A Phase II Trial of Nab-Paclitaxel Plus Cisplatin Plus Gemcitabine in Patients With Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma
Phase: PHASE2
Conditions: Pancreatic Ductal Adenocarcinoma
Sponsor: HonorHealth Research Institute

Protocol #: AX-CL-PANC-PI-13301 
CONFIDENTIAL 
The information contained in this document is confidential and the proprietary property of 
Sponsor. Any unauthorized use or disclosure of such information without the prior written 
authorization of the Sponsor is prohibited 
 
A PHASE II TRIAL OF NAB-PACLITAXEL PLUS CISPLATIN PLUS 
GEMCITABINE IN PATIENTS WITH PREVIOUSLY UNTREATED 
METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA 
NCT03915444 
IND Exempt 
 
Sponsor 
HonorHealth Research Institute 
 
Lead Principal Investigator 
 
Gayle S. Jameson, MSN, ACNP BC, AOCN 
HonorHealth Research Institute 
10510 N. 92nd Street 
Scottsdale, AZ 85258 
Tel: 480-323-1350 
Fax: 480-323-1359 
Email: gjameson@honorhealth.com 
 
Consulting Investigator 
 
Daniel D. Von Hoff, MD, FACP 
Translational Genomics Research Institute (TGen) 
445 N. Fifth Street. Phoenix, AZ 85004 
Tel. 602-343-8492 
dvh@tgen.org 
 
Sub-Investigator 
 
Erkut Borazanci, MD 
HonorHealth Research Institute 
10510 N. 92nd Street 
Scottsdale, AZ 85258 
Tel: 480-323-1350 
Fax: 480-323-1359 
Email: eborazanci@honorhealth.com 
Sub-Investigator 
 
Karen L. Ansaldo, PharmD 
HonorHealth Research Institute 
10510 N. 92nd St. 
Scottsdale, AZ 85258 
Tel. 480-323-1339 
KAnsaldo@HonorHealth.com 
Sub-Investigator 
 
Ludmil Alexandrov, PhD 
University of California, San Diego 
9500 Gilman Drive 
CMM East, Room 2042 
La Jolla, CA 92093-0695 
l2alexandrov@ucsd.edu 
Sub-Investigator 
 
Michael Barrett, PhD 
Mayo Clinic Arizona 
Mayo Collaborative Cancer 
Research Building, Cr2-111 
13208 E. Shea Blvd, Suite 
100 
Scottsdale, AZ 85259 

 
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Medical Monitor 
 
Michael Gordon, MD 
HonorHealth Research Institute 
10510 N. 92nd Street 
Scottsdale, AZ 85258 
480-323-1350 
Fax: 480-323-1359 
Email: mgordon@honorhealth.com 
 
Biostatistician 
 
Kevin Gosselin, M.Ed, M.S., Ph.D. 
Director, Academics and Biostatistics 
HonorHealth Research Institute 
10510 N. 92nd Street 
Scottsdale, AZ 85258 
Kgosselin@honorhealth.com 
480-323-3251 
Contract Research Organization (CRO) 
 
Triligent International 
27271 Las Ramblas, Suite 100 
Mission Viejo, CA 92691 
Email: AXCLPANC@triligent.com 
SOURCE OF SUPPORT 
This study is funded by 
 
VERSION DATES 
VERSION 5.1 JUN 16, 2021 
PREVIOUS VERSIONS: 
Version 4.0 OCT 15, 2020 
Version 3.0 DEC 19, 2019 
Version 2.0 MAY 28, 2019 
Version 1.1 April 17, 2019 
Version 1.0 April 01, 2019 

 
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INVESTIGATOR’S PROTOCOL AGREEMENT 
 
Protocol No.: AX-CL-PANC-PI-13301 
 
Study Title:  A Phase II Trial of Nab-Paclitaxel plus Cisplatin plus Gemcitabine in Patients with Previously 
Untreated Metastatic Pancreatic Ductal Adenocarcinoma 
 
Version Date:  Jun 16, 2021 
 
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 Research Institute (HRI), Celgene, and 
Triligent 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 sponsor 
and prior review and written approval from the IRB, except where necessary to eliminate an 
immediate hazard to the subjects 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 
becoming aware of the event) to the Sponsor (via Triligent) and Celgene as indicated in Section 7 of 
the protocol. 
• 
Assure access to study monitors. 
• 
Prepare and maintain adequate and accurate case histories designed to record all observations and 
other data pertinent to the investigation on each individual treated in the investigation. 
• 
Arrange for the transfer of appropriate data from case histories to case report forms for the collection 
and transmission of data to the Sponsor. 
• 
Cooperate fully with any study-related GCP audit as performed by quality assurance group specified 
by the sponsor. 
• 
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 via Medwatch Form 3500A along with the SAE Report Form Cover 
letter promptly to both Triligent and Celgene 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 email 
or alternatively by fax or phone (Refer to protocol section 7.9 Investigator Reporting Serious 
Adverse Events). 
  
Note:  Participating study sites should NOT report SAEs to the FDA.  Celgene will be 
responsible for reporting to FDA. 
 
SAE Reporting to the Sponsor (via CRO, Triligent): 
 
Phone: 
317-402-9777 
Fax: 
949-203-6151 
Email: 
SAE@Triligent.com 
AND 
Celgene Corporation 
Global Drug Safety and Risk Management 
86 Morris Avenue 
Summit, New Jersey 07901 
 
Phone: 
908-673-9667 
Toll Free:  
800-640-7854 
Fax: 
908-673-9115 
Email: 
drugsafety@celgene.com 
                                          
For any additional questions regarding reporting requirements of a SAE, please contact Triligent 
as listed in the study contact list.  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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List of Abbreviations 
AE 
Adverse Event 
ALT (SGPT) 
Alanine Aminotransferase (SGPT) 
ALP 
Alkaline Phosphatase 
ANC 
Absolute Neutrophil Count 
ASCO 
American Society of Clinical Oncology 
AST (SGOT) 
Aspartate Aminotransferase (SGOT) 
β-hCG 
Beta subunit of human chorionic gonadotrophin (hCG) 
BPI 
Brief Pain Inventory 
BSA 
 
Body Surface Area 
BUN 
Blood Urea Nitrogen 
CA-125 
Cancer antigen 125 
CA19-9 
Carbohydrate antigen 19-9  
CBC 
Complete Blood Count 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
Cmax 
Maximum observed plasma concentration 
CMH 
Cochran-Mantel-Hanzel 
CNV 
Copy Number Variants 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CR 
Complete Response  
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHHS 
Department of Health and Human Services 
ECG 
Electrocardiogram 
eCRF(s) 
Electronic Case Report Form(s) 
FDA 
Food and Drug Administration 
18F-FDG 
Fluorine-18 Fluoro-D-Glucose 
FFPE 
Formalin-Fixed Paraffin-Embedded 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factors 
HIPPA 
Health Insurance Portability and Accounting Act 
HIV 
Human Immunodeficiency Virus 
HRI 
HonorHealth Research Institute 
HUS 
Hemolytic Uremia Syndrome 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IV 
Intravenous 
KPS 
Karnofsky Performance Status 
LD 
Longest Diameter 
MDASI 
MD Anderson Symptom Inventory 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 

 
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List of Abbreviations 
Nab 
Nanoparticle albumin bound 
NCI 
National Cancer Institute 
NRS 
Numeric Rating Scale 
NS 
Normal Saline 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
PD 
Progressive Disease 
PDA 
Pancreatic Ductal Adenocarcinoma 
PFS 
Progression-Free Survival 
PO 
Orally 
PR 
Partial Response  
QC 
Quality Control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SGOT 
Serum Glutamate Oxaloacetic Transaminase 
SGPT 
Serum Glutamate Pyruvic Transaminase 
SIADH 
Syndrome of Inappropriate Antidiuretic Hormone Secretion 
SPARC 
Secreted Protein Acidic and Rich in Cysteine 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TGen 
Translation Genomic Research Institute 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 

 
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TRIAL SYNOPSIS 
 
Title and No: A Phase II Trial of Nab-Paclitaxel plus Cisplatin plus Gemcitabine in Patients 
with Previously Untreated Metastatic Pancreatic Ductal Adenocarcinoma.   
Protocol # AX-CL-PANC-PI-13301  
IND Exempt April, 2019 
Version 5.1 dated Jun 16, 2021 
Trial Funded by Celgene 
 
Sponsor: HonorHealth Research Institute, 10510 N. 92nd Street Scottsdale, AZ 85258 
 
Consulting Investigator:  
Daniel D. Von Hoff, MD 
Translational Genomics Research Institute (TGen) An Affiliate of City of Hope 
 
Principal Investigator Site: 
Gayle Jameson ACNP- BC, AOCN - HonorHealth Research Institute, Scottsdale, AZ 
 
Medical Monitor:  
Michael Gordon, MD 
Medical Director - HonorHealth Research Institute, Scottsdale, AZ 
 
Clinical Phase: Phase II Open-Label study 
 
Objectives: 
Primary: The primary objective of this study is to evaluate the 12-month overall survival rates in patients 
with metastatic PDA treated with nab-paclitaxel plus cisplatin plus gemcitabine. 
 
Secondary: 
1. Evaluate the safety of cisplatin plus nab-paclitaxel plus gemcitabine. 
 
2. Evaluate the efficacy of cisplatin plus nab-paclitaxel plus gemcitabine based on complete 
response rate (RECIST 1.1), disease control rate at 9 weeks, and change in CA 19-9 (or CA 
125, or CEA if not expressers of CA 19-9). 
 
3. Evaluate the participant’s self-reported quality of life and pain levels during this study. 
 
4. To expand understanding of the molecular mechanisms of treatment response. 
 
Trial Design: Open-label, single arm, study 
 
No. Patients: Total of 50 patients recruited 
 
Name, dose of drugs:  
 
Investigational Site’s commercial product inventory to be used. 
• 
Pre cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL with Magnesium Sulfate 2 
grams IV infusion over 2 hours on days 1 and 8 repeated every 21 days.  
 
• 
Palonosetron (Aloxi®) 0.25 mg IV, fosaprepitant (Emend®) 150 mg IV and dexamethasone 12 
mg IV, or equivalent antiemetic regimen 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. The type of 
antiemetic prophylaxis used can vary based on institutional procedures.  
 

 
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• 
Nab-paclitaxel 125mg/m2 over 30 minute IV infusion on days 1 and 8 repeated every 21 days. 
Following administration, the intravenous line should be flushed with sodium chloride 9 mg/ml 
(0.9%) solution for injection to ensure complete administration of the complete dose, according 
to local practice.  
 
• 
Cisplatin 25mg/m2 in 500 mL of NS (the investigator may reduce the volume to 250 mL of NS if 
clinically indicated) over 60 minute IV infusion on days 1 and 8 repeated every 21 days followed 
by: 
 
• 
Gemcitabine 1000mg/m2 in 500 mL of NS (the investigator may reduce the volume to 250 mL of 
if clinically indicated) over 30 minute IV infusion on days 1 and 8 repeated every 21 days. 
 
• 
Post cisplatin hydration: IV fluids up to 1000 mL (with additives as clinically indicated) IV given 
as infusion on days cisplatin is administered on days 1 and 8 repeated every 21 days. May start 
at the same time as the gemcitabine infusion.  Additional post-cisplatin hydration of 1 liter of IV 
fluids on days 2 & 9 required for Cycles 1-3. Volume may be reduced to 500 ml at the 
Investigator’s discretion.  Note:  If the cisplatin is held in any cycle, the additional hydration on 
day of chemotherapy or day after would not be needed. 
 
Patient Population: Patients with untreated metastatic pancreatic ductal adenocarcinoma. 
 
Endpoints: 
 
Primary: To evaluate the 12-month overall survival rates in patients with metastatic PDA. 
 
Secondary:  
• 
Treatment-related toxicities. 
 
• 
Complete response rate as defined by CT scan using RECIST 1.1 criteria and CA 19-9 (or CA 
125, or CEA if not expressers of CA 19-9) down to normal limits (from at least > 2X ULN).   
 
• 
Disease control rate (CR, PR and SD at 9 weeks) in patients with metastatic PDA. 
 
• 
Change in CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) in this patient population. 
 
• 
Rates of normalization of CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9). 
 
• 
Participant’s self-reported quality of life and pain levels during this study utilizing the MD 
Anderson Symptom Inventory (MDASI-GI) and Brief Pain Inventory (BPI). 
 
• 
To expand understanding of the molecular mechanisms of treatment response by performing 
genomic characterization on patient’s tumor biopsies. Our hypothesis is that the PDAs that 
respond to the nab-paclitaxel, cisplatin, gemcitabine regimen will have distinct mutational and 
CNV signatures.  
 
Inclusion criteria:  
1. 
Age ≥ 18 years of age; male or female. 
 
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%. 

 
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5. 
Life expectancy ≥ 12 weeks. 
 
6. 
Measurable tumor lesions according to RECIST 1.1 criteria. 
 
7. 
< Grade 2 pre-existing peripheral neuropathy per NCI CTCAE, Version 5.0  
 
8. 
Patient has acceptable coagulation status as indicated by an INR ≤1.5 x ULN. Patients on 
anticoagulation can be included at the discretion of the investigator. 
 
9. 
Patients must have normal organ and marrow function as defined below: 
 
• 
Absolute neutrophil count ≥1,500/mm3 
 
• 
Platelet concentration ≥100,000/mm3 with no platelet transfusions within 7 days prior to 
laboratory sample    
 
• 
Hemoglobin > 9.0g/dL 
 
• 
Hematocrit level > 27% 
 
• 
Total bilirubin within 1.25 times institutional upper limit of normal (ULN) 
 
• 
Alanine aminotransferase (ALT) and AST < 10 X institutional ULN 
 
• 
Serum creatinine  < 1.5 mg/dl 
 
10. Females of child-bearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy [the 
surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at least 24 
consecutive months [i.e., has had menses at any time during the preceding 24 consecutive 
months]) must: 
 
a. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a 
monthly basis), or agree to use, and be able to comply with, effective contraception without 
interruption, 28 days prior to starting IP therapy (including dose interruptions), and while on 
study medication or for a longer period if required by local regulations following the last 
dose of IP; and 
 
b. Have a negative serum pregnancy test (β -hCG) result at screening and agree to ongoing 
pregnancy testing during the course of the study, and after the end of study therapy.  This 
applies even if the subject practices true abstinence* from heterosexual contact. 
 
11. Male subjects must practice true abstinence* or agree to use a condom during sexual contact 
with a pregnant female or a female of childbearing potential while participating in the study, 
during dose interruptions and for 6 months following discontinuation from study treatment, even 
if he has undergone a successful vasectomy. 
 
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. 
[Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception]. 
 
 

 
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Exclusion criteria: 
1. 
Patients must have received no previous radiotherapy, surgery, chemotherapy or 
investigational therapy for the treatment of metastatic disease. Prior treatments in the 
neoadjuvant and/or adjuvant setting with gemcitabine and/or 5-FU based therapies or 
gemcitabine and/or 5FU 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. 
History of other malignancies (except cured basal cell carcinoma, superficial bladder cancer or 
carcinoma in situ of the cervix) unless documented free of cancer for ≥5 years. 
 
6. 
Current, serious, clinically significant cardiac arrhythmias as determined by the investigator. 
 
7. 
History of HIV infection. 
 
8. 
Active, clinically significant serious infection requiring treatment with antibiotics, anti-virals or 
anti-fungals. 
 
9. 
Major surgery within 4 weeks prior to initiation of study treatment. 
 
10. Any condition in the opinion of the principal investigator that might interfere with the patient’s 
participation in the study or in the evaluation of the study results. 
 
11. Any condition in the opinion of the principal investigator that is unstable and could jeopardize 
the patient’s participation in the study.  
 
Statistical Methods: The primary endpoint for this clinical trial is to evaluate the 12-month overall 
survival rates in patients with metastatic PDA.  42 patients are needed to detect a difference between 
35% and 55% 12-month OS rates with 80% power, hazard ratio of 0.57, and a one-sided 0.025 alpha-
level.  Time-to-event endpoints, including PFS and OS will be assessed using the Kaplan-Meier method.  
Objective response rates, clinical benefit response, and CA 19-9, will be summarized descriptively. 
 
Logistic regression will be used to assess the impact of patient characteristics on response and toxicity 
rates. 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 will be used to evaluate multivariable predictive models of time-to-event outcomes. 
 
Stopping Rules: The study will be stopped early based on either one of the following criteria being 
met:  
1. Treatment related deaths > 2 patients in the first 25 patients, as that is the number we observed 
in the original 25 patient study. 
2. Treatment related bleeding in the first 25 patients that is life threatening and/or fatal in > 1 
patient. 
 
 

 
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Table of Contents 
1 BACKGROUND ....................................................................................................... 15 
1.1 
Potential Risks of nab-Paclitaxel ................................................................................. 16 
1.2 
Potential risks of Cisplatin ........................................................................................... 16 
1.3 
Potential Risks of Gemcitabine ................................................................................... 16 
1.4 
Potential risks of nab-Paclitaxel plus Gemcitabine ...................................................... 17 
1.5 
Potential risks of nab-Paclitaxel, plus Cisplatin, plus Gemcitabine .............................. 18 
1.6 
Study and Dose Rationale .......................................................................................... 18 
1.7 
Sequence of Drug Administration and Rationale ......................................................... 18 
1.8 
Quality of Life and Pain Assessments ......................................................................... 18 
1.9 
Tumor Analysis ........................................................................................................... 19 
2 OBJECTIVES .......................................................................................................... 19 
2.1 
Primary Objective ....................................................................................................... 19 
2.2 
Secondary Objectives ................................................................................................. 19 
2.3 
Overview .................................................................................................................... 20 
2.4 
Primary Endpoints ...................................................................................................... 20 
2.5 
Secondary Endpoints.................................................................................................. 20 
3 STUDY POPULATION ............................................................................................ 21 
3.1 
Patient Selection and Study Duration ......................................................................... 21 
3.2 
Inclusion Criteria ......................................................................................................... 21 
3.3 
Exclusion Criteria ........................................................................................................ 22 
3.4 
Patient Enrollment ...................................................................................................... 23 
3.5 
Patient Discontinuation ............................................................................................... 23 
4 STUDY TREATMENT .............................................................................................. 24 
4.1 
Administration and Dosing .......................................................................................... 24 
4.2 
Body Surface Area Calculation ................................................................................... 25 
4.3 
Dose Modification for Toxicity ..................................................................................... 25 
4.3.1 
Hematological Toxicity .................................................................................... 25 
4.3.2 
Non-hematological Toxicity ............................................................................. 27 
4.3.2.1 Peripheral Neuropathy ....................................................................... 27 
4.3.2.2 Nephrotoxicity .................................................................................... 27 
4.3.2.3 Cutaneous Toxicity ............................................................................ 28 
4.3.2.4 Gastrointestinal Toxicity ..................................................................... 28 
4.3.2.5 Pulmonary Embolism ......................................................................... 28 
4.3.2.6 Interstitial Pneumonitis ....................................................................... 28 
4.3.2.7 Hypersensitivity Reactions ................................................................. 29 
4.3.2.8 Prophylaxis use of Colony Stimulating Factors ................................... 29 
4.3.2.9 Prophylaxis against Sepsis ................................................................ 29 
4.4 
Intended Dose Delays ................................................................................................ 29 
4.5 
Concomitant Therapy ................................................................................................. 30 
4.6 
Concomitant Therapies Requiring Caution ................................................................. 30 
5 STUDY ASSESSMENTS ......................................................................................... 30 
5.1 
Laboratory Assessments ............................................................................................ 30 
5.2 
Screening (Within 21 Days Prior to First Dose on C1/D1) ........................................... 30 
5.3 
On-Study Assessments .............................................................................................. 31 
5.3.1 
Tissue Analysis ............................................................................................... 31 
5.3.2 
Day 1 of each cycle (except where noted) ....................................................... 32 
5.3.3 
Day 8 of each cycle ......................................................................................... 33 
5.3.4 
Day 15 of each cycle ....................................................................................... 33 
5.3.5 
Tumor Assessments every three cycles (Prior to Cycles 4, 7, 10, etc.) ........... 34 

 
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5.4 
End of Treatment ........................................................................................................ 34 
5.5 
Follow-Up Assessments after End of Study or Early Termination ............................... 34 
6 EVALUATION OF RESPONSE ............................................................................... 35 
6.1 
Best Overall Response ............................................................................................... 35 
6.2 
Overall Tumor Response ............................................................................................ 35 
6.3 
Not Evaluable ............................................................................................................. 35 
6.4 
Progression-free Survival ........................................................................................... 35 
6.5 
Survival ...................................................................................................................... 35 
6.7 
Disease Definitions ..................................................................................................... 36 
6.8 
Methods of Measurement ........................................................................................... 36 
6.9 
Baseline Documentation of “Target” and “Non-target” Lesions ................................... 37 
6.10 Response Criteria ....................................................................................................... 38 
6.11 Evaluation of Best Overall Response .......................................................................... 39 
6.12 Duration of Overall Response ..................................................................................... 39 
6.13 Duration of Stable Disease ......................................................................................... 39 
7 SAFETY ................................................................................................................... 40 
7.1 
Adverse Events .......................................................................................................... 40 
7.2 
Serious Adverse Events ............................................................................................. 41 
7.3 
Adverse Event Severity .............................................................................................. 42 
7.4 
Duration ...................................................................................................................... 42 
7.5 
Action Taken .............................................................................................................. 42 
7.6 
Outcome ..................................................................................................................... 42 
7.7 
Causality Assessment ................................................................................................ 42 
7.8 
Patient Reporting of AEs and SAEs ............................................................................ 43 
7.9 
Investigator Reporting Adverse Events ....................................................................... 43 
7.9.1 
Expedited Reporting by Investigator to (Sponsor/Celgene) ............................. 44 
7.9.2 
IRB Notification of SAEs ................................................................................. 45 
7.10 SAE Follow-Up ........................................................................................................... 45 
7.10.1 Sponsor Notification of Post-Study SAEs ........................................................ 45 
7.11 Pregnancy .................................................................................................................. 45 
7.12 Overdose .................................................................................................................... 46 
8 STATISTICAL CONSIDERATIONS ........................................................................ 47 
8.1 
Trial Design ................................................................................................................ 47 
8.2 
Sample Size Considerations ....................................................................................... 47 
8.3 
Statistical Analysis Plan .............................................................................................. 47 
8.3.1 
Analysis of the Conduct of the Trial ................................................................. 47 
8.3.2 
Patient Disposition .......................................................................................... 47 
8.3.3 
Analysis of Patient Characteristics .................................................................. 48 
8.4 
Efficacy Analysis ......................................................................................................... 48 
8.5 
Safety and Tolerance  Analysis .................................................................................. 49 
8.5.1 
Stopping Rules ................................................................................................ 49 
8.6 
Laboratory Assessments ............................................................................................ 49 
8.6.1 
Hematology Parameters ................................................................................. 49 
8.6.2 
Clinical Chemistry ........................................................................................... 49 
8.6.3 
Peripheral Neuropathy .................................................................................... 50 
8.7 
Replacement of Patients ............................................................................................. 50 
9 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ........................................ 50 
9.1 
Ethics ......................................................................................................................... 50 
9.1.1 
Institutional Review Board/Ethics Committee Approval ................................... 50 
9.1.2 
Ethical Conduct of the Study ........................................................................... 50 
9.1.3 
Informed Consent ........................................................................................... 50 

 
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9.2 
Disclosure of Data ...................................................................................................... 51 
9.2.1 
Confidentiality ................................................................................................. 51 
9.2.2 
Publication ...................................................................................................... 51 
9.2.3 
Trial Registration and Results Posting Requirements ...................................... 51 
9.3 
Quality Assurance ...................................................................................................... 52 
9.3.1 
Study Data Monitoring Plan ............................................................................. 52 
9.3.2 
Data Safety and Monitoring ............................................................................. 52 
9.3.3 
On-site Audits ................................................................................................. 52 
9.5 
Investigator Documentation ........................................................................................ 53 
9.5.3 
Investigator Protocol Agreement ..................................................................... 53 
9.5.4 
Financial Disclosures ...................................................................................... 53 
9.5.5 
Laboratory Certification and Normal Ranges ................................................... 53 
9.5.6 
Records Retention .......................................................................................... 54 
10 DATA MANAGEMENT ............................................................................................ 54 
10.1 Case Report Forms .................................................................................................... 54 
10.2 Source Documents ..................................................................................................... 54 
REFERENCES .............................................................................................................. 55 
APPENDIX A: SCHEDULE OF TREATMENT AND EVALUATIONS .......................... 58 
APPENDIX B: KARNOFSKY PERFORMANCE STATUS ........................................... 61 
APPENDIX C: REVISED NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI CTCAE), VERSION 5.0 
(PUBLISHED 27 NOVEMBER 2017) ...................................................................... 62 
APPENDIX D: DRUG STUDY DRUG PREPARATION, DOSING, ADMINISTRATION 
AND STORAGE ...................................................................................................... 63 
APPENDIX E:  THE MD ANDERSON SYMPTOM INVENTORY GASTROINTESTINAL 
CANCER MODULE (MDASI-GI) (TO BE SUBMITTED SEPARATELY FROM 
PROTOCOL FOR IRB APPROVAL) ....................................................................... 64 
APPENDIX F:  THE BRIEF PAIN INVENTORY (BPI) – SHORT FORM (TO BE 
SUBMITTED SEPARATELY FROM PROTOCOL FOR IRB APPROVAL) ............ 65 
APPENDIX G:  2006 UPDATE OF ASCO PRACTICE GUIDELINE 
RECOMMENDATIONS FOR THE USE OF WHITE BLOOD CELL GROWTH 
FACTORS: GUIDELINE SUMMARY ...................................................................... 66 
  

 
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LIST OF TABLES 
Table 1. Dose Reduction Schema ............................................................................................ 25 
Table 2. Dose Modifications for Day 1 of Each Cycle (Hematologic Toxicity) ........................... 26 
Table 3. Dose Modification for Day 8 of Each Cycle (Hematologic Toxicity)* ............................ 26 
Table 4. Nab-paclitaxel and gemcitabine Dose Modifications for Day 1 of Each Cycle 
(Non-hematologic Toxicity)* ........................................................................................ 27 
Table 5. Nab-paclitaxel and gemcitabine Dose Modifications Day 8 Each Cycle 
(Non-hematological Toxicity) ...................................................................................... 27 
Table 6. RECIST 1.1 Target Lesion Response Criteria ............................................................ 38 
Table 7. RECIST 1.1 Non-target Lesion Response Criteria ...................................................... 38 
Table 8. RECIST Overall Response Criteria ............................................................................. 39 
 

 
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1 BACKGROUND 
Pancreatic cancer continues to be a highly lethal disease with an overall 5 year survival of only 
8%. Since 2004, the incidence of pancreatic cancer has been increasing by 1.5% per year and it 
is estimated that there will be 55,440 new cases diagnosed in the United States in 2018, with 
43,330 expected deaths. Pancreatic cancer is the fourth most common cause of cancer-related 
deaths in both men and women, and the incidence is slightly higher in men versus women (ACS 
2018). Of all types of pancreatic cancers, pancreatic ductal adenocarcinoma (PDA) is by far the 
most common, representing 80% of cases (Dragovich 2012). 
 
Due to the lack of adequate screening techniques, greater than 80% of patients at the time of 
diagnosis present with unresectable, advanced disease. Standard treatment options for 
inoperable patients with locally advanced and metastatic PDA have been quite limited. 
Gemcitabine monotherapy, approved by the FDA in 1996, demonstrated a median survival of 5.7 
months (Burris 1997), and has been the mainstay in treating patients with PDA. The first 
combination regimen to demonstrate any survival benefit compared with gemcitabine alone was 
gemcitabine plus erlotinib, with median survival of 6.24 months versus 5.91 months for single 
agent gemcitabine (Moore 2007).  
 
A meta-analysis of randomized trials by Heinemann and colleagues showed that patients with 
advanced pancreatic cancer and a good performance status may benefit from combination 
chemotherapy with gemcitabine plus a platinum agent or a fluoropyrimidine (Heinemann 2008). 
Multiple combination regimens are being utilized. 
 
Recently, 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, however, is 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 patients with head of the pancreas tumors (Conroy 2011, 
Assaf 2011). 
 
Current treatment regimens for advanced PDA although offering modest improvements in 
progression-free survival (PFS) and overall survival (OS), are clearly inadequate in achieving long 
term survival in these patients. Additional treatment strategies are desperately needed. 
 
Von Hoff and colleagues recently presented data supporting the use of nab-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. It is speculated that reducing the dense tumor stroma, 
using an albumin-coated nanoparticle (nab-paclitaxel) homing to the protein SPARC (secreted 
protein acidic and rich in cysteine), may allow the chemotherapy to reach the tumor tissue more 
efficiently (Von Hoff 2011). An international phase III trial comparing this combination to 
gemcitabine single agent has completed accrual and results demonstrated a statistically 
significant improvement in overall survival for advanced pancreatic cancer patients using the 
gemcitabine and nab-paclitaxel over gemcitabine alone (see Appendix D). 
 
Building on the design and mechanisms of action of the nab-paclitaxel and gemcitabine 
combination, this protocol introduces a third cytotoxic agent, cisplatin, to be added to this doublet. 
The rationale for adding cisplatin to nab-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 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 

 
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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 PDA. 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 2008).  
 
Through 2013, there had been no documented reports of the combination of cisplatin with nab-
paclitaxel and gemcitabine in the treatment of any human cancer. However, cisplatin has been 
combined with paclitaxel and gemcitabine in the treatment of patients with locally advanced or 
metastatic non-small cell lung cancer (NSCLC) patients and has shown substantial antitumor 
activity with an acceptable safety profile. In this phase I-II study of 65 patients with advanced 
NSCLC, the overall response rate was 57% (Frasci 1999). 
 
A recent pilot, phase IB/IIA study investigating the efficacy and safety of cisplatin with nab-
paclitaxel and gemcitabine in 25 patients with previously untreated metastatic PDA demonstrated 
a 67.5% 12-month overall survival and an acceptable toxicity profile at the MTD cisplatin dose of 
25mg/m2. There was a 71% overall response rate; 2 pts had a complete response (8.3%) and 15 
with partial responses (62.5%). In addition, 4 patients experienced stable disease (16.7%) 
(Jameson, 2019). These encouraging data are the basis for this protocol. 
1.1 
Potential Risks of nab-Paclitaxel  
The most common toxicities reported for nab-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, pruritus, hypotension, nail changes, vision changes, rash, pulmonary 
edema, irregular heartbeat (see Appendix D). 
1.2 
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), 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 typhilitis, 
optic neuritis, orthostatic hypotension, pancreatitis, papilledema, phlebitis, reversible posterior 
leukoencephalopathy 
syndrome 
(RPLS), 
SIADH, 
stroke, 
thrombophlebitis, 
thrombotic 
thrombocytopenic purpura (see Appendix D). 
1.3 
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 

 
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(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 D).  
1.4 
Potential risks of nab-Paclitaxel plus Gemcitabine 
The safety of nab-paclitaxel plus gemcitabine was initially reported by Von Hoff and colleagues 
(Von Hoff 2011). The most common toxicities seen at the recommended phase II dose were 
anemia, leukopenia, neutropenia, thrombocytopenia, fatigue, alopecia, sensory neuropathy and 
nausea (Von Hoff 2011).  
 
In subjects with metastatic pancreatic cancer, who received the combination of nab-paclitaxel and 
gemcitabine, there may be an increase of sepsis.  Pneumonitis appears to occur more often (4%) 
when the two drugs are given together.  This requires early detection and treatment as it may be 
life-threatening or even fatal.  In addition, acute renal or kidney failure and hemolytic uremic 
syndrome have been reported commonly and uncommonly, respectively, in combination of nab-
paclitaxel with gemcitabine. 
 
A very rare condition known as Posterior Reversible Encephalopathy Syndrome has occurred 
when gemcitabine is given alone or in combination with other chemotherapy medications. 
 
A very rare condition known as Capillary Leak Syndrome that causes leaking of fluid outside of 
blood vessels has occurred when gemcitabine is given alone or in combination with other 
chemotherapy medications. 
 
Additional side effects observed during post-marketing surveillance of gemcitabine, not otherwise 
noted above include: 
 
• 
vasculitis  
 
• 
gangrene 
 
Additional side effects observed during post-marketing surveillance of nab-paclitaxel, not 
otherwise noted above include:  
 
• 
cranial nerve palsies and vocal cord paresis  
 
• 
palmar-plantar erythrodysethesia syndrome 
 
• 
photosensitivity reaction  
 
• 
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme radiation 
pneumonitis, radiation recall phenomenon 
 
Elderly 
 
In subjects ≥ 65 years old, who received nab-paclitaxel and gemcitabine, a higher incidence of 
diarrhea, decreased appetite, dehydration, and epistaxis has been reported compared to subjects 
< 65 years old.  In subjects ≥ 75 years old, a higher incidence of serious adverse reactions and 
adverse reactions leading to treatment discontinuation has been reported.  
  
Adverse drug reactions reported from post-marketing experience, even though their frequency is 
unknown, have been similar in type and severity to those reported in nab-paclitaxel clinical trials. 

 
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1.5 
Potential risks of nab-Paclitaxel, plus Cisplatin, plus Gemcitabine 
The combination of nab-paclitaxel, cisplatin, and gemcitabine has not been reported. However, a 
similar combination of paclitaxel, cisplatin, and gemcitabine given on days 1 and 8 every 21 days 
studied by Frasci, et al, (see section 1.0), showed anticipated toxicities to include 
myelosuppression, neutropenia, neuropathy, nephrotoxicity diarrhea, vomiting, fatigue, 
musculoskeletal pain and rhinorrhagia. In that study, grade 2 neurotoxicity was seen in 8 patients 
(10.6%), grade 3 sensory and motor neuropathy was seen in one patient (1.3%). Mild or moderate 
nephrotoxicity occurred in a total of 7 patients (9.3%) (Frasci 1999). 
1.6 
Study and Dose Rationale 
This is a phase II open-label, study evaluating the efficacy and safety of nab-paclitaxel 125mg/m2, 
cisplatin 25 mg/m2, and gemcitabine 1000 mg/m2, all administered intravenously (IV) on Days 1 
and 8 every 21 days until development of toxicity that is unacceptable in the opinion of the patient 
or the Investigator or upon disease progression. The doses of the nab-paclitaxel and gemcitabine 
are taken from the phase I/II trial (Von Hoff 2011). Building upon this two drug foundation, a phase 
Ib/II pilot trial investigated the safety and efficacy of nab-paclitaxel and gemcitabine plus cisplatin 
by Jameson, et al. In 24 evaluable patients (n=25), a 71% overall response rate was noted with 
2 complete responses, 15 partial responses, 4 stable disease and 3 patients with progressive 
disease. The median overall survival rate was 16.4 months (95% CI 10.2, 25.3) with 16 (64%) 
patients alive at 1 year, 10 (40%) alive at 2 years, 4 (16%) at 3 years, and 1 (4%) patient alive at 
4 + years. Three patients remain alive as of last contact 12/05/18 (36-59.7 months OS).   Median 
PFS was 10.1 months (95% CI, 6.0 -12.5). The MTD of cisplatin was determined to be 25mg/m2. 
The dosing schedule of the 3 drug combination is taken from the aforementioned lung cancer 
study (Liang 2012). 
1.7 
Sequence of Drug Administration and Rationale 
The sequence of drug administration is nab-paclitaxel, then cisplatin, then gemcitabine. After 
adequate hydration (see Section 4.1), Nab-paclitaxel is given first, targets SPARC (secreted 
protein acidic and rich in cysteine) in tumor cells and may be taken up by the process of 
macropinocytosis. Then the cisplatin is given. Gemcitabine is given last because nab-paclitaxel 
decreases cytidine deaminase which potentiates gemcitabine activity (less degradation of 
gemcitabine by the enzyme). 
1.8 
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 
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, at the beginning of each cycle throughout treatment 
and at end of study. Please see Appendix (E) and (F) for information on instruments. 

 
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1.9 
Tumor Analysis 
Pancreatic adenocarcinoma tumors are known to have numerous driver mutations along with 
DNA repair problems (Barrett 2017). The identification of patterns of vulnerable target mutations 
would be very useful in further understanding not only tumor biology but response to therapy and 
treatment selection. Work done by Alexandrov and colleagues has illustrated a pattern of DNA 
mutations labeled, ‘Signature 3” (Alexandrov 2013). This signature of tumor mutations in 
pancreatic cancer includes the family of BRCA mutations.  Interestingly, in a sample of pancreatic 
cancer patients, all responders of platinum therapy exhibited this mutation signature including 
those that lacked defects in BRCA1 or BRCA2 (Alexandrov 2015). The correlation of the presence 
of this pattern on tumor cells with response to our “Triplet” platinum based therapy could 
potentially lead to improved selection of patients who would be respond to this therapy. Therefore, 
further study is warranted. We have included the tumor analysis of the signature 3 pattern of 
mutation in this study.  
 
The genomic analysis of fresh tissue or archived tumor paraffin blocks will be used to look for 
copy number variants (CNV), and gene mutations including Signature 3. The genes and pathways 
targeted by selected mutations in both responder and non-responder patients will provide highly 
favorable candidate markers and targets that can be advanced in future studies for improved 
patient care.  Preferably, this analysis will be conducted on the metastatic tumor tissue when 
available.  
 
Next generation sequencing will be conducted on the samples. All libraries and sequencing will 
be done in the Mayo Clinic Medical Genome Facility using their established protocols. Each tumor 
will then be assessed for the presence of mutational signatures that predict response to DNA 
damage and repair targeting therapies. The primary and secondary analyses of sequencing data 
will be done in collaboration with Mayo Clinic Bioinformaticians. 
 
Barrett Laboratory: 
Mayo Clinic Arizona 
Mayo Collaborative Cancer Research Building, Cr2-111 
Attn: Michael Barrett, PhD 
13208 E. Shea Blvd, Suite 100 
Scottsdale, AZ 85259 
 
Instructions for shipment of samples to the analysis laboratory are detailed in the Trial Lab 
Manual.  
2 OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the 12-month overall survival rates in patients 
with metastatic PDA treated with nab-paclitaxel plus cisplatin plus gemcitabine. 
2.2 
Secondary Objectives 
The secondary objectives of this study are to: 
 
• 
Evaluate the safety of cisplatin plus nab-paclitaxel plus gemcitabine 
 

 
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• 
Evaluate the efficacy of cisplatin plus nab-paclitaxel plus gemcitabine based on complete 
response rate (RECIST 1.1), disease control rate at 9 weeks, and change in CA 19-9 (or 
CA 125, or CEA if not expressers of CA 19-9) 
 
• 
Evaluate the participant’s self-reported quality of life and pain levels during this study 
 
• 
To expand understanding of the molecular mechanisms of treatment response  
2.3 
Overview  
This is a phase II open-label study evaluating the efficacy and safety of nab-paclitaxel cisplatin, 
and gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma. 
 
An individual cycle of therapy will be defined as Days 1 and 8 every 21 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 (Frese 2012). Time-to-event endpoints, including PFS and OS will 
be assessed using the Kaplan-Meier method (Kaplan 1958). Evaluation of stable disease at 9 
weeks will also be assessed. Toxicity (adverse events) will be recorded using the NCI CTCAE, 
version 5.0 (see Appendix C).  
2.4 
Primary Endpoints 
• 
To evaluate the 12-month overall survival rates in patients with metastatic PDA.  
2.5 
Secondary Endpoints 
To evaluate the following: 
 
• 
Treatment-related toxicities. 
 
• 
Complete response rate as defined by CT scan using RECIST 1.1 criteria and CA 19-9 
(or CA 125, or CEA if not expressers of CA 19-9) down to normal limits (from at least > 2X 
ULN).   
 
• 
Disease control rate (CR, PR and SD at 9 weeks) in patients with metastatic PDA. 
 
• 
Change in CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) in this patient 
population. 
 
• 
Rates of normalization of CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9). 
 
• 
Participant’s self-reported quality of life and pain levels during this study utilizing the MD 
Anderson Symptom Inventory (MDASI-GI) and Brief Pain Inventory (BPI). 
 
• 
To expand understanding of the molecular mechanisms of treatment response by 
performing genomic characterization on patient’s tumor biopsies. Our hypothesis is that 
the PDAs that respond to the nab-paclitaxel, cisplatin, gemcitabine regimen will have 
distinct mutational and CNV signatures. 

 
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3 STUDY POPULATION 
3.1 
Patient Selection and Study Duration 
Up to 50 patients will be recruited from up to 4 study centers in the United States with the goal of 
42 evaluable patients. The expected duration of this study is 36 months; 24 months for accrual 
and 12 months follow-up. 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 
or in the event that any of the stopping rules as defined in Section 8.5.1 are met.  
3.2 
Inclusion Criteria 
Patients must meet the following criteria to be included in the study: 
 
1. Age ≥18 years of age; male or female. 
 
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. < Grade 2 pre-existing peripheral neuropathy per NCI CTCAE, Version 5.0.  
 
8. Patient has acceptable coagulation status as indicated by an INR ≤1.5 x ULN. Patients 
on anticoagulation can be included at the discretion of the investigator. 
 
9. Patients must have normal organ and marrow function as defined below: 
 
• 
Absolute neutrophil count ≥1,500/mm3 
 
• 
Platelet concentration ≥100,000/mm3 with no platelet transfusions within 7 days prior 
to laboratory sample    
 
• 
Hemoglobin > 9.0g/dL 
 
• 
Hematocrit level > 27% 
 
• 
Total bilirubin within 1.25 times institutional upper limit of normal (ULN) 
 
• 
Alanine aminotransferase (ALT) and AST < 10 × institutional ULN  
 
• 
Serum creatinine  <1.5 mg/dl 
 
10. Females of child-bearing potential (defined as a sexually mature woman who (1) has not 
undergone hysterectomy [the surgical removal of the uterus] or bilateral oophorectomy 

 
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[the surgical removal of both ovaries] or (2) has not been naturally postmenopausal for at 
least 24 consecutive months [i.e., has had menses at any time during the preceding 24 
consecutive months]) must: 
 
a. Either commit to true abstinence* from heterosexual contact (which must be reviewed 
on a monthly basis), or agree to use, and be able to comply with, effective 
contraception without interruption, 28 days prior to starting IP therapy (including dose 
interruptions), and while on study medication or for a longer period if required by local 
regulations following the last dose of IP; and 
 
b. Have a negative serum pregnancy test (β -hCG) result at screening and agree to 
ongoing pregnancy testing during the course of the study, and after the end of study 
therapy.  This applies even if the subject practices true abstinence* from heterosexual 
contact. 
 
11. Male subjects must practice true abstinence* or agree to use a condom during sexual 
contact with a pregnant female or a female of childbearing potential while participating in the 
study, during dose interruptions and for 6 months following discontinuation from study 
treatment, even if he has undergone a successful vasectomy. 
 
* True abstinence is acceptable when this is in line with the preferred and usual lifestyle 
of the subject. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception]. 
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 
neoadjuvant and/or adjuvant setting with gemcitabine and/or 5-FU based therapies or 
gemcitabine and/or 5FU 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. History of other malignancies (except cured basal cell carcinoma, superficial bladder 
cancer or carcinoma in situ of the cervix) unless documented free of cancer for ≥5 
years. 
 
6. Current, serious, clinically significant cardiac arrhythmias as determined by the 
investigator. 
 

 
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7. History of HIV infection. 
 
8. Active, clinically significant serious infection requiring treatment with antibiotics, anti-
virals or anti-fungals. 
 
9. Major surgery within 4 weeks prior to initiation of study treatment. 
 
10. Any condition in the opinion of the principal investigator that might interfere with the 
patient’s participation in the study or in the evaluation of the study results. 
 
11. Any condition in the opinion of the principal investigator that is unstable and could 
jeopardize the patient’s participation in the study.  
3.4 
Patient Enrollment 
All patients must have a signed and dated current, IRB approved informed consent and HIPAA 
Authorization prior to any study specific screening procedures being performed.   
 
A trial and site specific screening number will be assigned by the site when the patient signs the 
Informed Consent Form.   Once all screening procedures have been completed and laboratory 
values have been reported, the investigator will register the patient into the study as follows: 
 
1. Completion of all data entry into the required screening eCRFs 
2. Provide HRI with the completed patient eligibility forms signed by the Investigator to HRI 
via fax or email. 
 
HRI will review the screening eCRFs within 48 hour and confirm eligibility of the patient and assign 
the trial specific patient enrollment number.   
  
If the patient is determined NOT eligible for the study, the patient will be determined a screen 
failure and the reason noted on the patient eligibility form and sent to the Investigator for the study 
records.  The Investigator, or delegated study team member, is responsible for entering all 
patients consented to the study in the EDC, including screen failures. 
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. 

 
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7. Non-compliance. 
4 STUDY TREATMENT 
4.1 
Administration and Dosing 
Treatment will be administered by qualified and trained site personnel in a hospital, clinic, or other 
outpatient setting appropriate for chemotherapeutic infusions. Investigator sites will utilize their 
own commercial supply for this trial.  
 
No investigational or commercial agents or therapies other than those described may be 
administered with the intent to treat the patient’s malignancy.  
 
The solution for infusion will be prepared at each investigational site. Detailed guidelines for the 
preparation and administration of nab-paclitaxel, cisplatin and gemcitabine are provided in 
Appendix D. The order of infusion with premedication is as follows: 
 
• 
Pre cisplatin hydration: 0.9% Sodium Chloride Injection 1000 mL with Magnesium Sulfate 
2 grams IV infusion over 2 hours on days 1 and 8 repeated every 21 days.  
 
• 
Palonosetron (Aloxi®) 0.25 mg IV, fosaprepitant (Emend®) 150 mg IV and 
dexamethasone 12 mg IV, or equivalent antiemetic regimen 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. The type of antiemetic prophylaxis used can vary based on 
institutional procedures.  
 
• 
Nab-paclitaxel 125mg/m2 over 30 minute IV infusion on days 1 and 8 repeated every 
21 days. Following administration, the intravenous line should be flushed with sodium 
chloride 9 mg/ml (0.9%) solution for injection to ensure complete administration of the 
complete dose, according to local practice. followed by:  
 
• 
Cisplatin 25mg/m2 in 500 mL of NS (the investigator may reduce the volume to 250 mL of 
NS if clinically indicated) over 60 minute IV infusion on days 1 and 8 repeated every 21 
days followed by: 
 
• 
Gemcitabine 1000mg/m2 in 500 mL of NS (the investigator may reduce the volume to 250 
mL of if clinically indicated) over 30 minute IV infusion on days 1 and 8 repeated every 21 
days. 
 
• 
Post cisplatin hydration: IV fluids up to 1000 mL (with additives as clinically indicated) IV 
given as infusion on days cisplatin is administered on days 1 and 8 repeated every 21 
days. May start at the same time as the gemcitabine infusion.  Additional post-cisplatin 
hydration of 1 liter of IV fluids on days 2 & 9 required for Cycles 1- 3. Volume may be 
reduced to 500 ml at the Investigator’s discretion.  Note:  If the cisplatin is held in any 
cycle, the additional hydration on day of chemotherapy or day after would not be needed. 
 
 

 
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In the event of extravasation during the infusion of nab-paclitaxel, cisplatin and gemcitabine, the 
infusion should be immediately terminated and patients treated according to local site protocols. 
The infusion should then be restarted in another vein. 
4.2 
Body Surface Area Calculation 
The calculation of the dose of cisplatin, gemcitabine, and nab-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 (Cycle 1 Day 1), the drug doses will be 
recalculated based on the new BSA value.  Doses are rounded to the nearest whole milligram.   
4.3 
Dose Modification for Toxicity 
Toxicities will be graded using the NCI CTCAE v5.0 (see Appendix C). 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). 
 
Doses of nab-paclitaxel and gemcitabine may be reduced in individual patients in accordance 
with the schedule in Table 1. 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.  
 
A maximum of a 3-week treatment delay is permitted to allow recovery of toxicities or other 
concurrent illness that prevents the patient from receiving chemotherapy. 
 
Table 1. Dose Reduction Schema 
Dose Level 
nab-Paclitaxel 
(mg/m2) 
Cisplatin Dose 1 
Gemcitabine (mg/m2) 
Level - 0 (baseline) 
125mg/m2 
No change 
1000mg/m2 
Level -1 
100mg/m2 
No change 
800mg/m2 
Level -2 
75mg/m2 
No change 
600mg/m2 
4.3.1 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 nab-paclitaxel, cisplatin, and gemcitabine may be adjusted as 
detailed in Table 2 and Table 3. 
 
During Cycle 1, if the patient experiences a grade 4 hematologic adverse event related to 
chemotherapy as determined by the investigator, dose reduce to Level -1 for Cycle 2.  
 
 
 
 
 
 
 
 
 

 
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Dose Modifications at Day 1 
 
Table 2. Dose Modifications for Day 1 of Each Cycle (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 
Delay by 1 week intervals until recovery 
 
Dose Adjustments within a Treatment Cycle 
 
In the event that patients must have treatment delayed within a treatment cycle due to hematologic 
toxicities, those doses held 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. 
 
Table 3. Dose Modification for Day 8 of Each Cycle (Hematologic Toxicity)* 
Day 8 
Laboratory Results 
Day 8 
Nab-paclitaxel 
Day 8 
Cisplatin 
Day 8 
Gemcitabine 
ANC > 1000  
and 
Platelets ≥ 75,000 
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) 
 
ANC < 500 
or 
Platelets < 50,000 
 
Hold 
 
Hold 
 
Hold 
 
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 
 
Recurrent 
Febrile 
Neutropenia 
(Grade 3 or 4) 
 
Decrease 2 dose levels  
(to 75 mg/m2) and do not 
re-escalate throughout  
the rest of treatment 
 
Hold 
 
Decrease 2 dose levels  
(to 600 mg/m2) and do not 
re-escalate throughout  
the rest of treatment. 
 
* see Table 1 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 (see 
Section 4.3.2.9). 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.   
 

 
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4.3.2 Non-hematological Toxicity 
Dose reductions for non-hematologic toxicity that occur despite adequate background medical 
therapy should be undertaken in accordance with Table 4. Cisplatin is addressed in sections 
4.3.2.1, 4.3.2.2, and 4.3.2.7 
 
Table 4. Nab-paclitaxel and gemcitabine Dose Modifications for Day 1 of Each Cycle 
(Non-hematologic Toxicity)*  
Non Hematologic Toxicity and/or Dose Hold with Previous Cycle 
Toxicity/dose held 
nab-paclitaxel + gemcitabine dose this cycle 
Grade 0, 1 or 2 toxicity 
Same as Day 1 previous cycle (except for Grade 2 cutaneous toxicity where 
doses of nab-paclitaxel and gemcitabine should be reduced to next lower dose 
level: please refer to Section 4.3.2.3) 
Grade 3 toxicitya,c 
Decrease nab-paclitaxel and gemcitabine to next lower dose levela 
Grade 4 toxicityb 
Off protocol treatmentb 
Dose held in 2 previous 
consecutive cycles 
Decrease nab-paclitaxel and gemcitabine to next lower dose level and continue 
throughout the rest of treatment 
* Excluding peripheral neuropathy (section 4.3.2.1) and nephrotoxicity (section 4.3.2.2). 
a If the toxicity only affects neuropathy, then only nab-paclitaxel should be reduced (please see Section 4.3.2.1). 
b Pulmonary embolism (a Grade 4 toxicity in the CTCAE tables) if mild or asymptomatic, will be exempt from this 
requirement (please see Section 4.3.2.5). 
c Excluding electrolyte abnormalities per judgment of the physician/investigator. 
 
 
Table 5. Nab-paclitaxel and gemcitabine Dose Modifications Day 8 Each Cycle 
(Non-hematological Toxicity) 
CTC Grade 
Percent of Day 1 
nab-paclitaxel + gemcitabine Dose 
Grade 0-2  
100%a 
Grade 3+  
Hold treatment until resolution to ≤ Grade 1 b,c.  
a Except for cutaneous toxicity: refer to 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 4.3.2.5). 
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. 
4.3.2.1 Peripheral Neuropathy 
Cisplatin and nab-paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 
peripheral neuropathy. Gemcitabine administration can continue during this period. Cisplatin may 
be resumed at the same dose and nab-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.  
 
Patients experiencing peripheral neuropathy that requires a delay in scheduled cisplatin and nab-
paclitaxel dosing for ≥ 21 days will discontinue study treatment, will have the end of treatment 
procedures completed per Section 5.4, and will continue to be followed for survival per Section 
5.5.  
4.3.2.2 Nephrotoxicity 
Cisplatin (cisplatin injection) produces cumulative nephrotoxicity which is potentiated by 
aminoglycoside antibiotics (see Appendix D). The serum creatinine, BUN, creatinine clearance, 

 
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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. 
4.3.2.3 Cutaneous Toxicity 
Patients who develop Grade 2 or 3 cutaneous toxicity should have their nab-paclitaxel and 
gemcitabine dose reduced to the next lower dose level as per Table 1. 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.  
4.3.2.4 Gastrointestinal Toxicity 
If Grade 3 mucositis or diarrhea occurs, all 3 study drugs should be withheld until resolution to 
≤ Grade 1, then reinstituted at the next lower dose level as per Table 1. Patients who develop 
Grade 4 mucositis or diarrhea should have treatment discontinued.  
4.3.2.5 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. 
4.3.2.6 Interstitial Pneumonitis 
Pulmonary toxicity has been reported for both gemcitabine and paclitaxel. Epidemiology reports 
show that gemcitabine monotherapy is weakly associated with lung toxicity. A retrospective 
review (Meadors 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 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 paclitaxel shows a higher incidence of 
pneumonitis (4%) compared to either drug alone. This requires early detection and treatment as 
it may be life-threatening or even fatal.   
 
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 
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. 
 
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. 
 

 
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• 
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. 
4.3.2.7 Hypersensitivity Reactions 
Hypersensitivity reactions are not usually expected with cisplatin, nab-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. 
4.3.2.8 Prophylaxis use of Colony Stimulating Factors 
Based on the ASCO guidelines- Appendix G (Smith 2015) 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 of each treatment cycle. Neulasta 
OnPro® may be given on Day 8 if patient is not returning for Day 9 hydration.  
Filgrastim may be administered at the Investigator’s discretion, e.g. after day 1 in cycles 2 and 
beyond to prevent neutropenia on day 8.  
 
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. Patients not experiencing resolution of neutropenia within 
21 days, despite uninterrupted G-CSF treatment, will discontinue study treatment.  
4.3.2.9 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 7.2 of this protocol to report the 
event as a Serious Adverse Event (SAE). 
4.4 
Intended Dose Delays 
Intended cycles may be delayed for non-toxicity reasons for up to 7 days (for reasons such as 
scheduling conflicts), but only with documentation and explanation in the CRF.  Dosing on day 8 
will not be delayed beyond +1 day.  If an individual dosing day needs to be delayed beyond +1 
day, that particular dose is not to be administered and will be considered a missed dose. 

 
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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. No 
concomitant cytotoxic therapy, whether conventional or investigational, will be allowed during this 
study. All concomitant medications and supportive therapy must be recorded on the appropriate 
CRF.  
 
Radiotherapy is not allowed while the patient is enrolled in this study. 
 
Routine prophylactic use of a colony-stimulating factor (G-CSF) should be used according to 
the American Society of Clinical Oncology guidelines (Appendix G) and recorded in the EDC. 
 
Erythropoietin is permitted if clinically indicated.  
4.6 
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. 
 
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. 
 
5 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 for each investigational site. 
 
 
Prior to study enrollment, each patient will have the following assessments completed (see 
Appendix A). 
5.2 
Screening (Within 21 Days Prior to First Dose on C1/D1) 
1. Written informed consent to be obtained prior to any study specific screening procedures 
being performed.* 
 
2. Review inclusion/exclusion criteria 
 
3. Medical history including concurrent baseline conditions (using NCI CTCAE version 5.0; 
Appendix C), prior cancer therapy (including documentation of prior surgery, adjuvant or 
neoadjuvant chemotherapy and radiotherapy)* 
 
4. Complete physical examination including height (cm) and weight (kg)* 
 
5. Karnofsky Performance Status (KPS) (see Appendix B)* 

 
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6. Vital signs (blood pressure, pulse, respiratory rate, and temperature)* 
 
7. 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. 
(see RECIST 1.1 criteria in Section 6) 
 
8. Electrocardiogram (ECG)*  
 
9. Complete blood count (CBC) with differential and platelet count* 
 
10. Serum chemistries (for hepatic and renal function tests) including: blood urea nitrogen 
(BUN), phosphorus, magnesium, creatinine, creatinine clearance (the Cockcroft-Gault 
equation may be used to calculate the creatinine clearance at any of the time points in 
this protocol), total protein, albumin, calcium, glucose, total bilirubin, alkaline phosphatase 
(ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
electrolytes (chloride, sodium, potassium, and bicarbonate)* 
 
11. CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9)* 
 
12. PT/INR*  
 
13. Urinalysis (lab): protein, specific gravity, glucose, and blood* 
 
14. Serum pregnancy test (if applicable)  
 
15. Concomitant medication notation (to include all medications taken within 30 days prior to 
study enrollment) 
 
16. Patient to complete MDASI-GI and BPI questionnaires 
 
* These procedures, if done prior to obtaining consent as usual medical care, can be accepted as 
screening procedures if completed within 21 days prior to cycle 1, day 1. 
 
Once eligibility is confirmed by the Investigator, the site is to register the patient following the 
procedures outlined in Section 3.4. 
5.3 
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. All assessments should be performed preferentially on the same day of the study visit 
but may be performed within 1 day prior if medical or scheduling conditions require.     
5.3.1 Tissue Analysis  
Once eligibility is confirmed, and the patient is enrolled in the study, the study site is to obtain, if 
available, the archived paraffin block of tumor specimen, metastatic tumor sample is preferred, 
for tissue analysis as detailed in Section 1.9. Availability of archival tissue is not required for 
patient to be deemed eligible for enrollment into the study. 
 

 
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Additionally patients will be provided the option to consent to provide fresh frozen tissue samples 
from a newly obtained core or excisional biopsy if performed recently (within the last 30 days prior 
to Cycle 1/Day 1) and during their participation in the study should they be scheduled for a biopsy 
as part of their standard of care during treatment or at the time of disease progression. The patient 
should be consented with the tissue collection informed consent prior to the biopsy.  If the patient 
consents to this optional tissue collection, the fresh tissue sample should be collected per the 
instructions in the laboratory manual for tissue analysis as detailed in Section 1.9. 
 
Any samples remaining after the trial specified analyses are completed will be transferred to and 
stored at HonorHealth for future research purposes at HonorHealth’s discretion. This includes the 
original specimen collected from the patient tumor tissue, as well as derivatives created from the 
original specimen (DNA, RNA, blocks or slides). Documentation of the transfer of all specimens 
will be recorded on the Sample Transfer Form- refer to Trial Laboratory Manual 
5.3.2 Day 1 of each cycle  
All assessments should be performed preferentially on the same day of the study visit but may 
be performed within 1 day prior to study dose administration if medical or scheduling conditions 
require. 
 
• 
Inclusion/exclusion review (Cycle 1 only) 
 
• 
Medical history review (Cycle 1 only) 
 
• 
Directed physical exam  
 
• 
Vital Signs (blood pressure, pulse, respiratory rate, and temperature) to be collected prior 
to treatment. 
 
• 
Measurement of weight (kg) and BSA calculation prior to dosing (BSA will be calculated 
before each new cycle, based on the actual height and weight of the patient. After Cycle 
1, if there has been a > 10% weight change from baseline (Cycle 1 Day 1), the drug doses 
will be recalculated based on the new BSA value.) (See Section 4.2). 
 
• 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
• 
Hematology: CBC with differential and platelet count (see Section 5.2)   
 
• 
Serum chemistries (see Section 5.2)   
  
• 
CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9)  
 
• 
PT/INR required only If patient is on anticoagulation with warfarin. 
 
• 
Urinalysis (see Section 5.2)  
 
• 
Serum Pregnancy if applicable. Negative result must be confirmed prior to dosing.  
 
• 
AEs using the NCI CTCAE (see Appendix C) 
 
• 
Concomitant medication notation 
 
• 
Patient to complete MDASI-GI and BPI questionnaires 

 
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• 
Administration of triple therapy as per Section 4.1 
 
5.3.3 Day 8 of each cycle 
All assessments should be performed preferentially on the same day of the study visit but may 
be performed within 1 day prior to study dose administration if medical or scheduling conditions 
require. 
• 
Directed physical exam  
 
• 
Vital Signs (blood pressure, pulse, respiratory rate, and temperature) to be collected 
prior to treatment.  
 
• 
Measurement of weight (kg)  
 
• 
Karnofsky Performance Status (KPS) (see Appendix B)  
 
• 
Hematology: CBC with differential and platelet count  
 
• 
Serum chemistries (see Section 5.2)  
 
• 
AEs using the NCI CTCAE (see Appendix C) 
 
• 
Concomitant medication notation 
 
• 
Administration of triple therapy as per Section 4.1 
5.3.4 Day 15 of each cycle 
 
Cycle 1 day 15 clinic visit can be conducted by telemedicine (video teleconference or phone 
call). All assessments should be performed preferentially on the same day of the study visit but 
may be performed within 1 day prior if medical or scheduling conditions require. Lab tests on 
day 15 of each cycle can be done at a local lab if the patient is unable to visit the site. Lab 
results are to be available to the investigator within 1 day to allow evaluation of potential 
adverse events and patient safety. 
 
• 
Directed physical exam (not required on Day 15 of cycles 2+) 
 
• 
Vital Signs (blood pressure, pulse, respiratory rate, and temperature) to be collected 
prior to treatment. Note: not required on Day 15 of cycles 2+ 
 
• 
Karnofsky Performance Status (KPS) (see Appendix B) (not required on Day 15 of 
cycles 2+) 
 
• 
Hematology: CBC with differential and platelet count 
 
• 
Serum chemistries (see Section 5.2) 
 
• 
AEs using the NCI CTCAE (see Appendix C) 
 

 
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• 
Concomitant medication notation 
 
5.3.5 Tumor Assessments every three cycles (Prior to Cycles 4, 7, 10, etc.)  
 
• 
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. 
 
• 
Reassessment of the extent of tumor should be made by the same imaging methods 
used to establish baseline tumor measurements.  
5.4 
End of Treatment 
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 medication: 
 
• 
Directed physical exam, if deemed necessary 
 
• 
Measurement of weight (kg) 
 
• 
Karnofsky Performance Status (KPS) (see Appendix B) 
 
• 
Vital signs (see Section 5.2) 
 
• 
Hematology: CBC with differential and platelet count 
 
• 
Serum chemistries (see Section 5.2) 
 
• 
CA 19-9 (or CA 125, or CEA if not expressers of CA 19-9) 
 
• 
Urinalysis (see Section 5.2) 
 
• 
Serum pregnancy if applicable 
 
• 
Concomitant medication notation 
 
• 
CT/MRI scan to evaluate disease status (using same imaging method as Baseline) 
 
• 
AEs using the NCI CTCAE version 5.0 (see Appendix C) 
 
• 
Patient to complete MDASI-GI and BPI questionnaires 
 
• 
Confirm contact information for patient and a designated family member and remind 
patient of FU telephone contact that will be conducted monthly for survival status for 
up to 12 months from time of enrollment.  
5.5 
Follow-Up Assessments after End of Study or Early Termination 
Follow-up assessments for survival, in person or by telephone, will be conducted for all patients 
30 days after the End of Study or Early Termination Visit and then monthly for up to 12 months 

 
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from the time of enrollment. In the event that a patient cannot be reached during the follow-up 
period, a designated family member may be contacted.  
6 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 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 in 
the absence of previous documentation of objective tumor progression will be censored at the 
last date the patient was known to be progression-free in patients who do not have objective tumor 
progression and who are: 1) still on study at the time of an analysis; 2) are given anti-tumor 
treatment other than the study treatment; or 3) are removed from study follow-up prior to 
documentation of objective tumor progression. 
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 
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.  
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 
 

 
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6.7 
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. 
 
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. 
6.8 
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.  
 

 
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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. 
6.9 
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 of 
these lesions are not required, but the presence or absence of each should be noted throughout 
follow-up. 

 
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6.10 Response Criteria 
Table 6. RECIST 1.1 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; 
 
Non-target lesion response will be classified according to the RECIST Non-Target Lesion 
Response Criteria in the following table. 
 
Table 7. RECIST 1.1 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). 
 

 
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6.11 Evaluation of Best Overall Response 
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 8. 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 = inevaluable 
6.12 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively 
documented, taking as reference for PD the smallest measurements recorded since the treatment 
started.  
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. 
 
 

 
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7 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 5.0 (see  Appendix C).  
 
Investigators are required to document all AEs regardless of causality, observed during the study 
period, starting with initial dose of study drug through the 30 days after patient’s last dose of study 
drug, or until the beginning of a new anti-cancer therapy, whichever occurs first per section 7.9. 
 
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 (Sponsor/Celgene) within 
24 hours of knowledge of their occurrence.  
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 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. 
 
Progression of disease is considered an efficacy outcome parameter and should not be captured 
as an AE. 
 
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. 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. 
 
An abnormal laboratory value is considered to be an AE if the abnormality: 
 
• 
results in discontinuation from the study; 
 
• 
requires treatment, modification/ interruption of IP dose, or any other therapeutic 
intervention;  
 
• 
or is judged to be of significant clinical importance, e.g., one that indicates a new disease 
process and/or organ toxicity, or is an exacerbation or worsening of an existing condition. 

 
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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, except for the 
following: 
 
o A standard procedure for protocol therapy administration. However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 
 
o Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
 
o The administration of blood or platelet transfusion as routine treatment of studied 
Indication.  However, hospitalization or prolonged hospitalization for a complication 
of such transfusion remains a reportable SAE. 
 
o A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling).  However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE. 
 
o Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
 
o A procedure that is planned (i.e., planned prior to starting of treatment on study); 
must be documented in the source document and the CRF.  Hospitalization or 
prolonged hospitalization for a complication remains a reportable SAE. 
 
o An elective treatment of or an elective procedure for a pre-existing condition 
unrelated to the studied indication. 
 
Emergency outpatient treatment or observation that does not result in admission, unless fulfilling 
other seriousness criteria above. 
 
• 
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. 

 
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7.3 
Adverse Event Severity  
AE will be graded according to the NCI CTCAE, Version 5.0 (see Appendix C)  
 
• 
Grade 1 Mild AE 
 
• 
Grade 2 Moderate AE 
 
• 
Grade 3 Severe AE 
 
• 
Grade 4 Life-threatening or disabling AE 
 
• 
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 
Duration 
For both AEs and SAEs, the Investigator will provide a record of the start and stop dates of the 
event. 
7.5 
Action Taken 
The Investigator will report the action taken for each trial treatment (including nab-paclitaxel, 
cisplatin, and gemcitabine) as a result of an AE or SAE, as applicable (e.g., discontinuation, 
interruption, or dose reduction of specified study treatment, as appropriate) and report if 
concomitant and/or additional treatments were given for the event. 
7.6 
Outcome 
The Investigator will report the outcome of the event for both AEs and SAEs.  All SAEs that have 
not resolved upon discontinuation of the subject’s participation in the study must be followed until 
recovered (returned to baseline), recovered with sequelae, not recovered or death (due to the 
SAE). 
7.7 
Causality Assessment 
All adverse events regardless of CTCAE grade must also be evaluated for relationship (in regards 
to each study treatment including/ trial interventions). This is to be recorded for each study 
treatment including nab-paclitaxel, cisplatin, and gemcitabine. 
  
The determination of the likelihood that trial treatment caused the adverse event will be provided 
by an investigator.  The Investigator must determine the relationship between the administration 
of study treatment and the occurrence of an AE/SAE as Not Suspected or Suspected as defined 
below: 
 
 

 
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Relationship 
Attribution 
Not Suspected 
Not Related 
Unlikely 
Suspected 
Possibly 
Probably 
Definite 
 
Not suspected: Means a causal relationship of the adverse event to IP administration is unlikely 
or remote, or other medications, therapeutic interventions, or underlying conditions provide a 
sufficient explanation for the observed event. 
 
Suspected: Means there is a reasonable possibility that the administration of IP caused the 
adverse event. ‘Reasonable possibility’ means there is evidence to suggest a causal relationship 
between the IP and the adverse event. 
 
Causality should be assessed and provided for every AE/SAE based on currently available 
information. Causality is to be reassessed and provided as additional information becomes 
available. 
 
The Medical Monitor will make the final determination of relationship between the administration 
of study treatment and the occurence of the reported AEs/SAEs.  
7.8 
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? 
7.9 
Investigator Reporting Adverse Events 
The Investigator is responsible for recording and following all Grade ≥3 AEs, all grade neuropathy 
adverse events, any AE that leads to study treatment discontinuation and any AE that is 
associated with and contributing to an SAE as determined by the Investigator regardless of 
causality, observed during the study period, starting with initial dose of study drug through the 30 
days after patient’s last dose of study drug, or until the beginning of a new anti-cancer therapy, 
whichever occurs first. 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 permit 
participation in this protocol – this should be recorded as an AE (rather than a pre-treatment sign 
or symptom). 
 

 
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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.   
 
The Investigator must assess AE/SAE causality for any patients treated at his/her site. 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 baseline visit will be recorded as pre-
treatment signs and symptoms.  
 
For the purposes of this study, only the following adverse events are to be recorded in the 
eCRFs: 
• 
Grade ≥ 3 AEs 
• 
All grade neuropathy adverse events 
• 
Any AE that leads to study treatment discontinuation 
• 
Any AE that is associated with and contributing to an SAE as determined by the 
Investigator  
 
In addition, all SAEs must be reported promptly to both Triligent and Celgene 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 email or alternatively by phone or fax; 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 the Investigator must email or fax a completed SAE report form along with 
the SAE Report Form Cover letter to (Triligent and Celgene) within 1 business days. For an event 
that is not life-threatening or fatal, the Investigator must email a completed SAE report form within 
2 business days after he/she recognizes/classifies the event as an SAE.  
 
The Investigator should follow all AEs/SAEs observed during the study until the AE has subsided, 
or until the condition stabilizes (in the case of persistent impairment), the patient receives 
alternative therapy, or the patient dies. 
 
For any additional questions regarding reporting requirements of a SAE, please contact the 
Triligent Project Lead as listed in the study contact list.  
7.9.1 Expedited Reporting by Investigator to (Sponsor/Celgene) 
Serious adverse events (SAE) are defined above in Section 7.2.  
 
The investigator must inform both the Sponsor (via CRO, Triligent) and Celgene in writing using 
a MEDWATCH 3500A form of any SAE within 24 hours of being aware of the event.  The 
Medwatch 3500A form along with the SAE Report Form Cover letter must be completed and 
supplied to Triligent and Celgene by email within 24 hours.  The initial report must be as complete 
as possible, including an assessment of the causal relationship between the event and each trial 
treatment (including nab-paclitaxel, cisplatin, and gemcitabine). 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 MEDWATCH 3500A form.  A final report to 
document resolution of the SAE is required.  The Celgene tracking number AX-CL-PANC-PI-
13301 and the institutional protocol number should be included on SAE reports (or on the cover 
letter) sent to Triligent and Celgene.  A copy of email or the fax transmission confirmation of the 

 
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SAE report to Triligent and Celgene should be attached to the SAE and retained with the patient 
records. 
 
Note:  Participating study sites should NOT report SAEs to the FDA.  Celgene will be 
responsible for reporting to FDA. 
 
SAE Reporting to the Sponsor (via CRO, Triligent): 
Email: SAE@Triligent.com  
Fax: 949-203-6151 
Telephone: 317-402-9777 
 
Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
86 Morris Avenue 
Summit, New Jersey 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
Telephone: 1-908-673-9667 
Toll Free: 1-800-640-7854 
7.9.2 IRB Notification of SAEs 
The Investigator is responsible for promptly notifying the IRB of all SAEs, including any follow-up 
information per local IRB guidelines, occurring at his/her site and any SAE regulatory reports and 
Investigational New Drug Safety Reports that he/she receives from (Sponsor/Celgene). 
7.10 SAE Follow-Up 
For all SAEs occurring after first dose of study medication or within 30 days of the last 
administration of study medication, the investigator must submit follow-up reports to 
(Sponsor/Celgene) 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.  
7.10.1 Sponsor Notification of Post-Study SAEs 
The Investigator should notify (Sponsor/Celgene) of any death or SAE occurring after a patient 
has withdrawn from the study, or after 30 days of the last study drug dose, whichever is later, 
when such death or SAE may reasonably be related to the medication used in the study. However, 
Investigators are not obligated to actively seek AEs in former study participants. 
7.11 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 (Sponsor/CRO) within 24 hours of knowledge of the 
pregnancy.  
 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of age 
or disease state) of a female subject occurring while the subject is on study treatment, or within 
30 days of the subject’s last dose study treatment, are considered immediately reportable events.  

 
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Study treatment is to be discontinued immediately. The pregnancy, suspected pregnancy, or 
positive pregnancy test must be reported to HRI and Celgene Drug Safety immediately by 
facsimile, or other appropriate method, using the Pregnancy Initial Report Form, or approved 
equivalent form. The female subject may be referred to an obstetrician-gynecologist (not 
necessarily one with reproductive toxicity experience) or another appropriate healthcare 
professional for further evaluation. 
 
The Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or abnormal 
outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.  
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the 
Investigator should report the abnormal outcome as an AE.  If the abnormal outcome meets any 
of the serious criteria, it must be reported as an SAE to Celgene Drug Safety immediately by 
facsimile, or other appropriate method, within 24 hours of the Investigator’s knowledge of the 
event using the SAE Report Form, or approved equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form, or approved equivalent form. 
 
Male Subjects 
 
If a female partner of a male subject taking investigational product becomes pregnant, the male 
subject taking IP should notify the Investigator, and the pregnant female partner should be 
advised to call their healthcare provider immediately. Male patients treated with nab-paclitaxel 
are advised not to father a child during and up to 6 months after treatment. 
7.12 Overdose 
Overdose, as defined for this protocol, refers to nab-Paclitaxel, cisplatin and gemcitabine dosing.   
 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified 
dose of nab-paclitaxel, cisplatin or gemcitabine assigned to a given patient, regardless of any 
associated adverse events or sequelae. 
 
 IV   10% over the protocol-specified dose  
 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the 
protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-specified 
rate.  For nab-paclitaxel, an infusion completed in less than 25 minutes may increase Cmax by 
approximately 20%, therefore a nab-paclitaxel infusion completed in less than 25 minutes will 
meet the infusion rate criterion for an overdose. 
 
Complete data about drug administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.   
 
Any sequela of an accidental or intentional overdose of study treatment should be reported as an 
AE.  If the sequela of an overdose is an SAE, then the sequela must be reported on a Medwatch 

 
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3500A form and as an AE.  The overdose resulting in the SAE should be identified as the cause 
of the event on the Medwatch 3500A form and CRF but should not be reported as an SAE itself.  
 
In the event of overdose, the subject should be monitored as appropriate and should receive 
supportive measures as necessary. There is no known specific antidote for nab-paclitaxel, 
cisplatin or gemcitabine overdose. Actual treatment should depend on the severity of the clinical 
situation and the judgment and experience of the treating physician. 
 
Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
86 Morris Avenue 
Summit, New Jersey 07901 
Fax: (908) 673-9115 
E-mail: drugsafety@celgene.com 
Telephone: 1-908-673-9667 
Toll Free:    1-800-640-7854         
8 STATISTICAL CONSIDERATIONS 
8.1 
Trial Design 
This is a phase II open-label trial, with the identity of the treatment known to the patients, 
Investigators, Triligent and Sponsor.  
8.2 
Sample Size Considerations 
The a-priori alpha level for all statistical tests will be set at .025 (one-sided). Sample size is based 
on the phase III IMPACT trial (Von Hoff, 2013), demonstrating a 12-month OS of 35%, versus 12-
month OS of 67.5% in the PCRT 12-001 trial (Jameson, 2017). The historic control rate of 55% 
was selected to provide a conservative estimate of survival for the current study. To detect a 
difference between 35% and 55% 12-month OS rates with 80% power, hazard ratio of 0.57, and 
a one-sided 0.025 alpha-level, 42 patients are needed. To account for attrition, a total of 50 
patients will be enrolled in the investigation. 
 
A log--rank test will be used to test the null hypothesis that there is no difference between the 
conditions in the probability of an event: 
H0: δ ≤ 1 vs. H1:δ > 1 
8.3 
Statistical Analysis Plan 
8.3.1 Analysis of the Conduct of the Trial 
Enrollment, major protocol deviations, and discontinuations for the trial will be summarized using 
a CONSORT diagram. 
8.3.2 Patient Disposition 
A detailed description of patient disposition will include: 
 
• 
A summary of data on patient discontinuation from treatment. 
 
• 
A summary of data on overall qualification status of all patients. 

 
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• 
An account of all identified protocol deviations. 
 
All patients enrolled in the study will be included in the summation. An evaluable patient is any 
patient who has received even one dose of any of the study medications. The number of patients 
who do not qualify for analysis, who die or discontinue before treatment begins, will be specified.  
8.3.3 Analysis of 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. 
8.4 
Efficacy Analysis 
The efficacy analysis will include the following parameters: objective response rate (CR + PR), 
disease control rate (CR + PR + SD at 9 weeks), progression-free survival (PFS), stable disease 
rate at 9 weeks (SD), and overall survival (OS). The efficacy analysis will only be conducted on 
patients who have received at least one dose of cisplatin, nab-paclitaxel and 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 9 weeks.  
 
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. For the estimation of 
progression-free and overall survival a Kaplan-Meier analysis will be performed.  
 
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).  
 
Time-to-event endpoints, including PFS and OS will be assessed using the Kaplan-Meier method 
(Kaplan 1958). 
 
Objective response rates, clinical benefit response, and CA 19-9, will be summarized 
descriptively. 
 

 
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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. Logistic regression will be used to assess 
the impact of patient characteristics on response and toxicity rates. 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 will be used 
to evaluate multivariable predictive models of time-to-event outcomes. 
8.5 
Safety and Tolerance  Analysis 
All patients who receive any amount of cisplatin, nab-paclitaxel and gemcitabine will be included 
in the safety analyses. 
 
The incidence of all AEs (regardless of causality) and all treatment-related AEs (those AEs 
thought to be suspected related to study drug) will be summarized by NCI CTCAE version 5.0 
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. 
8.5.1 Stopping Rules 
The study will be stopped early based on either one of the following criteria being met: 
 
1. Treatment related deaths > 2 patients in the first 25 patients, as that is the number we 
observed in the original 25 patient study. 
 
2. Treatment related bleeding in the first 25 patients that is life threatening and/or fatal in > 1 
patient 
8.6 
Laboratory Assessments 
8.6.1 Hematology Parameters 
To investigate the maximal degree of myelosuppression, the NCI CTCAE version 5.0 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 5.0 hematology values of Grade 3 or 4 that 
occurred after the first dose of study drug will be presented. Data for patients with Grade 3 or 4 
hematology values will be listed. 
8.6.2 Clinical Chemistry 
Liver and renal function will be summarized using the NCI CTCAE version 5.0 for alkaline 
phosphatase, ALT, AST, total bilirubin, BUN and creatinine. The number and percentage of 
patients who have more than one NCI CTCAE version 5.0 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 5.0 chemistry values of Grade 3 or 4 that 
occurred after the first dose of study drug will be presented. Data for patients with Grade 3 or 4 
chemistry values will be listed. 
 

 
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8.6.3 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. 
8.7 
Replacement of Patients 
Patients who are enrolled into the study, but fail to receive nab-paclitaxel, cisplatin, and 
gemcitabine may be replaced. 
9 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
9.1 
Ethics 
9.1.1 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 
(Sponsor/CRO) prior to submission to the IRB. The Investigator will forward to (CRO 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 (CRO 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. 
9.1.2 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. 
9.1.3 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). 
 

 
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Changes made by a participating site to the recommended informed consent must be forwarded 
to HRI/Triligent 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.  
9.2 
Disclosure of Data 
9.2.1 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 HRI 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 HRI/ Triligent/Celgene and its designees for the purposes of regulatory 
submissions, study publications, and drug approval. 
9.2.2 Publication 
The Investigator(s) is obligated, consistent with academic standards and with due regard to the 
protection of Celgene or Triligent 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 Celgene.  Celgene shall 
complete its review within 30 days after receipt of the proposed publication or presentation. Upon 
Celgene request, proposed publication or presentation will be delayed up to 60 additional days to 
enable Celgene to secure adequate intellectual property protection of property of Celgene that 
would be affected by such proposed publication or presentation. If Celgene believes in good faith 
that any proposed publication or presentation contains any confidential information and/or 
intellectual property Celgene shall have the right to require HRI to remove the information.  HRI 
agrees and will consider all other comments of Celgene in good faith. 
9.2.3 Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible 
for determining whether the trial and its results are patient to the requirements for submission to 
the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow patients 
to identify potentially appropriate trials for their disease conditions and pursue participation by 

 
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calling a central contact number for further information on appropriate trial locations and trial site 
contact information.   
9.3 
 Quality Assurance 
9.3.1 Study Data Monitoring Plan  
Data monitoring procedures will be carried out by Triligent International 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 
training and delegation) and review of drug infusion records 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 Principal Investigator and Clinical Research Coordinator 
responsible for the study will be provided with a follow-up letter for resolution of the findings.  
 
The CRO site monitor will complete a written monitoring report and forward it to the HRI.  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 HRI/Triligent Administration 
and the Triligent 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 Triligent International for follow-
up at the next monitoring session. 
9.3.2 Data Safety and Monitoring 
This treatment regimen combines 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 the sponsor 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 the Sponsor 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 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 Sponsor will provide listings of 
toxicities on a regular basis. 
9.3.3 On-site Audits 
Regulatory authorities, the IEC/IRB, HRI and/or Triligent 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. 
9.4 
Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the Lead Principal Investigator or 
HRI there is sufficient reasonable cause.  

 
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HRI 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  
 
• 
Should the study be closed prematurely, all study materials must be returned to HRI. 
 
9.5 
 Investigator Documentation 
9.5.1 Form FDA 1572 
The Investigator must provide HRI with a fully executed Form FDA 1572. Any additions to the 
study must be provided via a new fully executed Form FDA 1572.  Others should follow FDA 
guidance “Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs”. 
 
9.5.2 Curriculum Vitae 
The Investigator must provide HRI 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. 
9.5.3 Investigator Protocol Agreement 
The Investigator must sign the Investigator’s Protocol Agreement. The original must be kept on 
file at the Investigator site and a copy provided to HRI/Triligent. 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 (Sponsor/CRO). 
9.5.4 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. 
9.5.5 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, and dates of certifications, and. Normal 
ranges for all laboratory tests will be included with all reported results.  Updated versions of these 
documents must be provided to HRI/Triligent as appropriate. In the event the clinical laboratory 

 
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is changed during the study HRI /Triligent will be promptly notified, and the Form FDA 1572 will 
be updated. Appropriate documentation will be submitted to HRI/Triligent to verify the certification 
of the new laboratory. 
 
All radiology facilities being utilized outside the investigative site must be pre-approved by HRI. 
9.5.6 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.  HRI will 
inform the Investigator of the time period for retaining these records in order to comply with 
applicable regulatory requirements. 
 
HRI 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. 
 
10 DATA MANAGEMENT 
10.1 Case Report Forms 
All the clinical data will be captured by the site on electronic case report forms (eCRFs).   The 
eCRFs will be used for all consented patients. The investigator and trained trial personnel will 
enter and edit the data via a secure network, with secure identification and password requirement.  
A complete electronic audit trial will be maintained.  The investigator will be required to provide 
approval of all data to confirm accuracy.   Copies of the eCRFs will be provided to the investigator 
at the conclusion of the trial.    
 
Triligent International will monitor the study to verify study data, medical records, and eCRFs in 
accordance with current ICH GCP guidelines as well as other applicable regulations and 
guidelines.  
10.2 Source Documents  
Source documents serve as the evidence of the existence of the patient and the data collected 
for this trial.  Source documents will be the responsibility of the Investigator and will be filed at the 
site and available as needed by the Sponsor, Triligent, or assigned clinical monitor. 
 
Data captured on the eCRFs is to be transcribed from source document and must be consistent 
with any discrepancies explained and documented. 
 
 
 

 
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APPENDIX A: SCHEDULE OF TREATMENT AND EVALUATIONS 
 
 
 
Screening 
Within  
21 Days 
Cycle 1 
Cycle 2+ 
Prior to  
Cycles 
4, 7, 10, etc. 
End  
of Study  
or Early 
Termination11 
Follow-up 
Assessment 
Day  
1 
Day  
2 
Day  
8 
Day  
9 
Day  
15 
Day  
1 
Day  
2 
Day  
8 
Day  
9 
Day  
15 
Window 
 
+7 
days2 
 
+ 1 
day2 
 
- 1 
day 
+7 
days2 
 
+ 1 
day2 
 
- 1 
day 
 
 
 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signed Optional Tissue 
Informed Consent 
X8 
 
Review inclusion/exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
 
 
X 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (kg) 
X 
X3 
 
X3 
 
 
X3 
 
X3 
 
 
 
X 
 
BSA calculation 
 
X3 
 
 
 
 
X3,4 
 
 
 
 
 
 
 
Vital signs 
X 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
 
 
X 
 
Karnofsky PS 
X 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
 
 
X 
 
CT/ MRI scan / tumor 
measurements5 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/differential & PLTs 
X 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
X3 
 
X 
 
Serum chemistries 6,14 
X 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
X3 
 
X 
 
PT/INR 
 X 
X3,17 
 
 
 
 
X3,17 
 
 
 
 
 
 
 
CA 19-9 (or CA 125, or 
CEA if not expressers of 
CA 19-9) 
X 
X3 
 
 
 
 
X3 
 
 
 
 
 
X 
 
Urinalysis7 
X 
X3 
 
 
 
 
X3 
 
 
 
 
 
X 
 
Fresh Tissue and/or 
Archived blocks of tumor8 
X8 
 
 
Serum pregnancy  
X 
X3 
 
 
 
 
X3 
 
 
 
 
 
X 
 
Concomitant medications9 
X 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
X3 
 
X 
 
Adverse events10 
 
X3 
 
X3 
 
X3 
X3 
 
X3 
 
X3 
 
X 
 
Contact Information 
Review 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Telephone follow-up12 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MDASI-GI and BPI 
Questionnaires 
x 
x3 
 
 
 
 
x3 
 
 
 
 
 
x 
 

 
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Screening 
Within  
21 Days 
Cycle 1 
Cycle 2+ 
Prior to  
Cycles 
4, 7, 10, etc. 
End  
of Study  
or Early 
Termination11 
Follow-up 
Assessment 
Day  
1 
Day  
2 
Day  
8 
Day  
9 
Day  
15 
Day  
1 
Day  
2 
Day  
8 
Day  
9 
Day  
15 
Window 
 
+7 
Days2 
 
+ 1 
day 
- 
- 1 
day 
+7 
days2 
 
 
 
- 1 
day 
 
 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
Nab-pacilitaxel13 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Cisplatin13 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Gemcitabine13 
 
X 
 
X 
 
 
X 
 
X 
 
 
 
 
 
Post Chemotherapy 
Hydration 15 
 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
 
 
Pegfilgrastim 16 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Schedule of Events footnotes: 
1. To include concurrent baseline conditions (using NCI CTCAE, version 5.0), prior cancer therapy 
(including documentation of prior surgery, adjuvant or neoadjuvant chemotherapy and 
radiotherapy). 
 
2. Intended cycles may be delayed for non-toxicity reasons for up to 7 days (for reasons such as 
scheduling conflicts), but only with documentation and explanation in the CRF.  Dosing on day 8 
will not be delayed beyond + 1 day. Individual dosing days will not be delayed.  If an individual 
dosing day needs to be delayed beyond +1 day, that particular dose is not to be administered and 
will be considered a missed dose. 
3. All assessments should be performed preferentially on the same day of the study visit but may be 
performed within 1 day prior to study dose administration (on Days 1 and 8) if medical or 
scheduling conditions require. 
4. BSA only needs to be changed if there has been a change >10% in body weight from Cycle 1-Day 
1 (See Section 4.2). 
5. Computed tomography (CT) / magnetic resonance imaging (MRI) scan to document disease status 
(including chest, abdomen, pelvis, and other regions as clinically indicated.  In addition, a 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 within 5 days of starting chemotherapy. 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 6). Follow-up 
scans are due every 3 cycles (prior to cycle 4, 7, 10) 
6. 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). 
7. Lab urinalysis to include protein, specific gravity, glucose, and blood. 
8. Archived paraffin block of tumor specimen, metastatic tumor sample preferred.  If patient is 
scheduled to undergo a tumor biopsy for standard of care purposes at any time, they should be 
consented with the Optional Tissue Collection and Storage Informed Consent Form. 
9. To include all medications taken within 30 days prior to study enrollment. 
10. Patients will be followed for all Grade ≥3 AEs, all grade neuropathy adverse events, any AE that 
leads to study treatment discontinuation and any AE that is associated with and contributing to an 

 
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SAE as determined by the Investigator regardless of causality, observed during the study period, 
starting with initial dose of study drug through the 30 days after patient’s last dose of study drug, or 
until the beginning of a new anti-cancer therapy, whichever occurs first. 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. 
11. End of Study or Early Termination assessments can be completed 14-28 (+/- 2) days from the last 
dose of study medication.  
12. Follow-up assessments for survival in person or by telephone will be conducted in all patients 30 
days after the End of Study or Early Termination Visit and then monthly for up to 12 months from 
the time of enrollment. 
13. The sequence of drug administration is nab-paclitaxel, then cisplatin, then gemcitabine.  Post 
cisplatin hydration: IV fluids up to 1000 mL (with additives as clinically indicated) IV given as 
infusion on days cisplatin is administered on days 1 and 8 repeated every 21 days. May start at the 
same time as the gemcitabine infusion. Volume may be reduced to 500 ml at the Investigator’s 
discretion.  
14. The Cockcroft-Gault equation may be used in calculating the creatinine clearance at any of the 
time points in this protocol. 
15. Post cisplatin hydration: IV fluids up to 1000 mL (with additives as clinically indicated) IV given as 
infusion on days cisplatin is administered on days 1 and 8 repeated every 21 days. May start at the 
same time as the gemcitabine infusion.  Additional post-cisplatin hydration of 1 liter of IV fluids on days 
2 & 9 required for Cycles 1-3. Volume may be reduced to 500 ml at the Investigator’s discretion.  Note: 
If the cisplatin is held in any cycle, the additional hydration on day of chemotherapy or day after would 
not be needed. 
16. Pegfilgrastim will be administered subcutaneously on day 9 of each treatment cycle. Neulasta 
OnPro® may be given on Day 8 if patient is not returning for Day 9 hydration.  
17. PT/INR  required only If patient is on anticoagulation with warfarin. 

 
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APPENDIX B: KARNOFSKY PERFORMANCE STATUS 
 

 
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APPENDIX C: REVISED NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI CTCAE), 
VERSION 5.0 (PUBLISHED 27 NOVEMBER 2017) 
The National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0 can be viewed on-line at the 
following NCI web site: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf    
 

 
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APPENDIX D: DRUG STUDY DRUG PREPARATION, DOSING, 
ADMINISTRATION AND STORAGE 
See links below to website access 
Nab paclitaxel (Abraxane™) Prescribing Information (Updated 8/2020) – Accessed via 
Abraxane Website: https://media.celgene.com/content/uploads/abraxane-pi.pdf 
Cisplatin Prescribing Information (Updated 06/01/2015) – 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 5/2019) – Accessed via Gemzar 
Website: http://pi.lilly.com/us/gemzar.pdf 
 

 
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APPENDIX E:  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 F:  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 G:  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 post 
remission 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 post remission 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.  
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, 

 
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Setting/Indication 
Recommendation 
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.