex, n (%) 
 
 
 
Female 
 
 
 
Male 
 
 
 
Race/ethnicity, n (%) 
 
 
 
Asian 
 
 
 
Black 
 
 
 
White 
 
 
 
Hispanic 
 
 
 
Other 
 
 
 
Study site, n (%) 
 
 
 
HonorHealth Research Institute  
 
 
City of Hope 
 
 
 
Atlantic Health System 
 
 
 
Baylor Scott and White 
Research Institute 
 
 
 
University of Kansas Medical 
Center 
 
 
 
Medical College of Wisconsin 
 
 
 
Pancreatic tumor location, n (%) 
 
 
 
Head 
 
 
 
Body 
 
 
 
Tail 
 
 
 
Unknown 
 
 
 
Site of metastatic disease, n (%) 
 
 
 
Liver 
 
 
 
Lung 
 
 
 
Peritoneum 
 
 
 
No. of metastatic sites, n (%) 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
>3 
 
 
 
 
 


 
6 
Carbohydrate antigen (CA) 19-9 
 
 
 
Median, U/mL 
 
 
 
Range, U/mL 
 
 
 
Normal (0-35 U/mL), n (%) 
 
 
 
ULN to <59x ULN, n (%) 
 
 
 
≥59x ULN, n (%) 
 
 
 
Previous therapy, n (%) 
 
 
 
Radiation therapy 
 
 
 
Chemotherapy 
 
 
 
Whipple procedure 
 
 
 
Biliary stent 
 
 
 
 
 
 
 


 
7 
Figure 1. (A) Progression-free survival by investigator-assessment, (B) 
Progression-free survival by independent assessment, (C) Overall survival 
 
 
Table 2. Progression-free survival and overall survival in the intention-to-treat 
population 
Efficacy variable 
Pembrolizumab  
 
n = x 
Pembrolizumab 
+ Paricalcitol 
n = x 
Hazard 
ratio or 
Response-
rate ratio 
(95% CI) 
P 
value 
Progression-free 
survival by 
investigator-  
assessment 
 
 
 
 
RECIST 1.1 
 
 
 
 
Rate of progression-free 
survival, % (95% CI) 
 
 
 
 
6 mo 
 
 
 
 
12 mo 
 
 
 
 
Median progression-free 
survival, mo (95% CI) 
 
 
 
 
Progression-free 
survival by 
independent 
assessment 
 
 
 
 
Rate of progression-free 
survival, % (95% CI) 
 
 
 
 
6 mo 
 
 
 
 
12 mo 
 
 
 
 
Median progression-free 
survival, mo (95% CI) 
 
 
 
 
Overall survival 
 
 
 
 
Median overall survival, 
mo (95% CI) 
 
 
 
 
Survival rate, % (95% CI)  
 
 
 
6 mo 
 
 
 
 
12 mo 
 
 
 
 
 
 
 


 
8 
Table 3. Common adverse events of grade 3 or higher 
 
Event 
Pembrolizumab 
  
n = x 
Pembrolizumab 
+ Paricalcitol 
n = x 
P 
value 
Adverse event leading 
to death, no. (%) 
 
 
 
Serious Adverse Events  
 
 
Anemia 
 
 
 
Cataract 
 
 
 
Nausea 
 
 
 
Abdominal pain 
 
 
 
Diarrhea 
 
 
 
Vomiting 
 
 
 
Bloating 
 
 
 
Constipation 
 
 
 
Fatigue 
 
 
 
Gait disturbance 
 
 
 
Urinary tract infection 
 
 
 
AST increased 
 
 
 
ALT increased 
 
 
 
Alkaline phosphatase 
increased 
 
 
 
Arthralgia 
 
 
 
Pain in extremity 
 
 
 
Back pain 
 
 
 
Hypertension 
 
 
 
Note: these were the most common events on the Nov 2019 DSMB report (> 10% of 
patients)