Clinical trial NCT02754726
Conditions: Untreated Metastatic Pancreatic Ductal Adenocarcinoma
Sponsor: HonorHealth Research Institute
Start date: 2016-04-01; Completion date: 2024-03-22
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if the study drugs nivolumab, albumin- bound paclitaxel, paricalcitol, cisplatin, and gemcitabine given together are safe and effective when combined to treat advanced pancreatic cancer.

Detailed description:

Arms: arm 1: open label using combination therapy
Interventions: intervention 1: Nivolumab intervention 2: Albumin-bound paclitaxel intervention 3: Paricalcitol intervention 4: Cisplatin intervention 5: Gemcitabine
Intervention descriptions: intervention 1: Nivolumab 240mg 240 mg as a 60 minute infusion on days 1, 15, 29 per 42 day cycle intervention 2: 125 mg/m2 over 30 minutes IV infusion on days 1, 8 and 22, 29 per 42 day cycle intervention 3: 25 micrograms IV on days 1,4,8,12,15,18,22,26,29,32,36,39 (+/-1 day allowed for dosing per 42 day cycle intervention 4: 25 mg/m2 over 60 minutes IV infusion on days 1, 8 and 22, 29 per 42 day cycle intervention 5: 1000 mg/m2 over 30 minutes IV infusion on days 1, 8 and 22, 29 per 42 day cycle

Protocol documents:
Prot_SAP_000.pdf: 
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A PHASE II PILOT TRIAL OF NIVOLUMAB + ALBUMIN-BOUND PACLITAXEL + 
PARICALCITOL + CISPLATIN + GEMCITABINE (NAPPCG) IN PATIENTS  
WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL 
ADENOCARCINOMA 
IND Exempt 
SPONSOR 
HonorHealth 
 10510 North 92nd Street, Scottsdale, AZ, 85258 (via partial support from both the TGen Foundation and
from Bristol Myers Squibb (BMS protocol CA209-385) to HonorHealth) 
VERSION DATE 
Amendment 6, Version 7.0,  15Jul2020 
 
Protocol Amendment History 
Amendment 5, Version 6.0, 13 September 2019 
Amendment 4, Version 5.0, 06 July 2018 
Amendment 3, Version 4.0, 31 March 2017 
Amendment 2, Version 3.0, 25 September 2016 
Amendment 1, Version 2.0, 09 May 2016 
Original Protocol, Version 1.0, 11 January 2016 
 
Lead Principal Investigator 
HonorHealth Site Principal Investigator 
Erkut Borazanci, MD, MS 
HonorHealth Research Institute 
10510 N. 92nd Street 
Scottsdale, AZ  85258 
Tel: 480-323-1350 
Fax: 480-323-1359 
Email:  Erkut.Borazanci@honorhealth.com 
Special Consultant 
Daniel D. Von Hoff, MD, FACP 
Chief Scientific Officer 
    HonorHealth Research Institute 
Physician in Chief, Distinguished Professor    
Translational Genomics Research Institute (TGen) 
10510 N. 92nd Street 
    Scottsdale, AZ 85258 
Tel: 480-323-1350 
Fax: 480-323-1359 
Email: dvh@tgen.org 
 
 
Sub-Investigator 
Gayle S. Jameson, MSN, ACNP-BC, AOCN        
Honor Health Research Institute                 
10510 N. 92nd Street                         
Scottsdale, AZ 85258                         
Tel: 480-323-1350                            
Fax: 480-323-1359                           
Email: gayle.jameson@honorhealth.com 
Sub-Investigator 
Ron Korn, MD, PhD 
Scottsdale Medical Imaging, LTD 
PO Box 1573 
Scottsdale, AZ 85252 
Tel: 480-425-5000 
Fax: 480-425-5033 
Email: rkorn@imagingendpoints.com 
Sub-Investigator 
Lana Caldwell, RN, MSN 
Honor Health Research Institute 
10510 N. 92nd Street 
Scottsdale, AZ, 85258 
Sub-Investigator 
Karen L. Ansaldo, PharmD, BCPS 
Honor Health Research Institute 
Pharmacy 
10460 N. 92nd Street 


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Tel: 480-323-1074 
Fax: 480-323-1359 
Email: lana.caldwell@honorhealth.com 
Scottsdale, AZ, 85258 
Tel: 480-323-1019 
Fax: 480-323-1059 
Email: karen.ansaldo@honorhealth.com 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of HonorHealth. Any 
unauthorized use or disclosure of such information without the prior written authorization of HonorHealth is 
prohibited. 
 
 
SOURCE OF SUPPORT 
This study is partially funded by 
 
 
 
AND 
 
 
           Foundation 
 
  


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INVESTIGATOR’S PROTOCOL AGREEMENT 
Protocol No.: 
NAPPCG-EB 2015-001 
Version 7.0,  May 2020 
 
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 study specified herein. In particular, I/we have 
agreed to: 
 
 
Abide by all obligations stated on Form FDA 1572 and on other document(s) required by local 
regulatory authority. 
 
Retain records and documents related to this Trial for at least 7 years after the last approval of a 
marketing application in an International Conference on Harmonization (ICH) region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 7 years have 
elapsed since the formal discontinuation of clinical development of the investigational products. 
 
Comply with Good Clinical Practice (GCP) and all applicable regulatory requirements. 
 
Maintain confidentiality and assure security of HonorHealth confidential documents. 
 
Obtain Institutional Review  Board (IRB) approval of the protocol, any amendments to the protocol, 
and periodic re-approval as required, and to keep the IRB informed of adverse events and 
periodically report the status of the study to them. 
 
Not implement any deviations from or changes to the protocol without agreement from the Lead 
Sponsor-Investigator and HonorHealth 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 
study (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 study are adequately informed and trained about 
the investigational drug and of their study-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 
of the death and 2 business days of learning of the SAE) to HonorHealth. 
 
Assure access by HonorHealth monitors, 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 HonorHealth. 
 
Cooperate fully with any study-related GCP audit as performed by HonorHealth quality assurance 
group. 
 
Abide by the stipulations in the Disclosure of Data section and the manuscript preparation/authorship 
guidelines established at the outset of the study. 
Investigator’s Printed Name: 
Investigator’s Signature: 
Date: 
 


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SAE REPORTING 
 
All SAEs must be reported promptly to HonorHealth after the Investigator recognizes/ 
classifies the event as a SAE. For life-threatening or fatal events, the Investigator must 
report initial information on the SAE within 1 business day of becoming aware of the event, 
preferably by fax or alternatively by phone or email. 
 
HonorHealth Drug Safety Team 
24 Hour Phone #: 480-323-1350 
Fax # : 480-323-1560 
Email: DrugSafety@honorhealth.com  
 
 
 
 


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Protocol Schema 
 
Patient with metastatic pancreatic cancer previously untreated for their metastatic disease 
 
Signed informed consent 
 
If protocol eligible 
 
Cycles 1-4 and beyond if not on maintenance therapy 
A cycle is defined as 6 weeks (42 days) with the following treatment schedule 
- 
Nivolumab – 240 mg as a 60 minute infusion on days 1, 15, 29 
- Albumin-bound paclitaxel – 125 mg/m2 over 30 minutes IV infusion on days 1, 8 and 22, 
29 
- 
Cisplatin* – 25 mg/m2 over 60 minutes IV infusion on  days 1, 8 and 22, 29 
- Gemcitabine – 1000 mg/m2 over 30 minutes IV infusion on days 1, 8 and 22, 29 
- 
Paricalcitol – 25 micrograms IV on days 1,4,8,12,15,18,22,26,29,32,36,39 (+/-1 day 
allowed for dosing 
 
 
 
*Please see details in protocol for hydration and supportive care items 
 
 


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TABLE OF CONTENTS 
1 BACKGROUND AND RATIONALE ........................................................................ 12 
1.1 
Background ................................................................................................................ 12 
1.2 
Rationale .................................................................................................................... 13 
1.3 
Indications and Adverse Reactions of Nivolumab (Taken from Prescribing 
Information/Package Insert for Opdivo®) .................................................................... 14 
1.3.1 
Adverse Reactions .......................................................................................... 15 
1.4 
Potential Risks of Albumin-bound Paclitaxel (formerly known as nab-paclitaxel) ........ 15 
1.4.1 
Side Effects ..................................................................................................... 15 
1.5 
Potential Risks of Cisplatin ......................................................................................... 16 
1.6 
Potential Risks of Gemcitabine ................................................................................... 16 
1.7 
Potential Risks of Paricalcitol ...................................................................................... 16 
1.7.1 
Potential Risks ................................................................................................ 17 
1.8 
Potential Risks of Albumin-bound Paclitaxel + Gemcitabine ....................................... 18 
1.9 
Potential Risks of Albumin-bound Paclitaxel, + Cisplatin, +  Gemcitabine ................... 18 
1.10 Potential Risks of Nivolumab + Albumin-bound Paclitaxel + Paricalcitol + Cisplatin + 
Gemcitabine ............................................................................................................... 18 
1.11 Study and Dose Rationale .......................................................................................... 18 
1.12 Sequence of Drug Administration and Rationale ......................................................... 19 
2 OBJECTIVES .......................................................................................................... 19 
2.1 
Primary Objective ....................................................................................................... 19 
2.2 
Secondary Objective .................................................................................................. 19 
2.3 
Overview .................................................................................................................... 19 
2.4 
Primary Endpoints ...................................................................................................... 20 
2.5 
Secondary Endpoints.................................................................................................. 20 
2.6 
Exploratory Endpoints................................................................................................. 20 
3 STUDY POPULATION ............................................................................................ 20 
3.1 
Patient Selection and Study Duration ......................................................................... 20 
3.2 
Inclusion Criteria ......................................................................................................... 20 
3.3 
Exclusion Criteria ........................................................................................................ 21 
3.4 
Patient Enrollment ...................................................................................................... 22 
3.5 
Patient Discontinuation ............................................................................................... 23 
3.6 
Study Discontinuation ................................................................................................. 23 


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4 STUDY TREATMENT .............................................................................................. 23 
4.1 
Administration and Dosing .......................................................................................... 23 
4.2 
Body Surface Area Calculation ................................................................................... 25 
4.3 
Dose Modification for Toxicity ..................................................................................... 25 
4.3.1 
For Nivolumab ................................................................................................. 25 
4.3.2 
For albumin-bound paclitaxel or gemcitabine or cisplatin or paricalcitol .......... 25 
4.3.2.1 Hematological Toxicity ....................................................................... 26 
4.3.2.2 Non-hematological Toxicity ................................................................ 27 
4.3.2.3 Peripheral Neuropathy ....................................................................... 28 
4.3.2.4 Nephrotoxicity .................................................................................... 28 
4.3.2.5 Cutaneous Toxicity ............................................................................ 29 
4.3.2.6 Gastrointestinal Toxicity ..................................................................... 29 
4.3.2.7 Pulmonary Embolism ......................................................................... 29 
4.3.2.8 Interstitial Pneumonitis ....................................................................... 29 
4.3.2.9 Hypersensitivity Reactions ................................................................. 30 
4.3.2.10 Colony Stimulating Factors ................................................................ 30 
4.3.2.11 Prophylaxis against Sepsis ................................................................ 31 
4.3.3 
Intended Dose Delays ..................................................................................... 31 
4.4 
Special Warning and Precautions and Management for Possible Nivolumab 
Complications (See Nivolumab Prescribing Information for detailed AE incidence in 
key approval trials). .................................................................................................... 31 
4.4.1 
Immune –Mediated Pneumonitis ..................................................................... 31 
4.4.2 
Immune-Mediated Colitis ................................................................................ 31 
4.4.3 
Immune-mediated Hepatitis ............................................................................ 32 
4.4.4 
Immune-Mediated Nephritis and Renal Dysfunction ........................................ 32 
4.4.5 
Immune-Mediated Endocrinopathies ............................................................... 33 
4.4.5.1 Hypophysitis ...................................................................................... 33 
4.4.5.2 Adrenal Insufficiency .......................................................................... 33 
4.4.5.3 Hypothyroidism and Hyperthyroidism ................................................. 33 
4.4.5.4 Type 1 Diabetes Mellitus .................................................................... 34 
4.4.6 
Immune-Mediated Skin Adverse Reactions ..................................................... 34 
4.4.7 
Immune-Mediated Encephalitis ....................................................................... 34 
4.4.8 
Other Immune-Mediated Adverse Reactions ................................................... 35 
4.4.9 
Infusion Reactions .......................................................................................... 35 
4.5 
Concomitant Therapy ................................................................................................. 35 


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4.5.1 
Prohibited Concomitant Therapy ..................................................................... 35 
4.5.2 
Permitted Concomitant Therapy ...................................................................... 36 
4.5.3 
Concomitant Therapies Requiring Caution ...................................................... 36 
5 STUDY ASSESSMENTS ......................................................................................... 36 
5.1 
Laboratory Assessments ............................................................................................ 36 
5.2 
Quality of life and Pain Assessments .......................................................................... 36 
5.3 
Exploratory Biomarkers .............................................................................................. 37 
5.4 
Screening (Within 21 Days Prior to First Dose) ........................................................... 37 
5.5 
On-Study Assessments .............................................................................................. 38 
5.6 
End of Study ............................................................................................................... 41 
5.7 
Follow-Up Assessments after End of Study or Early Termination ............................... 42 
5.8 
Treatment Assignment ................................................................................................ 42 
5.9 
Patient Disposition ...................................................................................................... 42 
5.10 Patient Characteristics ................................................................................................ 42 
5.11 Statistical Considerations ........................................................................................... 42 
5.12 Efficacy Analysis ......................................................................................................... 43 
5.13 Safety Analysis ........................................................................................................... 43 
5.14 Replacement of Patients ............................................................................................. 44 
6 EVALUATION OF RESPONSE ............................................................................... 44 
6.1 
Best Overall Response ............................................................................................... 44 
6.2 
Overall Tumor Response ............................................................................................ 44 
6.3 
Not Evaluable ............................................................................................................. 44 
6.4 
Progression-free Survival ........................................................................................... 44 
6.5 
Survival ...................................................................................................................... 44 
6.6 
Analysis Plan .............................................................................................................. 44 
6.7 
Guidelines for Measuring Disease .............................................................................. 45 
6.8 
Disease Definitions ..................................................................................................... 45 
6.9 
Methods of Measurement ........................................................................................... 46 
6.10 Baseline Documentation of “Target” and “Non-target” Lesions ................................... 46 
6.11 Response Criteria ....................................................................................................... 47 
6.12 Evaluation of Best Overall Response .......................................................................... 47 
6.13 Duration of Stable Disease .......................................................................................... 49 
7 SAFETY ................................................................................................................... 49 
7.1 
Adverse Events .......................................................................................................... 49 


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7.2 
Serious Adverse Events ............................................................................................. 50 
7.3 
Adverse Event Severity .............................................................................................. 50 
7.4 
Causality Assessment ................................................................................................ 51 
7.5 
Safety and Tolerance Analysis ................................................................................... 51 
7.5.1 
Laboratory Assessments ................................................................................. 51 
7.5.1.1 Hematology Parameters .................................................................... 51 
7.5.1.2 Clinical Chemistry .............................................................................. 51 
7.5.2 
Peripheral Neuropathy .................................................................................... 52 
7.6 
Patient Reporting of AEs and SAEs ............................................................................ 52 
7.7 
Investigator Reporting Serious Adverse Events .......................................................... 52 
7.7.1 
Expedited Reporting by Investigator to HonorHealth ....................................... 53 
7.7.2 
IRB Notification of SAEs ................................................................................. 54 
7.8 
SAE Follow-Up ........................................................................................................... 54 
7.8.1 
Sponsor Notification of Post-Study SAEs ........................................................ 54 
7.9 
Pregnancy .................................................................................................................. 54 
8 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ........................................ 54 
8.1 
Ethics ......................................................................................................................... 54 
8.1.1 
Institutional Review Board/ Ethics Committee Approval .................................. 55 
8.1.2 
Ethical Conduct of the Study ........................................................................... 55 
8.1.3 
Informed Consent ........................................................................................... 55 
8.1.4 
Data Safety and Monitoring Committee ........................................................... 55 
8.2 
Disclosure of Data ...................................................................................................... 56 
8.2.1 
Study Data Monitoring Plan ............................................................................. 56 
8.2.2 
Confidentiality ................................................................................................. 57 
8.2.3 
Publication ...................................................................................................... 57 
8.3 
Protocol Compliance .................................................................................................. 57 
8.4 
Quality Assurance ...................................................................................................... 58 
8.5 
On-site Audits ............................................................................................................. 58 
8.6 
Premature Closure of the Study .................................................................................. 58 
8.7 
Investigator Documentation ........................................................................................ 58 
8.7.1 
Form FDA 1572 .............................................................................................. 58 
8.7.2 
Curriculum Vitae ............................................................................................. 59 
8.7.3 
Financial Disclosures ...................................................................................... 59 
8.7.4 
Laboratory Certification and Normal Ranges ................................................... 59 
8.8 
Records Retention ...................................................................................................... 59 


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8.9 
Protocol Deviations ..................................................................................................... 59 
9 DATA MANAGEMENT ............................................................................................ 60 
9.1 
Patient Enrollment Instructions ................................................................................... 60 
9.2 
Data Submission Instructions ..................................................................................... 60 
10 TERMINATION OF STUDY ..................................................................................... 60 
11 INVESTIGATOR’S PROTOCOL AGREEMENT ...................................................... 60 
12 REFERENCES ........................................................................................................ 61 
13 APPENDICES.......................................................................................................... 66 
APPENDIX A:  Schedule of Evaluations and Treatment ................................................ 66 
APPENDIX B: KARNOFSKY PERFORMANCE STATUS ............................................. 70 
Appendix C: List of Abbreviations ................................................................................. 71 
APPENDIX D: Revised National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), version 4.0 (published 28 May 2009) ....... 75 
APPENDIX E: Study Drug Preparation, Dosing, Administration and Storage ............... 76 
APPENDIX F: 2006 Update of ASCO Practice Guideline Recommendations for the Use 
of White Blood Cell Growth Factors: Guideline Summary ......................... 77 
APPENDIX G: MANAGEMENTALGORITHMS FOR ADVERSE EVENTS RELATED TO 
NIVOLUMAB THERAPY (FROM APPENDIX 3 OF INVESTIGATOR’S 
BROCHURE VERSION 13, 30 June 2015 FROM BMS-936558/MDX 
1106) ......................................................................................................... 80 
APPENDIX H:  Memo for dexamethasone dose reduction with concomitant 
administration of fosaprepitant .................................................................. 88 
APPENDIX I:  The MD Anderson Symptom Inventory Gastrointestinal Cancer Module 
(MDASI-GI) (to be submitted separately from protocol for IRB approval) .. 89 
APPENDIX J:  The Brief Pain Inventory (BPI) – Short Form (to be submitted separately 
from protocol for IRB approval) ................................................................. 90 
 
 
14  TABLES 
Table 1. Regimen Rationale……………………………………………………………. ............. ...13 
Table 2. Reduction Schema ............................................................................................. 25 
Table 3. Dose Modifications for Day 1 of Each Cycle with a cycle being defined as 42 days   
(Hematologic Toxicity) ....................................................................................... 26 
Table 4. Dose Modification for Days 8 or 29 of Each Cycle (Hematologic Toxicity). .............. 27 
Table 5. Albumin-bound paclitaxel and gemcitabine and cisplatin Dose                     
Modifications for Day 1 of Each Cycle (Non-hematologic Toxicity). ........................ 28 
Table 6. Albumin-bound paclitaxel and gemcitabine and cisplatin Dose Modifications Day 8 or 
29 of Each Cycle (Non-hematological Toxicity) .................................................... 28 


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Table 7. RECIST Target Lesion Response Criteria ............................................................ 47 
Table 8. RECIST Non-target Lesion Response Criteria .................................................... ..47 
Table 9.  RECIST Overall Response Criteria…………………………………………….... .......... 48 
 


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 BACKGROUND AND RATIONALE 
 
1.1 Background 
 
Despite decades of basic and clinical research, effective therapy for the treatment of patients 
with pancreatic ductal adenocarcinoma (PDAC) remains one of the greatest unmet clinical 
needs in oncology today.  Currently, PDAC accounts for approximately 7% of all cancer-related 
mortality and has the lowest 5-year survival rate among all cancer types in the United States 
(Siegel et al, 2015).   PDAC is currently the 4th leading cause of death from cancer in the U.S. 
with estimates in 2015 for 48,960 people diagnosed and  40,560 dying from the disease (Siegel 
et al, 2015).  Worldwide it will claim more than 300,000 lives this year (Torre et al, 2015).  It is 
projected that by 2030, pancreatic cancer will become the second leading cause of cancer-
related death in the US (Rahib et al, 2014).  Improved strategies for early detection and for 
treatment of PDAC are desperately needed.  Additionally, further investigation into patient-
reported quality of life and pain levels in this population needs to be explored. 
 
For  patients with advanced disease, the regimen of 5-fluorouracil/ leucovorin/ irinotecan/ 
oxaliplatin (FOLFIRINOX) compared with gemcitabine demonstrated improvement in both 
progression-free survival (6.4 vs. 3.3 months) and overall survival (11.1 vs. 6.8 months) for  
patients with a good performance status.  FOLFIRINOX is often associated with substantial 
grade 3 and 4 toxicities, including diarrhea, nausea, vomiting, fatigue, neutropenia and febrile 
neutropenia, and cannot be given to  patients > 76 years of age or in some cases to  patients 
with head of the pancreas tumors (Conroy 2011, Assaf 2011).   
 
Von Hoff and colleagues (2011) presented phase I/II data supporting the use of albumin-bound 
paclitaxel and gemcitabine in a phase I/II trial in  patients with previously untreated advanced 
PDA.  All patients at the recommended phase II dose (n=44) had a decrease in CA 19-9.  This 
regimen also demonstrated an objective response rate of 48% with median survival of 12.2 
months and 48% 1-year survival and 25% 2-year survival.   
 
An international phase III trial comparing the albumin-bound paclitaxel plus gemcitabine 
combination to gemcitabine single agent was conducted.  In that study published in 2013 (Von 
Hoff et al), a total of 861 patients were randomly assigned to albumin-bound paclitaxel plus 
gemcitabine (431 patients) or gemcitabine (430).  The median overall survival was 8.5 months 
in the albumin-bound paclitaxel plus gemcitabine group as compared to 6.7 months in the 
gemcitabine group (hazard ratio for death 0.72, 95% confidence interval (CI), 0.62 to 0.83; P 
<0.001).  The survival rate was 35% in the albumin-bound paclitaxel plus gemcitabine group 
versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years.  The median 
progression-free survival was 5.5 months in the albumin-bound paclitaxel-gemcitabine group 
versus 3.7 months the gemcitabine alone arm (hazard ratio for disease progression or death, 
0.69; 95%CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 
23% versus 7% in the two groups (P<0.001)  The most common adverse events of grade 3 or 
higher were neutropenia (38% in the albumin-bound paclitaxel-gemcitabine group vs. 27% in 
the gemcitabine group), fatigue (17% vs. 7%) and neuropathy (17% vs. 1%).  Febrile 
neutropenia occured in 3% versus 1% of the patients in the two groups respectively.  In the 
albumin-bound paclitaxel plus gemcitabine group, neuropathy of grade 3 or higher improved to 
grade 1 or lower in a median of 29 days. 
 
The conclusion from that study was in patients with metastatic pancreatic adenocarcinoma, 
albumin-bound paclitaxel plus gemcitabine significantly improved overall survival, progression 


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free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were 
increased. (funded by Celgene; ClinicalTrials.gov number NCT00844649) 
 
In a very recent long term follow up on the study (Goldstein et al, 2015),  the median overall 
survival was significantly longer for albumin-bound paclitaxel + gemcitabine versus gemcitabine 
alone (8.7 versus 6.6 months; hazard ratio = 0.72;95% confidence interval (CI) = 0.62 to 0.83, 
P<0.001.  Long term (> than three years) survivors were indentified in the albumin-bound 
paclitaxel plus gemcitabine arm  (4%).  There were no survivors in the single agent gemcitabine 
arm. 
 
1.2 Rationale 
 
The NAPPCG regimen proposed in this protocol is built on the rationale outlined in Table 1. 
Building on the design and mechanisms of action of the albumin-bound paclitaxel plus 
gemcitabine combination, we recently introduced a third cytotoxic agent, cisplatin, to be added 
to this doublet.  The rationale for adding cisplatin to albumin-bound paclitaxel and gemcitabine 
is that in a study of 1,029 patients whose pancreatic cancer tumors were sent for molecular 
profiling, 57% of these tumors were negative for ERCC1, indicating potential sensitivity to a 
platinum anti-tumor agent (Von Hoff, 2012). In addition to the above, in our whole 
genome/transcriptome sequencing analysis, we found that abnormal repair pathways were a 
feature of all of the pancreatic cancers that were sequenced (Liang 2012).  Cisplatin prevents 
cellular DNA repair by binding to and causing crosslinking of DNA, triggering apoptosis.  
Cisplatin has been used in other combination regimens to treat  patients with PDAC.  For 
example, the cisplatin, epirubicin, 5-fluorouracil and gemcitabine (PEFG) regimen had an 
acceptable toxicity profile and was associated with a 24% partial response rate, 5 month 
progression-free survival (PFS) and 8.3 month overall survival as second line therapy (Reni et 
al, 2008). 
 
Prior to 2015, there were no documented reports of the combination of cisplatin with albumin-
bound paclitaxel and gemcitabine in the treatment of any human cancer.  However, cisplatin 
had been combined with paclitaxel and gemcitabine in the treatment of patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) patients and had shown substantial 
antitumor activity with an acceptable safety profile.  In that phase I-II study of 65 patients with 
advanced NSCLC, the overall response rate was 57% (Frasci et al, 1999). 
More recently there has been even more compelling science indicating that one should consider 
DNA repair as an Achilles heel in pancreatic cancer (Evers et al, 2014)  A team led by Nurse 
Practitioner Gayle Jameson (Jameson et al, 2015) recently reported on the phase Ib/II trial of 
the combination of nanoparticle paclitaxel (now called albumin-bound paclitaxel) plus 
gemcitabine plus cisplatin.  In the first 10 patients with stage IV pancreatic cancer they reported 
20% Complete response (CR), 60% Partial response (PR), 10% stable disease, 10% 
progressing on the trial.  The trial is ongoing but is obviously very promising with an acceptable 
toxicity profile and complete responses (CR) . 
 
Most recently the spectacular work of Sherman et al (2015) has awakened the world of 
pancreatic cancer research to the possibility that Vitamin D could be a substantial player in 
normalizing the tumor microenvironment from an immunologically friendly (to the tumor) one to 
an immunologically hostile one (e.g. decreased IL6, decreased CXCL12 etc.). In addition, the 
vitamin D analog decreased production of collagen, decreased Myeloid derived Suppressor cell 
(MDSC) and decreased regulating T cells.  This work is begging to be looked at in a clinical 
situation and promises to turn around the problem that basically for patients with PDAC, there 


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has never been a substantial response to anti-immune blockade agents (Le et al, 2013; Royal et 
al, 2010). 
 
Based on the very promising clinical data with albumin-bound paclitaxel plus gemcitabine plus 
cisplatin plus the substantial modulation of the immune environment produced by albumin- 
bound paclitaxel  plus gemcitabine  plus paricalcitol (the synthetic Vitamin D) with infiltration of 
CD3 positive lymphocytes in an ongoing neoadjuvant trial (unpublished SU2C data courtesy of 
Drs. O’Dwyer and Drebin University of Pennsylviania ), we are now in a position to put together 
an ultimate attack against the disease. It is based on the above that we plan this bold approach 
of combining immuno-oncology  into a reengineered (normalized) microenvironment to look for 
a dramatic effect in  patients with advanced pancreatic cancer. 
 
Table 1  Regimen Rationale 
Agent 
Rationale 
Reference 
Nivolumab 
 
Presence of PD1 
Nomi et al, 2007 
Gattalica et al, 2014 
Gemcitabine 
 
Improved survival as single 
agent and in combination 
Burris et al, 1997 
Von Hoff et al, 2011, 2013 
Albumin-bound 
Paclitaxel 
 
Active as a single agent against 
pancreatic cancer 
 
Improved survival in combination 
with Gemcitabine 
 
Decreases tumor stroma by 
decreasing cancer associated 
fibroblasts with improving 
elasticity 
 
In combination allows 
penetration of lymphocytes 
Peddi et al, 2013 
Von Hoff et al, 2013 
Alvarez et al, 2013 
Paricalcitol 
 
Acts to reengineer the tumor 
stroma  decrease collagen and 
decrease IL6 plus CXCL12 
Sherman et al, 2014 
Cisplatin 
 
DNA repair abnormalities in 
patients with cancer 
Von Hoff et al, 2012 
Liang et al, 2012 
 
Please note that to date there is not a great deal of information on the use of nivolumab with 
conventional chemotherapies. What is known is that for combinations of nivolumab (maximum 
dose used 10 mg/kg) with gemcitabine/cisplatin, with pemetrexed/cisplatin or with 
carboplatin/paclitaxel that there were no dose limiting toxicities noted (nivolumab Investigator 
Brochure version No. 14, 30June2015).  
 
As of July 6, 2018, there have been 25 patients enrolled on the current protocol 
(NCT02754726) with the first 10 patient outcomes presented at the Gastrointestinal Cancer 
Symposium [Borazanci et al 2018]. In the first 10 patients that was presented, the overall 
response rate is 80% with 8/10 patients attaining a PR. In unpublished data from the 25 
patients the response rate remains above 80%, all partial responses 
 
 
1.3 Indications and Adverse Reactions of Nivolumab (Taken from Prescribing 


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Information/Package Insert for Opdivo®) 
 
See Appendix E for links to current prescribing information 
 
 
 Adverse Reactions 
Most common adverse reactions (>20%) in patients were:  fatigue, rash, musculoskeletal pain, 
pruritis, diarrhea, nausea, asthesia, cough, dyspnea, constipation, decreased appetite, back 
pain, arthralgia, upper respiratory tract infection, pyrexia.  
 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 
 
 
 
1.4 Potential Risks of Albumin-bound Paclitaxel (formerly known as nab-paclitaxel) 
 
The most common toxicities reported for albumin-bound paclitaxel include myelosuppression, 
predominantly neutropenia, infections (24%), dyspnea (12%), peripheral neuropathy and 
nausea and vomiting, myalgias and arthralgias, mucositis, alopecia, transaminitis, serum 
creatinine elevation.  Other reported infrequent toxicities include:  allergic reaction, loss of 
appetite, diarrhea, constipation, cough, edema, fever, pruitis, hypotension, nail changes, vision 
changes, rash, pulmonary edema, irregular heartbeat (see Appendix E for link to prescribing 
information). 
 
 Side Effects 
 
Hematologic disorders – Neutropenia was dose dependant and reversible.  
Among patients with metastatic breast  cancer in the randomized trial, neutrophil 
counts declined below 500 cells/mm3 (grade 4) in 9% of the patients treated with 
a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at 
a dose of 175 mg/m2. 
 
 
Infections – Infectious episodes were reported in 24% of the patients treated with 
paclitaxel.  Oral candidiasis, respiratory tract infections and pneumonia were the 
most frequently reported infectious complications.Pancytopenia has been 
observed in clinical trials. 
 
 
Hypersensitivity reactions (HSRs) – Grade 1 or 2 HSRs occured on the day of 
paclitaxel administration and consisted of dyspnea (1%) and flushing, 
hypotension, chest pain and arrhythmia (all < 1%).  The use of paclitaxel in 
patients previously exhibiting hypersensitivity to paclitaxel injection or human 
albumin has not been studied. 
 
 
Cardiovascular – Hypotension, during the 30-minute infusion, occured in 5% of 
patients. Bradycardia, during the 30-minute infusion, occurred in <1% of patients.   
These vital sign changes most often caused no symptoms and required neither 
specific therapy nor treatment discontinuation.  Severe cardiovascular events 
possibly related to single-agent paclitaxel occurred in approximately 3% of 
patients.  These events included cardiac ischemia/infarction, chest pain, cardiac 
arrest, supraventricular tachycardia, edema, thrombosis, pulmonary 


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thromboembolism, pulmonary emboili, and hypertension.  Cases of 
cerebrovascular attacks (strokes) and transient ischemic attacks have been 
reported.  Electrocardiogram (ECG) abnormalities were common among patients 
at baseline.  ECG abnormalities on study did not usually result in symptoms, 
were not dose-limiting, and required no intervention.  ECG abnormalities were 
noted in 60% of some patients. 
 
1.5 Potential Risks of Cisplatin 
 
The most common toxicities of cisplatin include nephrotoxicity (28-36%; acute renal failure and 
chronic renal insufficiency), peripheral neuropathy (dose and duration dependent), nausea and 
vomiting (76% to 100%), myelosuppression (25% to 30%; nadir: day 18-23; recovery: by day 
39; mild with moderate doses, mild-to-moderate with high-dose therapy), liver enzymes 
increased (especially SGOT and bilirubin), ototoxicity (10% to 30%; manifested as high 
frequency hearing loss; ototoxicity is especially pronounced in children) and  tissue irritation 
(extravasation). 
 
Other toxicities (<1%) include alopecia (mild), anaphylactic reaction, arrhythmias, arterial 
vasospasm (acute), blurred vision, bradycardia, diarrhea, heart block, heart failure, hemolytic 
anemia (acute), hemolytic uremic syndrome, hypercholesterolemia, hypocalcemia, 
hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, limb ischemia (acute), 
mesenteric ischemia (acute), myocardial infarction, myocardial ischemia, mouth sores, 
neutropenic typhlitis, optic neuritis, orthostatic hypotension, pancreatitis, papilledema, phlebitis, 
reversible posterior leukoencephalopathy syndrome (RPLS), Syndrome of Inappropriate 
antidiuretic hormone secretion (SIADH), stroke, thrombophlebitis and thrombotic 
thrombocytopenic purpura (see Appendix E for link to prescribing information). 
 
1.6 Potential Risks of Gemcitabine  
 
The most common toxicities reported for gemcitabine include myelosuppression, transient 
elevations in serum transaminases (approximately 70%), nausea and vomiting (69%), fever 
(41%), rash (30%), diarrhea (19%), flu syndrome, (19%), infection (16%), alopecia (15%), 
edema (13%), stomatitis (11%),) neurotoxicity (mild 10%, severe <1%), mild proteinuria and 
hematuria; Hemolytic Uremia Syndrome (HUS) reported rarely (0.25%), dyspnea (0.2%) and 
serious pulmonary toxicity (0.06%). Also reported include constipation and pruritus (see 
Appendix E for link to prescribing information). 
 
1.7 Potential Risks of Paricalcitol 
 
Paricalcitol [19-nor-1α, 25 – dihydroxyvitamin D2] (also known as Zemplar) is a vitamin D 
analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. We have 
selected paricalcitol as our Vitamin D analog based on its broad use over a decade in the 
management of calcium and Vitamin D homeostasis in  patients undergoing renal dialysis and 
because it is being used in an ongoing neoadjuvant clincial trial with albumin-bound paclitaxel + 
gemcitabine (PI  - Peter O’Dwyer) with good safety in the first 15 patients.  Paricalcitol is 
chemically designated as 19-nor-12,B (3),25-trihydroxy-9,10-secoergosta5(Z), 7 (E), 22 (E)–
triene, and is a non-metabolized vitamin D  analogue that has little hypercalcemic activity (see 
Appendix I for package insert).  As such, it is the ideal compound to effect the desired 
transcriptional change in the tumor microenvironment (Sherman et al, 2014).  In addition to well-
established effects on bone mineral homeostasis, there is increasing recognition that vitamin D 


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may play a role in renal and cardiovascular function, as well as T Cell function in some 
circumstances.  Randomized clinical trials showed a positive effect of paricalcitol in patients with 
chronic renal disease on mineral metabolism, on cardiovascular outcome, and on markers of 
kidney damage (Bellasi et al, 2013).  This positive effect on survival is observed not only in 
patients with elevated intact parathyroid hormone (iPTH), but even in those with low levels of 
this hormone (Ozzolino et al, 2012).  The recommended starting dose of paricalcitol is 0.04 
micrograms/kg (or about 3 micrograms per dose), but total weekly doses of 15 to 30 
micrograms are reported in the literature without safety concerns (Izanuerdo et al, 2012, Kettler 
et al, 2012, Tanblul et al, 2012). A trial in combination with taxol in breast cancer patients gave 
up to 7 micrograms per day for 12 weeks (Lawrence et al, 2013).   
 
There have been trials of paricalcitol in cancer patients also; In a population of prostate cancer 
patients  (mean age 74) thrice weekly paricalcitol was administered at doses up to 25 
micrograms, with no dose-limiting toxicity (Schwartz et al, 2005).  The authors suggested that 
higher doses could be explored.  However, we do not feel higher doses are needed in this trial, 
since all patients in their study showed a decline in iPTH, with minimal toxicity.  There was mild 
nausea in 8/18 patients, mild vomiting in 2/18 patients, and a photosensitive rash in 1/ 18.  Four 
patients developed hypercalcemia, only one higher than 12 mg/dl (and this only 14.3 mg/dl) 
(Schwartz et al, 2005).  Accordingly we propose to use a two times weekly IV schedule (given 
concerns regarding oral absorption in pancreatic cancer patients) at a flat dose of 25 
micrograms.  A detailed population  pharmacokinetic analysis including over 600 patients 
showed mean plasma clearance of 1.75l/h, and stable phosphorus and calcium levels in the first 
30 days of treatment (Nortersheusen et al, 2012).  This analysis lends support to both the dose 
and schedule chosen for our NAPPCG regimen, as well as lends support to the schedule of 
weekly electrolyte monitoring.   
 
 Potential Risks 
 
 
Gastrointestinal Disorders:  abdominal discomfort, constipation, diarrhea, nausea, 
vomiting, dysphagia, gastritis, intestinal ischemia, rectal hemorrhage, 
gastrointestinal hemorrhage, aspartate aminotransferase increased 
 
 
General Disorders and Administration Site Conditions:  asthenia, chest discomfort, 
chest pain, peripheral edema, fatigue, feeling abnormal, gait disturbance, injection 
site extravasation, injection site pain, pain, swelling, thirst, chills, fever 
 
 
Infections and Infestations:  nasopharyngitis, upper respiratory tract infection, 
vaginal infection, influenza, pneumonia, sepsis 
 
 
Metabolism and Nutrition Disorders:  decreased appetite, hypercalcemia, 
hyperkalemia, hyperphosphatemia, hypocalcemia, weight decreased 
 
 
Musculoskeletal and Connective Tissue Disorders: joint stiffness, muscle twitching, 
myalgia, arthralgia 
 
 
Neoplasms Benign, Malignant and Unspecified:  breast cancer 
 
 
Nervous System Disorders:  cerebrovascular accident, dizziness, dysgeusia, 
headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli 
 


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 
Psychiatric Disorders:  agitation, confusional state, delirium, insomnia, nervousness, 
restlessness 
 
 
Reproductive System and Breast Disorders: breast pain, erectile dysfunction 
 
 
Respiratory, Thoracic and Mediastinal Disorders:  cough, dyspnea, orthopnea, 
pulmonary edema, wheezing 
 
 
Skin and Subcutaneous Tissue Disorders:  alopecia, blister, hirsuitism, night 
sweats, rash (pruritic), pruritus, skin burning sensation, urticaria 
 
 
Vascular Disorders:  hypertension, hypotension, angioedema 
 
 
Other:  dry mouth 
 
(See Appendix E for link to prescribing information). 
 
1.8 Potential Risks of Albumin-bound Paclitaxel + Gemcitabine 
 
The safety of albumin-bound paclitaxel plus gemcitabine was reported by Von Hoff and 
colleagues (Von Hoff 2011, 2013). The most common toxicities seen in the phase III trial were 
anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, alopecia, sensory neuropathy and 
nausea.  
 
1.9 Potential Risks of Albumin-bound Paclitaxel, + Cisplatin, +  Gemcitabine 
 
The combination of albumin-bound paclitaxel, cisplatin, and gemcitabine has just been recently 
reported in a preliminary manner (Jameson et al, 2015).  In the report on the first 10 patients on 
that phase Ib/II trial overall grade 3 toxicities included anemia (30%); diarrhea (20%); C-difficile 
colitis (10%); hypoglycemia (10%); lung infection (20%); decreased lymphocyte count 
(10%);increased lymphocyte count (10%); nausea (10%); neutropenia (30%); peripheral motor 
neuropathy (10%); thrombocytopenia (50%); vomiting (10%).  Grade 4 toxicities included febrile 
neutropenia 10%); thrombocytopenia (50%); and sepsis (10%).  The study is being expanded at 
the cisplatin dose of 25mg/m2. 
 
1.10 Potential Risks of Nivolumab + Albumin-bound Paclitaxel + Paricalcitol + 
Cisplatin + Gemcitabine 
 
Since this will be the first time this regimen is given we can only speculate as to any potential 
increased risk over and above what we have seen with the individual agent and combination 
regimens described above.  Patients will be seen at least weekly so any toxicities  can be 
detected and monitored carefully and treated as indicated.  We will be particularly vigilant for 
pneumonitis which has been described for gemcitabine, albumin-bound paclitaxel and 
nivolumab (see below).  We will be vigilant for nephritis and renal dysfunction, colitis and thyroid 
issues (hypo and hyper thyroidism), along with other immune related toxicities. 
 
1.11 Study and Dose Rationale 
 
Since we already have good safety data (and excellent prelimimary efficacy) of the albumin-
bound paclitaxel + gemcitabine + cisplatin regimen with nivolumab  we feel it is safe in this 


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phase II pilot trial to continue at  the recommended dose of nivolumab which is 240mg dose and 
utilize that dose(see below). The dose of Nivolumab will be 240mg as a 60 minute infusion days 
1, 15, 29, etc.  
 
1.12 Sequence of Drug Administration and Rationale 
 
The sequence of drug administration is nivolumab, albumin-bound paclitaxel, then cisplatin, 
then gemcitabine.  Albumin-bound paclitaxel is given before the other chemotherapies because 
it may be taken up by the process of macropinocytosis. Then after adequate hydration (see 
Section 4.1),  the cisplatin is given. Gemcitabine is given next because albumin-bound paclitaxel 
potentially decreases cytidine deaminase which potentiates gemcitabine activity (less 
degradation of gemcitabine by the enzyme).(Frese et al, 2012).  Then paricalcitol is given last 
as it is in the ongoing SU2C neoadjuvant study.     
                                                               
                                                                                                                                                        
 OBJECTIVES 
 
2.1 Primary Objective 
 
The primary objective of this study is to determine the preliminary efficacy of the combination of 
nivolumab with albumin-bound paclitaxel plus paricalcitol plus cisplatin plus gemcitabine (the 
NAPPCG regimen) for patients with previously untreated (for their metastatic disease) 
metastatic pancreatic ductal cancer. This will be done by determining the complete response 
rate (CR), the overall response rate (ORR), progression free survival (PFS) and overall survival 
(OS).  
 
2.2 Secondary Objective  
 
The secondary objective of this study is to evaluate the safety of Nivolumab plus albumin-
bound paclitaxel plus paricalcitol plus cisplatin plus gemcitabine in patients with previously 
untreated (for their metastatic disease) metastatic pancreatic ductal cancer. An additional 
objective is to evaluate self-reported quality of life and pain levels in this patient population. 
 
2.3 Overview  
 
This is a phase II  pilot study evaluating the preliminary efficacy and safety of Nivolumab plus 
Albumin-bound Paclitaxel plus Paricalcitol plus Cisplatin plus Gemcitabine (NAPPCG) in 
patients with metastatic pancreatic ductal adenocarcinoma. Also, assessment of quality of life 
and pain levels will be explored in patients participating in this trial. 
An individual cycle of therapy will be defined as six weeks (42 days).  Multiple cycles may be 
administered until the patient is withdrawn from therapy. 
Overall response rates as well as individual categories of response (CR, PR, SD, and PD) will 
be determined using RECIST 1.1 (Eisenhower 2009). Time-to-event endpoints, including PFS 
and OS will be assessed using the Kaplan-Meier method (Kaplan 1958). Evaluation of stable 
disease at 12 weeks will also be assessed. Toxicity (adverse events) will be recorded using the 
NCI CTCAE, version 4.0 (published 28 May 2009) (see Appendix D).  


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2.4 Primary Endpoints 
 
 
To evaluate the partial rate (PR) as defined by CT scan using RECIST 1.1 criteria. 
We expect to accomplish this in ≥ 40% of patients.  
 
If 4 or more of 10 patients demonstrate a partial response, we will continue to enroll 
to a total of 35 patients.  Please note that to increase the number of patients 
enrolled from 10 to 35, more sites may need to be added to the study in order to 
reach enrollment goals. 
 
 
If intolerable adverse events or no clinical benefit are noted in the first 6 patients, we 
will discontinue study enrollment. 
 
2.5 Secondary Endpoints 
 
 
To evaluate the disease control rate (CR, PR and SD at 12 weeks) in patients 
with metastatic PDA. 
 
 
To evaluate the treatment-related toxicities in this patient population. 
 
 To evaluate the change in CA 19-9 (or CA 125, or CEA if not expressers of CA 
19-9) in this patient population. 
 
2.6 Exploratory Endpoints 
 
To evaluate the effects of combination therapy on immune biomarkers 
 
To evaluate cell-free DNA as biomarker for pancreatic cancer in relation 
to CA 19-9 and/or clinical response by RECIST 1.1 
 
To evaluate the commensal bacterial population and metabolites before 
and during anti-cancer immunotherapy along with correlating the patient’s 
pre-treatment gut microbiome and mycobiome and the associated 
response to immunotherapy.  
 
To evaluate the individuals baseline tissue molecular profile as it relates 
to treatment outcome.  
 
 
 STUDY POPULATION 
 
3.1 Patient Selection and Study Duration 
 
This study will enroll up to 35 patients.  The expected duration of this study is 36 months. 
Enrollment into the screening or treatment phase of the study will be stopped when the 
anticipated or actual patient numbers have been achieved across all study sites. 
 
3.2 Inclusion Criteria 
 
Patients must meet the following criteria to be included in the study: 


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1. 
Age ≥18 years of age. 
 
2. 
Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma. 
 
3. 
Capable of providing informed consent and complying with Trial procedures. 
 
4. 
Karnofsky Performance Status (KPS) of ≥ 70%. 
 
5. 
Life expectancy ≥ 12 weeks. 
 
6. 
Measurable tumor lesions according to RECIST 1.1 criteria. 
 
7. 
Women must not be able to become pregnant (e.g. post-menopausal for at least 1 year, 
surgically sterile, or agree to practice adequate birth control methods) for the duration of 
the study and for at least 5 months after the last dose of Nivolumab. Women of child 
bearing potential must have a negative serum or urine pregnancy test at the Screening 
Visit and be non-lactating. Both male and female  patients of reproductive potential 
must agree to use a reliable method of birth control during the study and for at least 5 
months (for women) and 7 months (for men with WOCBP partners) after last dose of 
Nivolumab. 
 
3.3 Exclusion Criteria 
 
Patients meeting the following criteria will not be enrolled: 
 
1. 
Patients must have received no previous radiotherapy, surgery, chemotherapy or 
investigational therapy for the treatment of metastatic disease. Prior treatments in the 
adjuvant setting with gemcitabine and/or 5-FU or gemcitabine administered as a 
radiation sensitizer are allowed, provided at least 6 months have elapsed since 
completion of the last dose and no lingering toxicities are present. 
 
2. 
Palliative surgery and/or radiation treatment less than 4 weeks prior to initiation of study 
treatment. 
 
3. 
Exposure to any investigational agent within 4 weeks prior to initiation of study 
treatment. 
 
4. 
Evidence of central nervous system (CNS) metastasis (negative imaging study, if 
clinically indicated, within 4 weeks of Screening Visit). 
 
5. Malignancies other than pancreatic cancer ≤5 years prior to cycle 1 day 1, with the 
exception of those with a negligible risk of metastasis or death and treated with 
expected curative outcomes (such as adequately treated carcinoma in situ of the cervix, 
basal or squamous cell skin cancer or ductal carcinoma in situ treated surgically with 
curative intent) or localised prostate cancer treated with curative intent and absence of 
PSA relapse or incidental prostate cancer (Gleason score ≤3 +4 and PSA <10ng/L 
undergoing active surveillance and treatment naïve). 
 
6. 
Laboratory values: Screening serum creatinine > 1.5 mg/dl; total bilirubin > (ULN); 
alanine aminotransferase (ALT) and AST ≥ 2.5 ULN or ≥ 3.0×ULN if liver metastases 


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are present; absolute neutrophil count <1,500/mm3, platelet concentration 
<100,000/mm3, hematocrit level <27% for females or <30% for males, or coagulation 
tests (prothrombin time [PT], partial thromboplastin time [PTT], International Normalized 
Ratio [INR]) >1.5×ULN unless on therapeutic doses of warfarin. 
 
7. 
Current, serious, clinically significant cardiac arrhythmias as determined by the 
investigator. 
 
8. 
History of HIV infection or active or chronic hepatitis B or C. 
 
9. 
Active, clinically significant serious infection requiring treatment with antibiotics, anti-
virals or anti-fungals. 
 
10. Major surgery within 4 weeks prior to initiation of study treatment. 
 
11. Any condition that might interfere with the patient’s participation in the study or in the 
evaluation of the study results. 
 
12. Any condition that is unstable and could jeopardize the patient’s participation in the 
study.  
 
13.  Patient has a transplanted organ. 
 
14.  Patients with a history of autoimmune disease. 
 
15. Prior PD-1 or PD-L1 therapy. 
 
16. Patients taking systemic corticosteroids (equivalent to > 20mg hydrocortisone per day), 
or any other immunosuppressive therapy.  Corticosteroids for treatment or prevention of 
nausea and vomiting, or to modulate symptoms from an event of suspected 
immunologic etiology are permitted.  Inhaled (nasal or pulmonary), ophthalmic, topical 
steroids and local steroid injections are permitted. 
 
17.  Patients cannot have > Grade 1 pre-existing peripheral neuropathy (per CTCAE). 
 
18. Women who are currently pregnant or breast-feeding or who are planning to become 
pregnant while on the study.  This includes patients who are unwilling to use adequate 
birth control as described in inclusion criteria # 7. 
 
19. Use of non-FDA approved cannabinoids are prohibited.  Total daily useage of up to 40 
mg per day of marinol is acceptable.  
 
 
3.4 Patient Enrollment 
 
This is an open-label study. A patient ID number will be assigned by the site when the patient 
signs the Informed Consent Form. A copy of the signed informed consent will be required for 
study entry. 
 


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The exact date and time of each administration of medications will be recorded in the case 
report form (CRF). Nivolumab, paricalcitol, cisplatin, albumin-bound paclitaxel and gemcitabine 
will be administered according to the clinical study protocol only to patients who have given 
written informed consent. Patients withdrawn from the study will retain their patient ID number. 
New patients must always be allotted a new patient ID number. 
 
 
3.5 Patient Discontinuation 
 
Patients will be discontinued from the treatment under the following circumstances: 
 
1. Disease progression. 
 
2. Patient’s physician considers a change of therapy would be in the best interest of the 
patient.  
 
3. Patient requests discontinuation. 
 
4. Continued unacceptable toxicities despite optimal treatment or dose reduction.  
 
5. Patient becomes pregnant or fails to use adequate birth control (for those patients who 
are fertile). 
 
6. Need for any treatment not allowed by the protocol. 
 
7. Non-compliance. 
 
 
3.6 Study Discontinuation 
 
HonorHealth has the right to terminate the participation of either an individual site or the study at 
any time. Reasons for terminating the study include, but are not limited to, the following: 
 
1. Incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
 
2. Patient enrollment is unsatisfactory. 
 
3. Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study. 
 
4. If a study protocol and procedure are deemed unsafe by the data safety and 
monitoring committee. 
 
 STUDY TREATMENT 
 
4.1 Administration and Dosing 
 


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Treatment must be administered in a hospital, clinic or other out-patient setting appropriate for 
chemotherapeutic infusions. No investigational or commercial agents or therapies other than 
those described may be administered with the intent to treat the patient’s malignancy.  
The names, titles, and addresses of the Investigators and study personnel who administer the 
study medication will be listed in the Site Contacts list for Protocol NAPPCG-EB 2015-001 and 
will be available from HonorHealth or its representative.  
 
The solution for infusion will be prepared at each investigational site, as outlined below. 
Guidance for preparation, compatibilities, stability and administration of nivolumab, paricalcitol, 
albumin-bound paclitaxel, cisplatin and gemcitabine are provided in each drug’s Prescribing 
Information document, referenced in Appendix E. There will be an administration window of -
5/+30 minutes. The order of infusion with premedication is as follows: 
 
 
Nivolumab will be given every two weeks as a 60 minute IV infusion.  The dose will 
be 240 mg fixed dose every two weeks.   
 
 
Pre cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL with Mannitol 12.5 
grams and Magnesium Sulfate 2 grams IV infusion over 2 hours on days 1, 8, 22 
and 29 repeated every 42 days.  NOTE: if supply of Mannitol is limited, then dose 
according to institutional policy and procedure. Pre cisplatin hydration may be given 
prior to the nivolumab. 
 
 
 Palonosetron (Aloxi®) 0.25 mg IV, fosaprepitant (Emend®) 150 mg IV and 
dexamethasone 12 mg IV within 30 minutes prior to treatment on days patient is 
receiving albumin-bound paclitaxel + cisplatin + gemcitabine. (See Appendix H for 
details of reduced dosing of dexamethasone with concomitant administration of 
fosaprepitant).  Patients will continue oral antiemetic prophylaxis at home with 
ondansetron 8 mg bid and dexamethasone 4 mg twice daily for 2 days after 
chemotherapy. Olanzapine 10 mg PO at bedtime x 3 days can be considered if 
additional antiemetic is needed. The type of antiemetic prophylaxis used can vary 
based on institutional procedures. 
 
Albumin-bound paclitaxel 125 mg/m2 over 30 minute IV infusion on days 1, 8, 22, 
and 29 repeated every 42 days, followed by:  
 
Cisplatin 25 mg/m2  in 500* mL of NS over 60 minute IV infusion on days 1, 8, 22, 
and 29 repeated every 42 days, followed by: 
 
Gemcitabine 1000 mg/m2 in 500* mL over 30 minute IV infusion on days 1, 8, 22, 
and 29  repeated every 42 days 
 
Post cisplatin hydration: 0.9% Sodium Chloride Injection 1000* mL IV infusion over 
3 hours on days cisplatin is administered. May start at the same time as the 
gemcitabine infusion. 
 
Paricalcitol will be given at a dose of 25 micrograms days 1, 4, 8, 12, 15, 18, 22, 26, 
29, 32, 36, and 39 repeated every 42 days +/- 1 day allowed for dosing 
 
The investigator may reduce the volume of 0.9% Sodium Chloride Injection to 250 mL for 
cisplatin and gemcitabine and/or post hydration volume to 500 mL if clinically indicated. The use 
of additive electrolytes (i.e. Magnesium, Potassium) may also be added if clinically indicated. 
 
In the event of extravasation during the infusion of Nivolumab, albumin-bound paclitaxel, 
paricalcitol, cisplatin or gemcitabine, the infusion should be immediately terminated and patients 
treated according to local site protocols. The infusion should then be restarted in another vein. 


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4.2 Body Surface Area Calculation 
 
The calculation of the dose of cisplatin, gemcitabine, and albumin-bound paclitaxel will be based 
on the patient’s body surface area (BSA) using the Mosteller formula (Verbraeken 2006). The 
BSA will be calculated before each new cycle, based on the actual height and weight of the 
patient. If there has been a > 10% weight change from baseline, the drug doses will be 
recalculated based on the new BSA value. Doses are rounded to the nearest whole milligram.  
The dose of paricalcitol will be a flat dose of 25 micrograms.  The dose of nivolumab will be a 
flat dose of 240 mg.  
 
4.3 Dose Modification for Toxicity 
 
Toxicities will be graded using the NCI CTCAE v4.0 (see Appendix D). If toxicity occurs during 
or after any treatment cycle, the toxicity will be graded and appropriate supportive care 
treatment may be administered to decrease the signs and symptoms (e.g. antiemetics, 
antidiarrheals, antipyretics, antihistamines). 
 
 For Nivolumab  
 
For management of immune-oncology adverse events related to Nivolumab therapy, 
please refer to section 4.5.4 and Appendix G.  Warnings and precautions regarding 
treatment with Nivolumab can be found in the Nivolumab Prescribing Information, link in 
Appendix E. 
 
 For albumin-bound paclitaxel or gemcitabine or cisplatin or paricalcitol 
 
Doses of albumin-bound paclitaxel and gemcitabine may be reduced in individual patients in 
accordance with the schedule in Tables  2, 3, 4, 5 and 6.  In general, doses that have been 
reduced for toxicity will not be escalated back to the starting level. Growth factors may be used 
to treat hematologic toxicity and will not constitute a dose reduction.  
 
 
Table 2   Dose Reduction Schema 
 
Dose Level 
albumin-bound 
Paclitaxel 
(mg/m2) 
Cisplatin 
Dose** 
(mg/m2) 
Gemcitabine (mg/m2) 
Paricalcitol* 
(micrograms) 
Level - 0 
(baseline) 
125mg/m2 
25** 
1000mg/m2 
25 micrograms 
Level -1 
100mg/m2 
25** 
800mg/m2 
25 micrograms 
Level -2 
75mg/m2 
25** 
600mg/m2 
25 micrograms 
*Note if any toxicity is deemed certainly relatable to the paricalcitol (e.g. renal stone, etc.) the 
paricalcitol will be discontinued 
**Note cisplatin should not be given unless creatinine is < 1.5 mg/dl. 
 


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4.3.2.1 Hematological Toxicity 
 
In the event dose modifications are required at the beginning of a cycle or within a cycle due to 
hematologic toxicities, doses of albumin-bound paclitaxel, cisplatin, and gemcitabine may be 
adjusted as detailed in Table 2. Please note that all 5 drugs will be held at the start of a new 
cycle if Table 3 criteria are not met. 
 
Dose Modifications at Day 1 or Day 22 
 
Table 3   Dose Modifications for Day 1 or Day 22 of Each Cycle with a cycle being defined as 42 
days   (Hematologic Toxicity) 
 
ANC 
 
Platelets 
Timing 
≥ 1.5 x 109/L 
And 
≥ 100 x 109/L 
Treat on time 
< 1.5 x 109/L 
Or 
< 100 x 109/L 
No treatment 
 
Dose Adjustments within a Treatment Cycle 
 
In the event that patients have missed doses within a treatment cycle due to hematologic 
toxicities, those doses not given during a cycle will not be made up. Dose modifications due to 
hematologic toxicity (as represented by the blood counts and toxicities, below) within a 
treatment cycle should be adjusted as outlined in Table 3. 
 


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Table 4 Dose Modification for Days 8 or 29 of Each Cycle (Hematologic Toxicity)* 
 
Day 8 or 29 
Laboratory  
Results 
Day 8 or 29 
Album-bound 
paclitaxel 
Day 8 or 29 
Cisplatin 
Day 8 or 29  
Gemcitabine 
Day 29 
Nivolumab 
Days 8 or 29 
Paricalcitol 
ANC > 1000  
and 
Platelets 
≥ 75,000 
100% 
100% 
100% 
100% 
100% 
ANC 500-1000a 
or Platelets 
50,000-74,999 
Decrease dose 
by 1 level  
(treat on time) 
100% 
Decrease dose 
by 1 level  
(treat on time) 
100% 
100% 
ANC < 500 
or 
Platelets < 
50,000 
Hold 
Hold 
Hold 
Hold 
100% 
Febrile  
Neutropenia 
(Grade 3 or 4)b 
Hold. 
Upon resuming 
dosing, decrease 
to next lower 
dose level 
and do not re-
escalate 
throughout the 
rest of treatment 
Hold 
Hold. 
Upon resuming 
dosing, decrease 
to next lower 
dose level 
and do not re-
escalate 
throughout  
the rest of 
treatment 
Hold 
100% 
Recurrent 
Febrile 
Neutropenia 
(Grade 3 or 4) b 
Hold. 
Upon resuming 
dosing, decrease 
2 dose levels  
(to 75 mg/m2) 
and do not 
re-escalate 
throughout  
the rest of 
treatment 
Hold 
Hold. 
Upon resuming 
dosing, decrease 
2 dose levels  
(to 600 mg/m2) 
and do not 
re-escalate 
throughout  
the rest of 
treatment. 
Hold 
100% 
* see Table 2 for dose reduction schedule 
a If patients do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, 
study treatment will be discontinued. 
b Febrile patients (regardless of neutrophil count) should have their chemotherapy treatment interrupted. A full 
sepsis diagnostic work-up should be performed while continuing broad spectrum antibiotics. If cultures are 
positive, the antibiotic may or may not be changed, depending on the sensitivity profile of the isolated organism. 
Patients with persisting fever after 3 weeks, despite uninterrupted antibiotic treatment, will discontinue study 
treatment. Febrile neutropenic patients can also receive G-CSF, in addition to antibiotic treatment, to hasten the 
resolution of their febrile neutropenia (following current institutional guidelines). In all cases, blood counts must 
have returned to baseline levels before resuming chemotherapy treatment. 
 
 
4.3.2.2 Non-hematological Toxicity 
 
Dose reductions for non-hematologic toxicity that occur despite adequate background medical 
therapy should be undertaken in accordance with Table 5. 
 
  


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Table 5 Albumin-bound paclitaxel and gemcitabine and cisplatin - Dose Modifications for Day 1 or 
Day 22 of Each Cycle (Non-hematologic Toxicity)*  
 
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
Albumin-bound paclitaxel + gemcitabine + cisplatin dose this cycle 
Grade 0, 1 or 2 toxicity 
Same as Day 1 previous cycle (except for Grade 2 cutaneous toxicity where 
doses of albumin-bound paclitaxel and gemcitabine should be reduced to next 
lower dose level: please refer to Section 4.3.2.5). Note cisplatin should not be 
given unless creatinine is < 1.5 mg/dL. 
Grade 3 toxicitya,c 
Decrease albumin-bound paclitaxel and gemcitabine to next lower dose levela 
(see table 1) 
Grade 4 toxicityb 
Off protocol treatmentb 
Dose held in 2 previous 
consecutive cycles 
Decrease albumin-bound paclitaxel and gemcitabine to next lower dose level 
and continue throughout the rest of treatment 
* Excluding peripheral neuropathy (section 4.3.2.3) and nephrotoxicity (section 4.3.2.4). 
a If the toxicity only affects neuropathy, then only albumin-bound paclitaxel should be reduced (please see Section 
4.3.2.3). 
b Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt from this 
requirement (please see Section 4.3.2.7). 
c Excluding electrolyte abnormalities per judgment of the physician/investigator. 
 
 
Table 6 Albumin-bound paclitaxel and gemcitabine and cisplatin Dose Modifications Day 8 or 29 of 
Each Cycle (Non-hematological Toxicity) 
CTC Grade 
Percent of Day 1 
albumin-bound paclitaxel + gemcitabine + cisplatin Dose 
0-2  
100%a 
3+  
Hold treatment until resolution to ≤ Grade 1 b,c.  
a Except for cutaneous toxicity: please refer to Section 4.3.2.5. 
b Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt from this 
requirement (please see Section 4.3.2.7). 
c Excluding electrolyte abnormalities per judgment of the physician/investigator. 
Please note when one drug is discontinued then it will be a matter of patient situation and clinical 
judgement as to whether some or all of the other agents are discontinued.  
  
 
 
4.3.2.3 Peripheral Neuropathy 
 
Cisplatin and albumin-bound paclitaxel treatment should be withheld in patients who experience 
≥ Grade 3 peripheral neuropathy. Gemcitabine, nivolumab and paricalcitol administration can 
continue during this period. Cisplatin may be resumed at the same dose and albumin-bound 
paclitaxel treatment may be resumed at the next lower dose level in subsequent cycles after the 
peripheral neuropathy improves to ≤ Grade 1. The time to resolution to Grade ≤ 1 should be the 
adverse event duration used for adverse event reporting.  
 
4.3.2.4 Nephrotoxicity 
 


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Cisplatin (cisplatin injection) produces cumulative nephrotoxicity which is potentiated by 
aminoglycoside antibiotics (see Appendix E). The serum creatinine, BUN, creatinine clearance, 
and magnesium, sodium, potassium, and calcium levels should be measured prior to initiating 
therapy, and prior to each subsequent course. Cisplatin should not be given unless serum 
creatinine is < 1.5 mg/dL . 
 
Please also note that as detailed in sections 1.3. that nivolumab can also cause immune 
mediated nephritis and renal dysfunction. Please see section 4.5 and Appendix G for 
delay/discontinuation instructions.  
 
4.3.2.5 Cutaneous Toxicity 
 
Patients who develop Grade 2 or 3 cutaneous toxicity due to gemcitabine or albumin-bound 
paclitaxel should have their doses reduced to the next lower dose level as per Table 2. If the 
patient continues to experience these reactions, despite dose reduction, treatment should be 
discontinued. Patients who develop Grade 4 cutaneous toxicity should have treatment 
discontinued. 
 
4.3.2.6 Gastrointestinal Toxicity 
 
If Grade 3 mucositis or diarrhea occurs, all 5 study drugs should be withheld until resolution to 
≤ Grade 1, then dose reduced as per Table 2.  
 
Please also note that as detailed in section 1.3 that nivolumab also causes colitis/diarrhea. 
Please see section 4.5 and Appendix G for delay/discontinuation instructions for Nivolumab. 
Patients who develop Grade 3 or 4 mucositis or diarrhea that is related to Nivolumab should 
have treatment discontinued as per management algorithms.  
 
4.3.2.7 Pulmonary Embolism 
 
Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular weight 
heparin without interruption of therapy. Moderate to severe pulmonary embolism will require 
permanent discontinuation of treatment. 
 
4.3.2.8 Interstitial Pneumonitis 
 
Pulmonary toxicity has been reported for gemcitabine, paclitaxel, and for nivolumab. 
Epidemiology reports show that gemcitabine monotherapy is weakly associated with lung 
toxicity. A retrospective review (Meadors et al, 2006) of pooled clinical trial data of 4,448 patients 
with mixed cancer indications reported an incidence of dyspnea of 0.2% and serious pulmonary 
toxicity of 0.06%. Paclitaxel monotherapy is weakly associated with lung toxicity (Rowinsky and 
Donnehouer 1995). Dyspnea with bronchospasm has been reported in 0.3 to 0.9%, with 30% of 
type 1 hypersensitivity reactions. Combination chemotherapy of gemcitabine and albumin-bound 
paclitaxel shows a higher incidence of this complication compared to either drug alone but the 
two are no more than additive (Von Hoff et al, 2013). Please see section 4.5 for details on 
nivolumab pneumonitis. 
 
During study participation, patients should be carefully monitored for signs and symptoms of 
pneumonitis (i.e. episodes of transient or repeated dyspnea with unproductive persistent cough 
or fever) and, if observed, immediate clinical evaluation and timely institution of appropriate 
management (emphasizing the need for corticosteroids if an infectious process has been ruled 


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out as well as appropriate ventilation and oxygen support when required). Administration of study 
drugs will be permanently discontinued upon making a diagnosis of interstitial pneumonitis. (See 
Section below and also see 4.5 for additional management, particularly for the possible 
nivolumab complications) 
 
Prevention, Surveillance and Management of Interstitial Pneumonitis 
 
 During study treatment, episodes of transient or repeated dyspnea with 
unproductive persistent cough or fever should be paid attention to. Radiographic 
evaluation with chest X-rays and CT scans (normal or high resolution) may be 
indicated to look for infiltrates, ground-glass opacities or honeycombing patterns. 
Pulse oximetry and pulmonary function tests can show respiratory and ventilation 
compromise. 
 
 Infections should be ruled out with routine immunological/ microbiological 
methods. Transbronchial lung biopsy is not recommended, given its limited value 
and risk of pneumothorax and hemorrhage, and should be reserved for cases 
with unclear etiology. 
 
 Study drug administration should be interrupted upon diagnosis of interstitial 
pneumonitis and patients permanently discontinued from further study drug 
treatment. After ruling out an infectious etiology, intravenous high-dose 
corticosteroid therapy and secondary pathogen coverage should be instituted 
without delay. Patients with an added immunological component may also 
require immune modulation with azathioprine or cyclophosphamide. Appropriate 
ventilation and oxygen support should be used when required. 
 
4.3.2.9 Hypersensitivity Reactions 
 
Hypersensitivity reactions are not usually expected with cisplatin, albumin-bound paclitaxel or 
gemcitabine. If they do occur, minor symptoms such as flushing, skin reactions, dyspnea, 
hypotension, or tachycardia may require temporary interruption of the infusion. However, severe 
reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, 
angioedema, or generalized urticaria require immediate discontinuation of the offending agent 
and aggressive symptomatic therapy. Patients who develop a severe hypersensitivity reaction 
should not be re-challenged. Please see section 4.5 for details on possible nivolumab immune 
reaction.  
 
4.3.2.10 Colony Stimulating Factors 
 
Based on the ASCO guidelines (Smith 2006) for use of granulocyte colony stimulating factors, 
(G-CSF) for regimens with at least a 20% risk of febrile neutropenia, pegfilgrastim will be 
administered subcutaneously on day 9 & 30 of each treatment cycle. G-CSF may also be given 
according to institutional guidelines for the treatment of neutropenic fever or infections 
associated with neutropenia and for the prevention of febrile neutropenia in patients with an 
ANC < 500 cells/μL (see Appendix F). Patients not experiencing resolution of neutropenia within 
21 days, despite uninterrupted G-CSF treatment, will discontinue study treatment.  
 
 


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4.3.2.11 Prophylaxis against Sepsis 
 
Due to the incidences of non-neutropenic sepsis, at the first occurrence of fever ≥ 38.5°C 
(regardless of neutrophil count), institution of ciprofloxacin (500 mg orally, twice daily) or 
amoxicillin/clavulanate (Augmentin®, 500 mg orally, 2-3 times daily) in patients with allergy to 
fluoroquinolones should be initiated. On their first visit, patients should be provided with enough 
ciprofloxacin (or the alternative antibiotic) for use at home, and they should be instructed to 
begin taking it when they first record a temperature of ≥ 38.5 °C (or if they feel they are 
developing a fever and a thermometer is not available). They should also immediately contact 
their physician for guidance on where to go for blood counts and to be evaluated for sepsis as 
soon as possible. Hospitalization or evaluation in the emergency room may be required 
depending on the clinical presentation. If hospitalization is required, please refer to Section 7.7 
of this protocol to report the event as a Serious Adverse Event (SAE). 
 
 Intended Dose Delays 
 
Intended cycles may be delayed for non-toxicity reasons for up to 14 days (for reasons such as 
scheduling conflicts), but only with documentation and explanation in the CRF after discussion 
with the study Principal Investigator. 
 
4.4 
Special Warning and Precautions and Management for Possible Nivolumab 
Complications (See Nivolumab Prescribing Information for detailed AE 
incidence in key approval trials). 
 
  Immune –Mediated Pneumonitis 
 
Nivolumab can cause immune-mediated pneumonitis, defined as requiring use of 
corticosteroids and no clear alternate etiology. Fatal cases have been reported.  In patients 
receiving nivolumab as a single agent, immune-mediated pneumonitis occurred in 3.1% 
(61/1994) of patients. The median time to onset of immune-mediated pneumonitis was 3.5 
months (range: 1 day to 22.3 months). Immune-mediated pneumonitis led to permanent 
discontinuation of nivolumab in 1.1%, and withholding of nivolumab in 1.3% of patients. 
Approximately 89% of patients with pneumonitis received high-dose corticosteroids (at least 40 
mg prednisone equivalents per day) for a median duration of 26 days (range: 1 day to 6 
months). Complete resolution of symptoms following corticosteroid taper occurred in 67% of 
patients. Approximately 8% of patients had recurrence of pneumonitis after re-initiation of 
nivolumab.  
Monitor patients for signs and symptoms of pneumonitis.  Administer corticosteroids at a dose of 
1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2), or up to 4 mg/kg/day 
prednisone equivalents for more severe (Grade 3-4) pneumonitis, followed by corticosteroid 
taper.  Permanently discontinue nivolumab for severe (Grade 3) or life-threatening (Grade 4) 
pneumonitis and withhold nivolumab until resolution for moderate (Grade2) pneumonitis. 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Immune-Mediated Colitis 
Nivolumab can cause immune-mediated colitis, defined as requiring use of corticosteroids with 
no clear alternate etiology.  In patients receiving nivolumab as a single agent, immune-mediated 
colitis occurred in 2.9% (58/1994) of patients; the median time to onset was 5.3 months (range: 


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2 days to 20.9 months). Immune-mediated colitis led to permanent discontinuation of nivolumab 
in 0.7% and withholding of nivolumab in 1% of patients. Approximately 91% of patients with 
colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a 
median duration of 23 days (range: 1 day to 9.3 months). Four patients required addition of 
infliximab to high-dose corticosteroids. Complete resolution occurred in 74% of patients. 
Approximately 16% of patients had recurrence of colitis after re-initiation of nivolumab. 
Monitor patients for immune-mediated colitis.  Administer corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life 
threatening (Grade 4) colitis.  Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day 
prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) of more than 5 
days duration: if worsening or no improvement occurs despite initiation of corticosteroids, 
increase dose to 1 to 2 mg/kg/day prednisone equivalents.  Withhold nivolumab for Grade 2 or 3 
immune-mediated colitis.  Permanently discontinue nivolumab for Grade 4 colitis or for recurrent 
colitis upon restarting nivolumab. 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Immune-mediated Hepatitis 
Nivolumab can cause immune-mediated hepatitis, defined as requiring use of corticosteroids 
and no clear alternate etiology.  In patients receiving nivolumab as a single agent, immune-
mediated hepatitis occurred in 1.8% (35/1994) of patients; the median time to onset was 3.3 
months (range: 6 days to 9 months). Immune-mediated hepatitis led to permanent 
discontinuation of nivolumab in 0.7% and withholding of nivolumab in 1% of patients. All patients 
with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents) for a 
median duration of 23 days (range: 1 day to 2 months). Two patients required the addition of 
mycophenolic acid to high-dose corticosteroids. Complete resolution occurred in 74% of 
patients. Approximately 29% of patients had recurrence of hepatitis after re-initiation of 
nivolumab. 
Monitor patients for abnormal liver tests prior to and periodically during treatment.  Administer 
corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid 
taper for severe (Grade 3) or life-threatening (Grade 4) transaminase elevations, with or without 
concomitant elevation in total bilirubin.  Administer corticosteroids at a dose of 0.5 to 1 
mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) 
transaminase elevations.  Withhold nivolumab for moderate (Grade 2) and permanently 
discontinue nivolumab for severe (Grade 3) or life-threatening (Grade 4) immune-mediated 
hepatitis.  
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Immune-Mediated Nephritis and Renal Dysfunction 
Nivolumab can cause immune-mediated nephritis, defined as renal dysfunction or ≥Grade 2 
increased creatinine, requirement for corticosteroids, and no clear alternate etiology. In patients 
receiving nivolumab as a single agent, immune-mediated nephritis and renal dysfunction 
occurred in 1.2% (23/1994) of patients; the median time to onset was 4.6 months (range: 23 
days to 12.3 months). Immune-mediated nephritis and renal dysfunction led to permanent 
discontinuation of nivolumab in 0.3% and withholding of nivolumab in 0.8% of patients. All 
patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for 


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a median duration of 21 days (range: 1 day to 15.4 months). Complete resolution occurred in 
48% of patients. No patients had recurrence of nephritis or renal dysfunction after re-initiation of 
nivolumab. 
Monitor patients for elevated serum creatinine prior to and periodically during treatment.  
Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by 
corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently 
discontinue nivolumab.  For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, 
withhold nivolumab and administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone 
equivalents followed by corticosteroid taper, if worsening or no improvement occurs, increase 
dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue 
Nivolumab.   
 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Immune-Mediated Endocrinopathies 
4.4.5.1 Hypophysitis 
In patients receiving nivolumab as a single agent, hypophysitis occurred in 0.6% (12/1994) of 
patients; the median time to onset was 4.9 months (range: 1.4 to 11 months). Hypophysitis led 
to permanent discontinuation of nivolumab in 0.1% and withholding of nivolumab in 0.2% of 
patients. Approximately 67% of patients with hypophysitis received hormone replacement 
therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per 
day) for a median duration of 14 days (range: 5 to 26 days). 
Monitor patients for signs and symptoms of hypophysitis. Administer hormone replacement as 
clinically indicated and corticosteroids at a dose of 1 mg/kg/day prednisone equivalents followed 
by corticosteroid taper for moderate (Grade 2) or greater hypophysitis. Withhold nivolumab for 
moderate (Grade 2) or severe (Grade 3). Permanently discontinue nivolumab for life-threatening 
(Grade 4) hypophysitis.  
 
4.4.5.2 Adrenal Insufficiency 
In patients receiving nivolumab as a single agent, adrenal insufficiency occurred in 1% 
(20/1994) of patients and the median time to onset was 4.3 months (range: 15 days to 21 
months). Adrenal insufficiency led to permanent discontinuation of nivolumab in 0.1% and 
withholding of nivolumab in 0.5% of patients. Approximately 85% of patients with adrenal 
insufficiency received hormone replacement therapy and 25% received high-dose 
corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 11 days 
(range: 1 day to 1 month). 
Monitor patients for signs and symptoms of adrenal insufficiency. Administer corticosteroids at a 
dose of 1 to 2 mg/kg/day prednisone equivalents followed by a corticosteroid taper for severe 
(Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Withhold nivolumab for moderate 
(Grade 2) and permanently discontinue nivolumab for severe (Grade 3) or life-threatening 
(Grade 4) adrenal insufficiency.  
 
4.4.5.3 Hypothyroidism and Hyperthyroidism 
 
In patients receiving nivolumab as a single agent, hypothyroidism or thyroiditis resulting in 
hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months 
(range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism received 
levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients.  


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Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving nivolumab as a single agent; 
the median time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of 
patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received 
propylthiouracil, and 9% received corticosteroids. Resolution occurred in 76% of patients. 
Monitor thyroid function prior to and periodically during treatment.  Administer hormone 
replacement therapy for hypothyroidism.  Initiate medical management for control of 
hyperthyroidism.  There are no recommended dose adjustments of nivolumab for 
hypothyroidism or hyperthyroidism. 
 
4.4.5.4 Type 1 Diabetes Mellitus 
In patients receiving nivolumab as a single agent, diabetes occurred in 0.9% (17/1994) of 
patients including two cases of diabetic ketoacidosis. The median time to onset was 4.4 months 
(range: 15 days to 22 months). 
Monitor for hyperglycemia. Withhold nivolumab in cases of severe (Grade 3) hyperglycemia until 
metabolic control is achieved. Permanently discontinue nivolumab for life-threatening (Grade 4) 
hyperglycemia. 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Immune-Mediated Skin Adverse Reactions 
Nivolumab can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and 
toxic epidermal necrolysis (TEN), some cases with fatal outcome.  In patients receiving 
nivolumab as a single agent, immune-mediated rash occurred in 9% (171/1994) of patients; the 
median time to onset was 2.8 months (range: <1 day to 25.8 months). Immune-mediated rash 
led to permanent discontinuation of nivolumab in 0.3% and withholding of nivolumab in 0.8% of 
patients. Approximately 16% of patients with rash received high-dose corticosteroids (at least 40 
mg prednisone equivalents per day) for a median duration of 12 days (range: 1 days to 8.9 
months) and 85% received topical corticosteroids. Complete resolution occurred in 48% of 
patients. Recurrence of rash occurred in 1.4% of patients who resumed nivolumab after 
resolution of rash. 
For symptoms or signs of SJS or TEN, withhold nivolumab and refer the patient for specialized 
care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue 
nivolumab. 
For immune-mediated rash, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone 
equivalents followed by a corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) 
rash. Withhold nivolumab for severe (Grade 3) rash and permanently discontinue nivolumab for 
life-threatening (Grade 4) rash. 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Immune-Mediated Encephalitis 
Nivolumab can cause immune-mediated encephalitis with no clear alternate etiology. Evaluation 
of patients with neurologic symptoms may include, but not be limited to, consultation with a 
neurologist, brain MRI, and lumbar puncture. 
In patients receiving nivolumab as a single agent, encephalitis occurred in 0.2% (3/1994). Fatal 
limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation 


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of nivolumab and administration of corticosteroids. In the other two patients encephalitis 
occurred post-allogeneic HSCT. 
Withhold nivolumab in patients with new-onset moderate to severe neurologic signs or 
symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic 
deterioration. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 
mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by 
corticosteroid taper. Permanently discontinue nivolumab for immune-mediated encephalitis. 
 
See Appendix G for Management Algorithms for Adverse Events Related to Nivolumab 
Therapy. 
 
 Other Immune-Mediated Adverse Reactions 
Nivolumab can cause other clinically significant immune-mediated adverse reactions.  Across 
clinical trials of nivolumab administered as a single agent or in combination with ipilimumab, the 
following clinically significant immune-mediated adverse reactions occurred in less than 1.0% of 
patients receiving nivolumab: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, 
demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barre syndrome, 
hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, 
histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, 
rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome. 
For any suspected immune-mediated adverse reactions, exclude other causes. Based on the 
severity of the adverse reaction, permanently discontinue or withhold nivolumab, administer 
high-dose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon 
improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 
month. Consider restarting nivolumab after completion of corticosteroid taper based on the 
severity of the event. 
 
 Infusion Reactions 
Nivolumab can cause severe infusion reactions, which have been reported in less than 1.0% of 
patients in clinical trials. In patients receiving nivolumab as a single agent, infusion-related 
reactions occurred in 6.4% (127/1994) of patients. 
Discontinue nivolumab in patients with severe or life-threatening infusion reactions. Interrupt or 
slow the rate of infusion in patients with mild or moderate infusion reactions.  
 
4.5 Concomitant Therapy 
 
Necessary supportive measures for optimal medical care may be given throughout the study, 
including IV antibiotics to treat infections, blood components, and antiemetics. Additional care 
will be administered as indicated by the treating physician and the patient’s medical need. All 
concomitant medications and supportive therapy must be recorded on the appropriate CRF.  
 
 
 Prohibited Concomitant Therapy  
 
No concomitant cytotoxic therapy, whether conventional or investigational, will be allowed 
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Immunosuppressive  corticosteroid use is not permitted while enrolled in the study. 
Corticosteroids for treatment or prevention of nausea and vomiting, or to modulate symptoms 
from an event of suspected immunologic etiology are permitted.  Inhaled (nasal or pulmonary), 
ophthalmic, topical steroids and local steroid injections are permitted. 
Radiotherapy is not allowed while the patient is enrolled in this study. 
The use of vitamins or supplements that have reported use for the treatment or prevention of 
cancer, or that may interact with any of the study medications is not permitted. 
The use of medical marijuana (except FDA-approved therapy) in any formulation should be 
avoided while enrolled in this study. 
The use of additional vitamin D supplements beyond replacement while receiving study-
administered paricalcitol should be avoided 
 
 Permitted Concomitant Therapy 
 
Routine prophylactic use of a granulocyte colony-stimulating factor (G-CSF) will be used 
according to the American Society of Clinical Oncology guidelines (Appendix F), on Day 9 and 
30 of the 42 days cycle.  
 
The use of erythropoietin stimulating agents (ESA) is permitted if clinically indicated.  
 
 Concomitant Therapies Requiring Caution 
 
Cisplatin nephrotoxicity may be exacerbated by treatment with other nephrotoxic drugs (e.g. 
aminoglycoside antibiotics, non-steroidal anti-inflammatory drugs). Caution with use of other 
nephrotoxic drugs. 
 
If anticoagulation with warfarin is necessary, frequent monitoring of prothrombin time and the 
International Normalized Ratio (INR) is recommended. Please see Appendix H for special 
precautions on the use of dexamethasone with concomitant fosaprepitant.  
 
 STUDY ASSESSMENTS 
 
5.1 Laboratory Assessments 
 
All hematology, blood chemistries, urinalyses, and serum or urine pregnancy tests (if applicable) 
will be performed by the local laboratory at each investigational site. 
Prior to study enrollment, each patient will have the following assessments (see Appendix A). 
 
5.2 Quality of life and Pain Assessments 
 
Two well-known tools will be utilized to assess participant’s self-reported quality of life and pain 
levels during this study. The MD Anderson Symptom Inventory (MDASI-GI) and Brief Pain 
Inventory (BPI) are valid, reliable, and sensitive instruments for assessing the severity of 
symptoms and their interference in patients’ daily functioning. The MDASI asks patients to rate 
the worst severity of symptoms during the past 24 hours (0 not present to 10 as bad as you can 


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imagine). It also rates the extent to which symptoms interfere with various aspects of life (e.g., 
general activity, mood, relations with other people, and enjoyment of life) using a scale ranging 
from 0 (did not interfere) to 10 (interfered completely). The BPI uses four pain severity items 
rated with a 0 to 10 numeric rating scale (NRS); the interference scale is similar to the MDASI (0 
= no interference to 10 = interferes completely). Internal consistency measures (reliability) in 
prior studies were high at 0.80 or more (Cronbach alpha) for the BPI and MDASI (Atkinson et al, 
2010; Cleeland et al, 2000; Janjan et al, 2007; Wang et al, 2010).  
 
Instruments will be administered at screening, weekly throughout treatment and at end of study. 
Please see Appendix L and M for information on instruments.  
 
5.3 Exploratory Biomarkers  
 
At Screening, individuals with core biopsies obtained previously will be obtained by the 
investigator’s site for further exploratory analysis. Up to a total of 7 micron slice slides will be 
obtained or a cellular block of tumor tissue. Future analysis will include PD-1, interferon gamma, 
B-catenin, and other immunological assays along with those that will assess for sensitivity to 
DNA repair targeted therapy. The sites may send the unstained core samples to HonorHealth to 
be stored at room temperature and will be analyzed at a later date.  
At screening and Day 39 stool sample collection kits will be distriuted for microbiome and 
mycobiome analysis. The stool sample needs to be returned to the site within 72 hours of 
collection. Prior analysis has shown correlation with the microbiome and mycobiome and 
treatment response along with toxicity [Frankel et al 2017, Gopalakrishnan et al 2018, Chaput et 
al 2017].  
On cycle 1 day 1 (up to 72 hours before) and every subsequent cycle until an individual stops 
participating in the study, 20 mLs of blood will be collected for exploratory analyses.  
 
5.4 Screening (Within 21 Days Prior to First Dose) 
 
 
Written informed consent  
 
Review inclusion and exclusion criteria 
 
Complete medical and surgical history including concurrent baseline conditions (using 
NCI CTCAE version 4.0; Appendix D). 
 
Prior cancer therapy (including documentation of prior surgery, adjuvant or neoadjuvant 
chemotherapy and radiotherapy)  
 
Complete physical examination including height (cm) and weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
Computed tomography (CT)/magnetic resonance imaging (MRI) scan to document 
disease status (including chest, abdomen, pelvis, and other regions as clinically 
indicated. In addition, brain scan is required to exclude brain metastases if clinically 
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 as close to 
the start of chemotherapy as possible. (See RECIST 1.1 criteria in Section 6). In 
addition, a baseline PET is desirable.  
 
Electrocardiogram (ECG)  
 
Complete blood count (CBC) with differential and platelet count 


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 
Serum chemistries (for hepatic and renal function tests) including blood urea nitrogen 
(BUN), phosphorus, magnesium, creatinine, creatinine clearance, total protein, albumin, 
calcium, glucose, total bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), and electrolytes (chloride, sodium, potassium, 
and bicarbonate) 
 
Vitamin D serum level  
 
Coagulation panel including PTT and PT/INR 
 
Thyroid Stimulating Hormone (TSH) to include reflex T3 and T4 if abnormal. 
 
CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) 
 
Urinalysis  
 
Serum pregnancy test for women of childbearing potential 
 
Concomitant medications (past 30 days) 
 
Obtain archived tissue samples 
 
Patient to complete MDASI-GI and BPI questionnaires 
 
Distribute stool sample collection kit for exploratory microbiome and mycobiome analysis  
o Note: the stool sample needs to be returned to the site within 72 hours of 
collection. 
 
Once eligibility is confirmed, site personnel will be provided a patient ID by HonorHealth. 
 
5.5 On-Study Assessments 
 
Patients must begin Cycle 1 within 21 days of signing the informed consent document and after 
the screening assessments. Treatment will be administered by qualified and trained site 
personnel in a hospital, clinic, or other out-patient setting appropriate for chemotherapeutic 
infusions. Each cycle is 42 days long and each visit has a window of +/- 24 hours. 
 
Day 1 of each cycle – all assessments completed prior to dosing must be completed 72 hours 
prior to dosing. 
 
Review inclusion and exclusion criteria 
 
Directed physical examination including weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
Adverse Events 
 
Body Surface Area (BSA) Calculation  
 
Complete blood count (CBC) with differential and platelet count 
 
Serum chemistries (for hepatic and renal function tests) including blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, 
total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
and electrolytes (chloride, sodium, potassium, and bicarbonate) 
 
Thyroid Stimulating Hormone (TSH) to include reflex T3 and T4 if abnormal. 
 
CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) 
 
Collect blood sample for exploratory biomarker assays 
 
Urinalysis  
 
Serum pregnancy test for women of childbearing potential 
 
Concomitant medications  
 
Administer Nivolumab (as per dosing guidelines) 
 
Administer Albumin-Bound Paclitaxel (as per dosing guidelines) 


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 
Administer Cisplatin (as per dosing guidelines) 
 
Administer Gemcitabine (as per dosing guidelines) 
 
Administer Paricalcitol (as per dosing guidelines) 
 
Patient to complete MDASI-GI and BPI questionnaires 
 
  
Day 2, 9, 23 and 30 of each cycle – all assessments completed prior to dosing must be 
completed 24 hours prior to dosing. 
 
Provide optional IV fluids if necessary 
 
Administer pegfilgrastim (Neulasta®) on Days 9 and 30 
 
Adverse Events 
 
Concomitant medications  
 
 
Day 4, 12, 18, 26, 32, 36 and 39 of each cycle – all assessments completed prior to dosing 
must be completed 24 hours prior to dosing. 
 
Administer Paricalcitol (as per dosing guidelines) 
 
Adverse Events 
 
Concomitant medications  
 
Complete blood count (CBC) with differential and platelet count (Day 36 only) 
 
Serum chemistries (for hepatic and renal function tests) including blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, 
total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
and electrolytes (chloride, sodium, potassium, and bicarbonate) (Day 36 only) 
 
Distribute stool sample collection kit for exploratory microbiome and mycobiome 
analysis (Day 39 only) 
o Note: the stool sample needs to be returned to the site within 72 hours of 
collection. 
 
Day 8 of each cycle – all assessments completed prior to dosing must be completed 24 hours 
prior to dosing. 
 
Directed physical examination including weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
Adverse Events 
 
Complete blood count (CBC) with differential and platelet count 
 
Serum chemistries (for hepatic and renal function tests) including blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, 
total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
and electrolytes (chloride, sodium, potassium, and bicarbonate) 
 
Concomitant medications  
 
Administer Albumin-Bound Paclitaxel (as per dosing guidelines) 
 
Administer Cisplatin (as per dosing guidelines) 
 
Administer Gemcitabine (as per dosing guidelines) 
 
Administer Paricalcitol (as per dosing guidelines) 
 
Patient to complete MDASI-GI and BPI questionnaires 
 
 


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Day 15 of each cycle – all assessments completed prior to dosing must be completed 24 hours 
prior to dosing. 
 
Directed physical examination including weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
Adverse Events 
 
Complete blood count (CBC) with differential and platelet count 
 
Serum chemistries (for hepatic and renal function tests) including blood 
urea nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine 
clearance, total protein, albumin, calcium, glucose, total bilirubin, alkaline 
phosphatase (ALP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), and electrolytes (chloride, sodium, potassium, 
and bicarbonate) 
 
Concomitant medications  
 
Administer Nivolumab (as per dosing guidelines) 
 
Administer Paricalcitol (as per dosing guidelines) 
 
Patient to complete MDASI-GI and BPI questionnaires 
 
 
Day 22 of each cycle – all assessments completed prior to dosing must be completed 24 hours 
prior to dosing. 
 
Directed physical examination including weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
Adverse Events 
 
Body Surface Area (BSA) Calculation  
 
Complete blood count (CBC) with differential and platelet count 
 
Serum chemistries (for hepatic and renal function tests) including blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, 
total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
and electrolytes (chloride, sodium, potassium, and bicarbonate) 
 
CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9)  
 
Thyroid Stimulating Hormone (TSH) to include reflex T3 and T4 if abnormal. 
 
Urinalysis  
 
Serum pregnancy test for women of childbearing potential 
 
Concomitant medications  
 
Administer Albumin-Bound Paclitaxel (as per dosing guidelines) 
 
Administer Cisplatin (as per dosing guidelines) 
 
Administer Gemcitabine (as per dosing guidelines) 
 
Administer Paricalcitol (as per dosing guidelines) 
 
Patient to complete MDASI-GI and BPI questionnaires 
 
 
Day 29 of each cycle – all assessments completed prior to dosing must be completed 24 hours 
prior to dosing. 
 
Directed physical examination including weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 


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 
Adverse Events 
 
Complete blood count (CBC) with differential and platelet count 
 
Serum chemistries (for hepatic and renal function tests) including blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, 
total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
and electrolytes (chloride, sodium, potassium, and bicarbonate) 
 
 
Concomitant medications  
 
Administer Nivolumab (as per dosing guidelines) 
 
Administer Albumin-Bound Paclitaxel (as per dosing guidelines) 
 
Administer Cisplatin (as per dosing guidelines) 
 
Administer Gemcitabine (as per dosing guidelines) 
 
Administer Paricalcitol (as per dosing guidelines) 
 
Patient to complete MDASI-GI and BPI questionnaires 
 
 
At the end of each cycle and before the next cycle begins, the following will be completed: 
 
CT/MRI tumor assessment 
 
Reassessment of the extent of tumor should be made by the same imaging 
methods used to establish baseline tumor measurements. When a CR is 
documented, a confirmatory FDG PET scan will be obtained. 
 
In order to more precisely determine time to progression, the investigator is 
encouraged to obtain radiological assessments earlier if there is a strong clinical 
suspicion of disease progression, in order to either confirm or refute the clinical 
impression. 
 
Patients who have not had any disease progression at the end of cycle 4 may be 
considered for Continuation Therapy. 
 
5.6  End of Study  
 
When the patient completes all cycles of study medication, or withdraws from treatment prior to 
completing all cycles, the following assessments will be performed 14-28 (+/- 2) days after 
completing the last dose of study treatment: 
 
Directed physical examination including weight (kg) 
 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
Vital signs (blood pressure, pulse, respiratory rate, and temperature) 
 
Adverse Events 
 
Complete blood count (CBC) with differential and platelet count 
 
Serum chemistries (for hepatic and renal function tests) including blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, 
total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
and electrolytes (chloride, sodium, potassium, and bicarbonate) 
 
Coagulation panel including PTT and PT/INR 
 
Thyroid Stimulating Hormone (TSH) to include reflex T3 and T4 if abnormal. 
 
Concomitant medications  
 
Patient to complete MDASI-GI and BPI questionnaires 
 


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5.7   Follow-Up Assessments after End of Study or Early Termination 
 
Follow-up assessments by telephone will be conducted for all patients every 12 weeks, start 12 
weeks after the last dose of study treatment, to determine the patient’s vital status, and date of 
death if applicable.  
 
 
5.8  Treatment Assignment 
 
This is a phase II open-label pilot trial, with the identity of the treatment known to the patients, 
Investigators, drug provider, and CRO.  
 
5.9  Patient Disposition 
 
Summaries of patient disposition will include: 
 
 
Patient discontinuation from treatment. 
 
 
Patient discontinuation from study 
 
 
Overall qualification status of all patients. 
 
All patients enrolled in the study will be included in the summation. The safety population will 
include all patients who have received at least one dose of any study drug. The number of 
patients who do not qualify for analysis, who die or discontinue before treatment begins, will be 
summarized.  
 
5.10  Patient Characteristics 
 
Patient characteristics will include a summary of the following: 
 
 
Patient demographics 
 
 
Baseline disease characteristics 
 
 
Pre-existing conditions 
 
 
Prior therapies 
 
 
Concomitant medications and treatments 
 
Other patient characteristics will be summarized as appropriate. 
 
5.11  Statistical Considerations 
 
The sample size of this pilot study will be 10 patients and if a partial response rate is noted in ≥ 
4 patients then the study size can be increased up to 25 patients. This is based on a test of a 
null hypothesis of a 5% partial response or less, versus an alternative hypothesis of a 30% 
partial response rate or greater. Four or more partial responders in 10 will be required in order 


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to proceed to the total enrollment of 25 patients. Eight or more partial responders out of 25 
patients will be sufficient evidence for rejection of the null hypothesis of insufficient activity of the 
regimen. This design has a power of 87% at a one-sided Type I error rate of 3%. 
 
Time-to-event endpoints, including PFS and OS will be assessed using the Kaplan-Meier 
method (Kaplan 1958). QOL instruments will both be assessed utilizing descriptive statistics 
(Means and SDs for the individual symptom and interference items) will be used to summarize 
patient responses. Longitudinal data will be examined and mean symptom severity and 
interference will be compared using descriptive analysis and t-tests (repeated measures). 
 
Objective response rates, clinical benefit response, and CA 19-9, will be summarized 
descriptively. 
 
5.12  Efficacy Analysis 
 
The efficacy analysis will include summaries for the following parameters: complete response 
rate (CR) (see section 6.11), objective response rate (CR + PR), disease control rate (CR + PR 
+ SD at 12 weeks), progression-free survival (PFS), stable disease rate at 12 weeks (SD), and 
overall survival (OS). The efficacy analysis will only be conducted on patients who have 
received at least one dose of nivolumab, albumin-bound paclitaxel, paricalcitol, cisplatin, 
gemcitabine and have at least one post baseline tumor assessment. 
 
Objective responses will be evaluated using the Response Evaluation Criteria in Solid Tumors 
1.1 (RECIST 1.1). Changes (i.e. improvements) in tumor measurements from baseline values 
will be assigned a status of CR or PR or SD. Objective response measurements will comprise 
the sum of CR plus PR. The overall response rate, as well as the rates for the individual 
categories of response (i.e. CR, PR, SD, and PD), will be estimated by the percentage of 
patients achieving these criteria. The disease control rate will consist of the sum of CR + PR + 
SD for 12 weeks. When a CR is documented, a confirmatory PET scan will be obtained. 
For the estimation of progression-free and overall survival, a Kaplan-Meier analysis will be 
performed.  
 
Progression-free survival is defined as the interval from the date of registration (i.e. assignment 
of patient number) to the earliest date of documented evidence of recurrent or progressive 
disease, or the date of death due to any cause, whichever occurs first. Patients who do not 
progress and remain alive will be censored at their last radiographic assessment date.  
Overall survival will be measured from the date of registration (i.e. assignment of patient 
number) to the date of death due to any cause, or the date of last contact (censored 
observations).  
 
5.13  Safety Analysis 
 
All patients who receive any amount of nivolumab, albumin-bound paclitaxel, paricalcitol, 
cisplatin, or gemcitabine will be included in the following safety analyses: 
 
 
The incidence, severity, duration, causality, seriousness, and type of AEs 
 
Changes in the patient’s physical examination, vital signs, and clinical laboratory results  
 
Grading of clinical laboratory results per CTCAE criteria for selected laboratory 
parameters 
 
Deaths 


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 
Concomitant medications 
 
5.14  Replacement of Patients 
 
Patients who are enrolled into the study, but fail to receive nivolumab, albumin-bound paclitaxel, 
paricalcitol, cisplatin, and gemcitabine may be replaced. 
 
 
 EVALUATION OF RESPONSE 
 
6.1 Best Overall Response 
 
Best overall response is defined as the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for tumor progression, the smallest 
measurements recorded since the treatment started). The patient’s best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
 
6.2 Overall Tumor Response  
 
The overall tumor response rate is defined as the total proportion of patients who have an 
objective tumor response (CR + PR). Rates for the individual categories of response (CR, PR, 
SD, and PD) will also be determined.  
 
6.3 Not Evaluable 
 
Patients will be defined as being not evaluable for response if a post-baseline radiological 
assessment cannot be made. These patients will be counted as treatment failures in the 
analysis of tumor response data. 
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of a CR depends upon this determination, it is recommended that the 
residual lesion be investigated by PET scan, fine needle aspirate or biopsy when possible 
before confirming the CR status.  
 
6.4 Progression-free Survival 
 
Progression-free survival (PFS) is defined as the time from enrollment (i.e. assignment of 
patient ID number) to first documentation of objective tumor progression or to death due to any 
cause. Patients who do not progress and remain alive will be censored at the date of their last 
tumor assessment. 
 
6.5 Survival 
 
Survival is defined as the time from enrollment (i.e. assignment of patient ID number) to date of 
death. In the absence of confirmation of death, survival time will be censored at the last date the 
patient is known to be alive. 
 
6.6 Analysis Plan 


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Continuous variables will be summarized using the mean (SD) or median (range). Frequency 
tables will be used to summarize categorical variables. The distribution of time-to-event 
endpoints (e.g. response duration, progression-free survival, overall survival) will be estimated 
using the Kaplan and Meier method. Cox (proportional hazards) regression may be used to 
evaluate multivariable predictive models of time-to-event outcomes. Additional details regarding 
statistical analyses will be presented in a Statistical Analysis Plan.  
 
6.7 Guidelines for Measuring Disease 
 
Antitumor activity will be evaluated by RECIST 1.1 criteria (Eisenhauer 2009). These response 
criteria are widely recognized and accepted as the standard criteria for determining response in 
patients with solid tumors.  
 
6.8 Disease Definitions 
 
Measurable disease is defined as the presence of 1 measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
 
At Baseline, tumor lesions will be categorized as: 
 
Measurable Lesions: lesions that can be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
 
 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 
 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
 
 
20 mm by chest X-ray 
 
Malignant lymph nodes: to be considered pathologically enlarged and measureable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At Baseline and follow-up, only the short axis will 
be measured and followed. 
 
OR 
 
Non-measurable Lesions: all other lesions, including small lesions (longest diameter <10 mm 
or pathological lymph nodes with ≥10 to <15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
 
For special considerations regarding lesion measurability for bone lesions, cystic lesions and 
lesions with prior local treatment, consult the RECIST 1.1 guidelines in the Study Manual. 
 


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All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before beginning of treatment.  
 
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.  
 
Clinical lesions will only be considered measurable when they are superficial (e.g. skin nodules 
and palpable lymph nodes). For the case of skin lesions, either a CT scan or documentation by 
color photography, including a ruler to estimate the size of the lesion, is to be done. 
 
6.9 Methods of Measurement 
 
Tumor measurements should be performed using the same method as well as the same staff 
member per patient, if possible, throughout the study. CT and MRI are the best currently 
available and reproducible methods to measure target lesions selected for response 
assessment. Conventional CT and MRI should be performed with cuts of 5 mm in slice 
thickness contiguously. This applies to tumors of the chest, abdomen, and pelvis.  
As a rule, the minimum size of the lesion should be no less than double the slice thickness.  
Lesions on chest x-rays are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.  
 
Ultrasound should not be used to measure tumor lesions. It is, however, a possible alternative 
to clinical measurements of superficial palpable lymph nodes, subcutaneous lesions, and 
thyroid nodules. Ultrasound might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is necessary. 
 
Tumor markers alone cannot be used to assess objective tumor response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  
 
Cytology and histology can be used to differentiate between partial response (PR) and complete 
response (CR) in rare cases (e.g. after treatment to differentiate between residual benign 
lesions and residual malignant lesions in tumor types such as germ cell tumors) if required by 
protocol. 
 
6.10  Baseline Documentation of “Target” and “Non-target” Lesions 
 
Target Lesions: all measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs will 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 [LD]), be representative of all involved organs, and their 
suitability for accurate repetitive measurements (either by imaging techniques or clinically). A 
sum of the LD for all target lesions will be calculated and reported as the baseline sum LD. The 
baseline sum of the LD will be used as reference to further characterize the objective tumor 
response. 
 
Non-target Lesions: all other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and will also be recorded at baseline. Measurements 


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of these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up. 
 
6.11 Response Criteria 
 
Table 7   RECIST Target Lesion Response Criteria 
 
Target Response Criteria 
Definition 
Complete Response (CR) 
The disappearance of all target lesions and no new sites or disease-
related symptoms confirmed at least 4 weeks after initial documentation. 
Any pathological lymph nodes (whether target or non-target) must have a 
reduction in short axis to < 10 mm. All sites must be assessed, including 
non-measurable sites, such as effusions, or markers. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of target lesions, 
taking as a reference the baseline sum of the diameters confirmed at least 
4 weeks after initial documentation. PR is also recorded when all 
measurable disease has completely disappeared, but a non-measurable 
component (i.e., ascites) is still present but not progressing. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for partial response nor sufficient 
increase to qualify for progressive disease.  
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum of the diameters recorded since on 
study (this includes the baseline sum if that is the smallest on study), which 
must also demonstrate an absolute increase of at least 5 mm; or the 
appearance of one or more new lesions. 
 
Table 8   RECIST Non-target Lesion Response Criteria 
 
Non-Target Response 
Criteria 
Definition 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker 
level confirmed at least 4 weeks after initial documentation. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-Complete Response/ 
Non- Progressive Disease 
(Non-CR/Non-PD) 
Persistence of one or more non-target lesions and/or the maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more non-target lesions and/or unequivocal 
progression of existing non-target lesions (“unequivocal progression” is 
defined as an overall level of substantial worsening in non-target disease 
that is of magnitude that, even in the presence of SD or PR in target 
disease, the treating physician would feel it important to change therapy). 
Non-target lesion response will be classified according to the RECIST Non-Target Lesion 
Response Criteria in the following table. 
 
6.12  Evaluation of Best Overall Response 
 


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The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements 
recorded since the treatment started). In general, the patient’s best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time will be classified as having “symptomatic 
deterioration.” Every effort will be made to document the objective evidence of disease 
progression even after discontinuation of treatment.  
 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status. 
 
Table 9 Immune-Related RECIST Response Criteria 
 
Response Criteria 
Definition 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no 
new lesions, and confirmation by a repeat consecutive assessment no less 
than 4 weeks from date first documented 
irPR 
Decrease in tumor burden >50% relative to baseline confirmed by repeat 
consecutive assessment at least 4 weeks later 
irSD 
Not meeting criteria for irCR or irPR in absence of ir PD 
irPD 
Increase in tumor burden >25% relative to nadir (minimum recorded tumor 
burden) confirmed by repeat consecutive assessment at least 4 weeks later 
 
 
 
Table 10   RECIST Overall Response Criteria 
 
Target Response 
Non-Target Response 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
 non-CR/non-PD 
No 
PR 
CR 
Not Evaluated 
No 
PR 
PR 
Non-PD or not evaluated 
No 
PR 
SD 
Non-PD or not evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE – Non-evaluable 


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6.13 Duration of Stable Disease 
 
Stable disease is measured from the start of the treatment until the criteria for disease 
progression are met, taking as reference the smallest measurements recorded since the 
treatment started. 
 
For the purposes of this Trial, the minimal time interval required between 2 measurements for 
determination of SD is 6 weeks (at least 2 consecutive assessments 6 weeks apart revealing 
SD). This time interval takes into account the expected clinical benefit that such a status may 
bring to the population under study. 
 
 SAFETY 
 
The investigator is responsible for monitoring the safety of patients who have enrolled in the 
study. All adverse events (AEs) occurring after any administration of the study medication will 
be followed until the event resolves, until the patient begins alternative treatment, or until the 
end of the study. Investigators will grade AEs using the NCI CTCAE, version 4.0 (published 28 
May 2009) (see 0).  
 
Investigators are required to document all Grades of AEs ( Grades 1, 2, 3 or 4) occurring during 
the clinical trial, commencing with the first dose of study medication and including the protocol-
defined post-treatment follow-up period (21 CFR §312.64[b]) on designated CRF pages. All 
Grades of AEs  occurring following the signature of the informed consent, but prior to the first 
dose of study drug, will not be reported as AEs. It is also important to record all AEs that result 
in permanent discontinuation of the investigational product being studied, whether serious or 
non-serious.  
 
Serious adverse events (SAEs), as defined below, must be reported to HonorHealth or its 
representative within 24 hours of knowledge of their occurrence. An independent Data Safety 
and Monitoring Committee (DSMC) will review all AEs and SAEs to ensure patient safety.  See 
section 8.1.4 for further details. 
 
7.1 Adverse Events 
 
An AE is any unfavorable medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, which does not necessarily have to have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product. All Grade 3 and 4 AEs, including 
observed or volunteered problems, complaints, or symptoms, are to be recorded on the CRF. 
Each AE is to be evaluated for duration, intensity, and causal relationship with the study 
medication or other factors. All Grade AEs that are considered related to the study treatment 
regimen must be followed to resolution or stabilization if improvement is not expected. 
Progression of disease is considered an efficacy outcome parameter and should not be 
captured as an AE. 
 


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A non-serious AE is any untoward medical occurrence that does not meet any of the criteria for 
SAEs. 
 
Patients should be instructed to report any AE that they experience to the Investigator, starting 
from the time of their first dose. Investigators should assess AEs at each visit. All grades of AEs  
occurring during the clinical trial, starting at the time of the initial study drug infusion, and the 
follow-up period should be recorded on the appropriate AE page of the CRF.  
 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the investigator and recorded on the CRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the investigator, it should be recorded as a separate AE on the CRF. 
 
7.2 Serious Adverse Events  
 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results in 
any of the following outcomes: 
 
 
Death 
 
 
A life-threatening adverse event 
 
 
Life-threatening is defined as an event with immediate risk of death from the event as 
it occurred. It does not include an event that might have caused death if it occurred 
with a greater severity. 
 
 
In-patient hospitalization or prolongation of existing hospitalization 
 
 
Results in a persistent or significant disability/incapacity 
 
 
A congenital anomaly/birth defect 
 
 
Important medical events that may not be immediately life-threatening, or result in 
death or hospitalization, but may jeopardize the patient or may require intervention to 
prevent one of the other listed outcomes above. 
. 
 
7.3 Adverse Event Severity 
 
AE will be graded according to the NCI CTCAE, Version 4.0 (see 0)  
 
 
Grade 1 Mild AE: asymptomatic or mild symptoms. Clinical intervention not indicated 
 
 
Grade 2 Moderate AE: Minimal local or noninvasive intervention indicated 
 
 
Grade 3 Severe AE: Severe or medically significant but no immediately life-threatening 
hospitalization or prolongation of hospitalization indicated; the event is disabling;  
 
 
Grade 4 Life-threatening or disabling AE: urgent intervention indicated;  
 


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 
Grade 5 Death related to AE 
 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 
headache). This is not the same as "seriousness," which is based on patient/event outcome at 
the time of the event. For example, the NCI CTCAE grade 4 (life-threatening or disabling AE) is 
assessed based on unique clinical descriptions of severity for each AE, and these criteria may 
be different from those used for the assessment of AE seriousness. An AE assessed as grade 4 
based on the NCI CTCAE grades may or may not be assessed as serious based on the 
seriousness criteria. 
 
7.4 Causality Assessment 
 
The relationship of an AE to the study drug must be classified as one of the following: 
 
 
Unrelated: The AE is clearly not related to the study medication; 
 
 
Unlikely Related: It is doubtful that the AE is related to study medication; 
 
 
Possibly Related: The AE may be related to the study medication; 
 
 
Probably Related: The AE is likely related to the study medication; 
 
 
Definitely Related: The AE is clearly related to the study medication; 
 
7.5 Safety and Tolerance Analysis 
 
The incidence of all AEs (regardless of causality) and all treatment-related AEs (those AEs 
thought to be possibly, probably, or definitely related to study drug) will be summarized by NCI 
CTCAE Version 4.0 term and maximum grade. The incidence of SAEs and AEs that lead to 
discontinuation of study drug will also be summarized. Listings of patients who discontinue 
study drug due to an AE and patients with SAEs and deaths will be presented. Narratives will be 
provided for patients who experience an SAE. 
 
 Laboratory Assessments 
 
7.5.1.1 Hematology Parameters 
 
To investigate the maximal degree of myelosuppression, the NCI CTCAE Version 4.0 grade for 
WBC, ANC, platelet count, and hemoglobin concentration will be summarized by the most 
severe grade in the first treatment cycle and by the most severe grade during the therapy for 
each treatment group; testing of treatment group differences will be performed using a CMH 
test. The incidence of patients with NCI CTCAE Version 4.0 hematology values of All AE 
Grades that occurred after the first dose of study drug will be presented. Data for patients with 
Grades, 1, 2, 3 or 4 hematology values will be listed. 
 
7.5.1.2 Clinical Chemistry 
 
Liver and renal function will be summarized using the NCI CTCAE Version 4.0 for alkaline 
phosphatase, ALT, AST, total bilirubin, BUN and creatinine. The number and percentage of 


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patients who have more than one NCI CTCAE Version 4.0 grade will be summarized using the 
most severe Grade for the first cycle of therapy and for anytime during therapy for each 
treatment group; testing of treatment group differences will be performed using a Cochran-
Mantel-Hanzel test. The incidence of patients with NCI CTCAE Version 4.0 chemistry values of 
Grade 1, 2, 3 or 4 that occurred after the first dose of study drug will be presented. Data for 
patients with Grade 1, 2, 3 or 4 chemistry values will be listed. 
 
 Peripheral Neuropathy 
 
Peripheral neuropathy events will be captured according to protocol and reported by 
Investigators and investigative staff in accordance with adverse event and SAE reporting 
standards. 
 
 
7.6 Patient Reporting of AEs and SAEs 
 
Patients are to be encouraged to call the site to report any unexpected symptoms or problems 
they encounter between office visits. These events should be considered in the same fashion as 
if they had been reported at a scheduled office visit. At each scheduled office visit, after the 
patient has had an opportunity to spontaneously mention any problems, the Investigator should 
inquire about AEs by asking the following standard questions  
 
 
Have you had any (other) medical problems since your last clinic visit? 
 
 
Have you taken any new prescribed or over-the-counter medicines or herbal/vitamin 
preparations, other than those given to you in this study, since your last 
visit/assessment? 
 
 
Have any new procedures been performed since your last study visit? 
 
7.7 Investigator Reporting Serious Adverse Events 
 
The Investigator is responsible for notifying the appropriate health authorities (HAs), ethics 
committees (ECs), and other investigators, of any expedited, annual, or other periodic safety 
reports in accordance with applicable regulations.  The Investigator is also responsible for 
notifying the local ECs in accordance with local regulations. Reporting will be coordinated 
through  HonorHealth Research Institute Administration. Generally, Expedited Safety Reports 
are required for all SAEs that are assessed to be unexpected and possibly, probably or 
definitely related to study drug(s), as specified ICH EG Good Clinical Practices.   However, 
certain Regulatory Agencies may have additional requirements for expedited safety report 
submissions. 
 
The Investigator is responsible for recording, reporting and following all Grade 1,2, 3 or 4 AEs, 
regardless of causality, observed during the study period, starting with initial dose of study drug 
and ending at the time the patient goes off study or 30 days after patient’s last dose of study 
drug, whichever is later. The Investigator should follow AEs until the event is resolved or 
stabilized, the patient is lost to follow-up, or the event is otherwise explained. Events occurring 
within 30 days prior to study drug administration should be recorded as pre-treatment signs and 
symptoms. The only exception to this is for an AE that occurs prior to the first dose of study drug 
but is due to a procedure associated with assessments carried out to determine eligibility or to 


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permit participation in this protocol – this should be recorded as an AE (rather than a pre-
treatment sign or symptom).  
 
The Investigator or designee must completely and promptly record each AE in the source 
documentation, regardless of relationship to study drug as determined by the Investigator. 
Grade 1, 2, 3 and 4 AEs must be recorded in the CRF. The Investigator must assess AE/SAE 
causality for any patients treated at his/her site and for any patients treated under the 
direct care of his/her sub-Investigators. The Investigator should attempt, if possible, to 
establish a diagnosis based on the patient's signs and symptoms. When a diagnosis for the 
reported signs or symptoms is known, the Investigator should report the diagnosis, not the 
symptoms, as the AE.  
 
Clinically significant laboratory abnormalities present at the initial treatment visit will be recorded 
as pre-treatment signs and symptoms.  
 
All Grades (Grade 1, 2, 3 or 4) of adverse events and SAEs should be reported on the 
appropriate case report forms. In addition, all SAEs must be reported promptly to 
HonorHealth after the Investigator recognizes/classifies the event as a SAE. The specific 
reporting time frame depends on the type of SAE. For life-threatening or fatal events, the 
Investigator must report initial information on the SAE within 24 hours/ 1 business day of 
becoming aware of the event, preferably by fax or alternatively by phone or email; at a 
minimum, a description of the event and the Investigator’s judgment of causality must be 
provided at the time of the initial report. If an SAE is reported by phone or by e-mail, the 
Investigator must fax a completed SAE report form to HonorHealth within 1 business days. The 
Investigator should follow all AEs/SAEs observed during the study until they resolve or 
stabilize, the patient is lost to follow-up, or the events are otherwise explained. The 
HonorHealth Drug Safety Team is responsible for notifying the relevant regulatory 
authorities and Bristol Myers Squibb of certain Serious Adverse Events. 
 
For any additional questions regarding reporting requirements of a SAE, please contact 
the following individual: 
 
HonorHealth Drug Safety Team 
After hours, weekends, holidays:  480-323-1350 
Business hours phone: 480-323-1323  
E-mail: DrugSafety@honorhealth.com 
 
 Expedited Reporting by Investigator to HonorHealth  
 
Serious adverse events (SAE) are defined above. The Investigator must inform HonorHealth in 
writing of any SAE within 24 hours (for life threatening or fatal event) of being aware of the 
event. The date of awareness should be noted on the report. This must be documented on a  
HonorHealth Drug Safety Reporting Form.  
 
This form must be completed and supplied to HonorHealth Research Institute  within 24 hours/ 
1 business day at the latest on the following working day. The initial report must be as complete 
as possible, including details of the current illness and (serious) adverse event, and an 
assessment of the causal relationship between the event and the investigational product(s). 


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Information not available at the time of the initial report (e.g., an end date for the adverse event 
or laboratory values received after the report) must be documented on a follow-up  HonorHealth 
Research Institute  Reporting Form. A final report to document resolution of the SAE is required. 
The Study protocol number NAPPCG-EB 2015-001) and the institutional protocol number 
should be included on SAE reports to P HonorHealth Research Institute.  A copy of the fax 
transmission confirmation of the SAE report or copy of email  sent to HonorHealth Research 
Institute   should be attached to the SAE and retained with the patient records. 
 
 IRB Notification of SAEs 
 
The Investigator is responsible for promptly notifying the IRB of all SAEs, including any follow-
up information, occurring at his/her site and any SAE regulatory reports and Investigational New 
Drug Safety Reports that he/she receives from HonorHealth Drug Safety. 
 
7.8 SAE Follow-Up 
 
For all SAEs occurring after first dose of study medication or within 100 days of the last 
administration of study medication, the investigator must submit follow-up reports to  
HonorHealth   or its representative regarding the status of the SAE and the patient’s subsequent 
course until the SAE has subsided, or until the condition stabilizes (in the case of persistent 
impairment), the patient receives alternative therapy, or the patient dies.  
 
 Sponsor Notification of Post-Study SAEs 
 
The Investigator should notify HonorHealth of any new SAEs occurring within 30 days after a 
patient has withdrawn from the study and/or after the last study treatment if the SAE is 
determined to  be related or possibly to the study medication used in the study. Additional 
information regarding any ongoing SAE determined to be related or possibly to the study 
medication used in the study should be reported to the Sponsor after the first telephone call to 
assess survival status that is conducted at 12 weeks after the last study treatment.  Any 
information collected at these timepoints will be reported to Bristol-Myers Squibb if the SAE is 
determined to be related or possibly to treatment with Nivolumab.  However, Investigators are 
not obligated to actively seek AEs in former study participants. 
 
7.9 Pregnancy 
 
While not considered a SAE unless a serious criterion is met, pregnancies occurring in patients 
enrolled on the study or in their partners must be reported. The investigator should complete the 
pregnancy report form and fax it to  HonorHealth  within 24 hours of knowledge of the 
pregnancy. Male and female subjects will be required to use contraception while receiving study 
medication and for 5 months after the last dose is given.  Any pregnancies that occur, whether a 
female subject participating in the study or a partner of a male subject participant, will need to 
be reported to the Sponsor while the subject is receiving study medication and for 5 months 
after the last dose is given. 
 
 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
 
8.1 Ethics 


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 Institutional Review Board/ Ethics Committee Approval  
 
Before study 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  HonorHealth prior to submission to the IRB. The Investigator will forward to  
HonorHealth or Sponsor-nominated designee 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 CFR 56 of the Code of Federal Regulations, as well as those 
of the applicable regulatory bodies in all other participating countries outside of the U.S.  
In addition, the Investigator will be responsible for forwarding to HonorHealth or 
Sponsor-nominated designee a description of the IRB board 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 
FDA and other appropriate regulatory requirements. In addition, the labeling for all approved 
study drugs should be submitted to the IRB for informational 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  HonorHealth or other sponsor-nominated designee prior to 
drug shipment. 
 
 Ethical Conduct of the Study 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
Guidelines of the International Conference on Harmonization (ICH) of Technical Requirements 
for Registration of Pharmaceuticals for Human Use, and in full compliance with the World 
Medical Association Declaration of Helsinki and its most recent amendments. 
 
 Informed Consent 
 
Written informed consent of the patient to participate in the study must be obtained and 
documented by the Investigator in accordance with the FDA regulations set forth in 21 CFR 50 
as well as the applicable regulatory bodies in all other participating countries outside the United 
States.  
 
The Investigator must provide the patient with a copy of the informed consent form in a 
language understandable to the patient. Written consent should be obtained before any 
protocol-required procedures are performed, including any procedure not part of normal patient 
care (e.g., withdrawal of current medications). 
 
Changes made by a participating site to the recommended informed consent must be must be 
forwarded to  HonorHealth for approval prior to submission to the corresponding IRB. A copy of 
the signed informed consent will be given to the patient or their legal representative and a copy 
must be retained in the Investigator’s study records.  
 
 Data Safety and Monitoring Committee 
 
An independent Data Safety and Monitoring Committee (DSMC) will be formed to evaluate the 
safety and effectiveness of the study medication for each subject as well as study conduct of 


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each site. The DSMC will also review all SAEs reported by each site. The DSMC will review 
study data to determine if endpoints are being met and if the study can continue with or without 
changes to the protocol or if the study should be terminated immediately due to safety concerns 
or lack of data to support study endpoints. Findings and  recommendations of the DSMC will be 
reported to the Sponsor after each meeting.  The DSMC will meet on a quarterly basis or more 
frequently as needed if safety concerns are raised. Furthermore, prior to the expansion from 10 
to 25 patients in the trial a review by the DSMC will be conducted.  This treatment regimen 
combines 2 chemotherapeutic agents with known toxicity profiles, with a subsequent treatment 
of a combination of 3 chemotherapeutic agents with known toxicity profiles. Because cancer is a 
life-threatening disease, treatments that result in Grade 3 and 4 toxicities are considered to 
have an acceptable risk profile. Data reported to  HonorHealth will be received by the Lead 
Principal Investigator on a regular basis and not less than once a month. In addition, SAEs will 
be reported to  HonorHealth immediately and reviewed as they are received. Any unacceptable 
toxicities or severe toxicities that occur more frequently than expected will be discussed by the 
Lead Principal Investigator, the Medical Monitor, and the site Principal Investigators who will 
decide jointly whether the study should be modified, interrupted, or stopped. A monthly 
conference call will be held with investigators participating in the study. The statistical group will 
provide listings of toxicities on a regular basis. 
 
8.2 Disclosure of Data 
 
 Study Data Monitoring Plan 
 
HonorHealth  ensures that appropriate monitoring procedures are performed before, during and 
after the study. Before the study is initiated at a site visit or at an investigator meeting, all 
aspects of the study are reviewed with the Investigator and the staff. Prior to enrolling patients 
into the study, a HonorHealth representative will review the protocol, CRFs, procedures for 
obtaining informed consent, record keeping, and reporting of AEs/SAEs with the Investigator. 
Monitoring will include on-site visits with the Investigator and study team as well as any 
appropriate communications by mail, email, fax, or telephone. 
 
Data monitoring procedures will be carried out by HonorHealth 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 documentation (including 
radiology review), review of study related regulatory documents and logs (e.g., enrollment, study 
site staff, drug accountability), and review of drug accountability will 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.  
 
At the conclusion of the monitoring visit, the site 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 
study will be provided with a copy of the written monitoring notes for resolution of the findings.  
The HonorHealth site monitor will complete a written monitoring report and forward it to the site 
Principal Investigator and to  HonorHealth Administration. 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 HonorHealth Administration  and the 


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HonorHealth site monitor. A copy of the monitoring forms, final monitoring reports, and 
Corrective Action Plan will be kept in the site monitor’s study file at HonorHealth  for follow-up at 
the next monitoring session. 
 
 Confidentiality 
 
The Investigator and any other study personnel involved in this study shall not disclose, or use 
for any purposes (other than for the performance of this study), any data, records, or other 
information (hereinafter collectively “information”) disclosed to the Investigator or other study 
personnel. Such information shall remain the confidential and proprietary property of  
HonorHealth, and shall be disclosed only to the Investigator or other designated study 
personnel.  
 
The obligation of non-disclosure shall not apply to the following: 
 
 
relevant disclosure to potential study participants for the purpose of obtaining informed 
consent; 
 
 
information after such time that it is or becomes publicly available through no fault of the 
Investigator or other study personnel; and 
 
 
information after such time that it is disclosed to the Investigator by a third party entitled 
to disclose such information. 
 
If the study site is a ‘covered site’ under the definitions of the Health Insurance Portability and 
Accounting Act (HIPAA), the Investigator will ensure that the patient consents to the use of data 
by  HonorHealth and its designees for the purposes of regulatory submissions, study 
publications, and drug approval. 
 
 Publication 
 
The Investigator(s) shall have the right, consistent with academic standards and with due regard 
to the protection of HonorHealth confidential information and intellectual property, to publish or 
present the results of work performed in accordance with the study; provided that any proposed 
publication or presentation is first reviewed and approved in writing by  HonorHealth shall 
complete its review within 60 days after receipt of the proposed publication or presentation. 
Upon  HonorHealth request, proposed publication or presentation will be delayed up to 60 
additional days to enable  HonorHealth to secure adequate intellectual property protection of 
property of HonorHealth  that would be affected by such proposed publication or presentation. If  
HonorHealth believes in good faith that any proposed publication or presentation contains any 
confidential information and/or intellectual property HonorHealth shall have the right to remove 
references to any such confidential information and/or intellectual property.  
 
8.3 Protocol Compliance 
 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB/IEC and the appropriate regulatory authority(ies). Changes to the protocol 
will require approval from  HonorHealth, in addition to written IRB/IEC approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an 
immediate hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authority(ies) 


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permit, expedited review and approval/favorable opinion for minor change(s) in ongoing studies 
that have the approval /favorable opinion of the IRB/IEC. The investigator will submit all protocol 
modifications to HonorHealth and the regulatory authority(ies) in accordance with the governing 
regulations. Any departures from the protocol must be fully documented in the source 
documents. 
 
8.4 Quality Assurance 
 
All aspects of the study will be carefully monitored by HonorHealth  and/or its authorized 
representative for compliance with applicable government regulations with respect to current 
ICH GCP guidelines as well as other applicable regulations and guidelines.  
 
8.5 On-site Audits 
 
Regulatory authorities, the IEC/IRB, and/or HonorHealth may request access to all source 
documents, data capture records, and other study documentation for on-site audit or inspection. 
Direct access to these documents must be guaranteed by the investigator, who must provide 
support at all times for these activities. 
 
8.6  Premature Closure of the Study 
 
This study may be prematurely terminated, if in the opinion of the Lead Principal Investigator or  
HonorHealth there is sufficient reasonable cause.  
 
HonorHealth has the right to discontinue the study under the conditions specified in the clinical 
Trials agreement. Written notification documenting the reason for study termination will be 
provided to the site investigator by the terminating party.  
 
Circumstances that may warrant termination include, but are not limited to: 
 
 
Determination of unexpected, significant, or unacceptable risk to patients  
 
 
Failure to enter patients at an acceptable rate  
 
 
Insufficient adherence to protocol requirements  
 
 
Insufficient complete and/or evaluable data  
 
 
Plans to modify, suspend or discontinue the development of the drug  
 
 
Recommendation from the DSMC to close the study 
 
Should the study be closed prematurely, all study materials must be returned to  HonorHealth. 
 
8.7  Investigator Documentation 
 
 Form FDA 1572 
 
The Investigator must provide HonorHealth with a fully executed Form FDA 1572. Any updates 
must be provided via a new fully executed Form FDA 1572. 


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 Curriculum Vitae 
 
The Investigator must provide HonorHealth with his/her current signed and dated curriculum 
vitae and a current signed and dated curriculum vitae for each sub-Investigator listed on Form 
FDA 1572. Current signed and dated curriculum vitae is defined as updated within 2 years of 
study start up. 
 
 Financial Disclosures 
 
The Investigator and sub-Investigator(s) must complete a Clinical Investigator Financial 
Certification/Disclosure Statement to report financial interests and arrangements that may be of 
concern to FDA per 21 CFR 54. 
 
 Laboratory Certification and Normal Ranges 
 
The Investigator will indicate on the Form FDA 1572 the name and location of any local 
laboratories that will be used for laboratory assessments. The Investigator will provide a copy of 
all clinical laboratory certifications, certification numbers, dates of certifications, and a list of the 
normal ranges for all laboratory tests for all facilities listed. Updated versions of these 
documents must be provided to HonorHealth as appropriate. In the event the clinical laboratory 
is changed during the study, HonorHealth will be promptly notified, and the Form FDA 1572 will 
be updated. Appropriate documentation will be submitted to HonorHealth to verify the 
certification of the new laboratory. 
 
All radiology facilities being utilized outside the investigative site must be pre-approved by  
HonorHealth, and included on the Form FDA 1572. 
 
8.8 Records Retention 
 
In accordance with applicable regulatory requirements, following closure of the study, the 
Investigator will maintain a copy of all site study records in a safe and secure location.  
HonorHealth will inform the Investigator of the time period for retaining these records in order to 
comply with applicable regulatory requirements. 
 
HonorHealth reserves the right to terminate the study for refusal of the Investigator and/or 
investigational site to comply with any requirements stated in this study protocol. 
 
8.9 Protocol Deviations 
 
Deviations from the protocol must be addressed as protocol amendments with IRB approval 
required prior to implementation. Apart from the regulatory requirements, it is vital to the 
success of the study that the Investigator adheres to the details of the protocol and thus holds to 
a minimum the number of cases that may be later classified as “incomplete,” “unusable,” or “not 
evaluable.” 
 
 


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 DATA MANAGEMENT 
 
9.1 Patient Enrollment Instructions 
 
Potential study participating screening packages will be submitted to Sponsor for review.  If 
patient eligible for participation, Sponsor/designee shall assign subject ID and provide 
documentation to study site. 
 
 
9.2 Data Submission Instructions 
 
This study uses an Electronic Database Capture system for data submission through the data 
management services of HonorHealth. The original reports, traces and films must be retained 
by the Investigators for future reference. 
 
Screening Form: at time of screening 
 
Enrollment Form: after eligibility confirmed.  
 
All screening/baseline/treatment/off-treatment Forms: within 2 weeks of occurrence.  
 
Adverse Event Form: within 2 weeks of each scheduled adverse events evaluation until adverse 
events have resolved following permanent discontinuation of treatment, documenting adverse 
event information, including toxicities indicated by lab testing.  
 
NOTE: all Serious Adverse Events must also be reported on the Adverse Event Form. 
 
Serious Adverse Events (SAE) documentation: submit directly to HonorHealth and the Site 
Principal Investigator within the time frame and per the guidelines specified in Section 7.7. 
Any deaths that the site is notified of will be reported using the Adverse Event Form and 
submitted within 2 weeks of knowledge of death. 
 
 
 TERMINATION OF STUDY  
 
HonorHealth reserves the right to discontinue this study at any time. 
 
 INVESTIGATOR’S PROTOCOL AGREEMENT 
 
The Investigator must sign the Investigator’s Protocol Agreement (Page 3 of this document). 
The original must be kept on file at HonorHealth 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 by HonorHealth. 


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Z, McGinniss MJ. Actionable targets in pancreatic cancer detected by 
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 APPENDICES 
APPENDIX A: 
SCHEDULE OF EVALUATIONS AND TREATMENT 
Assessment 
Screening 
within 21 
days 
Cycle 1 – 4+ 
 
After 
cycle 
each  
cycle  
(+/- 2 
days)  
At time 
of CR by 
CT scan 
and 
marker 
EOS/ 
Early 
Term10 
 
Survival 
FU 
Day 
1 
 
Day 
2* 
Day 
4* 
Day 
8* 
Day 
9* 
Day 
12* 
Day 
15* 
Day 
18* 
Day 
22* 
Day 
23* 
Day 
26* 
Day 
29* 
Day 
30* 
Day 
32* 
Day 
36* 
Day 
39* 
Signed Informed 
Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/ 
Exclusion 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History1 
x 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
Physical Examination 
x 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
Height (cm) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg)  
x 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
BSA Calculation 
 
x 
 
 
 
 
 
 
 
x2 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
x 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
Karnofsky PS 
x 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
 
 
 
 
x 
 
CT/MRI scan/ tumor 
measurements3 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
PET/CT4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
ECG 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
with Plts 
 
x 
x 
 
 
x 
 
 
x 
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 


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Assessment 
Screening 
within 21 
days 
Cycle 1 – 4+ 
After 
cycle 
each  
cycle  
(+/- 2 
days) 
At time 
of CR by 
CT scan 
and 
marker 
EOS/ 
Early 
Term10 
 
Survival 
FU 
Day 
1 
Day 
2* 
Day 
4* 
Day 
8* 
Day 
9* 
Day 
12* 
Day 
15* 
Day 
18* 
Day 
22* 
Day 
23* 
Day 
26* 
Day 
29* 
Day 
30* 
Day 
32* 
Day 
36* 
Day 
39* 
Serum Chemistries5 
x 
x 
 
 
x 
 
 
x  
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
CA 19-9 ( or 
CA125,or CEA if not 
expressors of CA19-
9) 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
Urinalysis6 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
TSH15 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
Blood Sample for 
Exploratory 
Biomarkers  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fecal Sample 
Collection  
x19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x20 
 
 
 
 
Vitamin D Levels 
serum 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Panel16 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archived blocks of 
tumor specimen for 
CGH and Immune 
Assays7 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy17 
x 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
 
Con Meds8 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
 
Adverse Events9 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
x 
 
Telephone Follow up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Nivolumab13 
 
x  
 
 
 
 
 
x 
 
 
 
 
x  
 
 
 
 
 
 
 
 


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Assessment 
Screening 
within 21 
days 
Cycle 1 – 4+ 
 
After 
cycle 
each  
cycle  
(+/- 2 
days) 
At time 
of CR by 
CT scan 
and 
marker 
EOS/ 
Early 
Term10 
 
Survival 
FU 
Day 
1 
Day 
2* 
Day 
4* 
Day 
8* 
Day 
9* 
Day 
12* 
Day 
15* 
Day 
18* 
Day 
22* 
Day 
23* 
Day 
26* 
Day 
29* 
Day 
30* 
Day 
32* 
Day 
36* 
Day 
39* 
Albumin-bound 
Paclitaxel12 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
Cisplatin12 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
Gemcitabine12 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
Paricalcitol14 
 
x14   
 
x14 
x14 
 
x14 
x14   
x14 
x14 
 
x14 
x14   
 
x14 
x14 
x14 
 
 
 
 
Neulasta 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Optional IV fluids 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
 
 
MDASI-GI and BPI 
Questionnaires 18 
x 
x  
 
 
x 
 
 
x  
 
x 
 
 
x 
 
 
x 
 
 
 
x 
 
*  Visit windows will be +/- 24 hours as indicated.  All assessments that occur on dosing days mush occur within 24 hours prior to dosing.  


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Schedule of Events footnotes: 
 
1. 
To include concurrent baseline conditions (using NCI CTCAE, version 4.0), prior cancer therapy (including documentation of 
prior surgery, adjuvant or neoadjuvant chemotherapy and radiotherapy). 
2. 
BSA is recalculated on Day 1 of each cycle. Drug doses will be recalculated only if there has been a ≥10% change in body 
weight from baseline. (See Section 4.3). 
3. 
Computed tomography (CT) / magnetic resonance imaging (MRI) scan to document disease status (including chest, 
abdomen, pelvis, and other regions as clinically indicated. In addition, brain scan required to exclude brain metastases). 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 as close to start of chemotherapy as possible. . In addition to the CT / MRI scan, tumor size may also 
be assessed utilizing visual or palpable lesions on physical examination including full assessment of all known metastases 
(see RECIST 1.1 criteria in Section 7). Follow-up scans are due every 6 weeks,  (prior to each cycle)   
4. 
When a CR is documented, a confirmatory PET scan will be obtained. 
5. 
To include BUN, phosphorus, magnesium, creatinine, total protein, albumin, calcium, glucose, total bilirubin, alkaline 
phosphatase, AST, ALT, and electrolytes (chloride, sodium, potassium, and bicarbonate) and CA 19-9 (or CA 125, or CEA if 
not expressers of CA 19-9). 
6. 
Lab urinalysis with micro, culture if indicated- to include protein, specific gravity, glucose, and blood. 
7. 
Archived paraffin block of tumor specimen, if collected, prior to treatment.  
8. 
To include all medications taken within 30 days prior to study enrollment. 
9. 
Patient will be followed until resolution of any drug-related AE or SAE occurring during the study, including, within 30 days 
of last administration of study medication, or when the patient begins alternative therapy; whichever is sooner.  
10. End of Study or Early Termination assessments can be completed 14-28 (+/- 2) days from the last dose of study medication 
11. Follow-up assessments by telephone will be conducted in all patients every 12 weeks, start from last dose of chemotherapy, 
to determine date of response, date of disease progression, and date of death. 
12. The sequence of drug administration is albumin-bound paclitaxel, then cisplatin, then gemcitabine. 
13. Nivolumab is given every 2 weeks 
14. Paricalcitol is given 2  times per week days 1,4,8,12,15,18,22,26,29,32,36,39 etc, (+/- 1 day allowed for dosing) 
15. If TSH is abnormal, obtain T3 and free T4 levels 
16. Coagulation Panel to include PTT and PT/INR 
17. Performed only for women of child bearing potential 
18. There will be a +/- 48 hour completion window for the MDASI-GI and BPI Questionnaires 
19. At home collection kit shall be provided at screening to be collected and returned within 72 hours of C1D1 pre-dose. 
20. At home collection kit shall be provided on C(X)D39 and is to be collected and returned within 72 hours of C(X)D1. 
 


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APPENDIX B: KARNOFSKY PERFORMANCE STATUS 
 
 
 
 


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APPENDIX C: LIST OF ABBREVIATIONS 
Term 
Definition 
Abraxis 
Abraxis BioScience, Inc 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Aminotransferase (SGPT) 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate Aminotransferase (SGOT) 
AUC 
Area Under the Curve 
BCC 
Basal Cell Carcinoma 
β-hCG 
Beta subunit of human chorionic gonadotrophin (hCG) 
BMS 
Bristol-Myers Squibb 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
˚C 
Degrees Celsius 
CA 125 
Carbohydrate Antigen 125 
CA19-9 
Carbohydrate Antigen 19-9 
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic antigen 
CFR 
CGH 
Code of Federal Regulations 
Comparative Genomic Hybridization 
CI 
Confidence Interval 
CIB 
Clinical Investigator’s Brochure 
Cmax 
Maximum observed plasma concentration 
CMH 
Cochran-Mantel-Haenszel 
CML 
Chronic myelogenous leukemia 
CrEL 
Cremophor-EL 
CRF 
Case Report Form  
CR 
Complete Response 


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Term 
Definition 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHHS 
Department of Health and Human Services 
DLT 
Dose Limiting Toxicity 
DSMC 
Data Safety and Monitoring Committee 
DVT 
Deep Vein Thrombosis 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EPR 
Enhanced Permeability and Retention 
EORTC 
European Organization for Research and Treatment of Cancer 
EORTC QLQ-C30 
Questionnaire to assess quality of life of patients with cancer 
EORTC QLQ-BM22 
EORTC QLQ Bone metastases module 
EOS 
End of Study 
FAS 
Full Analysis Set 
˚F 
Degrees Fahrenheit 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice(s) 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GTX 
Gemzar plus Taxotere plus Xeloda 
HA 
Human Albumin 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C antibody 
Hgb 
Hemoglobin 
Hh 
Hedgehog 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 


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Term 
Definition 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous(ly) 
KPS 
Karnofsky Performance Status 
LDH  
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Minor Response 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ND 
Not Done 
NIH 
National Institutes of Health 
non-DEHP  
Non-(di(2-ethylhexyl) phthalate) 
ORR 
Overall Response Rate 
PD 
Progressive Disease 
PDAC 
PET 
Pancreatic Ductal Adenocarcinoma 
Positron-Emission Tomography 
PFS 
Progression Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PPS 
Per Protocol Set 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QD 
Daily 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 


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Term 
Definition 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SCLC 
Small-cell lung cancer 
SD 
Stable Disease 
S.D. 
Standard Deviation 
SGOT 
Serum Glutamate Oxaloacetic Transaminase 
SGPT 
Serum Glutamate Pyruvic Transaminase 
SOP 
Standard Operating Procedure 
SPARC 
Secreted Protein Acidic and Rich in Cysteine (a glycoprotein) 
SUV 
Standard Uptake Value 
Tmax 
Time of Maximum Observed Plasma Concentration 
TEAE 
Treatment Emergent Adverse Event 
TEAV 
TGen 
Treatment Emergent Abnormal Laboratory Value 
Translational Genomics Research Institute 
TKI 
Tyrosine Kinase Inhibitor 
TTP 
Time to Progression 
ULN 
Upper Limit of Normal  
US 
United States 
WBC 
White Blood Cell 
WCBP 
Women of Child-Bearing Potential 
WHO 
World Health Organization 
WHODD 
WHO Drug Dictionary 
 
 
 
 


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APPENDIX D: REVISED NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI CTCAE), 
VERSION 4.0 (PUBLISHED 28 MAY 2009) 
Revised National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), 
version 4.0 (published 28 May 2009) 
The National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 can be viewed on-line at the following NCI web site: 
http://evs..nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E: STUDY DRUG PREPARATION, DOSING, ADMINISTRATION 
AND STORAGE 
See links below to website access 
Nivolumab (OPDIVO™) Prescribing Information (updated 2014) – Accessed via OPDIVO Website 
http://www.opdivo.bmscustomerconnect.com/gateway  
Albumin-bound paclitaxel (Abraxane™) Prescribing Information (Updated 1/2012) – Accessed via 
Abraxane Website: http://www.abraxane.com/docs/Abraxane_PrescribingInformation.pdf 
Cisplatin Prescribing Information (updated 2012) – Accessed via Daily Med (National Library of Medicine) 
http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=a440f077-46f6-4688-a209-65bce38d1c92 
Gemcitabine (Gemzar™) Prescribing Information (Updated 2/2011) – Accessed via Gemzar Website: 
http://pi.lilly.com/us/gemzar.pdf 
Paricalcitol (Zemplar®) Prescribing Information (Updated 2012) – Accessed via Zemplar Website 
http://www.zemplar.com/  
 
 


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APPENDIX F: 2006 UPDATE OF ASCO PRACTICE GUIDELINE 
RECOMMENDATIONS FOR THE USE OF WHITE BLOOD CELL GROWTH 
FACTORS: GUIDELINE SUMMARY 
Setting/Indication 
Recommendation 
Primary prophylaxis 
Primary prophylaxis is recommended for the prevention of FN in 
patients who have a high risk of FN based on age, medical 
history, disease characteristics, and myelotoxicity of the 
chemotherapy regimen. For “dose-dense” regimens, CSF is 
required and recommended. Clinical Trial data support the use of 
CSF when the risk of FN is in the range of 20% or higher.  
Primary prophylaxis: 
Special circumstances 
Certain clinical factors predispose to increased complications 
from prolonged neutropenia, including: patient age > 65 years; 
poor performance status; previous episodes of FN; extensive 
prior treatment including large radiation ports; administration of 
combined chemoradiotherapy; bone marrow involvement by 
tumor-producing cytopenias; poor nutritional status; the presence 
of open wounds or active infections; more advanced cancer, as 
well as other serious comorbidities. In such situations, primary 
prophylaxis with CSF is often appropriate, even with regimens 
with FN rates of < 20%.  
Secondary prophylaxis 
Secondary prophylaxis with CSF is recommended for patients 
who experienced a neutropenic complication from a prior cycle of 
chemotherapy (for which primary prophylaxis was not received), 
in which a reduced dose may compromise disease-free or overall 
survival or treatment outcome. In many clinical situations, dose 
reduction or delay may be a reasonable alternative. 
Therapeutic use: 
Afebrile neutropenia 
CSF should not be routinely used for patients with neutropenia 
who are afebrile. 
Therapeutic use: 
Febrile neutropenia 
CSF should not be routinely used as adjunctive treatment with 
antibiotic therapy for patients with fever and neutropenia. 
However, CSF should be considered in patients with fever and 
neutropenia who are at high-risk for infection-associated 
complications, or who have prognostic factors that are predictive 
of poor clinical outcomes. High-risk features include expected 
prolonged (> 10 days) and profound (< 0.1 × 109/L) neutropenia, 
age > 65 years, uncontrolled primary disease, pneumonia, 
hypotension and multi-organ dysfunction (sepsis syndrome), 
invasive fungal infection, or being hospitalized at the time of the 
development of fever. 
Dose intensity/density of 
chemotherapy 
Dose-dense regimens should only be used within an 
appropriately designed clinical Trial or if supported by convincing 
efficacy data. 


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Setting/Indication 
Recommendation 
Adjuncts to progenitor-
cell transplantation 
Administration of CSF to mobilize PBPC often in conjunction with 
chemotherapy, and their administration after autologous, but not 
allogeneic, PBPC transplantation is the current standard of care. 
AML: Initial or repeat 
induction chemotherapy 
CSF use following initial induction therapy is reasonable, though 
there has been no favorable impact on remission rate, remission 
duration, or survival. Patients > 55 years of age may be most 
likely to benefit from CSF use. 
AML: CSF for priming 
effects 
Use of CSF for priming effects is not recommended. 
AML: Consolidation 
chemotherapy 
CSF use can be recommended after the completion of 
consolidation chemotherapy because of the potential to decrease 
the incidence of infection and eliminate the likelihood of 
hospitalization in some patients receiving intensive postremission 
chemotherapy. There seems to be more profound shortening of 
the duration of neutropenia after consolidation chemotherapy for 
patients with AML in remission than for patients receiving initial 
induction therapy. As yet there is no information about the effect 
of longer-acting pegylated CSFs in patients with myeloid 
leukemias, and they should not be used in such patients outside 
of clinical Trials. 
MDS 
Intermittent administration of CSF may be considered in a subset 
of patients with severe neutropenia and recurrent infection. 
ALL 
CSF administration is recommended after the completion of the 
initial first few days of chemotherapy of the initial induction or first 
postremission course, thus shortening the duration of neutropenia 
of < 1,000/mm3 by approximately 1 week.  
Acute leukemia in 
relapse 
CSF should be used judiciously, or not at all, in patients with 
refractory or relapsed myeloid leukemia since the expected 
benefit is only a few days of shortened neutropenia.  
Radiotherapy ± 
chemotherapy 
CSF should be avoided in patients receiving concomitant 
chemotherapy and radiation therapy, particularly involving the 
mediastinum. In the absence of chemotherapy, therapeutic use of 
CSF may be considered in patients receiving radiation therapy 
alone if prolonged delays secondary to neutropenia are expected.  
Older patients 
Prophylactic CSF for patients aged ≥ 65 years with lymphoma 
treated with curative chemotherapy (CHOP or more aggressive 
regimens) should be given to reduce the incidence of FN and 
infections.  


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Setting/Indication 
Recommendation 
Pediatric patients 
As in adults, the use of G-CSF is reasonable for the primary 
prophylaxis of pediatric patients with a likelihood of FN. Similarly, 
the use of G-CSF for secondary prophylaxis or for therapy should 
be limited to high-risk patients. However, the potential risk for 
secondary myeloid leukemia or myelodysplastic syndrome 
associated with G-CSF represents a concern in children with ALL 
whose prognosis is otherwise excellent. For these reasons, the 
specific use of G-CSF in children with ALL should be considered 
carefully.  
Comparative clinical 
activity of G-CSF and 
GM-CSF 
No guideline recommendation can be made regarding the 
equivalency of the two colony-stimulating agents. Further Trials 
are recommended to study the comparative clinical activity, 
toxicity, and cost-effectiveness of GCSF and GM-CSF.  
Treatment for radiation 
injury 
Current recommendations for the management of patients 
exposed to lethal doses of total-body radiotherapy, but not doses 
high enough to lead to certain death due to injury to other organs, 
includes the prompt administration of CSF or pegylated G-CSF.  
Abbreviations: CSF, colony-stimulating factors; FN, febrile neutropenia; PBPC, peripheral-blood 
progenitor cell; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; ALL, acute 
lymphocytic leukemia; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; G-CSF, 
filgrastim; GM-CSF, sargramostim; pegylated G-CSF, pegfilgrastim. 
 
 
 


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APPENDIX G: MANAGEMENTALGORITHMS FOR ADVERSE EVENTS RELATED TO 
NIVOLUMAB THERAPY (FROM APPENDIX 3 OF INVESTIGATOR’S BROCHURE 
VERSION 13, 30 JUNE 2015 FROM BMS-936558/MDX 1106)  
 
 
 
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all immuno-
oncology agents and regimens. 
 
A general principle is that differential diagnoses should be diligently evaluated according to standard 
medical practice. Non-inflammatory etiologies should be considered and appropriately treated. 
 
Corticosteroids  are  a  primary  therapy  for  immuno-oncology  drug-related  adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-grade 
toxicity. The lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids. 
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or therapeutic 
procedure, is recommended. 
 
The frequency and severity of the related adverse events covered by these algorithms will depend on the 
immuno-oncology agent or regimen being used. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Management 
• Continue  I-O therapy per 
protocol 
• Symptomatic treatment 
• Delay I-O therapy per protocol 
• Symptomatic treatment 
• Discontinue I-O therapy per 
protocol 
• 1.0 to 2.0 mg/kg/day 
methylprednisolone  IV or  IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider lower endoscopy 
Follow-up 
• Close monitoring for worsening symptoms. 
• Educate patient to report worsening immediately 
If worsens: 
• Treat as Grade 2 or 3/4 
If improves to grade 1: 
•  Resume I-O therapy per protocol 
If persists > 5-7 days or recur: 
•  0.5-1.0 mg/kg/day methylprednisolone or oral equivalent 
•  When symptoms improve to grade 1, taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol. 
If worsens or persists > 3-5 days with oral steroids: 
•  Treat as grade 3/4 
If improves: 
• Continue steroids until grade 1, then taper over at 
least 1 month 
If persists > 3-5 days, or recurs after improvement: 
• Add infliximab 5 mg/kg (if no contraindication). 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
GI Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics 
may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis. 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 
Grade of Diarrhea/ 
Colitis 
(NCI CTCAE v4) 
Grade 1 
Diarrhea:< 4 stools/day over baseline; 
Colitis: asymptomatic 
Grade 2 
Diarrhea: 4-6 stools per day over 
baseline; IV fluids indicated <24 hrs; 
not interfering with ADL 
Colitis: abdominal pain; blood in stool 
Grade 3-4 
Diarrhea (G3): ≥7 stools per day over 
baseline; incontinence; IV fluids ≥24 
hrs; interfering with ADL 
Colitis (G3):  severe abdominal pain, 
medical intervention indicated, 
peritoneal signs 
G4: life-threatening, perforation 


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Renal Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy 
 
Grade of Creatinine 
Elevation 
(NCI CTCAE v4) 
 
Management 
Follow-up 
 
Grade 1 
Creatinine > ULN and  > 
than baseline but  ≤ 1.5x 
baseline 
 
• Continue I-O therapy per protocol 
• Monitor creatinine weekly 
If returns to baseline: 
•Resume routine creatinine monitoring per protocol 
If worsens: 
•Treat as Grade 2 or 3/4 
 
 
 
 
Grade 2-3 
Creatinine > 1.5x baseline 
to ≤ 6x ULN 
 
• Delay I-O therapy per protocol 
• Monitor creatinine every 2-3 days 
• 0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or oral 
equivalent 
• Consider renal biopsy 
If returns to Grade 1: 
•Taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume I-O therapy 
and routine creatinine monitoring per protocol 
 
If elevations persist > 7  days or worsen: 
•Treat as Grade 4 
 
 
 
 
 
Grade 4 
Creatinine > 6x ULN 
• Discontinue I-O therapy per 
protocol 
• Monitor creatinine daily 
• 1.0-2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Consult nephrologist 
• Consider renal biopsy 
 
 
If returns to Grade 1: Taper steroids over at least 1 month and 
add prophylactic antibiotics for opportunistic infections 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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Pulmonary Adverse Event Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Evaluate with imaging 
and pulmonary consultation. 
 
Grade of 
Pneumonitis 
(NCI CTCAE v4) 
Management 
Follow-up 
 
 
Grade 1 
Radiographic changes only 
• Consider delay of I-O therapy 
• Monitor for symptoms every 2-3 
days 
• Consider Pulmonary and ID 
consults 
 
• Re-image at least every 3 weeks 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
 
Grade 2 
Mild to moderate  new 
symptoms 
 
 
 
 
 
 
Grade 3-4 
Severe new symptoms; 
New/worsening hypoxia; 
Life-threatening 
• Delay I-O therapy per protocol 
• Pulmonary and ID consults 
• Monitor symptoms daily, consider 
hospitalization 
• 1.0 mg/kg/day methyl- 
prednisolone IV or oral equivalent 
• Consider  bronchoscopy  , lung 
biopsy 
 
• Discontinue  I-O therapy per 
protocol 
• Hospitalize 
• Pulmonary and ID consults 
• 2-4  mg/kg/day 
methylprednisolone IV or IV 
equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consider bronchoscopy, lung 
biopsy 
• Re-image every 1-3 days 
If improves: 
• When symptoms return to near baseline, taper steroids over 
at least 1 month and then resume I-O therapy per protocol 
and consider prophylactic antibiotics 
If not improving after 2 weeks  or worsening: 
• Treat as Grade 3-4 
 
 
 
 
If improves to baseline: 
• Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
• Add additional immunosuppression 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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Hepatic Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 
obstruction. 
 
Grade of Liver 
Test  Elevation 
(NCI CTCAE v4) 
 
Management 
Follow-up 
 
Grade 1 
AST or ALT > ULN  to 3.0 x 
ULN and/or T. bili > ULN 
- 1.5 x ULN 
 
 
• Continue I-O therapy per protocol 
 
• Continue LFT monitoring per protocol 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
 
Grade 2 
AST or ALT > 3.0 to ≤ 5 x 
ULN and/or T. bili > 1.5 
to ≤ 3 x ULN 
 
 
• Delay I-O therapy per protocol 
• Increase frequency of monitoring 
to every 3 days 
If returns to baseline: 
•Resume routine monitoring, resume I-O therapy per protocol 
 
If elevations persist > 5-7 days or worsen : 
• 0.5-1 mg/kg/day methylprednisolone or oral equivalent and 
when LFT returns to grade 1 or baseline, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per protocol 
 
 
 
 
Grade 3-4 
AST or ALT > 5 x ULN 
or T.bili >3 x ULN 
 
• Discontinue  I-O therapy* 
• Increase frequency of monitoring 
to every 1-2 days 
•  1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent** 
• Add prophylactic antibiotics for 
opportunistic infections 
• Consult gastroenterologist 
 
If returns to grade 2: 
• Taper steroids over at least 1 month 
 
 
If does not improve in >3-5 days, worsens or rebounds: 
• Add mycophenolate mofetil 1 g BID 
• If no response within an additional 3-5 days, consider other 
immunosuppressants per local guidelines 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*I-O therapy may be delayed rather than discontinued  if AST/ALT  ≤ 8 x ULN and T.bili ≤ 5 x ULN. 
**The recommended  starting dose for grade 4 hepatitis is 2 mg/kg/day methylprednisolone IV. 


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Endocrinopathy Management Algorithm 
 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider visual field testing, 
endocrinology consultation, and imaging. 
 
Asymptomatic 
TSH elevation 
• Continue I-O therapy per protocol 
• If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 2 subsequent measurements: include fT4 at 
subsequent cycles as clinically indicated; consider endocrinology consult 
 
 
 
 
 
 
Symptomatic 
endocrinopathy 
 
• Evaluate endocrine function 
• Consider pituitary scan 
 
Symptomatic with abnormal lab/pituitary scan: 
• Delay I-O therapy per protocol 
•  1-2 mg/kg/day methylprednisolone IV or  PO equivalent 
• Initiate appropriate hormone therapy 
 
No abnormal lab/pituitary MRI scan but symptoms persist: 
• Repeat labs in 1-3 weeks / MRI in 1 month 
If improves  (with or without 
hormone replacement): 
• Taper steroids over at least 1 
month and consider prophylactic 
antibiotics for opportunistic 
infections 
• Resume I-O therapy per protocol 
• Patients with adrenal 
insufficiency may need to 
continue steroids with 
mineralocorticoid component 
 
 
 
Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness 
• Delay or discontinue I-O therapy per protocol 
• Rule out sepsis 
• Stress dose of IV steroids with mineralocorticoid activity 
• IV fluids 
• Consult endocrinologist 
• If adrenal crisis ruled out,  then treat as above for symptomatic 
endocrinopathy 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, 
once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids. 


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Follow-up 
If persists > 1-2 weeks or recurs: 
• Consider skin biopsy 
• Delay I-O therapy per protocol 
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral  equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol 
If worsens: 
• Treat as Grade 3-4 
If improves to Grade 1: 
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections 
• Resume I-O therapy per protocol 
Skin Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
 
 
Grade of 
Rash 
(NCI CTCAE v4) 
 
Management 
 
 
 
 
Grade 1-2 
Covering  ≤ 30% 
BSA* 
 
• Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
• Continue I-O therapy per protocol 
 
 
 
 
 
 
Grade 3-4 
Covering >30% BSA; 
Life threatening 
consequences*^ 
• Delay or discontinue I-O therapy per 
protocol 
• Consider skin biopsy 
• Dermatology consult 
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent 
 
 
 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids  (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement  is observed.  Lower bioavailability of oral corticosteroids  should be taken into account when switching to the equivalent dose of oral corticosteroids. 
*Refer to NCI CTCAE v4 for term-specific  grading criteria. 
^If SJS/TEN is suspected, withhold I-O therapy and refer patient for specialized care for assessment and treatment. If SJS or TEN is diagnosed, permanently discontinue I-O therapy.


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Neurological Adverse Event Management Algorithm 
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 
 
Grade of 
Neurological 
Toxicity 
(NCI CTCAE v4) 
 
 
Management 
Follow-up 
 
Grade 1 
Asymptomatic or 
mild symptoms; 
Intervention not 
indicated 
 
 
• Continue I-O therapy per protocol 
 
Continue to monitor the patient. 
If worsens: 
• Treat as Grade 2 or 3-4 
 
 
Grade 2 
Moderate symptoms; 
Limiting instrumental 
ADL 
• Delay I-O therapy per protocol 
• Treat symptoms per local guidelines 
• Consider  0.5 to 1.0 mg/kg/day 
methylprednisolone  IV or  PO 
equivalent 
 
If improves to baseline: 
•Resume I-O therapy per protocol when improved to baseline 
If worsens: 
• Treat as Grade 3-4 
 
 
Grade 3-4 
Severe symptoms; 
Limiting self-care 
ADL; 
Life-threatening 
• Discontinue I-O therapy per protocol 
• Obtain neurology consult 
• Treat symptoms per local guidelines 
•  1.0-2.0 mg/kg/day IV 
methylprednisolone  IV or IV equivalent 
• Add prophylactic antibiotics for 
opportunistic infections 
 
If improves to Grade 2: 
• Taper steroids over at least 1 month 
 
If worsens or atypical presentation: 
• Consider IVIG or other immunosuppressive therapies per 
local guideline
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral 
corticosteroids. 


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APPENDIX H:  MEMO FOR DEXAMETHASONE DOSE REDUCTION 
WITH CONCOMITANT ADMINISTRATION OF FOSAPREPITANT 
 
The current protocol recommends the following prophylactic medication regimen: 
 
Aloxi (palonosetron) 0.25mg IV, Emend (fosaprepitant) 150 mg IV and dexamethasone 20mg IV within 30 
minutes prior to treatment on days 1 and 8, repeated every 21 days. Patients will continue oral antiemetic 
prophylaxis at home with ondansetron 8mg bid and dexamethasone 4mg bid for 2 days after chemotherapy.  
 
 Fosaprepitant is a moderate inhibitor of CYP3A4, resulting in an increased serum concentration of 
dexamethasone.  The dose of dexamethasone, especially on day 1 and day 8, must be decreased to 
account for the drug-drug interaction. 
 
Per EMEND® Prescribing Information for the 150mg (Single Dose Regimen of EMEND): 
 
EMEND for Injection 150 mg is administered intravenously on Day 1 only as an infusion over 20-30 
minutes initiated approximately 30 minutes prior to chemotherapy. No capsules of EMEND are 
administered on Days 2 and 3. EMEND for Injection should be administered in conjunction with a 
corticosteroid and a 5-HT3 antagonist as specified in Table 1.  
 
Table 1 
Recommended dosing (Single Dose Regimen of EMEND) for the prevention of nausea 
and vomiting associated with highly emetogenic cancer chemotherapy 
 
Day 1 
Day 2 
Day 3 
Day 4 
EMEND 
150 mg 
intravenous 
none 
none 
none 
Dexamethasone* 
12 mg orally 
8 mg orally 
8 mg orally twice 
daily 
8 mg orally twice 
daily 
5-HT3 antagonist 
See the package insert 
for the selected 5-HT3 
antagonist for 
appropriate 
Dosing information. 
none 
none 
none 
* Dexamethasone should be administered 30 minutes prior to chemotherapy treatment on Day 1 and in the 
morning on Days 2 through 4. The dose of dexamethasone accounts for drug interactions. 
 
Due to similar bioavailability of oral and IV dexamethasone, the IV dexamethasone dose should be 
decreased to 12mg as recommended.  The protocol has already conservatively adjusted the dose of oral 
dexamethasone on days 2 and 3 of treatment to 4mg BID.  The next protocol amendment will reflect this 
recommendation. 
 
 
Karen Ansaldo, PharmD, BCPS 
Virginia G. Piper Cancer Center Clinical Trials 
Scottsdale Healthcare 
10510 N. 92nd St., Suite 200 
Scottsdale, AZ  85258 
 
 
 


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APPENDIX I:  THE MD ANDERSON SYMPTOM INVENTORY 
GASTROINTESTINAL CANCER MODULE (MDASI-GI) (TO BE 
SUBMITTED SEPARATELY FROM PROTOCOL FOR IRB 
APPROVAL) 
 
MD Anderson Symptom Inventory (MDASI) modules augment the 19 core MDASI symptom and 
interference items with additional items identified as unique to a particular patient population. 
MDASI modules may be disease-specific, disease-site-specific, or treatment-specific. 
The MDASI gastrointestinal cancer module (MDASI-GI) is a site-specific module. Along with the 
core MDASI’s 13 symptom items and 6 interference items, the MDASI-GI also assesses 5 
symptoms specific to gastrointestinal cancer:  
 
Constipation 
 
diarrhea or watery stools 
 
difficulty swallowing 
 
change in taste 
 
feeling bloated 
 
MDASI-GI Features 
 
 
Purpose: To assess the severity of multiple gastrointestinal cancer-related symptoms 
and the impact of these symptoms on daily functioning 
 
Population: Patients with symptoms caused by gastrointestinal cancer and its treatment 
 
Assessment areas: Severity of multiple symptoms and the impact of symptoms on daily 
functioning during the last 24 hours 
 
Method: Self-report; paper-and-pencil form or tablet PC (self-administered or via 
interview), or telephone-based interactive voice response (IVR) system 
 
Time required: Five minutes 
 
Scoring: Please see the MDASI User's Guide 
 
Reliability: Cronbach alpha reliability ranges from 0.80 to 0.87 
 
 
 
 
 
 


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APPENDIX J:  THE BRIEF PAIN INVENTORY (BPI) – SHORT FORM (TO 
BE SUBMITTED SEPARATELY FROM PROTOCOL FOR IRB 
APPROVAL) 
 
The Brief Pain Inventory (BPI) is available in two formats: the BPI short form, which is used for 
clinical trials and is the version used for the foreign-language translations; and the BPI long 
form, which contains additional descriptive items that may be clinically useful (for example, 
items that expand the possible descriptors of pain, such as burning, tingling, etc.). For brevity’s 
sake and for the patient’s ease of use, however, we recommend the short form of the BPI. 
 
In response to the US Food and Drug Administration (FDA) guidance for the pharmaceutical 
industry on the use of patient-reported outcome measures in medical product development to 
support labeling claims, we have prepared a BPI User's Guide to provide documentation of the 
BPI's development and psychometric properties. The information offered therein addresses the 
recommendations in the FDA guidance and establishes the BPI's adequacy as a measure to 
support medical product claims. 
 
BPI Features 
 
Purpose: To assess the severity of pain and the impact of pain on daily functions 
 
Population: Patients with pain from chronic diseases or conditions such as cancer, 
osteoarthritis and low back pain, or with pain from acute conditions such as 
postoperative pain 
 
Assessment areas: Severity of pain, impact of pain on daily function, location of pain, 
pain medications and amount of pain relief in the past 24 hours or the past week 
 
Responsiveness: Responds to both behavioral and pharmacological pain interventions 
 
Method: Self-report or interview 
 
Time required: Five minutes (short form), 10 minutes (long form) 
 
Scoring: No scoring algorithm, but "worst pain" or the arithmetic mean of the four 
severity items can be used as measures of pain severity; the arithmetic mean of the 
seven interference items can be used as a measure of pain interference 
• 
Reliability: Cronbach alpha reliability ranges from 0.77 to 0.91 
 
 
 
 
 
 
 


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APPENDIX K:  FECAL SAMPLES FOR 16S GUT MICROBIOME/MYCOBIOME RRNA 
ANALYSIS [CHAPUT ET AL 2017]  
The instructions below will be provided to each subject and will be submitted separately for 
review.  
Fecal Sample Collection Instructions (to be included in collection kit) 
 
You have been provided with a Commode Specimen Collection System.  The collection system 
includes three items: a specimen container, container lid, and container frame pictured below.  
Please follow the instructions below. 
 
                                                   
 
 
 
 
 
 
 
 
1. Assemble the container and frame, as pictured below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. Place the frame and container under the toilet seat and pushed the container all the way 
to the rear of the commode.  
3. Defecate into the container without allowing any urine into the container.  
4. Carefully retrieve the container from the commode and remove the frame. 
 
5. Place the lid on the container as pictured. 
 
 
 
 
 
 
 
 
 
 
6. Write the date and time of collection under your assigned subject ID on the label affixed 
to the lid. Please do NOT write anything else on the lid or container.     
7. Place the specimen container inside the provided specimen bag. 
8. Store the specimen container in the provided specimen bag in a cool place, such as a 
refrigerator (at approximately 4 °C).   Sample can be transported in the car without need 
for ice packs as long as the car is air-conditioned.  If the car is not air-conditioned, 
please transport specimen on ice to keep cool. 
9. Return the sample to the clinic within 72-hours of collection. This should correspond with 
your next scheduled study visit. IMPORTANT: If you cannot return the collected sample 
within 72 hours of collection, please contact the study team to make arrangements for 
return of the sample. 
 
 
 
 

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RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
 
 
TITLE: 
A Phase II Pilot Trial of Nivolumab + Albumin- Bound Paclitaxel 
+ Paricalcitol + Cisplatin + Gemcitabine (NAPPCG) in Patients 
with 
Previously 
Untreated 
Metastatic 
Pancreatic 
Ductal 
Adenocarcinoma 
 
PROTOCOL NO.: 
NAPPCG-EB 2015-001 
 
WIRB® Protocol # 20160267 
 
SPONSOR: 
HonorHealth Research Institute 
 
INVESTIGATOR: 
Erkut Borazanci, MD, MS. 
 
10510 North 92nd Street 
 
Scottsdale, AZ  85258 
 
United States 
 
STUDY-RELATED  
PHONE NUMBER(S): 
Erkut Borazanci, MD 
 
480-323-1350 (24 hours/day) 
 
 
INTRODUCTION 
You are being asked to take part in a clinical trial, a type of research study. Your participation is 
entirely voluntary. To allow you to make an informed decision as to whether you want to take 
part in this research study, this document describes the purpose of the study, your rights and 
obligations, the procedures needed by the study, and the possible benefits and risks of 
participating. You should read all of this information carefully and discuss your questions and 
concerns with your study doctor or healthcare team. You may take home an unsigned copy of 
this consent form to think about or discuss your decision with your family, friends and anyone 
you choose. You should not join this research study until all of your questions are answered. A 
person who takes part in a research study is called a research or study subject. In this consent 
form, “you” always refers to the research subject.  
 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision. If you have any questions, you can ask your study doctor for more explanation about 
the clinical trial, this form, or your disease. This consent form may contain words that you do not 
understand. Please ask the study doctor or study staff to explain any words or information that 
you do not understand. 
 
Things to know before deciding to take part in a research study: 
 The main goal of a research study is to learn things to help patients in the future. 
 The main goal of regular medical care is to help each patient. 
 The decision to join or not join the research study will not cause you to lose any medical 
benefits. If you decide not to take part in this study, your doctor will continue to treat 
you. 


 
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 Parts of this study may involve standard medical care. Standard care is the treatment 
normally given for a certain condition or illness. 
 Other parts of this study may involve experimental (investigational) drugs or procedures 
that are being tested for a certain condition or illness. An investigational drug is one that 
has not been approved by the U.S. Food & Drug Administration (FDA). 
 After reading the consent form and having a discussion with the research staff, you 
should know which parts of the study are experimental and which are standard medical 
care. 
 Your medical records may become part of the research record. If that happens, your 
medical records may be looked at and/or copied by the sponsor of this study and 
government agencies or other groups associated with the study. 
 Your medical insurance may be billed for any standard medical care you receive during 
the research study. If your insurance company is billed then it may have access to the 
research records. Insurance companies may not pay for treatment that is part of a research 
study. 
 
You are being asked to participate because you have been diagnosed with advance pancreatic 
cancer and your doctor has determined that you may be a good candidate for the treatment 
being offered to the study participants that qualify for the study. 
 
PURPOSE OF THE STUDY 
The purpose of this study is to find out if the experimental combination of study drugs 
nivolumab, albumin- bound paclitaxel, paricalcitol, cisplatin, and gemcitabine given together are 
safe and effective. 
 
The combination of albumin-bound paclitaxel plus gemcitabine has been studied in treating 
patients with pancreatic cancer, and as of September 2013, was approved by the FDA for the 
treatment of patients with advanced pancreatic cancer. 
 
In the present study, the agents paricalcitol (a synthetic vitamin D analog), nivolumab (a drug 
that stimulates the immune system to fight the cancer), and the anticancer agent cisplatin will be 
added to albumin-bound paclitaxel plus gemcitabine combination, and tested in people who have 
not yet had any cancer therapy for the diagnosis of advanced pancreatic cancer. The goal of this 
study is to improve response to treatment. 
 
Nivolumab is approved for the treatment of advanced melanoma (an aggressive type of skin 
cancer), a subtype of lung cancer called squamous cell lung cancer, advanced renal cell cancer 
(type of kidney cancer), Hodgkin Lymphoma that has progressed after stem cell transplant, and 
squamous cell carcinoma of the head and neck. It is not approved by the FDA for the treatment 
of advanced pancreatic cancer. 
 
Paricalcitol is a potent form of Vitamin D used to prevent bone loss is patients with advanced 
kidney disease. Paricalcitol is not approved by the FDA for treatment of advanced pancreatic 
cancer. 
 


 
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Cisplatin is approved by the FDA for the treatment of advanced bladder cancer, advanced 
ovarian cancer, and advanced testicular cancer and other childhood cancers. However, cisplatin 
is not approved by the FDA for the treatment of advanced pancreatic cancer. 
 
Gemcitabine was approved by the FDA in 1996 for the treatment of pancreatic cancer. It is also 
an approved treatment for ovarian cancer, lung cancer, and breast cancer. 
 
The Food and Drug Administration has determined that this study meets the requirements for 
Investigational New Drug (IND) Exemption. 
 
How Many Subjects Will Take Part in the Study? 
This study will be conducted at up to 2 cancer centers in the US. 10 individuals will initially be 
enrolled. Based upon safety and efficacy analysis, an additional 25 individuals may be enrolled 
for a total of 35 individuals in the US. Enrollment into this study will be competitive meaning 
first come first served. 
 
PROCEDURES 
The study will consist of the following parts: 
 Screening Evaluation 
 Study Treatment Assessments 
 Office Visit after Last Dose of Study Treatment 
 Continuation of Therapy Treatment Assessments 
 Post-Study Follow-up  
 
Screening Evaluation: 
In the first part of the study, you will have an extensive evaluation of your medical condition.  
The purpose of this evaluation is to find out if you qualify for this research study.  Screening 
procedures for this study include: 
 Sign the informed consent form 
 Complete medical history including pre-existing/current conditions, prior cancer therapy, 
and prior surgery 
 Complete physical examination including height and weight 
 Karnofsky Performance Status  
 Vital signs (blood pressure, pulse, respiratory rate, and temperature). 
 Computed tomography (CT) and/or magnetic resonance imaging (MRI) scan of your 
chest, abdomen, pelvis, and other regions as necessary. A brain scan may be done if 
necessary. If a CT scan was taken within 28 days prior to first dose, a new scan is not 
necessary. 
 Electrocardiogram (ECG) 
 Collect blood for laboratory tests. About 3 tbsp. will be taken for the following tests: 
o Hematology - Complete blood count (CBC) with differential and platelet count 


 
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o Serum chemistries (for hepatic and renal function tests) including: blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, total 
protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
electrolytes (chloride, sodium, potassium, and bicarbonate). 
o Thyroid Stimulating Hormone (TSH) to include reflex T3 and T4 if abnormal 
o Vitamin D levels 
o Coagulation Panel including PTT and PT/INR 
o CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) 
o Serum pregnancy test (if applicable). 
 Collect a urine sample for a urinalysis 
 Receive stool sample collection kit with instructions to be reviewed with study staff. 
Note: the stool sample will need to be returned to the site within 72 hours of collection. 
 Review all medications taken within the last 30 days 
 Collect any archived tumor tissue, if available 
 Complete questionnaires regarding quality of life and pain 
 
Study Treatment and Assessments: 
If you meet the study requirements during the screening period, you will then begin the study 
treatment phase of the study. You will receive the following study treatment regimen over a 6 
week period of time. This 6 week period is called a cycle. 
 Nivolumab 240 mg will be given over one hour as an intravenous (IV) infusion on days 
1, 15, and 29. 
 Albumin-bound paclitaxel 125 mg/m2 will be given over 30 minutes as an IV infusion on 
days 1, 8, 22 and 29 
 Cisplatin - 25 mg/m2 will be given over one hour as an IV infusion after the albumin-
bound paclitaxel is completed on days 1, 8, 22 and 29. On the days you are to receive 
cisplatin you will be given a total of about 4 hours of hydration (IV fluid) to reduce the 
risk of damage to your kidneys. You will be given 2 hours of hydration prior to the 
chemotherapy and 2 hours of hydration after the chemotherapy is complete 
 Gemcitabine 1000 mg/m2 will be given over 30 minutes as an IV infusion after the 
cisplatin dose is completed on days 1, 8, 22 and 29 
 Paricalcitol 25 mcg will be given intravenously on days 1, 4, 8, 12, 15, 18, 22, 26, 29, 32, 
36, and 39 
 On the days you are to receive albumin-bound paclitaxel, cisplatin and gemcitabine you 
will also receive medication to help prevent nausea and vomiting prior to the 
chemotherapy 
 
During dosing in this study treatment, you will receive another medicine called granulocyte 
colony-stimulating factor (G-CSF) which is also known as pegfilgrastim (Neulasta). G-CSF 
helps your body form more white blood cells and may help some of the common side effects of 
the study drugs. The type, dose level, and administration of the G-CSF will be determined by 
your study doctor. 
 


 
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On your first visit, you will be provided ahead of time with enough supply of an antibiotic called 
ciprofloxacin (or an alternative antibiotic) for use at home. If you develop a fever, you should 
begin taking the antibiotic when you first record a temperature of about 38.5 °C (about 101°F) or 
if you feel you are developing a fever and a thermometer is not available. In addition, if you 
develop a fever, you should notify your study doctor immediately or his/her team as soon as 
possible. You may be asked to return to the study location for evaluation and possible treatment. 
 
With nivolumab and albumin-bound paclitaxel, or gemcitabine alone or in combination, a few 
patients in other studies have had a condition called interstitial pneumonitis—a very serious lung 
condition. Therefore, during dosing in this study treatment, if you experience shortness of breath 
or develop a dry cough, you should notify your study doctor or his/her team as soon as 
possible. You may be asked to return to the study location for evaluation and possible treatment. 
 
In addition, the drug nivolumab has been associated with inflammation of the colon. If you have 
more than 3 stools per day, you should notify your study doctor or health team as soon as 
possible. Nivolumab has also been associated with inflammation of the thyroid, liver and/or 
kidneys. The blood testing that is done for you by the study team will be used to monitor for that 
inflammation. 
 
The following evaluations will be performed prior to dosing on Day 1, 22 and 29 of each cycle  
 Directed physical exam 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature). 
 Measurement of weight 
 Body Surface Area (BSA) calculation prior to dosing 
 Karnofsky Performance Status 
 Collect blood for laboratory tests. About 2 Tbsp will be taken for the following tests: 
o Hematology: CBC with differential and platelet count 
o Serum chemistries (for hepatic and renal function tests) including: blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, total 
protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
electrolytes (chloride, sodium, potassium, and bicarbonate). 
o CA 19-9 (or CA 125 or CEA if not expressers of CA 19-9) 
o Thyroid Stimulating Hormone (TSH) to include reflex T3 and T4 if abnormal 
o Peripheral Blood BioMarker 
o Serum Pregnancy (if applicable) 
 Collect a urine sample for a urinalysis 
 Review any changes to your health since the last visit 
 Review any changes to your medications since the last visit 
 Complete questionnaires regarding quality of life and pain 
 


 
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The following evaluations will be performed on Day 8, 15 and 36 of each cycle 
 Directed physical exam 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature). 
 Measurement of weight (weight will not be measured on Day 15 and 36) 
 Karnofsky Performance Status (KPS) 
 Collect blood for laboratory tests. About 1 Tbsp will be taken for the following tests: 
o Hematology: CBC with differential and platelet count 
o Serum chemistries (for hepatic and renal function tests) including: blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, total 
protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
electrolytes (chloride, sodium, potassium, and bicarbonate). 
 Review any changes to your health since the last visit 
 Review any changes to your medications since the last visit 
 Complete questionnaires regarding quality of life and pain (Days 8 and 15 only) 
 
The following evaluation will be performed on Day 39 of each cycle 
 Receive stool sample collection kit with instructions to be reviewed with study staff. 
Note: the stool sample will need to be returned to the site within 72 hours of collection. 
 
Every 6 weeks prior to each cycle 
 CT scans of the chest, abdomen, and pelvis or any other studies required for tumor 
imaging (such as MRI), will be done every 6 weeks while you are on treatment. This will 
be the same type of imaging that you had at the screening evaluation 
 It will also be determined by your physician/nurse if a PET scan is necessary depending 
on your tumors response to the treatment. 
 
You will be treated until one or more of the following occur: 
 your cancer becomes worse 
 side effects arise which prevent further study treatment 
 you decide to withdraw from the study 
 changes in your condition occur that lead your study doctor to believe that it would be 
harmful for you to receive further study treatment 
 you become pregnant or fail to use adequate birth control (if you are of child-bearing 
potential) 
 another anticancer medication is started 
 you cannot or will not follow the instructions for participation in the study 
 the study doctor decides it is in your best interest not to continue in the study. 
 
Office Visit after Last Dose of Study Treatment: 
An End of Study Treatment office visit will be performed when your study drug treatment ends 
for any reason. The End of Study Treatment evaluations include the following: 
 Directed physical exam 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature). 


 
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 Measurement of weight 
 Karnofsky Performance Status 
 Collect blood for laboratory tests. About 2 Tbsp will be taken for the following tests: 
o Hematology: CBC with differential and platelet count 
o Serum chemistries (for hepatic and renal function tests) including: blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, total 
protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
electrolytes (chloride, sodium, potassium, and bicarbonate). 
o CA 19-9 
o Thyroid Stimulating Hormone (TSH) and any reference tests as required 
o Serum Pregnancy (if applicable) 
 Collect a urine sample for a urinalysis 
 CT scan of chest, abdomen, and pelvis and any other studies required for tumor imaging 
(only if your previous CT scan was >5 weeks ago) 
 Review any changes to your health since the last visit 
 Review any changes to your medications since the last visit 
 Complete questionnaires regarding quality of life and pain 
 
Note that there may be additional blood draws throughout this study required for safety purposes; 
these will be considered “standard of care”, for medical care and evaluation, and not for research 
purposes. 
 
Post-Study Follow-up: 
All subjects will continue to be evaluated by telephone after study completion or withdrawal. 
The study staff will contact you or your regular doctor by telephone every 3 months. 
 
If after your last dose of study drugs you have ongoing side effects or other medical problems 
that started during the study, the study personnel might need to follow those conditions for a 
certain time or until they reach an acceptable level. 
 
Follow-up evaluations for side effects or other medical problems that started during the study 
may include the following: 
 Directed physical exam 
 Vital signs (blood pressure, pulse, respiratory rate, and temperature). 
 Measurement of weight 
 Karnofsky Performance Status 
 Collect blood for laboratory tests. About 1 Tbsp will be taken for the following tests: 
o Hematology: CBC with differential and platelet count 
o Serum chemistries (for hepatic and renal function tests) including: blood urea 
nitrogen (BUN), phosphorus, magnesium, creatinine, creatinine clearance, total 
protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
electrolytes (chloride, sodium, potassium, and bicarbonate). 
 Review any changes to your health since the last visit 
 Review any changes to your medications since the last visit 


 
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Other Study Requirements: 
You must not use any prescription medication during the study without first checking with the 
study doctor. You must agree to not participate in any other research study while participating in 
this study. You must have stopped taking any research medications at least 4 weeks prior to 
enrolling in this study. You must have also stopped all other anti-cancer medications for this 
research study. Your study doctor will inform you of how long you must be off those 
medications to participate in this research study. 
 
How Long Will the Study Last? 
The length of time that you participate in the trial will depend on whether your cancer gets better 
or worse in response to the study treatment. It is expected that you will stay on study treatment as 
long as your cancer improves or is stable or until your cancer gets worse, side effects become 
intolerable, or you or your study doctor decide to not continue in the study. Long term follow-up 
will take place for 24 months after you stop study treatment. 
 
RISKS AND DISCOMFORTS 
Participation in this research study may involve added risks and discomforts, including the 
possible side effects of the study treatments described in this form, (see table below). There also 
may be other potentially serious side effects that are not yet known.  Let your study doctor know 
about any side effects you are experiencing. Your study doctor may be able to give you other 
drugs to make side effects less serious or uncomfortable. Many side effects go away after the 
study treatment is stopped but, in some cases, these side effects may be serious and/or long 
lasting. Rarely, side effects could be fatal (causing death). 
 
Nivolumab 
Common side effects related to Nivolumab: 
• 
Adrenal disorders 
• 
Anemia (low red blood cell count – which may cause you to feel tired, look pale, and 
have shortness of breath) 
• 
Appetite loss 
• 
Diarrhea 
• 
Difficulty breathing 
• 
Fatigue 
• 
Fever 
• 
Joint and muscle pain 
• 
Nausea 
• 
Rash - * skin reactions including rash, itching, hives, redness and dry skin toxic epidural 
necrolysis, a potentially life threatening disease characterized by blistering and peeling of 
the skin resembling a severe burn has been seen in one patient receiving ipilimumab after 
nivolumab. 
 
Less common side effects related to Nivolumab: 
• 
Constipation 
• 
Abnormal liver function tests 
• 
Low platelet count (which can lead to bruising or bleeding) 


 
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• 
Thyroid abnormalities 
• 
Vomiting 
 
Rare but potentially serious side effects related to Nivolumab: 
• 
Allergic reaction 
• 
Blood and protein in the urine 
• 
Cough 
• 
Difficulty breathing 
• 
Abnormal kidney function / failure 
• 
Low blood oxygen level 
• 
Acute lung injury or failure 
• 
Collection of fluid around the lungs 
• 
Inflammation of the appendix 
• 
Increase in inflammatory blood proteins (e.g. lipase) 
• 
Adrenal gland abnormalities 
• 
Pituitary gland inflammation 
• 
Changes in vision (including decreased or blurry vision), inflammation of the eye or 
bleeding into the eye 
• 
Liver inflammation 
• 
Acute kidney injury or failure 
• 
Abnormal blood cell production 
• 
Inflammation of the mouth and lining of the digestive tract 
• 
Swelling of the face, arms or legs 
• 
Inflammation of the pancreas 
• 
Back pain 
• 
Autoimmune disorders, including Guillain-Barre syndrome (associated with progressive 
muscle weakness or paralysis) 
• 
Chest discomfort 
• 
Heart palpitations 
• 
Inflammation of the heart or its lining 
• 
Collection of fluid around the heart 
• 
Increased blood sugar 
• 
Dehydration 
• 
Infections: including sepsis, lung infections, and skin infections 
• 
Decreased movement of the intestines 
• 
Disorientation 
• 
Swelling of the optic disc 
• 
Inflammation of the optic nerve 
• 
Inflammation of the lining of the brain and spinal cord 
• 
Drug reaction with rash, blood cell abnormalities, enlarged lymph nodes, and internal 
organ involvement (including liver, kidney, and lung); known as Drug Reaction with 
Eosinophilia and Systemic Symptoms (DRESS) 
• 
Myasthenia Gravis, a nerve disease which may cause weakness of eye, face, breathing, 
and swallowing muscles. 
• 
Abnormal brain function due to brain inflammation 


 
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• 
Rhabdomyolysis (muscle fiber released into the blood stream which could damage your 
kidneys) and polymyositis (chronic muscle inflammation with muscle weakness) has 
been reported in one patient 
 
Albumin-Bound Paclitaxel 
Common side effects of Albumin Bound Paclitaxel: 
• 
Anemia 
• 
Fatigue 
• 
Hair loss (reversible) 
• 
Joint and muscle pain 
• 
Low white blood cell count (which may temporarily place you at risk for infection) 
• 
Nausea 
• 
Numbness, tingling or burning of hands and feet 
• 
Tiredness and weakness 
 
Less common side effects related to Albumin Bound Paclitaxel: 
• 
Appetite loss 
• 
Constipation 
• 
Diarrhea 
• 
Edema (fluid retention) 
• 
Fever 
• 
Irregular heartbeat 
• 
Irritation or bruising at the site of the infusion 
• 
Itching 
• 
Mouth or lip sores 
• 
Nail changes 
• 
Vomiting 
 
Rare side effects related to Albumin bound Paclitaxel: 
• 
Allergic reaction 
• 
Cough 
• 
Difficulty breathing 
• 
Heart Congestive heart failure (the heart does not pump blood effectively) 
• 
Left ventricular dysfunction (when a part of the heart, the left ventricle muscle, does not 
contract as well as it should which may lead to heart failure) 
• 
Kidney (abnormal function or failure) 
• 
Liver function tests abnormal 
• 
Low blood pressure 
• 
Low platelet count (which can lead to bruising or bleeding) 
• 
Pulmonary edema (fluid in lungs) 
• 
Rash 
• 
Visual disturbances (temporary), (Flashing lights or blurry vision) 
 


 
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Cisplatin 
Common side Effect related to Cisplatin: 
• 
Kidney (abnormal function or failure) 
• 
Nausea 
• 
Numbness, tingling or burning of hands and feet 
• 
Vomiting 
 
Less common side effects related to Cisplatin: 
• 
Anemia (low red blood cell count – which may cause you to feel tired, look pale, and 
have shortness of breath) 
• 
Fatigue 
• 
Hearing loss 
• 
Irritation or bruising at the site of the infusion 
• 
Liver function test abnormal 
• 
Low platelet count (which can lead to bruising or bleeding) 
• 
Low white blood cell count (which may temporarily place you at risk for infection) 
 
Rare toxicities related to Cisplatin: 
• 
Allergic reaction 
• 
Diarrhea 
• 
Electrolyte imbalance 
• 
Myocardial infarction (heart attack) 
• 
Heart block 
• 
Heart failure 
• 
Irregular heartbeat 
• 
Arterial vasospasm (constriction of the blood vessels) 
• 
Low blood pressure 
• 
Stroke 
• 
Hemolytic anemia (destruction of red blood cells) 
• 
Thrombotic thrombocytopenic purpura (syndrome of abnormal clotting and bleeding) 
• 
Hemolytic uremic syndrome (abnormal clotting and kidney failure) 
• 
Limb and mesenteric ischemia (decreased blood flow to limbs and gut) 
• 
Pancreatitis (inflammation of the pancreas) 
• 
Papilledema (swelling of blood vessels in the eyes) 
• 
Neutropenic typhlitis (infection in the gut due to low white blood cells) 
• 
Reversible posterior leukoencephalopathy syndrome (a syndrome characterized by 
headache, confusion, seizures and visual loss) 
• 
Visual disturbances (temporary), (Flashing light or blurry vision) 
• 
Mouth or lip sores 
• 
Hair loss (reversible) 
 


 
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Gemcitabine 
Common side effects related to Gemcitabine: 
• 
Anemia (low red blood cell count – which may cause you to feel tired, look pale, and 
have shortness of breath) 
• 
Cough 
• 
Constipation 
• 
Diarrhea 
• 
Fever 
• 
Flu-like symptoms (fever, feeling tired, loss of appetite, chills and cough) 
• 
Hair loss (reversible) 
• 
Liver function tests abnormal 
• 
Low platelet count (which can lead to bruising or bleeding) 
• 
Low white blood cell count (which may temporarily place you at risk for infection) 
• 
Nausea 
• 
Rash 
• 
Vomiting 
 
Less common side effects related to Gemcitabine: 
• 
Edema (fluid retention) 
• 
Fatigue 
• 
Irritation or bruising at the site of the infusion 
• 
Itching 
• 
Mouth or lip sores 
• 
Tingling, prickling of the skin 
 
Rare toxicities related to Gemcitabine: 
• 
Allergic reaction 
• 
Blood and protein in the urine 
• 
Difficulty breathing 
• 
Abnormal kidney function or failure 
• 
Hemolytic uremic syndrome (abnormal clotting and kidney failure) 
• 
Serious lung toxicity 
 
Paricalcitol 
Rare toxicities related to Paricalcitol: 
• 
High blood calcium 
• 
Kidney stones 
 
Risk of Infection: 
In another study in subjects receiving the albumin bound paclitaxel, cisplatin, and gemcitabine 
combination treatment there were increased risks of infection. Subjects over the age of 80 years 
have a greater risk of developing this infection. Subjects that develop a fever should notify 
their study doctor or his team as soon as possible and may be asked to return to the study 
location for evaluation and possible treatment. If you develop a fever, you should begin taking 
the antibiotic provided to you at the first visit immediately. 


 
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Other Medications 
Before each dose of study drug(s), your study doctor may decide to administer certain 
medications to help control side effects. The lowered blood counts may temporarily place you at 
risk for infection or bleeding, although this is uncommon. 
 
If necessary, these events may require a reduction in the dose of the study drug(s) and/or you will 
be given medication to help relieve any pain or discomfort. 
 
Side Effects of G-CSF or pegfilgrastim (Neulasta®): 
The most common side effect of G-CSF is aching in the bones and muscles. Depending on the 
type of G-CSF given, possible but rare side effects include the following: 
 serious allergic reactions that may be life-threatening (symptoms can include rash, 
shortness of breath, wheezing, dizziness from a drop in blood pressure, swelling around 
the mouth or eyes, fast pulse, and/or sweating) 
 enlarged or ruptured spleen 
 adult respiratory distress syndrome (a condition caused by fluid buildup in the lungs that 
prevents normal breathing) 
 sickle cell crisis in subjects with Sickle Cell disease. 
 Swelling of the optic disc (symptoms include headache, blind spot, blurring of vision 
and/or loss of vision) 
 
Side Effects of palonosetron (Aloxi®): 
Less serious side effects that can occur include: 
 headache 
 constipation 
 pain, redness swelling or a lump under your skin where the needle is placed 
 
More serious side effects that can occur include: 
 allergic reaction (symptoms include hives, swelling of the face or hands, trouble 
breathing, tingling in your mouth or throat and/or chest tightness) 
 anxiety 
 restlessness 
 fever 
 sweating 
 muscle spasms 
 nausea and/or vomiting 
 diarrhea 
 lightheadedness, dizziness, fainting 
 chest pain and/or irregular heartbeat 
 


 
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Side Effects of fosaprepitant (Emend®): 
Less serious side effects that can occur include: 
 nausea and/or vomiting 
 heartburn 
 stomach pain 
 diarrhea or constipation 
 loss of appetite 
 hiccups 
 increased thirst or hot, dry skin 
 weakness, dizziness, tired feeling 
 headache 
 ringing in your ears 
 fever, chills, body aches, flu symptoms 
 sleep problems (insomnia) 
 pain or a hard lump where the medicine was injected. 
 
More serious side effects that can occur include: 
 feeling light-headed  
 fainting 
 slow heart rate 
 pale skin, easy bruising or bleeding 
 pain or burning when you urinate 
 
Side Effects of dexamethasone: 
Less serious side effects that can occur include: 
 upset stomach 
 stomach irritation 
 vomiting 
 headache 
 dizziness 
 insomnia 
 restlessness 
 depression 
 anxiety 
 acne 
 increased hair growth 
 easy bruising 
 irregular or absent menstrual periods 
 
More serious side effects that can occur include: 
 skin rash 
 swollen face, lower legs, or ankles 
 vision problems 


 
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 cold or infection that lasts a long time 
 muscle weakness 
 black or tarry stool 
 
Side Effects of ondansetron (Zofran®): 
Less serious side effects that can occur include: 
 headache 
 constipation 
 weakness 
 tiredness 
 chills 
 drowsiness 
 
More serious side effects that can occur include: 
 blurred vision or vision loss 
 rash 
 hives 
 itching 
 swelling of the eyes, face, lips, tongue, throat, hands, feet, ankles, or lower legs 
 hoarseness 
 difficulty breathing or swallowing 
 chest pain 
 shortness of breath 
 dizziness, light-headedness, or fainting 
 fast, slow or irregular heartbeat 
 agitation 
 hallucinations (seeing things or hearing voices that do not exist) 
 fever 
 excessive sweating 
 confusion 
 nausea, vomiting, or diarrhea 
 loss of coordination 
 stiff or twitching muscles 
 seizures 
 coma (loss of consciousness) 
 
Risks with Intravenous (IV) Drug Administration: 
Nivolumab, albumin bound paclitaxel, cisplatin, and gemcitabine are given as IV infusions. 
Temporary irritation and bruising may occur at the infusion site. There may also be discomfort, 
pain, or bruising from the needle puncture. In rare cases, an infection may also occur at the site 
of the needle stick. 
 


 
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Risks of a Blood Draw: 
Risks can also occur during blood draws. The risk of blood drawing may include bleeding, 
pain, lightheadedness, fainting, bruising, clotting, discomfort, and/or infection at the site of the 
needle stick. 
 
Your blood will be drawn weekly during the study. Depending on your condition, your study 
doctor may wish to perform additional blood draws. 
 
Electrocardiogram (ECG) 
This test uses small sticky pads that are placed on your chest and limbs to measure the electrical 
activity of your heart. There may be mild discomfort from the sticky pads and a possibility of the 
skin being irritated by the adhesive on the sticky pads. Chest hair may need to be shaved prior to 
the placement of the sticky pads. 
 
Risks of CT Scans, MRI Scans and PET Scans: 
CT scanning uses X-rays to create images of tissue below the skin. The risk of X-rays is slight. 
The amount of X-ray exposure that most people receive in a lifetime is not known to produce 
any illness. An allergic reaction to the dyes used to perform the CT scans is a possible risk of the 
procedure. 
 
MRI uses magnetic fields to produce high-quality images of tissue below the skin. 
Therefore, subjects with metal in their bodies (such as cardiac pacemakers, metal 
prostheses [artificial body parts] and magnetic clips) will not be imaged. Otherwise, the 
risk of MRI is slight. 
 
PET (positron emission tomography) scan is an imaging technique that uses positively charged 
particles (radioactive positrons) to detect subtle changes in the body's metabolism and chemical 
activities. A PET scan provides a color-coded image of the body's function, rather than its 
structure. You may experience a mild skin prick when a substance called a tracer is injected into 
the vein. The tracer is radioactive but short lived and poses little to no risk. 
 
Risks to Women of Child Bearing Potential: 
Women of childbearing potential are women who are biologically capable of becoming pregnant.  
 
This includes women who are using contraceptives or whose sexual partner is either sterile or 
using contraceptives. 
 
The study drugs may affect an unborn child or nursing infant. The risks to an unborn child or 
nursing infant are not fully known. These drugs may also cause changes to eggs in women. 
 
The following information is for women who are able to become pregnant: 
 It is important that you do not become pregnant while in this study. 
 You must have a negative serum (blood) pregnancy test before you start taking the study 
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 If you do become pregnant or suspect you are pregnant, while you are on this study or for 
5 months after the last dose of study drug, you must notify your study doctor 
immediately. 
 If you become pregnant, you will be taken off this study. 
 You must agree to use two forms of highly effective birth control at the same time that 
are medically acceptable to your study doctor, throughout the study and for 5 months 
after the last dose of study medications. The study doctor will discuss the appropriate 
methods of contraception with you. NOTE:  Hormonal contraceptives alone (the 
“pill”) are not considered an acceptable method of birth control for this study.  
 
You must not breast feed at any time you are in this study since any drugs you are taking may 
also affect the child. 
 
Risks to Men of Reproductive Potential: 
The study drugs may have a harmful effect on sperm. This can lead to damage to a fetus or 
embryo (developing unborn baby). If you are a fertile male, you must not impregnate a female 
while in this study. You must agree to use a form of birth control, along with the method your 
partner is using, that is medically acceptable to your study doctor during the study. You should 
continue the use of your birth control methods following your last dose of study drugs and for 5 
months after your last dose. If your partner becomes pregnant while you are on the study or 
within 5 months of receiving the last dose of study medication, you will need to report this to 
your study doctor.  
 
Unknown Risks: 
In addition to the risks already described, there may be other discomforts or risks from the study 
drugs or study procedures which are unknown. You will be observed carefully for signs and 
symptoms of possible side effects. If you experience any unusual symptoms, please inform your 
study doctor immediately.  
 
If you have any questions about the risks of participating in this research study, you may ask the 
study doctor, another study team doctor, or your regular doctor. You may ask questions now or 
you may call the study doctor at the phone number on the first page of this form. 
 
There may be side effects that are not known at this time. Your condition may not get better or 
may get worse during this study. 
 
NEW INFORMATION  
You will be told about anything new that might change your decision to be in this study. You 
may be asked to sign a new consent form if this occurs. 
 
BENEFITS 
There may or may not be direct medical benefits to you from taking part in this study, except you 
may gain information about your health from the different tests (ECGs, laboratory tests, and 
physical exams) that are done. The expected benefit of taking part in the study may be similar to 
that of getting commonly used chemotherapy. Gemcitabine combined with albumin bound 


 
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paclitaxel has been shown to be effective in patients with metastatic pancreatic cancer. However, 
it is unknown if nivolumab plus albumin bound paclitaxel plus paricalcitol plus cisplatin given 
together with gemcitabine will be as effective, more effective, or less effective than other 
commonly used chemotherapies. 
 
The information learned from this study may help future patients with metastatic pancreatic 
cancer. 
 
COSTS 
The sponsor, HonorHealth, will pay for all procedures and tests done specifically for this 
research study. Those treatments, procedures (including drug infusions) and tests that you would 
be likely to receive whether you were in the study or not, are not paid for by the study sponsor, 
and are considered “standard of care” for your medical condition. If you have health insurance, 
the cost of these “standard of care” services will be billed to your insurance company. Your 
health insurance may not cover these costs because of your participation in this research study. If 
it does not, the costs will be your responsibility. If you do not have health insurance, the cost of 
these “standard of care” services will be billed to you. 
 
You may want to talk with your insurance company about its payment policy for standard 
medical care given during a research study. If your insurance company does not pay, you may be 
billed for those charges. 
 
You might have unexpected expenses from being in this study. Ask your study doctor to discuss 
the costs that will or will not be covered by the sponsor. This discussion should include who will 
pay the costs of treating possible side effects. 
 
PAYMENT FOR PARTICIPATION 
You will not be paid for being in this study. 
 
ALTERNATIVE TREATMENT 
There are other treatment options for metastatic pancreatic cancer. These options include other 
chemotherapy regimens, radiation, or other experimental therapy. You could receive nab-
paclitaxel, gemcitabine, and cisplatin without being in the study. 
 
Other options include capecitabine. Your study doctor will explain the other options available to 
you. You do not have to participate in this study to receive treatment for your condition. You 
may also choose to receive no treatment for your cancer. 
 
If you decide that you don’t want any more active treatment, one of your options is called 
“comfort care.” Comfort care includes pain medication and other support. It aims to maintain 
your comfort and dignity rather than cure disease. Usually this care can be provided at home. 
 
If you think you might prefer comfort care, please discuss this with your family, friends and your 
doctor. 
 


 
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CONFIDENTIALITY OF YOUR INFORMATION COLLECTED DURING THE STUDY 
As required by the Federal Health Insurance Portability and Accountability Act (HIPAA), every 
effort will be made to safeguard the confidentiality of information that identifies you and relates 
to your past, present and future physical and mental health. We will do our best to make sure that 
the personal information obtained during the course of this research study will be kept private. 
However, we cannot guarantee total privacy. Your personal information may be given out if 
required by law. 
 
Unless required by law, you will not be identified on any electronic form by name, social 
security number, address and telephone number or any other information that can directly 
identify you. The information shared with the Sponsor is protected by the use of a code, which is 
a number specifically assigned to you. The study doctor is in control of the code needed to 
connect your data to you, but the study doctor will not send the list with the code to the Sponsor. 
However, the study forms may contain other information about you, such as your age, sex and 
medical history. It is possible that this other information could be used to identify you even 
though your name does not appear. 
 
The results of this study may be published by the Sponsor, including in a medical journal and 
shown at medical meetings. You will not be identified (by name or any other means, e.g., photo) 
in any of these publications. 
 
Because this research is regulated by the Food and Drug Administration (FDA), the FDA may 
inspect records related to this research, which may include your protected health information or 
other information about you derived or maintained as part of this study. 
 
Information derived from this study may be used for research purposes that may include 
publication and teaching. However, information used for publication and teaching will not 
disclose your identity. 
 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES 
The United States government has issued a privacy rule to protect the privacy rights of patients. 
This rule was issued under a law called the Health Insurance Portability and Accountability Act 
of 1996 (HIPAA). The Privacy Rule is designed to protect the confidentiality of your protected 
health information (PHI). The document you are reading, called an “Authorization,” explains 
how your PHI will be used and disclosed (shared) for purposes of the research study and 
describes your rights with respect to such information. 
 
What information may be used and given to others? 
The study doctor will get your personal and medical information. For example: 
 
Past and present medical records 
 
Research records 
 
Records about phone calls made as part of this research 
 
Records about your study visits. 
 


 
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Who may use and give out information about you? 
The study doctor and the research staff conducting the research. 
 
Who will receive your personal and medical information collected? 
Information from this study will be given to the study sponsor. “Sponsor” is the person or entity that 
initiates, provides oversight of activities within the study, and includes any persons or companies 
that are contracted by the sponsor to have access to the research information during and after the 
study. Medical records which identify you and the consent form signed by you will be looked at and 
collected for research purposes by: 
 HonorHealth, the Sponsor 
 HonorHealth Research Institute, the study site 
 
Your information may be given to: 
 The U.S. Food and Drug Administration (FDA), 
 Department of Health and Human Services (DHHS) agencies, 
 Governmental agencies in other countries, 
 Governmental agencies to whom certain diseases (reportable diseases) must be reported, and 
 Western Institutional Review Board® (WIRB®) 
 HonorHealth Human Subjects Research Protection Program (HSRPP) 
 Bristol Myers Squibb who is supplying the drug and supporting some of the costs of the 
study 
 
The HonorHealth HSRPP and the HonorHealth Research Institute have the authority to review 
and monitor all records related to this research. 
 
Why will this information be used and/or given to others? 
 for research purposes as described in this consent form, 
 for consideration by the FDA or any governmental agencies in other countries for drug 
approval, 
 to make sure the study was conducted as approved by the FDA and IRB. 
 to be used for future research purposes 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 
Will you have access to the information collected during the study? 
To maintain the integrity of this research study, you will not have access to your personal health 
information related to this research until the study is complete. At the conclusion of the research 
and at your request, you may request access to your health information that HonorHealth 
maintains in a designated record set, which means a set of data that includes medical information 
or billing records used in whole or in part by your doctors or other health care providers at 
HonorHealth. If it is necessary for your care, your health information will be provided to you or 
your physician. 
 


 
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Does this authorization expire? 
This authorization does not expire unless it is canceled by you in writing. 
 
Can this authorization be withdrawn or canceled? 
You may withdraw or take away your permission to use and disclose your health information at 
any time. You do this by sending written notice to the study doctor. If you withdraw your 
permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you will be 
gathered after that date. Information that has already been gathered may still be used and given to 
others. 
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your permission. Absolute 
confidentiality cannot be guaranteed because of the need to give information to these parties. 
 
COMPENSATION FOR INJURY 
We will make every effort to prevent study-related injuries and illness. If you are injured or 
become ill while you are in the study and the illness or injury is due to your participation in this 
study, you may go to any emergency room or urgent care facility to seek medical treatment. The 
costs of this care will be charged to you or to your health insurer. No funds are routinely 
available from HonorHealth to compensate you for a study-related injury or illness. This does 
not mean that you are giving up any of your legal rights. 
 
The study doctor will provide you medical care if you need it, and will also treat you for any 
complications that may occur during your participation in the study. If you become ill or are 
injured as a direct result of your participation in this study, you will be provided the reasonable 
and necessary treatment for that injury or illness. The bills for the injury or illness will be billed 
to your insurance or to your third party or governmental programs in which you participate.  
 
If you have out of pocket expenses not covered by your insurance, the Sponsor may reimburse 
you. Please speak with your study doctor to make sure you understand your options regarding 
compensation for injury. 
 
LABORATORY SAMPLES FOR FUTURE RESEARCH 
HonorHealth would like to use any leftover blood and tissue samples for biomarker testing and 
for future research. By agreeing to participate in this study you are authorizing HonorHealth to 
use any leftover blood and tissue samples for biomarker testing and for future research, not 
defined at this time. If your samples are used in future research, they may be shared with 
researchers who are not part of HonorHealth. All samples will be stored with no identifying 
information attached to the sample. 
 
In addition, HonorHealth will be collecting stool samples from you for gut microbiome and/or 
mycobiome testing. By agreeing to participate in this study you are authorizing HonorHealth to 
collect and send your stool samples for microbiome testing and for future research, not defined at 
this time. All samples will be send with no identifying information attached to the sample. 


 
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VOLUNTARY PARTICIPATION AND WITHDRAWAL 
Your participation in this study is voluntary. You may decide not to take part or you may leave 
the study at any time. Your decision will not cause any penalty or loss of benefits to which you 
are entitled. 
 
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
without your consent for any of the following reasons: 
 serious side effects of the study drug; 
 worsening of your cancer despite treatment with the study drug; 
 a change in your condition that prevents you from continuing with the study; 
 your being unable to follow the schedule or procedures required by the study; 
 the sponsoring company may stop your participation if study drug ceases to be available or 
for other reasons; 
 You become pregnant; 
 you do not consent to continue in the study after being told of changes in the research that 
may affect you; 
 at the discretion of the study doctor for any reason 
 
If you leave the study before the planned final visit, you may be asked by the study doctor to 
have some tests or procedures done so that you leave the study safely. 
 
QUESTIONS 
Contact Erkut Borazanci, MD at 480-323-1350 for any of the following reasons: 
 if you have any questions about your participation in this study, 
 if at any time you feel you have had a research-related injury or a reaction to the study drug, 
or 
 if you have questions, concerns, or complaints about the research 
 
If you have questions about your rights as a research subject or if you have questions, concerns or 
complaints about the research, you may contact: 
 
 
Western Institutional Review Board® (WIRB®) 
 
1019 39th Avenue SE, Suite 120 
 
Puyallup, Washington 98374 
 
Telephone: 1-800-562-4789 (toll free) or 360-252-2500 
 
E-mail: Help@wirb.com 
 
WIRB® is a group of people who independently review research. 
 
WIRB® will not be able to answer some study-specific questions, such as questions about 
appointment times. However, you may contact WIRB® if the research staff cannot be reached or 
if you wish to talk to someone other than the research staff.  
 
Do not sign this consent form unless you have had a chance to ask questions and have gotten 
satisfactory answers. 


 
IRB APPROVED 
 
AS MODIFIED 
 
Aug 22, 2020 
 
 
 
ICF Version 9 dated 15Jul2020 
Page 23 of 23 
If you agree to be in this study, you will receive a signed and dated copy of this consent form for 
your records. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
CONSENT 
I have read this consent form and understand what has been discussed. All my questions about 
the study and my part in it have been answered. I voluntarily consent to be in this research study. 
 
I authorize the use and disclosure of my health information to the parties listed in the authorization 
section of this consent for the purposes described above.  
 
By signing this consent form, I have not given up any of my legal rights. 
 
 
 
 
Subject Name 
 
 
 
 
 
 
Signature of Subject  
Date 
 
 
 
 
 
 
Signature of Person Conducting Informed 
Date 
Consent Discussion