Conditions: Pancreatic Neoplasms Digestive System Neoplasms Neoplasms by Site Neoplasms Endocrine Gland Neoplasms Pancreatic Diseases Digestive System Diseases Endocrine System Diseases Gemcitabine Antimetabolites, Antineoplastic
Keywords: Resectable pancreatic cancer resected resectable PDA adenocarcinoma surgically resected adjuvant Abraxane nab-paclitaxel ABI-007 gemcitabine Gemzar Phase 3
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 866
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare whether there is a delay or prevention of recurrence or death in participants with surgically removed pancreatic cancer who then take nab-Paclitaxel in combination with gemcitabine compared to those who take gemcitabine alone.

Detailed description:
ABI-007-PANC-003 is a Phase 3, international, multicenter, randomized, open-label, controlled study that will compare the efficacy of nab-paclitaxel in combination with gemcitabine to gemcitabine alone as adjuvant treatment for 6 cycles in patients with surgically resected pancreatic adenocarcinoma.

Arms:
arm 1: Participants received nab-Paclitaxel 125 mg/m\^2 administered as an intravenous (IV) infusion over 30 to 40 minutes, followed by gemcitabine 1000 mg/m\^2 as an IV infusion over 30 to 40 minutes on Days 1, 8 and 15 of each 28-day treatment cycle for 6 cycles, unless there was evidence of radiologic disease recurrence, unacceptable toxicity, subject or physician decision, withdrawal of consent, or death. arm 2: Participants received gemcitabine 1000 mg/m\^2 administered as an IV infusion over 30 to 40 minutes on Days 1, 8 and 15 of each 28-day treatment cycle for 6 cycles, unless there was evidence of radiologic disease recurrence, unacceptable toxicity, subject or physician decision, withdrawal of consent, or death.

Interventions: intervention 1: nab-Paclitaxel intervention 2: Gemcitabine
Intervention descriptions: intervention 1: nab-Paclitaxel 125 mg/m\^2 on Days 1, 8, and 15 of every 28 day treatment cycle by intravenous (IV) administration for a total of 6 cycles. intervention 2: Gemcitabine 1000 mg/m\^2 on Days 1, 8, and 15 of a 28 day cycle by IV administration for a total of 6 cycles.

Protocol document:
Prot_002.pdf: 
Official Title of Study: 
A Phase 3, Multicenter, Open-label, Randomized Study of nab-Paclitaxel Plus Gemcitabine 
Versus Gemcitabine Alone as Adjuvant Therapy in Subjects With Surgically Resected 
Pancreatic Adenocarcinoma 
 
PROTOCOL(S) ABI-007-PANC-003 
 
NCT Number: NCT01964430 
  
Document Date (Date in which document was last revised): September 3, 2019 


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
1
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
TITLE PAGE
A PHASE 3, MULTICENTER, OPEN-LABEL, 
RANDOMIZED STUDY OF nab®-PACLITAXEL PLUS 
GEMCITABINE VERSUS GEMCITABINE ALONE AS
ADJUVANT THERAPY IN SUBJECTS WITH 
SURGICALLY RESECTED PANCREATIC 
ADENOCARCINOMA
INVESTIGATIONAL PRODUCT (IP):
nab-Paclitaxel
PROTOCOL NUMBER:
ABI-007-PANC-003
DATE FINAL:
06 Sep 2013
AMENDMENT No. 1 Date:
23 Jun 2014
AMENDMENT No. 2 Date:
03 Dec 2015
AMENDMENT No. 3 Date:
21 Dec 2016
AMENDMENT No. 4 Date:
12 Sep 2018
AMENDMENT No. 5 Date
03 Sep 2019
EudraCT NUMBER:
2013-003398-91
IND NUMBER:
115027
SPONSOR NAME / ADDRESS:
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
CONFIDENTIAL
This protocol is provided to you as an investigator, potential investigator, or consultant for review by 
you, your staff, and ethics committee/institutional review board.  The information contained in this 
document is regarded as confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by law or regulations.  
Persons to whom the information is disclosed must be informed that the information is confidential 
and may not be further disclosed by them.
                                               
nab® is a registered trademark of Abraxis Bioscience, LLC
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
2
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:
Title:
Address: Celgene Corporation, 86 Morris Avenue Summit, NJ 07901
Phone:
E-mail:
Note: The back-up 24 hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24 Hour Global Emergency Contact Call Center: 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
CELGENE THERAPEUTIC AREA HEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature of Celgene Therapeutic Area Head
dd mmm yyyy
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.  
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
4
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
dd mmm yyyy
Printed Name of Site Principal Investigator
Institution Name: _______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Ethics Committee (EC) procedures, instructions from 
Celgene representatives, the Declaration of Helsinki, ICH Good Clinical Practices 
Guidelines, and local regulations governing the conduct of clinical studies.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
5
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
COORDINATING PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Coordinating Principal Investigator
dd mmm yyyy
Printed Name of Coordinating Principal Investigator
Institution Name: _______________________________________
By my signature, I agree the protocol has been written to comply with ICH Good 
Clinical Practices guidelines and agree to offer guidance throughout the study as 
needed.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
6
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Open-label, Randomized Study of nab-Paclitaxel Plus Gemcitabine 
Versus Gemcitabine Alone as Adjuvant Therapy in Subjects With Surgically Resected 
Pancreatic Adenocarcinoma
Indication
nab-Paclitaxel, in combination with gemcitabine, is indicated as adjuvant treatment in subjects
with pancreatic adenocarcinoma following complete macroscopic surgical resection with no 
prior radiotherapy or neo-adjuvant chemotherapy.
Objectives
Primary Objective

To compare disease-free survival (DFS) between subjects randomized to nab-
paclitaxel in combination with gemcitabine and subjects randomized to gemcitabine 
alone
Secondary Objectives

To assess overall survival (OS) between subjects randomized to nab-paclitaxel in 
combination with gemcitabine and subjects randomized to gemcitabine alone

To assess safety and tolerability of the 2 treatment regimens
Exploratory Objectives

To assess tumor molecular heterogeneity and associate identified tumor molecular 
subtypes with clinical outcome

To investigate whether circulating tumor nucleic acids are associated with disease
recurrence

To evaluate the effect of nab-paclitaxel in combination with gemcitabine and 
gemcitabine alone on subject’s quality of life (QoL)
Study Design
This is a Phase 3, international, multicenter, randomized, open-label, controlled study to assess 
the efficacy of nab-paclitaxel in combination with gemcitabine (Arm A) compared with 
gemcitabine alone (Arm B) as adjuvant treatment for 6 cycles. Subjects will be assigned to 
treatments by a stratified randomization with 1:1 ratio.
The stratification factors will include:

Resection Status: R0 (tumor-free margin) versus R1 (microscopically positive 
margin)

Nodal Status: lymph node (LN)+ versus LN-

Region (North America, Europe and Australia versus Asia Pacific)
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
7
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
Study Population
The study will enroll adult male and female subjects with confirmed resected pancreatic 
adenocarcinoma with macroscopic complete resection (R0 and R1) and no evidence of 
metastases.  Subjects will consent for study participation postresection, however, subjects should
be randomized to the study as early as adequately recovered from surgery, but no later than 12 
weeks postsurgery.  Subjects must have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1 at screening, ie, ≤14 days prior to randomization, and must have 
had no prior neo-adjuvant treatment or radiation therapy for pancreatic adenocarcinoma.
Length of Study
Enrollment is expected to take approximately 30 months and approximately 9 additional months 
of follow-up.  
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary, and/or exploratory analysis, as pre-specified in the protocol.
Study Treatments
Arm A will receive nab-paclitaxel 125 mg/m2 administered IV followed by gemcitabine
1000 mg/m2 given intravenously (IV) weekly on Days 1, 8, and 15 of a 28-day cycle for a total 
of 6 cycles.
Arm B will receive gemcitabine 1000 mg/m2 administered IV weekly on Days 1, 8, and 15 of a 
28-day cycle for a total of 6 cycles.
Dose interruptions, and up to 2 dose reductions to 100 mg/m2 and 75 mg/m2 for nab-paclitaxel
and 800 mg/m2 and 600 mg/m2 for gemcitabine, are allowed.
Overview of Efficacy Assessments
Subjects will be assessed by computed tomography (CT) scan performed within 14 days prior to 
randomization (during the screening period), every 8 weeks for the first 24 weeks after 
randomization, then every 12 weeks for the next 2.5 years (130 weeks) until 3 years after 
randomization, and then every 24 weeks thereafter until disease recurrence for the next 2.5 years
(130 weeks) up to 5.5 years after randomization. Magnetic resonance imaging (MRI) can be used 
based on the investigator’s judgment or institution policy, as long as the same modality is used 
throughout the study. Subjects who are discontinued from treatment prior to completing the 6 
cycles of treatment in the absence of disease recurrence (eg, subjects discontinued for 
unacceptable toxicity or subject/investigator discretion) should undergo repeat imaging until 
disease recurrence, death, or the start of new anticancer therapy is documented.
During the study, DFS will be determined by independent radiologist(s) who are blinded to the 
treatment assignment. The independent radiologic review will follow a separate imaging charter.
Imaging assessments for disease recurrence will be stopped after the number of events for the 
primary endpoint have been achieved and after the final analysis of DFS by independent 
radiology.  At this point, any ongoing subjects who have not had disease recurrence should 
follow local standard of care for any additional imaging assessments.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
8
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
Subjects will be followed for survival every 12 weeks from end of treatment, or more frequently 
as needed, until death, withdrawal of consent, or the study closes, whichever is the earliest. This 
evaluation may be made by record review and/or telephone contact.
Overview of Safety Assessments
Safety and tolerability will be monitored through continuous reporting of adverse events (AEs), 
AEs of special interest (identified based on previous experience in a similar population, 
including such AEs as myelosuppression, pneumonitis, and sepsis), laboratory abnormalities, and 
incidence of subjects experiencing dose modifications, dose delay/dose not given, dose 
interruptions, and/or premature discontinuation of IP due to an AE. All AEs will be recorded by 
the investigator from the time the subject signs informed consent until 28 days after the last dose 
of IP and those serious adverse events (SAEs) made known to the investigator at any time 
thereafter that are suspected of being related to IP. 
Physical examination (source documented only), vital signs, laboratory assessments (eg, serum 
chemistry, hematology), peripheral neuropathy and ECOG performance status will be monitored.
All SAEs (regardless of relationship to IP) will be followed until resolution. Laboratory analysis 
will be performed as per study schedule.
Overview of Statistical Methods
This Phase 3 randomized study is designed to compare the DFS of nab-paclitaxel plus 
gemcitabine versus gemcitabine alone as adjuvant therapy in subjects with resected pancreatic 
adenocarcinoma.  A permuted-block randomization method and an Interactive Randomization 
Technology (IRT) will be used to carry out a central randomization. One interim analysis for 
safety is planned after the first 100 subjects have completed 2 cycles of treatment, and 1 interim 
analysis on efficacy is planned after observing 163 DFS events to assess futility. A second 
interim analysis on efficacy had been planned for futility and superiority after observing 70% 
DFS events or enrollment of 800 subjects, whichever was later. However, at the time of Protocol 
Amendment 3, the interim analysis for futility at 163 DFS events has been performed and no 
subjects are receiving further investigational product (IP). To avoid premature interruption of the 
trial, and to ensure that the study has sufficient duration of follow-up to verify clinical benefit 
and assess benefit-risk in this setting, this second interim analysis has been removed from the 
study. An independent Data Monitoring Committee (DMC) will be established to review the 
interim safety and efficacy data.
Efficacy Analyses:
The primary efficacy endpoint is DFS, which is defined as the time from the date of 
randomization to the date of disease recurrence or death, whichever is earlier. Disease recurrence 
will be determined by the independent radiological review of CT (or MRI) scans.  The survival 
distribution of DFS will be estimated using the Kaplan-Meier method; medians and two-sided 
95% confidence intervals (CIs) will be provided by treatment arms. The comparison of DFS 
between the 2 arms will be conducted using a stratified log-rank test, with the stratification 
factors of resection status (R0 versus R1), nodal status (LN+ versus LN-) and region, and p-
values will be provided. The associated hazard ratios (HRs) and two-sided 95% CIs will be 
provided using the stratified Cox proportional hazard model. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
9
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
The secondary efficacy endpoint will be OS, which is defined as the time from the date of 
randomization to the date of death. Subjects who are alive will be censored on the last-known-to-
be-alive date. The survival distribution of OS will be estimated using the Kaplan-Meier method;
medians and two-sided 95% CIs will be provided by treatment arms.  The survival rates at 
different time points will be provided. P-values based stratified log-rank test will be provided. 
The associated HRs and two-sided 95% CIs will be provided using the Cox proportional hazard 
model.
Safety Analyses:
The treated population, which includes all randomized subjects who received at least 1 dose of 
IP, will be the analysis population for all safety analyses.  Adverse events will be analyzed in 
terms of treatment-emergent adverse events (TEAE), defined as any event that begins or worsens 
in grade after the start of the IP through 28 days after the last dose of the IP.  All events will be 
coded using Medical Dictionary for Regulatory Activities (MedDRA).  Treatment-emergent 
adverse events will be summarized per treatment arms by MedDRA system organ class and
preferred terms. Grade 3 or higher TEAEs, SAEs, TEAEs leading to dose reduction, and dose 
interruption, and TEAEs leading to treatment discontinuation, and TEAEs with an outcome of 
death will be summarized per treatment arms by MedDRA system organ class and preferred 
terms. Additionally, adverse events of special interest of the nab-paclitaxel plus gemcitabine 
combination will be summarized in the same manner.
In order to investigate the maximal degree of myelosuppression, the National Cancer Institute
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grade for absolute 
neutrophil count (ANC), white blood cell count (WBC), platelet count, and hemoglobin will be 
summarized for each treatment group by the most severe grade in each treatment cycle and by 
the most severe grade at any time during the treatment.  Hepatic and renal function will be 
summarized for each treatment group using the most severe NCI CTCAE grade for alanine 
aminotransferase (ALT/SGPT), aspartate transaminase (AST/SGOT), total bilirubin, and 
creatinine by cycle during the study and at any time during the treatment.
Sample Size
The primary objective is to compare DFS in subjects who received nab-paclitaxel in combination 
with gemcitabine and subjects who received gemcitabine alone. 
The hypotheses are the following: 
H0: HRA+G/G = 1
versus 
H1: HRA+G/G ≠1
where HR A+G/G is the hazard ratio between the nab-paclitaxel in combination with gemcitabine 
arm and the gemcitabine alone arm. 
With the assumption of the true median DFS of 13.5 months in the gemcitabine arm and 18.5
months in the nab-paclitaxel in combination with gemcitabine arm, which is equivalent to an
HRA+G/G of 0.73, approximately 438 DFS events from 800 subjects are required to allow 90% 
power to detect a 27% reduction of risk in disease recurrence or death from the treatment arm at 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
10
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
a two-sided significance level of 0.05. One interim analysis on efficacy is planned at about 33% 
information time to assess the futility.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
11
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
1.
INTRODUCTION..................................................................................................17
1.1.
Pancreatic Cancer ...................................................................................................17
1.2.
Treatment for Resectable Pancreatic Cancer ...........................................................17
1.3.
nab-Paclitaxel (ABRAXANE)................................................................................19
1.3.1.
Preclinical and Clinical Experience with nab-Paclitaxel Plus Gemcitabine in 
Pancreatic Cancer ...................................................................................................20
1.4.
Study Rationale ......................................................................................................22
1.4.1.
Rationale for Stratification Factors .........................................................................23
2.
STUDY OBJECTIVES...........................................................................................24
2.1.
Primary Objective...................................................................................................24
2.2.
Secondary Objectives .............................................................................................24
2.3.
Exploratory Objectives ...........................................................................................24
3.
STUDY ENDPOINTS............................................................................................25
3.1.
Primary Endpoint....................................................................................................25
3.2.
Secondary Endpoint(s)............................................................................................25
3.3.
Exploratory Endpoint(s)..........................................................................................25
4.
OVERALL STUDY DESIGN ................................................................................26
4.1.
Study Design ..........................................................................................................26
4.2.
Study Duration .......................................................................................................28
4.3.
End of Trial ............................................................................................................28
5.
TABLE OF EVENTS.............................................................................................29
6.
PROCEDURES......................................................................................................32
6.1.
Central Laboratory and Central Imaging .................................................................32
6.2.
Screening Evaluations.............................................................................................32
6.3.
Randomization and Treatment Phase Evaluations ...................................................33
6.3.1.
Day 1 Assessments .................................................................................................34
6.3.2.
Per Cycle Evaluations.............................................................................................34
6.3.3.
Assessment of Disease Recurrence .........................................................................34
6.4.
End of Treatment (EOT) Evaluations......................................................................35
6.5.
Follow-up Period (for Disease Recurrence).............................................................36
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
12
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
6.6.
Follow-up Period for Overall Survival and Anticancer Therapy..............................37
6.7.
Biomarker and Pharmacogenomic Testing..............................................................37
7.
STUDY POPULATION.........................................................................................39
7.1.
Number of Subjects and Sites .................................................................................39
7.2.
Inclusion Criteria....................................................................................................39
7.3.
Exclusion Criteria...................................................................................................40
8.
DESCRIPTION OF STUDY TREATMENTS........................................................42
8.1.
Description of Investigational Products...................................................................42
8.1.1.
ABRAXANE (nab-Paclitaxel)................................................................................42
8.1.2.
Gemcitabine ...........................................................................................................42
8.2.
Treatment Administration and Schedule .................................................................42
8.2.1.
Rules for Dose Omissions and Modified Schedules ................................................43
8.2.1.1.
Dose Modification Tables.......................................................................................44
8.2.2.
Overdose ................................................................................................................48
8.3.
Method of Treatment Assignment...........................................................................48
8.4.
Packaging and Labeling..........................................................................................48
8.5.
Investigational Product Accountability and Disposal ..............................................48
8.6.
Investigational Product Compliance........................................................................49
9.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................50
9.1.
Permitted Concomitant Medications and Procedures...............................................50
9.2.
Prohibited Concomitant Medications and Procedures..............................................50
9.3.
Required Concomitant Medications and Procedures................................................50
10.
STATISTICAL ANALYSES..................................................................................51
10.1.
Overview................................................................................................................51
10.2.
Study Population Definitions ..................................................................................51
10.2.1.
Intent-to-treat Population........................................................................................51
10.2.2.
Treated Population..................................................................................................51
10.2.3.
Per-Protocol Population..........................................................................................51
10.3.
Sample Size and Power Considerations...................................................................51
10.4.
Background and Demographic Characteristics........................................................53
10.5.
Subject Disposition.................................................................................................53
10.6.
Efficacy Analysis....................................................................................................53
10.6.1.
Primary Efficacy Analyses......................................................................................53
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
13
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
10.6.2.
Secondary Efficacy Analyses..................................................................................54
10.7.
Safety Analysis.......................................................................................................54
10.7.1.
Adverse Events.......................................................................................................54
10.7.2.
Laboratory Results..................................................................................................54
10.8.
Interim Analysis .....................................................................................................54
10.9.
Other Topics...........................................................................................................55
10.9.1.
Data Monitoring Committee ...................................................................................55
10.9.2.
Steering Committee ................................................................................................55
10.10.
Exploratory Analyses..............................................................................................55
10.10.1.
Tumor Markers.......................................................................................................55
10.10.2.
Quality of Life........................................................................................................55
11.
ADVERSE EVENTS..............................................................................................56
11.1.
Monitoring, Recording, and Reporting of Adverse Events ......................................56
11.2.
Evaluation of Adverse Events.................................................................................56
11.2.1.
Seriousness.............................................................................................................56
11.2.2.
Severity / Intensity..................................................................................................57
11.2.3.
Causality ................................................................................................................58
11.2.4.
Duration .................................................................................................................59
11.2.5.
Action Taken..........................................................................................................59
11.2.6.
Outcome.................................................................................................................59
11.3.
Abnormal Laboratory Values..................................................................................59
11.4.
Pregnancy...............................................................................................................59
11.4.1.
Females of Childbearing Potential: .........................................................................59
11.4.2.
Male Subjects.........................................................................................................60
11.5.
Reporting of Serious Adverse Events......................................................................60
11.5.1.
Safety Queries ........................................................................................................61
11.6.
Expedited Reporting of Adverse Events..................................................................61
12.
DISCONTINUATIONS .........................................................................................62
12.1.
Discontinuation from Investigational Product .........................................................62
12.2.
Discontinuation from the Study ..............................................................................62
13.
EMERGENCY PROCEDURES.............................................................................63
13.1.
Emergency Contact.................................................................................................63
14.
REGULATORY CONSIDERATIONS...................................................................64
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
14
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
14.1.
Good Clinical Practice............................................................................................64
14.2.
Investigator Responsibilities ...................................................................................64
14.3.
Subject Information and Informed Consent.............................................................64
14.4.
Confidentiality........................................................................................................65
14.5.
Protocol Amendments.............................................................................................65
14.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................65
14.7.
Ongoing Information for Institutional Review Board / Ethics Committee................66
14.8.
Closure of the Study ...............................................................................................66
15.
DATA HANDLING AND RECORDKEEPING.....................................................67
15.1.
Data/Documents .....................................................................................................67
15.2.
Data Management...................................................................................................67
15.3.
Record Retention....................................................................................................67
16.
QUALITY CONTROL AND QUALITY ASSURANCE........................................69
16.1.
Study Monitoring and Source Data Verification......................................................69
16.2.
Audits and Inspections............................................................................................69
17.
PUBLICATIONS ...................................................................................................70
18.
REFERENCES.......................................................................................................71
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
15
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
LIST OF TABLES
Table 1:
Disease-free Survival and Overall Survival in Randomized Controlled 
Studies of Adjuvant Chemotherapy in Pancreatic Cancer........................................18
Table 2:
Relapse-free Survival and Overall Survival in JASPAC-01a ...................................19
Table 3:
Table of Events.......................................................................................................29
Table 4:
Dose Modifications.................................................................................................44
Table 5:
Dose Recommendation and Modifications for Neutropenia and/or 
Thrombocytopenia at the Start of a Cycle or Within a Cycle...................................45
Table 6:
Dose Modifications for Other Adverse Drug Reactions...........................................46
Table 7:
Power Calculation for Overall Survival with N = 800 .............................................53
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
16
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................27
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
17
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
1.
INTRODUCTION 
1.1.
Pancreatic Cancer
Worldwide, pancreatic cancer is the thirteenth most common cancer, with 278,684 new cases 
diagnosed in 2008.  The prognosis is poor, and as a result, pancreatic cancer is the eighth leading 
cause of cancer-related death worldwide, with an estimated 266,669 deaths in 2008 (CancerStats,
2011).  Pancreatic cancer is the fourth leading cause of cancer-related death in the United States 
(US), with an estimated 38,460 deaths from the disease and an estimated 45,220 new cases 
expected in 2013 (Siegel, 2013).  The incidence of pancreatic cancer is higher in men than 
women and increases with age, with 90% of pancreatic cancer presenting in subjects over the age 
of 55 years and more than 70% presenting over the age of 65 years (Howlader, 2013).  In 
Europe, pancreatic cancer is the fourth leading cause of cancer-related death with 80,266 deaths 
predicted in 2013 (Malvezzi, 2013).  Forecasts from the United Nations, World Population 
Prospects, GLOBOCAN 2008 data for cancer incidence and mortality predicted that the
incidence of new cases of pancreatic cancer in the European Union (EU) to be 77,241 cases by 
2015 (Ferlay, 2010).  As in the US, the pancreatic cancer incidence in the EU is higher in men 
than women (Seufferlein, 2012), and incidence also increases with age.
The pancreas is composed of two main cell types: exocrine (cells that produce digestive 
enzymes) and endocrine (cells of the islets of Langerhans, that produce among others the 
hormones insulin and glucagon).  Exocrine tumors are by far the most common type of 
pancreatic cancer, with adenocarcinoma accounting for about 95% of cancers of the exocrine 
pancreas (ACS, 2013).  The focus of the proposed indication is pancreatic adenocarcinoma.
Initial staging classifies pancreatic cancers as resectable, borderline resectable, locally advanced, 
and metastatic (NCCN, 2013).  In the case of resectable disease, the entire tumor can be 
surgically removed with curative intent, whereas for both locally advanced and metastatic 
disease, surgery may not be an option because the tumor cannot be completely removed and 
surgery would only be conducted to relieve symptoms (Seufferlein, 2012).  Most patients (80%
to 85%) have unresectable disease at the time of diagnosis (Corbo, 2012). For all stages of 
pancreatic cancer combined, the 5-year OS rate is about 6%, which is the lowest 5-year OS rate 
of any cancer in the US (Siegel, 2013). At less than 10% survival at 5 years reported within 
Europe, pancreatic cancer is one of the most fatal cancers (Berrino, 2007).
1.2.
Treatment for Resectable Pancreatic Cancer
Surgical resection, using procedures such as pancreaticoduodenectomy (Whipple procedure) or 
total pancreatectomy, offers patients an improved chance of long-term survival, especially with 
advances in perioperative and postoperative care. In patients able to undergo a successful 
curative resection, median OS ranges from 17 to 20 months, and the 5-year OS rate is 9% to 14% 
(Neoptolemos, 2009; Neuhaus, 2008; Oettle, 2007). 
In general, results of meta-analyses suggest that adjuvant chemotherapy with either fluorouracil
(5-FU) and folinic acid, or gemcitabine is efficacious (Boeck, 2007; Stocken, 2005). A formal 
comparison of gemcitabine and 5-FU plus folinic acid found no substantive difference in terms 
of DFS or OS. However, gemcitabine treatment was associated with less toxic side effects 
compared with bolus fluorouracil (Neoptolemos, 2010). Adjuvant chemotherapy with either 
gemcitabine or fluorouracil, using the Mayo Clinic bolus fluorouracil schedule improved the 5-
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
18
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
year survival rate from ~10% to ~20% in patients (Neoptolemos, 2004; Oettle, 2007; Seufferlein, 
2012).
Meta-analyses and randomized controlled studies showed evidence that adjuvant chemotherapy 
after surgery improves both survival rates and DFS in patients with pancreatic cancer (Table 1
and Table 2) (Boeck, 2007; Neoptolemos, 2001a; Neoptolemos, 2004; Oettle, 2007; Stocken, 
2005):
Table 1:
Disease-free Survival and Overall Survival in Randomized Controlled 
Studies of Adjuvant Chemotherapy in Pancreatic Cancer
Parameter
Study
Chemotherapy
No Chemotherapy
Significance
Median DFS
(months)
CONKO-001a
13.4 (95% CI = 11.4 - 15.3)
6.9 (95% CI = 6.1 - 7.8)
p < 0.001
ESPAC -1b
15.3 (95% CI = 10.5 – 19.2) 9.4 (95% CI = 8.4 – 15.2)
p = 0.02
JSAP -02c
11.4
5.0
p = 0.01, HR = 0.60
(95% CI = 0.40–
0.89)
Median OS 
(months)
CONKO-001d
22.8
20.2
p = 0.005
ESPAC -1b
20.1 (95% CI = 6.5-22.7)
15.5 (95% CI = 13.0 –
17.7)
p = 0.009, HR = 0.71
JSAP -02c
22.3
18.4
p = 0.19, HR = 0.77
(95% CI = 0.51-1.14)
OS at
2 years
CONKO-001a
47%
42%
NA
ESPAC -1b
40%
30%
NA
JSAP -02c
48.3%
40%
NA
Abbreviations: CI = confidence interval; CONKO = Charité Onkologie; DFS = disease-free survival; ESPAC = 
European Study Group for Pancreatic Cancer; HR = hazard ratio; NA = not available; OS = overall survival; JSAP
= Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer.
a Oettle, 2007 – treatment: 6 cycles of gemcitabine, primary endpoint: DFS.
b Neoptolemos, 2004 – treatment: 6 cycles of 5-FU/Leucovorin, primary endpoint: OS.
c Ueno 2009 – treatment: 3 cycles of gemcitabine, primary endpoint: OS.
d Neuhaus, 2008 – updated data for median OS; initial data from Oettle, 2007 indicated chemotherapy median OS of 
22.1 months (95% CI, 18.4-25.8) and nonchemotherapy median OS of 20.2 months (95% CI, 17-23.4), p = 0.06.
A meta-analysis of 875 patients showed a 25% significant reduction in the risk of death with 
chemotherapy versus surgery alone, and the 5-year survival rate almost doubled with the use of 
adjuvant chemotherapy compared with no chemotherapy (Stocken, 2005). Another analysis of 
951 patients enrolled in randomized studies showed a significant survival benefit for median 
survival after adjuvant chemotherapy, but not for the 5-year survival rate (Boeck, 2007). This 
analysis also provided evidence that adjuvant therapy substantially prolonged DFS along with 
improving OS (Boeck, 2007).
Although there is no European- or US-approved medicine for adjuvant treatment of pancreatic 
adenocarcinoma, standard pancreatic adenocarcinoma treatment guidelines provided by National 
Comprehensive Cancer Network (NCCN) are followed in the US and China (NCCN, 2013), 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
19
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
while in Europe, guidance on standard of care for treatment of subjects with pancreatic cancer is 
provided by the European Society for Medical Oncology (ESMO) (Seufferlein, 2012).
The NCCN guidelines recommend 6 treatment options for the postoperative adjuvant setting. 
Enrollment into a clinical study is the first recommended treatment option, followed by either 
gemcitabine or fluorouracil/leucovorin before or after chemoradiation, and then chemotherapy 
alone with gemcitabine or fluorouracil/leucovorin, and lastly, capecitabine (NCCN, 2013). 
The ESMO guidelines (Seufferlein, 2012) recommend 6 months of gemcitabine or fluorouracil 
given postoperatively based on the results of three randomized studies (Neoptolemos, 2004;
Neoptolemos, 2010; Oettle, 2007). Since there is no evidence of any advantage of adjuvant 
chemoradiation as compared to adjuvant chemotherapy alone, the ESMO guidelines recommend 
that chemoradiation in the adjuvant or additive setting should only be performed within 
randomized, controlled clinical studies. 
In early 2013, data from a study conducted in Japan (JASPAC-01) revealed significant 
improvements in 2-year relapse-free survival (RFS) and OS rates with a new investigative 
product, S-1, a combination of tegafur (an oral fluoropyrimidine), gimeracil, and oteracil 
potassium, versus gemcitabine (Table 2; Uesaka, 2013). S-1 was originally developed as a 
gastric cancer treatment in Japan where it is used as a standard of care since its initial approval 
there in 1999. S-1 is not approved for use as adjuvant therapy in patients with surgically resected 
pancreatic adenocarcinoma, and the study was limited to only Japanese patients. The appropriate 
dose and efficacy is not established in non-Asian patients.
Table 2:
Relapse-free Survival and Overall Survival in JASPAC-01a
Parameter
Gemcitabine
S-1b
Significance
Median RFS 
(months)
11.2 months
(95% CI = 9.7-13.5)
23.2 months
(95% CI = 17.5-32)
p < 0.0001, HR = 0.56
(95% CI = 0.43 to 0.71)
Median OS (months)
25.9 months
Not matured
p < 0.0001, HR = 0.56
(98.8% CI = 0.36 to 0.87)
OS at 2 years
53%
(95% CI = 46-60)
70%
(95% CI = 63-76)
NA
Abbreviations: CI = confidence interval; HR = hazard ratio; JASPAC = Japan Adjuvant Study Group of Pancreatic 
Cancer; NA = not available; OS = overall survival; RFS = relapse-free survival.
a Uesaka, 2013 – primary endpoint: OS.
b S-1: tegafur, gimeracil, and oteracil potassium.
At the interim analysis, moderate improvement in survival in resectable pancreatic cancer was 
achieved with adjuvant chemotherapy, with median OS of 20 to 24 months and 21% to 24% 5-
year OS rates (Seufferlein, 2012).  More efficacious treatment options are needed.
1.3.
nab-Paclitaxel (ABRAXANE)
nab-Paclitaxel (interchangeable with ABRAXANE and ABI-007) is a unique protein formulation 
of a noncrystalline, amorphous form of paclitaxel in an insoluble particle state. nab-Paclitaxel 
was designed to improve the chemotherapeutic effects of paclitaxel by exploiting endogenous 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
20
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
transport pathways to deliver higher doses of paclitaxel to the tumor and to reduce the solvent-
related hypersensitivity and other toxicities associated with Taxol® (paclitaxel) injections, the 
solvent Cremophor EL, and ethanol vehicle. nab-Paclitaxel provides more rapid tissue 
distribution and increased tumor accumulation compared to Cremophor-EL paclitaxel (Desai 
2006, Gardner 2008, Chen 2014).  Mechanistically, albumin receptor-mediated transport across 
the endothelium, binding to interstitial proteins, and macropinocytic or receptor-mediated uptake 
into tumor cells as well as sequestration of paclitaxel by Cremophor-EL may contribute to the 
observed differences.  Furthermore, nab-paclitaxel synergizes with gemcitabine in preclinical 
models. The Cremophor-EL-free medium enables nab-paclitaxel to be given at a higher dose and 
in a shorter duration without the need for premedication to prevent solvent-related 
hypersensitivity reactions (Desai, 2006).
As of March 2014, nab-paclitaxel is approved under the trade name of ABRAXANE in over 45
countries/regions, including the US, Canada, India, European Union/European Economic Area, 
South Korea, China, Australia, Bhutan, United Arab Emirates, Nepal, New Zealand, Japan, 
Russia, Sri Lanka, Argentina, Hong Kong, and Lebanon for the treatment of patients with 
metastatic breast cancer. ABRAXANE is also approved for the first-line treatment of locally 
advanced or metastatic non small cell lung cancer (NSCLC) in the US, Japan, Argentina, 
Australia, and New Zealand, for treatment of advanced gastric cancer in Japan, and for first-line 
treatment of metastatic adenocarcinoma of the pancreas in the US, EU/EEA, Australia, New 
Zealand and Argentina. nab-Paclitaxel alone and in combination is being evaluated as 
chemotherapeutic agent for the treatment of patients with various solid tumor malignancies. 
Please refer to the Investigator’s Brochure for more detail on and concerning the available 
preclinical, pharmacology, toxicology, drug metabolism, clinical study data, and AE profile of 
nab-paclitaxel.
1.3.1.
Preclinical and Clinical Experience with nab-Paclitaxel Plus Gemcitabine in 
Pancreatic Cancer 
Preclinical studies have demonstrated that nab-paclitaxel may play a role in sensitizing the tumor 
to chemotherapeutic agents and specifically increases the antitumor efficacy when combined 
with gemcitabine.  While the mechanism of action for the synergy is unclear, preclinical studies 
have generated hypothetical models.  One hypothesis is a remodeling and weakening of the 
stroma barrier, allowing the chemotherapeutic agents to have better access to the tumor cells. 
Weakening the tumor-stroma barrier is particularly important in cancer that is characterized by 
dense stroma, such as pancreatic cancer. In mice with primary patient derived pancreatic tumor
xenografts, nab-paclitaxel plus gemcitabine versus gemcitabine alone resulted in increased tumor 
regression and depleted the desmoplastic stroma as observed by the less dense, disorganized, 
wisps of collagen type 1 fibers after 4 weeks of treatment (Von Hoff, 2011). In this study, the 
intratumoral concentration of gemcitabine was increased by 2.8-fold after 5 days of treatment 
when nab-paclitaxel was added to gemcitabine. It was hypothesized that nab-paclitaxel may play 
a role in reducing the dense stroma and may have contributed to the increased intratumoral 
gemcitabine uptake. Additional preclinical studies in a genetically engineered mouse model of 
pancreatic adenocarcinoma, coadministration of nab-paclitaxel and gemcitabine also 
demonstrated tumor regression and increased intratumoral gemcitabine levels after 8 days of 
treatment.  Apoptosis of tumor epithelial cells were observed; however, there were no changes in 
stromal components or collagen density in this short term treatment model (Frese, 2012). The 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
21
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
increased intratumoral gemcitabine levels were attributed to a marked decrease in the primary 
gemcitabine metabolizing enzyme, cytidine deaminase, by nab-paclitaxel. Finally, a recent
clinical study in subjects with resectable pancreatic cancer treated with neoadjuvant nab-
paclitaxel plus gemcitabine showed reduction in fibrotic collagenous stroma, further supporting a 
stroma active mechanism for nab-paclitaxel (Alvarez, 2013).
In a clinical Phase 1/2 dose ranging study (CA040, NCT003980860), nab-paclitaxel plus 
gemcitabine antitumor activity and tolerability were established in patients who had no prior 
treatment for metastatic pancreatic cancer (Von Hoff, 2011). The maximum tolerated dose and 
recommended dose for further studies was determined to be 125 mg/m2 nab-paclitaxel in 
combination with 1000 mg/m2 gemcitabine. 
In the subsequent randomized international Phase 3 study (MPACT, CA046, NCT00394251) 
that enrolled 861 patients with metastatic pancreatic cancer, nab-paclitaxel in combination with 
gemcitabine exhibited a clinically meaningful, statistically significant improvement in OS and 
progression-free survival (PFS). The median OS (primary endpoint) in the intent-to-treat 
population was 8.5 months (95% CI = 7.89-9.53) with nab-paclitaxel/gemcitabine compared 
with 6.7 months (95 % CI = 6.01-7.23) with gemcitabine, p < 0.0001, HR = 0.72 (95% CI = 
0.617-0.835). Long-term survival was improved in the nab-paclitaxel/gemcitabine arm versus 
gemcitabine alone, with a 59% increase at 1 year (35% versus 22%) and doubling at 2 years (9% 
versus 4%). The secondary (PFS, overall response rate [ORR]) and all other efficacy endpoints
showed consistent, statistically significant improvements with nab-paclitaxel/gemcitabine, 
supporting the results from the primary analysis of OS. Specifically, PFS (by independent 
review) was 5.5 months (95% CI = 4.47-5.95) versus 3.7 months (95% CI = 3.61-4.04) in the 
nab-paclitaxel/gemcitabine arm versus gemcitabine alone arms, respectively p < 0.0001; HR =0
.69; 95% CI = 0.581-0.821). The improvement in PFS corresponded to a 31% reduction in the 
risk of progression or death with nab-paclitaxel/gemcitabine. Furthermore, in this study of 
metastatic unresectable adenocarcinoma of the pancreas, subjects in the combination arm were 
on therapy longer than those receiving single agent gemcitabine, indicating disease improvement 
and tolerable treatment (Von Hoff, 2013). The suitability of the dosing regimen was confirmed 
by the observation that the majority of patients did not require a dose reduction, and that 71% of 
nab-paclitaxel doses were delivered at the starting dose of 125 mg/m2. The safety profile for both 
regimens was consistent with previous reports. Serious life threatening toxicities were not 
increased; AEs were acceptable and manageable. The most notable differences in toxicity 
between the 2 treatment arms was peripheral neuropathy, which was cumulative and rapidly 
reversible with dose delay and reduction, and neutropenia, which was manageable with dose 
delays and dose reductions. The incremental risks of sepsis and pneumonitis were managed by 
protocol amendments to increase awareness, and for early diagnosis and treatment to reduce the 
risk of fatal outcomes.
Since the above described initial analysis of the MPACT study, the updated OS with a cutoff of 
May 2013 showed that the benefit continued to improve with nab-paclitaxel in combination with 
gemcitabine, with 8.7 versus 6.6 median months, respectively (Goldstein, ASCO GI 2014). The 
updated survival rates also significantly favored nab-paclitaxel plus gemcitabine at year 1 (35% 
versus 22%), year 2 (10% versus 5%), and year 3 (4% versus 0%) as compared with gemcitabine 
alone.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
22
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
To date, the only other trial that resulted in clinically meaningful improvement in OS in 
pancreatic adenocarcinoma was the Phase 2/3 FOLFIRINOX versus gemcitabine study, which 
was conducted in 1 country (Conroy, 2011).  While numerous promising Phase 2 studies have 
been conducted in advanced pancreatic cancer, most subsequent large Phase 3 studies have failed 
to show significant improved survival (Colucci, 2010; Cunningham, 2009; Kindler, 2010; Oettle,
2005; Philip, 2010; Poplin, 2009; Rocha Lima, 2004). 
As a result of the clinically meaningful benefit observed in the MPACT trial, the 2013 NCCN 
guidelines were updated to include nab-paclitaxel plus gemcitabine under treatment option 
category 1 for patients with metastatic pancreatic adenocarcinoma (NCCN, 2013).
1.4.
Study Rationale
Currently no adjuvant chemotherapy regimen for pancreatic adenocarcinoma can claim 
superiority and the approaches to treatment differ only slightly between the US and the EU 
(Herreros-Villanueva, 2012). Despite the noted improvements of chemotherapy following 
surgery, recurrence rates are still high and survival rates poor, and there remains a high unmet 
medical need for more effective adjuvant therapies.
The positive results from the global pivotal Phase 3 Study CA046 with nab-paclitaxel plus 
gemcitabine in the metastatic setting form the basis for the evaluation of this combination in the 
adjuvant therapy setting. 
Gemcitabine is proposed as the active comparator in this study as it is considered a standard 
chemotherapy for the treatment of subjects with surgically resected pancreatic adenocarcinoma 
and is one of the recommended treatments in the NCCN guidelines and a recommended 
treatment of choice by ESMO guidelines (NCCN, 2013; Seufferlein, 2012).
The goal of adjuvant treatment is to cure or induce a longer disease-free period (versus a shorter 
disease-free period requiring early and possibly longer symptom control), thus the primary 
measurement of a disease-free state is clinically relevant. This was paramount when selecting the 
endpoint of the proposed adjuvant study. Selecting DFS as an endpoint is most appropriate in 
settings, as in pancreatic cancer, where it is predicted that disease recurrence represents a major 
component of morbidity and mortality in the treated population (Gill, 2006). Using OS as a 
primary endpoint in the adjuvant setting presents a major challenge, with confounding factors,
such as the subsequent anticancer therapies after disease recurrence which would impact the OS 
results.
The evidence obtained from studies of other cancer types with established adjuvant therapy 
supports the use of DFS as a valid and reliable measure of clinical benefit. From both a patient’s 
and physician’s perspective, the prevention or delay of pancreatic cancer recurrence and 
associated improved survival is meaningful. 
DFS and OS were highly correlated in more than 20,000 patients with resected high-risk colon 
cancer treated in Phase 3 adjuvant clinical studies, both within subjects and across studies 
(Sargent, 2005). A recent meta-analysis of more than 7,000 subjects from 25 clinical studies 
provided evidence that DFS is a valid surrogate endpoint for OS in operable NSCLC in the 
adjuvant chemotherapy setting (Michiels, 2011). In this meta-analysis, a high level of correlation 
was seen between DFS and improvement in OS.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
23
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
As detailed in Section 1.3, in published studies of adjuvant chemotherapy in subjects with 
surgically resected pancreatic cancer, the results suggest that prolonged DFS was associated with 
survival benefit in these subjects. 
Although there can be challenges with using DFS as the primary endpoint in a clinical study, 
these can be overcome as demonstrated by the studies that have supported registration of the 
medicinal products described above. This protocol proposes to address these known challenges 
with DFS in the proposed adjuvant study by implementing the following:

Ensure the symmetrical disease evaluation and assessment between the two treatment 
arms

Mitigate assessment bias from the investigator assessment through the use of an 
independent blinded radiology review

Include clearly defined censoring rules in the statistical plan to address the impact of 
missing or unscheduled visits.
Based on the improvement in survival with nab-paclitaxel in combination with gemcitabine in 
subjects with metastatic pancreatic cancer (Von Hoff, 2013), nab-paclitaxel plus gemcitabine 
adjuvant therapy may extend DFS compared with gemcitabine alone and provide a meaningful 
clinical benefit in subjects with surgically resectable pancreatic adenocarcinoma.
1.4.1.
Rationale for Stratification Factors
Subjects are proposed to be stratified at randomization based on:

Resection Status: R0 versus R1

Nodal Status: LN+ versus LN-

Region (North America, Europe, and Australia versus Asia Pacific)
The resection status and nodal status are known prognostic factors in pancreatic cancer and have 
been selected based on their use in a previous successful Phase 3 study of adjuvant therapy in 
subjects with resected pancreatic cancer (Oettle, 2007), as well as previous reports describing the 
prognostic relationship between these factors and survival. In the CONKO-001 study, LN-
versus LN+ categories were associated with longer survival (Oettle, 2007). Lymph node invasion 
also showed a statistically significant correlation with early relapse in a small retrospective 
analysis of patients with resected pancreatic cancer (Fischer, 2012). Because of the possible 
regional differences in this global study, randomization will be stratified by region as well. 
One of the main pathologic predictors of survival after surgery is resection margin status. 
Resection of margin-positive (R1) pancreatic tumors have poorer prognosis than R0. Results 
from the ESPAC-1 study showed that both R1 and R0 patients benefit from both resection and 
adjuvant chemotherapy, but not chemoradiation; however, the magnitude of benefit for 
chemotherapy treatment was reduced for patients with R1 margins versus those with R0 margins 
(Neoptolemos, 2001b). 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
24
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
2.
STUDY OBJECTIVES
2.1.
Primary Objective
The primary objective of the study is to compare DFS between subjects randomized to nab-
paclitaxel in combination with gemcitabine and subjects randomized to gemcitabine alone.
2.2.
Secondary Objectives
The secondary objectives of the study are to:

Assess OS between subjects randomized to nab-paclitaxel in combination with 
gemcitabine and subjects randomized to gemcitabine alone

Evaluate safety and tolerability
2.3.
Exploratory Objectives
The exploratory objectives of the study are to:

Assess tumor molecular heterogeneity and associate identified tumor molecular 
subtypes with clinical outcome

Investigate whether circulating nucleic acids are associated with disease recurrence

Evaluate the effect of nab-paclitaxel in combination with gemcitabine and 
gemcitabine alone on subject quality of life (QoL)
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
25
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
3.
STUDY ENDPOINTS
3.1.
Primary Endpoint
The primary endpoint of the study is independently assessed DFS, determined by an independent
radiologist(s) who is blinded to the treatment assignment, which is defined as the time from the 
date of randomization to the date of disease recurrence or death, whichever is earlier.
3.2.
Secondary Endpoint(s)
The secondary endpoints of the study are: 

OS, which is defined as the time from the date of randomization to the date of death

The incidence of TEAEs, SAEs, laboratory abnormalities and other safety parameters
3.3.
Exploratory Endpoint(s)
The exploratory endpoints of the study are:

Molecular profiling of tumor tissue

Identification of tumor nucleic acids from blood

Differences in outcomes between the European Organization for Research and 
Treatment of Cancer (EORTC) quality of life questionnaires (QLQ), EORTC QLQ-
C30 and QLQ-PAN26, during and after treatment versus at baseline
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
26
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
4.
OVERALL STUDY DESIGN
4.1.
Study Design
This is a Phase 3, international, multicenter, randomized, open-label, controlled study assessing
the efficacy of nab-paclitaxel in combination with gemcitabine versus gemcitabine alone as 
adjuvant therapy in adult subjects with surgically resected pancreatic adenocarcinoma. See 
Figure 1 for Overall Study Design.
Subjects will be screened and if eligible, randomized 1:1 to receive:
Arm A - nab-Paclitaxel 125 mg/m2, IV infusion over 30 to 40 minutes, followed by 
gemcitabine 1000 mg/m2 IV infusion over 30 to 40 minutes, given once weekly for 3 weeks 
(Days 1, 8 and 15) followed by a week of rest (28-day cycle) for 6 cycles
or 
Arm B - Gemcitabine 1000 mg/m2, IV infusion over 30 to 40 minutes, given weekly for 3 
weeks (Days 1, 8 and 15) followed by a week of rest (28-day cycle) for 6 cycles.
Subjects will be administered 6 cycles of treatment, unless there is evidence of radiologic disease 
recurrence, unacceptable toxicity, subject or physician decision, withdrawal of consent, or death.  
Subjects will be assessed by CT scan at screening (≤14 days prior to randomization), at the 
schedule specified in Section 6.3.3. Magnetic resonance imaging can be used based on the 
investigator’s judgment or institution policy, as long as the same modality is used through-out 
the study. Imaging assessments for disease recurrence should be continued until after the final 
analysis of DFS, at which point, any ongoing subjects who have not had disease recurrence 
should follow local standard of care for any additional imaging assessments. All subjects will 
also be followed for survival. The initiation and the types of new anticancer therapies will be 
collected.
The study will enroll approximately 800 subjects.  Randomization will be stratified between
treatment arms by:

Resection Status: R0 (tumor-free margin) versus R1 (microscopically positive 
margin)

Nodal Status: LN+ versus LN-

Region (North America, Europe, and Australia versus Asia Pacific)
A DMC (Section 10.9.1) and a Steering Committee (SC) (Section 10.9.2) will be assembled to 
assess the ongoing conduct of this study.
There will be 2 interim analyses conducted during the course of the study, as described in 
Section 10.8.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
27
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
Figure 1:
Overall Study Design
Collect tumor and normal tissues
and blood samples
Randomization to the study should
occur as early as the subject is adequately
recovered from surgery, up to a
maximum of 12 weeks
Randomization 1:1
N=800
Arm A
nab-Paclitaxel
+
Gemcitabine
End of Treatment
Treat for 6 cycles unless discontinued early for 
evidence of radiologic disease recurrence, death, 
unacceptable toxicity, subject/physician decision, or 
withdrawal of consent.
Follow-Up
Safety until 28 days post treatment.
Radiologic evaluation until disease recurrence, 
new cancer therapy, or death, whichever is 
earlier, for up to 5 years.
For survival up until death or the study closes.
Screening
Eligibility Check
Arm B
Gemcitabine
alone
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
28
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
4.2.
Study Duration
Eligible subjects should be randomized to the study as early as adequately recovered from
surgery, but no later than 12 weeks postsurgery.  Study treatment should start within 3 days of 
randomization. Enrollment is expected to take approximately 30 months, and approximately 9 
months of follow-up is needed to observe the required number of DFS events.
4.3.
End of Trial
The End of Trial is defined as either the date of the last visit of the last subject to complete the 
study, or the date of receipt of the last data point from the last subject that is required for 
primary, secondary and/or exploratory analysis, as prespecified in the protocol.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
29
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
5.
TABLE OF EVENTS
Table 3:
Table of Events
Assessment
a
Screening
b
Cycle 1 through Cycle 6
(Treatment Period)
End of Treatment 
(EOT) Visitd
Follow-up 
Period
Day 1
c
Day 8
Day 15
Informed Consent
X
Randomization
Xe
Demographics
X
Medical History
X
Physical Examination
X
X
X
Height and Weight
X
Xf
Xf
Urinalysis
X
BSA Calculationg
X
Prior/Concomitant Medication Evaluation
X
X
X
X
Until 28 days after 
the last dose of IP
Prior/Concurrent Procedures Evaluation
X
X
X
X
Until 28 days after 
the last dose of IP
Peripheral Neuropathy Evaluation
X
X
X
Vital Signsh
X
X
X
X
X
ECOG PS
X
X
X
X
X
Pregnancy Testi
X
X
ECG (12 lead)
X
Clinical Chemistry Panel
X
X
X
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
30
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Table 3:
Table of Events (Continued)
Assessment
a
Screeningb
Cycle 1 through Cycle 6
(Treatment Period)
End of Treatment 
(EOT) Visitd
Follow-up 
Period
Day 1c
Day 8
Day 15
CBC, Differential, Platelet Count
X
X
X
X
X
PT, PTT, INR
X
Collect mandatory surgical primary pancreatic tumor 
sample j
X
Collect mandatory surgical normal (duodenum or 
other) sample 
X
Biomarker blood sample n
X
Upon disease recurrence at any time during treatment or follow-up period, until
the number of events for the primary endpoint is achieved sample must be 
collected prior to the start of new therapy
Collect tumor sample from biopsy k, n
Upon disease recurrence, if available, and until the number of events for the 
primary endpoint is achieved
CT /MRI Scan n
X

8 weeks after randomization for the first 24 weeks

then every 12 weeks for the next 2.5 years (130 weeks) until 3 years after 
randomization

then every 24 weeks thereafter until disease recurrence for the next 2.5 years 
Serum CA19-9 n
X
Same schedule, or on the same week, as CT/MRI
Quality of Life n
X
Cycle 4 day 1 only
X
Xl
Treatment Arm A: nab-Paclitaxel/Gemcitabine Arm 
X
X
X
Treatment Arm B: Gemcitabine-only Arm
X
X
X
Adverse Events
Continuous starting from signing of Informed Consent until 28 days after last dose of IP
Follow-up for Survival and Anticancer Therapym
X
Abbreviations:  AE = adverse event; BSA = body surface area; β-hCG = beta-human chorionic gonadotropin; CA19-9 = carbohydrate antigen 19-9; CBC = complete blood count; 
CT = computed tomography; ECG – electrocardiogram; EOT = end of treatment; MRI = magnetic resonance imaging; ECOG PS= Eastern Cooperative Oncology Group 
performance status; INR= International Normalized Ratio; PT = prothrombin time; PTT = partial thromboplastin time.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
31
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
a Unless otherwise specified, visits must occur within ± 2 days of the planned visit date.
b Screening evaluations to be obtained ≤14 days prior to randomization. 
c Cycle 1 Day 1 evaluations can be omitted if screening evaluations are performed within 72 hours of Cycle 1 Day 1.
d For subjects who complete 6 cycles of treatment, the EOT visit should be performed as soon as possible after end of Cycle 6 (ie, after Cycle 6 Day 28), but no later than 14 days 
after Cycle 6 Day 28. For subjects who discontinue treatment prior to completing 6 cycles of treatment, the EOT visit should be performed as soon as possible after the decision 
is made to discontinue treatment.
e Randomization to occur within 72 hours of planned Cycle 1 Day 1.
f Weight only.
g Body Surface Area calculations to be performed Cycle 1 Day 1 and recalculated per the site’s standard of care, or when body weight changes by more than 10%. 
h Vital signs include temperature, systolic and diastolic blood pressure, and pulse.
i For females of childbearing potential only.  A serum β-hCG pregnancy test must be performed to assess subject eligibility at screening prior to first IP administration (negative 
results required for IP administration).  Urine pregnancy test will be performed at EOT (can be done locally) and as clinically indicated as per institutional guidelines.
j Samples will be collected any time prior to first IP administration, but after informed consent is signed. It is mandatory for patients to provide surgical samples, if they are 
available and local regulations allow it. FFPE tumor blocks are preferred.  Normal surgical sample (ie, duodenum, negative margin) will be collected for molecular marker 
analysis.
k Biopsy surgical sample: FFPE tumor tissue from biopsy will be collected (tumor blocks are preferred – refer to Laboratory Manual for details). Ensure the surgical pathology 
report is submitted with tumor tissue sample
l Quality of Life questionnaires (EORTC QLQ-C30 and QLQ-PAN26) will be collected prior to dosing. During the follow-up period, follow the same schedule, or on the same 
week, when a CT or MRI is performed until disease recurrence.  The QLQ-PAN26 questionnaire will not be collected in Finland, Portugal and Singapore.
m Follow-up for survival and subsequent anticancer therapy can be performed by telephone contact every 3 months or more frequently if needed, from EOT.
n All the procedures during the follow-up period, except for the follow up for survival and anticancer therapy, will be terminated once the number of events for the primary 
endpoint is achieved.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
32
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
6.
PROCEDURES
6.1.
Central Laboratory and Central Imaging
Central imaging and a Clinical Laboratory Improvement Amendments (CLIA) approved central 
laboratory will be used for laboratory testing. 
Sites will be required to use the designated central lab(s) for the study. Central labs must be 
drawn for all eligibility assessments, but subjects may be randomized based on local lab results
only if the central lab results are not readily available to permit randomization and dosing.  The 
local lab results should be well within the range for eligibility as to likely yield central lab results 
that will confirm the eligibility criteria.  Subject eligibility for the study will be defined by 
central lab results, except for coagulation tests which are acceptable locally. Specific 
instructions regarding specimen collection and handling may be found in the Laboratory Manual.  
Decisions with respect to IP dosing can be made based on a local lab draw if the central 
laboratory results have not been received. EOT pregnancy test may be done locally.
A central imaging reviewer(s) blinded to treatment will provide an independent review for 
disease recurrence for all subjects enrolled into the study. Prospective collection of all on-study 
scans for all subjects enrolled in the study will be included as part of the review. 
Films or electronic copies should be collected by the investigative sites and sent to the central 
imaging reviewer(s) and a copy of the file will be kept on site. Complete details regarding image 
handling and submission can be found in the Radiology Manual. Additional details on when 
scans will be obtained on subjects are found in Sections 6.2, 6.3, 6.4, 6.5.
6.2.
Screening Evaluations
Screening evaluations will be performed for all subjects to determine study eligibility.  These 
evaluations must be obtained ≤14 days prior to randomization. Any questions regarding subject 
eligibility should be directed to Celgene or other sponsor-nominated representatives or designees
for approval. 
The following evaluations will be performed at screening after informed consent has been 
obtained:

Demographics (if allowed by local regulations, collect initials, date of birth, sex, race, 
and ethnicity)

Medical history (including cancer history and specific information regarding any 
prior therapy)

Physical examination (source documented only)

Height and weight assessment

Urinalysis (a urine dipstick may be used)

Prior/concomitant medication evaluation: all medications taken ≤ 28 days prior to 
screening 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
33
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018

Prior/concurrent procedures evaluation: all procedures done ≤ 28 days prior to 
screening 

Peripheral neuropathy evaluation

Vital signs (temperature, systolic and diastolic blood pressure, and pulse)

ECOG performance status

Serum beta-human chorionic gonadotropin (β-HCG) pregnancy test (for women of 
childbearing potential only) will be conducted prior to first IP administration 
(negative results required for IP administration)

12-lead ECG

Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, blood urea nitrogen (BUN), alkaline phosphatase, AST/SGOT, ALT/SGPT, 
serum albumin, total bilirubin and creatinine);

Complete blood count (CBC), differential and platelet count

Coagulation studies (eg, PT/PTT, local lab results allowed to confirm subject 
eligibility)

Collect archival surgical primary pancreatic tumor sample for molecular and 
biomarker analysis (mandatory if available).  Collect archival surgical normal sample 
(duodenum or other) for baseline analysis (mandatory, if available)

Collect pathology report from surgical tumor sample

Collect a biomarker blood sample (mandatory)

CT or MRI scan

Serum carbohydrate antigen 19-9 (CA19-9)

QoL questionnaire completion: EORTC QLQ-C30 and QLQ-PAN26

Adverse event assessment (refer to Section 11.1 for details)
6.3.
Randomization and Treatment Phase Evaluations
The subject may be randomized once all inclusion/exclusion criteria are met during screening
and is adequately recovered from surgery. Subjects should return within 3 days of randomization
to begin Cycle 1 of IP dosing.

Subjects should have Cycle 1 day 1 (C1D1) dosing planned for within 3 days of 
randomization.  If the subject cannot be dosed within this time, it will need to be 
discussed with the sponsor
Unless otherwise specified, visits where disease recurrence assessments are not performed must 
occur within ±2 days of the planned visit date. 
If the investigator suspects a drug-related toxicity, an unscheduled visit with additional 
laboratory tests may be performed.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
34
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
nab-Paclitaxel and gemcitabine should be administered for 6 cycles as specified in Section 8.2.
6.3.1.
Day 1 Assessments
The following assessments will be performed on Day 1 of each of the 6 treatment cycles:

Physical examination (source documented only)

Weight assessment

BSA calculation

Concomitant medication evaluation

Concurrent procedures evaluation

Peripheral neuropathy evaluation

Vital signs (temperature, systolic and diastolic blood pressure, and pulse)

ECOG performance status

Clinical chemistry panel (including but not limited to sodium, potassium, chloride, 
glucose, BUN, alkaline phosphatase, AST/SGOT, ALT/SGPT, serum albumin, total 
bilirubin and creatinine)

CBC, differential and platelet count

QoL questionnaire completion (only at Cycle 4 Day 1 prior to dosing) 

AE assessment
Day 1 evaluations for Cycle 1 may be omitted if screening evaluations are performed within 72 
hours of Cycle 1 Day 1.
6.3.2.
Per Cycle Evaluations
On Day 8 and Day 15 of each of the 6 treatment cycles, the following assessments will be 
performed:

Concomitant medication evaluation

Concurrent procedures evaluation

Vital signs

ECOG performance status

CBC, differential and platelet count

AE assessment
6.3.3.
Assessment of Disease Recurrence
Disease recurrence will be assessed by CT; image preparation and evaluation for new lesions 
will follow the specifications provided in the Response Evaluation Criteria in Solid Tumors 
(RECIST), Version 1.1. RECIST will be used only as a guidance to identify new lesions: new 
lesions will not be followed.  Magnetic resonance imaging can be used based on the 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
35
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
investigator’s judgment or institution policy, as long as the same modality (CT or MRI) is used 
at screening and throughout the study. 
CT/MRI scan of the chest and abdomen/pelvis is to be performed at the following frequency
until disease recurrence irrespective of treatment status:

≤14 days prior to randomization (screening period)

every 8 weeks after randomization for the first 24 weeks

followed by every 12 weeks for the next 2.5 years (130 weeks) until 3 years after 
randomization

followed by every 24 weeks thereafter until disease recurrence for the next 2.5 years 
(130 weeks) up to 5.5 years after randomization
Scans can be done +/- 7 days from the time of the planned assessment. An unscheduled scan for 
suspected disease recurrence may be performed at any time. However, adherence to the planned 
imaging schedule is critical regardless of dose delays or unscheduled or missed assessments.
CA19-9 values will be obtained on the same week as the CT scans, but are not to be used alone 
as evidence of disease recurrence.
During the evaluation for disease recurrence, subjects may develop suspicious lesions or 
accumulate ascites, pleural or other fluids that may or may not be suspected to be recurrent 
disease.  In such cases, it is recommended that a biopsy be obtained.  Pathology reports from 
these biopsies should be submitted, and in the setting of a positive biopsy for disease recurrence, 
a tumor sample should be sent to the central laboratory, if available.  
In all subjects who have had disease recurrence (regardless of whether a biopsy was obtained), a 
blood sample will also be collected prior to the start of any new therapy.
At the time of disease recurrence, if a biopsy is performed, a tumor sample will be collected and 
sent to the central laboratory, if available. Ensure that the surgical pathology report is submitted 
with the tumor tissue sample. Refer to the Laboratory Manual for processing and shipping
details. 
6.4.
End of Treatment (EOT) Evaluations
An EOT evaluation should be performed for all subjects according to the following schedule:

For subjects who complete 6 cycles of treatment, as soon as possible after end of 
Cycle 6 (ie, after Cycle 6 Day 28), but no later than 14 days after Cycle 6 Day 28

For subjects who discontinue treatment prior to completing 6 cycles of treatment, as 
soon as possible after the decision is made to discontinue treatment
A completed subject is defined as a subject that has completed 6 cycles of treatment and received 
at least 2 doses during Cycle 6.
A discontinued subject is defined as not completing all 6 cycles of treatment, or only received 1 
dose during Cycle 6.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
36
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
The following procedures will be completed at the EOT Visit:

Physical examination (source documented only)

Weight assessment

Concomitant medication evaluation and ≤ 28 days after the last dose of IP 

Concurrent procedures evaluation and ≤ 28 days after the last dose of IP 

Peripheral neuropathy evaluation

Vital signs (temperature, systolic and diastolic blood pressure, and pulse)

ECOG performance status

Urine pregnancy test for females of childbearing potential (can be done locally)

Clinical chemistry panel (to include sodium, potassium, chloride, glucose, BUN, 
alkaline phosphatase, AST/SGOT, ALT/SGPT, serum albumin, total bilirubin and 
creatinine);

CBC, differential and platelet count

QoL questionnaire completion

AE assessment
6.5.
Follow-up Period (for Disease Recurrence)
Subjects who are discontinued from study treatment in the absence of disease recurrence (eg, 
subjects who completed 6 cycles of treatment or are removed for unacceptable toxicity or 
subject/investigator discretion) are followed for disease recurrence.  Subjects should undergo 
repeat imaging until disease recurrence, death, or the start of new anticancer therapy is 
documented (except as noted below), whichever is earlier.  CT/MRI scans should be performed
until disease recurrence (as specified in Section 6.3.3) irrespective of treatment status.
Adherence to the planned imaging schedule is critical regardless of dose delays or unscheduled 
or missed assessments.  
All subjects will be followed for survival and subsequent or new anticancer therapies (recorded 
on the respective electronic case report form [eCRF]) unless the subject withdraws consent from 
the entire study or dies. 
Subsequent anticancer therapy (including radiation) should not be instituted until disease 
recurrence is documented. If a subject starts subsequent anticancer therapy prior to disease 
recurrence, then repeat imaging assessments should be discontinued, except as follows:

Subjects randomized to nab-paclitaxel + gemcitabine who receive subsequent 
therapy with nab-paclitaxel, or gemcitabine, or both (without any other agents)

Subjects randomized to gemcitabine who receive subsequent therapy with
gemcitabine (without any other agents)
CA19-9 values will be obtained on the same week as the CT scans, but are not to be used alone 
as evidence of disease recurrence.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
37
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
QoL questionnaire will also be completed on the same week as the CT or MRI scans.
Imaging assessments for disease recurrence, QoL, CA19-9, and biopsy collection will be stopped 
after the number of events for the primary endpoint have been achieved and after the final 
analysis of DFS by independent radiology.  At this point, any ongoing subjects who have not had 
disease recurrence should follow local standard of care for any additional imaging assessments 
and laboratory testing.
6.6.
Follow-up Period for Overall Survival and Anticancer Therapy
Post-treatment OS and any subsequent anticancer therapy information status will be monitored 
every 3 months or more frequently as needed, until death, withdrawal of consent, or the study 
closes, whichever is earliest.  This evaluation may be by record review and/or telephone contact.
6.7.
Biomarker and Pharmacogenomic Testing
The key objective of the tumor molecular profiling is to identify specific markers that are 
predictive of response or emerging resistance to the combination of nab-paclitaxel and 
gemcitabine or gemcitabine alone. The key objective of the biomarker blood sampling is to 
investigate whether blood sampling can serve as a “liquid biopsy” to monitor disease recurrence.
When surgical tumor tissue is available, the collection of formalin fixed paraffin embedded 
(FFPE) tumor blocks (preferred) or 15 unstained slides is mandatory for all subjects for 
biomarker and pharmacogenomic testing. Additionally, a surgical normal tissue sample, such as 
from the duodenum, is requested if available (FFPE tumor block or 15 unstained slides). A 
biomarker blood sample at screening is mandatory. A surgical pathology report will be collected 
for each tumor sample provided.
A blood sample will be collected at the time of disease recurrence prior to the start of new anti-
cancer therapy. It is highly recommended that a biopsy is performed at the time of disease 
recurrence, when possible. A tumor sample should be collected at the time of biopsy and sent to 
the central laboratory along with the surgical pathology report. The suspected tumor recurrence 
biopsy should represent a core needle or greater sized sample that would be sufficient for 
molecular analysis.  Data have been emerging on potential markers of treatment resistance, and 
will potentially lead to the development of new therapeutic interventions for these subsets of 
patients.  Therefore, it is highly recommended that a biopsy be submitted for further analysis 
whenever clinically feasible.
Details on processing and shipping subject samples are described in the Laboratory Manual.
Overview of Biomarker and Pharmacogenomic Testing

FFPE tumor and normal blocks: 
o
Tumor tissue sample: In order to achieve the key objective of identifying a 
biomarker, it is essential that the tissue samples be as uniform as possible. 
Therefore, primary pancreatic tumor tissue from the surgical resection is 
requested. If necessary, resected lymph node tissue may be substituted.
o
Normal tissue sample: The normal duodenum or other normal tissue sample 
provides a baseline for biomarker analyses that is comparably processed. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
38
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018

Tumor molecular profiling:

Tumor tissue RNA and DNA will be profiled and compared with normal 
tissue RNA and DNA to identify genomic markers that correlate with clinical 
outcome with a key objective to identify specific markers that are predictive 
of response to the combination of nab-paclitaxel and gemcitabine. Analyses of 
the profiles will be performed to characterize the range of molecular 
heterogeneity for the tumors and to look for evidence of molecular subtypes of 
tumors. If tumor molecular subtypes are identified, correlations between 
subtypes and clinical outcome will be explored. Specific assays will be 
prioritized after study completion, as informed by emerging data and 
methodologies.

It is preferred that a surgical specimen FFPE block representative of the 
diagnosis be sent so that sections from each specimen can be generated at the 
central testing laboratory. However, in cases where FFPE blocks may not be 
released from the custody of the site and additional FFPE blocks cannot be 
provided from the surgically resected tumor, the sections may be prepared at 
the site. At least 15 slides are requested for the molecular profiling work (refer 
to the Laboratory Manual for details). The surgical pathology report for the 
tumor should be sent with the tissue.

If a biopsy is performed upon recurrent disease, FFPE tumor block from the 
biopsy (or 15 slides, refer to the Laboratory Manual) should be provided, if 
available. The surgical pathology report should be sent with the tissue.

Immunohistochemistry (IHC) analysis:

Human equilibrative nucleoside transporter 1 (hENT1) and secreted protein 
acidic and rich in cysteine (SPARC) are examples of proteins that may be
analyzed by IHC. SPARC is associated with prognosis of pancreatic cancer in 
the adjuvant setting (Infante, 2007; Sinn, 1997). hENT1 may be a predictor of 
response to gemcitabine-based chemotherapy (Neoptolemos, 2013).

Biomarker blood samples:

Cell-free DNA Blood Collection Tubes (BCT) collected at:

Screening

Upon disease recurrence (regardless if tissue was collected)
Nucleic acids extracted from blood will be used for normal genome (if needed) and circulating 
tumor nucleic acid profiling.  The collection of a blood sample upon disease recurrence is highly 
recommended as it may provide important data on drug resistance mechanisms.  Methodologies 
for circulating tumor nucleic acid identification may include but are not limited to DNA profiling 
or targeted gene sequencing, as informed by emerging data and methodologies.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
39
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
7.
STUDY POPULATION
7.1.
Number of Subjects and Sites
Approximately 800 subjects will be enrolled at approximately 160 sites globally.
7.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Histologically confirmed resected ductal pancreatic adenocarcinoma with macroscopic 
complete resection (R0 and R1). Subjects with neuroendocrine (and mixed type) tumors 
are excluded. 
2. Pancreatic cancer staging: T 1-3, N0-1, M0.
3. Subject should be able to start treatment no later than 12 weeks postsurgery. 
4. Male or non-pregnant, non-lactating females who are ≥18 years of age at the time of 
signing the informed consent form (ICF).
5. ECOG performance status of 0 or 1
6. Acceptable hematology parameters:

Absolute neutrophil count ≥1500 cell/mm3

Platelet count ≥100,000/mm3

Hemoglobin (Hgb) ≥9 g/dL
7. Acceptable blood chemistry levels:

AST/ SGOT and ALT/ SGPT ≤2.5 × upper limit of normal range (ULN)

Total bilirubin ≤ ULN (subjects with Gilbert’s syndrome can have bilirubin of up to 
1.5 x ULN)

Alkaline phosphatase ≤ 2.5 x ULN

Serum creatinine within upper limits of normal or calculated clearance 
≥50 mL/min/1.73 m2.  If using creatinine clearance, actual body weight should be 
used for calculating creatinine clearance (eg, using the Cockroft-Gault formula). For 
subjects with a Body Mass Index (BMI) >30 kg/m2, lean body weight should be used 
instead
8. CA19-9 < 100 U/mL assessed within 14 days of randomization
9. Acceptable coagulation studies (eg, PT or INR, and PTT within normal limits, ±15%) 
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 [ie, has had menses at any time during the preceding 24 
consecutive months]) must:
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
40
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018

Agree to the use of two physician-approved contraceptive methods (oral, injectable, 
or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier 
contraceptive with spermicide; or vasectomized partner) while on study IP; and for 3 
months following the last dose of IP; and

Has negative serum pregnancy test (β -hCG) result at screening 
11. Male subjects:
a.
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 IP discontinuation, even if he 
has undergone a successful vasectomy. 
12. Understand and voluntarily sign an ICF prior to any study related assessments or 
procedures being conducted.
13. Be able to adhere to the study visit schedule and other protocol requirements.
7.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Prior neo-adjuvant treatment, radiation therapy, or systemic therapy for pancreatic
adenocarcinoma
2. Presence of or history of metastatic or locally recurrent pancreatic adenocarcinoma
3. Any other malignancy within 5 years prior to randomization, with the exception of 
adequately treated in-situ carcinoma of the cervix, uteri, or nonmelanomatous skin cancer 
(all treatment of which should have been completed 6 months prior to randomization)
4. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, 
defined as ongoing signs/symptoms related to the infection without improvement despite 
appropriate antibiotics, antiviral therapy, and/or other treatment
5. Known history of human immunodeficiency virus (HIV) infection, or known history of 
active hepatitis B or C and are currently serologically positive with evidence of prior or 
signs of active chronic hepatitis
6. History of allergy or hypersensitivity to nab-paclitaxel or gemcitabine or any of their 
excipients
7. Serious medical risk factors involving any of the major organ systems, or serious 
psychiatric disorders, which could compromise the subject's safety or the study data 
integrity. These include, but are not limited to:
a.
History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa) 
                                               
True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic 
abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception).
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
41
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
b. History of interstitial lung disease, slowly progressive dyspnea and unproductive 
cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary 
hypersensitivity pneumonitis or multiple allergies 
c.
History of the following within 6 months prior to Cycle 1 Day 1: a myocardial 
infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, 
New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled 
hypertension, clinically significant cardiac dysrhythmia or ECG abnormality, 
cerebrovascular accident, transient ischemic attack, or seizure disorder 
d. Peripheral neuropathy > Grade 2
e.
Concomitant use of immunosuppressive or myelosuppressive medications that would 
in the opinion of the investigator, increase the risk of serious neutropenic 
complications
8. Enrollment in any other clinical protocol or investigational study with an interventional 
agent or assessments that may interfere with study procedures
9. Any significant medical condition, laboratory abnormality, or psychiatric illness that 
would prevent the subject from participating in the study
10. Any condition including the presence of laboratory abnormalities, which places the 
subject at unacceptable risk if he/she were to participate in the study
11. Any condition that confounds the ability to interpret data from the study
12. Unwillingness or inability to comply with study procedures
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
42
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
8.
DESCRIPTION OF STUDY TREATMENTS
8.1.
Description of Investigational Products
nab-Paclitaxel will be supplied by the sponsor and labeled appropriately as investigational 
material for this study. Labels will bear Celgene’s name and address, the protocol number, 
EudraCT number (if applicable), product name, dosage form and strength, medication 
identification/kit number, lot number, expiry date, dosing instructions, storage conditions, the 
quantity of IP contained, and required caution statements and/or regulatory statements as 
applicable.
Gemcitabine will be supplied or obtained according to local clinical study agreement and in 
accordance with local guidelines.
Additional information may be included on the label as needed or applicable. Label(s) for IP 
supplied to sites outside the US will contain information as required per local health authority.
IP supply will be managed by Interactive Randomization Technology (IRT). All IP must be 
stored in accordance with the product label in a secured area to prevent unauthorized access.
8.1.1.
ABRAXANE (nab-Paclitaxel)
nab-Paclitaxel will be supplied by the sponsor, Celgene Corporation, in single-use vials in single 
count cartons. 
 
Please see local prescribing information for Abraxane for detailed instructions on the 
reconstitution, storage conditions and IV administration of nab-paclitaxel.
Temperature records for nab-paclitaxel must be made available to Celgene or other sponsor-
nominated monitoring teams for verification of proper IP storage.
8.1.2.
Gemcitabine
Gemcitabine is a nucleoside metabolic inhibitor.
Gemcitabine will be supplied or obtained according to local clinical study agreement and in 
accordance with local guidelines. 
Please see gemcitabine prescribing information for more details on available formulations, 
preparation, storage conditions, the approved indications, known precautions, warnings, and 
adverse reactions of gemcitabine (see current version of Prescribing Information).
8.2.
Treatment Administration and Schedule
Treatment cycles are 28 days in duration and subjects are to complete 6 cycles. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
43
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Investigational Product, Dose, and Mode of Administration

Arm A

nab-Paclitaxel 125 mg/m2 as a 30- to 40-minute infusion followed by gemcitabine 
1000 mg/m2 as a 30- to 40-minute infusion on Days 1, 8 and 15 of a 28-day cycle 
for 6 cycles.  Following administration of nab-paclitaxel, the intravenous line 
should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection to 
ensure administration of the complete dose, according to local practice. 

Arm B

Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion administered on Days 1, 
8 and 15 of a 28-day cycle for 6 cycles
Subjects do not require premedication prior to nab-paclitaxel administration, as hypersensitivity 
reactions are not expected. If a hypersensitivity reaction occurs, the infusion should be stopped 
and not restarted. If felt to be in the subject’s best interest, at the investigator’s discretion, 
treatment may continue on subsequent cycles using the premedication regimen the institution 
typically uses for solvent-based paclitaxel.
For gemcitabine, the prescribing information for recommended premedication strategies needs to 
be followed. 
Supportive care per the institution’s normal standard of care including concomitant medications 
can be provided at the investigator’s discretion.
8.2.1.
Rules for Dose Omissions and Modified Schedules
If, for administrative reasons, treatment cannot be administered on the planned visit date, IP may 
be administered plus or minus 2 days from the scheduled date.
Day 1 Dose Missed
If the dose held or missed was to be given on Day 1 of the next cycle, that next cycle will not be 
considered to start until the day the first dose is actually administered to the subject (ie, 
1-2-3-Rest, X-1-2-3-Rest, etc).
Day 8 Dose Is Missed
Cycle continues per protocol, with one dose not given (ie, 1-2-3-Rest, 1-X-3-Rest, 1-2-3-Rest, 
etc).
Day 15 Dose Missed
That week becomes the week of rest.  Next dose (if counts and chemistries permit) becomes Day 
1 of a new cycle, and the subject is considered to have had a x2q3 (21-day) cycle (ie, 1-2-3-Rest, 
1-2-X, 1-2-3-Rest, etc).
The maximum delay between a missed scheduled dose, due to drug related toxicity, and the next 
one (whichever dose was missed) should not be longer than 21 days (except for peripheral 
neuropathy; see Table 6). 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
44
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
8.2.1.1.
Dose Modification Tables
Doses will be reduced, one level at a time, for hematologic and other toxicities.  Dose 
adjustments are to be made according to the system showing the greatest degree of toxicity.  
Toxicities will be graded using the NCI CTCAE Version 4.0. 
Two levels of dose modifications are permitted, for each drug, according to the criteria below.  If 
a toxicity requiring dose modification occurs following the second dose reduction of either IP, 
additional dose reductions are not permitted.  However, further treatment should be discussed 
with the sponsor. 
Table 4:
Dose Modifications
Dose Level
nab-Paclitaxel Dose (mg/m2)
a
Gemcitabine (mg/m2)a
Study Dose
125
1000
-1
100
800
-2
b
75
600
a Dose reductions may or may not be concomitant, refer to Table 5.  If the dose is withheld due to hematologic 
toxicity on Day 15, with either a held dose, or no dose modification on Day 8, subjects should be considered for 
either treatment at the next lower dose level and/or addition of white blood cell (WBC) growth factor support 
when the subject has adequate absolute neutrophil count (ANC) and platelet counts to begin Day 1 of the next 
cycle. Refer to Table 5 for specific recommendations regarding dose modifications for Day 1.
The lowest dose level for each drug in a single dose administration is 75 mg/m2 nab-paclitaxel or 
600 mg/m2 gemcitabine.
8.2.1.1.1. Dose Modifications
In the event dose modifications are required at the start of a cycle or within a cycle due to 
hematologic toxicities of neutropenia and/or thrombocytopenia, doses of nab-paclitaxel and 
gemcitabine may be adjusted as detailed in Table 5. In the combination arm, the investigator 
may hold one agent while continuing the other and remain on study. The combination may be 
restarted at the discretion of the treating physician. 
WBC growth factor may 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 subjects with an ANC < 500 cells/mm3. Subjects not experiencing resolution of 
neutropenia within 21 days, despite uninterrupted WBC growth factor treatment, will discontinue 
study treatment. In addition, WBC growth factors may be administered as supportive therapy to 
recover ANC adequately such that dosing levels may be maintained. If a dose reduction was 
required due to neutropenia, a dose re-escalation may be considered with continued growth 
factor support. If a dose reduction is required for a reason other than neutropenia, a dose re-
escalation could be permitted after discussion with the sponsor. If hematologic toxicity is 
restricted to platelet counts alone, dose modification of only gemcitabine could be considered 
after discussion with the sponsor.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
45
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Table 5:
Dose Recommendation and Modifications for Neutropenia and/or 
Thrombocytopenia at the Start of a Cycle or Within a Cycle
Cycle 
Day
ANC 
(cells/mm3)
Platelet count 
(cells/mm3)
nab-Paclitaxel Dose
Gemcitabine Dose
Day 1
≥ 1500 
AND
≥ 100,000
Treat on time at current dose levels
< 1500 
OR
< 100,000
Delay doses until recovery
Day 8
≥ 1000 
AND
≥ 75,000 
Treat on time at current dose levels
≥ 500 but
< 1000
OR
≥ 50,000 but < 
75,000
Reduce doses 1 dose level
< 500
OR
< 50,000
Withhold doses 
Day 15:   IF Day 8 doses were given without modification:
Day 
15
≥ 1000 
AND
≥ 75,000  
Treat on time at current dose levels
≥ 500 but
< 1000
OR
≥ 50,000 but 
< 75,000
Reduce doses 1 dose level from Day 8; 
consider following with WBC growth factors 
for support*
< 500
OR
< 50,000
Withhold doses
Day 15:    IF Day 8 doses were reduced:
Day 
15
≥ 1000 
AND
≥ 75,000 
Treat with same doses as Day 8; consider 
following with WBC growth factors for 
support* 
≥ 500 but
< 1000
OR
≥ 50,000 but 
< 75,000
Reduce doses 1 dose level from Day 8; 
consider following with WBC growth factors 
for support* 
< 500
OR
< 50,000
Withhold doses
Day 15:    IF Day 8 doses were withheld:
Day 
15
≥ 1000 
AND
≥ 75,000 
Option A: Maintain dose level from Day 1 
and follow with WBC growth factors for 
support*
OR
Option B: Reduce doses 1 dose levels from 
Day 1  
≥ 500 but
< 1000
OR
≥ 50,000 but 
< 75,000
Option A: Reduce 1 dose level from Day 1 
and follow with WBC growth factors for 
support*
OR
Option B: Reduce doses 2 dose levels from 
Day 1 
< 500
OR
< 50,000
Withhold doses
Abbreviations: ANC = absolute neutrophil count; WBC = white blood cell.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
46
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
* The use of WBC growth factors is only applicable if the dose limiting hematologic toxicity was limited to 
neutropenia or febrile neutropenia.
Dose modifications for other adverse drug reactions are provided in Table 6.
Table 6:
Dose Modifications for Other Adverse Drug Reactions
Adverse Drug Reaction
nab-paclitaxel Dose
Gemcitabine Dose
Febrile Neutropeniaa:
    Grade 3 or 4
Withhold doses until fever resolves and ANC is ≥ 1500; resume 
at next lower dose levelb
Peripheral Neuropathy:
    Grade 3 or 4
Withhold dose until improvement to 
≤Grade 1;
resume at next lower dose levelb
Treat with same dose
Cutaneous Toxicity:
    Grade 2 or 3
Reduce doses to next lower dose levelb;
discontinue treatment if ADR persists
For all other nonhematologic 
toxicities (except nausea, 
vomiting, alopecia and pulmonary 
embolismc) of > Grade 3
Withhold dose of either or both agent(s) until improvement to 
≤Grade 1;
resume at next lower dose levelb
Abbreviations: ADR, adverse drug reaction; ANC = absolute neutrophil count.
a White blood cell growth factor may 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 subjects with an 
ANC of < 500 cells/mm3.
b See Table 4 for dose level reductions. 
c See Section 8.2.1.1.3.
8.2.1.1.2. Administration of IP to Subjects with Abnormal Hepatic Function
Hepatic toxicity may occur, but it is uncommon.  Therefore, hepatic dysfunction that occurs 
while the subject is on study should prompt an evaluation to determine the cause, including the 
possibility of metastatic disease and hepatotoxicity from concurrent medications, alcohol use, or 
other factors.
8.2.1.1.3. Pulmonary Embolism and Deep-vein Thrombosis
To resume IP administration in the event of a pulmonary embolism or deep-vein thrombosis, 
subjects must be started on low molecular weight heparin or similar anticoagulation therapy. 
Grade 4 events must be resolved to Grade ≤ 3 within 21 days to continue IP.
8.2.1.1.4. Interstitial Pneumonitis
While participating in this study, subjects should be carefully monitored to prevent or minimize 
the occurrence of interstitial pneumonitis. Careful prestudy screening with continuous on-study 
monitoring for signs and symptoms is required. Should a subject develop symptoms of 
pneumonitis during this study, the timely initiation of appropriate management is required. 
Recommended guidelines are as follows:
1. Before enrollment, evaluate candidate subjects for familial, environmental, or 
occupational exposure to opportunistic pathogens, and do not enroll those with a history 
of slowly progressive dyspnea and unproductive cough, or of conditions such as 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
47
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity 
pneumonitis, or multiple allergies (controlled or uncontrolled) that in the opinion of the 
investigator may pose a risk to the subject or study.
2. During study treatment, provide close attention to episodes of transient or repeated 
dyspnea with unproductive persistent cough or fever. Radiographic evaluation with chest 
x-rays and CT scans (normal or high resolution) may be indicated to evaluate for 
infiltrates, ground-glass opacities, or honeycombing patterns. Pulse oximetry and 
pulmonary function tests can show respiratory and ventilation compromise. 
3. 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. 
4. Administration of IP should be interrupted upon diagnosis of interstitial pneumonitis and 
subjects permanently discontinued from further study drug treatment. After ruling out an 
infectious etiology, intravenous high-dose corticosteroid therapy should be instituted 
without delay, with appropriate premedication and secondary pathogen coverage. 
Subjects with an added immunological agent may also require immune modulation with 
azathioprine or cyclophosphamide. Appropriate ventilation and oxygen support should be 
used when required. 
8.2.1.1.5. Prophylaxis Against Sepsis
In the metastatic pancreatic cancer Phase 3 study (CA046), an increase in cases of non-
neutropenic sepsis was observed with the combination of nab-paclitaxel and gemcitabine. An 
exploratory analysis suggested that the presence of biliary stents may have increased the risk of 
sepsis in that population. Investigators were to provide oral broad spectrum antibiotics to 
subjects who were then to initiate these antibiotics at the first occurrence of fever. Subjects 
enrolled in this clinical trial may not have the same risk of sepsis as metastatic pancreatic cancer 
patients. Subjects should be advised that there could be an increased risk of serious infection and 
they should contact their physician for evaluation when they develop a fever. Fever or similar 
symptoms should be fully evaluated as an early sign of a serious infection. Broad spectrum 
antibiotics such as fluoroquinolones may be provided to subjects to treat or as prophylaxis for 
infection at the discretion of the treating physician.
8.2.1.1.6. Hypersensitivity Reactions
Hypersensitivity reactions are infrequent with nab-paclitaxel. 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 IP administration and aggressive symptomatic therapy.
Subjects who develop a severe hypersensitivity reaction to nab-paclitaxel should not be 
rechallenged.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
48
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
8.2.2.
Overdose
On a per dose basis, an overdose is defined as 10% over the protocol-specified dose of IP 
assigned to a given subject, regardless of any associated AEs or sequelae.
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. 
Complete data about IP administration, including any overdose, regardless of whether the 
overdose was accidental or intentional, should be reported in the case report form.  See Section 
11.1 for the reporting of AEs associated with overdose.
8.3.
Method of Treatment Assignment
Subjects who enter screening will be assigned the next available subject number. All eligible 
subjects will be randomized to receive either nab-paclitaxel in combination with gemcitabine or 
gemcitabine alone.  The permuted block randomization method will be used to generate the 
randomization codes and the randomization will be performed by IRT to ensure a 1:1 treatment 
assignment ratio. The randomization schedule will be generated by the sponsor or its designee.
The randomization will be stratified by the factors described in Section 4.1.
8.4.
Packaging and Labeling
The label(s) for IP will include sponsor name, address and telephone number, the protocol 
number, IP name, dosage form and strength (where applicable), amount of IP per container, lot 
number, expiry date (where applicable), medication identification/kit number, dosing 
instructions, storage conditions, and required caution statements and/or regulatory statements as 
applicable. Additional information may be included on the label as applicable per local 
regulations.
8.5.
Investigational Product Accountability and Disposal 
Celgene (or its designee) will review with the investigator and relevant site personnel the process 
for IP return, disposal, and/or destruction, including the responsibilities for the site versus
Celgene (or designee).
Investigational product containers that are not completely empty should be disposed of in 
accordance with institutional/regional requirements, unless otherwise agreed with Celgene. 
Completely used containers should be destroyed according to local guidelines, and disposition 
should be recorded on the Investigational Drug Accountability Record Form.
The investigator, or designee, shall record the dispensing of IP to subjects in the IP 
accountability record form. The IP record will be made available to Celgene, or other authorized 
Celgene-designated monitoring personnel, for the purpose of accounting for the IP supply. 
Inspections of the IP supply for inventory purposes and assurance of proper storage will be 
conducted as necessary. Any significant discrepancy will be recorded and reported to Celgene or 
its designee and a plan for resolution will be documented.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
49
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Investigational product will not be loaned or dispensed by the investigator to another investigator 
or site. Under certain circumstances, and with sponsor permission, cooperative groups may 
manage IP between locations within their network as clinical study agreement and local 
guidelines permit.
8.6.
Investigational Product Compliance
Accurate recording of all IP administration will be made in the appropriate section of the 
subject’s electronic case report form (eCRF) and source documents. The investigator or designee 
is responsible for accounting for all study-specific IP either administered or in their custody 
during the course of the study.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
50
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
9.
CONCOMITANT MEDICATIONS AND PROCEDURES
All concomitant treatments, including blood and blood products, must be reported on the eCRF. 
9.1.
Permitted Concomitant Medications and Procedures
Over the course of this study, additional medications may be required to manage aspects of the 
disease state of the subjects, including side effects from study treatments or disease recurrence.  
Supportive care, including but not limited to antiemetic medications, may be administered at the 
discretion of the investigator.  
WBC growth factors may be administered at the discretion of the investigator, consistent with 
institutional guidelines (refer to Section 8.2.1.1.1 for details) and with the Prescribing 
Information for such growth factors. WBC growth factors should be used only in patients who 
have demonstrated prior events of neutropenia; primary prophylaxis with WBC growth factors is 
not permitted.
Erythropoietin may be administered at the discretion of the investigator, consistent with 
institutional guidelines.
Subjects receiving warfarin should be closely followed for therapeutic levels of anticoagulation; 
low-molecular weight heparins (LMWH) may be used instead.  As the chemotherapy regimens 
may result in thrombocytopenia, subjects receiving full dose aspirin, clopidogrel or other 
potential platelet depleting agents should be closely monitored.
The potential drug-drug interactions precautions contained in the nab-paclitaxel prescribing 
information will be applied to this study, unless otherwise specified in the protocol (refer to 
Prescribing Information). Specifically, the metabolism of paclitaxel is catalyzed by cytochrome 
P450 isozymes CYP2C8 and CYP3A4. Caution is recommended when administering 
nab-paclitaxel concomitantly with substrates or inhibitors of the cytochrome P450 isozymes 
CYP2C8 and CYP3A4.
For information regarding other drugs that may interact with either nab-paclitaxel or gemcitabine 
and affect their metabolism, pharmacokinetics, or excretion, please see the gemcitabine and nab-
paclitaxel package inserts (refer to Prescribing Information).
9.2.
Prohibited Concomitant Medications and Procedures
Radiation treatment is not allowed during the study.  Administration of other chemotherapy, 
immunotherapy, or antitumor therapy during the study is not allowed until documented disease 
recurrence.  
9.3.
Required Concomitant Medications and Procedures
Not applicable.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
51
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
10.
STATISTICAL ANALYSES
10.1.
Overview
This is a Phase 3, international, multicenter, open-label, randomized, controlled study of weekly 
nab-paclitaxel plus gemcitabine versus gemcitabine alone as adjuvant therapy in subjects with 
surgically resected pancreatic adenocarcinoma. Subjects will be randomized in a 1:1 ratio to two 
treatment arms following permuted block randomization methods. The randomization will be
stratified by the following factors: 

Resection Status: R0 (tumor-free margin) versus R1 (microscopically positive 
margin)

Nodal Status: LN+ versus LN-

Region (North America, Europe, and Australia versus Asia Pacific)
A DMC will be used to review the safety and efficacy results from the planned interim analyses. 
The sections below provide an overview of the proposed statistical considerations and analyses. 
The final statistical analysis methods will be documented in detail in the statistical analysis plan 
(SAP).
10.2.
Study Population Definitions
10.2.1.
Intent-to-treat Population
The intent-to-treat (ITT) population will consist of all randomized subjects regardless of whether 
the subject received any IP or had any efficacy assessments collected. 
10.2.2.
Treated Population
The treated population will consist of all randomized subjects who received at least one dose of 
IP. The treatment groups for the safety analyses are based on the treatment as received if 
different from the assigned treatment by randomization. 
10.2.3.
Per-Protocol Population
The per-protocol population consists of all treated as randomized subjects who met all eligibility 
criteria and had no radiological evidence of pancreatic cancer prior to randomization by 
independent review.
10.3.
Sample Size and Power Considerations
The primary objective is to compare the DFS in subjects who received nab-paclitaxel in 
combination with gemcitabine and subjects who received gemcitabine alone. 
The hypotheses are the following: 
H0: HRA+G/G = 1
versus 
H1: HRA+G/G ≠1
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
52
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
where HRA+G/G is the hazard ratio (HR) of DFS between the nab-paclitaxel in combination with 
gemcitabine arm and the gemcitabine alone arm. 
Disease-free survival was reported with a median of 13.4 months and 14.3 months for patients 
with surgically resected pancreatic adenocarcinoma who received gemcitabine as adjuvant 
treatment in two separate randomized Phase 3 studies (Neoptolemos, 2010; Oettle, 2007).  With 
the assumption of the true median DFS of 14 months in the gemcitabine arm and 19 months in 
the nab-paclitaxel in combination with gemcitabine arm which is equivalent to a HRA+G/G of 
0.74, at least 489 DFS events from 800 subjects are required to allow 90% power to detect a 26% 
reduction of risk in disease recurrence or death from the treatment arm at a two-sided 
significance level of 0.05. One interim analysis of efficacy is planned at about 33% information 
time (ie, after 163 DFS events) to assess futility. The accrual rate is estimated to be 
approximately 26.7 subjects per month for a total estimated enrollment period of 30 months. The 
nonbinding stopping boundary will be based on the Gamma family spending function with 
parameter = -2 (Hwang, 1990) to control the Type 2 error rate at 10%. The HR boundary for 
futility at 33% information time is ≥ 0.98, however the actual boundary may vary depending on 
the number of DFS events at the time of analysis.
As of April 2016, a total of 866 subjects were enrolled in the study. After enrollment to this 
protocol was completed, more contemporaneous Phase III studies with gemcitabine in the 
targeted population of surgically resected pancreatic adenocarcinoma have shown consistently 
that DFS for patients may be lower than the median DFS of 14 months in the CONKO-001 study
(Oettle, 2007), which provided the rationale for the timing and duration of the DFS assessments 
in the ABI-007-PANC-003 study. Results from the CONKO-005 (Sinn, 2017) and PRODIGE 24 
(Conroy, 2018) studies showed a median DFS with adjuvant gemcitabine of 11.4 and 12.8 
months, respectively. Based on these new data, Protocol Amendment 4 will revise the final DFS 
analysis to be earlier than originally planned (489 events).With the assumption of the true 
median DFS of 13.5 months in the gemcitabine arm and 18.5 months in the nab-paclitaxel in 
combination with gemcitabine arm, which is equivalent to an HRA+G/G of 0.73, approximately
438 DFS events are required to allow 90% power to detect a 27% reduction of risk in disease 
recurrence or death from the treatment arm at a two-sided significance level of 0.05. The data 
cutoff date for the revised final DFS analysis is projected to be December 2018, by which time 
438 DFS events may be reached. 
Overall survival data will be analyzed as supportive analyses. The reported median survival 
from 2 randomized Phase 3 studies in subjects with surgically resected pancreatic 
adenocarcinoma who received gemcitabine as adjuvant treatment (Neoptolemos, 2010; Oettle, 
2007) ranged from 22 months to 24 months. Table 7 illustrates the probability that the nominal 
two-sided p-value would be less than 0.05 under different assumptions when approximately 630 
events are observed. It is projected that between 410 and 440 deaths will have occurred at the 
time of the data cut-off for the final DFS analysis and all subjects remaining on study will have 
at least 32 months of survival follow-up.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
53
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Table 7:
Power Calculation for Overall Survival with N = 800
Hazard Ratio of OS
Median OS (months)
Number of Deaths/N
Power
0.85
MG = 22
MA+G = 26
624/800
55%
0.80
MG = 22
MA+G = 27.5
633/800
82%
0.75
MG = 22
MA+G = 29
630/800
95%
Abbreviations: MG = median for gemcitabine arm; MA+G = median for nab-paclitaxel/gemcitabine arm; OS = overall 
survival.
10.4.
Background and Demographic Characteristics
Subjects’ age, height, weight, and baseline characteristics will be summarized using descriptive 
statistics, while gender, race, and other categorical variables will be provided using frequency 
tabulations. Medical history data will be summarized using frequency tabulations by system 
organ class and preferred term.
10.5.
Subject Disposition
Subject disposition (analysis population allocation, entered, discontinued, along with primary 
reason for discontinuation) will be summarized using frequency and percentage for both 
treatment and follow-up phases. 
10.6.
Efficacy Analysis
All efficacy analysis will be conducted based on the ITT population. The primary and secondary 
efficacy analyses will also be conducted based on the treated population and per-protocol 
population.  While key analyses are described in this section, additional analyses, including 
sensitivity analyses and subgroup analyses, will be specified in the SAP.
10.6.1.
Primary Efficacy Analyses
The primary efficacy endpoint will be DFS which is defined as the time from the date of 
randomization to the date of disease recurrence or death, whichever is earlier. Disease recurrence 
will be determined by the independent radiological review of CT or MRI scans.  Subjects who 
received new anti-cancer therapy or cancer-related surgery prior to disease recurrence or death 
will be censored.  Detailed censoring rules will be documented in the SAP.
The survival distribution of DFS will be estimated using the Kaplan-Meier method: medians and 
two-sided 95% CIs will be provided by treatment arms. The comparison of DFS between the two 
arms will be conducted using stratified log-rank test, with the stratification factors: resection 
status (R0 versus R1), nodal status (LN+ versus LN-), and region (North America, Europe, and
Australia versus Asia Pacific). The associated HR and two-sided 95% CIs will be provided using 
the Cox proportional hazard model.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
54
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
10.6.2.
Secondary Efficacy Analyses
The secondary efficacy endpoint will be OS which is defined as the time from the date of 
randomization to the date of death. Subjects who are alive will be censored on the last-known-to-
be-alive date. The survival distribution of OS will be estimated using the Kaplan-Meier methods:
medians and two-sided 95% CIs will be provided by treatment arms.  The survival rates at 
different time points will be provided. P-values based on stratified log-rank test will be provided.
The associated HRs and two-sided 95% CIs will be provided using the Cox proportional hazard 
model.
10.7.
Safety Analysis
All safety analyses will be conducted based on the treated population. 
10.7.1.
Adverse Events
The safety population, which includes all randomized subjects who received at least 1 dose of IP, 
will be the analysis population for all safety analyses.  Adverse events will be analyzed in terms 
of TEAE defined to be any event that begins or worsens in grade after the start of IP through 28 
days after the last dose of IP. All events will be coded using MedDRA. AEs will be summarized 
by severity/grade based on the NCI CTCAE Version 4.0. If a subject experiences the same AE 
multiple times during the treatment, the event will be counted only once and by the greatest 
severity.
Treatment-emergent adverse events, Grade 3 or higher TEAEs, serious AEs, TEAEs leading to 
dose reduction, and dose interruption, TEAEs leading to treatment discontinuation, and TEAEs 
with an outcome of death will be summarized per treatment arms by MedDRA system organ 
class and preferred terms. Adverse events of special interest of the nab-paclitaxel plus 
gemcitabine combination identified in previous trials in a similar population will be summarized 
in the same manner.
10.7.2.
Laboratory Results
In order to investigate the maximal degree of myelosuppression, the NCI CTCAE Version 4
grade for ANC, WBC, platelet count, and hemoglobin will be summarized for each treatment 
group by the most severe grade in each treatment cycle and by the most severe grade at any time 
during the treatment. 
Hepatic and renal function will be summarized for each treatment group using the most severe 
NCI CTCAE grade for ALT(SGPT), AST(SGOT), total bilirubin, and creatinine by cycle and at 
any time during the treatment.
10.8.
Interim Analysis
One interim analysis on safety is planned after the first 100 subjects have completed 2 cycles of 
treatment. Additionally, one interim analysis on efficacy is planned at about 33% information
time (ie, after 163 DFS events). A second interim analysis on efficacy had been planned for 
futility and superiority after observing 70% DFS events or enrollment of 800 subjects, 
whichever was later. However, at time of Protocol Amendment 3, the interim analysis for 
futility at 163 DFS events has been performed and no subjects are receiving investigational
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
55
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
product (IP). To avoid premature interruption of the trial, and to ensure that the study has 
sufficient duration of follow-up to verify clinical benefit and assess benefit-risk in this setting, 
this second interim analysis has been removed from the study. The analysis will be conducted 
by an independent third party statistician and the DMC will examine the interim results and 
provide recommendations to continue the study or terminate the study early. Additional details
will be provided in the DMC charter and SAP.
10.9.
Other Topics
10.9.1.
Data Monitoring Committee
A DMC will be convened that will include medical oncologists with experience in treating 
subjects with pancreatic cancer and a statistician, all of whom are not otherwise involved in the 
study conduct. During the course of the study, the DMC will review the safety and efficacy data 
in accordance with the guidelines for the preplanned interim analyses.  The committee will 
review safety data after the first 100 subjects have completed 2 cycles of the treatment. One 
interim analysis on efficacy is planned at about 33% information time (ie, after 163 DFS events). 
The DMC will review the interim efficacy results and provide the recommendation on whether 
the study should be discontinued due to lack of efficacy.  An independent third party will prepare 
the reports of aggregate data summaries and individual subject data listings, as appropriate, to the 
DMC members for each scheduled meeting. Operational details for the DMC will be detailed in 
the DMC charter.
10.9.2.
Steering Committee
The conduct of this trial will be overseen by a SC, presided over by the coordinating principal 
investigator and if possible the representative regional investigators from countries participating 
in this study.  The SC will serve in an advisory capacity to the Sponsor.  Operational details for 
the SC will be detailed in a separate SC charter.
Note: The SC is separate from the DMC.
10.10.
Exploratory Analyses
10.10.1.
Tumor Markers
Statistical analysis of the exploratory data collected from plasma and tissue samples will be 
described in an analysis plan separate from the SAP and reported in a stand-alone report separate 
from the CSR.
10.10.2.
Quality of Life
Quality of life will be evaluated for both nab-paclitaxel in combination with gemcitabine and 
gemcitabine alone using the EORTC-QLQ-30 and EORTC QLQ- PAN26 questionnaires. The 
QLQ-PAN26 questionnaire will not be collected in Finland, Portugal and Singapore.  The 
differences in quality of life outcomes between the two study arms will be statistically 
investigated cross-sectionally and longitudinally, sample size and data permitting. Changes from 
baseline in overall score and sub-scores will be analyzed using methodologies, such as 
ANOVA/ANCOVA.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
56
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
11.
ADVERSE EVENTS
11.1.
Monitoring, Recording, and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen 
in a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria below), regardless of etiology. Any worsening 
(ie, any clinically significant adverse change in the frequency or intensity of a preexisting 
condition) should be considered an AE.  A diagnosis or syndrome should be recorded on the AE 
page of the eCRF rather than the individual signs or symptoms of the diagnosis or syndrome. 
Disease recurrence and death due to the progression of disease will not be recorded as an AE.
Abuse, withdrawal, sensitivity or toxicity to an investigational product should be reported as an 
AE. Overdose, accidental or intentional, whether or not it is associated with an AE should be 
reported on the overdose CRF. (See Section 8.2.2. for the definition of overdose.) Any sequela 
of an accidental or intentional overdose of an investigational product should be reported as an 
AE on the AE CRF. If the sequela of an overdose is an SAE, then the sequela must be reported 
on an SAE report form and on the AE CRF. The overdose resulting in the SAE should be 
identified as the cause of the event on the SAE report form and CRF but should not be reported 
as an SAE itself.
All subjects will be monitored for AEs during the study.  Assessments may include monitoring 
of any or all of the following parameters:  the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures.
All AEs will be recorded by the investigator from the time the subject signs informed consent 
until 28 days after the last dose of IP and those SAEs made known to the investigator at any time 
thereafter that are suspected of being related to IP. AEs and SAEs will be recorded on the AE 
page of the eCRF and in the subject’s source documents. All SAEs must be reported to Celgene 
Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, or other 
appropriate method, using the SAE Report Form, or approved equivalent form.
11.2.
Evaluation of Adverse Events
A qualified investigator will evaluate all AEs as to: 
11.2.1.
Seriousness 
An SAE is any AE occurring at any dose that:

Results in death

Is life-threatening (ie, in the opinion of the investigator, the subject is at immediate 
risk of death from the AE)

Requires in-patient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an in-patient admission, regardless of length of stay)
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
57
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018

Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Constitutes an important medical event
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above.  
Medical and scientific judgment should be exercised in deciding whether such an AE should be 
considered serious.
Events not considered to be SAEs are hospitalizations for:

A standard procedure for protocol therapy administration.  However, hospitalization 
or prolonged hospitalization for a complication of therapy administration will be 
reported as an SAE. 

Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition.

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.

A procedure for protocol/disease-related investigations (eg, 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.

Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE.

A procedure that is planned (ie, planned prior to starting of treatment on study); must 
be documented in the source document and the eCRF.  Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE.

An elective treatment or elective procedure of a preexisting condition unrelated to the 
studied indication. 

Emergency out-patient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above.
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report Form 
must be completed.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to IP, action taken regarding IP, and outcome.
11.2.2.
Severity / Intensity
For both AEs and SAEs, the investigator must assess the severity / intensity of the event. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
58
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of NCI CTCAE Version 4.0.
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40
AEs that are not defined in the CTCAE should be evaluated for severity / intensity according to 
the following scale:
Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required
Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be needed; 
no or minimal medical intervention/therapy required
Grade 3 = Severe – marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalization is possible
Grade 4 = Life threatening – extreme limitation in activity, significant assistance required; 
significant medical intervention/therapy required, hospitalization or hospice care probable
Grade 5 = Death - the event results in death
The term “severe” is often used to describe the intensity of a specific event (as in mild, moderate 
or severe myocardial infarction); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This criterion is not the same as “serious,” which is 
based on subject/event outcome or action criteria associated with events that pose a threat to a 
subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations.
11.2.3.
Causality 
The investigator must determine the relationship between the administration of IP and the 
occurrence of an AE/SAE as Not Suspected or Suspected as defined below:
Not suspected:
Means a causal relationship of the AE 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 AE.  “Reasonable possibility” means there is 
evidence to suggest a causal relationship between the IP and the 
AE
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.
If an event is assessed as suspected of being related to a comparator, ancillary, or additional IP 
that has not been manufactured or provided by Celgene, please provide the name of the 
manufacturer when reporting the event.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
59
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
11.2.4.
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
11.2.5.
Action Taken
The investigator will report the action taken with IP as a result of an AE or SAE, as applicable 
(eg, discontinuation. Interruption, or reduction of IP, as appropriate), and report whether 
concomitant and/or additional treatments were given for the event. 
11.2.6.
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, recovered with sequelae, not recovered, or death (due to the SAE). 
11.3.
Abnormal Laboratory Values
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

is judged to be of significant clinical importance
Regardless of severity grade, only laboratory abnormality that fulfills a seriousness criterion 
needs to be documented as an SAE. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis 
or syndrome should be recorded on the AE page/screen of the eCRF.  If the abnormality was not 
a part of a diagnosis or syndrome, then the laboratory abnormality should be recorded as the AE.  
If possible, the laboratory abnormality should be recorded as a medical term and not simply as an 
abnormal laboratory result (eg, record thrombocytopenia rather than decreased platelets).
11.4.
Pregnancy
11.4.1.
Females of Childbearing Potential:
Pregnancies or suspected pregnancies (including a positive pregnancy test regardless of age or 
disease state) of a female subject occurring while the subject is on IP, or within 28 days of the 
subject’s last dose of IP, are considered immediately reportable events.  Investigational product
is to be discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy 
test must be reported to 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 or another appropriate 
healthcare professional for further evaluation.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
60
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
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 (eg, spontaneous 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 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 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.
11.4.2.
Male Subjects
If a female partner of a male subject taking the IP becomes pregnant, the male subject taking the
IP should notify the investigator, and the pregnant female partner should be advised to call her 
healthcare provider immediately.
11.5.
Reporting of Serious Adverse Events
Any AE that meets any criterion for an SAE requires the completion of an SAE Report Form in 
addition to being recorded on the AE page/screen of the eCRF.  All SAEs must be reported to 
Celgene Drug Safety within 24 hours of the investigator’s knowledge of the event by facsimile, 
or other appropriate method, using the SAE Report Form, or approved equivalent form.  This 
instruction pertains to initial SAE reports as well as any follow-up reports.
The investigator is required to ensure that the data on these forms is accurate and consistent.  
This requirement applies to all SAEs (regardless of relationship to IP) that occur during the study 
(from the time of signing of the informed consent form to 28 days after the last dose of IP), and 
those made known to the investigator at any time thereafter that are suspected of being related to 
IP.
The SAE report should provide a detailed description of the SAE and include a concise summary 
of hospital records and other relevant documents.  If a subject died and an autopsy has been 
performed, copies of the autopsy report and death certificate are to be sent to Celgene Drug 
Safety as soon as these become available.  Any follow-up data will be detailed in a subsequent 
SAE Report Form, or approved equivalent form, and sent to Celgene Drug Safety. 
Where required by local legislation, the investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
The investigator must keep copies of all SAE information on file including correspondence with 
Celgene and the IRB/EC.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
61
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
11.5.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Celgene Drug Safety to the site via 
facsimile or electronic mail.  The response time is expected to be no more than five (5) business 
days.  Urgent queries (eg, missing causality assessment) may be handled by phone.
11.6.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Celgene Drug Safety will determine the expectedness of 
events suspected of being related to nab-paclitaxel based on the Investigator Brochure.
In the United States, all suspected unexpected serious adverse reactions (SUSARs) will be 
reported in an expedited manner in accordance with 21 CFR 312.32.  For countries within the 
European Economic Area (EEA), Celgene or its authorized representative will report in an 
expedited manner, to all Regulatory Authorities and Ethics Committees concerned, suspected 
unexpected serious adverse reactions (SUSARs) in accordance with Directive 2001/20/EC and 
the Detailed Guidance on collection, verification and presentation of adverse reaction reports 
arising from clinical trials on investigational products for human use (ENTR/CT3) and also in 
accordance with country-specific requirements. 
For the purpose of regulatory reporting in the EEA, Celgene Drug Safety will determine the 
expectedness of events suspected of being related to the other IP, gemcitabine, based on the UK 
Summary of Product Characteristics (SmPC).  For the purpose of regulatory reporting in the 
EEA, Celgene non-IMP gemcitabine SAEs and nonserious SAEs will be reported to the 
Regulatory Authorities, in accordance with Regulation (EC) No. 726/2004 and/or Directive 
2001/83/EC as amended, and also in accordance with country-specific requirements for countries 
within the EEA.
Celgene or its authorized representative shall notify the investigator of the following information

Any AE suspected of being related to the use of IP in this study or in other studies 
that is both serious and unexpected (ie, SUSAR)

Any finding from tests in laboratory animals that suggests a significant risk for 
human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity
Where required by local legislation, the investigator shall notify his/her IRB/EC promptly of 
these new serious and unexpected AE(s) or significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence with Celgene and the IRB/EC.  (See Section 15.3 for record retention 
information,)
Celgene Drug Safety Contact Information:
For Celgene Drug Safety contact information, please refer to the SAE Report Form Completion 
Guidelines or to the Pregnancy Report Form Completion Guidelines.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
62
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
12.
DISCONTINUATIONS
12.1.
Discontinuation from Investigational Product
The following events are considered sufficient reasons for discontinuing a subject from the IP:

AE(s) (that are intolerable)

Disease recurrence

Physician decision

Withdrawal of consent (from treatment only)

Death

Lost to follow up

Protocol violation

Other (to be specified on the eCRF)
The reason for treatment discontinuation should be recorded in the eCRF and in the source 
documents.
12.2.
Discontinuation from the Study
The following events are considered sufficient reasons for discontinuing a subject from the 
study:

Withdrawal of consent

Death

Lost to follow up

Protocol violation

Other (to be specified on the eCRF)
The reason for study discontinuation should be recorded in the eCRF and in the source 
documents.
At the time of withdrawal, it should be determined whether the subject is withdrawing from 
treatment alone, or from treatment and collection of further data (eg, survival).
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
63
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
13.
EMERGENCY PROCEDURES
13.1.
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after the title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on 
the Emergency Contact Information page of the protocol (after the title page). This global 
Emergency Call Center is available 24 hours a day and 7 days a week. The representatives are 
responsible for obtaining your call-back information and contacting the on-call Celgene/CRO 
Medical Monitor, who will then contact the investigator promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if the 
investigator is not able to reach the Clinical Research Physician(s) or Medical Monitor or 
designee for emergency calls. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
64
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
14.
REGULATORY CONSIDERATIONS
14.1.
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed to ensure that Celgene, its authorized representative, 
and investigator abide by Good Clinical Practice (GCP), as described in International Conference 
on Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles 
outlined in the Declaration of Helsinki. The study will receive approval from an IRB/EC prior to 
commencement. The investigator will conduct all aspects of this study in accordance with 
applicable national, state, and local laws of the pertinent regulatory authorities.
14.2.
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for GCP and in the local 
regulations.  Celgene staff or an authorized representative will evaluate and approve all 
investigators, who in turn will select their staff.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, amendments, and study treatments, as well as study-related duties and 
functions including obligations of confidentiality of Celgene information. The investigator 
should maintain a list of subinvestigators and other appropriately qualified persons to whom he 
or she has delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an Informed Consent 
Form (ICF) and are screened for entry into the study.  Subjects who fail screening must have the 
reason(s) recorded in the subject’s source documents.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries, and allow direct access to subject records (eg, 
medical records, office charts, hospital charts, and study-related charts) for source data 
verification.  The investigator must ensure timely and accurate completion of eCRFs and queries.
14.3.
Subject Information and Informed Consent
The investigator must obtain informed consent of a legal representative prior to any study related 
procedures.
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source documents
including the date.  The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the investigator’s study files and a copy given to the study subject.  In addition, if a protocol is 
amended and it impacts on the content of the informed consent, the ICF must be revised.  Study 
subjects participating in the study when the amended protocol is implemented must be 
reconsented with the revised version of the ICF.  The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the investigator’s 
study files and a copy given to the study subject. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
65
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
14.4.
Confidentiality
Celgene affirms the subject's right to protection against invasion of privacy and will be in 
compliance with ICH and other local regulations (whichever is most stringent). Celgene requires 
the investigator to permit Celgene's representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the investigator to obtain such permission in 
writing from the appropriate individual.
14.5.
Protocol Amendments
Any amendment to this protocol must be approved by the Celgene Clinical Research 
Physician/Medical Monitor.  Amendments will be submitted to the IRB/EC for written approval.  
Written approval must be obtained before implementation of the amended version occurs.  The 
written signed approval from the IRB/EC should specifically reference the investigator name, 
protocol number, study title, and amendment number(s) that is applicable. Amendments that are 
administrative in nature do not require IRB/IEC approval but will be submitted to the IRB/IEC 
for information purposes.
14.6.
Institutional Review Board/Independent Ethics Committee Review 
and Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB/EC with a cover letter or a form listing the documents submitted, their 
dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with 
local legal requirements.
IP can only be supplied to an investigator by Celgene or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Celgene or its authorized representative. This documentation must also include a list of the 
members of the IRB/EC and their occupation and qualifications. If the IRB/EC will not disclose 
the names, occupations, and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. 
Formal approval by the IRB/EC should mention the protocol title, number, amendment number 
(if applicable), study site (or region or area of jurisdiction, as applicable), and any other 
documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/EC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICF should also be revised.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
66
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
The investigator must keep a record of all communication with the IRB/EC and, if applicable, 
between a coordinating investigator and the IRB/EC. This statement also applies to any 
communication between the investigator (or coordinating investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by Celgene and the 
IRB/EC prior to use.  
14.7.
Ongoing Information for Institutional Review Board / Ethics 
Committee
If required by legislation or the IRB/EC, the investigator must submit to the IRB/EC:

Information on serious or unexpected AEs as soon as possible; 

Periodic reports on the progress of the study

Deviations from the protocol or anything that may involve added risk to subjects
14.8.
Closure of the Study
Celgene reserves the right to terminate this study at any time for reasonable medical or 
administrative reasons. Any premature discontinuation will be appropriately documented 
according to local requirements (eg, IRB/EC, regulatory authorities).
In addition, the investigator or Celgene has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such as:

Unsatisfactory enrollment

GCP noncompliance

Inaccurate or incomplete data collection

Falsification of records

Failure to adhere to the study protocol
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
67
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
15.
DATA HANDLING AND RECORDKEEPING 
15.1.
Data/Documents
The investigator must ensure that the records and documents pertaining to the conduct of the 
study and the distribution of the investigational product are complete, accurate, filed, and 
retained.  Examples of source documents include: hospital records; clinic and office charts; 
laboratory notes; memoranda; subject’s diaries or evaluation checklists; dispensing records; 
recorded data from automated instruments; copies or transcriptions certified after verification as 
being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy; and 
the laboratories, as well as copies of eCRFs or CD-ROM.
15.2.
Data Management
Data will be collected via eCRF and entered into the clinical database per Celgene standard 
operating procedures (SOPs). These data will be electronically verified through use of 
programmed edit checks specified by the clinical team.  Discrepancies in the data will be brought 
to the attention of the clinical team, and investigational site personnel, if necessary.  Resolutions 
to these issues will be reflected in the database.  An audit trail within the system will track all 
changes made to the data.
15.3.
Record Retention
Essential documents must be retained by the investigator for a minimum of 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the IP. The investigator must retain these 
documents for the time period described above or according to local laws or requirements, 
whichever is longer. Essential documents include, but are not limited to, the following:

Signed ICF for all subjects

Subject identification code list, screening log (if applicable), and enrollment log

Record of all communications between the investigator and the IRB/EC

Composition of the IRB/EC

Record of all communications between the investigator, Celgene, and their authorized 
representative(s)

List of subinvestigators and other appropriately qualified persons to whom the 
investigator has delegated significant study-related duties, together with their roles in 
the study, curriculum vitae, and their signatures

Copies of eCRFs and of documentation of corrections for all subjects

IP accountability records

Record of any body fluids or tissue samples retained

All other source documents (subject records, hospital records, laboratory records, 
etc.)
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
68
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018

All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Study)
The investigator must notify Celgene if he/she wishes to assign the essential documents to 
someone else, remove them to another location or is unable to retain them for a specified period.  
The investigator must obtain approval in writing from Celgene prior to destruction of any 
records. If the investigator is unable to meet this obligation, the investigator must ask Celgene 
for permission to make alternative arrangements. Details of these arrangements should be 
documented. 
All study documents should be made available if required by relevant health authorities. The 
investigator/institution should take measures to prevent accidental or premature destruction of 
these documents.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
69
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
16.
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by Celgene or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
16.1.
Study Monitoring and Source Data Verification
Celgene ensures that appropriate monitoring procedures are performed before, during and after 
the study. All aspects of the study are reviewed with the investigator and the staff at a study 
initiation visit and/or at an investigator meeting.  Prior to enrolling subjects into the study, a 
Celgene representative will review the protocol, eCRF, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the investigator.  Monitoring will 
include on-site visits with the investigator and his/her staff as well as any appropriate 
communications by mail, email, fax, or telephone.  During monitoring visits, the facilities, 
investigational product storage area, CRFs, subject’s source documents, and all other study 
documentation will be inspected/reviewed by the Celgene representative in accordance with the 
Study Monitoring Plan.  
Accuracy will be checked by performing source data verification that is a direct comparison of 
the entries made onto the eCRF against the appropriate source documentation.  Any resulting 
discrepancies will be reviewed with the investigator and/or his/her staff.  Any necessary 
corrections will be made directly to the eCRF or via queries by the investigator and/or his/her 
staff. Monitoring procedures require that informed consents, adherence to inclusion/exclusion 
criteria, and documentation of SAEs and their proper recording be verified.  Additional 
monitoring activities may be outlined in a study-specific monitoring plan.
16.2.
Audits and Inspections
In addition to the routine monitoring procedures, a Good Clinical Practice Quality Assurance 
unit exists within Celgene.  Representatives of this unit will conduct audits of clinical research 
activities in accordance with Celgene SOPs to evaluate compliance with Good Clinical Practice 
guidelines and regulations.
The investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, regulatory authorities (eg, FDA, EMA, Health Canada), and 
company authorized representatives.  The investigator should make every effort to be available 
for the audits and/or inspections.  If the investigator is contacted by any regulatory authority 
regarding an inspection, he/she should contact Celgene immediately.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
70
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
17.
PUBLICATIONS
The results of this study may be published in a medical publication, journal, or may be used for 
teaching purposes.  Additionally, this study and its results may be submitted for inclusion in all 
appropriate health authority study registries, as well as publication on health authority study 
registry websites, as required by local health authority regulations. Selection of first authorship 
will be based on several considerations, including, but not limited to study participation, 
contribution to the protocol development, and analysis and input into the manuscript, related 
abstracts, and presentations in a study.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
71
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
18.
REFERENCES
American Cancer Society. Pancreatic Cancer 2013.
Alvarez R, Musteanu M, Garcia-Garcia E, et al. Stromal disrupting effects of nab-paclitaxel in 
pancreatic cancer. Br J Cancer. 2013;109(4):926-33.
Berrino F, De Angelis R, Sant M, et al. Survival for eight major cancers and all cancers 
combined for European adults diagnosed in 1995-99: results of the EUROCARE-4 study. Lancet 
Oncol 2007;5:773-783.
Boeck S, Ankerst D, Heinemann V. The Role of adjuvant chemotherapy for patients with 
resected pancreatic cancer: Systematic review of randomized controlled trials and meta-analysis. 
Oncology 2007;72:314-321.
Cancer Research UK. CancerStats: Cancer Worldwide. Sep 2011.
Chen N, Li Y, Ye Y, et al: Pharmacokinetics and pharmacodynamics of nab-paclitaxel in 
patients with solid tumors: Disposition kinetics and pharmacology distinct from solvent-based 
paclitaxel. J Clin Pharmacol, 2014 in press.
Colucci G, Labianca R, Di Costanzo F, et al. Randomized phase III trial of gemcitabine plus 
cisplatin compared with single-agent gemcitabine as first-line treatment of patients with 
advanced pancreatic cancer: The GIP-1 Study. J Clin Oncol 2010;28:1645-1651. 
Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer. N Engl J Med 2011;364:1817-1825. 
Conroy T, Hammel P,Hebbar M, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: A 
multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus 
gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol
2018 ASCO Annual Meeting Abstracts. 2018;36, (18 suppl): Abstract LBA4001.
Corbo V, Giampaolo T, Scarpa A. Molecular pathology of pancreatic cancer: From bench-to-
bedside translation.  Curr Drug Targets 2012;13:744-752. 
Cunningham D, Chau I, Stocken D, et al. Phase III randomized comparison of gemcitabine 
versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 
2009;27:5513-5518.
Dawson SJ, Tsui D, Muhammed M, et al.  Analysis of circulating tumor DNA to monitor 
metastatic breast cancer.  N Engl J Med 2013.  DOI: 10.1056/NEMJoa1213261. 
Desai N, Trieu V, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and 
endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with 
cremophor-based paclitaxel. Clin Cancer Res 2006;12:1317-1324.
FDA. Guidance for Industry: Clinical trial endpoints for the approval of cancer drugs and 
biologics. May 2007. 
Ferlay J, Shin HR, Bray F, et al. GLOBOCAN 2008 v2.0, Cancer incidence and mortality 
worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for 
Research on Cancer; 2010. Available from: http://globocan.iarc.fr.
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
72
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Fischer R, Brediert M, Keck T, et al. Early recurrence of pancreatic cancer after resection and 
during adjuvant chemotherapy.  Saudi J Gastroenterol 2012;18:118-121. 
Frese KK, Neesse A, Cook N, et al. nab-Paclitaxel potentiates gemcitabine activity by reducing
cytidine deaminase levels in a mouse model of pancreatic cancer.  Cancer Discov 2012;2:260-
269.
Gardner ER, Dahut WL, Scripture CD, et al: Randomized crossover pharmacokinetic study of 
solvent-based paclitaxel and nab-paclitaxel. Clin Cancer Res 14:4200-4205, 2008.
Gill S, Sargent D. End points for adjuvant therapy trials: Has the time come to accept disease-
free survival as a surrogate end point for overall survival? The Oncologist 2006;11:624-629.
Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2010, 
National Cancer Institute. 2013. 
Huerros-Villanueva M, Hijona E, Cosme A, et al. Adjuvant and neoadjuvant treatment in 
pancreatic cancer. World J Gastroenterol 2012;18:1565-1572.
Hwang I, Weichung S, De Cani J. Group sequential designs using a family of type I error 
probability spending functions. Stat Med 1990;9:1439-1445.
Infante J, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient 
outcome with resectable pancreatic adenocarcinoma. J Clin Oncol 2007;25:319-25.
Kindler H, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with 
gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the 
Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010;28:3617-22.
Malvezzi M, Bertuccio P, Levi F, et al. European cancer mortality predications for the year 2013. 
Ann Oncol 2013;24:792-800.
Michiels S, Mauguen A, Fisher D, et al. Evaluation of disease-free survival as surrogate endpoint 
for overall survival using two individual patient data meta-analyses of adjuvant chemotherapy in 
operable non-small cell lung cancer. ASCO Meeting Abstracts; JCO 2011;29(suppl; abstr 7004).
NCCN. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma v2. 2012.
Neoptolemos J, Dunn J, Stocken D, et al. Adjuvant chemoradiotherapy and chemotherapy in 
resectable pancreatic cancer: a randomised controlled trial.  Lancet 2001a;358:1576-1585.
Neoptolemos J, Stocken D, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic 
acid vs gemcitabine following pancreatic cancer resection.  JAMA 2010;304:1073-1081. 
Neoptolemos J, Stocken D, Dunn J, et al. Influence of resection margins on survival for patients 
with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 
randomized controlled trial. Ann Surg 2001b;234:758-768.
Neoptolemos J, Stocken D, Friess H, et al. A randomized trial of chemoradiotherapy and 
chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-1210.
Neoptolemos J, Stocken D, Smith C, et al. Adjuvant 5-fluorouracil and folinic acid vs 
observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J 
Cancer 2009;100:246-250. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
73
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Neuhaus P, Riess H, Post S, et al. CONKO-001: Final results of the randomized, prospective, 
multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in 
patients with resected pancreatic cancer. J Clin Oncol 2008;26 (suppl; abstr LBA4504).
Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine 
versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 
2005;16:1639-45.
Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in 
patients undergoing curative-intent resection of pancreatic cancer. JAMA 2007;297:267-277. 
Philip P, Benedetti J, Corless C, et al. Phase III study comparing gemcitabine plus cetuximab 
versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology 
Group-directed intergroup trial S0205. J Clin Oncol. 2010;28:3605-3610.
Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin 
versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) 
in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. 
J Clin Oncol 2009;27:3778-3785.
Rocha Lima C, Green M, Rotche R, et al. Irinotecan plus gemcitabine results in no survival 
advantage compared with gemcitabine monotherapy in patients with locally advanced or 
metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004;22:3776-
3783.
Sargent D, Wieand H, Haller D, et al. Disease-free survival versus overall survival as a primary 
end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 
randomized trials. J Clin Oncol. 2005;23:8664-8670. 
Seufferlein T, Bachet J, Van Cutsem E, et al. Pancreatic adenocarcinoma: ESMO-ESDO clinical 
practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23:vii33-vii40.
Siegel R, Naishadham D, Jemal A. Cancer Statistics 2013. CA Cancer J Clin. 2013;63:11-30
Sinn M, Sinn B, Striefler J, et al. SPARC in pancreatic cancer: Results from the CONKO-001 
study. ASCO Meeting Abstracts; JCO 31: 2013 (suppl; abstr 4016).
Sinn M, Bahra M, Liersch T, et al. CONKO-005: Adjuvant chemotherapy with gemcitabine plus 
erlotinib versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a 
multicenter randomized phase III trial. J Clin Oncol. 2017;35(29):3330-3337.
Stocken D, Büchler M, Dervenis C, et al. Meta-analysis of randomised adjuvant therapy trials for 
pancreatic cancer. Br J Cancer. 2005;92:1372-1381. 
Ueno H, Kosuge T, Matsuyama Y, et al. A randomised phase III trial comparing gemcitabine 
with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant 
Therapy for Pancreatic Cancer. Br J Cancer. 2009;101:908-915.
Uesaka K, Fukutomi A, Boku N, et al. Randomized phase III trial of adjuvant chemotherapy 
with gemcitabine versus S-1 for resected pancreatic cancer patients (JASPAC 01 study). ASCO 
2013 Gastrointestinal Cancers Symposium. January 15,2013; San Francisco, CA. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
nab-Paclitaxel
Protocol ABI-007-PANC-003
Celgene Corporation 
Confidential and Proprietary
74
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2018
Von Hoff D, Ramanathan R, Borad M, et al. Gemcitabine plus nab-paclitaxel is an active 
regimen in patients with advanced pancreatic cancer: A phase I/II trial. J Clin Oncol.
2011;29:4548-4554. 
Von Hoff D, Ervin T, Arena F, et al. nab-Paclitaxel plus gemcitabine improve survival of 
patients with pancreatic cancer. NEJM. 2013;369(18):1691-703. 
Approved
1.0
v


EDMS Doc. Number: 24063939 - 18595591
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Wednesday, 04 September 2019, 11:36 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================
Approved
1.0
v


EDMS Doc. Number: 24063939 - 19600545
nab-Paclitaxel
Summary of Changes ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PANC-003 Amendment 5 Final: 03 Sep 2019
1.
JUSTIFICATION FOR AMENDMENT

Revise the protocol procedures to be performed after achieving the primary 
endpoint.
This amendment is being issued since the primary endpoint of DFS by central review was 
achieved.  At this point, some procedures can be stopped as they would not be necessary for any 
additional potential data analysis.  In this amendment we list all the procedures that can be 
stopped based on achieving the primary endpoint. All study subjects are off study-related 
treatment and are currently undergoing follow up for disease recurrence and survival; therefore 
there is no risk for the safety of the subjects still in the study.
Revised sections:
Protocol Summary
3.1 Primary Endpoint
4.1 Study Design
5 Table 3
6.5 Follow-Up Period (For Disease Recurrence)
Approved
1.0
v


EDMS Doc. Number: 22977531 - 19600545
nab-Paclitaxel
Summary of Changes ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PANC-003 Amendment 4 Final: 12 Sep 2018
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Revised the final disease-free survival (DFS) analysis to be earlier than was originally 
planned (489 events)
The current protocol (Protocol Amendment 3) targets 5 months improvement in median DFS 
based on the assumption of the true median DFS of 14 months in the gemcitabine arm and 19 
months in the nab-paclitaxel in combination with gemcitabine arm which was translated to a 
hazard ratio (HR)A+G/G of 0.74, assuming exponential distributions. At least 489 DFS events from 
800 subjects are required to allow 90% power to detect a 26% reduction of risk in disease 
recurrence or death from the treatment arm at two-sided significance level of 0.05. More 
contemporaneous Phase III studies with gemcitabine in the targeted population of surgically 
resected pancreatic adenocarcinoma have shown consistently that DFS for patients may be lower 
than the median DFS of 14 months in the CONKO-001 study (Oettle, 2007).  This provides the 
rationale for the adjustment of the timing and duration of the DFS follow-up assessments in 
Amendment 4 of the ABI-007-PANC-003 study. Results from the CONKO-005 (Sinn, 2017) and 
PRODIGE 24 (Conroy, 2018) studies showed a median DFS with adjuvant gemcitabine of 11.4 
and 12.8 months, respectively. Based on these available data, the same targeted 5 months 
improvement in median DFS based on the assumption of the true median DFS of 13.5 months in 
the gemcitabine arm and 18.5 months in the nab-paclitaxel in combination with gemcitabine arm 
translates to an HRA+G/G of 0.73, assuming exponential distributions.  At least 438 DFS events 
are required to allow 90% power to detect a 27% reduction of risk in disease recurrence or death 
at a two-sided significance level of 0.05. 
The data cutoff date for the revised final DFS analysis is projected to be December 2018.  
Although enrollment of all 866 subjects was completed in April 2016, due to an unexpected and 
ongoing low rate of independently assessed DFS events, 438 DFS events may be reached by the 
December 2018 data cutoff.
Overall survival data will be analyzed as supportive analyses. The reported median survival 
from 2 randomized Phase 3 studies in subjects with surgically resected pancreatic 
adenocarcinoma who received gemcitabine as adjuvant treatment (Neoptolemos, 2010; Oettle, 
2007) ranged from 22 months to 24 months. It is projected that between 410 and 440 deaths will 
have occurred at the time of the data cut-off for the final DFS analysis and all subjects remaining 
on study will have at least 32 months of survival follow-up.
Revised sections: Protocol Summary, Section 10.3 Sample Size and Power Considerations, and 
Section 18 References

The amendment also includes other minor clarifications and corrections:
Other clarifications, corrections of minor typographical errors and incidental formatting changes 
were made throughout the document.
Approved
1.0
v


EDMS Doc. Number: 21592635 - 19600545
nab-Paclitaxel
Summary of Changes ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PANC-003 Amendment 3 Final: 21 Dec 2016
1.
JUSTIFICATION FOR AMENDMENT

Removal of the second interim analysis of efficacy 
The protocol stated that two interim analyses of efficacy were planned: the first is to be
conducted at about 33% information time (ie, after 163 disease-free survival [DFS] events) to 
assess futility and the second is to be conducted after 70% information time (ie, after 342 DFS 
events) have been observed or the completion of accrual of 800 subjects, whichever is later, to 
assess both futility and superiority.
At the time of the futility analysis, and time of Protocol Amendment 3, 866 subjects have been 
randomized and completed or discontinued treatment.
Based on health authority recommendation to avoid premature interruption of the trial, and to 
ensure that the study has sufficient duration of follow-up to verify clinical benefit and assess 
benefit-risk in this setting, the second interim analysis to assess both futility and superiority will 
not be conducted.
Revised sections: Protocol Summary, 4.1 Study Design, 10.3 Sample Size and Power 
Considerations, and 10.8 Interim Analysis
The Section 10.9.1 Data Monitoring Committee (DMC) is revised to reflect the impact of the 
second interim analysis on efficacy removal on DMC review. With the removal of the second 
interim analysis on efficacy, the DMC has reviewed the safety data after the first 100 subjects 
have completed 2 cycles of the treatment, and data from the interim analysis on efficacy planned 
at about 33% information time (ie, after 163 DFS events).
Revised sections: 10.9.1 Data Monitoring Committee

Modification of stratification by Region
Per Protocol Amendment 1 the subjects are to be stratified at randomization based on Region 
(North America versus Europe versus Australia versus Asia Pacific).
To reflect the reality of the stratification applied to the randomization, which is based on the 
original protocol, the wording is revised as follows: per Region (North America, Europe and 
Australia versus Asia Pacific).
Revised sections: Protocol Summary, 1.4.1 Rationale for Stratification Factors, 4.1 Study 
Design, 10.1 Overview, and 10.6.1 Primary Efficacy Analyses

Clarification on biomarker collection rationale
The Section 6.7 Biomarker and Pharmacogenomic Testing is revised to add more rationale on 
the collection of recurrent biopsies.
Revised sections: 6.7 Biomarker and Pharmacogenomic Testing
Approved
1.0
v


EDMS Doc. Number: 20716374 - 19600545
nab-Paclitaxel
Summary of Changes ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
ABI-007-PANC-003 Amendment 2 Final: 03 Dec 2015
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Clarification on collection of central versus local labs
The protocol had stated that central lab results are required to determine eligibility for study 
entry, except for coagulation tests which may be done locally.  Central labs will need to be 
drawn regardless, and the use of local labs will allow additional time flexibility for sites and their 
subjects to ease randomization. The local lab results should be well within the range for 
eligibility as to likely yield central lab results that will confirm the eligibility criteria.  In 
addition, sites have been making dosing decisions based on local lab results – this does not 
impact the eligibility of the patients.  
Revised sections: Section 6.1

Added language to clarify length of time allowed from randomization to Cycle 1 Day 
1 dosing.
The protocol had stated that subjects should return within 3 days of randomization to begin 
Cycle 1 of IP dosing.  The change allows for flexibility for some subjects who for unforeseen 
reasons cannot be dosed within 3 days of randomization.  Subjects should still have met the 
protocol defined eligibility requirements (especially disease free status) within the original 
protocol defined allotted time between screening and starting study treatment. This will allow
for additional time and provide flexibility while maintaining the patient population as being 
disease free within the same interval before start of treatment.
Revised sections: Section 6.3

Clarification on how to define a subject that has completed 6 cycles of study 
treatment versus discontinued early from study treatment
Further clarification to help ensure subjects are uniformly categorized as those who completed 6 
cycles of treatment versus those who discontinued early from study treatment.  A subject that 
completed 6 cycles of study treatment received at least 2 doses during cycle 6 and a 
discontinued subject only received one dose during Cycle 6 or discontinued before Cycle 6.  
Revised sections: Section 6.4

Clarification on what is considered to be new/subsequent anticancer therapy
Subjects are censored for disease free survival (DFS) if a new anticancer therapy is started before 
disease recurrence or death.  If a subject only continues one or more of the anticancer therapy 
(regardless of dose or schedule) identical to the study treatment they were randomized to, it will 
not be considered to be new therapy. This would not represent new effective anticancer therapy 
and therefore will not be censored. 
Revised sections: Section 6.5, Section 10.6.1

Updated treatment administration and schedule section to include flushing 
requirement
Approved
1.0
v


EDMS Doc. Number: 20716374 - 19600545
nab-Paclitaxel
Summary of Changes ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
4
ABI-007-PANC-003 Amendment 2 Final: 03 Dec 2015
Added standard language to be consistent with information previously provided to sites requiring 
that nab-paclitaxel must be flushed after administration of the dose to ensure the complete dose 
is given to subjects. 
Revised sections: Section 8.2

Clarification on dose modifications
The protocol had only allowed for two levels of dose modifications. Sites should contact the 
sponsor for additional guidance prior to discontinuing subjects from the study. This will allow 
subjects to have access to as much adjuvant therapy possible, based on data from the European 
Study Group for Pancreatic Cancer (ESPAC)-3 study. 
The protocol is unclear on what the starting dose should be if the Day 15 dose was held. 
Guidance is provided on how to start Day 1 dosing based off of what was done on Day 8.  
Removed the sentence, subjects experiencing IP related toxicities that require a delay in 
scheduled nab-paclitaxel or gemcitabine dosing for ≥21 days will be discontinued from further 
treatment in this study (except for peripheral neuropathy). This will allow subjects to have access 
to as much adjuvant therapy possible.
Provided clarity for subjects randomized to the combination arm, for the possibility to withhold 
treatment with one agent and continue with the other agent and remain on study. This will allow 
for maximum access to therapy. 
Dose re-escalations not related to neutropenia will need to be discussed with the sponsor.
For all non-hematologic toxicities, both or either agent can be held until improvement to grade ≤ 
1.  This was changed to be consistent with the language within other sections on the guidance to 
withhold one or both agents for dose modifications to ensure maximum therapy for subjects. 
Revised sections: Section 8.2.1.1, Table 4 footnote, Section 8.2.1.1.1, Table 6

Clarification on how to dose subjects with abnormal hepatic function
Removed sentence that says IP should only be administered if hepatic function is within the 
parameters established in the eligibility criteria.  Sites have reported they do not interrupt dosing 
for subjects with lower grade liver enzyme elevations. No additional toxicities are noted in these 
subjects.  This will help ensure maximum dosing to all subjects randomized onto the study, and 
is consistent with other non-hematologic toxicity management. 
Revised sections: Section 8.2.1.1.2
The amendment also includes several other minor clarifications:

Clarified imaging scans can be done at anytime during the week of the planned 
assessment with +/- 7 days from time of planned assessment.

Clarify that a drug related toxicity should be the reason for the maximum of 21 days 
dose delay between a missed scheduled dose and the next one

Further clarity on the definition of the per-protocol population

Updated censoring rules

Updated TEAE definition
Approved
1.0
v


EDMS Doc. Number: 19745556 - 19600545
nab-Paclitaxel
Summary of Changes ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
  ABI-007-PANC-003Amendment 1:  23 June 2014
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Regional stratification: Changes were made to update stratification that there is no 
“other” category and to clarify that all regions will be analyzed independently and 
compared to each other. 

Sample size calculation: Changes were made to correct an error in the hypotheses for 
sample size calculation.

Assessment of Disease Recurrence: Changes were made  to clarify that 1) recurrent 
disease will not be followed 2) clarify the frequency of scans, 3) biopsies from recurrent 
disease is recommended and if done then samples will be collected along with pathology 
report.

Follow-up Period: Changes were made to remove repetition on the description of scan 
frequency and indicate CA19-9 and QoL assessments during the follow-up period.

Exploratory Biomarker and Pharmacogenomic Testing: Language was updated to 
clarify and specify details for tumor and blood samples for biomarker and 
pharmacogenomic testing. Added recommendation for blood sample collection at disease 
recurrence.

Eligibility: Changes were made to clarify language that males and non-lactating, non-
pregnant females are eligible who do not show recurrent disease at screening, have not 
received prior systemic therapy and do not have high grade peripheral neuropathy.
Additionally, patient with active hepatitis B or C are not eligible.

Obtaining gemcitabine and handling and storing Abraxane: Changes were made to 
clarify that local regulations should be followed.

Adverse events: General changes were made to reflect the Celgene-specific safety 
language update, to clarify recommended guidelines about pneumonitis, defining
overdose, and to describe permitted and prohibited concomitant medications and 
precautions in more details.
Approved
1.0
v

SAP_001.pdf: 
',6&/2685(
5('$&7('67$7,67,&$/$1$/<6,63/$1
$%,3$1&
$3+$6(08/7,&(17(523(1/$%(/5$1'20,=('678'<2)
QDE3$&/,7$;(/3/86*(0&,7$%,1(9(5686*(0&,7$%,1(
$/21($6$'-89$177+(5$3<,168%-(&76:,7+685*,&$//<
5(6(&7('3$1&5($7,&$'(12&$5&,120$
7KHLQIRUPDWLRQFRQWDLQHGLQWKHDWWDFKHGUHSRUWLVWKHSURSHUW\RI&HOJHQHDQGVKRXOGQRWEHVKDUHGRU
XVHGIRUDQ\SXUSRVHRWKHUWKDQWKDWIRUZKLFKLWZDVSURYLGHG

&HOJHQHLVFRPPLWWHGWRSURYLGLQJLQIRUPDWLRQDERXWLWVFOLQLFDOWULDOVWRUHVHDUFKHUVDQGSDWLHQWVZLWKWKH
JRDORIIXUWKHULQJVFLHQFHDQGHQKDQFLQJKHDOWKFDUHZRUOGZLGH/DZVDQGUHJXODWLRQVUHTXLUHKRZHYHU
WKDW&HOJHQHSURWHFWVSDWLHQWSULYDF\7KHFRPSDQ\PD\IXUWKHUKDYHOHJDORUFRQWUDFWXDOREOLJDWLRQVQRW
WRGLVFORVHFRPPHUFLDORUWHFKQLFDOLQIRUPDWLRQSURYLGHGE\RUUHODWHGWRFHUWDLQSDUWQHUFRPSDQLHVRU
YHQGRUV

7KHDWWDFKHGUHSRUWLVSUHVHQWHGLQLWVRULJLQDOIRUPDWEXWFHUWDLQLQIRUPDWLRQKDVEHHQUHGDFWHGLQRUGHU
WRFRPSO\ZLWKWKHDIRUHPHQWLRQHGREOLJDWLRQVRUWRSURWHFW&HOJHQH¶VFRQILGHQWLDOFRPPHUFLDO
LQIRUPDWLRQ7KHUHGDFWLRQVDUHEDVHGRQWKHIROORZLQJSULQFLSOHV

x
5HGDFWHGLQIRUPDWLRQKDVEHHQUHSODFHGE\JUH\VSDFHPDLQWDLQLQJRULJLQDOVSDFLQJDQGSDJLQDWLRQ
x
$Q\LQIRUPDWLRQWKDWPLJKWDOORZWKHLGHQWLILFDWLRQRILQGLYLGXDOVKDVEHHQUHGDFWHGIRU
DQRQ\PL]DWLRQ
x
$WWDFKPHQWVWRWKLVUHSRUWWKDWFRQWDLQFRQILGHQWLDOLQIRUPDWLRQDUHQRWPDGHDYDLODEOH6XFK
DWWDFKPHQWVLQFOXGHWKRVHWKDWFRQWDLQLGHQWLILDEOHSDWLHQWLQIRUPDWLRQVXFKDVVXEMHFWOLVWLQJV
QDUUDWLYHVDQGSURILOHV7KH\DOVRPD\FRQWDLQFRQILGHQWLDOFRPPHUFLDOLQIRUPDWLRQVXFKDV
PHWKRGRORJLHVDQGK\SRWKHVLVJHQHUDWLQJDQGH[SORUDWRU\DQDO\VHV
x
&URVVUHIHUHQFHVWRWKHVHDWWDFKPHQWVVXFKDVOLQNVWRVXEMHFWOLVWLQJVLQ6HFWLRQDUHQRW
UHGDFWHGIURPWKHERG\RIWKHUHSRUW+RZHYHUWKHK\SHUOLQNVLQWKHHOHFWURQLFGRFXPHQWDUHQR
ORQJHUIXQFWLRQDO
x
,QIRUPDWLRQDERXW&HOJHQHYHQGRUVDQGWKHLUVHUYLFHVDUHUHGDFWHGEHFDXVHPDQ\FRQWUDFWVSURKLELW
GLVFORVXUHRIWKDWLQIRUPDWLRQ)XUWKHUODZVDQGUHJXODWLRQVSUHYHQWXVIURPGLVFORVLQJFHUWDLQ
LQIRUPDWLRQDERXWRXUYHQGRUVRUWKHLUVHUYLFHVEHFDXVHLWLVSURWHFWHGE\FRS\ULJKW

,QIRUPDWLRQDERXW&HOJHQH¶VUHGDFWLRQSROLFLHVDQGWKHDYDLODELOLW\RIDGGLWLRQDOGDWDIURPWKLVUHSRUWPD\
EHIRXQGDWKWWSZZZFHOJHQHFRPUHVHDUFKGHYHORSPHQWFOLQLFDOWULDOVFOLQLFDOWULDOVGDWDVKDULQJ


&(/*(1(35235,(7$5<,1)250$7,21
WEHVKDUHGR
EHVKDUHG
KHUVDQGSDWL
HUVDQGSDWL
XODWLRQVUHT
DWLRQVU
RUFRQWUDFWX
RUFRQWUDFW
RFHUWDLQSDU
FHUWDLQSD
QLQIRUPDWLR
LQIRUPDW
&HOJHQH¶VFR
&HOJHQH¶VF
LQFLS
LQFL OHV
HV
VSDFHPDLQ
VSDFHPD
FDWLRQRILQ
FDWLRQRILQ
FRQILGHQWLDO
RQILGHQWL
LQLGHQWLILDE
LQLGHQWLI
RPD\FRQWD
RPD\FRQWD
VJHQHUDWLQJ
JHQHUDWLQJ
WDFKPHQWV
WDFKPHQWV
RIWKHUHSRUW
WKHUHSRUW
&HOJHQHYHQ
&HOJHQHY
DWLQIRUPDWLR
WLQIRUPDWL
ERXWRXUYH
ERXWRXUYH
QDERXW&HOJ
DERXW&HOJ
GDWKWWSZZ
GDWKWWSZ


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
1
STATISTICAL ANALYSIS PLAN
A Phase 3, Multicenter, Open-label, Randomized Study of nab®-Paclitaxel Plus Gemcitabine Versus 
Gemcitabine Alone as Adjuvant Therapy in Subjects With Surgically Resected Pancreatic 
Adenocarcinoma
STUDY DRUG:
nab-Paclitaxel
PROTOCOL NUMBER:
ABI-007-PANC-003
DATE FINAL:
15 Aug 2016
AMENDMENT DATE:
17 Jan 2019
Prepared by:
On behalf of 
Celgene Corporation
86 Morris Avenue
Summit, NJ 07901
___________________________________________
nab® is a registered trademark of Abraxis Bioscience, LLC
CONFIDENTIAL
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.
&&,
&&,
&(/*(1(3
formation 
formation 
except to t
except to
disclosed
disclosed
regu
regu
35235,(7$5<,1)250$7,21
f of 
f of
e Corporatio
Corporatio
6 Morris Av
Morris Av
Summit,
Summ
in
in
35
3
(/
(/


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
2
TABLE OF CONTENTS
SIGNATURE PAGE...................................................................................................................6
1.
LIST OF ABBREVIATIONS...................................................................................7
2.
INTRODUCTION....................................................................................................9
3.
STUDY OBJECTIVES...........................................................................................10
3.1.
Primary Objective...................................................................................................10
3.2.
Secondary Objectives .............................................................................................10
3.3.
Exploratory Objectives ...........................................................................................10
4.
INVESTIGATIONAL PLAN .................................................................................11
4.1.
Overall Study Design and Plan ...............................................................................11
4.2.
Study Endpoints .....................................................................................................12
4.2.1.
Primary Efficacy Endpoint......................................................................................12
4.2.2.
Secondary Efficacy Endpoint..................................................................................12
4.2.3.
Exploratory Efficacy Endpoint(s)............................................................................12
4.2.4.
Safety Endpoints.....................................................................................................13
4.3.
Stratification and Randomization............................................................................13
4.4.
Sample Size Determination.....................................................................................13
5.
GENERAL STATISTICAL CONSIDERATIONS .................................................15
5.1.
Reporting Conventions ...........................................................................................15
5.2.
Analysis Populations ..............................................................................................16
5.2.1.
Intent-to-Treat Population.......................................................................................16
5.2.2.
Treated Population..................................................................................................16
5.2.3.
Per-Protocol Population..........................................................................................16
6.
SUBJECT DISPOSITION......................................................................................17
7.
PROTOCOL VIOLATIONS ..................................................................................18
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................19
8.1.
Demographics.........................................................................................................19
8.2.
Cancer History and Surgery....................................................................................19
8.3.
Baseline Disease Status ..........................................................................................20
8.4.
Medical History......................................................................................................20
8.5.
Prior Therapy..........................................................................................................20
CCI
&(/*(1(35235,(7$5<,1)250$7,21
10
10
........10
10
............
............10
1
..............
...........
.............
.........
.............
.....
..............
..........
.............
...........
..............
............
.............
.......... .
.............
..........
..............
.......
..............
.............
CONSIDE
CONSIDE
..............
...........
.............
.............
Popul
opulati
ation
o
ulat
ula ion....
...
ocol Popul
col Popu
JECT DIS
JECT DIS
PROTOCO
PROTOCO
DEM
DEMO
De
De
8.2.
.2.
3


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
3
8.5.1.
Prior Other Anti-cancer Therapy.............................................................................20
8.5.2.
Prior Radiation Therapy for Other Diseases............................................................20
8.5.3.
Prior Cancer Surgery for Other Diseases.................................................................20
8.6.
Prior and Concomitant Medications........................................................................20
8.6.1.
Prior Medications ...................................................................................................20
8.6.2.
Concomitant Medications .......................................................................................21
8.7.
Concomitant Procedures/Surgeries .........................................................................21
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE....................................22
9.1.
Treatment Duration.................................................................................................22
9.2.
Cumulative Dose ....................................................................................................22
9.3.
Dose Intensity.........................................................................................................22
9.4.
Percentage of Protocol Dose ...................................................................................22
9.5.
Dose Reduction/Delay/Omission ............................................................................23
10.
EFFICACY ANALYSIS ........................................................................................24
10.1.
Multiplicity.............................................................................................................24
10.2.
Analysis of Primary Efficacy Endpoint...................................................................24
10.2.1.
Primary Efficacy Analysis on DFS .........................................................................24
10.2.2.
Sensitivity Analyses on DFS...................................................................................26
10.3.
Analyses of Secondary Efficacy Endpoint...............................................................27
10.4.
Subgroup Analysis..................................................................................................27
11.
SAFETY ANALYSIS ............................................................................................29
11.1.
Adverse Events.......................................................................................................29
11.2.
Adverse Events of Special Interest..........................................................................31
11.2.1.
AE of Special Interest.............................................................................................31
11.2.2.
Pneumonitis and Sepsis ..........................................................................................32
11.2.3.
Peripheral Neuropathy............................................................................................32
11.3.
Clinical Laboratory Evaluations..............................................................................33
11.3.1.
Hematology............................................................................................................33
11.3.2.
Clinical Chemistry..................................................................................................33
11.4.
Vital Sign Measurements........................................................................................33
11.5.
ECOG Performance Status......................................................................................33
11.6.
Physical Examination .............................................................................................34
&&,
CCI
&(/*(1(352
YSIS
SIS ......
.
ts...........
...
Events of S
Events of
f Special In
f Special In
neumo
eumonit
nitisi
Peri
Peripher
pher
i
235,(7$5<,1)250$7,21
1
.......21
2
..........
.... 22
2
..............
...........
..............
............
.............
.............
..............
............
.............
.............
.............
.....
..........
..... .......
.............
.............
.............
............
..............
..........
cy Endpoin
Endpoin
y
.............
....
Clin
Cli
1.3.1.
1.3.1.
11.3.2.
1.3.2.
523


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
4
11.7.
Electrocardiograms.................................................................................................34
11.8.
Pregnancy Test .......................................................................................................34
12.
QUALITY OF LIFE ANALYSIS...........................................................................35
13.
INTERIM ANALYSIS...........................................................................................36
13.1.
General Information................................................................................................36
13.2.
Statistical Approaches for Control of Alpha and Beta .............................................36
14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF THE 
PROTOCOL...........................................................................................................37
15.
REFERENCE.........................................................................................................38
16.
APPENDICES........................................................................................................39
16.1.
Handling of Dates...................................................................................................39
16.2.
Date Imputation Guideline......................................................................................39
16.2.1.
Impute Missing Adverse Events/ Prior or Concomitant 
Medications/Procedures..........................................................................................39
16.2.2 
Impute Missing Cancer History Dates.....................................................................41
16.2.3 
Impute Missing Subsequent Anti-cancer Therapy ...................................................41
&&,
&(/*(1(35235,(7$5<,1)250$7,21
6
........
.......37
37
..............
............ 3
.............
.......
.............
.............
..............
.......
..............
...........
..............
.............
rapy
apy .......
..


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
5
LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms..........................................................................7
Table 2:
Power Calculation for Overall Survival (OS) with N=800.......................................14
Table 3:
Censoring Rules for DFS........................................................................................25
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
6
SIGNATURE PAGE
STATISTICAL ANALYSIS PLAN (SAP) AND SAP AMENDMENT APPROVAL SIGNATURE PAGE
SAP TITLE
ABI-007-PANC-003 Statistical Analysis Plan
SAP AMENDMENT 
VERSION, DATE
Final 17 Jan 2019
SAP AMENDMENT
AUTHOR
Printed Name and Title
Signature and Date
PROTOCOL TITLE
A Phase 3, Multicenter, Open-label, Randomized Study of nab®-Paclitaxel Plus 
Gemcitabine Versus Gemcitabine Alone as Adjuvant Therapy in Subjects With 
Surgically Resected Pancreatic Adenocarcinoma
INVESTIGATIONAL 
PRODUCT
nab-Paclitaxel
PROTOCOL NUMBER
ABI-007-PANC-003
PROTOCOL VERSION, 
DATE
Amendment 4, 12 Sep 2018
SIGNATURE 
STATEMENT
By my signature, I indicate I have reviewed this SAP and find its contents to be 
acceptable.
Statistical Therapeutic Area Head
Signature
{See appended electronic signature page}
Printed Name
Date
Lead Clinical Research Physician / Clinical Research Physician
Signature
{See appended electronic signature page}
Printed Name
Date
Lead Product Safety Physician
Signature
{See appended electronic signature page}
Printed Name
Date
&&,
33'
&(/*(1(35
sician / Clin
ian / Clin
35235,(7$5<,1)250$7,21
$7
$7
$7
$7
$7
$7
$7
0$
0$
0$
clitaxel Plus
clitaxel Plus
n Subjects W
n Subjects W
0
)2
,1
< ,
$5
$5
ve reviewed t
e reviewed t
$5
(7
tronic signa
ronic sig
23
52
35
{See appe
{See app
ame
me
1
(
Product 
roduct Saf
Saf
*
&
Signa
Sign
&


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
7
1.
LIST OF ABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
BMI
Body mass index
BSA
Body surface area
CA19-9
Carbohydrate antigen 19-9
CI
Confidence interval
CRF
Case report form
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
DFS
Disease-free survival
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of treatment
HR
Hazard ratio
LN
Lymph nodes
IP
Investigational product
IPMN
Intraductal papillary mucinous neoplasm
IRT
Interactive Response Technology
ITT
Intent-to-treat
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
NA
Not applicable
&&,
&(/*(1(35235,(7$5<,1)250$7,21
Events
Event
ology Grou
logy Grou
ion for Rese
ion for Rese
nt
ioio
ph nodes
ph nodes
Investigation
nvestigatio
Intradu
Intradu
In
In
V
MedDR
MedD


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
8
NCI
National Cancer Institute
OS
Overall survival
PET
Positron emission tomography
PN
Peripheral neuropathy
PP
Per-protocol
PT
Preferred term
QLQ
Quality of life questionnaires
QOL
Quality of life
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SMQ
Standardised MedDRA Query
SOC
System organ class
STDEV
Standard deviation
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WBC
White blood cell
WHO
World Health Organization
WNL
Within normal limit
&&,
&(/*(1(35235,(7$5<,1)250$7,21
rse event
se event
th Organiza
h Organiz
normal lim
ormal lim


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
9
2.
INTRODUCTION
This statistical analysis plan (SAP) describes the analyses and data presentations for Celgene’s protocol 
ABI-007-PANC-003 “A Phase 3, Multicenter, Open-label, Randomized Study of nab®-Paclitaxel Plus 
Gemcitabine Versus Gemcitabine Alone as Adjuvant Therapy in Subjects With Surgically Resected 
Pancreatic Adenocarcinoma” which was originally issued on 06 Sep 2013 and subsequently amended on 
23 Jun 2014 (Amendment No. 1) and on 03 Dec 2015 (Amendment No. 2). It contains definitions of 
analysis populations, derived variables and statistical methods for the analysis of efficacy and safety.
Following finalization of the SAP on 15 Aug 2016, Protocol Amendment No. 3 and 4 were released on 21 
Dec 2016 and 12 Sep 2018, respectively. This SAP amendment reflects all changes to the planned 
analysis. Other clarifications and incidental formatting changes were made throughout the document.
This study includes 2 protocol pre-planned interim analyses, one final analysis on disease-free survival 
(DFS) and one supportive analysis on overall survival (OS). Throughout this SAP, the treatment arms will 
be referred to as nab-paclitaxel in combination with gemcitabine (Arm A) and gemcitabine alone (Arm 
B). The name “nab-paclitaxel” is interchangeable with “ABRAXANE®”. The purpose of the SAP is to 
ensure the credibility of the study findings by pre-specifying the statistical approaches to any data 
analysis prior to database lock. This SAP amendment will be finalized and signed prior to the clinical 
database lock for the final analysis on DFS. All statistical analyses detailed in the SAP amendment will 
be conducted using SAS® Version 9.2 or higher. The clinical cutoff date will be determined based on the 
occurrence of DFS or OS events as specified in the SAP amendment. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
on 21
on 
ument.
ument.
free surviva
free surviv
treatment a
treatment
citabine alon
citabine al
urpose of
urpose o th
pproaches to
proaches t
d signed prio
igned p
ailed in the 
ed in the
date will be
date will
ment
ent.


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
10
3.
STUDY OBJECTIVES
3.1.
Primary Objective
The primary objective of the study is to compare DFS between subjects randomized to nab-paclitaxel in 
combination with gemcitabine and subjects randomized to gemcitabine alone.
3.2.
Secondary Objectives
The secondary objectives of the study are to:
!
Assess overall survival (OS) between subjects randomized to nab-paclitaxel in combination with 
gemcitabine and subjects randomized to gemcitabine alone
!
Evaluate safety and tolerability of the 2 treatment regimens
3.3.
Exploratory Objectives
The exploratory objectives of the study are to:
!
 
!
!
Evaluate the effect of nab-paclitaxel in combination with gemcitabine and gemcitabine alone on 
subject’s quality of life (QoL)
&&,
CCI
CCI
&(/*(1(35235,(7$5<,1)250$7,21
on with 
on with 
ith gemcitab
ith gemcitab
,1)
5<


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
11
4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a Phase 3, international, multicenter, randomized, open-label, controlled study to assess the 
efficacy of nab-paclitaxel in combination with gemcitabine (Arm A) compared with gemcitabine alone 
(Arm B) as adjuvant treatment for 6 cycles. The study will enroll approximately 800 subjects and subjects 
will be assigned to treatments by a stratified randomization with 1:1 ratio.
The stratification factors will include:
!
Resection Status: R0 (tumor-free margin) versus R1 (microscopically positive margin)
!
Nodal Status: lymph node (LN+ versus LN-)
!
Region (North America, Europe and Australia versus Asia Pacific)
The study will consist of the following visits: 
Screening Evaluations: To be obtained ≤14 days prior to randomization. 
Randomization: Eligible subjects should be randomized to the study as early as adequately recovered 
from surgery, but no later than 12 weeks postsurgery. Subjects should be dosed within 3 days of 
randomization. If the subject cannot be dosed within this time, it will need to be discussed with the 
sponsor. 
Treatment: The treatment cycles are 28 days and the study drug (s) are administered for 6 cycles as 
specified in protocol Section 8.2. The dosing schedule for each treatment arm is as follows: 
!
Arm A
∀
nab-Paclitaxel 125 mg/m2 as a 30- to 40-minute infusion followed by gemcitabine 1000 
mg/m2 as a 30- to 40-minute infusion on Days 1, 8 and 15 of a 28-day cycle for 6 cycles. 
Following administration of nab-Paclitaxel, the intravenous (IV) line should be flushed 
with sodium chloride 9 mg/ml (0.9%) solution for injection to ensure administration of 
the complete dose, according to local practice. 
!
Arm B
∀
Gemcitabine 1000 mg/m2 as a 30- to 40-minute infusion administered on Days 1, 8 and 
15 of a 28-day cycle for 6 cycles
Disease Recurrence Assessments: Subjects will be evaluated for disease recurrence by computed 
tomography (CT) scans; image preparation and evaluation for new lesions will follow the specification 
provided in the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. RECIST 
(Eisenhauer, 2009) will be used only as a guidance to identify new lesions; new lesions will not be 
followed. Magnetic resonance imaging (MRI) can be used based on the investigator’s judgment or 
institution policy, as long as the same modality (CT or MRI) is used at screening and through the study. 
The CT/MRI scan of the chest and abdomen/pelvis is to be performed ≤ 14 days prior to randomization 
(screening period), every 8 weeks after randomization for the first 24 weeks, then every 12 weeks for the 
next 2.5 years until 3 years after randomization, and then every 24 weeks thereafter until disease 
recurrence for the next 2.5 years up to 5.5 years after randomization. Scans can be done ± 7 days from the 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
as early as 
as early as 
ould be dose
uld be dos
it will need 
it will need 
tudy drug (s
tudy drug (s
le for each t
le for each
as a 30
s a 30- to 4
to
inute infusi
inute infu
ation of 
ation of nab
na
oride 9 mg/m
ide 9 mg
dose, accord
dose, acco
mcitabine 100
citabine 10
5 of a 28
5 of a 28-da
da
rrence Ass
rrence Ass
hy (CT) scan
(CT) sca
ed in the Re
ed in the Re
senhauer, 20
enhauer, 20
(
followed. M
ollowed. M
institutio
nstituti
e C


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
12
time of the planned assessment. An unscheduled scan for suspected disease recurrence may be performed 
at any time. However, adherence to the planned imaging schedule is critical regardless of dose delays or 
unscheduled or missed assessments. 
Carbohydrate Antigen 19-9 (CA19-9) will be obtained at the same week as the CT scans, but are not to be 
used alone as evidence of disease recurrence. 
End-of-Treatment (EOT) Evaluation: An EOT evaluation should be performed for all subjects 
according to the following schedule: for subjects who complete 6 cycles of treatment, as soon as possible 
after end of Cycle 6 (ie, after Cycle 6 Day 28), but no later than 14 days after Cycle 6 Day 28; for subjects 
who discontinue treatment prior to completing 6 cycles of treatment, the EOT visit should be performed 
as soon as possible after the decision is made.
A completed subject is defined as a subject that has completed 6 cycles of treatment and received at least 
2 doses during Cycle 6; a discontinued subject is defined as not completing all 6 cycles of treatment or 
only received 1 dose during Cycle 6. 
Follow-up for Disease Recurrence: Subjects who are discontinued from study treatment in the absence 
of disease recurrence (e.g., subjects removed for unacceptable toxicity or subject/investigator discretion) 
are followed for disease recurrence. Subjects should undergo repeat imaging until disease recurrence, 
death or the start of new anticancer therapy is documented (except as noted below), whichever is earlier. 
Subsequent anticancer therapy (including radiation) should not be instituted until disease recurrence is 
documented. If a subject starts a subsequent anticancer therapy prior to disease recurrence, then repeat 
imaging and tumor response assessments should be discontinued except as follows:
!
Subjects randomized to nab-Paclitaxel + gemcitabine who receive subsequent therapy with nab-
Paclitaxel or gemcitabine, or both (without any other agents);
!
Subjects randomized to gemcitabine who receive subsequent therapy with gemcitabine (without 
any other agents). 
Follow-up for Overall Survival and Anticancer Therapy: Post-treatment OS and any subsequent anti-
cancer therapy information status will be monitored every 3 months or more frequently as needed until 
death, withdrawal of consent, or the study closes, whichever is earliest. This evaluation may be by record 
review and/or telephone contact. 
4.2.
Study Endpoints
4.2.1.
Primary Efficacy Endpoint
The primary endpoint of the study is independently assessed DFS, which is defined as the time from the 
date of randomization to the date of disease recurrence or death, whichever is earlier.
4.2.2.
Secondary Efficacy Endpoint
The secondary efficacy endpoint of the study is OS, which is defined as the time from the date of 
randomization to the date of death.
4.2.3.
Exploratory Efficacy Endpoint(s)
Other efficacy endpoints of interest include:
&&,
&(/*(1(35235,(7$5<,1)250$7,21
ects
cts
rmed 
rmed 
ceived at lea
ceived at le
of treatment
of treatmen
treatment in
treatment in
ject/investig
ect/invest
ng until dis
g until dis
noted below)
ed below
instituted u
instituted u
prior to dis
prior to dis
nued excep
nued excep
itabine who 
tabine who 
any other ag
any other a
ho receive su
o receive s
Anticancer T
nticancer
ll be monito
ll be monit
he study clo
e study c
ct.
ct.
points
oints
ry Efficacy
ry Efficacy
endpoint of t
endpoint of
domization 
omization
Seco
Sec
The second
The second
andomi
andom


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
13
!
!
!
Difference in outcomes between the European Organization for Research and Treatment of 
Cancer (EORTC) quality of life questionnaires (QLQ), EORTC QLQ-C30 and QLQ-PAN26, 
during and after treatment versus at baseline.
Statistical analysis of the exploratory data collected from plasma and tissue samples will be described in 
an analysis plan separate from this SAP. Similarly, the QoL analyses will be addressed separately in a 
different analysis plan. 
4.2.4.
Safety Endpoints
The safety/tolerability endpoints are:
!
Incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse 
events (SAEs), grade 3 or higher TEAEs, TEAEs leading to dose reduction and dose interruption, 
TEAEs leading to treatment discontinuation and TEAEs with an outcome of death coded by 
Medical Dictionary for Regulatory Activities (MedDRA) and categorized and graded according 
to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
V4.0); incidence of adverse events of special interest of the nab-paclitaxel plus gemcitabine 
combination identified in previous trials in a similar population
!
Centrally reviewed laboratory results (chemistries and blood counts) analyzed using NCI CTCAE 
V4.03
!
Incidence of dose reductions, delays and omissions and reasons for dose reduction.
4.3.
Stratification and Randomization
Randomization will be performed by Interactive Randomization Technology (IRT) to ensure a 1:1 
assignment ratio between two treatment arms. The permutated-block randomization will be used and the 
randomization will be stratified by the following factors: 
!
Resection Status: R0 (tumor-free margin) versus R1 (microscopically positive margin)
!
Nodal Status: lymph node (LN+ versus LN-)
!
Region (North America, Europe and Australia versus Asia Pacific)
4.4.
Sample Size Determination
The primary objective is to compare DFS in subjects who received nab-paclitaxel in combination with 
gemcitabine and subjects who received gemcitabine alone.
The hypotheses are the following:
Ho: HRA+G/G = 1
H1: HRA+G/G ≠1 
where HRA+G/G is the hazard ratio (HR) between the nab-paclitaxel in combination with gemcitabine arm 
and the gemcitabine alone arm.
&&,
CCI
CCI
&(/*(1(35235,(7$5<,1)250$7,21
nt serious ad
serious a
n and dose i
n and dose 
me of death
e of de
orized and g
orized and g
Adverse Eve
Adverse Ev
ab
ab-paclitaxe
pac
lation
lation
d blood coun
blood co
ssions and re
sions and r
ctive Rando
ctive Rand
arms. The p
arms. Th
e following 
e following 
mor
mor-free ma
free m
h node (LN+
ode (LN+
America, Eu
America, 
ple Size Det
le Size De
objective is 
objective is
ne and subje
and subje
ypotheses a
ypotheses 


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
14
With the assumption of the true median DFS of 14 months in the gemcitabine arm and 19 months in the 
nab-paclitaxel in combination with gemcitabine arm which is equivalent to a HRA+G/G of 0.74, at least 489 
DFS events from 800 subjects are required to allow 90% power to detect a 26% reduction of risk in 
disease recurrence or death from the treatment arm at two-sided significance level of 0.05. One interim 
analysis for efficacy is planned at about 33% information time (ie, after 163 DFS events) to assess futility.
As of April 2016, a total of 866 subjects were enrolled in the study. After enrollment to this study was 
completed, more contemporaneous Phase 3 studies with gemcitabine in the targeted population of 
surgically resected pancreatic adenocarcinoma have shown consistently that DFS for patients may be 
lower than the median DFS of 14 months in the CONKO-001 study (Oettle, 2007), which provided the 
rationale for the timing and duration of the DFS assessments in the ABI-007-PANC-003 study. Results 
from the CONKO-005 (Sinn, 2017) and PRODIGE 24 (Conroy, 2018) studies showed a median DFS 
with adjuvant gemcitabine of 11.4 and 12.8 months, respectively. Based on these new data, with the 
assumption of the true median DFS of 13.5 months in the gemcitabine arm and 18.5 months in the nab-
paclitaxel in combination with gemcitabine arm, which is equivalent to an HRA+G/G of 0.73, approximately
438 DFS events are required to allow 90% power to detect a 27% reduction of risk in disease recurrence 
or death from the treatment arm at a two-sided significance level of 0.05. The data cutoff date for the 
revised final DFS analysis is projected to be December 2018, by which time 438 DFS events may be 
reached.
OS data will be analyzed as supportive analysis. Table 2 illustrates the probability that the nominal two-
sided p-value would be less than 0.05 under different assumptions when approximately 630 events are 
observed. It is projected that between 410 and 440 deaths will have occurred at the time of the data cut-off 
for the final DFS analysis and all subjects remaining on study will have at least 32 months of survival 
follow-up. 
Table 2:
Power Calculation for Overall Survival (OS) with N=800
Hazard Ratio of OS
Median OS (months)
Number of Death/N
Power
0.85
MG = 22
MA+G = 26
624/800
55%
0.80
MG = 22
MA+G = 27.5
633/800
82%
0.75
MG = 22
MA+G = 29
630/800
95%
Abbreviations: MG = median for gemcitabine arm; MA+G = median for nab-paclitaxel/gemcitabine arm
&&,
&(/*(1(352
MG = 22
= 22
MA+G
A+G
M
235,(7$5<,1)250$7,21
the
he
Results
sults 
an DF
n DFS 
S 
, with the
 with the
onths in the 
onths in the 
f 0.73,
f 0.7
appr
appr
sk in disease
k in disease
data cutoff 
data cuto
me 438 DFS 
438 DFS 
the probabi
the proba
ns when app
when ap
ll have occu
ll have occ
tudy will ha
udy will 
all Surviva
all Surviva
mon
onths)
ths)
5,
5,
5,
5,
5
=
2
M
3
1(
1(
1(
1(
*(1
tions:
ns: MG =


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
15
5.
GENERAL STATISTICAL CONSIDERATIONS
5.1.
Reporting Conventions
!
For each dry-run prior to database lock, the treatment arm on the tables, listings, figures (TLFs) 
will be displayed in the blinded format using dummy codes;
!
Data from all study centers will be combined for analysis;
!
All stratified efficacy analyses will use the stratification factors including resection status (R0 
versus R1) and nodal status (LN+ versus LN-), unless specified differently in specific analysis; 
!
All statistical tests of the treatment effect will be interpreted based on the stopping boundaries at 
each pre-specified interim analysis;
!
P-values will be rounded to 4 decimal places. P-values that round to 0.0000 will be presented as 
‘<0.0001’ and p-values that round to 1.000 will be presented as ‘>0.9999’; 
!
Confidence intervals (CIs) will be presented as 2-sided 95% CIs unless specified differently in 
specific analysis;
!
Summary statistics will consist of the number and percentage of subjects (or cycles, if 
appropriate) in each category for discrete variables, and the sample size, mean, median, standard 
deviation (STDEV), minimum and maximum for continuous variables;
!
All mean and median values will be formatted to one more decimal place than the measured 
value. Standard deviation values will be formatted to two more decimal places than the measured 
value;
!
All percentages will be rounded to whole numbers. The number and percentage will be presented 
in the form XX (XX), where the percentage is in the parentheses. The percentages greater than 0 
but rounded to 0 will be presented as <1 and the percentages less than 100 but rounded to 100
will be presented as >99 in the parentheses;
!
All listings will be sorted for presentation in order of treatment arm, study site, subject 
identification number, and date of procedure or event;
!
All analysis and summary tables will have the analysis population sample size (ie, number of 
subjects) for each treatment group in the column heading;
!
The day of the first dose of any investigational product (IP) will be defined as Day 1; 
!
Each cycle starts with the date of the first dose date of the cycle, and the end date of the cycle is 
the date before the first dose date of the subsequent cycle; 
!
For the last cycle, the end date of the cycle is the date the subject completed 6 cycles of treatment 
or the treatment discontinuation date recorded on the Treatment Disposition case report form 
(CRF). For subjects who are still on treatment at the time of the clinical cutoff, a nominal 28 days 
will be used as the last cycle duration. If the end date based on the planned duration is beyond the 
clinical cutoff date, the cutoff date will be used as the end date;
!
In by cycle analyses, assessments taken pre-dose on Day 1 of a given cycle (e.g. laboratory 
measures) will be grouped with the previous cycle;
&&,
&(/*(1(35235,(7$5<,1)250$7,21
sis; 
is;
ndaries at 
ndaries at 
l be presente
l be present
specified di
pecifie
f subjects (or
subjects (o
ample size, 
ample 
ous variable
ous variable
more decim
more dec
d to two mor
d to two mor
numbers. Th
numbers. Th
ntage is in th
tage is in t
s <1 and the
s <1 and t
arentheses
arenthes
;
r presentatio
r presentat
d date of pr
d date of p
mmary tables
ary tables
h treatment g
h treatment 
he first dose
he first dose
cle starts wi
cle starts w
ate before th
ate before th
For the last 
For the last 
or the tre
or the tr
(CRF
(CRF
wi
wi


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
16
!
Baseline value will be defined as the last non-missing value before the first dose of IP is 
administered; if multiple values are present for the same time point, the assessment with better 
result either by normal range or NCI CTCAE grade will be used; otherwise, the average of these 
values will be used as the baseline. For subjects who were not treated, the baseline will be the 
assessment value taken on the visit of Cycle 1 Day 1 if available; otherwise, the value on or prior 
to randomization date will be used; 
!
Partial dates will be imputed based on the rules specified in Section 16.2;
!
All laboratory data will be reported using standard international (SI) units; 
!
Summaries of the most severe toxicity grade in clinical laboratory in each treatment cycle and 
most severe grade post-baseline overall and shifts from baseline to most severe toxicity grade 
post-baseline overall will include all scheduled and unscheduled assessments. The similar 
approach will be used for summaries in physician assessment of peripheral neuropathy (PN) 
grades;
!
For safety parameters, the Final Evaluation will be defined as the last on-treatment value which is 
the last non-missing assessment on or prior to last dose date + 28 days or the treatment 
discontinuation date, whichever is later;
!
SAS# Version 9.2 (or higher) will be the statistical software package used to produce all other 
data summaries, listings, graphs, and statistical analyses.
5.2.
Analysis Populations
5.2.1.
Intent-to-Treat Population
The Intent-to-treat (ITT) population includes all randomized subjects regardless of whether the subject 
received any IP or had any efficacy assessment collected. 
5.2.2.
Treated Population
The Treated population includes all randomized subjects who received at least one dose of IP. If a subject 
receives IP other than the subject’s randomized treatment assignment, then the subject is assigned to the 
treatment arm reflecting the treatment that the subject actually received during the study. Unless 
otherwise specified, the Treated population will be the analysis population for all safety analyses. Only 
subjects with clear documentation that no IP was administered will be excluded from the Treated 
population.
5.2.3.
Per-Protocol Population
The Per-protocol (PP) population includes all treated as randomized subjects who met all eligibility 
criteria, and had no radiological evidence of pancreatic cancer prior to randomization by independent 
review. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
e and 
and 
y grade
y grade
similar 
imilar 
ropathy (P
ropathy (PN
treatment v
treatment 
ys or the trea
s or the tre
package use
ackag
andomized 
andomized 
t collected.
t collected.
randomized
randomize
t’s randomiz
t’s randomi
reatment tha
atment th
reated popu
reated pop
umentation 
umentation
er-Protocol
Protocol
protocol (PP
protocol (P
ia, and had n
a, and had
view. 
ew. 


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
17
6.
SUBJECT DISPOSITION
The number of subjects screened, the number and percentage of subjects randomized and not randomized 
with screen failure, and the eligibility criteria failed will be summarized. The above percentages will be 
based on the number of subjects screened.
Analysis population allocation will be summarized. The number and percentage of subjects who were 
randomized and treated, completed, and discontinued the treatment period, and the number and 
percentage of subjects who discontinued the study will be presented for the ITT, Treated and PP 
populations by treatment arm and for all subjects combined. Each reason for treatment discontinuation
and each reason for study discontinuation collected on the CRF will be summarized in the subject 
disposition table. 
The randomization will be summarized by all strata and treatment arms. Enrollment will be summarized 
by treatment arm, and by region, country and study site. The number and percentage of subjects eligible 
or not eligible for the study and of subjects randomized under each protocol amendment will be 
summarized.
Subject disposition listing will include all subjects in the ITT population with reason for treatment 
discontinuation or reason for study discontinuation displayed for discontinued subjects. Listings of 
subject eligibility and subjects excluded from PP population will be provided. The listing for subjects 
randomized but not treated and the randomization scheme will also be provided. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
on
be summariz
e summar
f subjects el
f subjects 
ment will be
ment will b
th r
h reason fo
eason fo
inued subje
nued subj
provided. Th
rovide
o be provide
o be provid


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
18
7.
PROTOCOL VIOLATIONS
The protocol violations will be identified and assessed by clinical research physician or designee 
following institution standard operational procedures. The protocol violations will be summarized by 
treatment arm for the ITT population. 
A listing of subjects with protocol violations in the ITT population will be provided. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
19
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
The demographics and baseline characteristics will be summarized for the ITT population by treatment 
arm and for all subjects combined. Individual subject listings will be provided to support the summary 
tables.
8.1.
Demographics
Age (years), height (cm), weight (kg), body mass index (BMI) (weight [kg]/ height [m2]) at baseline, and 
body surface area (BSA) (m2) at baseline will be summarized by sample size, mean, median, STDEV, 
minimum, and maximum values. Age category (< 65 years and > 65 years, < 75 years and ≥ 75 years), 
sex, race, ethnicity, region, country, ECOG performance status at baseline, PN at baseline and tobacco 
history (never smoked, passive smoker, past smoker, current smoker, and smokeless tobacco user) will be 
summarized by number and percentage of subjects in each category.
Age will be calculated as follows: Age = maximum integer ∃([Date of randomization – Date of Birth +1] 
/ 365.25). 
The summary for demographics will be provided for the ITT, Treated and PP populations.
8.2.
Cancer History and Surgery
The number and percentage of subjects in each of the following categories will be presented:
!
Type of surgery;
!
Laparoscopic surgery; 
!
Pancreas position;
!
Surgical staging;
!
TNM classification;
!
Nodal status;
!
Resection status;
!
Histology of primary diagnosis; 
!
Tumor grade;
!
Presence of perineural invasion; 
!
Presence of lymphovascular invasion; 
!
Presence of local invasion; 
!
Intraductal papillary mucinous neoplasm (IPMN) being identified
Baseline value for CA19-9 from central lab data will also be summarized descriptively by treatment arm. 
The frequency summary of baseline CA 19-9 categories (within normal limit [WNL], upper limit of 
normal [ULN] - < 100 U/mL and ≥ 100 U/mL) will be provided.
Time from primary diagnosis to randomization, time from surgery to randomization, time from primary 
diagnosis to surgery, time from randomization to the first dose, tumor size, number of lymph nodes 
removed, and number of lymph nodes involved with cancer will be summarized descriptively by 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
,
ars), 
ars), 
tobacco
obacco
o user) will 
o user) will 
on 
on – Date of
Date of
P population
P population
ategori
ategor es wil
w
diagnosis;
diagnosis;
perineural in
perineural in
e of 
of lympho
lymph
sence of loc
ence of loc
Intraductal
Intraductal
seline value
eline value
The freque
The freque
or
orma
mal


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
20
treatment arm. For microscopic distance from tumor to the closest margin, the frequency summary of
categories (< 1 mm and ≥ 1 mm) will be provided by treatment arm. 
8.3.
Baseline Disease Status
Subjects will be summarized by disease status (either being disease free or having residual disease) prior 
to randomization, based on independent radiological assessment of scans. The subject who has no 
baseline scan by independent radiological assessment is presented as “Not Evaluable”. 
8.4.
Medical History
A summary of medical history collected on CRF will be presented by MedDRA system organ class 
(SOC) and preferred term (PT).
8.5.
Prior Therapy
Any prior therapy will be collected at screening and only subjects who had no prior neo-adjuvant 
treatment or radiation therapy or systemic therapy for pancreatic adenocarcinoma will be eligible for this 
study. The prior therapies will be provided in listings.
8.5.1.
Prior Other Anti-cancer Therapy
Prior other anti-cancer therapies will be coded to therapeutic drug classes and preferred drug names using 
the World Health Organization (WHO) Drug Dictionary. The incidence by therapeutic drug class and 
preferred drug name will be summarized.
8.5.2.
Prior Radiation Therapy for Other Diseases
The number and percentage of subjects who had any prior radiation therapy for other diseases will be 
presented. For subjects with prior radiation therapy, the number and percentage of subjects with each type 
of radiation therapy will be presented. 
8.5.3.
Prior Cancer Surgery for Other Diseases
The number and percentage of subjects who had any prior cancer surgery for other diseases will be 
presented.
8.6.
Prior and Concomitant Medications
Medications reported on the Prior and Concomitant Medications CRF will be coded to therapeutic drug 
classes and preferred drug names using the WHO drug dictionary. All medication taken prior to screening 
and ≤ 28 days after the last dose of IP will be collected and included. 
8.6.1.
Prior Medications
A prior medication will be any medication stopped prior to the date of the first dose of IP. A summary 
will be presented showing the number and percentage of subjects who took prior medications by 
therapeutic drug class and preferred drug name, as well as the number and percentage of subjects that 
took any prior medication.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
lass s
or neo
or neo-adjuv
adjuv
ma will be e
a will b
g classes and
classes and
incidence b
ncidence
seases
eases
any prior ra
any prior ra
erapy, the n
erapy, the n
for Other D
for Other 
ubjects who
ubjects who
Concomita
Concomit
rted on the P
ted on the 
ferred drug 
rred drug
ys after the 
s after the 
Prior
rio
A prior med
A prior med
will be pr
will be 
rap


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
21
8.6.2.
Concomitant Medications
Concomitant medication is defined as the medication that was either initiated before the first dose of IP 
and continued during the study treatment, or initiated on/after the date of the first dose of IP but on or 
before 28 days after the last dose of IP. 
A summary will be presented showing the number and percentage of subjects who took concomitant 
medications by WHO therapeutic drug class and preferred drug name, as well as the number and 
percentage of subjects who took any concomitant medications. 
Separate summary focusing on subjects receiving concomitant white blood cell (WBC) growth factors, 
transfusions with blood and blood-derived products, erythropoietin, narcotics, and systemic anti-infective 
(oral or IV, excluding topical medications and vaccines) will be provided.
Listing of prior and concomitant medications by subject will be provided. 
8.7.
Concomitant Procedures/Surgeries
Procedures/Surgeries reported on the Concomitant Procedures/Surgeries CRF will be coded using 
MedDRA SOC and PT, which including those done prior to the first dose of IP. 
A concomitant procedure/surgery is defined in a manner similar to the concomitant medication (Section 
8.6.2). A summary will be presented showing the number and percentage of subjects who had 
concomitant procedures/surgeries by SOC and preferred term, as well as the number and percentage of 
subjects who had any concomitant procedures/surgeries. 
Listing of concomitant procedures/surgeries collected on Concomitant Procedures/Surgeries CRF by 
subject will be provided.
&&,
ors,s, 
nfective
nfective
will be code
ll be co
f IP
f IP.
concomitan
ncomita
entage of sub
ntage of s
s well as the
well as th
Concomita
Concomi


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
22
9.
STUDY TREATMENTS AND EXTENT OF EXPOSURE
Study treatment and extent of exposure summaries will be provided based on the Treated population. 
9.1.
Treatment Duration
The treatment start date is the date of the first dose of IP. The treatment end date is the date the subject 
completed 6 cycles of treatment, or on which the decision was made by investigator to discontinue 
subject’s treatment and record it on the treatment disposition page. Specifically, for the subjects who 
completed 6 cycles of treatment, the treatment end date will be the dosing date for Cycle 6 Day 15 + 13 
days or the dosing date for Cycle 6 Day 8 + 20 days if the Cycle 6 Day 15 dosing date is missing. For 
subjects who are still on treatment at the time of study closure or clinical cutoff, the treatment end date 
will be the last date of the planned cycle (27 days after first dose of the last cycle). If the end date based 
on the planned duration is beyond the clinical cutoff date, the cutoff date will be used as the end date. 
Treatment duration (in weeks) is calculated as (treatment end date – the date of the first dose of IP + 1) / 7 
and rounded to one decimal place. Summary statistics for treatment duration (in weeks), as well as a 
frequency summary of treatment duration categories (< 4 weeks, ≥ 4 to < 8 weeks, ≥ 8 to < 12 weeks, ≥ 
12 to < 16 weeks, ≥ 16 to < 20 weeks, ≥ 20 to < 24 weeks, and ≥ 24 weeks) will be provided. The 
descriptive statistics and frequency summary for total number of treatment cycles subject received and 
number of subjects dosed at each cycle will be provided by treatment arm. The descriptive statistics for 
the number of doses administered separately for nab-paclitaxel and gemcitabine will be provided by 
treatment arm. The number of doses by treatment cycle will be summarized separately for nab-paclitaxel 
and gemcitabine by treatment arm.
9.2.
Cumulative Dose
Cumulative dose is defined as the sum of all administered doses in mg/m2. The descriptive statistics for 
the cumulative dose (mg/m2) separately for nab-paclitaxel and gemcitabine will be provided. 
9.3.
Dose Intensity
Dose intensity will be calculated as the cumulative dose divided by the treatment duration in weeks which 
is defined in Section 9.1. The descriptive statistics for the dose intensity (mg/m2/week) for nab-paclitaxel
and gemcitabine will be provided separately. 
9.4.
Percentage of Protocol Dose
Percentage of protocol dose will be calculated as the dose intensity divided by the protocol weekly dose x 
100%.
!
For nab-paclitaxel the protocol weekly dose is 125*3/4 = 93.75 mg/m2/week; 
!
For gemcitabine: the protocol weekly dose is 1000*3/4 = 750 mg/m2/week.
Summary statistics for percentage of protocol dose and as well as a frequency summary of subjects within 
each percentage of protocol dose categories ( ≥ 90%, < 90% to 80%, < 80% to 70%, and < 70%) will be 
provided separately for nab-paclitaxel and gemcitabine by treatment arm. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
13 
13 
For 
For
end date
end date
d date based
d date base
the end dat
the end da
first dose of
first dose 
weeks), as w
weeks), as 
weeks, ≥ 8 to
eeks, ≥ 8 t
s) will be pr
will be pr
ment cycles 
nt cycles
nt arm. The 
nt arm. Th
and gemcitab
d gemcit
e summariz
summar
dministered 
ministered
nab
nab-paclitax
pacli
as the cumu
s the cumu
descriptive s
descriptive
ovided separ
ovided se
ge of Proto
e of Proto
tocol dose w
tocol dose w
r nab
na -pacli
pacli
For gemc
For gem
Summary sta
ummary sta
each perc
ach perc
ovidid


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
23
9.5.
Dose Reduction/Delay/Omission
Dose reduction is defined as when the dose administered after Cycle 1 Day 1 dose is at the lower dose 
level than the one subject received from the previous dosing visit. 
Dose delay is defined as when the actual dose is administered ≥ 3 days after the scheduled dosing date. 
Dose omission is defined as when the scheduled dose was not given for the scheduled visit which does 
not include dose delay. 
Dose reduction/delay/omission will be summarized by treatment arm as follows:  
!
Separately for nab-paclitaxel and gemcitabine, the number and percentage of subjects with at 
least 1 dose reduction, number of dose reductions, reasons for reduction, and dose reduction for 
each treatment cycle;
!
Separately for nab-paclitaxel and gemcitabine, the number and percentage of subjects with at 
least 1 dose delay, number of dose delays, and dose delay for each treatment cycle; 
!
Separately for nab-paclitaxel and gemcitabine, the number and percentage of subjects with at 
least 1 dose omitted, number of dose omissions, and dose omission for each treatment cycle.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
th at 
h a
uction for 
uction for 
ubjects with
ubjects w
nt cycle;
nt cycl
tage of subje
ge of s
for each tre
for each tre


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
24
10.
EFFICACY ANALYSIS
All efficacy evaluations will be conducted using the ITT population. Supportive analysis of the primary 
and key secondary efficacy endpoints using the Treated and PP population will be conducted for the final 
analysis. Statistical comparisons will be made between nab-paclitaxel + gemcitabine and gemcitabine 
arm. Efficacy results that will be considered statistically significant after consideration of the strategy for 
controlling the family-wise Type 1 error rate are described in Section 13. All statistical tests will be two-
sided at the significance levels which were pre-specified for each interim analyses and the final analysis, 
and the corresponding p-values and two-sided confidence intervals (CIs) for intended point estimates will 
be reported. Listings of lesion assessments by independent review and by investigator review will be 
provided. 
10.1.
Multiplicity
There is no multiplicity adjustment for the secondary endpoint OS. 
10.2.
Analysis of Primary Efficacy Endpoint
10.2.1.
Primary Efficacy Analysis on DFS 
The primary efficacy endpoint is DFS which is defined as the time from the date of randomization to the 
date of disease recurrence or death due to any cause, whichever is earlier. Disease recurrence will be 
determined by the independent radiological review of CT or MRI scans. Subjects who did not have 
disease recurrence or did not die will be censored at the last tumor assessment date with disease-free 
status or the randomization date if the last tumor assessment with disease-free status was missing. 
Disease-free status refers to a status that is neither being disease recurrent nor indeterminate or not 
evaluable. Subjects who received new anti-cancer therapy or cancer-related surgery prior to disease 
recurrence or death will be censored at the date of last tumor assessment with disease-free status prior to 
the start of new anti-cancer therapy or cancer-related surgery or the randomization date. The censoring 
rule is illustrated in Table 3:
.
&&,
&(/*(1(35235
erer-
35,(7$5<,1)250$7,21
will
ill
be
om the date
m the
earlier. Dis
earlier. Dis
MRI scans. S
RI scans. S
tumor asse
tumor asse
ment with di
ment with d
ing disease 
ng disease 
therapy or c
therapy or 
of last t
of last tum
um
t
related su
related 


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
25
Table 3:
Censoring Rules for DFS
Value of Disease-free Survival 
Date (ADT)
Censored 
(Y,N) 
Derivation
ADT = min(death date, disease 
recurrence date)
N
If a subject died or had disease recurrence and did 
not receive any new anti-cancer therapy or cancer-
related surgery before death or disease recurrence. 
ADT = the last tumor 
assessment date with disease –
free status/randomization date 
Y
If a subject did not die or had no disease 
recurrence, and did not receive any subsequent new 
anticancer therapy or cancer-related surgery. 
If the last tumor assessment date with disease –free 
status is missing, ADT = the randomization date.
ADT = the last tumor 
assessment date with disease-
free status prior to start of 
subsequent new anticancer 
therapy or cancer-related 
surgery/randomization date
Y
If a subject did not die or had no disease recurrence 
prior to the start of subsequent new anticancer 
therapy or cancer-related surgery 
If the last tumor assessment date with disease-free 
status prior to the start of subsequent new anti-
cancer therapy or cancer-related surgery is missing, 
ADT = the randomization date.
ADT = randomization date
Y
If there was residual or recurrent disease at 
baseline or no baseline scan assessment.
ADT =Analysis Date ; N = no; Y = yes.
The null (Ho) and alternative (H1) hypotheses for testing the primary efficacy endpoint of DFS are: 
Ho: HRA+G/G = 1
H1: HRA+G/G ≠ 1 
Where HRA+G/G is the hazard ratio (HR) of DFS between the nab-paclitaxel in combination with 
gemcitabine and the gemcitabine alone arm.
The survival distribution of DFS will be estimated using Kaplan-Meier method, the quartiles (25th, 50th, 
and 75th percentile) including two-sided 95% CIs for each treatment arm will be provided. The survival 
distributions for two treatment arms will be compared using the stratified log-rank test adjusting for 
stratification factors of resection status (R0 versus R1) and nodal status (LN+ versus LN-) based on IRT 
data, and p-value will be provided. The associated HR and two-sided 95% CI will be estimated by using 
stratified Cox proportional hazard model adjusting for the same stratification factors as for stratified log-
rank test. Kaplan-Meier curves will be provided by treatment arm. The survival rates will be provided for 
different time points.
&&,
$7
uent new
nt new
rgery.
rgery.
ith disease
th disease
ndomization
ndomization
$7
$7
$7
had no dise
ad no d
bsequent
sequent new
new
elated surge
elated surg
r assessmen
r assess
to the start 
o the star
herapy or ca
erapy or 
= the rando
= the rando
)2
If there wa
f there w
baseline
baselin
(7
5
es.s.
5
23
) hypothese
) hypothes
G 
G = 1
HRA+G/G 
A+G/G ≠ 1 
≠ 1 
G is the haza
is the haza
e and the ge
and the ge
rvival distri
rvival distri
75
75thth pe
percen
rcen
distributions
istributions
stratifica
tratific
a a


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
26
The DFS will be analyzed by the randomization stratification factors: 
!
Resection status (R0 versus R1);
!
Nodal status (LN+ versus LN-);
!
Region (North America, Europe and Australia versus Asia Pacific).
When using stratified Cox proportional hazard model or estimating stratified log-rank p-value, resection 
status or nodal status will not be included as a stratification factor for the DFS analysis by resection status
or nodal status, respectively. Kaplan-Meier curves will be provided by treatment arm and by stratum 
within each stratification factor. 
Medians with two-sided 95% CIs estimated through Kaplan-Meier methods, and the associated HRs with 
two-sided 95% CIs from Cox model will be provided for all randomization strata. 
A multivariate analysis on DFS will be conducted by using Cox proportional hazard model to evaluate the 
treatment effect adjusted for the stratification factors. The associated HRs with two-sided 95% CIs, and p-
values for treatment effect and stratification factors as covariates will be displayed.
10.2.2.
Sensitivity Analyses on DFS
The following sensitivity analyses will be conducted to evaluate the robustness of the DFS results: 
1.
To evaluate the robustness of the treatment effect based on different censoring time calculation, a 
sensitivity analysis will be performed by censoring the subjects who had no DFS event and no 
post-baseline scan with disease-free status at the last survival follow-up date, if available. If the 
censoring date is still missing, the randomization date (similar to the primary DFS analysis) will 
be used. 
2.
A sensitivity analysis will be performed where disease recurrence will be determined by the 
independent radiological review of CT or MRI scans or confirmed biopsy. 
3.
Missing assessment analysis: If a subject died or had disease recurrence by independent review, 
and the time interval between the death date/disease recurrence date and the previous tumor 
assessment date with disease-free status or the randomization date is more than two scheduled 
tumor assessment visits, the subject will be censored at the last tumor assessment date with 
disease-free status or the randomization date. 
4.
The DFS by independent review will also be compared between two treatment arms by using 
non-stratified log-rank test, p-value will be provided. The HR and two-sided 95% CI will be 
estimated using non-stratified Cox proportional hazard model. 
5.
A sensitivity analysis will be performed to evaluate the impact of surgery date. In this analysis, 
DFS is defined as the time from the date of surgery to the date of disease recurrence by the 
independent radiological review of CT or MRI scans or death due to any cause, whichever is 
earlier. Subjects who had residual or recurrent disease at baseline will be censored to the surgery 
date. For those subjects who were disease-free at baseline, had no DFS event and no post-baseline 
scans with disease-free status, they will be censored to the baseline scan date. The rest of 
censoring rules remain the same as the primary analysis of DFS by independent review. 
6.
An analysis of DFS based on disease recurrence assessed by investigator or determined by biopsy 
will be conducted. All censoring rules remain the same as the primary analysis of DFS by 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
d HRs with 
d HRs with
odel to evalu
odel to eval
sided 95% C
sided 95%
ed.
ed.
bustness of 
tness of
n different c
n different 
subjects wh
subjects wh
t survival fo
t survival fo
n date (simil
n date (sim
where disea
where disea
T or MRI sc
T or MRI s
a subject die
a subject
the death d
e death d
se
se-free statu
free statu
s, the subjec
s, the subjec
r the random
he random
dependent re
dependent
d log
d log-rank t
rank t
d using non
d using non
nsitivity ana
nsitivity ana
DFS is define
is defin
independe
independe
earlier
earlier
date
date


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
27
independent review. The concordance in disease recurrence between by independent review and 
by investigator’s review will be summarized and Kappa statistics will be presented. 
For the sensitivity analyses, the analyses by randomization factors or by randomization strata or the 
multivariate analysis will not be conducted.
10.3.
Analyses of Secondary Efficacy Endpoint
The secondary efficacy endpoint is OS, which is defined as the time from the date of randomization to the 
date of death due to any cause. Subjects who are alive at the end of study or clinical data cut will be 
censored on the last-known-to-be-alive date or the clinical cutoff date, whichever is earlier. 
The survival distribution of OS will be estimated using Kaplan-Meier method, the quartiles (25th, 50th, and 
75th percentile) including two-sided 95% CIs for each treatment arm will be provided. The survival
distributions for two treatment arms will be compared using the stratified log-rank test adjusting for 
stratification factors of resection status (R0 versus R1) and nodal status (LN+ versus LN-) based on IRT 
data, and p-value will be provided. The associated HR and two-sided 95% confidence interval will be 
estimated by using stratified Cox proportional hazard model adjusting for the same stratification factors as 
for stratified log-rank test. Kaplan-Meier curves will be provided by treatment arm. The survival rates 
will be provided for different time points. A sensitivity analysis on OS will be conducted by censoring 
subjects on the start date of subsequent new anticancer therapy or cancer-related surgery. 
A sensitivity analysis will also be performed to evaluate the impact of surgery date. In this analysis, OS is 
defined as the time from the date of surgery to the date of death due to any cause.
The OS will also be analyzed by the randomization stratification factors: 
!
Resection status (R0 versus R1);
!
Nodal status (LN+ versus LN-);
!
Region (North America, Europe and Australia versus Asia Pacific).
When using stratified Cox proportional hazard model or estimating stratified log-rank p-value, resection 
status or nodal status will not be included as a stratification factor for the OS analysis by resection status
or nodal status, respectively. Kaplan-Meier curves will be provided by treatment arm and by stratum 
within each stratification factor. 
Medians with two-sided 95% CIs estimated through Kaplan-Meier methods, and the associated HRs, with 
two-sided 95% CIs from Cox model will be provided for all randomization strata. 
A multivariate analysis on OS will be conducted by using Cox proportional hazard model to evaluate the 
treatment effect adjusted for the stratification factors. The associated HRs with two-sided 95% CIs, and p-
values for treatment effect and stratification factors as covariates will be displayed. 
10.4.
Subgroup Analysis
The primary analysis of DFS and OS will also be analyzed within the following subgroups, note that the 
geographic region, resection status (R0 versus R1), nodal status (LN+ versus LN-) will be based on the 
clinical data instead of IRT data: 
1.
Geographic Region (North America, Europe, Australia and Asia Pacific);
2.
Age (< 65 years and ≥ 65 years); 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
e
5 h, 50
, 50thth, and
, an
survival
survival
djusting for
djusting for
LN
LN-) based
based
ence interva
nce interva
same
me stratifi
stra
ent arm. Th
nt arm. Th
will be cond
ill be cond
ncer
cer-related 
rel
act of surge
ct of surg
ath due to an
ath due to a
ification fac
fication fa
nd Australia
d Australi
l hazard mo
hazard m
cluded as a 
luded as a 
plan
plan-Meier 
Meier 
or. 
r
95% CIs es
95% CIs es
rom Cox mo
om Cox mo
nalysis on O
nalysis on
ect adjusted 
ect adjusted
treatment e
eatment e
Sub
Sub
The primary
The primary
geograph
eograp
i


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
28
3.
Sex (male and female); 
4.
ECOG PS (0 and 1);
5.
Pancreatic cancer location (head and other); 
6.
Surgical staging; 
7.
Tumor grade (well differentiated, moderately differentiated, poorly differentiated and 
undifferentiated);
8.
Resection status (R0 versus R1);
9.
Nodal status (LN+ versus LN-);
10. Level of CA19-9 at baseline if indicated by the data (WNL, ULN - < 100 U/mL and ≥ 100 
U/mL);
11. Microscopic distance from tumor to the closest margin (< 1 mm and ≥ 1 mm).
If too few subjects fall in any of the above subgroups determined based on data review prior to database 
lock, the analysis within that subgroup may not be performed. 
The methods described in Sections 10.2.1 and 10.3 for the endpoints of DFS and OS respectively, will be 
used for each subgroup. Resection status or nodal status will not be included as a stratification factor for 
the resection status or nodal status subgroup analysis, respectively, in the stratified Cox proportional
hazard model or when estimating stratified log-rank p-value. 
A forest plot will be provided based on the stratified HRs for each subgroup. 
Additional subgroup analyses may be conducted if the overall treatment effect is significant and further 
understanding of the treatment effect within subgroups is of interest. 
A multivariate analysis on DFS and OS will be conducted by using Cox proportional hazard model to 
identify potential prognostic factors by including treatment group, and all the subgroups mentioned above 
using stepwise method with selection level of 0.10. 
A summary table of serum CA19-9 values and changes from baseline by cycle and treatment arm based 
on central lab data will be provided. 
The subsequent anti-cancer therapies and clinically reviewed subsequent new anti-cancer therapies or 
cancer-related surgeries will be summarized by treatment arm. Listings will be provided. 
 
&&,
CCI
&(/*(1(35235,(7$5<,1)250$7,21
≥ 100
≥ 100
m).
m)
review prio
eview 
DFS and OS
DFS and O
ncluded as a
clude
y, in the stra
y, in the stra
for each sub
for each 
e overall tre
 overall tre
oups is of in
oups is of in
be conducted
e conducte
luding treat
uding trea
evel of 0.10.
vel of 0.1
9 values and
9 values and
ided.
ded.
r therapies a
therapie
will be sum
will be su
(1(
*(
/*(


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
29
11.
SAFETY ANALYSIS
All safety analyses will be conducted based on the Treated population. Safety analyses will be evaluated 
by the incidence of TEAEs, SAEs, grade 3 or higher TEAEs, TEAEs leading to dose reduction and dose 
interruption, TEAEs leading to treatment discontinuation, TEAEs with an outcome of death, AEs of 
special interest [based on risk definitions (search criteria) as outlined in the Abraxane Risk Management 
Plan], laboratory abnormalities, and other safety parameters during the treatment.
11.1.
Adverse Events
Adverse events will be analyzed in terms of TEAEs which are defined as any event that begins or worsens 
in grade after the start of IP through 28 days after the last dose of IP. All events will be coded using the 
MedDRA 
A treatment-related TEAE is defined as TEAE which was considered to be related to the IPs and reported 
as “Suspected” on the CRF. For the treatment Arm A, a treatment related TEAE is a TEAE with 
relationship reported as “Suspected” to either nab-paclitaxel or gemcitabine. AEs with a missing 
relationship will be treated as “treatment-related.”
The incidence of TEAE will be summarized by MedDRA SOC and PT. The intensity of AEs will be 
graded 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0. For all other AEs not described in the CTCAE criteria, the intensity will be 
assessed by the investigator as mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening 
(grade 4) or death (grade 5). Tables summarizing the incidence of TEAEs will be generated for each of 
the following:
!
All TEAEs;
!
All TEAEs by maximum CTCAE grade as well as grade 1 or 2 vs. ≥ grade 3, and ≥ grade 3 vs. all 
grades;
!
All TEAE with CTCAE grade≥ 3;
!
TEAEs reported as treatment-related; 
!
Treatment-related grade 3 or higher TEAEs;
!
Treatment-related grade 3 or higher TEAEs by cycle;
!
Serious TEAE;
!
Serious TEAE by SAE criteria; 
!
Treatment-related serious TEAEs;
!
Treatment-related serious TEAEs by SAE criteria;
!
TEAEs with action of study drug withdrawn;
!
Treatment-related TEAEs with action of study drug withdrawn;
!
TEAEs with action of study drug dose reduced;
!
Treatment-related TEAEs with action of study drug dose reduced;
!
TEAEs with action of study drug interrupted;
&&,
&(/*(1(35235,(7$5<,1)250$7,21
worsens 
worsens 
sing the
sing the
e IPs and re
e IPs and re
TEAE with
TEAE with
wi
with
th a m
a m
h
iss
iss
m
The intensity
The intensi
minology Cr
minology C
he CTCAE c
e CTCAE
2), severe (g
 severe (
ce of TEAE
ce of TEA
as well as g
as well as g
3;3;
ntnt-re
related;
lated;
e 3 or highe
e 3 or highe
grade 3 or h
grade 3 o
;
EAE by SA
EAE by SA
ment
ment-relate
relate
Treatment
tment-rer
TEAEs 
TEAEs 
!
Tre
Tre
!


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
30
!
Treatment-related TEAEs with action of study drug interrupted;
!
TEAEs with outcome of death;
!
Treatment-related TEAEs with outcome of death;
!
All death within 28 days of last dose by cause of death category as collected on Death CRF;
!
Most frequent ( ≥ 5% in either arm; no SOC) TEAEs;
!
Most frequent treatment-related TEAEs ( ≥ 5% in either arm; no SOC) TEAEs;
!
TEAEs for the following baseline subgroups (provided the number of subjects are sufficient):
-
Sex (male and female);
-
Geographic Region (North America versus Europe versus Australia versus Asia Pacific).
For subgroup with age (< 65 years and ≥ 65 years, and < 75 years and ≥ 75 years), the following analyses 
will be provided: 
!
All TEAEs;
!
Grade 3 or higher TEAEs; 
!
Serious TEAEs; 
!
TEAEs with action of study drug withdrawn; 
!
TEAE with action of study drug dose reduced;
!
TEAE with action of study drug interrupted;
!
TEAEs with outcome of death
If a subject experiences the same AE more than once with different toxicity grade, then the event with the 
maximum grade will be tabulated in “by grade” tables. If a subject experiences multiple AEs under the 
same SOC/PT, then the subject will be counted only once for that SOC/PT. If the severity of an AE is 
missing for one or more occurrences, the maximum severity of the remaining occurrences will be used. If 
the severity is missing for all occurrences of the AE, the subject will be counted only once in the 
‘Missing’ category for severity.
The analysis of TEAE by cycle will be based on the onset date of AE to determine the cycle. AEs with a 
duration that overlaps multiple cycles will only be counted in the first overlapped cycle. 
The TEAE tables will be sorted by the frequencies of SOC and PT within SOC in a descending order 
within nab-paclitaxel plus gemcitabine treatment arm. 
The AE Listing will be provided that includes the verbatim term, PT, and SOC as well as full details of 
AEs for subjects in the ITT population. Non-TEAEs will be flagged on this listing. 
Separate listings for subjects in Treated population will be prepared for grade 3 or higher TEAEs, serious 
TEAEs, TEAEs with action of study drug withdrawn, TEAEs with action of study drug dose reduced, 
TEAEs with action of study drug dose interrupted and TEAEs with outcome of death. The listing of 
inpatient hospitalizations will be provided. All deaths will be listed with the cause of death category from 
Death CRF form.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
t):
s Asia Pacif
s Asia Pacif
following a
following
n once with 
once with
ade” tab
ade” tables. 
le
ounted only
ounted o
 the maximu
the maxim
urrences of t
rrences of t
y.
cycle will b
cycle will 
multiple cyc
multiple cy
will be sorte
will be sorte
litaxel
taxel plus 
plus
sting will be
ng will b
r subjects in
r subjects in
parate listing
arate listin
TEAEs, TE
TEAEs, TE
TEAEs 
EAEs


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
31
11.2.
Adverse Events of Special Interest
11.2.1.
AE of Special Interest
TEAEs of special interest based on risk definitions (search criteria) as outlined in the Abraxane Risk 
Management Plan or included based on inherent risks of the study design using MedDRA coding are as 
follows:
!
Myelosuppression (anaemia, neutropenia, and thrombocytopenia);
!
Peripheral neuropathy;
!
Gastrointestinal events;
!
Myalgia and arthralgia;
!
Hypersensitivity reactions;
!
Cranial nerve paralysis;
!
Cardiotoxicity;
!
Cardiotoxicity-Congestive Heart Failure/Left Ventricular Dysfunction;
!
Stevens-Johnson Syndrome/Toxic epidermal necrolysis;
!
Pneumonitis;
!
Infusion site reactions/extravasation;
!
Cystoid macular edema; 
!
Hepatic toxicity (Drug-induced liver injury); 
!
Acute renal failure and Hemolytic-uremic syndrome (including HUS in combination with 
gemcitabine); 
!
Clinically severe infections, sepsis; 
!
Drug-induced lupus erythematosus;
!
Haemorrhage and bleeding (AESI specific for the study);
!
Motility Disorders (Post-surgical complications specific for this study);
!
Fistula/Leak (Post-surgical complications specific for this study);
!
Haemorrhage (Post-surgical complications specific for this study); 
!
Hyperglycemia/Diabetes (Post-surgical complications specific for this study);
!
Pancreatitis (Post-surgical complications specific for this study)
After review of data, there may be other AEs of special interest identified and summarized.
The following summaries will be provided for TEAEs included in the above-mentioned AEs of interest: 
!
All TEAEs; 
!
Grade 3 or higher TEAEs; 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
function;
nct
ury);
ury);
uremic synd
uremic syn
, sepsis; 
, sepsis; 
ythematosus
ythemato
bleeding (A
bleeding 
rders (Post
ders (Post
eak (Post
eak (Post-su
morrhage (P
morrhage (P
Hyperglyce
Hyperglyce
!
Pancrea
Pancre
After revie
After revie
e fo
f


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
32
!
Serious TEAEs; 
!
TEAEs with action of study drug withdrawn; 
!
TEAE with action of study drug dose reduced;
!
TEAE with action of study drug interrupted;
!
TEAEs with outcome of death. 
The similar summaries will also be presented by age group (< 65 years and ≥ 65 years) and (< 75 years
and ≥ 75 years). 
In addition, sub-risks of AE of special interest as defined in subjects older than 75 years are to be 
analyzed by age group < 65 years, 65-74 years and ≥ 75 years for the TEAEs of special interest in this 
population as specified below:
!
Myelosuppression (anemia, neutropenia, febrile neutropenia, thrombocytopenia);
!
Peripheral neuropathy;
!
Clinically severe infections – pneumonia;
!
Clinically severe infections – sepsis;
!
Clinically severe infections – pneumonia and sepsis;
!
Dehydration;
!
Decreased appetite;
!
Diarrhea;
!
Epistaxis;
!
Fatigue;
!
Peripheral edema.
TEAEs of special interest listings will be provided similarly as AE listings. TEAEs of special interest as 
defined for subjects older than 75 years old will be also provided. 
11.2.2.
Pneumonitis and Sepsis
If warranted (i.e., substantial subjects have pneumonitis or sepsis), in the final analysis, pneumonitis (as 
defined by broad scope of Standardised MedDRA Query [SMQ] interstitial lung disease) and sepsis (as 
defined by ad-hoc preferred terms) will be examined through the following analyses: 
1.
Time to onset; 
2.
Duration of events in days for pneumonitis only.
The time to onset of pneumonitis and sepsis respectively and duration of pneumonitis events will be 
summarized descriptively.
11.2.3.
Peripheral Neuropathy
The physician will assess PN using the NCI CTCAE Version 4.0 of “Neuropathy – Sensory” and record 
grades on CRF. The frequency of each PN grade (0 – 5) by physician assessment at baseline, the most
&&,
&(/*(1(35235,(7$5<,1)250$7,21
est in this
t in this
nia);
a);
will be provid
ill be provi
5 years old w
5 years old 
and Sepsis
and Sepsi
tantial subje
antial subj
cope of Stan
cope of Stan
hoc preferred
oc preferre
me to onset
e to onset
Duration 
Duratio
The time to o
he time to o
summariz
ummariz


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
33
severe PN grade in each treatment cycle and on Final Evaluation will be presented. The frequency of 
worst PN grade during treatment (i.e. any time after the first dose of IP) will also be presented. A shift 
table representing the shift from the baseline grade to the most severe grade during treatment will be 
provided.
Additionally, PN events will be reported as AEs of special interest and will be analyzed (as defined by 
broad scope of SMQ peripheral neuropathy) as outlined in Section 11.2.1.
If warranted (i.e., substantial subjects have grade 3 or higher PN as defined by SMQ), time to first 
occurrence of grade 3 or higher PN from the first dose date will be descriptively summarized. Time to 
improvement from grade 3 or higher PN by at least 1 grade and the time to improvement of grade 3 or 
higher PN to grade 1 or better will be analyzed using Kaplan-Meier methods based on PN SMQ. Subjects
who are not experiencing improvement will be censored at the last time the subjects are evaluated for 
AEs.
11.3.
Clinical Laboratory Evaluations
The central laboratory results will include laboratory assessments which were collected from screening to 
the date of last dose date + 28 days or the treatment discontinuation date, whichever is later. The central 
laboratory values will be graded using NCI CTCAE V4.03. For hematologic and chemistry laboratory 
values fall outside of the grade criteria of NCI CTCAE V4.03, the grade of 0 will be assigned. The 
collected local laboratory results will be listed. 
11.3.1.
Hematology
In order to investigate the maximal degree of myelosuppression, the NCI CTCAE grade for absolute 
neutrophil counts (ANC), WBC, platelet counts, and hemoglobin will be summarized by the most severe 
grade in each treatment cycle and by the most severe grade during treatment. The number and percentage 
of subjects with each NCI CTCAE grade will be presented by treatment arm. A shift table representing 
the shift from the baseline grade to the most severe grade during treatment will be provided by treatment 
for these laboratory results.
11.3.2.
Clinical Chemistry
Hepatic and renal function will be summarized using the NCI CTCAE grade for alkaline phosphatase, 
ALT (SGPT), AST (SGOT), total bilirubin, and creatinine. The number and percentage of subjects that 
have each NCI CTCAE grade will be summarized by treatment arm using the most severe grade for each 
treatment cycle and overall during treatment. A shift table representing the shift from the baseline grade 
to the most severe grade during treatment will be provided by treatment arm for each of these laboratory 
tests.
11.4.
Vital Sign Measurements
For vital signs, listings will be provided. 
11.5.
ECOG Performance Status
For ECOG performance status, the shift from baseline to the worst during treatment will be displayed in 
cross–tabulations for each treatment arm. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
3 or 
3 or 
. Subjects
. Subject
uated for 
uated for 
collected fro
llected
hichever is 
hichever is
ogic and ch
ogic and ch
ade of 0 wil
de of
pression, the
pression, th
d hemoglobi
hemoglob
vere grade d
vere grade d
be presente
be presente
st severe gra
severe gr
ill be summa
l be summ
T), to
T), tal bilir
l bi
E grade will 
grade wi
overall duri
overall duri
re grade dur
e grade d
Vital S
Vital S
r vital signs
r vital signs
11.5.
1.5


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
34
11.6.
Physical Examination
Any findings from physical examination before the start of IP are documented as medical history and any 
findings after the start of IP are documented as adverse events on CRF. Therefore, there will be no 
separate analysis for physical examination. 
11.7.
Electrocardiograms
The overall electrocardiogram (ECG) 12 lead interpretation is documented on screening. A listing will be 
provided. 
11.8.
Pregnancy Test
For pregnancy test, a listing will be provided. 
&&,
&(/*(1(35235,(7$5<,1)250$7,21


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
35
12.
QUALITY OF LIFE ANALYSIS
QOL will be analyzed using the EORTC-QLQ C-30 and QOL-PANC26 questionnaires which are 
collected at screening, at cycle 4 Day 1 prior to dosing, EOT, then on the same days when a CT or MRI is 
performed until disease recurrence. Details for the quality of life analysis will be provided in a separate 
document. 
&&,


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
36
13.
INTERIM ANALYSIS
13.1.
General Information
There were 2 interim analyses conducted during the course of the study. The first interim analysis on 
safety was planned after the first 100 subjects have completed 2 cycles of treatment. Additionally, one
interim analysis on efficacy was planned at about 33% information time (ie, after 163 DFS events) to 
assess futility. A second interim analysis on efficacy had been planned for futility and superiority at 
either 70% information time (ie, after 342 DFS events) or the completion of accrual of 800 subjects, 
whichever is later. However, at time of Protocol Amendment 3, the interim analysis for futility at about 
163 DFS events has been performed and no subjects are receiving IP. To avoid premature interruption 
of the trial, and to ensure that the study has sufficient duration of follow-up to verify clinical benefit 
and assess benefit-risk in this setting, this second interim analysis has been removed from the study.
An independent DMC was convened which was composed of two medical oncologists with experience in 
treating subjects with pancreatic adenocarcinoma and a statistician, all of whom are not otherwise 
involved in the study as investigators. During the course of the study, the DMC will review the efficacy 
data in accordance with the guidelines for the pre-planned interim analysis. The committee will also 
review safety data. Operational details for the DMC and the algorithm and its validation by an expert 
panel will be detailed in the DMC charter. 
13.2.
Statistical Approaches for Control of Alpha and Beta
The nonbinding stopping boundary will be based on the Gamma family spending function with parameter 
= -2 (Hwang, 1990) to control the Type 2 error rate at 10%. The HR boundary for futility at 33% 
information time is ≥0.98, however, the actual boundaries for the interim analyses may vary depending 
on the actual number of DFS events at the time of analysis.
&&,
about
bout
errupti
erruption
on
al benefit
al benefit
om the study
m the stud
ts with expe
ts with exp
re not other
re not other
C will review
will rev
The commi
The comm
nd its valida
d its valid
d Beta
 Beta
Gamma fami
amma fa
10%
10%. The H
The H
ndaries for t
daries for
of analysis.
of analysis.


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
37
14.
CHANGES TO THE STATISTICAL ANALYSES SECTION OF 
THE PROTOCOL
The subgroup analysis was added in this SAP. The multivariate analysis through Cox proportional hazard 
model using stepwise selection method to identify potential prognostic factors for DFS and OS would be 
performed when overall treatment effect is significant and exploratory analysis is needed. 
After randomization was completed but prior to database lock, stratification categories were examined for 
sparse data cells and it was decided to remove region from the stratified efficacy analyses due to the small 
number for Asia Pacific group in region. Therefore, in all the stratified analyses, only two stratification 
factors (resection status [R0 versus R1] and nodal status [LN+ versus LN-]) will be included.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
llll
on
on


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
38
15.
REFERENCE
Conroy T, Hammel P, Hebbar M, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter 
international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients 
with resected pancreatic ductal adenocarcinomas. J Clin Oncol 36, 2018 ASCO Annual Meeting 
Abstracts. 2018;36, (18 suppl): Abstract LBA4001.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Hwang I, Weichung S, De Cani J. Group sequential designs using a family of type I error probability 
spending functions. Stat Med 1990;9:1439-1445.
Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients 
undergoing curative-intent resection of pancreatic cancer. JAMA 2007;297:267-277. 
Sinn M, Bahra M, Liersch T, et al. CONKO-005: Adjuvant chemotherapy with gemcitabine plus erlotinib 
versus gemcitabine alone in patients after R0 resection of pancreatic cancer: a multicenter randomized 
phase III trial. J Clin Oncol. 2017;35:3330-3337.
&&,
&(/*(1(35235,(7$5<,1)
g
)250$7,21
bility
bility
tion in patie
tion in pati
emcitabine
emcitabine
a multicente
multicent


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
39
16.
APPENDICES 
16.1.
Handling of Dates 
Dates will be stored as numeric variables in the SAS analysis files and reported in DDMMMYYYY 
format (ie, the Date9. datetime format in SAS).  Dates in the clinical database are classified into the 
categories of procedure dates, log dates, milestone dates, outcome dates, and special dates.
Procedure Dates are the dates on which given protocol-specified procedure are performed.  
They include the dates of laboratory testing, physical examinations, tumor scans, etc.  
They should be present whenever data for a protocol-specified procedure are present and 
should only be missing when a procedure are marked as NOT DONE in the database.  
Procedure dates will not be imputed.
Log Dates are dates recorded in CRF data logs. Specifically, they are the start and end dates 
for adverse events and concomitant medications/procedures.  They should not be missing 
unless an event or medication is marked as ongoing in the database.  Otherwise, 
incomplete log dates will be imputed according to the rules in Appendix 16.2 (eg, for 
duration or cycle assignment, etc). However, in listings, log dates will be shown as 
recorded without imputation.
Milestone Dates are dates of protocol milestones such as randomization, study drug start 
date, study drug termination date, study closure date, etc.  They should not be missing if 
the milestone occurs for a subject.  They will not be imputed.
Outcome Dates are dates corresponding to study endpoints such as survival and disease 
recurrence.  In most cases they are derived either from a milestone (eg, the survival date 
is derived from the death date), or a procedure date (eg, the disease recurrence date is 
derived from the date of the tumor scan that was used to determine disease recurrence).  
They may be subject to endpoint-specific censoring rules if the outcome did not occur or 
disease recurrence or death following more than 1 missing tumor assessment, but are not 
otherwise subject to imputation.
Special Dates cannot be classified in any of the above categories and they include the date of 
birth.  They may be subject to variable-specific censoring and imputation rules. 
Dates recorded in comment fields will not be imputed or reported in any specific format. 
16.2.
Date Imputation Guideline
16.2.1.
Impute Missing Adverse Events/ Prior or Concomitant Medications/Procedures 
Incomplete Start Date:
Missing day and month
If the year is the same as the year of the first dosing date, then the day and month of the first 
doing date will be assigned to the missing fields.
If the year is prior to the year of first dosing date, then December 31 will be assigned to the 
missing fields.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
  
ent and 
nt and 
tabase. 
abase. 
art and end
art and e
houl
ould not b
d not 
e.  Otherwi
e.  Otherwi
Appendix 1
Appendix 
dates will b
ates will b
s rando
s rand miza
miz
ate, etc.  Th
te, etc.  Th
ot be im
t be imput
put
m
dy
dy endpo
endpo
y
inin
ed eit
ed either fr
her 
procedure d
rocedure d
scan that w
scan that w
nt-specific c
-specific
following m
ollowing 
tation.
tation.
clclassified i
assified i
e subject to
subject to
comment f
commen
Imputation
Imputation
Im
Impute Mi
pute Mi
m
plete Start 
plete Start
Missing day a
Missing day a
If the
f the


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
40
If the year is after the year of first dosing, then January 1 will be assigned to the missing 
fields.
Missing day only 
If the month and year are the same as the year and month of first dosing date, then the first 
doing date will be assigned to the missing day.
If either the year of the partial date is before the year of the first dosing date or the years of 
the partial date and the first dosing date are the same but the month of partial date is 
before the month of the first dosing date, then the last day of the month will be assigned 
to the missing day.
If either the year of the partial date is after the year of the first dosing date or the years of the 
partial date and the first dose date are the same but the month of partial date is after the 
month of the first dosing date, then the first day of the month will be assigned to the 
missing day.
If the stop date is not missing, and the imputed start date is after the stop date, the start date 
will be imputed by the stop date. 
Missing day, month, and year
No imputation is needed, the corresponding AE will be included as TEAE. 
Incomplete Stop Date: If the imputed stop date is before the start date, then the imputed stop date will be 
equal to the start date.
Missing day and month
If the year of the incomplete stop date is the same as the year of the last dosing date, then the 
day and month of the last dosing date will be assigned to the missing fields. 
If the year of the incomplete stop date is prior to the year of the last dosing date or prior to 
the year of the first dosing date, then December 31 will be assigned to the missing fields. 
If the year of the incomplete stop date is prior to the year of the last dosing date but is the 
same as the year of the first dosing date, then the first dosing date will be assigned to the 
missing date. 
If the year of the incomplete stop date is after the year of the last dosing date, then January 1 
will be assigned to the missing fields.
Missing day only 
If the month and year of the incomplete stop date are the same as the month and year of the 
last dosing date, then the day of the last dosing date will be assigned to the missing day. 
If either the year of the partial date is not equal to the year of the last dosing date or the 
years of the partial date and the last dosing date are the same but the month of partial date 
is not equal to the month of the last dosing date, then the last day of the month will be 
assigned to the missing day.  
&&,
&(/*(1(35235,(7$5<,1)250$7,21
gned 
ned 
years of th
ears of th
e is
e is after
after t
signed to th
igned to
stop date, t
op dat
ncluded as 
ncluded as
start date, th
tart date,
the
the sam
same a
ate will be 
ate will be 
date is
date is prio
date, then D
e, then D
te stop date
stop date
the first dos
he first d
inco
ncomp
mplete
le
signed to th
igned to th
ly
month and
onth and
last dosin
last dosin
If eit
If either t
her t
ye
ye


EDMS Doc. Number:
nab-Paclitaxel
Statistical Analysis Plan Amendment. Protocol ABI-007-PANC-003
Celgene Corporation
Confidential and Proprietary
41
16.2.2 
Impute Missing Cancer History Dates 
When necessary for analysis purposes, the diagnosis dates without a specific day of the month given (i.e., 
JAN2008) will be assigned the 15th day of the month and dates without a specific day or month (i.e., 
2008) will be assigned the 30th day of June to complete the date. If the above imputation inappropriately 
results in a diagnosis date on or after surgical date or randomization date, then the incomplete date will be 
assigned to the day prior to surgical date or randomization date, whichever is earlier. The similar 
imputation rule will be used for the partial surgical date.
16.2.3 
Impute Missing Subsequent Anti-cancer Therapy 
When necessary for analysis purposes, the subsequent anti-cancer therapy dates without a specific day of 
the month given (i.e., JAN2008) will be assigned the 15th day of the month and dates without a specific 
day or month (i.e., 2008) will be assigned the 30th day of June to complete the date. If the above 
imputation inappropriately results in a date on or before the last dose date, then the incomplete date will 
be assigned to the day following the last dose date. If imputation results in an imputed start date after the 
corresponding stop date, then the start date will be set to the day prior to the stop date.
&&,
&(/*(1(35235,(7$5<,1)250$7,21
c day of 
day of 
t a specific
a specific
above
above
omplete date
omplete date
ed start date
ed start date
date.
date.


EDMS Doc. Number:
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
8VHU1DPH
7LWOH
'DWH7KXUVGD\-DQXDU\30(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
8VHU1DPH
7LWOH
'DWH7KXUVGD\-DQXDU\30(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
8VHU1DPH
7LWOH
'DWH7KXUVGD\-DQXDU\30(DVWHUQ'D\OLJKW7LPH
0HDQLQJ$SSURYHGQRFKDQJHVQHFHVVDU\
                                                
&&,
33'
33'
33'
33'
33'
33'
&(/*(1(35235,(7$5<,1)250$7,21
Q'D\OLJKW7
'D\OLJKW7
         
      
3

QJHVQHFHV
HVQHFHV
         
        
235


EDMS Doc. Number:
nab-Paclitaxel
Summary of Changes Statistical Analysis Plan. ABI-007-PANC-003 Celgene Corporation
Confidential and Proprietary
4
1.
JUSTIFICATION FOR AMENDMENT
Following finalization of the SAP on 15 Aug 2016, Protocol Amendment No. 3 and 4 were 
released on 21 Dec 2016 and 12 Sep 2018, respectively. This SAP amendment reflected all 
changes to the planned analysis. Other clarifications and incidental formatting changes were 
made throughout the document. 
Significant changes included in this amendment are summarized below:
!
Modification of Stratification by Region
Per Protocol Amendment 1 and 2, the subjects are to be stratified at randomization based on
Region (North America versus Europe versus Australia versus Asia Pacific). To reflect the 
reality of the stratification applied to the randomization, which is based on original protocol, the 
wording is revised to Region (North America, Europe and Australia versus Asia Pacific). 
Revised sections: SAP Section 4.1 Overall Study Design and Plan, Section 4.3 Stratification and 
Randomization, and Section 10.2 and 10.3 for analysis of disease-free survival (DFS) or overall 
survival (OS) by the randomization stratification factors, respectively
!
Update the stratification factors for stratified efficacy analyses (stratified Cox 
proportional hazard model and stratified log-rank test for p-value) by exclusion of region
due to the small number for Asia Pacific group in Region. 
Revised sections: SAP Section 10.2.1 Primary Efficacy Analysis on Disease-free Survival 
(DFS), Section 10.3 Analysis of Secondary Efficacy Endpoints, and Section 10.4 Subgroup 
Analysis
!
Added languages to clarify one more change to the Statistical Analyses Section of the 
Protocol about exclusion of region as the stratification factor for the stratified efficacy 
analyses 
Revised section: SAP Section 14
!
Removal of the second interim analysis of efficacy
Final SAP stated that two interim analyses of efficacy were planned: the first is to be conducted 
at about 33% information time (ie, after 163 DFS events) to assess futility and the second at 
either 70% information time (ie, after 342 DFS events) or the completion of accrual of 800 
subjects, whichever is later, to assess both futility and superiority. At the time of Protocol 
Amendment 3, a total of 866 subjects have been randomized and completed or discontinued 
treatment. Based on health authority recommendation to avoid premature interruption of the 
trial, and to ensure that the study has sufficient duration of follow-up to verify clinical benefit 
&&,
&(/*(1(35235,(7$5<,1)250$7,21
n based
based on
on
To reflect th
reflect t
original pro
original pr
us Asia Pa
s Asia
ecti
ction 4.3 
on 4.3
free surviv
ree surviv
ctively
ctively
fficacy
fficacy ana
ana
y
g rank test f
rank test 
group in R
group in R
ary
ry Efficacy
Efficacy
y
ry
ry Efficacy
Efficacy
y
arify one m
arify one m
usio
sion of re
n of re
P Sect
Sectioion
moval
oval of
of
l
the
th
f
AP 
AP stated
tated t
out 33% in
out 33% i
th
ther 70% i
er 70% 
subjects, 
ubjects, 
men
men


EDMS Doc. Number:
nab-Paclitaxel
Summary of Changes Statistical Analysis Plan. ABI-007-PANC-003 Celgene Corporation
Confidential and Proprietary
5
and assess benefit-risk in this setting, the second interim analysis has been removed from the 
study.
Revised sections: SAP Section 4.4 Sample Size Determination, Section 13.1 General Information
and Section 13.2 Statistical Approaches for Control of Alpha and Beta. Original Table 3 
Stopping Boundaries for Interim Analysis and Final Analysis on Efficacy was removed from the 
SAP Section 13.2.
!
Revised the final DFS analysis to be earlier than was originally planned (489 events)
As of April 2016, a total of 866 subjects were enrolled in the study. After enrollment to this 
protocol was completed, more contemporaneous Phase 3 studies with gemcitabine in the targeted 
population of surgically resected pancreatic adenocarcinoma have shown consistently that DFS 
for patients may be lower than the median DFS of 14 months in the CONKO-001 study (Oettle, 
2007), which provided the rationale for the timing and duration of the DFS follow-up 
assessments in the ABI-007-PANC-003 study. Results from the CONKO-005 (Sinn, 2017) and 
PRODIGE 24 (Conroy, 2018) studies showed a median DFS with adjuvant gemcitabine of 11.4 
and 12.8 months, respectively. Based on these new data, with the assumption of the true median 
DFS of 13.5 months in the gemcitabine arm and 18.5 months in the nab-paclitaxel in 
combination with gemcitabine arm, which is equivalent to an HRA+G/G of 0.73, at least 438 DFS 
events are required to allow 90% power to detect a 27% reduction of risk in disease recurrence or 
death from the treatment arm at a two-sided significance level of 0.05. The data cutoff date for 
the revised final DFS analysis is projected to be December 2018, by which time 438 DFS events 
may be reached.
For the OS, it is projected that between 410 and 440 deaths will have occurred at the time of the 
data cut-off for the final DFS analysis and all subjects remaining on study will have at least 32 
months of survival follow-up. 
Revised sections: Section 4.4 Sample Size Determination and Section 15 Reference. 
Other minor clarifications and updates are listed below:
!
Updated the CTCAE version from 4.0 to 4.03 for centrally reviewed laboratory results 
grading 
Revised sections: SAP Section 4.24 Safety Endpoints and Section 11.3 Clinical Laboratory 
Evaluations 
!
Clarify that the percentages greater than 0 but rounded to 0 will be presented as <1 and 
the percentages less than 100 but rounded to 100 will be presented as >99 in the 
parentheses
Revised section: SAP Section 5.1 Reporting Conversion
&&,
&(/*(1(35235,(7$5<,1)250$7,21
his 
is 
the targete
the targete
ntly that DF
tly that D
01 study
01 study (
y O
ollow
ollow-up 
-up 
005 (
005 (Sinn,
Sinn
uvant gem
vant gemc
ssumption o
sumption o
the nab
n
-pac
pa
HR
HRA+G/G
A+G/G
R
of
duction of r
uction of
e level o
e level of 0
ember 2018
ember 20
nd 440 deat
nd 440 deat
all subjects
ll subject
le Size Det
e Size De
nd update
nd update
CAE versi
CAE vers
: SAP Sec
: SAP Sec
Cl
Clarify
arify t
y
th
the p
e p
pa
pa
visi


EDMS Doc. Number:
nab-Paclitaxel
Summary of Changes Statistical Analysis Plan. ABI-007-PANC-003 Celgene Corporation
Confidential and Proprietary
6
!
Updated “prior and concurrent procedures/surgeries” into “concomitant 
procedure/surgeries” to be consistent with the corresponding Case Report Form name 
Revised sections: SAP Section 8.7 Concomitant Procedures/Surgeries 
!
Added language to clarify the CA19-9 analysis is based on central lab 
Revised sections: SAP Section 8.2 Cancer History and Surgery and Section 10.4 Subgroup 
Analysis
!
Clarification on baseline definition
Further clarification are provided when there are multiple assessments on the same time point
prior to first dose. In the case of multiple values with various levels (ie. normal range or CTCAE 
toxicity), the assessment with better result will be defined.  
Revised section: SAP Section 5.1 Reporting Conversion
!
Added language for the summary of time from primary diagnosis to surgery
Revised section: SAP Section 8.2 Cancer History and Surgery 
!
Added language to define the baseline disease status as “Not Evaluable” for the subject 
who has no baseline scan by independent radiological review
Revised section: SAP Section 8.3 Baseline Disease Status 
!
Added language to clarify the censoring rule for the subject who has no baseline scan by 
independent radiological review 
Revised section: SAP Section 10.2.1 Primary Efficacy Analysis on DFS and Table 3 Censoring 
Rules for DFS within this section
!
Shifted power calculation for OS from SAP Section 13.2 Statistical Approaches for 
Control of Alpha and Beta to SAP Section 4.4 Sample Size Determination
!
As specified in Section 11.5 ECOG Performance Status, for ECOG performance status, 
the shift from baseline to the worst during treatment will be displayed in cross–
tabulations for each treatment arm. ‘Eastern Cooperative Oncology Group (ECOG) 
performance status and’ was removed from Section 5.1 Reporting Conventions, to be 
consistent with Section 11.5. 
Revised section: SAP Section 5.1 Reporting Conventions
&&,
&(/*(1(35235,(7$5<,1)250$7,21
me time po
e time poi
al range or 
range or C
diagnosis 
diagno
y
gery
ry
ase status 
ase statu
nt radio
t radiololog
Disease St
Disease S
the censori
he censori
l review
l review
on 10.2
n 10.2.1 P
.1
s sect
s sectioion
power calcu
power calcu
olol of
of
l
Al
Al
f
pha
pha
l
As spec
As spec
th
the sh
e s
tab
ta