Clinical trial NCT02993731
Conditions: Carcinoma, Pancreatic Ductal
Keywords: Neoplasms Neoplasms by Site Digestive System Neoplasms Endocrine Gland Neoplasms Pancreatic Neoplasms Adenocarcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Digestive System Diseases Pancreatic Diseases Endocrine System Diseases Albumin-Bound Paclitaxel Gemcitabine
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2016-12-01; Completion date: 2020-03-01
Enrollment: 1134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, open-label, multi-center, phase 3 study of napabucasin plus weekly nab-paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine for adult patients with Metastatic Pancreatic Ductal Adenocarcinoma.

Detailed description:

Arms: arm 1: Patients randomized to this arm will receive napabucasin administered orally, twice daily in combination with weekly nab-paclitaxel and gemcitabine administered intravenously, once weekly, on 3 of every 4 weeks. arm 2: Patients randomized to this arm will receive weekly nab-paclitaxel and gemcitabine administered intravenously, once weekly, on 3 of every 4 weeks.
Interventions: intervention 1: Napabucasin intervention 2: Nab-paclitaxel intervention 3: Gemcitabine
Intervention descriptions: intervention 1: Napabucasin will be administered orally, twice daily, with doses separated by approximately 12 hours. intervention 2: Nab-paclitaxel 125 mg/m\^2 immediately followed by gemcitabine 1000 mg/m\^2 will be administered on Days 1, 8 and 15 of every 28-day cycle via intravenous infusion. intervention 3: Nab-paclitaxel 125 mg/m\^2 immediately followed by gemcitabine 1000 mg/m\^2 will be administered on Days 1, 8 and 15 of every 28-day cycle via intravenous infusion.

Protocol documents:
Prot_000.pdf: 


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DOCUMENT REVISION HISTORY
Document
Version Date
Original protocol
18 October 2016
Original protocol (Rev.1)
18 October 2016
Amendment 1
23 February 2017 (Local – USA)
Amendment 2
16 June 2017
Amendment 3
16 February 2018
Amendment 4
4 December 2018
Amendment 5
31 July 2019


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ABBREVIATIONS & DEFINITIONS
ADLs
Activities of Daily Living
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
BMI
Body Mass Index
BP
Blood pressure
CHF
Congestive Heart Failure
CR
Complete Response
CRC
Colorectal cancer
CRO
Contract Research Organization 
CSC
Cancer Stem Cell 
DCR
Disease Control Rate
DSMB
Data Safety and Monitoring Board
EDC
Electronic Data Capture
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire
FFPE
Formalin Fixed Paraffin Embedded
FOLFIRINOX
5-FU, leucovorin, irinotecan and oxaliplatin
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HCG
Human Chorionic Gonadotropin 
HED
Human Equivalent Dose 
Hgb
Hemoglobin
HIV
Human Immunodeficiency Virus
HRT
Hormone Replacement Therapy
ICH
International Conference on Harmonization
IHC
Immunohistochemical
IND 
Investigational New Drug
IRB
Institutional Review Board
ITT
Intention to Treat
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System 
MMP7
Matrix Metalloproteinase-7
mOS 
Median Overall Survival
mPFS
Median Progression-Free Survival
MTD
Maximum Tolerated Dose
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NOAEL 
No Observed Adverse Effect Level
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive Disease
PDAC
Pancreatic ductal adenocarcinoma 
PFS
Progression-Free Survival
PK
Pharmacokinetics  
PR
Partial Response


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PS
Performance Status
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QoL
Quality of Life
RECIST
Response Evaluation Criteria In Solid Tumors 
RP2D
Recommended Phase 2 Dose
RTSM
Randomized Trial Supply Management
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Study Day
SD
Stable Disease
SU
Safety Updates
TCPS
Tri-Council Policy Statement
ULN
Upper Limit of Normal
WOCBP
Women of Child Bearing Potential


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STUDY SYNPOSIS
Study Title:
A Phase III Study of BBI-608 plus nab-Paclitaxel with Gemcitabine in Adult 
Patients with Metastatic Pancreatic Adenocarcinoma.
Study Number:
CanStem111P 
Study Phase: 
III
Study Drug:
BBI-608 (also called napabucasin, BBI608, BB608) is a small molecule that is 
hypothesized to affect multiple oncogenic cellular pathways, including inhibition of 
the STAT3 pathway, which has been implicated in cancer stem cell viability.
Primary 
Objective: 
To compare overall survival (OS) of patients with metastatic pancreatic 
adenocarcinoma (PDAC) treated with BBI-608 plus weekly nab-paclitaxel with 
gemcitabine (Arm 1) versus weekly nab-paclitaxel with gemcitabine (Arm 2).  
Secondary 
Objectives: 
Key Secondary Objectives
x
To compare Progression-Free Survival (PFS) in patients with metastatic 
PDAC treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine 
versus weekly nab-paclitaxel with gemcitabine. 
x
To compare Disease Control Rate (DCR) in patients with metastatic PDAC
treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine versus 
weekly nab-paclitaxel with gemcitabine.  
x
To compare Overall Response Rate (ORR) in patients with metastatic PDAC 
treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine versus 
weekly nab-paclitaxel with gemcitabine.
Other Secondary Objectives
x
To evaluate the safety profile of BBI-608 administered daily plus weekly nab-
paclitaxel and gemcitabine in patients with metastatic PDAC with safety 
assessed according to the National Cancer Institute Common Toxicity Criteria 
for Adverse Events (NCI CTCAE) version 4.0. 
x
To compare the Quality of Life (QoL), as measured using the European 
Organization for Research and Treatment of Cancer Quality of Life 
questionnaire (EORTC-QLQ-C30), in patients with metastatic PDAC treated 
with BBI-608 plus weekly nab-paclitaxel with gemcitabine versus weekly 
nab-paclitaxel with gemcitabine.  
Exploratory Objectives
x
To compare OS in patients treated with BBI 608 plus weekly nab paclitaxel 
with gemcitabine (Arm 1) versus weekly nab paclitaxel with gemcitabine 
(Arm 2) in biomarker positive PDAC patients.
x
To compare PFS in patients with metastatic PDAC treated with BBI 608 plus 
weekly nab paclitaxel with gemcitabine versus weekly nab paclitaxel with 
gemcitabine in biomarker positive patients.
x
To compare DCR in patients with metastatic PDAC treated with BBI 608 plus 
weekly nab paclitaxel with gemcitabine versus weekly nab paclitaxel with 
gemcitabine in biomarker positive patients.


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x
To compare ORR in patients with metastatic PDAC treated with BBI 608 plus 
weekly nab paclitaxel with gemcitabine versus weekly nab paclitaxel with 
gemcitabine in biomarker positive patients.
Study Design:
This is a randomized, open-label, multi-center, phase III study of BBI-608 plus weekly 
nab-paclitaxel with gemcitabine (Arm 1) vs. weekly nab-paclitaxel with gemcitabine
(Arm 2) for adult patients with metastatic PDAC.
1132 patients will be randomized in a 1:1 ratio, stratified according to geographical 
region (North America/Western Europe/Australia vs. Japan/Korea vs. Rest of the 
World), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), 
and presence of liver metastases (yes vs. no). Enrollment was completed prior to this 
amendment.  
Until the time of this amendment, the study proceeded in 28-day (4-week) cycles. BBI-
608 was administered orally, twice daily, with doses separated by approximately 12 
hours. BBI-608 administration began 2-5 days prior to the first nab-paclitaxel with 
gemcitabine infusion. Nab-paclitaxel
125 mg/m2
immediately followed by 
gemcitabine 1000 mg/m2 were administered on Days 1, 8 and 15 of every 28-day cycle
via intravenous infusion.  
From the time of this amendment, and since the outcome of the interim analysis which 
was futile, patients may continue protocol therapy if it is believed to be in their best 
interest by the investigator and patient, and with the patient’s informed consent.
Patients will receive BBI-608, nab-paclitaxel and/or gemcitabine at the same dose and 
schedule that they were receiving prior to the amendment. Patients on Arm 1 may 
continue BBI-608 with the Sponsor’s approval. Patients on Arm 1 may also 
discontinue BBI-608 but choose to continue with nab-paclitaxel and gemcitabine
alone.  
Tumor assessments will be performed every 8 weeks after randomization until 
objective disease progression or treatment discontinuation due to toxicity.
The protocol will continue to be followed for all endpoints until study completion. The 
study is planned for completion on February 28th, 2020. 
Study Population: 
This study will enroll patients with histologically or cytologically confirmed 
adenocarcinoma of the pancreas that is metastatic (Stage IV). Patients with local 
recurrence following surgical resection will be excluded. At randomization, patients 
will not have received systemic chemotherapy for metastatic pancreatic 
adenocarcinoma previously (with a fluoropyrimidine or gemcitabine administered as
a radiation sensitizer in the adjuvant setting allowed). Other inclusion criteria for all 
patients include: age \ears(&2*SHUIRUPDQFHVWDWXVDQGDGHTXDWHKHSDWLF
renal, and bone-marrow function.  
Test Product, 
Dose, and Mode of 
Administration:
Until the time of this amendment, patients randomized to Arm 1 on this study received
BBI-608 orally, daily, at 240 mg bid (480 mg total daily dose). BBI-608 was taken 
daily continuously throughout each 4 week (28 day) study cycle in combination with 
nab-paclitaxel and gemcitabine. BBI-608 was administered twice daily, one hour prior 
or two hours after meals, with the first dose taken in the morning and doses separated 
by approximately 12 hours. 
Patients randomized to Arm 1 received BBI-608 in combination with nab-paclitaxel
and gemcitabine. Patients randomized to Arm 2 received nab-paclitaxel and 
gemcitabine alone. Nab-paclitaxel 125 mg/m2 was administered intravenously starting 


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on Day 1 of Cycle 1. Gemcitabine 1000 mg/m2 was administered intravenously
following nab-paclitaxel infusion. This regimen was repeated on Days 1, 8 and 15 of 
every 28-day cycle.
Dose modification of BBI-608 and/or nab-paclitaxel and/or gemcitabine was allowed.
There were no dose reductions or adjustments for lymphopenia or alopecia.  
From the time of this amendment, and since the outcome of the interim analysis was 
communicated to investigators, patients may continue protocol therapy if it is believed
to be in their best interest by the investigator and patient, and with the patient’s 
informed consent. Patients will receive BBI-608, nab-paclitaxel and/or gemcitabine at 
the same dose and schedule that they were receiving prior to the amendment. Patients 
on Arm 1 may continue BBI-608 with the Sponsor’s approval. Patients on Arm 1 may 
discontinue BBI-608 but choose to continue with nab-paclitaxel and gemcitabine.. 
Duration of 
Treatment: 
Patients may continue to receive assigned protocol therapy as long as they have not 
experienced any adverse events requiring permanent discontinuation of study 
medication, have not demonstrated disease progression based on Response Evaluation 
Criteria In Solid Tumors (RECIST) 1.1 criteria, it is believed to be in the patient’s best 
interest by the investigator and patient, or until February 28th, 2020, whichever occurs 
first. If nab-paclitaxel and/or gemcitabine is/are discontinued due to toxicity, BBI-608 
may be continued until another discontinuation criterion is met with the Sponsor’s 
approval, if it is believed to be in the patient’s best interest by the investigator and 
patient, and with the patient’s informed consent. If BBI-608 is discontinued due to 
toxicity, nab-paclitaxel and gemcitabine
may be continued until another 
discontinuation criterion is met. 
The study is planned for completion on February 28th, 2020. 
Statistical 
Methods: 
The primary study endpoint is Overall Survival (OS), defined as the time from 
randomization until death from any cause.  
A multiplicity adjustment strategy will be applied to control the overall Type I error 
rate with respect to several sources of multiplicity in the trial. This multiplicity 
adjustment will account for the analysis of the treatment effect on the primary (OS) 
and key secondary (PFS, DCR, ORR) endpoints.
The study is designed to have a power of 90% and a one-sided alpha of 2.5% to detect 
a 20% reduction in the continuous risk of death (HR 0.80, which corresponds to an 
increase of median survival from 8.5 to 10.63 months) in the Intention to Treat (ITT) 
general study population. It is estimated that 864 events will be required to detect this 
reduction which would be observed by randomizing 1132 patients enrolled over 24 
months with patient follow up for an additional 12 months, for total study duration of 
36 months. It is anticipated that up to 5% dropout rate will occur for the entire study.  
The primary hypothesis is: 
H0: BBI-608 + nab-paclitaxel with gemcitabine QDE-paclitaxel with gemcitabine 
versus
H1: BBI-608+ nab-paclitaxel with gemcitabine > nab-paclitaxel with gemcitabine. 
This hypothesis will be evaluated for the superiority of BBI-608 by performing a 
stratified log-rank test adjusting for the stratification variables at randomization. The 
final analysis will be performed when 864 OS events have been observed.


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The overall power of the study will be approximately 90% after the multiplicity control 
procedure is considered.
Prior to this amendment, there was one interim analysis presented to the independent 
Data Safety and Monitoring Board (DSMB). Additionally, the DSMB reviewed safety 
during conduct of the study. The role and responsibility of the DSMB are defined in a 
separate Charter.
The interim analysis involved a stratified log-rank test. Nominal p-values were based 
on the Lan-DeMets error spending function using an O’Brien-Fleming stopping 
boundary in order to preserve the overall one-sided alpha level at 0.025.  
The interim analysis was performed when approximately 432 deaths (50% of the 
required events) were observed. The interim analysis was for futility only, with the
futility boundary set at HR > 1. 


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TABLE OF CONTENTS
DOCUMENT REVISION HISTORY .......................................................................................................... ii 
ABBREVIATIONS & DEFINITIONS ....................................................................................................... iii 
STUDY SYNPOSIS...................................................................................................................................... v 
TABLE OF CONTENTS ............................................................................................................................ ix 
STUDY ACKNOWLEDGMENT/DISCLOSURE ....................................................................................... 1 
TREATMENT SCHEMA ............................................................................................................................. 2 
1.0 
OBJECTIVES................................................................................................................................... 4 
1.1 
Primary Objective ........................................................................................................................................... 4 
1.2 
Secondary Objectives...................................................................................................................................... 4 
2.0 
BACKGROUND INFORMATION AND RATIONALE................................................................ 5 
2.1 
Pancreatic Ductal Adenocarcinoma ............................................................................................................... 5 
2.2 
Cancer Stem Cells (CSC) and PDAC.............................................................................................................. 5 
2.3 
BBI-608 
 ....................................................................................................................................................... 6 
2.4 
Summary  ....................................................................................................................................................... 8 
3.0 
TRIAL DESIGN ............................................................................................................................. 10 
3.1 
Stratification..................................................................................................................................................10 
3.2 
Randomization ..............................................................................................................................................10 
3.3 
Inclusion of Women and Minorities ..............................................................................................................11 
3.4 
Pharmaceutical Data ....................................................................................................................................11 
4.0 
STUDY POPULATION ................................................................................................................. 13 
4.1 
Inclusion Criteria..........................................................................................................................................13 
4.2 
Exclusion Criteria .........................................................................................................................................16 
5.0 
PRE-RANDOMIZATION (BASELINE) SCHEDULE OF EVENTS (SEE APPENDICES I and II)
 
 
 ........................................................................................................................................ 20 
6.0 
ENTRY/RANDOMIZATION PROCEDURES ............................................................................. 22 
6.1 
Entry Procedures ..........................................................................................................................................22 
6.2 
Stratification..................................................................................................................................................22 
6.3 
Randomization ..............................................................................................................................................22 
7.0 
PROTOCOL TREATMENT .......................................................................................................... 24 
7.1 
Treatment Plan..............................................................................................................................................24 
7.2 
Drug Administration .....................................................................................................................................24 
7.3 
Adverse Event Prophylaxis............................................................................................................................25 
7.4 
BBI-608 Dose Modification ..........................................................................................................................27 
7.5 
Nab-paclitaxel and Gemcitabine Dose Modification....................................................................................29 
7.6 
Blinding/Unblinding......................................................................................................................................32 
7.7 
Patient Monitoring........................................................................................................................................32 
7.8 
Concomitant Medications/Procedures..........................................................................................................32 
7.9 
Duration of Therapy......................................................................................................................................33 
7.10 
Patient Compliance.......................................................................................................................................33 
8.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ....................................... 35 
8.1 
Evaluation During Protocol Treatment ........................................................................................................35 
8.2 
Evaluation after permanent Protocol Treatment Discontinuation................................................................37 
9.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS .................................................. 39 
9.1 
Definitions .....................................................................................................................................................39 
9.2 
Response and Evaluation Endpoints.............................................................................................................40 
9.3 
Response Duration........................................................................................................................................42 
9.4 
Stable Disease Duration................................................................................................................................42 
9.5 
Methods of Measurement ..............................................................................................................................42 
10.0 
SERIOUS ADVERSE EVENT REPORTING ............................................................................... 44 
10.1 
Definition of a Protocol Reportable Serious Adverse Event .........................................................................44 


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10.2 
Serious Adverse Event Reporting Instructions..............................................................................................44 
10.3 
Procedures In Case Of an Overdose.............................................................................................................45 
10.4 
Other Protocol Reportable Events – Pregnancy/Exposure Reporting..........................................................45 
10.5 
Responsibility for Reporting Serious Adverse Events to Regulatory Agencies .............................................46 
10.6 
Reporting Safety Reports to Investigators.....................................................................................................47 
11.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ALL 
STUDY TREATMENT ............................................................................................................................... 48 
11.1 
Criteria for Discontinuing Protocol Treatment ............................................................................................48 
11.2 
Duration of Protocol Treatment....................................................................................................................48 
11.3 
Therapy After Protocol Treatment is permanently discontinued ..................................................................48 
11.4 
Follow-up Off Protocol Treatment................................................................................................................48 
12.0 
CENTRAL REVIEW PROCEDURES, TISSUE COLLECTION, AND CORRELATIVE STUDIES
 
 
 ........................................................................................................................................ 50 
12.1 
Central Radiology Review.............................................................................................................................50 
12.2 
Central Pathology Review.............................................................................................................................50 
12.3 
Tissue Collection...........................................................................................................................................50 
12.4 
Sparse Pharmacokinetic Plasma Sample Collection – Nab-paclitaxel with gemcitabine and BBI-608 (Arm 1 
only) 
 
 .....................................................................................................................................................50 
13.0 
STATISTICAL CONSIDERATIONS ........................................................................................... 52 
13.1 
Objectives and Design...................................................................................................................................52 
13.2 
Study Endpoints and Analysis .......................................................................................................................52 
13.3 
Sample Size and Duration of Study...............................................................................................................54 
13.4 
Safety Monitoring..........................................................................................................................................55 
13.5 
Interim Analysis ............................................................................................................................................55 
13.6 
Correlative Studies........................................................................................................................................55 
13.7 
Sparse Pharmacokinetic Analysis .................................................................................................................57 
14.0 
PUBLICATION ............................................................................................................................. 58 
15.0 
RESEARCH OUTSIDE THE TERMS OF THIS PROTOCOL .................................................... 59 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ............................................... 60 
16.1 
Regulatory Considerations............................................................................................................................60 
16.2 
Inclusivity in Research ..................................................................................................................................60 
16.3 
Obtaining Informed Consent.........................................................................................................................61 
16.4 
Discontinuation of the Trial..........................................................................................................................62 
16.5 
Retention of Patient Records and Study Files...............................................................................................62 
16.6 
On-Site Monitoring/Auditing.........................................................................................................................62 
16.7 
Case Report Forms .......................................................................................................................................63 
REFERENCES 
 ........................................................................................................................................ 64 
APPENDIX I - PATIENT EVALUATION FLOW SHEET: Arm 1 (treatment with nab-paclitaxel and 
gemcitabine with BBI-608) ......................................................................................................................... 68 
APPENDIX II - PATIENT EVALUATION FLOW SHEET: Arm 2 (treatment with nab paclitaxel and 
gemcitabine) 
 ........................................................................................................................................ 70 
APPENDIX III - PERFORMANCE STATUS SCALES/SCORES ........................................................... 72 
APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ................. 73 
APPENDIX V - QUALITY OF LIFE ASSESSMENT .............................................................................. 74 


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STUDY ACKNOWLEDGMENT/DISCLOSURE
I understand that this protocol contains information that is confidential and proprietary to Boston Biomedical, 
Inc.
I have read the protocol and agree that it contains all necessary details for carrying out the study as described. 
I will conduct this protocol as outlined herein, and according to Good Clinical Practice and any applicable 
local regulations. I will make a reasonable effort to complete the study within the time designated. I confirm 
that I and study personnel participating under my supervision have adequate resource to fulfill their 
responsibilities as outlined in this protocol. I will maintain documentation of any Investigator responsibilities 
assigned to participating study personnel. I confirm that all data will be submitted in a timely manner and will 
be accurate, complete and supported by source documents. I will complete any protocol specific training 
required by the sponsor and that I understand the requirement to inform additional site personnel with delegated 
duties of this information.  
I will provide copies of the protocol and access to all information furnished by Boston Biomedical, Inc. and/or 
the designated Contract Research Organization (CRO) to the study personnel under my supervision. I will 
discuss this material with them to ensure that they are fully informed about the investigational product and the 
study.  
I understand that this trial will be registered on a public trial registry and that my contact information and site 
name will be included in the registry listing. 
The contents of this protocol may not be used in any other clinical trial and may not be disclosed to any other 
person or entity without the prior written permission of Boston Biomedical, Inc. The foregoing shall not apply 
to disclosure required by governmental regulations or laws; however, I will give prompt notice to Boston 
Biomedical, Inc. of any such disclosure. 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to Boston Biomedical Inc., 
and/or the designated CRO. The study may be terminated at any time by Boston Biomedical, Inc. with or 
without cause. 
Any supplemental information that may be added to this document is also confidential and proprietary to 
Boston Biomedical, Inc. and must be kept in confidence in the same manner as the contents of this protocol.
___________________________________________________ 
_________________________ 
Principal Investigator
Date
(Printed Name and Signature)
Site Name: ___________________________________________ 
Protocol Number: CanStem111P  


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TREATMENT SCHEMA
This is an international multi-center, prospective, open-label, randomized phase III trial of the cancer stem cell 
inhibitor BBI-608 plus nab-paclitaxel with gemcitabine (Arm 1) versus nab-paclitaxel with gemcitabine (Arm 
2) in patients with metastatic PDAC.
Stratification:
x
Geographical region (North America/Western Europe/Australia vs. Japan/Korea vs. Rest of the World)  
x
ECOG performance status (0 versus 1)
x
Presence of liver metastases (yes versus no)
Metastatic
PDAC
RANDOMIZE
ա
A
r
m
1
BBI-608 orally, 
twice daily
plus 
Nab-Paclitaxel + 
Gemcitabine IV, 
weekly
Disease 
progression based 
on RECIST 
criteria1,2
or 
Unacceptable 
toxicity occurs 
OS
ĺ
ĺ
բ
A
r
m
2
Nab-Paclitaxel + 
Gemcitabine IV, 
weekly
1If no other standard therapies are available at the time of disease progression, and the patient has not 
experienced any adverse events requiring permanent discontinuation, BBI-608 may be continued in 
monotherapy. 
2From the time of this amendment, and since the outcome of the interim analysis was communicated to 
investigators, patients may continue protocol therapy if it is believed to be in their best interest by the 
investigator and patient, and with the patient’s informed consent. Patients on Arm 1 may continue BBI-608 
with the Sponsor’s approval. Patients on Arm 1 may discontinue BBI-608 but choose to continue with nab-
paclitaxel and gemcitabine.
Primary Objective: 
x
Overall Survival in the general study population 
Key Secondary Objectives: 
x
Progression-Free Survival (PFS) in the general study population. 


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x
Disease Control Rate (DCR) in the general study population.  
x
Objective Response Rate (ORR) in the general study population. 
Other Secondary Objectives:
x
Safety profile  
x
QoL in the general study population
Exploratory Objectives:
x
OS in the predefined biomarker sub population¥
x
PFS in the predefined biomarker positive sub population¥
x
DCR and ORR in the predefined biomarker positive sub population¥
¥This biomarker-positive sub-population is defined as those patients with phospho-STAT3 positivity on 
immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) tumor tissue.
Sample Size:
Planned sample size is 1132 patients (566 on Arm 1 and 566 on Arm 2).  


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1.0
OBJECTIVES
1.1
PRIMARY OBJECTIVE
To compare overall survival (OS) of patients with metastatic (Stage IV) PDAC treated with BBI-608 
plus weekly nab-paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine.  
1.2
SECONDARY OBJECTIVES
Key Secondary Objectives
x
To compare Progression Free Survival (PFS), in patients treated with BBI-608 plus weekly nab-
paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine.  
x
To compare DCR in patients treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine
versus weekly nab-paclitaxel with gemcitabine. 
x
To compare ORR in patients treated with BBI-608 plus weekly nab-paclitaxel with gemcitabine 
versus weekly nab-paclitaxel with gemcitabine. 
Other Secondary Objectives
x
To evaluate the safety profile of BBI-608 administered daily plus weekly nab-paclitaxel with 
gemcitabine, with safety assessed according to the National Cancer Institute Common Toxicity 
Criteria for Adverse Events (NCI CTCAE) version 4.0. 
x
To compare the Quality of Life (QoL), as measured using the EORTC-QLQ-C30, in patients with 
treatment-naive metastatic PDAC treated with BBI-608 plus weekly nab-paclitaxel with 
gemcitabine versus weekly nab-paclitaxel with gemcitabine. 
Exploratory Objectives:
x
To compare the OS in patients treated with BBI 608 plus weekly nab paclitaxel with gemcitabine 
(Arm 1) versus weekly nab-paclitaxel with gemcitabine (Arm 2) in biomarker positive PDAC 
patients.
x
To compare the PFS in patients treated with BBI 608 plus weekly nab paclitaxel with gemcitabine 
versus weekly nab-paclitaxel with gemcitabine in biomarker positive PDAC patients.
x
To compare the ORR and DCR in patients treated with BBI 608 plus weekly nab paclitaxel with 
gemcitabine versus weekly nab-paclitaxel with gemcitabine in biomarker positive PDAC patients.


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2.0
BACKGROUND INFORMATION AND RATIONALE
2.1
PANCREATIC DUCTAL ADENOCARCINOMA
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer with the 
worst prognosis of all solid tumors (Corbo, 2012; Klimstra, 2007). PDAC is the fourth leading cause 
of cancer death in the United States with an estimate of 38,460 deaths closely following the number
of 45,220 diagnoses in 2013 (Siegel, 2013). Surgery is considered the only potentially curative 
treatment, however, more than 80% of patients present with locally advanced or metastatic disease 
(Davis, 2012). Out of the minority of presenting patients who qualify for curative surgery, most will 
develop disseminated advanced disease with a 5-year survival rate of less than 5% (Hidalgo, 2010).
Standard treatment for unresectable and metastatic disease currently includes first-line combination 
regimen with FOLFIRINOX (5-FU, leucovorin, irinotecan and oxaliplatin), a regimen that provides a 
median overall survival (OS) of 11.1 months in patients with treatment-naïve disease (Conroy, 2011).
Moreover, a number of uncontrolled studies have shown that modified FOLFIRINOX 
(mFOLFIRINOX) regimen results in decreased toxicity while maintaining efficacy in patients with 
pancreatic adenocarcinoma (Blazer, 2015; Mahaseth, 2013). Most recently, a liposomal irinotecan 
formulation was shown to improve overall survival by 1.9 months (6.1 months vs 4.2 months) in 
combination with 5-FU and leucovorin in patients with metastatic PDAC progressing on gemcitabine-
based first-line treatment as compared to patients treated with 5-FU and leucovorin alone (Chen, 2015). 
An alternative regimen for this patient population is a combination of nab-paclitaxel with gemcitabine.
A recent updated survival analysis of the phase II/III study, MPACT (Von Hoff, 2013), randomizing 
861 patients with metastatic PDAC to gemcitabine versus gemcitabine in combination with nab-
paclitaxel, revealed a sustained difference in OS between the 2 arms with median survival of 8.7 
months in the combination group compared to 6.6 months in the gemcitabine monotherapy group and 
more importantly a first ever 3-year survival rate of 4% in the combination treatment group (Goldstein,
2014). These results encourage continued efforts to build upon these backbones to further extend 
survival. Currently, a patient with advanced disease progressing in first-line therapy has limited 
treatment options. Given the morbidity associated with this disease, there is an urgent need to identify 
novel therapies to improve the outcome of patients with advanced unresectable PDAC. 
2.2
CANCER STEM CELLS (CSC) AND PDAC
CSCs or cancer cells with stemness phenotypes are a sub-population of cancer cells that have self-
renewal capability, are highly malignant and are considered to be fundamentally responsible for 
malignant growth, recurrence, drug-resistance and metastasis. Moreover, CSCs are highly resistant to 
chemotherapies and current targeted agents. CSCs have been isolated from almost all major tumor 
types, including PDAC (Lee, 2008; Boman, 2008; Clevers, 2011; Gupta, 2009; Hanahan, 2011; 
Gupta, 2011).
Accumulating evidence indicates that CSCs may play a key role in the pathogenesis of PDAC (Lee, 
2008). Cancer stem cells have been isolated from human pancreatic adenocarcinomas using a
combination of three cell surface markers including CD44, CD24, and ESA (Li, 2007). These CSCs 
isolated from pancreatic adenocarcinoma patients display tumour-initiating properties (Shah, 2007; Li, 
2007). Additionally, the CD133 cell surface marker also discriminates for pancreatic cancer cells with 
potent proliferative capacity (Hermann, 2007) and pancreatic cancer cells positive for both CD133 and 
CXCR4 cell surface markers have the ability to migrate and metastasize in addition to having a potent 


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proliferative capacity (Hermann, 2007). Moreover, CSCs in PDAC display resistance to therapeutics 
as it has been observed that treatment with ionizing radiation and chemotherapy results in enrichment 
of cancer stem cells in pancreatic adenocarcinoma. Exposure of pancreatic cancer cell line to 
gemcitabine results in enrichment of the CSC population (Hermann, 2007; Hong, 2009). Finally, as is 
the case with other cancers including colorectal, breast, prostate, and ovarian carcinoma, expression 
of CSC markers in pancreatic tumors correlates with diminished survival (Rasheed, 2012; Maeda, 
2008; Ohara, 2013). These findings suggest that the development of cancer stem cell inhibitors may 
represent a novel strategy for potential use in the treatment of PDAC.
2.3
BBI-608 
BBI-608 (also called napabucasin, BBI608, BB608) is a small molecule that is hypothesized to affect 
multiple oncogenic cellular pathways, including inhibition of the STAT3 pathway, which has been 
implicated in cancer stem cell viability. For further pre-clinical information, please refer to the 
Investigator Brochure.
BBI-608 has been evaluated in multiple clinical trials as both a monotherapy and as a component of 
combination therapy with standard anti-cancer therapeutics. Available data from many of these trials, 
including detailed adverse event (AE) tables and pharmacokinetic information, can be found in the IB.  
Highlighted below are general information on the BBI-608 safety profile and a summary of the 
BBI608-118 (aka BBI608-201PANC) phase I/II clinical trial of BBI-608 in combination with standard 
chemotherapy for advanced PDAC.
2.3.1
Pre-Clinical Rationale
The pre-clinical rationale for the development of BBI-608 can be found in the Investigator Brochure. 
2.3.2
Safety Profile
The predominant adverse drug reactions (ADRs) associated with BBI-608 are gastrointestinal in 
nature. BBI-608 appears to irritate the gastrointestinal epithelium, which can result in diarrhea, 
abdominal pain, nausea, vomiting, and decreased appetite (anorexia). Fatigue is also reported.  
These ADRs are predominantly mild (grade 1 or grade 2), but can be severe (grade 3). Gastrointestinal 
or other ADRs that are grade 4 in severity are rare (<1%). However, even mild or moderate events, if 
persistent, can result in dehydration; which, if severe, can lead to other events such as hypovolemia, 
hypotension, electrolyte abnormalities, and increased serum creatinine/acute kidney injury. Other 
sequelae such as dizziness or falls could also occur.  
The common ADRs for BBI-608 are shown in Table 1 below. The table shows two sets of frequencies 
or rates. The first set (3rd column) is the range of rates reported for each event as a non-serious 
occurrence across the clinical trials. Different rates are observed in each trial because of different study 
populations and the different combination therapeutics involved. The second set of rates (4th column) 
is the overall frequency in which the event is reported as a serious adverse drug reaction.  


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Table 1: Frequency of Common Adverse Drug Reactions
System Organ Class (SOC)
Preferred Term (PT)
Event Rates (Range)¥
Non-serious
Serious Event Rate¥
Gastrointestinal disorders
Diarrhoea
60 – 80%
3.2%
Vomiting
20 – 30%
1.4%
Nausea
30 – 50%
1.1%
Abdominal pain
20 – 40%
0.7%
General disorders
Fatigue
25 – 40%
0.5%
Asthenia
5 – 10%
0.3%
Metabolism and nutrition disorders Decreased appetite
30 – 50%
0.1%
Dehydration
10 – 15%
1.6%
Electrolyte disorders*
5 – 10%
0.2%
Renal and urinary disorders
Acute kidney injury*
1 – 2%
0.5%
Vascular disorders
Hypotension*
1 – 2%
0.1%
*Event can occur secondary to dehydration or fluid loss as the result of nausea, vomiting, diarrhea, abdominal pain, 
decreased appetite, or a combination of these events.
¥The ranges presented are the event rates observed across different trials that involve different populations and different 
combination therapeutics, out of ~2500 exposed patients.
Refer to the current version of the Investigator’s Brochure for more comprehensive safety data.
2.3.3
BBI-608 for Pancreatic Cancer 
The BBI608-118 (aka BBI608-201PANC) study was initiated to evaluate BBI-608 in combination 
with standard chemotherapy for advanced PDAC. The primary objectives of the study included 
determination of the safety, tolerability, pharmacokinetic characteristics, and recommended phase II 
dose (RP2D) of BBI-608 in combination with each of the backbone regimens. Secondary objectives 
included evaluation of preliminary anti-tumor activity. The study has completed accrual and analysis 
is ongoing. 
Patients with PDAC were eligible if they were appropriate to receive treatment with one of several 
standard regimens for advanced pancreatic cancer: albumin-bound paclitaxel (nab-paclitaxel) plus 
gemcitabine, FOLFIRINOX, liposomal irinotecan (Onivyde [MM-398]) plus 5FU/Leucovorin, or 
FOLFIRI. The trial was not randomized and a treatment arm was selected by investigators based on 
the specific clinical context for each patient. 
Once enrolled, patients received twice daily administration of BBI-608 in combination with a standard 
chemotherapeutic backbone as set forth above. RP2D was determined to be 240 mg BID (480 mg total 
daily) for all combination arms. 
In the BBI-608 in combination with gemcitabine plus nab-paclitaxel study arm, patients received 
gemcitabine 1000 mg/m2 intravenously plus nab-paclitaxel 125 mg/m2 intravenously on days 1, 8, and
15 of a 28-day study cycle. Dose adjustment of either BBI-608 or gemcitabine/nab-paclitaxel (either 
agent) was permitted in the event of toxicity.
Out of 71 patients enrolled, a total of 66 patients had not previously received BBI-608. A majority of 
these patients had not received any systemic therapy, with approximately 25% having received 
adjuvant therapy with recurrence at less than 6 months of the last adjuvant dose.  
As of September 1, 2017, 64 out of the 66 patients enrolled had protocol treatment dose-administration 
confirmed in the study database. These 64 patients were included in an analysis of safety and efficacy. 
Objective response per RECIST 1.1 was observed in 31 (48%) of patients, including 2 (3%) with 
complete response (CR) and 29 (45%) with partial response (PR). An additional 19 (30%) patients had 


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stable disease (SD), and the disease control rate (DCR, proportion with CR, PR, or SD per RECIST 
1.1) was 78%. There were 39 (61%) patients with a progression event and 43 (67%) patients who died, 
with a median progression-free survival (mPFS) of 7.4 months and a median overall survival (mOS) 
of 10.9 months.  
Adverse events (AEs) in the clinical database as of September 1st, 2017 and observed in at least 10% 
of study patients are presented in Table 2 below. Updated clinical data from this trial, if available, can 
be found in the IB. 
Table 2: BBI608-118 Adverse Events - BBI-608 + Gemcitabine/nab-Paclitaxel 
(n = 64*) 
7UHDWPHQWHPHUJHQWDGYHUVHHYHQWVLQRIpatients
Worst grade reported, data extract: 01SEP2017
System Organ Class
Preferred Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Total
n
%
N
%
n
%
n
%
N
%
n
%
Gastrointestinal
Diarrhoea
31
48.4
11
17.2
4 
6.3
1 
1.6
0 
0 
47
73.4
Nausea
19
29.7
10
15.6
1
1.6
0
0
0
0
30
46.9
Abdominal pain
12
18.8
10
15.6
3
4.7
0
0
1
1.6
26
40.6
Vomiting
10
15.6
9
14.1
1
1.6
1
1.6
0
0
21
32.8
Constipation
4
6.3
5
7.8
1
1.6
0
0
0
0
10
15.6
Dyspepsia
5
7.8
2
3.1
0
0
0
0
0
0
7
10.9
General, administration site Fatigue
18
28.1
14
21.9
12
18.8
0
0
0
0
44
68.8
Oedema peripheral
19
29.7
5
7.8
3
4.7
0
0
0
0
27
42.2
Pyrexia
17
26.6
2 
3.1
2 
3.1
1 
1.6
0 
0 
22
34.4
Mucosal inflammation
5
7.8
2
3.1
0
0
0
0
0
0
7
10.9
Metabolism and nutrition 
Decreased appetite
11
17.2
10
15.6
0
0
0
0
0
0
21
32.8
Hypokalaemia
4
6.3
4
6.3
4
6.3
0
0
0
0
12
18.8
Dehydration
1
1.6
8
12.5
2
3.1
0
0
0
0
11
17.2
Hyponatraemia
4
6.3
1
1.6
3
4.7
0
0
0
0
8
12.5
Nervous system
Neuropathy peripheral
15
23.4
6
9.4
4
6.3
0
0
0
0
25
39.1
Dysgeusia
8
12.5
0
0
0
0
0
0
0
0
8
12.5
Headache
7
10.9
0
0
0
0
0
0
0
0
7
10.9
Respiratory
Dyspnoea
6
9.4
4
6.3
3
4.7
0
0
0
0
13
20.3
Cough
7
10.9
1
1.6
0
0
0
0
0
0
8
12.5
Skin and subcutaneous tissue Alopecia
6
9.4
15
23.4
0
0
0
0
0
0
21
32.8
Rash
11
17.2
2 
3.1
0 
0 
0 
0 
0 
0 
13
20.3
Blood and lymphatic system Neutropenia
1
1.6
0
0
13
20.3
4
6.3
0
0
18
28.1
Anaemia
1
1.6
6
9.4
8
12.5
0
0
0
0
15
23.4
Thrombocytopenia
4
6.3
1
1.6
6
9.4
0
0
0
0
11
17.2
Investigations
Weight decreased
6
9.4
5
7.8
0
0
0
0
0
0
11
17.2
1HXWURSKLOFRXQWĻ
3
4.7
1
1.6
0
0
3
4.7
0
0
7
10.9
Musculoskeletal
Pain in extremity
5
7.8
2
3.1
1
1.6
0
0
0
0
8
12.5
Psychiatric
Depression
4
6.3
3
4.7
0
0
0
0
0
0
7
10.9
Renal and urinary
Chromaturia
8
12.5
0
0
0
0
0
0
0
0
8
12.5
*Protocol therapy administration records were not available as of data extract for 2 of the 66 cohort patients.
Refer to the current version of the Investigator’s Brochure for more comprehensive safety data.
2.4
SUMMARY


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BBI-608 at a dose of 240 mg BID (480 mg total daily) combined with a standard regimen of 
gemcitabine and nab-paclitaxel was tolerated in patients with advanced pancreatic cancer.  The clinical 
activity observed in the BBI608-118 (BBI608-201PANC) study, paired with the unmet medical need 
for additional effective therapies in pancreatic cancer, provides a rationale for further clinical 
investigation. CanStem111P is designed to evaluate the role of BBI-608 in combination with nab-
paclitaxel and gemcitabine as frontline therapy for metastatic PDAC.


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3.0
TRIAL DESIGN
This is an international multi-center, prospective, open label, randomized phase III trial of BBI-608 
plus nab-paclitaxel with gemcitabine (Arm 1) versus nab-paclitaxel with gemcitabine (Arm 2) in adult 
patients with metastatic pancreatic adenocarcinoma.
Following the interim analysis, the trial will continue with patients who have not yet achieved the 
primary study endpoint (death), and with patients currently on protocol therapy and who may receive 
BBI-608 and/or gemcitabine and/or nab-paclitaxel on study based on the clinical judgement of the 
investigator that this is in the patient’s best interest, provided the patient is fully informed, in agreement
and has provided consent. Patients will receive protocol treatment until any of the discontinuation 
criteria are met or until February 28th, 2020, whichever occurs first. The protocol will continue to be 
followed for all endpoints until study completion.  
3.1
STRATIFICATION
At randomization, patients will be stratified by:
1.
Geographical region (North America/Western Europe/Australia vs. Japan/Korea vs. Rest of the 
World)  
2.
ECOG performance status (ECOG 0 vs ECOG 1) 
3.
Presence of liver metastases (yes vs no) 
3.2
RANDOMIZATION
Patients will be randomized to the study according to a 1:1 ratio using a permuted block randomization 
procedure to receive one of the following 2 treatments:
1.
Arm 1: BBI-608 plus nab-paclitaxel with gemcitabine  
2.
Arm 2: nab-paclitaxel with gemcitabine  
Total planned sample size for this study is 1132 patients.
Patients will be randomized to one of the following two arms: 
Arm
Study Treatment
Agent(s)
Dose and Route
Duration
1
BBI-608
240 mg orally two times daily1,2
Patients may continue to receive protocol 
therapy as long as they have not 
experienced any adverse events requiring 
permanent discontinuation of study 
medication and have not demonstrated 
disease progression based on RECIST 1.1 
criteria.4,5
Nab-paclitaxel 
with gemcitabine
Nab-Paclitaxel 125 mg/m2 IV 
and
Gemcitabine 1000 mg/m2 IV, 
on Days 1, 8 and 153
2
Nab-paclitaxel 
with gemcitabine
Nab-Paclitaxel 125 mg/m2 IV 
and
Gemcitabine 1000 mg/m2 IV, 


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on Days 1, 8 and 153
1
BBI-608 should be taken one hour before or two hours after a meal, two times daily, with approximately 12 
hours between doses. BBI-608 administration will begin 2 days prior to the backbone chemotherapy infusion 
on Day 1 of Cycle 1. These two days are referred to as Run-in Day 1 and Run-in Day 2. The Run-in period 
may be extended by up to 3 additional calendar days. Run-in Day 1 should occur within 2 calendar days of 
patient randomization.
2
Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking 
BBI-608 with approximately 250 mL of fluid over the course of 30 minutes after the dose.
3
Nab-paclitaxel 125 mg/m2 will be administered intravenously over approximately 30 minutes starting on Day 
1 of Cycle 1, at least 2 hours after the first daily dose of BBI-608. Gemcitabine 1000 mg/m2 will be 
administered intravenously over approximately 30-60 minutes immediately following nab-paclitaxel 
infusion. The infusions will repeat on Days 1, 8 and 15 of every 28-day cycle. 
4
If nab-paclitaxel and/or gemcitabine is/are discontinued due to toxicity, BBI-608 may be continued as 
monotherapy until another criterion for stopping treatment is met with the Sponsor’s approval, if it is believed
to be in the patient’s interest by the investigator and patient, and with the patient’s informed consent. If BBI-
608 is discontinued due to toxicity, nab-paclitaxel and gemcitabine may be continued until another criterion 
for stopping treatment is met.
5
If at the time of disease progression based on RECIST 1.1 criteria on nab-paclitaxel and gemcitabine with 
BBI-608, the patient has not experienced any adverse events requiring permanent discontinuation of BBI-
608, the patient is not a candidate for second-line chemotherapy, it is believed to be in the patient’s best
interest by the investigator and patient, and with the patient’s informed consent, BBI-608 may be continued 
in monotherapy following discontinuation of nab-paclitaxel and gemcitabine with the Sponsor’s approval.
3.3
INCLUSION OF WOMEN AND MINORITIES
Patients enrolled in this study will be representative of the mix of genders, races and ethnicities seen 
in the general population of patients with PDAC. The effect of the intervention under investigation 
will be analyzed in gender, racial and ethnic subgroups, with recognition of the potentially limited 
statistical power of this analysis.
3.4
PHARMACEUTICAL DATA
3.4.1
BBI-608  
Supplied: BBI-608 is supplied in 80 mg strength capsules. 
Stability: Initial product use dating is 24 months from the date of manufacture and can be extended to 
a maximum of 5 years from date of manufacture assuming acceptable results at re-assay time-point 
testing.
Storage: BBI-608 capsules should be stored in a tightly closed container at a temperature between 15 
to 25ºC (59 °F to 77 °F).  
Route of Administration: Oral: Patients should take BBI-608 twice daily, approximately one hour prior 
to or two hours after meals, with the first dose given in the morning and the second dose given 
approximately 12 hours later (ideally between 10 and 14 hours from the previous dose). 
3.4.2
Nab-Paclitaxel and Gemcitabine 


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Please refer to the nab-paclitaxel and gemcitabine Product Labels for product description, stability 
information, storage instructions, and route of administration. 


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4.0
STUDY POPULATION
The trial population will consist of subjects with metastatic histologically or cytologically confirmed 
PDAC. Subjects will not have received systemic chemotherapy for their metastatic PDAC.
4.1
INCLUSION CRITERIA
Questions about eligibility criteria should be addressed prior to randomization. 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are standards 
used to ensure that patients who enter this study are medically appropriate candidates for this therapy, 
as well as to ensure that the results of this study can be useful for making treatment decisions regarding 
other patients with similar diseases. 
Eligibility criteria will be verified by the sponsor and/or sponsor designee prior to patient 
randomization. 
Patients must fulfill all of the following criteria to be eligible for admission to the study:
4.1.1
Written, signed consent for trial participation must be obtained from the patient appropriately 
in accordance with applicable ICH guidelines and local and regulatory requirements prior to 
the performance of any study specific procedure.
4.1.2
Must have histologically or cytologically confirmed advanced PDAC that is metastatic. The 
definitive diagnosis of metastatic PDAC will be made by integrating the histopathological data 
within the context of the clinical and radiographic data. Patients with islet cell neoplasms are 
excluded. 
4.1.3
Must not have previously received chemotherapy or any investigational agent for the treatment 
of PDAC.
x
A fluoropyrimidine or gemcitabine administered as a radiation sensitizer in the adjuvant 
setting is allowed for as long as last dose was administered > 6 months prior to 
randomization and no lingering toxicities are present. 
4.1.4
Nab-paclitaxel with gemcitabine therapy is appropriate for the patient and recommended by 
the Investigator.
4.1.5
Patient has one or more metastatic tumors evaluable by CT scan with contrast (or MRI, if 
patient is allergic to CT contrast media) per RECIST 1.1. Imaging investigations including 
CT/MRI of chest/abdomen/pelvis or other scans as necessary to document all sites of disease
must be performed within 14 days prior to randomization. Qualifying scans performed as part 
of standard of care prior to patient signature of the study informed consent will be acceptable 
as baseline scanning as long as scanning is performed < 14 days prior to randomization. 
4.1.6
Must have ECOG Performance Status of 0 or 1, assessed within 14 days prior to 
randomization. Two observers qualified to perform assessment of the performance status will 
be required to perform this assessment. If discrepant, the one with the most deteriorated 
performance status will be considered true.


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x
Patients must not require any help with activities of daily living (ADLs), including eating, 
dressing, washing or using the toilet.  
x
Patients must not need to stay in bed or chair for 50% or more of waking hours. 
x
Patients with factors that limit accurate assessment of performance status will not be 
eligible for the study. This includes but is not limited to patients with pre-existing 
conditions preventing them from full mobility (including but not limited to spinal or 
orthopedic conditions, amputees, morbid obesity defined by BMI > 40).
4.1.7
Must have life-expectancy of > 12 weeks.
4.1.8
Must be \HDUVRIDJH.  
x
Due to increased risk of sepsis in patients >80 years old, candidate patients in this age 
group should be thoroughly evaluated prior to study randomization to ensure they are fit 
to receive chemotherapy. In addition to all of the inclusion/exclusion criteria listed, 
clinical judgment should be used regarding patients’ susceptibility to infection (including 
but not limited to presence of ascites or diabetes mellitus increasing risk of infection). 
Furthermore, the expected stability of their performance status while receiving repeat 
weekly chemotherapy cycles should be given special attention. Patients in this age group 
should not be randomized on the study should there be any hesitation on any of these 
considerations. 
4.1.9
For male or female patients of child producing potential: Must agree to use contraception or 
take measures to avoid pregnancy during the study and for 180 days after the final dose of 
nab-paclitaxel and gemcitabine or for 30 days for female patients and for 90 days for male 
patients, after the final BBI-608 dose if nab-paclitaxel and gemcitabine were not administered. 
Adequate contraception is defined as follows:
1.
Complete true abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. 
2.
Consistent and correct use of one of the following methods of birth control: 
a.
male partner who is sterile prior to the female subjects entry into the study and is the 
sole sexual partner for that female subject; or 
b.
implants of levonorgesterol; or 
c.
injectable progestagen; or
d.
any intrauterine device (IUD) with a documented failure rate of less than 1% per year; 
or 
e.
any intrauterine hormone-releasing system (IUS) with a documented failure rate of 
less than 1% per year; or
f.
oral contraceptive pill (either combined or progesterone only); or 
g.
one barrier method, for example diaphragm with spermicide or condom with 
spermicide in combination with either implants of levonorgesterol or injectable 
progestagen, any intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS) with a documented failure rate of less than 1% per year, or oral contraceptive 
pill (either combined or progesterone only). 
4.1.10 Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy 
test within 3 days prior to randomization. The minimum sensitivity of the pregnancy test must 
be 25 IU/L or equivalent units of human chorionic gonadotropin (HCG). 


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WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhoea > 12 consecutive months; 
or women on hormone replacement therapy (HRT) with documented serum follicle 
stimulating hormone (FSH) level > 35 mIU/mL). Even women who are using oral, implanted 
or injectable contraceptive hormones or mechanical products such as an intrauterine device or 
barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing 
abstinence or where partner is sterile (e.g. vasectomy), should be considered to be of child 
bearing potential. 
4.1.11 Patient has adequate biological parameters as demonstrated by the following blood counts at 
baseline (obtained < 14 days prior to randomization; laboratory testing performed as part of 
standard of care prior to patient signature of informed consent for the study will be acceptable 
as baseline laboratory work as long as testing is performed < 14 days prior to randomization):
x
Absolute neutrophil count (ANC) > 1.5 x 109/L  
x
Platelet count > 100,000/mm3 (100 x 109/L). Must not have required transfusion of 
platelets within 1 week of baseline platelet count assessment.
x
Hemoglobin (Hgb) > 9 g/dL. Must not have required transfusion of red blood cells within 
1 week of baseline Hgb assessment.
4.1.12 Patient has the following blood chemistry levels at baseline (obtained < 14 days prior to 
randomization; laboratory testing performed as part of standard of care prior to patient 
signature of informed consent for the study will be acceptable as baseline laboratory work as 
long as testing is performed < 14 days prior to randomization):
x
AST (SGOT) and ALT (SG37îLQVWLWXWLRQDOXSSHUOLPLWRIQRUPDO8/1>î
ULN in presence of liver metastases] 
x
7RWDOELOLUXELQ1.5 x institutional ULN. If total bilirubin is > ULN and < 1.5 x ULN, it 
must be non-rising for at least 7 days.
x
Serum creatinine within normal limits or calculated clearance > 60 mL/min/1.73 m2 for 
patients with serum creatinine levels above or below the institutional normal value. If 
using creatinine clearance, actual body weight should be used for calculating creatinine 
clearance (eg. Using the Cockroft-Gault formula). For patients with a Body Mass Index 
(BMI) > 30 kg/m2, lean body weight should be used instead. 
4.1.13 Patient not on anticoagulation has acceptable coagulation studies (obtained < 14 days prior to 
randomization; laboratory testing performed as part of standard of care prior to patient 
signature of informed consent for the study will be acceptable as baseline laboratory work as 
long as testing is performed < 14 days prior to randomization) as demonstrated by prothrombin 
time (PT) and partial thromboplastin time (PTT) below or within normal limits (+15%). 
x
Patients on anticoagulation must have coagulation values within the therapeutic range 
appropriate for the anti-coagulation indication. 
4.1.14 Patient has no clinically significant abnormalities on urinalysis results (obtained < 14 days 
prior to randomization; laboratory testing performed as part of standard of care prior to patient 
signature of informed consent for the study will be acceptable as baseline laboratory work as 
long as testing is performed < 14 days prior to randomization). 
4.1.15 Patient must have adequate nutritional status with Body Mass Index (BMI) > 18 kg/m2 and 
body weight of > 40 kg with serum albumin > 3 g/dL. 


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4.1.16 Baseline laboratory evaluations must be done within 14 days prior to randomization and some 
must be repeated < 72 hours prior to randomization, as listed in Section 5.0.  
4.1.17 Patients requiring biliary stent placement must have biliary stent placed > 7 days prior to 
screening.  
4.1.18 Pain symptoms should be stable (of tolerable Grade 2 or less). 
4.1.19 Only patients with available archival tumor tissue must consent to provision of, and 
Investigator(s) must confirm access to and agree to submit a representative formalin fixed 
paraffin block of tumor tissue in order that the specific correlative marker assays proscribed 
in Section 13.6 (Correlative Studies) of this protocol may be conducted. Submission of the 
tissue does not have to occur prior to randomization. Where local center regulations prohibit 
submission of blocks of tumor tissue, two 2 mm cores of tumor from the block and 5-20 
unstained slides of whole sections of representative tumor tissue are preferred. Where it is not 
possible to obtain two 2 mm cores of tumor from the block, 5-20 unstained slides of 
representative tumor tissue are also acceptable. 
x
Where no previously resected or biopsied tumor tissue exists or is available, on the
approval of the Sponsor/designated CRO, the patient may still be considered eligible for 
the study.  
4.1.20 Patient must consent to provision of a sample of blood in order that the specific correlative 
marker assays proscribed in Section 13.6 (Correlative Studies) may be conducted. 
4.1.21 Patients must be accessible for treatment and follow-up. Patients registered on this trial must 
receive protocol treatment and be followed at the participating center. This implies there must 
be reasonable geographical limits placed on patients being considered for this trial. 
Investigators must ensure that the patients randomized on this trial will be available for 
complete documentation of the treatment, response assessment, adverse events, and follow-
up.
4.1.22 Protocol treatment is to begin within 2 calendar days of patient randomization for patients 
randomized to Arm 1. Patients randomized to Arm 2 must begin protocol treatment within 7
calendar days of randomization. 
4.1.23 The patient is not receiving therapy in a concurrent clinical study and the patient agrees not to 
participate in other interventional clinical studies during their participation in this trial while 
on study treatment. Patients participating in surveys or observational studies are eligible to 
participate in this study.
4.2
EXCLUSION CRITERIA
Patients who fulfill any of the following criteria are not eligible for admission to the study:
4.2.1
Patients with no evidence of metastatic disease as well as patients with a local recurrence 
following surgical resection of primary lesion.
4.2.2
Patient has experienced a decline in ECOG performance status between Baseline visit and 


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within 72 hours prior to randomization.
4.2.3
Patient has a > 20% decrease in serum albumin level between Baseline visit and within 72 
hours prior to randomization.
4.2.4
Patient has a > 10% decrease in weight between Baseline visit and within 72 hours prior to 
randomization. 
4.2.5
Any prior anti-cancer chemotherapy, biologic or investigational therapy for PDAC.
a.
Patients receiving immunotherapy for non-cancer related treatment within < 4 weeks of 
first planned dose of study treatment will be excluded. 
b.
A fluoropyrimidine or gemcitabine administered as a radiation sensitizer in the adjuvant 
setting is allowed for as long as last dose was administered > 6 months prior to 
randomization. 
4.2.6
Major surgery within 4 weeks prior to randomization. 
4.2.7
Any known brain or leptomeningeal metastases are excluded, even if treated.
4.2.8
Patients with clinically significant ascites or pleural effusions. 
4.2.9
Women who are pregnant or breastfeeding. Women should not breastfeed while taking study 
treatment and for 4 weeks after the last dose of BBI-608 or while undergoing treatment with 
nab-paclitaxel and gemcitabine and for 180 days after the last dose of nab-paclitaxel and 
gemcitabine.
4.2.10 Gastrointestinal disorder(s) which, in the opinion of the Principal Investigator, would 
significantly impede the absorption of an oral agent (e.g. active Crohn’s disease, ulcerative 
colitis, extensive gastric and small intestine resection).
4.2.11 Unable or unwilling to swallow BBI-608 capsules daily.
4.2.12 Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, 
clinically significant non-healing or healing wounds, symptomatic congestive heart failure, 
unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary 
disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric 
illness/social situations that would limit compliance with study requirements. 
a.
History of cardiac disease: congestive heart failure (CHF) > NYHA Class II; active 
coronary artery disease, myocardial infarction or coronary stenting within 6 months prior 
to randomization; unevaluated new onset angina within 3 months or unstable angina 
(angina symptoms at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta 
blockers or digoxin are permitted). 
b.
Current uncontrolled hypertension (systolic blood pressure [BP] > 150 mmHg or diastolic 
pressure > 90 mmHg despite optimal medical management) as well as prior history of 
hypertensive crisis or hypertensive encephalopathy. 
c.
Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic 
peripheral vascular disease including claudication, Leo Buerger’s disease). Treated 
peripheral vascular disease that is stable for at least 6 months is allowed. 


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d.
Evidence of bleeding diathesis or clinically significant coagulopathy.  
e.
Major surgical procedure (including open biopsy, significant traumatic injury, etc.) within 
28 days, or anticipation of the need for major surgical procedure during the course of the 
study as well as minor surgical procedure (excluding placement of a vascular access 
device or bone marrow biopsy) within 7 days prior to randomization.  
f.
Patients with clinically significant abnormalities on urinalysis at < 14 days prior to 
randomization. 
g.
History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 6 months prior to randomization.  
h.
Ongoing serious, non-healing wound, ulcer, or bone fracture.  
i.
Known infection with Human Immunodeficiency Virus (HIV), and/or active infection 
with hepatitis B, or hepatitis C.
j.
History of interstitial lung disease, history of slowly progressive dyspnea and 
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary 
hypersensitivity pneumonitis or multiple allergies. 
k.
History of hemolytic-uremic syndrome. 
l.
History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa). 
m. Serious medical risk factors involving any of the major organ systems, or serious 
psychiatric disorders that could compromise the patient’s safety or the study data integrity.
4.2.13 Known hypersensitivity to gemcitabine, taxanes or any of their excipients, or the patient 
exhibits any of the events outlined in the Contraindications or Special Warnings and 
Precautions sections of the product or comparator SmPC or Prescribing Information. Possible 
hypersensitivity to BBI-608 or one of the excipients which include the azo dyes sunset yellow 
and allura red.
4.2.14 Neurosensory neuropathy > grade 2 at baseline. 
4.2.15 Uncontrolled chronic diarrhea > grade 2 at baseline. 
4.2.16 Patients being treated with Warfarin. 
4.2.17 Patients with active, uncontrolled bacterial, viral or fungal infection(s) requiring systemic 
therapy 
4.2.18 Patients with a history of other malignancies except: adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated 
by surgery alone or surgery plus radiotherapy with no evidence of disease continuously for > 
5 years.
4.2.19 Any active disease condition which would render the protocol treatment dangerous or impair 
the ability of the patient to receive protocol therapy.
4.2.20 Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with 
the protocol, including patients with history of poor compliance or history of drug/alcohol 
abuse, or excessive alcohol beverage consumption that would interfere with the ability to 


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comply with the study protocol. Patients planning to take a vacation for 14 or more consecutive 
days during the course of the study are ineligible. 


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5.0
PRE-RANDOMIZATION (BASELINE) SCHEDULE OF EVENTS (SEE APPENDICES I AND
II) 
Baseline evaluations will be performed for all patients to determine study eligibility. These evaluations 
must be obtained < 14 days prior to randomization.  
Repeat of screening laboratory tests will be allowed only in the event of a laboratory error or for 
patients who halted screening previously without having failed any of the screening tests/evaluations 
or inclusion criteria for this study. Otherwise, re-screening will not be allowed. 
Any questions regarding patient eligibility should be directed to Sponsor or other Sponsor-nominated 
designee for written approval.  
Additional testing will be repeated < 72 hours prior to randomization: ECOG performance status (PS),
vital signs, weight, concurrent medication list and serum albumin will be repeated at < 72 hours prior 
to randomization after first being performed as part of Baseline testing. Total bilirubin will be repeated 
< 72 hours prior to randomization for patients with total bilirubin > 1 and < 1.5 x ULN at Baseline 
testing with at least 7 days between Baseline and repeat assessments.
All appropriate eCRF pages must be completed for patients prior to obtaining pre-randomization 
approval and following completion of additional testing at < 72 hours prior to randomization, in 
accordance with the eCRF completion guidelines and the Eligibility Verification Procedure Flow 
Chart. 
Investigations
Timing of Baseline 
Evaluation prior to 
randomization
Additional Testing at <
72 hrs prior to 
randomization3
Informed Consent1
•
Signature
< 14 days
Patient History and 
Evaluation including:
•
All known prior medical and therapeutic history2
•
Physical examination11, 14
•
Vital signs5,11
•
Height, weight12, ECOG performance status11
•
Concurrent medication list11
< 14 days
x
ECOG performance 
status
x
Vital signs5
x
Weight
x
Concurrent 
medication list4
Hematology
•
CBC + 5-part differential
•
Platelet count
< 14 days11
-
Biochemistry
•
Creatinine6, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, LDH, Albumin, Sodium, Potassium, 
Magnesium, Phosphate, BUN (blood urea nitrogen)
< 14 days11
x
Serum Albumin
x
Total Bilirubin12,13
Urinalysis
•
Dipstick (including protein, specific gravity, 
glucose and blood)
< 14 days11
-
Coagulation
•
PT
•
PTT
< 14 days11
-
Tumor Marker
•
CA 19-9
< 14 days11
-
Cardiac Assessment
•
ECG (12 lead)
< 14 days11
-
Radiology & Imaging7
•
CT/MRI scan of chest/abdomen/pelvis with tumor 
measurement and evaluation by RECIST 1.1 criteria
< 14 days
-
Correlative Studies 
•
Submission of representative diagnostic tumor 
tissue8
On request
-
•
Blood sample collection8
< 14 days
-


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Other Investigations
•
Serum or urine pregnancy test9
< 3 days
-
Adverse Events10
•
Baseline adverse event evaluation (to document 
residual adverse event from previous therapy and 
baseline symptoms)
< 14 days
-
Quality of Life
•
EORTC QLQ-C30 
< 14 days
-
1
Study participants will undergo signature of informed consent prior to randomization.
2
Medical history must include date of diagnosis including histological or cytological documentation of malignancy. 
3
Patient will be excluded from participation if any of the following occurs at < 72 hours prior to randomization: increase in ECOG PS
(two observers will be required to assess KPS on each occasion and if discrepant, the one with the most deteriorated performance status
will be considered true), weight loss of >10% from baseline testing, > 20% decrease in serum albumin from baseline testing, or in the 
event of a clinically-significant change in vital signs. 
4
Any anesthesia procedures, such as spinal block or other injections administered for pain control following Baseline Evaluation will be 
reported at < 72 hours prior to randomization.
5
Vital signs include temperature, heart rate, blood pressure, respiratory rate and O2 saturation on room air.
6
Baseline creatinine or creatinine clearance may be used to demonstrate eligibility as per section 4.1.
7
Standard tumor measurement procedures will be followed to assess response to therapy. The same method of assessment and the same 
technique should be used to identify and report each lesion at baseline and at reassessment. Qualifying scans performed as part of 
standard of care prior to patient signature of the study informed consent will be acceptable as baseline scanning as long as scanning is 
performed < 14 days prior to randomization. Should clinical or radiologic progression occur from the time of baseline imaging prior to 
randomization, a new baseline scan will need to be obtained prior to randomization. 
8
Details for collection, processing, storing and shipping these samples will be provided in a separate laboratory procedure manual.
9
In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG.
10
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see Appendix IV). 
11
Laboratory testing performed as part of standard of care prior to patient signature of the study consent will be acceptable as baseline 
labwork as long as testing is performed < 14 days prior to randomization. If required laboratory tests cannot be performed within 
indicated timelines due to technical reasons, lab retest and prolongation of the screening period for 3 working days is allowed.
12
Total bilirubin assessment at < 72 hours prior to randomization will be performed only for patients who had total bilirubin of > 1 and < 
1.5 x ULN at baseline measurement. Patients with total bilirubin < 1 ULN at baseline measurement will not require repeat total bilirubin 
measurement at < 72 hours prior to randomization.
13
At least 7 days must pass between Baseline and < 72 hour measurements of total bilirubin for patients with baseline total bilirubin 
measurement of > 1 and < 1.5 x ULN.
14
A physical exam should include general appearance, HEENT (head, eyes, ears, nose), dermatological, respiratory, 
cardiovascular/circulatory, abdomen, lymphatic, genitourinary, musculoskeletal, and neurological assessments.


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6.0
ENTRY/RANDOMIZATION PROCEDURES
6.1
ENTRY PROCEDURES
Repeat of screening laboratory testing will be allowed only in case of laboratory error. Otherwise, re-
screening will not be allowed for patients who screen fail during initial screening procedures. 
Following Sponsor approval of patient eligibility pre-randomization, patients will be randomized. All 
randomizations will be done through the randomization and trial supply management (RTSM) system.
Complete details regarding obtaining a password, accessing the system and registering/randomizing 
patients will be provided at the time of study activation.  
All patients screened for the study by the participating treatment center will be assigned a subject 
screening number and all eligible patients enrolled on the study will be assigned an additional subject 
randomization number; these must be used on all documentation and correspondence. 
The following information will be required:
x
patient’s date of birth (as allowed by local regulations) and age 
x
patient's initials (as allowed by local regulations)  
x
confirmation of the requirements listed in sections 4.1 and 4.2 
x
stratification factors 
6.2
STRATIFICATION
The permuted block randomization procedure will balance between treatment arms within each of the 
following stratification factors:
x
Geographical region (North America/Western Europe/Australia vs. Japan/Korea vs. Rest of the 
World)  
x
ECOG performance status (0 vs. 1)
x
Presence of liver metastases (yes vs. no)
6.3
RANDOMIZATION
Patients will be randomized 1:1 between the two treatment arms and the randomization will be 
provided electronically (via RTSM). 
Note: The validity of results of the trial depends on the authenticity of, and the follow-up of, all 
patients entered into the trial. Under no circumstances, therefore, may an allocated patient’s data be 
withdrawn prior to final analysis, unless the participant withdraws from the trial and requests that data 
collection/submission cease from the point in time of withdrawal.
All eligible patients randomized to the trial will be followed by the coordinating center. It is the 
responsibility of the physician investigator to have full satisfaction in that the patient is indeed eligible 
before requesting randomization. 


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All randomized patients are to be followed until death or until the study sponsor or sponsor’s designee
inform sites that further follow-up is no longer required. 


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7.0
PROTOCOL TREATMENT
7.1
TREATMENT PLAN
Protocol treatment is to begin within 2 calendar days of patient randomization for patients randomized 
to Arm 1. Patients randomized to Arm 2 must begin protocol treatment within 7 calendar days of 
randomization. 
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be permitted for all patients on this trial. Details of interventions (e.g. medications such 
as antibiotics, analgesics, antihistamines, steroids, G-CSF, erythropoietin), procedures (e.g. 
paracentesis, thoracentesis), or blood products (e.g. blood cells, platelets, or fresh frozen plasma 
transfusions) should be recorded on the case report forms.
Patients may continue to receive assigned protocol therapy until any of the discontinuation criteria are 
met or until February 28th, 2020, when the study is planned for completion, whichever occurs first.
7.2
DRUG ADMINISTRATION
One treatment cycle is defined as 4 weeks (28 days) with BBI-608 administered continuously, and 
nab-paclitaxel with gemcitabine administered weekly for 3 consecutive weeks with the fourth week 
off. BBI-608 administration will begin 2 days prior to the first nab-paclitaxel and gemcitabine infusion 
administered on Day 1 of Cycle 1. These two days are referred to as Run-In Day 1 and Run-In Day 2. 
The Run-in period may be extended by up to 3 additional calendar days. In case of gastrointestinal 
toxicity secondary to BBI-608, administration of nab-paclitaxel with gemcitabine may be delayed for 
as long as necessary until resolution of symptoms.
Arm
Agent(s)
Dose and Route
Duration
1 
BBI-608  
240 mg orally two times daily1,2 
Patients may continue to receive protocol 
therapy as long as they have not experienced 
any adverse events requiring permanent 
discontinuation of study medication and have 
not demonstrated disease progression based on 
RECIST 1.1 criteria. 4,5
Gemcitabine
+nab-Paclitaxel
Nab-Paclitaxel 125 mg/m2 IV and
Gemcitabine 1000 mg/m2 IV, on Days 
1, 8 and 153
2 
Gemcitabine
+nab-Paclitaxel  
Nab-Paclitaxel 125 mg/m2 IV and
Gemcitabine 1000 mg/m2 IV, on Days 
1, 8 and 153
1
BBI-608 should be taken one hour before or two hours after a meal, two times daily, with approximately 12 hours 
between doses. BBI-608 administration will begin 2 days prior to the nab-paclitaxel and gemcitabine infusions on 
day 1 of cycle 1. These two days are referred to as Run-in Day 1 and Run-in Day 2 (run-in period may be extended 
by up to 3 additional calendar days). Run-in Day 1 should occur within 2 calendar days of patient randomization
for patients randomized to Arm 1. Patients randomized to Arm 2 must begin protocol treatment within 7 calendar 
days of randomization. In case of gastrointestinal toxicity secondary to BBI-608, administration of nab-paclitaxel 
and/or gemcitabine may be delayed for as long as necessary until resolution of symptoms.
2
Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking BBI-
608 with approximately 250 mL of fluid over the course of 30 minutes after the dose.
3
Nab-paclitaxel 125 mg/m2 will be administered intravenously over approximately 30 minutes starting on Day 1 of 
Cycle 1, at least 2 hours after the first daily dose of BBI-608. Gemcitabine 1000 mg/m2 will be administered 


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intravenously over approximately 30-60 minutes immediately following nab-paclitaxel infusion. The infusions will 
repeat on Days 1, 8 and 15 of every 28-day cycle. 
4
If either nab-paclitaxel and/or gemcitabine is discontinued due to toxicity, BBI-608 may be continued as 
monotherapy until another criterion for stopping treatment is met with the Sponsor’s approval, if it is believed to 
be in the patient’s best interest by the investigator and patient, and with the patient’s informed consent. If BBI-608
is discontinued due to toxicity, nab-paclitaxel and/or gemcitabine may be continued until another criterion for 
stopping treatment is met.
5
If at the time of disease progression based on RECIST 1.1 criteria on nab-paclitaxel and gemcitabine with BBI-
608, the patient has not experienced any adverse events requiring permanent discontinuation of BBI-608,the patient 
is not a candidate for second-line chemotherapy, it is believed to be in the patient’s best interest by the investigator 
and patient, and with the patient’s informed consent, BBI-608 may be continued in monotherapy following 
discontinuation of nab-paclitaxel and gemcitabine with the Sponsor’s approval. 
Patients will receive BBI-608 two times daily, approximately one hour prior to or two hours after 
meals, with the first dose given in the morning and the second dose given approximately 12 hours 
later.
Detailed instructions for the preparation, premedication, and administration of nab-paclitaxel with 
gemcitabine are provided in the Product Labels approved by US FDA and/or Summary of Product 
Characteristics. Nab-paclitaxel 125 mg/m2 will be administered intravenously over approximately 30 
minutes starting on Day 1 of Cycle 1, following the first dose of BBI-608. Gemcitabine 1000 mg/m2
will be administered intravenously over approximately 30-60 minutes immediately following nab-
paclitaxel infusion. The infusions will repeat on Day 1, 8 and 15 of every 28-day cycle. In case of 
toxicity, dose adjustment is permitted.  
If either gemcitabine and/or nab-paclitaxel is/are permanently discontinued due to toxicity, BBI-608 
may be continued as monotherapy until another criterion for stopping treatment is met with the 
Sponsor’s approval, it is believed to be in the patient’s best interest by the investigator and patient, and 
with the patient’s informed consent. If BBI-608 is permanently discontinued due to toxicity, nab-
paclitaxel with gemcitabine may be continued until another criterion for stopping treatment is met. 
Handling instructions for BBI-608 will be provided to all sites. Investigators may refer to the 
Investigator Brochure for detailed instructions.
Drug Dosing Schedule
Week1
1
2
3
4
5
6
7
8
nab-Paclitaxel/Gemcitabine
Cycle 1
Cycle 2 and 
Beyond
X
X
X
X
X
X
BBI-6082
Cycle 1
Cycle 2 and 
Beyond
X
X
X
X
X
X
X
X
1
Nab-Paclitaxel/Gemcitabine weekly dosing is scheduled once weekly for 3 consecutive weeks 
with forth week off. 
2
BBI-608 dosing is scheduled twice daily continuously throughout the study. 
7.3
ADVERSE EVENT PROPHYLAXIS
7.3.1
BBI-608 
Gastrointestinal Prophylaxis


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The major adverse events associated with the use of BBI-608 are gastrointestinal events (nausea, 
diarrhea, and abdominal cramping) and fatigue. Fatigue is often secondary to gastrointestinal events. 
There is no hematologic toxicity associated with BBI-608. We strongly recommend that pre-existing 
laxative bowel regimens, such as stool softeners, be held starting the day prior to first dose of study 
treatment and may be resumed in cases of no bowel movement during the first 2 days of protocol 
treatment. Fiber supplementation may be continued. Additionally, prophylactic anti-diarrheal 
medications, such as Loperamide and/or Diphenoxylate/Atropine, starting 1 day prior to start of BBI-
608 are strongly recommended for all patients without history of constipation (just prior to 
randomization) for the first 4 weeks of study treatment with BBI-608. Antidiarrheal prophylaxis should 
be held if constipation develops. Details regarding the use of prophylactic medication for the 
management of common BBI-608 related gastrointestinal adverse events are specified in the 
supplementary Adverse Event Management handout as well as in the Pharmacy Manual.
No hematologic toxicity related to BBI-608 treatment has been observed.
BBI-608 Pre-Medication Recommendations:
Category
Specific Measures
Start
End
Anti-Diarrheal
Loperamide 4 mg BID
or
Diphenoxylate/Atropine 
5 mg BID
24 hours prior to the 
first dose of BBI608 
on Run-In Day 1
Stop anti-diarrheal if there are no 
bowel movements during the first 2 
days of administration of BBI-608. 
Should be continued for the first 4 
weeks of treatment with BBI-608.
Can be continued and/or modified 
at the discretion of the treating 
investigator
Anti-Emetic
Ondansetron 8 mg once
or
Other anti-emetic  (5HT3-
antagonist preferred)
Approx. 1 hour prior 
to the first dose of 
BBI608 on Run-In 
Day 1
Should be continued for the first 4 
weeks of treatment with BBI-608.
May be continued and/or modified 
at discretion of treating investigator
7.3.2
Nab-Paclitaxel and Gemcitabine
Anti-Emetic Prophylaxis
Initial antiemetic prophylaxis is strongly recommended with a 5HT3 agent (PO or IV) in combination 
with dexamethasone 8 or 10 mg (PO or IV) prior to administration of Gemcitabine. Dexamethasone 
may be continued at the dose of 4 mg twice daily or three times daily for 3-4 days at the Investigator’s 
discretion. If a patient experiences nausea and/or vomiting following the first dose, Institutional 
guidelines and Investigator’s recommendations should be followed for breakthrough antiemetic 
management.  
Hematopoietic Support Administration
G-CSF support may be given according to Institutional standards for the treatment of neutropenia 
and/or thrombocytopenia, neutropenic fever or infections associated with neutropenia and for the 
prevention of febrile neutropenia in patients with an ANC < 500 cells/ml. Patients not experiencing 
resolution of neutropenia within 21 days, despite uninterrupted granulocyte stimulating factor 
treatment, will discontinue study treatment. Erythropoietin may be administered at the discretion of 
the Investigator, consistent with Institutional guidelines.


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Sepsis Prophylaxis 
At the first occurrence of fever > 38.5 0C, patients should be instructed to immediately contact their 
physician. Prophylactic institution of broad-spectrum antibiotics (such as amoxicillin/clavulanate 500 
mg PO 2-3 times daily) should be considered for febrile patients at the Investigator discretion and/or 
as per Institutional standards. On day of randomization, patients should be provided with enough 
antibiotic for use at home, and they should be instructed to begin taking it when they first record a 
temperature of > 38.5 0C (or if they feel they are developing a fever and a thermometer is not available). 
They should also immediately contact their physician for guidance on where to go for blood counts to 
be evaluated for sepsis as soon as possible. Hospitalization or evaluation in the emergency room may 
be required depending on their clinical presentation. Administration of prophylactic antibiotics to 
otherwise uncomplicated patients with biliary stents will be at the discretion of the Investigator. Biliary 
stents should be monitored closely to determine need for replacement. 
Due to increased risk of sepsis in patients >80 years old, candidate patients in this age group should 
be carefully followed clinically throughout study treatment. This patient population will also be 
carefully monitored by the independent DSMB. 
7.4
BBI-608 DOSE MODIFICATION
The major adverse events associated with the use of BBI-608 are gastrointestinal events (nausea, 
diarrhea, and abdominal cramping) and fatigue. Fatigue is often secondary to gastrointestinal events. 
There is no hematologic toxicity associated with BBI-608. We recommend that pre-exiting laxative 
bowel regimens, such as stool softeners, be held starting the day prior to first dose of BBI-608 
treatment and may be resumed in cases of no bowel movement during the first 2 days of BBI-608 
treatment. Fiber supplementation may be continued. Additionally, prophylactic anti-diarrheal 
medications, such as Loperamide and/or Diphenoxylate/Atropine, starting 1 day prior to start of BBI-
608 are strongly recommended for all patients treated with BBI-608. 
The guidelines that follow outline dosing modifications and recommended interventions should the 
above adverse events occur. 
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 (see Appendix IV). If a patient experiences several adverse events and there are 
conflicting recommendations, please use the recommended dose adjustment that reduces the dose to 
the lowest level.
BBI-608 Dose Modification Recommendations For Gastrointestinal Adverse Events:
Suspected BBI-608 -Related 
Adverse Event
Investigator Action
Grade 1 or tolerable Grade 2 Symptoms
Patient should remain at current dose. Attempt pharmacologic measures to 
minimize symptoms (see symptom specific treatment table below).
Intolerable Grade 2 Symptoms
If intolerable symptoms persist despite optimized medical management, 
dose reduction and sufficient oral hydration are recommended. A dose 
interruption of ½ to 3 days prior to reduction can also be considered. 
Dosing should be reduced to the next Modification Level on the dose 
modification table. Pharmacologic symptom support and/or prophylaxis 
should be maintained. 


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After a dose reduction, AM and PM doses may be increased in 80 mg 
increments every 3-7 days as tolerated.*, **
Grade 3 or 4 Symptoms
A dose interruption of ½ to 3 days is recommended until symptoms are 
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Dosing should be reduced to the next Modification Level on the dose 
modification table. Pharmacologic symptom support and/or prophylaxis 
should be maintained. 
After a dose reduction, AM and PM doses may be increased in 80 mg 
increments every 3-7 days as tolerated.*, **
* 
If, during the course of re-escalation, a dosing regimen is not tolerated despite optimized medical management, 
dosing should return to the highest previously tolerated dosing regimen.
** Asymmetry between AM and PM dose is allowed during re-escalation (e.g. 160 mg AM/240 mg PM).
BBI-608 Dose Modification Table: 
Dose Level
Dose
Full dose
240 mg twice daily (q12h)
Modification Level-1 
80 mg twice daily (q12h), up-titrate as tolerated**
Modification Level-2 
80 mg once daily*, up-titrate as tolerated**
*
If 80 mg once daily is not tolerated, a dose interruption of 1-3 days followed by re-challenge at 80 mg once daily is 
recommended.
**
Morning and evening doses can be increased in 80 mg increments every 3-7 days or slower as tolerated, up to 240
mg two times daily. 
Recommended symptom-specific supportive treatment for common BBI-608-related adverse events is 
as follows (unless contraindicated). Prophylactic anti-diarrheal medications, such as Imodium and/or 
lomotil, starting 1 day prior to start of BBI-608 are strongly recommended for all patients: 
BBI-608 GI Toxicity/Adverse Event Supportive Treatment:
Diarrhea & Abdominal Cramping
Nausea, Vomiting, or Anorexia
Dicyclomine (e.g., Bentyl): Recommended when the 
predominant issue is cramping or abdominal pain
1st
line:
5HT3-inhibitors 
(Ondansetron, 
Palonosetron, Granisetron)
Diphenoxylate/atropine (Lomotil)
Loperamide (Imodium)
These agents 
may be also 
be useful in 
combination
2nd line:
Dexamethasone (Decadron), ideally in 
combination with a 5HT3-inhibitor. Short term use 
can be very effective
Systemic opioids (e.g. Dilaudid, Codeine): have been 
found effective in reducing abdominal pain and watery 
diarrhea
Other  agents: anti-histamines, benzodiazepines, 
proton pump inhibitors/H2 antagonists, dopamine 
antagonists, and cannabinoids
Hyoscine (Buscopan, Scopolamine, Levsin):
Anti-
spasmodic agents helpful for abdominal cramping


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Budesonide (Entocort EC): Corticosteroid with limited 
systemic absorption;  9 mg once daily for 8 to 12 weeks
Details regarding the use of supportive medication for the management of common BBI-608-related 
adverse events are specified in the supplementary Adverse Event Management handout as well as in 
the Pharmacy Manual.
7.4.1
Hematologic Adverse Events
No hematologic toxicity related to BBI-608 treatment has been observed. Should a study subject 
experience a Grade 1 or 2 hematologic adverse event, dosing may continue while an alternate 
explanation is sought and/or a therapeutic intervention is undertaken.  
In the unlikely event of a Grade 3 or 4 hematologic adverse event, continued dosing will be at the 
discretion of the study Investigator. Since a Grade 3 or 4 hematologic event attributed to BBI-608 has 
not been reported, a prompt evaluation for an alternate explanation is strongly recommended.  
7.4.2
Non-Hematologic (Gastrointestinal) Adverse Events
The dose modifications above should be followed in the occurrence of gastrointestinal adverse events 
or in the event of their sequelae. BBI-608 dose modification should not be followed for non-
gastrointestinal events as they are not expected with use of BBI-608. Toxic effects will be graded using 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (Appendix IV).  
7.4.3
Other Situations 
Change in Urine Color and Odor: Occasionally, subjects have reported an orange-brown color change 
to their urine. Rarely, subjects also report a new odor to their urine. All subjects should be made aware 
of the possibility of these effects. Dosing can be continued in the presence of these events. 
7.5
NAB-PACLITAXEL AND GEMCITABINE DOSE MODIFICATION
Dose modifications for hematologic and non-hematologic toxicities (using NCI CTCAE Version 4.0) 
expected from nab-paclitaxel with gemcitabine
should be performed according to the 
recommendations outlined below. Dose modifications for non-gastrointestinal toxicities expected 
from nab-paclitaxel with gemcitabine may also follow institutional guidelines. There will no dose 
reductions or adjustments for lymphopenia or alopecia. Dose level modifications of nab-paclitaxel and 
gemcitabine will occur at two dose levels. Any toxicity requiring dose level modification beyond the 
second dose modification warrants treatment discontinuation. Any further dose modification may be 
allowed in line with clinical practice per Sponsor and Investigator agreement..  
When a dose reduction is required, no dose reescalation will be permitted for the duration of study 
treatment (with exception for hematologic toxicity on Day 15 when re-escalation with G-CSF support 
is permitted following a dose reduction on Day 8 of the same cycle). 
Nab-Paclitaxel and Gemcitabine Dose Modification Table: 
Dose Level
Nab-Paclitaxel (mg/m2)1
Gemcitabine (mg/m2)1
Starting Dose
125
1000


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Modification Dose Level 1
100
800
Modification Dose Level 22
75
600
1
Dose reductions may or may not be concomitant. Please refer to specific hematologic and other toxicity 
modification recommendations outlined below.
2
A maximum of 2 dose level reductions is allowed. 
7.5.1
Hematologic Toxicity
Prior to each dose of nab-paclitaxel with gemcitabine, the ANC and platelet count should be evaluated. 
Dose modifications for hematologic toxicities expected from nab-paclitaxel with gemcitabine should 
be performed depending to their occurrence within a given cycle and according to the following 
Product label recommendations:  
Cycle 
Day
ANC
(cells/mm3)
Platelet 
Count 
(cells/mm3)
Gemcitabine Dosing1,2
nab-Paclitaxel Dosing1,2
1
< 1500
Or 
< 100,000
Delay dosing by 1 week intervals 
until recovery
Delay dosing by 1 week 
intervals until recovery
8
500 to 1000
Or
50,000 to < 75,000
Reduce dosing by 1 Dose Level 
and treat on time
Reduce dosing by 1 Dose 
Level and treat on time
< 500
Or
< 50,000
Hold dosing 
Hold dosing
Day 15: IF Day 8 doses were unmodified:
500 to 1000
Or
50,000 to < 75,000
Treat on time with Full Dose 
Level and give G-CSF3
Treat on time with Full Dose 
Level and give G-CSF3
< 500
Or
< 50,000
Hold dosing and give G-CSF3
Hold dosing and give G-
CSF3
Day 15: IF Day 8 doses were reduced:
> 1000
Or
> 75,000
Return to Previous Dose Level, 
treat on time and give G-CSF3
Return to Previous Dose 
Level, treat on time and give 
G-CSF3
500 to 1000
Or
50,000 to < 75,000
Treat on time with same Dose 
Level as Day 8 and give G-CSF3
Treat on time with same 
Dose Level as Day 8 and give 
G-CSF3
< 500
Or
< 50,000
Hold dosing and give G-CSF3
Hold dosing and give G-
CSF3
Day 15: IF Day 8 doses were held:
> 1000
Or
> 75,000
Decrease Day 1 Dose by 1 Level, 
treat on time and give G-CSF3
Decrease Day 1 Dose by 1 
Level, treat on time and give 
G-CSF3
500 to 1000
Or
50,000 to < 75,000
Decrease Day 1 Dose by 2
Levels, treat on time and give G-
CSF3
Decrease Day 1 Dose by 2
Levels, treat on time and give 
G-CSF3
< 500
Or
< 50,000
Hold dosing and give G-CSF3
Hold dosing and give G-
CSF3
Grade 3-4 Febrile Neutropenia at any point in the cycle
(defined as temperature > 101 oF with a neutrophil count of
< 1000 cells/ml)4
Hold 
dosing 
until 
fever 
resolution and ANC > 1500 and 
resume at next lower dose level 
and do not re-escalate throughout 
the rest of treatment.
Hold dosing 
until 
fever 
resolution and ANC > 1500 
and resume at next lower 
dose level and do not re-
escalate throughout the rest 
of treatment.
Recurrent Grade 3-4 Febrile Neutropenia at any point in 
the cycle5
Decrease dosing 2 Dose Levels 
(to 600 mg/m2) and do not re-
escalate throughout the rest of 
treatment.
Decrease dosing to next 
lower Dose Level and do not 
re-escalate throughout the 
rest of treatment.
1
Once a dose of any drug is decreased for toxicity, re-escalation is not permitted (with exception of hematologic toxicity 
on Day 15 when re-escalation with G-CSF support is permitted following a dose reduction on Day 8 of the same cycle).
2
Dose level reductions should be performed as shown in the dose modification table above. 
3
G-CSF administration is optional if only platelet count meets G-CSF administration criterion and ANC count is above 
threshold. 


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4
Febrile patients (regardless of neutrophil count) should have a full sepsis diagnostic work-up while continuing broad 
spectrum antibiotics. Patients with persisting fever after 3 weeks, despite uninterrupted antibiotic treatment, will 
discontinue study treatment. Febrile neutropenic patients may also receive G-CSF to hasten the resolution of their febrile 
neutropenia (following Institutional guidelines and Investigator judgment). In all cases blood counts must return to 
baseline before resuming chemotherapy treatment. 
5
If patients do not experience resolution of neutropenia within 21 days, despite uninterrupted G-CSF treatment, study 
treatment will be discontinued.
7.5.2
Other Non-Hematologic Toxicities
Dose modification for other toxicities specified below expected from nab-paclitaxel with gemcitabine
regimen occurring ON DAY 1 of any cycle or WITHIN a cycle should be performed according to the 
following recommendations: 
Other Adverse Event
Occurrence ON DAY 1 of Each 
Cycle
Occurrence WITHIN a Cycle
Grade 0, 1 or 2 toxicity including Grade 3 
alopecia and Grade 3 nausea/vomiting1
Same as Day 1 of previous cycle 
except for Grade 2 cutaneous 
toxicity.2
Same as Day 1 of the ongoing cycle 
except 
for 
Grade 
2 
cutaneous 
toxicity.2
Grade 3 Toxicity (except for Grade 3 
nausea/vomiting/diarrhea/mucositis, alopecia, 
cutaneous toxicity and neuropathy)1,2,3,5
Decrease dose of both nab-
paclitaxel and gemcitabine to the 
next lower Dose Level. 
Hold either nab-paclitaxel
and/or 
gemcitabine 
until 
resolution 
of 
toxicity to < Grade 1. Then resume 
treatment with both drugs at the next 
lower Dose Level. 
Grade 4 Toxicity1,2,3,4,5 (except for Grade 4 
diarrhea/mucositis, 
pulmonary 
embolism, 
cutaneous toxicity and neuropathy)
Hold either nab-paclitaxel and/or gemcitabine depending on the type of non-
hematologic toxicity and the judgment of the Physician/Investigator.
Treatment discontinuation depending on the judgment of the Investigator.
Dose Held in 2 Previous Consecutive Cycles
Decrease gemcitabine dose to next lower Dose Level and continue 
throughout the rest of treatment
Grade 3-4 Diarrhea/Mucositis5
Hold dosing with both nab-paclitaxel and gemcitabine until improvement to 
< Grade 1 and resume both nab-paclitaxel and gemcitabine at next lower 
Dose Level.
Interstitial Pneumonitis (any Grade)
Discontinue study treatment.
1
For treatment of Grade 3-4 nausea/vomiting, Initial antiemetic prophylaxis is recommended with a 5HT3 agent (PO or 
IV) in combination with dexamethasone 8 or 10 mg (PO or IV) prior to administration of gemcitabine to be continued 
at 4 mg BID or TID for 3-4 days at the Investigator’s discretion. Institutional guidelines and Investigator’s 
recommendations should be followed for breakthrough antiemetic management. BBI-608 dosing modification as 
outlined in Section 7.4 may be appropriate depending on the judgment of the Investigator.
2
Grade 2 or 3 cutaneous toxicity on Day 1 of any cycle requires reduction of both nab-paclitaxel and gemcitabine to the 
next lower Dose Level. If Grade 2-3 cutaneous toxicity recurs despite dose reduction, treatment should be discontinued. 
3
For Grade > 3 neuropathy, nab-paclitaxel treatment should be held and gemcitabine may be continued. Nab-paclitaxel 
treatment may be resumed at next lower level if neuropathy improves to < Grade 1. Discontinuation of treatment with 
nab-paclitaxel is recommended in cases of peripheral neuropathy resulting in > 21 day delay in nab-paclitaxel 
administration unless not deemed appropriate in the judgment of the Investigator.
4
Except for mild or asymptomatic pulmonary embolism treated with low-molecular-weight heparin without interruption 
of therapy. Moderate to severe pulmonary embolism will require permanent discontinuation of treatment.
5
For initial treatment of Grade 3-4 diarrhea/mucositis BBI-608 dosing modification may be initiated as per Section 7.4 
prior to modification of backbone chemotherapy dosing.
When laboratory parameters or adverse events indicate that either or both nab-paclitaxel and/or 
gemcitabine infusions should be delayed, the infusions scheduled for that day are not given. The 
infusions will be considered skipped and not made up. The next infusion will be administered on the 
following scheduled infusion day if the toxicity is resolved to an acceptable level. Laboratory 
parameters should be evaluated prior to the next scheduled infusion and actions taken according to the 
protocol parameters.
If toxicity is thought by the Investigator to be related to both BBI-608 and nab-paclitaxel and 


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gemcitabine, then the dose modification rules for both treatment regimens should be followed.
If either gemcitabine and/or nab-paclitaxel is/are held or discontinued for toxicities solely related to 
gemcitabine and/or nab-paclitaxel, BBI-608 therapy may be continued until another discontinuation 
criterion for stopping therapy is met with the Sponsor’s approval, if it is believed to be in the patient’s 
best interest by the investigator and patient, and with the patient’s informed consent. 
If BBI-608 is permanently discontinued due to toxicity, nab-paclitaxel and gemcitabine therapy may
be continued until another discontinuation criterion for stopping therapy is met. 
7.6
BLINDING/UNBLINDING
This is an open label study. The primary endpoint of this study is overall survival, the assessment of 
which is unlikely to be impacted by the open-label nature of the study. 
However, to comply with ICH E6 (R2) Guideline for Good Clinical Practice (2016) recommending 
the 
blinded 
review 
of 
planned 
analyses 
[http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Ste
p_4_2016_1109.pdf ], and to minimize the risk of any potential bias in the interim and final analyses, 
a blinding plan was implemented by the Sponsor and by the CRO to maximize the integrity of the 
study. The Sponsor  blinding plan outlines the internal communication processes, data access levels, 
and firewalls that will be utilized to achieve study blinding internally. 
7.7
PATIENT MONITORING
For the duration that patients are on study therapy, adverse event monitoring will be done continuously. 
Patients will be evaluated for adverse events at each visit, and are to be instructed to call their physician 
to report any adverse events between visits.
7.8
CONCOMITANT MEDICATIONS/PROCEDURES
7.8.1
Permitted Treatments
All information regarding concomitant treatments (medications or procedures) must be recorded on 
the patient’s CRF (including the name of the medication or procedure and duration of treatment).  
Palliative and supportive care is permitted for disease-related symptoms for all patients. 
All palliative and supportive care measures may be administered to patients in any study arm at the 
Investigator’s discretion. Incident palliative radiotherapy is permitted in any study arm while on study, 
but requirement of radiation to the target lesion(s) will qualify the patient as having disease 
progression. 
Overall, CYP isoenzymes have an insignificant role in the biotransformation of BBI-608. The CYP 
P450 isoform 1A2 is the predominant isoform involved in the drug’s metabolism. Although the 
following drugs are permitted while on study treatment, all reasonable measures should be done to 
avoid use of drugs that are strong inhibitors of CYP1A2 unless there is medical necessity for their use. 


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Strong CYP1A2 inhibitors include:  
o
Ciprofloxacin and other fluoroquinolones 
o
Fluvoxamine 
o
Enoxacin 
o
Zafirlukast
Investigators may refer to the Investigator Brochure for additional information. 
Patients who require use of concomitant medications metabolized by the CYP1A2, 2D6, 2C19, 3A4 
and 2C9 enzymes should be monitored, as per drug product label, as use of BBI-608 can inhibit the 
abovementioned CYP enzymes leading to increased drug concentrations of the enzyme metabolites.
In addition, nab-paclitaxel is metabolized by CYP2C8 and CYP3A4; caution should be exercised when 
administering with drugs which are CYP2C8 or CYP3A4 inducers or inhibitors, e.g. amiodarone, 
cyclosporine, grapefruit juice, simvastatin etc.
7.8.2
Non-Permitted Treatments
Concurrent chemotherapy, hormonal therapy (except corticosteroids), immunotherapy, biologic 
therapy OR other experimental agents should not be given to study patients while on protocol 
treatment.
7.9
DURATION OF THERAPY
Patients may continue to receive protocol therapy as long as they have not experienced any adverse 
events requiring permanent discontinuation of protocol treatment, have not demonstrated disease 
progression based on RECIST 1.1 criteria, it is believed to be in the patient’s best interest by the 
investigator and patient, or until February 28th, 2020, whichever occurs first. For details concerning 
toxicity, please consult sections 7.3, 7.4 and 7.5. For a complete list of general criteria for stopping 
study treatment, please see section 11.0.  
Following disease progression based on RECIST 1.1 criteria, patients will permanently discontinue 
treatment with nab-paclitaxel and gemcitabine, but may continue BBI-608 treatment with the 
Sponsor’s approval for as long as in the opinion of the investigator and patient that it is believed to be 
in the patient’s best interest and with the patient’s informed consent, until February 28th, 2020 or the 
following requirements are met: 
1.
Patient does not demonstrate a clinically apparent decline in performance status.
2.
Patient does not demonstrate clinically significant worsening of disease related symptoms.
3.
Patient does not have any new radiographic findings to warrant emergent intervention to
prevent morbidity (for example, impending cord compression). 
4.
Patient demonstrates a tolerable toxicity profile with BBI-608 administration. 
7.10
PATIENT COMPLIANCE
Treatment compliance for BBI-608 is defined as the ratio, expressed as a percentage, of the number of 
BBI-608 capsules taken by a patient over the course of a time interval to the number of capsules 


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intended to be taken over that same time interval. 
Treatment compliance for nab-paclitaxel with gemcitabine is defined as the ratio, expressed as a 
percentage, of the amount of each of the component drugs administered to a patient (milligrams/m2)
over the course of a time interval to amount of the component IV drug intended to be administered
over that same time interval. 
Treatment compliance in all study arms will be monitored by drug accountability, as well as the 
monitoring of patient-reported compliance. 


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8.0
EVALUATION DURING AND AFTER PROTOCOL TREATMENT
Evaluations will be performed at different intervals throughout the study. If dose delays occur for any 
reason on the study, other study assessments, including assessment by physician and QoL 
questionnaires, will not be delayed, but should continue at the time indicated from randomization.
8.1
EVALUATION DURING PROTOCOL TREATMENT
Investigations
Timing
Patient history and 
Evaluation
y Physical examination
y Vital signs (temperature, heart rate, 
respiratory rate, blood pressure, O2
saturation on room air)
y ECOG Performance status
y Concurrent medication list
y Weight
Day 1 of every 28 day study cycle, starting with Cycle 
2 (+/-3 days) or within 72 hours prior to each nab-
paclitaxel with gemcitabine infusion
Hematology
y CBC + differential, Platelet count
Days 1, 8 and 15 of every 28 day study cycle starting 
with Cycle 1 (+/-3 days)
(Hematology investigations should be performed 
within 72 hours prior to Day 1 of each study cycle, or 
within 72 hours prior to each nab-paclitaxel with 
gemcitabine infusion)
Biochemistry
y Creatinine, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, LDH, Albumin, 
Sodium, Potassium, Magnesium, Phosphate,
BUN (blood urea nitrogen)
Day 1 of every 28 day study cycle, starting with Cycle 
1 (+/-3 days)
(Biochemistry and Urinalysis investigations should be 
performed within 72 hours prior to Day 1 of each study 
cycle, or within 72 hours prior to first nab-paclitaxel 
with gemcitabine infusion of each cycle)
Urinalysis
y Dipstick (including protein, specific gravity, 
glucose and blood)
Other Investigations
y Serum or urine pregnancy test 1
Day 1 of every 28 day study cycle, starting with Cycle 
2 (+/-3 days)
Adverse Events 2
y Adverse Event evaluation must be done at 
each study visit
Days 1, 8 and 15 of every 28 day study cycle
y Adverse Event evaluation by phone
On Run-in Day 2 
Serious Adverse 
Events 3
Serious Adverse Event evaluation will be done from the time of informed consent signature and for 30 
days following the last dose of protocol therapy.


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Cardiology 
Assessment
y ECG 
Within 2 hours of completion of nab-paclitaxel with 
gemcitabine infusion on first day of nab-paclitaxel 
with gemcitabine treatment and as clinically indicated 
thereafter
Radiology & Imaging
y CT/MRI scan as per baseline assessment 
with tumor measurement and evaluation by 
RECIST 1.1 criteria 4, 5
Every 8 weeks (every 56 days) after randomization4, 5
(+/-5 days)
Correlative Studies
y Submission of blood samples 6
At 4 weeks after Cycle 1 Day 1 (+/-3 days)
Sparse PK Collection
y Submission of blood samples to central lab 6
At Days 8 and 15 of Cycle 1, and at Day 1 of Cycle 2 
(corresponding to the 2nd, 3rd and 4th nab-paclitaxel 
with gemcitabine infusion days)
Quality of Life
y EORTC QLQ-C307
At 4, 8, 12, 16 and 24 weeks after Cycle 1 Day 1 (+/- 3
days)
Nab-paclitaxel with 
gemcitabine 
Administration
y IV nab-paclitaxel with gemcitabine infusion 
Days 1, 8 and 15 of every 4 week (28 day) study cycle, 
starting with Cycle 1 (+/-3 days)
1
In women of childbearing potential only a negative pregnancy test must be demonstrated every 4 weeks until 4 weeks 
after the administration of the final dose of protocol therapy. The minimum sensitivity of the pregnancy test must be 
25 IU/L or equivalent units of HCG.
2
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (see Appendix IV). Adverse event assessment by phone on Run-in day 2 is only applicable to patients receiving 
BBI-608.
3
Serious adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (see Appendix IV).
4
The same method of assessment and the same technique should be used to identify and report each lesion at baseline and 
at reassessment during treatment. Tumor evaluations will continue until progressive disease is documented (as described 
in section 9.0). For patients who remain on protocol therapy after objective disease progression has been documented, no 
further imaging assessments are mandated, but where these occur as a component of care, tumor measurements and 
assessment must be reported. 
5
Copies of imaging assessments may be requested.
6
Details for collection, processing, storing and shipping these samples will be provided in a separate procedure manual. 
7
To be completed in clinic. Questionnaires should be completed prior to any interactions with clinical team to avoid any 
influence.


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8.2
EVALUATION AFTER PERMANENT PROTOCOL TREATMENT DISCONTINUATION  
Investigations
Timing
Patient History and 
Evaluation  
y Physical Examination
y Vital signs (temperature, heart rate, 
respiratory rate, blood pressure, O2
saturation on room air)
y Weight + ECOG Performance status
y Subsequent cancer therapy1
y Concurrent medication list
At the first regularly scheduled 4 week assessment at 
which the patient has been off study therapy for a 
minimum of 28 days. (+/- 3 days)
Adverse Events 2
y Adverse Event evaluation2
Serious Adverse 
Events 3
Serious Adverse Event evaluation will be done from the time of informed consent signature and for 30
days following the last dose of protocol therapy.
Overall Survival
y Assess for survival of patient 4
Starting at the first regularly scheduled 4 week 
assessment at which the patient has been off study 
therapy for a minimum of 28 days, every 4 weeks 
thereafter for 6 months, then every 3 months thereafter.
(+/- 7 days)
Other 
Investigations
y Serum or urine pregnancy test 5
At the first regularly scheduled 4 week assessment at 
which the patient has been off study therapy for a 
minimum of 28 days (+/- 3 days)
Hematology
y CBC + differential, Platelet count
Biochemistry
y Creatinine, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, LDH, Albumin, 
Sodium, Potassium, Magnesium, Phosphate,
BUN (blood urea nitrogen)
Urinalysis
y Dipstick (including protein, specific gravity, 
glucose and blood)
Cardiology 
Assessment
y ECG 
At the first regularly scheduled 4 week assessment at 
which the patient has been off study therapy for a 
minimum of 28 days (+/- 3 days)
Radiology & 
Imaging
y CT/MRI scan as per baseline assessment 
with tumor measurement and evaluation by 
RECIST 1.1 criteria 6
Every 8 weeks (56 days) after randomization until 
objective disease progression is documented.6  
(+/- 5 days)
Correlative studies
y Submission of blood samples7
At first regularly scheduled 4 week assessment at which 
the patient has been off study therapy for a minimum of 
28 days (+/- 3 days)
Quality of Life
y EORTC QLQ-C308
At first regularly scheduled 4 week assessment at which 
the patient has been off study therapy for a minimum of 
28 days (+/- 3 days) 


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1
After permanent protocol treatment discontinuation of nab-paclitaxel and gemcitabine and BBI-608, Physical 
examination, vital signs, ECOG status and subsequent cancer treatment will be recorded at the first regularly scheduled 4 
week assessment at which the patient has been off study therapy for a minimum of 28 days (+/- 3 days). Subsequent cancer 
treatment will be captured until end of study. 
2
Adverse events related to protocol treatment will be recorded and graded according to the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (see Appendix IV). Adverse events relevant to cancer or to subsequent cancer 
treatments will not be captured. Attribution of adverse events will continue to be recorded following treatment 
discontinuation.
3
Serious adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (see Appendix IV). 
4
Post permanent study treatment discontinuation, overall survival status will be monitored on a monthly basis for 6 months 
and then every 3 months thereafter until death, the study closes or 3 years have elapsed since subject discontinuation from 
treatment. In the event that patient is unable to attend clinic, post-progression follow-up may be by means of telephone 
contact.
5
In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of HCG.
6
The same method of assessment and the same technique should be used to identify and report each lesion at baseline and 
at reassessment during treatment. Tumor evaluations will continue until progressive disease is documented (as described 
in section 9.0). If a patient discontinues protocol treatment for a reason other than objective progression, every effort 
should be made to obtain this assessment on the same schedule until progression is observed. It is recommended that 
subsequent therapy not be instituted until disease progression is documented. If a patient starts a new anti-cancer therapy 
prior to disease progression, then repeat imaging and tumor response assessments should be discontinued.
7
Details for collection, processing, storing and shipping these samples will be provided in a separate procedure manual. 
The samples will be collected only if the patient discontinues protocol treatment prior to 4 weeks of therapy with nab-
paclitaxel with gemcitabine with or without BBI-608.  
8
To be completed in clinic. Questionnaires should be completed prior to any interactions with clinical team to avoid any 
influence. Questionnaire will be collected in the post-treatment discontinuation period only if the patient discontinues 
nab-paclitaxel and gemcitabine with or without BBI-608 protocol treatment prior to 24 weeks of therapy and has an ECOG 
PS of less than 4 and has not been hospitalized for end of life care.


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9.0
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS
9.1
DEFINITIONS
9.1.1
Evaluable for Adverse Events
All patients who have received at least one dose of study drug (BBI-608 or Nab-Paclitaxel or 
Gemcitabine) will be evaluable for adverse events from the time of their first dose.
9.1.2
Evaluable for OS
All randomized patients will be included in the analysis of OS, which is defined as the time interval 
between the date of randomization and the date of death from any cause. Patients who are still alive at 
the time of the final analysis, or who have become lost to follow-up will be censored at their last date 
known to be alive.  
9.1.3
Evaluable for PFS
All randomized patients will be included in the analysis of PFS, which is defined as the time interval 
between the date of randomization and the date of objective disease progression or death, whichever 
comes first. If neither event has been observed, then the patient will be censored at the date of the last 
tumor assessment.
Disease progression is defined as objective progression per RECIST 1.1 (Eisenhauer, 2009). It is 
required to perform, whenever possible, a radiological confirmation of the clinical suspicion of tumor 
progression. In the situation where there is clinical suspicion of progression but objective progression 
cannot be determined per RECIST 1.1, disease is defined as clinical deterioration without objective 
evidence of progression. 
The date of disease progression is defined as the date when the criteria for objective progression are 
first met. 
9.1.4
Evaluable for DCR
Patients who have measurable disease by RECIST 1.1 at randomization will be included in the analysis 
of DCR which is defined as a composite of Stable Disease, Partial Response and Complete Response 
as classified according to the definitions set out below (Eisenhauer, 2009). For patients who 
discontinue protocol therapy prior to their first objective assessment of response, it is imperative that 
an objective response assessment be undertaken as close to the protocol specified schedule as possible.
9.1.5
Evaluable for ORR
Patients with measurable disease by RECIST 1.1 at randomization will be included in the analysis of 
ORR which is defined as a composite of Partial Response and Complete Response as classified 
according to the definitions set out below (Eisenhauer, 2009). For patients who discontinue protocol 
therapy prior to their first objective assessment of response, it is imperative that an objective response 
assessment be undertaken as close to the protocol specified schedule as possible.
9.1.6
Evaluable for QoL Assessment


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All patients who have completed the baseline quality of life questionnaire and at least one other QoL 
questionnaire are evaluable.
9.2
RESPONSE AND EVALUATION ENDPOINTS
Response and progression will be evaluated in this study using the revised international criteria (1.1) 
proposed by the RECIST committee. 
9.2.1
Measurable Disease
Measurable tumor lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as > 20 mm with chest x-ray and as > 10 mm with CT 
scan, or clinical examination. Bone lesions are considered measurable only if assessed by CT scan and 
have an identifiable soft tissue component that meets these requirements (soft tissue component > 10 
mm by CT scan). Malignant lymph nodes must be > 15mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). Previously irradiated lesions are not 
considered measurable unless progression has been documented in the lesion. 
9.2.2
Non-Measurable Disease
All other lesions (or sites of disease), including small lesions are considered non-measurable disease. 
Bone lesions without a measurable soft tissue component, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, lymphangitic 
involvement of lung or skin and abdominal masses followed by clinical examination are all non-
measurable. Lesions in previously irradiated areas are non-measurable, unless progression has been 
demonstrated. 
9.2.3
Target Lesions
When more than one measurable tumor lesion is present at baseline all lesions up to a maximum of 5 
lesions total (and a maximum of 2 lesions per organ) representative of all involved organs should be 
identified as target lesions and will be recorded and measured at baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated measurements.
Note that pathological nodes must meet the criterion of a short axis of > 15 mm by CT scan and only 
the short axis of these nodes will contribute to the baseline sum. All other pathological nodes (those 
with short axis > 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a 
short axis < 10 mm are considered non-pathological and should not be recorded or followed (see 
10.2.4). At baseline, the sum of the target lesions (longest diameter of tumor lesions plus short axis of 
lymph nodes: overall maximum of 5) is to be recorded. 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately measured but 
are deemed to be present, a default value of 5 mm may be used. If lesions are too small to measure and 
indeed are believed to be absent, a default value of 0 mm may be used.
9.2.4
Non-Target Lesions


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All non-measurable lesions (or sites of disease) plus any measurable lesions over and above those 
listed as target lesions are considered non-target lesions. Measurements are not required but these 
lesions should be noted at baseline and should be followed as “present” or “absent”.
9.2.5
Response 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
Complete Response (CR): disappearance of target and non-target. Pathological lymph nodes must 
have short axis measures < 10 mm (Note: continue to record the measurement even if < 10 mm and 
considered CR). Residual lesions (other than nodes < 10 mm) thought to be non-malignant should be 
further investigated (by cytology specialized imaging or other techniques as appropriate for individual 
cases (Eisenhauer, 2009)) before CR can be accepted. 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for tumor 
lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of 
diameters. Non-target lesions must be non-PD. 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify 
for PD taking as reference the smallest sum of diameters on study.
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions taking 
as references the smallest sum of diameters recorded on study (including baseline) AND an absolute 
increase of > 5mm. Appearance of new lesions will also constitute progressive disease (including 
lesions in previously unassessed areas). For patients with on-study tumor assessments with 
questionable findings of new lesions, such as cases where it is possible that the lesions were present at 
baseline imaging albeit less visible, the patient may continue treatment (if patient is clinically doing 
well) for an additional 4-8 weeks, until the next scan which will either confirm presence of a new 
lesion finding or exclude it. In exceptional circumstances, unequivocal progression of non-target 
disease may be accepted as evidence of disease progression, where the overall tumor burden has 
increased sufficiently to merit discontinuation of treatment or where the tumor burden appears to have 
increased by at least 73% in volume. Modest increases in the size of one or more non-target lesions 
are NOT considered unequivocal progression. If the evidence of PD is equivocal (target or non-target), 
treatment may continue until the next assessment, but if confirmed, the earlier date must be used. 
Table 2: Integration of Target, non-Target and New Lesions into Response Assessment
Target Lesions
Non-Target Lesions
New 
Lesions
Overall Response
Best Response for this 
Category also Requires
Target Lesions ± Non Target Lesions
CR
CR
No
CR
Tumor nodes < 10mm
CR
Non-CR/Non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD/ not all 
evaluated
No
PR
SD
Non-PD/ not all 
evaluated
No
SD
Documentation at least once > 6
wks. from baseline
Not all evaluated
Non-PD
No
NE


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PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
Non-Target Lesions ONLY
N/A
CR
No
CR
Tumor nodes < 10mm
N/A
Non-CR/non-PD
No
Non-CR/non-PD
N/A
Not all evaluated
No
NE
N/A
Unequivocal PD
Any
PD
N/A
Any
Yes
PD
Note:
Patients with a global deterioration of health status requiring discontinuation of treatment without radiological 
progression having been observed at that time should be reported as “symptomatic deterioration”. This is NOT 
objective PD. Every effort should be made to document the objective progression even after discontinuation of 
treatment.
9.3
RESPONSE DURATION
Response duration will be measured from the time measurement criteria for CR/PR (whichever is first 
recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including baseline).
9.4
STABLE DISEASE DURATION
Stable disease duration will be measured from the time of randomization until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline).
9.5
METHODS OF MEASUREMENT
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Assessments should be identified on a calendar 
schedule and should not be affected by delays in therapy. While on study, all lesions recorded at 
baseline should have their actual measurements recorded at each subsequent evaluation, even when 
very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but 
too small to measure, a default value of 5 mm should be assigned. For lesions which fragment/split 
add together the longest diameters of the fragmented portions; for lesions which coalesce, measure the 
maximal longest diameter for the “merged lesion”.
Additionally, for optimal tumor assessment scanning options are listed below in the decreasing order 
of preference:
Order 
of 
Preference
Scanning Option
1
Chest-Abdomen-Pelvis CT with oral and I.V. contrast
2
Chest CT without I.V. contrast PLUS MRI Abdomen-Pelvis with oral and 
I.V. contrast1
3
Chest-Abdomen-Pelvis CT with oral contrast2
1
If Iodine contrast media is medically contraindicated.


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2
If Iodine contrast media is medically contraindicated and MRI cannot be performed. 
9.5.1
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and > 10 mm as assessed 
using callipers (e.g. skin nodules). For the case of skin lesions, documentation by colour photography 
including a ruler to estimate the size of the lesion is recommended. If feasible, imaging is preferred.
9.5.2
Chest X-ray
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since 
CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions > 20 mm 
on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated 
lung.  
9.5.3
CT/MRI
CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the assumption
that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in 
certain situations (e.g. for body scans). Other specialized imaging or other techniques may also be 
appropriate for individual case (Eisenhauer, 2009). For example, while PET scans are not considered 
adequate to measure lesions, PET-CT scans may be used providing that the measures are obtained 
from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic CT (with IV and 
oral contrast). 
9.5.4
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT is advised.
9.5.5
Endoscopy/Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. However, they can 
be useful to confirm complete pathological response when biopsies are obtained or to determine 
relapse in trials where recurrence following complete response or surgical resection is an endpoint. 
9.5.6
Histology
These techniques can be used to differentiate between PR and CR in rare cases (for example, residual 
lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment when the measurable tumor has met criteria for response or stable disease is mandatory to 
differentiate between response or stable disease (an effusion may be a side effect of the treatment) and 
progressive disease.


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10.0
SERIOUS ADVERSE EVENT REPORTING
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) and Serious Adverse Event (SAE) reporting 
(version can be found in Appendix IV).  
All appropriate treatment areas should have access to a copy of the CTCAE. A copy of the CTCAE 
can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse events 
must be recorded on case report forms. All SAEs must be reported to the Sponsor within 24 hours 
(Section 10.2).    
10.1
DEFINITION OF A PROTOCOL REPORTABLE SERIOUS ADVERSE EVENT
All serious adverse events must be reported in an expedited manner (see Section 10.2 for reporting 
instructions). These include events occurring from the time the patient signs informed consent until 30 
days after last protocol treatment administration. Determination of relationship between the event and 
study drug should be made by a qualified physician Investigator.  
A serious adverse event (SAE) is any adverse event that at any dose:

results in death;

is life-threatening;

requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration); 

results in persistent or significant disability or incapacity;

is a congenital anomaly/birth defect.

is an important medical event. 
 
 
Note: clinically significant test results should be recorded on the AE CRF using the appropriate 
CTCAE description and grading scale. 
10.2
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS
SAE reporting will commence following the signature of the informed consent and continue for 30
days following the last dose of BBI-608 and/or Nab-Paclitaxel and/or Gemcitabine. Any SAE 
occurring following patient signature of informed consent and prior to patient randomization must be 
submitted to the Sponsor/Sponsor Designee for review and confirmation of randomization eligibility
prior to patient randomization and/or study drug administration, even if the patient completely 
recovered from the SAE. Additionally, any SAE occurring at any time following administration of the 
final dose of protocol treatment that is suspected to be related to study treatment must be reported.
All SAEs must be reported using the SAE Report Form for this trial. 
Within 24 hours: 
Submit Initial Serious Adverse Event Report 


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Within 7 days:
Submit Follow-up Serious Adverse Event Report updated with as much 
detail as possible. 
 
 
 
Detailed instructions for the submission of SAE Reports will be provided separately.  
10.3
PROCEDURES IN CASE OF AN OVERDOSE
Use of BBI-608 in doses in excess of that specified in the protocol should be reported in the following 
manner: 
If an adverse event(s) is associated with (“results from”) the overdose of BBI-608, the overdose and 
adverse event are reported on the SAE Report Form, even if no other criteria for serious are met. The 
SAE Report Form should be submitted within 24 hours. The overdose should also be recorded on the 
relevant AE form in the eCRF using the term “accidental or intentional overdose with adverse effect.”
If the overdose of BBI-608 is not associated with an adverse event, the overdose is reported as a non-
serious AE, on the relevant AE form in the eCRF within 24 hours, using the event term “accidental or 
intentional overdose without adverse effect.” The Clinical Research Associate responsible for the 
investigational center should also be notified of the event within 24 hours. 
Investigators/site personnel are to consult the local, approved product labels for nab-paclitaxel with 
gemcitabine treatment regimen for guidance on the definition of an overdose of these agents as well 
as for guidance on reporting of any AE or SAE associated with overdose of either nab-paclitaxel or 
gemcitabine. Overdose of either nab-paclitaxel or gemcitabine should also be reported to the Sponsor 
in accordance with overdose reporting guidelines above. 
10.4
OTHER PROTOCOL REPORTABLE EVENTS – PREGNANCY/EXPOSURE REPORTING
WOCBP may be enrolled in this clinical trial. WOCBP are defined as women who have had a 
menstrual period during the last year and have not had a hysterectomy. Precautions are required to be 
taken to prevent pregnancy during the clinical trial when the research population includes WOCBP. 
This includes pregnancy testing, use of effective methods of birth control, and pregnancy as an 
exclusion factor. The trial sample informed consent form includes the potential for unidentified risks 
to the embryo/fetus. It also includes general information on pregnancy prevention and the required 
minimum period during which birth control must be utilized.  
10.4.1 Pregnancy Prevention
WOCBP and males who are enrolled in the trial must be informed of the requirement to use 
contraception as outlined in the eligibility criteria (Sections 4.1 and 4.2). Investigators are advised to 
inform the female partners of male participants when appropriate and compliant with local policy.  
A highly effective method of birth control is defined as those which result in a failure rate of <1% per 
year when used consistently and correctly. 
10.4.2 Pregnancy Occurring in WOCBP Exposed to Study Agent 
Any female participant who becomes pregnant during the course of the trial should be instructed to 


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stop taking study medication immediately.
The Investigator should provide counselling and discuss the risks and possible side effects to the 
embryo/fetus from BBI-608 and nab-paclitaxel with gemcitabine. Monitoring should continue until 
conclusion of the pregnancy. The same should occur for female partners of a male participant, or any 
female exposed to BBI-608 when appropriate and compliant with local policy. 
10.4.3 Pregnancy/Exposure Reporting 
The Investigator is required to report to the sponsor any pregnancy where the embryo/fetus could have 
been exposed to BBI-608. This means pregnancies occurring in female participants, female partners 
of male participants, or females exposed through direct contact with the agent during their pregnancy 
(for example, environmental exposure involving direct contact with the agent). Pregnancies occurring 
until 30 days in female patients and until 90 days in partners of male patients, after the completion of 
BBI-608 must also be reported. Pregnancies occurring until 180 days in female patients and until 180 
days in partners of male patients, after the completion of nab-paclitaxel and/or gemcitabine must also 
be reported. 
The Investigator is required to inform the Sponsor within 24 hours of learning of the pregnancy using 
the SAE reporting form appropriate for the trial as indicated above. In the Adverse Event column 
please enter the following: “pregnancy, puerperium and perinatal conditions – other, specify” (fetal 
exposure). Please note that the patient identification number must correspond to the participant in the 
main trial. Specifically, in the case of pregnancy in the female partner of a male participant, the male 
participant’s patient identification number should be used for reporting purposes.  
The SAE form must be updated to reflect the outcome of the pregnancy. For example: 
y
“pregnancy, puerperium and perinatal conditions – other, specify” (normal live birth),
y
“pregnancy, puerperium and perinatal conditions – other, specify” (therapeutic abortion), or 
y
another term under "pregnancy, puerperium and perinatal conditions" as applicable. 
Information on the medical history of the parents that may relate to assessing any potential fetal 
outcomes is requested, as is information on the health of the newborn. The narrative section of the 
SAE form should be used to communicate all relevant information pertaining to the pregnancy. 
10.5
RESPONSIBILITY FOR REPORTING SERIOUS ADVERSE EVENTS TO REGULATORY 
AGENCIES
Boston Biomedical, or the delegated CRO, will provide expedited reports of SAEs to FDA and other 
applicable regulatory authorities, for those events which meet regulatory requirements for expedited 
reporting, i.e. events which are BOTH serious AND unexpected, AND which are related to treatment
BBI-608 (suspected unexpected serious adverse reaction [SUSAR]):
y
Unexpected adverse events are those which are not consistent in either nature or severity with the 
reference safety information contained in the Investigator’s Brochure  
y
Adverse events considered related to protocol treatment are those events which have a 
reasonable possibility of being related to BBI-608. 
Boston Biomedical will determine which SAEs meet the criteria for regulatory reporting.  


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10.6
REPORTING SAFETY REPORTS TO INVESTIGATORS 
Boston Biomedical, or the delegated CRO, will notify Investigators of all Safety Reports (Serious 
Adverse Events (SAEs) from this trial and Safety Updates (SUs) from other clinical trials) that are 
reportable to regulatory authorities. This includes all serious events that are unexpected and related 
(i.e. possibly, probably, or definitely) to protocol treatment.  


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11.0
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
ALL STUDY TREATMENT
11.1
CRITERIA FOR DISCONTINUING PROTOCOL TREATMENT
Patients should stop protocol treatment in the following instances:
y
Progressive Disease (see section 9.2.5) 
y
Pregnancy
y
Intercurrent illness which would, in the judgement of the Investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy 
y
Unacceptable toxicity
y
Request by the patient
If a patient discontinues protocol treatment for objective progression on nab-paclitaxel and 
gemcitabine with BBI-608 (Arm 1), the patient together with their investigator, may elect to continue 
treatment with BBI-608 in monotherapy with the Sponsor’s approval, provided no discontinuation 
criterion involving BBI-608-related adverse events is met, it is believed to be in the patient’s best 
interest by the investigator and patient, and with the patient’s informed consent.
If a patient permanently discontinues protocol treatment for a reason other than objective progression, 
every effort should be made to obtain tumor evaluations on the same schedule until progression is 
observed. 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if patients 
discontinue protocol treatment prematurely and/or no longer attend the participating institution.  
11.2
DURATION OF PROTOCOL TREATMENT 
Patients may continue to receive protocol treatment as long as they have not experienced any adverse 
events requiring permanent discontinuation of study medication and have not demonstrated disease 
progression based on RECIST criteria, if it is believed to be in the patient’s best interest or until 
February 28th, 2020, when the study is planned for completion, whichever occurs first.  
There will be no cross-over to BBI-608-containing study arm in combination with nab-paclitaxel and 
gemcitabine (Arm 1) from the nab-paclitaxel and gemcitabine only study arm (Arm 2) and vice versa. 
11.3
THERAPY AFTER PROTOCOL TREATMENT IS PERMANENTLY DISCONTINUED
Treatment after all protocol therapy has been permanently discontinued is at the discretion of the 
Investigator. Information on post-study anti-cancer treatment will be collected in this study.
11.4
FOLLOW-UP OFF PROTOCOL TREATMENT


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Follow-up will continue after treatment completion according to the plan described in the protocol (see 
Section 8.2). Efforts should be made to maintain the investigations schedule and continue follow-up, 
even if patients permanently discontinue protocol treatment prematurely and/or no longer attend the 
participating institution. 


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12.0
CENTRAL REVIEW PROCEDURES, TISSUE COLLECTION, AND CORRELATIVE 
STUDIES 
12.1
CENTRAL RADIOLOGY REVIEW
There will be no central radiology review for this study. 
12.2
CENTRAL PATHOLOGY REVIEW
There will be no central pathology review for this study. 
12.3
TISSUE COLLECTION
Protocol-Mandated Correlative Studies: 
The submission of a representative diagnostic tumor tissue and of a blood sample for correlative studies 
defined in Section 13.6 (Correlative Studies) is mandatory for participation in this trial (although 
submission of the tissue does not have to occur prior to randomization). Where local center regulations 
prohibit submission of blocks of tumor tissue, two 2 mm cores of tumor from the block and 5-20
unstained slides of representative tumor tissue are requested. Where 2 mm cores of tumor from the 
block are unavailable, 5-20 unstained slides of representative tumor tissue are requested. Where no 
previously resected or biopsied tumor tissue exists, on the approval of the Sponsor/designated CRO, 
the patient may still be considered eligible for the study.
After patient consent, blood sample and paraffin tumor blocks will be the preferred tissue material to 
collect. If tumor blocks are unavailable, then two 2 mm cores of tumor from the block and 5-20 
specimen slides are preferred. If two 2 mm cores of tumor from the block are unavailable, 5-20 
specimen slides will be acceptable. If, at any time, the submitting hospital requires the block to be 
returned for medical or legal concerns, it will be returned by courier on request. 
Samples will be used for research purposes only and will not be sold. Patients will not be identified by 
name. The only identification of tissue will be by a patient study number assigned at the time of 
randomization to the trial. Material issued to researchers will be anonymous and only identified by a 
coded number. 
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out without 
the expressed consent of the patient.  
All patients on whom a blood sample and/or diagnostic tumor block is collected will be aware of this 
retrieval and will have given their consent.
12.4
SPARSE PHARMACOKINETIC PLASMA SAMPLE COLLECTION – NAB-PACLITAXEL 
WITH GEMCITABINE AND BBI-608 (ARM 1 ONLY)  
Plasma samples for sparse pharmacokinetics (PK) analysis will be obtained from all patients 
randomized to nab-paclitaxel with gemcitabine and BBI-608 study arm (Arm 1) at the study visits 
occurring on Days 8 and 15 of Cycle 1, and Day 1 of Cycle 2 (corresponding to nab-paclitaxel with 


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gemcitabine infusion days). Patients randomized to nab-paclitaxel and gemcitabine arm alone (Arm 2) 
will not undergo collection of blood for sparse PK analysis.  
Day 8 (Cycle 1) Study Visit: 
The Day 8 (Cycle 1) visit should be scheduled prior to 10 AM. On the day of this visit, patients should 
be instructed to wait to take their first daily dose of BBI-608 until they arrive in clinic. After arrival in 
the clinic, but approximately 5 minutes prior to administration of the first daily dose of BBI-608, a 
plasma sample will be obtained. Nab-paclitaxel infusion will be started approximately 2 hours after 
BBI-608 administration. A second plasma sample will be obtained within 60-180 minutes after the 
start of nab-paclitaxel infusion. A third plasma sample will be obtained within 240-480 minutes after 
the start of nab-paclitaxel infusion.  
Day 15 (Cycle 1) Study Visit: 
The Day 15 (Cycle 1) visit should be scheduled prior to 10 AM. On the day of this visit, patients should 
be instructed to take their first daily dose of BBI-608 until they arrive in clinic. After arrival in the 
clinic, but approximately 5 minutes prior to administration of the first daily dose of BBI-608, a plasma 
sample will be obtained. Nab-paclitaxel infusion will be started approximately 2 hours after BBI-608 
administration. A second plasma sample will be obtained within 60-180 minutes after the start of nab-
paclitaxel infusion. A third plasma sample will be obtained within 240-480 minutes after the start of 
nab-paclitaxel infusion.  
Day 1 (Cycle 2) Study Visit: 
The Day 1 (Cycle 2) visit should be scheduled prior to 10 AM. On the day of this visit, patients should 
be instructed to wait to take their first daily dose of BBI-608 until they arrive in clinic. After arrival in 
the clinic, but approximately 5 minutes prior to administration of the first daily dose of BBI-608, a 
plasma sample will be obtained. Nab-paclitaxel infusion will be started approximately 2 hours after 
BBI-608 administration. A second plasma sample will be obtained within 60-180 minutes after the 
start of nab-paclitaxel infusion. A third plasma sample will be obtained within 240-480 minutes after 
the start of nab-paclitaxel infusion.  
For all days during which a plasma sample is obtained for PK analysis, the precise time of all doses of 
BBI-608 (on the day of sampling and the day prior), the precise time of the initiation of nab-paclitaxel 
and gemcitabine administration, and the precise time of all PK sampling must be captured. 
Samples will be processed, stored and shipped according to the instructions provided in the separate
Sparse PK sampling laboratory manual for this study.


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13.0
STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study will be 
documented in a statistical analysis plan (SAP), which will be maintained by the sponsor.  The SAP 
may modify the plans outlined in the protocol; however, any major modifications of the primary 
endpoint definition and/or its analysis will also be reflected in a protocol amendment. 
13.1
OBJECTIVES AND DESIGN 
The primary objective of this study is to assess the effect of orally administered BBI-608 plus weekly 
nab-paclitaxel with gemcitabine (Arm 1), in comparison to weekly nab-paclitaxel with gemcitabine
(Arm 2) on the Overall Survival (OS) in patients with metastatic PDAC. 
Key secondary objectives for this study include comparisons of PFS in the general population, DCR
in the general population and ORR in the general population. Other secondary objectives include
Adverse Events and Quality of Life Assessment in the general population between the two treatment 
arms.
This is a multi-center, prospective, open-label, randomized Phase III trial. Patients will be randomized 
to receive either BBI-608 plus weekly nab-paclitaxel with gemcitabine, or weekly nab-paclitaxel with 
gemcitabine in a 1:1 ratio and will be stratified by geographical region (North America/Western 
Europe/Australia vs. Japan/Korea vs. Rest of the World), ECOG performance status (ECOG 0 versus 
ECOG 1), and presence of liver metastases (yes versus no).
13.2
STUDY ENDPOINTS AND ANALYSIS
13.2.1 Primary Endpoint 
OS in the General Study Population 
Unless otherwise specified, all efficacy analyses will be based on the Primary Analysis Set, which 
includes all randomized patients. Patients will be analyzed as randomized. As a sensitivity analysis, 
the Per Protocol population will also be analyzed for key efficacy endpoints. 
Overall Survival in the general study population, the primary endpoint of this study, is defined as the 
time from randomization to death from any cause. Patients who are alive at the time of the final analysis 
or who have become lost to follow-up will be censored at their last date known to be alive. Patients 
will be analyzed in the arm to which they are randomized regardless of the treatment they received 
(intent-to-treat analysis). The survival experience of patients in both treatment groups will be 
summarized by the Kaplan-Meier method and compared primarily by a stratified log-rank test 
adjusting for stratification variables at randomization.  
Sensitivity analyses based on stratified Cox proportional hazards model will also be performed. These 
sensitivity analyses are not included in the multiplicity adjustment for secondary outcomes detailed 
below and, as such, do not control for type I error. Geographical region (North America/Western 
Europe/Australia vs. Japan/Korea vs. Rest of the World), ECOG performance status (ECOG 0 versus
ECOG 1), and presence of liver metastases (yes versus no) will be the stratification factors to define 


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the stratified Cox proportional hazards model.  
Subgroup analysis and the corresponding forest plot analysis may be performed using the stratification 
factors mentioned above as well as the following factors: 
x
Primary tumor location (head versus other)
x
Level of CA19-9 (normal versus <59 x ULN versus >59 x ULN)
x
Age (< 65 versus > 65)
x
Sex (male versus female)
x
Number of metastatic sites at baseline (1 versus > 2) 
x
Race (white, black, Asian, other)
x
Country (Canada, USA, Europe, others) 
13.2.2 Key Secondary Endpoints 
The following secondary outcomes will be assessed. 
PFS in the General Study Population 
PFS in the general study population is defined as the time from randomization to the first objective 
documentation of disease progression or death due to any cause. If a patient has not progressed or died 
at the time of final analysis, PFS will be censored on the date of the last tumor assessment. This 
includes patients who are lost to follow-up or have withdrawn consent.  
DCR in the General Study Population
DCR is defined as the proportion of patients with a documented complete response, partial response, 
and stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate of DCR will be based 
on patients with measurable disease by RECIST 1.1 at randomization.  
ORR in the General Study Population
ORR is defined as the proportion of patients with a documented complete response and partial response 
(CR + PR) based on RECIST 1.1. The primary estimate for ORR will be based on patients with 
measurable disease by RECIST 1.1 at randomization. 
13.2.3 Other Secondary Endpoints 
Safety Analysis
All patients who have received at least one dose of study drug will be included in the safety analysis. 
The incidence of adverse events will be summarized by type of adverse event and severity using the 
NCI Common Terminology Criteria for Adverse Events Version 4.0. A Fisher’s exact test may be used 
to compare adverse events between the two arms.
QoL Analysis 
The QoL of patients will be assessed using EORTC QLQ-30 while the patient remains on BBI-608 as 
per Section 8.1. The EORTC QLQ-30 is a self-administered cancer specific questionnaire with multi-
dimensional scales. It consists of both multi-item scales and single item measures, including five 
functional domains, a global quality of life domain, three symptom domains, and six single items. 
Scoring of the EORTC QLQ-30 data will be completed following the procedures recommended by the 


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EORTC Study Group on Quality of Life. For each domain or single item measure a linear 
transformation will be applied to standardize the raw score to range between 0 and 100. The quality of 
life data will be analyzed to look for statistically and clinically significant differences between the 
BBI-608 plus nab-paclitaxel with gemcitabine versus nab-paclitaxel with gemcitabine groups. 
Questionnaire compliance rates will be ascertained for each group at each measurement time point. 
Mean baseline scores for each subscale and summary scores will be calculated.
The endpoints in QoL analysis are the mean EORTC QLQ-C30 QoL change scores from baseline at 
time 2 (~8 weeks from Cycle 1 Day 1) and time 4 (~16 weeks from Cycle 1 Day 1) for the physical 
function and global health status/quality of life subscale scores. Wilcoxon tests will be used to compare 
the difference at each of these two time points between two treatment arms for each of these two 
subscales. The proportion of patients in either arm with at least a minimum of 10 unit(s) deterioration 
in change scores at both 8 and 16 weeks from Cycle 1 Day 1 will be compared by means of Fisher’s 
exact test.
13.2.4 Exploratory Endpoints 
OS in the Predefined Biomarker-positive Population
OS in the general predefined biomarker-positive population is defined as the time from randomization 
to death due to any cause. If a patient has not died at the time of final analysis, OS will be censored on 
the date of the last follow up assessment. This includes patients who are lost to follow-up or have 
withdrawn consent.  
PFS in the Predefined Biomarker-positive Population
PFS in the predefined biomarker-positive population is defined as the time from randomization to the 
first objective documentation of disease progression or death due to any cause. If a patient has not 
progressed or died at the time of final analysis, PFS will be censored on the date of the last tumor 
assessment. This includes patients who are lost to follow-up or have withdrawn consent.  
ORR and DCR in the Predefined Biomarker-positive Population
ORR in the predefined biomarker-positive population is defined as the proportion of patients with a 
documented complete response and partial response (CR + PR) based on RECIST 1.1. The primary 
estimate for ORR will be based on patients with measurable disease by RECIST 1.1 at randomization. 
DCR in the predefined biomarker-positive population is defined as the proportion of patients with a 
documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 
1.1. The primary estimate of DCR will be based on patients with measurable disease by RECIST 1.1 
at randomization.  
13.3
SAMPLE SIZE AND DURATION OF STUDY
The primary study endpoint for all patients on the study is OS.  
The study is designed to have a power of 90% and a one-sided alpha of 2.5% to detect a 20% reduction 
in the continuous risk of death (HR 0.80, which corresponds to an increase of median survival from 
8.5 to 10.63 months) in the Intention to Treat (ITT) general study population. The 864th event will 
trigger the final analysis. It is estimated that 864 events will be required to detect a 20% reduction in 
the risk of death which would be observed by randomizing 1132 patients over 24 months with patient 
follow up for an additional 12 months, for total study duration of 36 months. It is anticipated that up 
to 5% dropout rate will occur for the entire study.


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The overall power of the study will be approximately 90% after the multiplicity control procedure is 
considered.
When the required number of events for the primary endpoint has been reached, all randomized 
patients still alive will continue study follow up through to their deaths.  
13.4
SAFETY MONITORING
Adverse events will be monitored on an on-going basis by central review. 
13.5
INTERIM ANALYSIS
Prior to this amendment, there was one interim analysis presented to the independent DSMB. 
Additionally, DSMB reviewed safety data during conduct of the study. The role and responsibility of 
the DSMB are defined in a separate Charter.
The interim analysis involved a stratified log-rank test. Nominal p-values were based on the Lan-
DeMets error spending function using an O’Brien-Fleming stopping boundary in order to preserve the 
overall one-sided alpha level of 0.025. 
The interim analysis was performed when approximately 432 deaths (50% of the required events) were
observed.  The interim analysis was for futility only, with the futility boundary set at HR > 1. Safety 
data and primary analysis based on approximately 432 events were presented to the DSMB on June 
24th, 2019. The DSMB reviewed the results on July 1st, 2019. Based on the recommendation of the 
DSMB, the Sponsor informed investigators on July 2nd, 2019 that the study would be discontinued due 
to futility. For patients enrolled to Arm 1, the Sponsor advised that patients stop treatment with BBI-
608 but given that no safety concerns were identified by the DSMB, in cases in which a patient appears 
to be deriving benefit from BBI-608 in the opinion of the investigator and with the patient’s informed 
consent, continuation of protocol therapy was permitted. Patients enrolled to Arm 2 were given the 
option to continue receiving standard of care therapy within the study.  
Patients may continue to receive protocol therapy until a discontinuation criterion is met, if believed 
to be in the patient’s best interest by the investigator and patient, and with the patient’s informed 
consent, or until February 28th, 2020, whichever occurs first. 
At study completion, analysis will be conducted for primary endpoint of OS as outlined in Section 13. 
Additionally, all secondary and exploratory analyses will be performed as outlined in the protocol.  
13.6
CORRELATIVE STUDIES
The correlative science component of the CanStem111P trial will include tumor and blood based 
assays to identify biomarkers of benefit from BBI-608 therapy, as well as biomarkers of BBI-608 
resistance. The purpose of these studies is to explore the possible relationship between biomarkers and 
disease response. The research aims to validate molecular markers such as genes (DNA) and gene 
products (mRNA or proteins), with measurements of their sequence, post translation modifications or 


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degree of expression, that can guide the use of appropriate therapeutic treatment regimens. The 
ultimate goal of identifying molecular markers is to improve subject responses and other measures of 
clinical benefit by matching an individual subject’s tumor diagnostic profile with an anticancer agent 
that has demonstrated a therapeutic advantage in subjects with a similar diagnostic profile. If such a 
marker can be identified, the samples and results may also aid in the development of diagnostic 
devices.
Using data from this and other trials, the relationship between a number of molecular markers 
DVVRFLDWHGZLWKWKH67$7ȕ-catenin and other related pathways, and the clinical outcomes with BBI-
608 therapy may be explored. Multiple molecular markers in a paraffin-embedded tumor tissue sample 
can be determined by analyzing RNA and protein in the tissue sample. 
In addition to analysis of potential biomarkers of benefit from BBI-608 therapy, an analysis of markers 
of resistance to BBI-608 will be conducted using blood samples drawn at baseline as well at 4 weeks 
post initiation of therapy. This analysis may involve SNPs, CYPS, and metabolomics.
Paraffin-embedded tumor specimens, or cores (two 2 mm cores of tumor from the block) and 5-20 
unstained slides obtained from paraffin embedded specimens will be required. Where it is not possible 
to obtain two 2 mm cores of tumor from the block, 5-20 unstained slides of representative tumor tissue 
are also acceptable. Patients who do not have available archival tissue may enroll on the study with 
permission of the Sponsor/CRO.
Blood samples will be collected prior to dosing with BBI-608 and then at week 4 while on BBI-608 in 
combination with nab-paclitaxel and gemcitabine. 
The following analysis will be performed to investigate the relationship between endpoints and 
biomarker levels (e.g. phospho-STAT3, etc): 
For each biomarker, Cox Proportional Hazards model will be used to model the relationship between 
Overall Survival, Progression-Free Survival and duration of response with baseline value of the 
biomarker. The model will also include assigned treatment, interaction between treatment and 
biomarker, and will be stratified by baseline ECOG performance status. 
For biomarkers with post-baseline measurements, similar analysis will be done with change from 
baseline of a biomarker as a covariate, for both time points. An additional model that includes 
prognostic factors may be investigated. 
The relationship between the endpoint and binary biomarkers (e.g. baseline phospho-STAT3 status, ß-
catenin, etc) will be also examined using the log-rank test, stratified by treatment and baseline ECOG 
performance status. Subgroup analysis by the status of the binary biomarker may also be performed. 
The Kaplan-Meier method will be used to describe overall survival, progression-free survival and 
duration of response by the status of the biomarker (e.g. phospho-STAT3-high vs. phospho-STAT3-
low) and by treatment group. 
The relationships between the binary response variable (e.g. objective response, DCR) with baseline 
values of biomarkers as well as with their change from baseline and at week 4 time point during 
treatment with nab-paclitaxel and gemcitabine with or without BBI-608 will be investigated using 
logistic regression that includes assigned treatment and biomarker value and treatment-by-biomarker 
interaction, stratified by baseline ECOG performance status. An additional model that includes 
prognostic factors may be investigated. The relationship between response and binary biomarkers (e.g. 


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baseline phospho-STAT3 status or STAT3 status) will also be examined using the CMH test, stratified 
by treatment and baseline ECOG performance status. Subgroup analysis by the status of the binary 
biomarker may also be performed. 
Exploratory analyses, in addition to those described in this section, such as alternative modeling 
approaches and analyses of other biomarkers are expected and may be performed. All analyses 
described in this section are based on availability of data.
13.7
SPARSE PHARMACOKINETIC ANALYSIS
Exploratory analyses will be performed on the bioanalytic data obtained from sparse plasma sampling 
in order to characterize the population pharmacokinetics of BBI-608. Demographic and 
pathophysiologic factors that affect plasma concentration of BBI-608 and nab-paclitaxel with 
gemcitabine in this population of patients with metastatic PDAC will be examined. The exposure-
response relationship between clinical and safety endpoints and BBI-608/nab-paclitaxel with 
gemcitabine exposure will also be examined.


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14.0
PUBLICATION
Boston Biomedical, Inc.
acknowledges that the Investigator(s) have certain professional 
responsibilities to report to the scientific community on findings in clinical investigations they conduct. 
A Principal Investigator shall have the right to publish the results of research performed under this 
protocol; provided, such publication does not disclose any Confidential Information or trade secrets of 
Boston Biomedical (other than the Clinical Results).  
If the Study is conducted as part of a multi-center protocol, Principal Investigator at each institution 
agrees not to independently publish their findings except as part of an overall multi-center publication. 
No other publication is allowed before the primary peer-reviewed scientific publication
The primary author agrees to, prior to submitting a manuscript, abstract, or any other written or oral 
presentation describing the Results for publication or presentation, forward to Boston Biomedical a 
copy of the item to be submitted for publication or presentation no less than forty-five (45) days prior 
to their submission. Upon reasonable request by Boston Biomedical, the primary author agrees to 
withhold such publication an additional 30 days to permit the preparation and filing of related patent 
applications. In addition, Boston Biomedical shall have the right to require the primary author to delete 
from any publication or presentation any Confidential Information (other than the Clinical Results) of 
Boston Biomedical’s and to require that any publication or presentation concerning the Study 
acknowledge the Sponsor’s support.  


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15.0
RESEARCH OUTSIDE THE TERMS OF THIS PROTOCOL
Boston Biomedical has a legal responsibility to report fully to the regulatory authorities all the results 
of administration of its investigational drugs.
No investigative procedures other than those described in this protocol shall be undertaken on subjects 
enrolled in this study (unless required for the care of the subject), without the agreement of the 
IRB/Ethics Committee and Boston Biomedical. The nature and results of any such procedures must be 
recorded and reported by a method agreed between Boston Biomedical and the Investigator. The 
consent of the subjects must be obtained before any such procedures are undertaken.
The investigative drug provided to the Investigator for use under this protocol may not be used for any 
other purpose, including another study, compassionate use, or personal use. 


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16.0
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES
16.1
REGULATORY CONSIDERATIONS
All institutions must conduct this trial in accordance with International Conference on Harmonization-
Good Clinical Practice (ICH-GCP) Guidelines. 
The conduct of this trial must comply with local laws and national regulations [e.g. in the United States 
of America with applicable US FDA Regulations; in Canada with Division 5 of the Canadian 
Regulations Respecting Food and Drugs (Food and Drugs Act)] relevant to the use of new therapeutic 
agents in the country of conduct. 
16.2
INCLUSIVITY IN RESEARCH
Individuals must not be excluded from participation in clinical trials on the basis of attributes such as 
culture, religion, race, national or ethnic origin, colour, mental or physical disability (except 
incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal record, unless 
there is a valid reason (i.e. safety) for the exclusion.  
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), 
vulnerable persons or groups will not be automatically excluded from a clinical trial (except for 
incompetent persons) if participation in the trial may benefit the patient or a group to which the person 
belongs.  
However, extra protections may be necessary for vulnerable persons or groups. It is the responsibility 
of the local Investigator and Institutional Review Board (IRB) to ensure that appropriate mechanisms 
are in place to protect vulnerable persons/groups. In accordance with TCPS, researchers and IRB 
should provide special protections for those who are vulnerable to abuse, exploitation or 
discrimination. As vulnerable populations may be susceptible to coercion or undue influence, it is 
especially important that informed consent be obtained appropriately.  
Centers are expected to ensure compliance with local IRB or institutional policy regarding 
participation of vulnerable persons/groups. It is the center’s responsibility to ensure compliance with 
all local SOPs. 
Persons who cannot give informed consent (i.e. mentally incompetent persons, or those physically 
incapacitated such as comatose persons) are not to be recruited to this study. It is the responsibility of 
the local Investigator to determine the subject’s competency, in accordance with applicable local 
policies and in conjunction with the local IRB (if applicable). 
Subjects who were competent at the time of enrollment in the clinical trial but become incompetent 
during their participation do not automatically have to be removed from the study. When re-consent 
of the patient is required, Investigators must follow applicable local policies when determining if it is 
acceptable for a substitute decision maker to be used. The Sponsor will accept re-consent from a 
substitute decision maker. If this patient subsequently regains capacity, the patient should be re-
consented as a condition of continuing participation. 


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16.3
OBTAINING INFORMED CONSENT
Informed consent will be obtained for each participant/potential participant in this trial, in accordance 
with ICH-GCP section 4.8. The center is responsible for ensuring that all local policies are followed.
Additionally, in accordance with GCP 4.8.2, the Sponsor may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential participant’s 
willingness to participate in the study. 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a participating 
Investigator (as defined on the participants list) is ultimately responsible, in terms of liability and 
compliance, for ensuring informed consent has been appropriately obtained. The Sponsor recognizes 
that in many centers other personnel (as designated on the participants list) also play an important role 
in this process. In accordance with GCP 4.8.5, it is acceptable for the Principal Investigator to delegate 
the responsibility for conducting the consent discussion. 
The Sponsor requires that each participant sign a consent form prior to their enrolment in the study to 
document his/her willingness to take part. The Sponsor may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during the 
course of the study. In conjunction with GCP 4.8.2, the communication of this information should be 
documented. 
The Sponsor allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local center. Centers should follow applicable local policies when procuring or 
using a translator for the purpose of obtaining informed consent to participate in a clinical trial. 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read, then informed consent may be 
obtained by having the consent form read and explained to the subject. This process must be thoroughly 
documented. 
16.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male partner) 
should not be collected about or from them unless or until they are a willing participant in the research. 
The rights and protections offered to participants in research apply and consent must be obtained prior 
to collecting any information about or from them. If the pregnant female is not a participant in the 
main trial, consent should be obtained via use of the exposure/pregnancy follow-up consent form. 
In the case of information collected about a newborn, consent should be provided by the legal 
guardian. In cases where the legal guardian is the participant in the main trial, consent is obtained 
via the main consent. If the legal guardian is not the trial participant, consent should be obtained via 
the exposure/pregnancy follow-up consent.  
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing permission 
to provide information related to the pregnancy/exposure. Similarly, male participants will not be 
withdrawn from the main study should their partner refuse/withdraw permission. 


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16.4
DISCONTINUATION OF THE TRIAL
The study is planned for completion on February 28th, 2020, at which time the Sponsor will cease 
provision of protocol treatment.
If this trial is discontinued for any reason by the Sponsor prior to February 28th, 2020, all centers will 
be notified in writing of the discontinuance and the reason(s) why. If the reason(s) for discontinuance 
involve any potential risks to the health of patients participating on the trial or other persons, the 
Sponsor will provide this information to centers as well.
If this trial is discontinued at any time by the center (prior to closure of the trial by the Sponsor), it is 
the responsibility of the Principal Investigator to notify the Sponsor of the discontinuation and the 
reason(s) why.  
Whether the trial is discontinued by the Sponsor or locally by the center, it is the responsibility of the 
Principal Investigator to notify the local Institutional Review Board and all clinical trials subjects of 
the discontinuance and any potential risks to the subjects or other persons.
Following trial closure after demonstrating overall survival benefit, and until the time that BBI-608 is 
commercially available, all patients randomized on the trial may have an opportunity to receive 
treatment with BBI-608; provided, that the Principal Investigator has determined that such continued 
treatment would be in the best interest of the patient, and subject to approval by the applicable 
regulatory authorities. This will be done via a new, open label extension study, or in another manner 
as determined by the Sponsor, requiring additional regulatory approval. 
16.5
RETENTION OF PATIENT RECORDS AND STUDY FILES
All essential documents must be maintained in accordance with ICH-GCP. 
The Principal Investigator must ensure compliance with GCP Guideline from every person involved 
in the conduct of the clinical trial at the site. 
Essential documents must be retained for 25 years following the completion of the trial at the center
(25 years post final analysis, last data collected, or closure notification to IRB, whichever is later), or 
until notified by the Sponsor that documents no longer need to be retained. 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, IRB or regulatory authority, the 
Investigator/institution must make all required trial-related records available for direct access. 
The Sponsor will inform the Investigator/Institution as to when the essential documents no longer need 
to be retained. 
16.6
ON-SITE MONITORING/AUDITING
In addition to the routine review of case report forms and supporting documents sent to the central 
office, site monitoring will be conducted at participating centers in the course of the study as part of 
the overall quality assurance programme. The monitors/auditors will require access to patient medical 
records to verify the data, as well as pharmacy, essential document binders, standard operating 


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procedures (including electronic information) and ethics documentation. 
At any time, your site may be subject to an inspection by a regulatory agency such as the Health 
Canada Inspectorate or the FDA. Your site may also be subject to an audit by the Sponsor.  
16.7
CASE REPORT FORMS
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. Details 
for accessing the EDC system and completing the on-line Case Report Forms will be provided 
separately. 


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translation. Current Drug Targets,13(6), 744-752. 
Corcoran, R. B., Contino, G., Deshpande, V., Tzatsos, A., Conrad, C., Benes, C. H., ... & Bardeesy, N. (2011). 
STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Research, 71(14), 5020-5029. 
Davis, J., Pandalai, P., Ripley, R., Langan, R., & Avital, I. (2012). Expanding Surgical Treatment of Pancreatic 
Cancer. Pancreas, 41(5), 678-684.  
Denley, S., Jamieson, N., McCall, P., Oien, K., Morton, J., & Carter, C. et al. (2013). Activation of the IL-
6R/Jak/Stat Pathway is Associated with a Poor Outcome in Resected Pancreatic Ductal Adenocarcinoma. 
Journal of Gastrointestinal Surgery, 17(5), 887-898.  
Eisenhauer, E., Therasse, P., Bogaerts, J., Schwartz, L., Sargent, D., & Ford, R. et al. (2009). New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer,
45(2), 228-247.  


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Fofaria, N. M., & Srivastava, S. K. (2014). STAT3 induces anoikis resistance, promotes cell invasion and 
metastatic potential in pancreatic cancer cells. Carcinogenesis, bgu233. 
Fukuda, A., Wang, S., Morris, J., Folias, A., Liou, A., & Kim, G. et al. (2011). Stat3 and MMP7 Contribute to 
Pancreatic Ductal Adenocarcinoma Initiation and Progression. Cancer Cell, 19(4), 441-455.  
Goldstein D, El Maraghi RH et al. (2014). Updated survival from a randomized phase III trial (MPACT) of 
nab-Paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of 
the pancreas. Journal of Clinical Oncology, 32, suppl 3, abstr 178.
Gupta, P., Chaffer, C., & Weinberg, R. (2009). Cancer stem cells: mirage or reality?. Nature Medicine, 15(9), 
1010-1012.  
Gupta, P., Fillmore, C., Jiang, G., Shapira, S., Tao, K., Kuperwasser, C., & Lander, E. (2011). Stochastic State 
Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells. Cell, 147(5), 1197.  
Hanahan, D., & Weinberg, R. (2011). Hallmarks of Cancer: The Next Generation. Cell, 144(5), 646-674.  
Hermann, P., Huber, S., Herrler, T., Aicher, A., Ellwart, J., & Guba, M. et al. (2007). Distinct Populations of 
Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer. Cell Stem 
Cell, 1(3), 313-323.  
Hidalgo, M. (2010). Pancreatic Cancer. New England Journal of Medicine, 362(17), 1605-1617.  
Hochberg, Y. (1988). A Sharper Bonferroni Procedure for Multiple Tests of Significance. Biometrika, 75(4), 
800.  
Holland, S., DeLeo, F., Elloumi, H., Hsu, A., Uzel, G., & Brodsky, N. et al. (2007). STAT3 Mutations in the 
Hyper-IgE Syndrome. New England Journal of Medicine, 357(16), 1608-1619.  
Hong, S., Wen, J., Bang, S., Park, S., & Song, S. (2009). CD44-positive cells are responsible for gemcitabine 
resistance in pancreatic cancer cells. International Journal of Cancer, 125(10), 2323-2331.  
Ibrahem, S., Al-Ghamdi, S., Baloch, K., Muhammad, B., Fadhil, W., Jackson, D., ... & Ilyas, M. (2014). 
STAT3 paradoxically stLPXODWHVȕ-FDWHQLQH[SUHVVLRQEXWLQKLELWVȕ-catenin function. International Journal of 
Experimental Pathology, 95(6), 392-400. 
Kawada, M., Seno, H., Uenoyama, Y., Sawabu, T., Kanda, N., & Fukui, H. et al. (2006). Signal Transducers 
and Activators of Transcription 3 Activation Is Involved in Nuclear Accumulation of Â -Catenin in Colorectal 
Cancer. Cancer Research, 66(6), 2913-2917.  
Klimstra, D. (2007). Nonductal neoplasms of the pancreas. Mod Pathol, 20(1s), S94-S112.  
Lee, C., Dosch, J., & Simeone, D. (2008). Pancreatic Cancer Stem Cells. Journal of Clinical Oncology, 26(17), 
2806-2812.  
Lesina, M., Kurkowski, M., Ludes, K., Rose-John, S., Treiber, M., & Kloppel, G. et al. (2011). Stat3/Socs3 
Activation by IL-6 Transsignaling Promotes Progression of Pancreatic Intraepithelial Neoplasia and 
Development of Pancreatic Cancer. Cancer Cell, 19(4), 456-469.  


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Li, C., Heidt, D., Dalerba, P., Burant, C., Zhang, L., & Adsay, V. et al. (2007). Identification of Pancreatic 
Cancer Stem Cells. Cancer Research, 67(3), 1030-1037.  
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is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic 
cancer. Br J Cancer, 98(8), 1389-1397.  
Li, Y.Z., Rogoff, H.A., Keates, S., Gao, Y., Murikipudi, S., Mikule, K., Leggett, D., Li, W., Pardee, A.B., Li, 
C.J. (2015) PNAS, 112(6), 1839-1844. 
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Regimen With Improved Safety and Maintained Efficacy in Pancreatic Adenocarcinoma. Pancreas, 42(8), 
1311-1315.  
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mediated via activation of STAT3. Genes & Development, 12(13), 2048-2060.  
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prognostic importance of CD44+/CD24+/EpCAM+ expression in clinical pancreatic cancer. Cancer Science,
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adenocarcinoma. Journal of Gastroenterology And Hepatology, 27, 15-18.  
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confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer, 103(11), 
1671-1679.  
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Gemcitabine plus nab-Paclitaxel is an active regimen in patients with advanced pancreatic cancer: a Phase I/II 
trial. Journal of Clinical Oncology, 29(34), 4548-4554. 
:KLWH%&KLHQ$	'DZVRQ''\VUHJXODWLRQRI:QWȕ-Catenin Signaling in Gastrointestinal
Cancers. Gastroenterology, 142(2), 219-232.  
Winter, J., Cameron, J., Campbell, K., Arnold, M., Chang, D., & Coleman, J. et al. (2006). 1423 
Pancreaticoduodenectomies for Pancreatic Cancer: A Single-Institution Experience. Journal of 
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Signaling Is Required for Pancreatic Carcinogenesis. Cancer Research, 73(15), 4909-4922.  


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APPENDIX I - PATIENT EVALUATION FLOW SHEET: ARM 1 (TREATMENT WITH NAB-
PACLITAXEL AND GEMCITABINE WITH BBI-608) 
1
Patient will be excluded from participation if any of the following occurs at < 72 hours prior to randomization: increase in 
ECOG PS (two observers will be required to assess performance status on each occasion and if discrepant, the one with the 
highest deterioration of performance will be considered true), weight loss of >10% from baseline testing, > 20% decrease in 
serum albumin from baseline testing, or clinically significant change in vital signs. 
2
Medical history must include date of diagnosis including histological or cytological documentation of malignancy.
3
Any anesthesia procedures, such as spinal block or other injections administered for pain control following Baseline 
Evaluation will be reported at < 72 hours prior to randomization.
4
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see 
Appendix IV). Following permanent protocol treatment discontinuation, patients will be assessed for any protocol treatment 
related adverse events every 8 weeks, starting with the 4 week post-protocol treatment discontinuation visit.
5
Adverse event assessment by phone should be performed on Run-In Day 2. 
6
Baseline creatinine or creatinine clearance may be used to demonstrate eligibility.
7
If required laboratory tests cannot be performed prior to randomization within indicated timelines due to technical reasons, 
lab retest and prolongation of the screening period for 3 working days is allowed. Laboratory testing performed as part of 
1
2
1
8
15
1
8
15
<14 days prior to 
randomization
<3 days prior to 
randomization
1
4 weeks post 
protocol treatment 
(+/- 7 days)
Every 4 weeks for the first 
6 months, then every 3 
months thereafter (+/- 7 
days)
X
X
X7
X
X
X7
X
X
X
X7
X7
X
X
X
X7
X
X
X
X
X3
X
X
X
X5
X
X
X
X
X
X
X
X
X7
X
X
X
X
X
X
X
X7
X
X
X
X7
X
X
X
X
X7
X
X
X
X
X7
X
X
X
X7
X7
X
X
X
X7
X
X
X
X
X12
X12
X
X
X12
X
X
X14
X
X
X
X
X
X
X
X
X
X
X
X
X
Submission of representative block of diagnostic tumor 
tissue 
Upon request after randomization
Assessment for survival of patient19
Blood collection for correlative studies
Blood collection for sparse PK analysis
Quality of Life Assessment (EORTC QLQ-C30)13
Begin BBI-608 Administration15
Gemcitabine with Nab-Paclitaxel Infusion17
Subsequent Cancer Therapy18
Dispense BBI-60816
Radiology & Imaging11
Every 8 weeks (56 days) +/- 5 days from randomization until progressive disease is 
documented
Tumor marker (CA 19-9)
Coagulation (PT + PTT)
Hematology9, 10
Albumin10
Biochemistry6, 10
Urinalysis 10
Total Bilirubin10
Tests & Procedures
Day
Adverse Event Assessment4
Pregnancy test, serum or urine (if applicable)7,8
ECG (12-lead)
Timing & Window
Height
Weight
ECOG Performance Status
Concurrent Medication List
After Permanent 
Treatment 
Discontinuation
Run-In
Cycle 1
Cycle 2 & Beyond 
Pre-
Randomization 
(Baseline)
During Protocol Treatment
+/- 3 days
Informed Consent
Prior Medical and Therapeutic History2
Physical Examination
Vital Signs (temperature, heart rate, blood pressure, 
respiratory rate, O2 saturation on room air)
To begin <2 
days after 
randomization15
Can be 
extended up to 
3 days


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standard of care prior to patient signature of the informed consent for the study will be acceptable as baseline labwork as long 
as testing is performed < 14 days prior to randomization.
8
In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units 
of HCG.
9
Hematology should be done within 72 hours prior to nab-paclitaxel + gemcitabine administration. Laboratory testing 
performed as part of standard of care prior to patient signature of the informed consent for the study will be acceptable as 
baseline labwork as long as testing is performed < 14 days prior to randomization.
10 Laboratory investigations should be performed within 72 hours prior to Day 1 of each Cycle of protocol treatment. Laboratory 
testing performed as part of standard of care prior to patient signature of the informed consent for the study will be acceptable 
as baseline labwork as long as testing is performed < 14 days prior to randomization. Total bilirubin will need to be repeated 
at <72 hours prior to randomization only for patients with Baseline total bilirubin >1 and <1.5 x ULN.
11 Standard tumor measurement procedures will be followed to assess response to therapy. The same method of assessment and 
the same technique should be used to identify and report each lesion at baseline and at reassessment during treatment. Tumor 
evaluations will continue until progressive disease is documented. For patients who remain on protocol therapy after objective 
disease progression has been documented, no further imaging assessments are mandated, but where these occur as a 
component of care, tumor measurements and assessment must be reported. Tumor assessments should be obtained within +/- 
5 days of protocol specified schedule. Qualifying scans performed as part of standard of care prior to patient signature of the 
study informed consent will be acceptable as baseline scanning as long as scanning is performed < 14 days prior to 
randomization.
12 Sample will be collected 4 weeks after Day 1 Cycle 1 and will not be performed beyond Cycle 2. A sample will be collected 
following protocol treatment discontinuation if discontinuation occurs prior to 4 weeks of therapy.
13 To be completed in clinic. Questionnaires should be completed at baseline and at 4, 8, 12, 16 and 24 weeks from Cycle 1 Day 
1 for as long as patient remains on protocol therapy or until deterioration to ECOG PS 4 or hospitalization for end of life care.
14 EORTC QLQ-C30 questionnaire will be collected in the post-protocol discontinuation period only if the patient discontinues 
protocol treatment prior to 24 weeks of therapy and has an ECOG PS of less than 4 and has not been hospitalized for end of 
life care.
15 BBI-608 administration will begin 2 days prior to the nab-paclitaxel+gemcitabine infusion on Day 1 of Cycle 1. These two 
days are referred to as Run-in Day and Run-in Day 2. Run-in Day 1 should occur within 2 calendar days of patient 
randomization. The run-in period may be extended by up to 3 additional calendar days.
16 Patients continuing on BBI-608 monotherapy post disease progression on nab-paclitaxel and gemcitabine will maintain the 
same schedule of events, except no longer have visits or bloodwork or AE assessment on Day 8 or Day 15 of the cycle 
following treatment discontinuation of nab-paclitaxel and gemcitabine. 
17 Nab-paclitaxel with gemcitabine administration should proceed according to institutional standard practice (with respect to 
pre-treatment laboratory evaluation, clinical assessment, pre-medication, and monitoring during and after infusion).
18 Subsequent cancer treatment will be captured until end of study.
19 After the first visit at which the patient has been off protocol treatment (BBI-608 and nab-paclitaxel with gemcitabine) for 4 
weeks, monitored on a monthly basis for 6 months and then every 3 months thereafter until death, the study closes or 3 years 
have elapsed since subject discontinuation from treatment. In the event that patient is unable to attend clinic, post-progression 
follow-up may be by means of telephone contact.


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APPENDIX II - PATIENT EVALUATION FLOW SHEET: ARM 2 (TREATMENT WITH NAB 
PACLITAXEL AND GEMCITABINE)  
1
8
15
1
8
15
<14 days prior to 
randomization
<3 days prior to 
randomization1
4 weeks post 
protocol treatment 
(+/- 7 days)
Every 4 weeks for the first 
6 months, then every 3 
months thereafter (+/- 7 
days)
X
X
X6
X
X
X6
X
X
X
X6
X6
X
X
X
X6
X
X
X
X
X3
X
X
X
X
X
X
X
X
X
X
X
X6
X
X
X
X
X
X
X
X6
X
X
X
X7
X
X
X
X
X6
X
X
X
X
X6
X
X
X
X6
X6
X
X
X
X6
X
X
X
X
X11
X11
X
X
X13
X
X
X
X
X
X
X
X
X
X
Submission of representative block of diagnostic tumor 
tissue 
Upon request after randomization
Assessment for survival of patient16
Blood collection for correlative studies
Quality of Life Assessment (EORTC QLQ-C30)12
Gemcitabine with Nab-Paclitaxel Infusion14
Subsequent Cancer Therapy15
Radiology & Imaging10
Every 8 weeks (56 days) +/- 5 days from randomization until progressive 
disease is documented
Tumor marker (CA 19-9)
Coagulation (PT + PTT)
Hematology8, 9
Albumin9
Biochemistry5,9
Urinalysis9
Tests & Procedures
Day
Adverse Event Assessment4
Pregnancy test, serum or urine (if applicable)6,7
ECG (12-lead)
Timing & Window
Height
Weight
ECOG Performance Status
Concurrent Medication List
Total Bilirubin9
After Permanent 
Treatment 
Discontinuation
Cycle 1
Cycle 2 & Beyond 
Pre-
Randomization 
(Baseline)
During Protocol Treatment
C1D1 to begin <4 days after randomization
+/- 3 days
Informed Consent
Prior Medical and Therapeutic History2
Physical Examination
Vital Signs (temperature, heart rate, blood pressure, 
respiratory rate, O2 saturation on room air)
1
Patient will be excluded from participation if any of the following occurs at < 72 hours prior to randomization: increase in
ECOG PS (two observers will be required to assess performance status on each occasion and if discrepant, the one with the 
highest deterioration of performance will be considered true), weight loss of >10% from baseline testing, > 20% decrease in 
serum albumin from baseline testing, or clinically significant change in vital signs.
2
Medical history must include date of diagnosis including histological or cytological documentation of malignancy.
3
Any anesthesia procedures, such as spinal block or other injections administered for pain control following Baseline 
Evaluation will be reported at < 72 hours prior to randomization.
4
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see 
Appendix IV). Following permanent protocol treatment discontinuation, patients will be assessed for any protocol treatment 
related adverse events every 8 weeks, starting with the 4 week post-protocol treatment discontinuation visit.


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5
Baseline creatinine or creatinine clearance may be used to demonstrate eligibility.
6
If required laboratory tests cannot be performed prior to randomization within indicated timelines due to technical reasons, 
lab retest and prolongation of the screening period for 3 working days is allowed. Laboratory testing performed as part of 
standard of care prior to patient signature of the informed consent for the study will be acceptable as baseline labwork as long 
as testing is performed < 14 days prior to randomization.
7
In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units 
of HCG.
8
Hematology should be done within 72 hours prior to nab-paclitaxel + gemcitabine administration. Laboratory testing 
performed as part of standard of care prior to patient signature of the informed consent for the study will be acceptable as 
baseline labwork as long as testing is performed < 14 days prior to randomization.
9
Laboratory investigations should be performed within 72 hours prior to Day 1 of each Cycle of protocol treatment. Laboratory 
testing performed as part of standard of care prior to patient signature of the informed consent for the study will be acceptable 
as baseline labwork as long as testing is performed < 14 days prior to randomization. Total bilirubin will need to be repeated 
at <72 hours prior to randomization only for patients with Baseline total bilirubin >1 and <1.5 x ULN.
10 Standard tumor measurement procedures will be followed to assess response to therapy. The same method of assessment and 
the same technique should be used to identify and report each lesion at baseline and at reassessment during treatment. Tumor 
evaluations will continue until progressive disease is documented. For patients who remain on protocol therapy after objective 
disease progression has been documented, no further imaging assessments are mandated, but where these occur as a 
component of care, tumor measurements and assessment must be reported. Tumor assessments should be obtained within +/- 
5 days of protocol specified schedule. Qualifying scans performed as part of standard of care prior to patient signature of the 
study informed consent will be acceptable as baseline scanning as long as scanning is performed < 14 days prior to 
randomization.
11 Sample will be collected 4 weeks after Day 1 Cycle 1 and will not be performed beyond Cycle 2. A sample will be collected 
following protocol treatment discontinuation if discontinuation occurs prior to 4 weeks of therapy.
12 To be completed in clinic. Questionnaires should be completed at baseline and at 4, 8, 12, 16 and 24 weeks from Cycle 1 Day 
1 for as long as patient remains on protocol therapy or until deterioration to ECOG PS 4 or hospitalization for end of life care.
13 EORTC QLQ-C30 questionnaire will be collected in the post-protocol discontinuation period only if the patient discontinues 
protocol treatment prior to 24 weeks of therapy and has an ECOG PS of less than 4 and has not been hospitalized for end of 
life care.
14 Nab-paclitaxel with gemcitabine administration should begin within 7 calendar days of randomization and proceed according 
to institutional standard practice (with respect to pre-treatment laboratory evaluation, clinical assessment, pre-medication, and 
monitoring during and after infusion).
15 Subsequent cancer treatment will be captured until end of study.
16 After the first visit at which the patient has been off protocol treatment (nab-paclitaxel with gemcitabine) for 4 weeks, 
monitored on a monthly basis for 6 months and then every 3 months thereafter until death, the study closes or 3 years have 
elapsed since subject discontinuation from treatment. In the event that patient is unable to attend clinic, post-progression 
follow-up may be by means of telephone contact.


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APPENDIX III - PERFORMANCE STATUS SCALES/SCORES
PERFORMANCE STATUS CRITERIA
Karnofsky and Lansky performance scores are intended to be multiples of 10.
ECOG (Zubrod)
Karnofsky
Lansky*
Score
Description
Score
Description
Score
Description
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction.
100
Normal, no complaints, no 
evidence of disease.
100
Fully active, normal.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
90
Minor restrictions in physically 
strenuous activity.
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g. light housework, 
office work.
80
Normal activity with effort; some 
signs or symptoms of disease.
80
Active, but tires more quickly.
70
Cares for self, unable to carry on 
normal activity or do active work.
70
Both greater restriction of and 
less time spent in play activity.
2 
Ambulatory and capable of all 
selfcare but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
60
Up and around, but minimal 
active play; keeps busy with 
quieter activities.
50
Requires considerable assistance 
and frequent medical care.
50
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities.
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours.
40
Disabled, requires special care and 
assistance.
40
Mostly in bed; participates in 
quiet activities.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
30
In bed; needs assistance even for 
quiet play.
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair.
20
Very sick, hospitalization 
indicated. Death not imminent.
20
Often sleeping; play entirely 
limited to very passive activities.
10
Moribund, fatal processes 
progressing rapidly.
10
No play; does not get out of bed.
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.


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APPENDIX IV - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (AE) reporting. All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from 
the CTEP web site:
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm).


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APPENDIX V - QUALITY OF LIFE ASSESSMENT
Introduction 
The assumption that control of symptoms will automatically improve quality of life is probably true but hasn't 
yet been tested, especially in determining how certain symptoms may or may not affect quality of life. Current 
literature reveals interesting things; two in particular are:
x additional and useful information may be obtained from quality of life measurements
x a growing consensus that the goal of medical care today for most patients is the preservation of function 
and well-being in everyday life
We have reached the stage where the collection of information about psychological distress, social disruption, 
emotional trauma and painful side-effects is not only necessary but a routine component in many protocols. 
Quality of life data can be used in a variety of ways:
x
to try to achieve the best possible outcome for patients
x
to evaluate the extent of change in the quality of life of an individual or group across time
x
to evaluate new treatments and technologies
x
to support approval of new drug applications 
x
to try to provide the best value for health care dollars 
x
to compare costs and benefits of various financial and organizational aspects of health care services
In the future, approval of not only drugs but also new therapies or methods of delivery will most likely be 
based on a combination of quality of life, survival, response, and adverse event data.
Instructions for Administration of a Quality of Life Questionnaire.  
The instructions below are intended as a guide for the administration of the Quality of Life questionnaire. 
1. Preamble
Quality of life data are collected for research purposes, and will usually not be used for the patient’s individual 
medical care. The assessment is in the form of a self-report questionnaire. Therefore, it must be completed by 
the patient only, without translation, coaching or suggestions as to the "correct" answer by relatives or health 
care personnel.
The usual scheduled times to obtain the questionnaires are as follows: 
x
pre-randomization or pre-registration (baseline)
x
during treatment 
x
during follow-up 
The information provided by the patient in the completed questionnaire is confidential and should not be 
discussed with or shown to anyone who is NOT mentioned in the consent form signed by the patient. 
If a particular question has not been answered, please document the reason(s) in the appropriate space on the 


CanStem111P
Protocol Date: 2019-JUL-31
Amendment #5 
  
CONFIDENTIAL
75
CONFIDENTIAL
questionnaire. If the whole questionnaire has not been completed, please document the reason(s) on the 
appropriate case report forms.
2. Pre-Treatment Assessment
It should be explained to the patient that the purpose of the questionnaire is to assess the impact of treatment 
on different areas of the patient's life, e.g.: psychological distress, social disruption, side-effects, et cetera.
Study staff should collect the questionnaire as soon as it has been completed, check to see that each question 
has been answered and gently remind the patient to answer any inadvertently omitted questions. If a patient 
states that s/he prefers not to answer some questions and gives a reason(s), the reason(s) should be noted on 
the questionnaire. If a specific reason is not given, this also should be noted on the questionnaire. 
3. Assessments During Treatment
The quality of life questionnaire should be given to the patient before being seen by the doctor, and prior to 
treatment on the day of treatment, as required by the schedule in the protocol. If the patient does not have a 
doctor visit scheduled, or if it was not possible for the patient to complete the questionnaire before being seen 
by the doctor, s/he should still complete the questionnaire prior to treatment.
4. Assessments During Follow-up 
The quality of life questionnaire should be given to the patient before being seen by the doctor, for as long as 
the patient continues on Protocol therapy, as required by the schedule at approximately: 
4, 8, 12, 16 and 24 weeks or until deterioration to ECOG PS 4 or hospitalization for end of life care  
the first regularly scheduled 4 week assessment at which the patient has been off study therapy for a minimum 
of 28 days (+/- 3 days) if study therapy discontinuation occurred prior to 24 weeks and until deterioration to 
ECOG PS 4 or hospitalization for end of life care 
A patient may, on occasion, be reluctant to complete the questionnaire because they feel unwell. In that case, 
you may express sympathy that things are below par, but state that this is exactly the information we require 
if we are to understand more about how quality of life is affected. You may also remind them that it takes only 
a few minutes to complete.
It defeats the whole purpose of the assessment if it is delayed until the patient feels better!
5. What If . . .
The patient should complete the questionnaires at the clinic. The exception is that the design of some trials 
may require the patient to take the questionnaire home with them after leaving the clinic, and complete it on 
the specific day, because a return visit to the clinic is not scheduled.
There may be circumstances when the patient does not complete the questionnaire as required in the clinic. 
Three situations are described below. In these cases, it is beneficial if quality of life data can still be collected.
A. The patient leaves the clinic before the questionnaire could be administered, or someone forgets to give the 
questionnaire to the patient.  
Contact the patient by phone informing him or her that the questionnaire was not completed. Ask the patient 
if s/he is willing to complete one: 


CanStem111P
Protocol Date: 2019-JUL-31
Amendment #5 
  
CONFIDENTIAL
76
CONFIDENTIAL
If yes, mail a blank questionnaire to the patient, and make arrangements for return of the questionnaire in a 
timely fashion. Record the date it was mailed and the date received on the questionnaire.
If this is not feasible, then ask the patient if s/he is willing to complete a questionnaire over the phone. If the 
patient agrees, read out the questions and range of possibilities, and record the answers. Make a note on the 
questionnaire that the questionnaire was completed over the phone. 
If no, note the reason why the questionnaire was not completed on the appropriate case report form.
B. The patient goes on an extended vacation for several months and won't attend the clinic for regular visit(s).
Ensure that the patient has a supply of questionnaires, with instructions about when to complete them, and how 
to return them. If it is known beforehand, give the patient blank questionnaires at the last clinic visit; if the 
extended absence is not known in advance, mail the blank questionnaires to the patient. Written instructions 
may help ensure that the patient stays on schedule as much as possible.  
C. The patient does not want to complete the questionnaire in clinic. 
Should the patient not wish to answer the questionnaire in the clinic but insists on taking it home, and failing 
to comply with the patient's wishes is likely to result in the questionnaire not being completed at all, then the 
patient may take the questionnaire home with instructions that it is to be completed the same day. When the 
questionnaire is returned, the date on which the questionnaire was completed should be noted and a comment 
made on the questionnaire as to why the patient took it away from the clinic before completion.  


This box to be completed by the clinical research coordinator: Study ID #: ___________  Pt. Initials: ____ ____ ____ 
Page 1 of 3
Please go on to the next page
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.)
European Organization for Research and Treatment of Cancer (EORTC)
Quality of Life Questionnaire
We are interested in some things about you and your health. Please answer all of the questions yourself by 
circling the number that best applies to you. There are no "right" or "wrong" answers. The information that 
you provide will remain strictly confidential.
Not
At All
A
Little
Quite
a Bit
Very
Much
1.
Do you have any trouble doing strenuous activities, like 
carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the 
house?
1
2
3
4
4.
Do you need to stay in a bed or a chair during the day?
1
2
3
4
5.
Do you need help with eating, dressing, washing yourself 
or using the toilet?
1
2
3
4
During the past week:
Not
At All
A
Little
Quite
a Bit
Very
Much
6.
Were you limited in doing either your work or other daily 
activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or other 
leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4


This box to be completed by the clinical research coordinator: Study ID #: ___________  Pt. Initials: ____ ____ ____ 
Page 2 of 3
Please go on to the next page
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.)
During the past week:
Not
At All
A
Little
Quite
a Bit
Very
Much
9.
Have you had pain?
1
2
3
4
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things, like 
reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4


This box to be completed by the clinical research coordinator: Study ID #: ___________  Pt. Initials: ____ ____ ____ 
Page 3 of 3
EORTC QLQ-C30 (Core 30 Questionnaire Version 3.0 © copyright 1995 EORTC Quality of Life Study Group. All rights reserved.)
During the past week:
Not
At All
A
Little
Quite
a Bit
Very
Much
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment interfered 
with your family life?
1
2
3
4
27. Has your physical condition or medical treatment interfered 
with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment caused 
you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that best applies to you.
29. How would you rate your overall health during the past week?
1
Very Poor
2
3
4
5
6
7
Excellent
30. How would you rate your overall quality of life during the past week?
1
Very Poor
2
3
4
5
6
7
Excellent
Please check to make sure you have answered all the questions.
Please fill in your initials to indicate that you have completed this questionnaire: ______________
Today's date (Year, Month, Day): ________________________________ 
Thank you. 

SAP_001.pdf: 
SDPO CONFIDENTIAL
Page 1
SAP CanStem111P
A Phase III Study of BBI-608 plus nab-Paclitaxel with 
Gemcitabine in Adult Patients with Metastatic 
Pancreatic Adenocarcinoma
Statistical Analysis Plan
(SAP)
Version: 5.0
Author: Emma Foos (Biostatistics—Cambridge)
Date:
16-October-2020
: Emma Foos (Biostatistics—Cambridge)


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 2
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 
1.0
August 
6, 
2017
Emma Foos
Statistical Analysis Plan 
Version 
2.0
August 10, 
2018
Emma Foos
x
Efficacy claim (no stopping for 
efficacy) in the first interim 
analysis has been removed. 
x
Additional covariates have 
been added. 
x
Laboratory variables have been 
edited. 
x
Additional subgroup analysis 
have been specified. 
x
Summary of key efficacy 
analysis has been added.
Version 
3.0
April 
12, 
2019
Emma Foos
x
Biomarker endpoints have 
been moved to exploratory
x
Baseline value for efficacy has 
been edited
x
PFS, DCR, and ORR have 
been marked as key secondary 
endpoints and quality of life as 
other secondary endpoint
x
Multiplicity adjustment to 
control for Type I error rate 
has been incorporated
x
Quality of Life detailed 
analysis has been added
x
More details to the analyses of 
the primary and secondary 
endpoints has been added
Emma Foos
Emma Foos
Emma Foos


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 3
x
Summarization of new 
anticancer therapy, physical 
examination, and ECOG have 
been added
x
ECG analysis has been edited
x
Adverse Events of Clinical 
Relevance (AECR) have been 
added
x
Elevated liver function test 
results have been edited 
x
Dose intensity section has been 
edited
x
By cycle and cycle 1 
summaries for treatment 
compliance have been 
removed
x
Sensitivity analysis for PFS 
has been added
x
Censoring hierarchy for PFS 
has been edited
Version 
4.0
October 24, 
2019
Emma Foos
x
Changing BBI-608 to 
napabucasin
x
Adding language after futility 
boundary was met in first 
interim analysis
x
Per Protocol Analysis Set has 
been deleted
x
Coutry subgroup analysis has 
been deleted
x
Methods for handling missing 
data has been edited
Emma Foos


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 4
x
Baseline assessment window 
has been edited from 14 days 
to 28 days
x
Censoring rules for time to 
event analysis of New Anti-
cancer therapy has been added
x
Dose Intensity section has 
been edited
x
Appendix 1.4 has been added
Version 
4.1
April 
24, 
2020
Emma Foos
x
Compliance section has been 
edited
Version 
4.2
June 
25, 
2020
Emma Foos
x
Primary and Secondary 
Analyses has been edited
Version 
4.3
August 18, 
2020
Emma Foos
x
BBI has been changed to 
SDPO
x
Primary and Secondary 
Analyses has been edited
x
Added pSTAT3 unknown to 
potential biomarker analysis
x
AECR has been changed to 
Clustered TEAE and 
associated SMQs and terms 
have been changed
Version 
5.0
October 16, 
2020
Emma Foos
x
Dose Intensity section has 
been edited 
x
PD/Biomarker Analysis Set 
has been deleted
x
Dose Changes section has been 
edited
Emma Foos
Emma Foos
Emma Foos
Emma Foos


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 5
STATISTICAL ANALYSIS PLAN APPROVAL
Author:
_________________________________________ Date: _____/_____/_________
Emma Foos
Senior Biostatistician, Sumitomo Dainippon Pharma Oncology, Inc.
Approved by:
_________________________________________ Date: _____/_____/_________
Bo Jin, PhD
Executive Director, Head of Biostatistics, Sumitomo Dainippon Pharma Oncology, Inc.
_________________________________________ Date: _____/_____/_________
Edgar Braendle, MD
Chief Medical Officer, Sumitomo Dainippon Pharma Oncology, Inc.
 
Author:
____________________ Date:
___
____
_________________________________________ Date: _____ _____ _________
_
Bo Jin, PhD
Executive Director, Head of Biostatistics, Sumitomo Dainippon Pharma Oncology, Inc.
_________________________________________ Date: _
_
_
_ ___/_____/_________
_
Edgar Braendle, MD
Chief Medical Officer, Sumitomo Dainippon Pharma Oncology, Inc.
___
___
_____
_______________
: _____/_____/_________
Emma Foos
Senior Biostatistician, Sumitomo Dainippon Pharma Oncology, Inc.
Approved by:
____


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 6
TABLE OF CONTENTS 
ABBREVIATIONS & DEFINITIONS .....................................................................9 
1. AMENDMENTS FROM PREVIOUS VERSION(S) .........................................11 
2. INTRODUCTION ...............................................................................................11 
2.1. Study Design ...........................................................................................11 
2.2. Study Objectives......................................................................................12 
Primary Objectives .....................................................................12 
Key Secondary Objectives..........................................................12 
Other Secondary Objectives .......................................................13 
Exploratory Objectives ...............................................................13 
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS .13 
3.1. Primary Endpoint(s) ................................................................................13 
3.2. Key Secondary Endpoints .......................................................................13 
3.3. Other Secondary Endpoints.....................................................................14 
3.4. Exploratory Endpoints.............................................................................14 
3.5. Safety Endpoints......................................................................................14 
Adverse Events and Laboratory Abnormalities..........................14 
3.6. Covariates................................................................................................14 
4. HYPOTHESES AND DECISION RULES.........................................................15 
4.1. Statistical Hypotheses..............................................................................15 
4.2. Statistical Power and Sample Size Calculation.......................................15 
5. INTERIM ANALYSES, FINAL ANALYSIS, AND UNBLINDING................15 
5.1. INTERIM ANALYSES AND FINAL ANALYSIS ...............................15 
5.2. UNBLINDING AND DATA SAFETY AND MONITORING 
COMMITTEE.......................................................................................16 
6. ANALYSIS SETS ...............................................................................................16 
6.1. Intent-to-Treat Analysis Set ....................................................................16 
6.2. Safety Analysis Set..................................................................................16 
6.3. Response Analysis Set (RAS).................................................................17 
6.4. PK Analysis Set.......................................................................................17 
6.5. Treatment Misallocations........................................................................17 
7. DATA HANDLING ............................................................................................17 
7.1. Methods for Handling Missing Dates .....................................................17 


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 7
7.2. Definition of Baseline Values .................................................................20 
7.3. Study Day................................................................................................20 
7.4. Visit Windows.........................................................................................20 
7.5. Dropouts..................................................................................................21 
7.6. Pharmacokinetics.....................................................................................21 
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........21 
8.1. Statistical Methods ..................................................................................21 
Analysis for Time to Event Data ................................................21 
Analysis for Binary Data ............................................................21 
Analysis for Continuous Data.....................................................22 
Analysis for Quality of Life Data ...............................................22 
8.2. Statistical Analyses..................................................................................22 
Standard Analysis .......................................................................22 
Analysis for Primary Endpoint ...................................................27 
8.2.2.1. Overall Survival ........................................................27 
Analyses for Secondary Endpoints.............................................28 
8.2.3.1. Key Secondary Efficacy Endpoints Analysis............28 
8.2.3.2. Other Secondary Endpoint Analysis .........................29 
8.2.3.3. PK Analysis...............................................................31 
8.2.3.4. Biomarker Analysis - Correlative Studies.................32 
Analyses for Other Safety Endpoints .........................................32 
8.2.4.1. Adverse Events..........................................................32 
8.2.4.2. Laboratory Data.........................................................35 
8.2.4.3. Electrocardiograms....................................................36 
8.2.4.4. Vital Signs.................................................................36 
8.2.4.5. Physical Exam...........................................................36 
8.2.4.6. ECOG........................................................................36 
9. REFERENCES ....................................................................................................37 
10. APPENDICES ...................................................................................................38 
10.1. Appendix 1.1 DATA DERIVATION DETAILS..................................38 
10.2. Appendix 1.2 Censoring for Time to Event Data..................................40 
10.3. Appendix 1.3 Summary of Key Efficacy Analysis ...............................44 
10.4. Appendix 1.4 Response and Evaluation Endpoints...............................48 


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 8
1.1.1 
Measurable Disease................................................................48 
1.1.2 
Non-Measurable Disease........................................................48 
1.1.3 
Target Lesions ........................................................................48 
1.1.4 
Non-Target Lesions................................................................49 
1.1.5 
Response.................................................................................49 
1.2 
Response Duration................................................................................50 
1.3 
Stable Disease Duration........................................................................50 
1.4 
Methods of Measurement .....................................................................50 
1.4.1 
Clinical Lesions......................................................................51 
1.4.2 
Chest X-ray.............................................................................51 
1.4.3 
CT/MRI ..................................................................................51 
1.4.4 
Ultrasound ..............................................................................52 
1.4.5 
Endoscopy/Laparoscopy ........................................................52 
1.4.6 
Histology ................................................................................52 


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 9
ABBREVIATIONS & DEFINITIONS 
ADR
Adverse Drug Reaction
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
BMI
Body Mass Index
BOR
Best Overall Response
BP
Blood pressure
CI
Confidence Interval
CMH
Cochran-Mantel_Haenszel
CR
Complete Response
CRF
Case Report Form
CRO
Contract Research Organization 
DCR
Disease Control Rate
DSMB
Data Safety and Monitoring Board
EDC
Electronic Data Capture
EORTC-QLQ-C30
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire
IA
Interim Analysis
ITT
Intent to Treat
M&N
Miettinen and Nurminen
mOS 
Median Overall Survival
mPFS
Median Progression-Free Survival
MTD
Maximum Tolerated Dose
NCI CTCAE
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NOAEL 
No Observed Adverse Effect Level
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PDAC
Pancreatic ductal adenocarcinoma 
PFS
Progression-Free Survival
PH
Proportional Hazards
PK
Pharmacokinetics  
PR
Partial Response
pSTAT3
Phospho-STAT3
QoL
Quality of Life
RAS
Response Analysis Set
RECIST
Response Evaluation Criteria In Solid Tumors 
RP2D
Recommended Phase 2 Dose


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 10
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
ULN
Upper Limit of Normal


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 11
1. AMENDMENTS FROM PREVIOUS VERSION(S)  
This is the version 5.0 of the statistical analysis plan, based on the CanStem111P protocol 
amendment dated July 31, 2019. The major changes in this amendment include changing 
Boston Biomedical Inc to Sumitomo Dainippon Pharma Oncology, Inc, changing BBI-608
to napabucasin, adding language after futility boundary was met during first interim 
analysis, deleting the Per Protocol Analysis Set and the PD/Biomarker Analysis Set, editing 
the methods for handling missing data section, deleting country subgroup analysis, editing 
the baseline assessment window from 14 days to 28 days, adding censoring rules for time 
to event analysis of New Anti-cancer therapy, editing the dose intensity section, editing the 
Dose Changes section, editing the Adverse Events of Clinical Relevance section to 
Clustered TEAEs and the SMQs and sponsor derived terms associated with the analysis, 
adding pSTAT3 unknown to the biomarker analysis, editing the Primary and Secondary 
analyses from stratified for subgroup analyses to unstratified, removing PFS sensitivity 
analyses using alternative censoring hierarchy, editing DCR and ORR unstratified analyses 
using normal approximation and the z test, and adding Appendix 1.4: Response and 
Evaluation Endpoints.  
As noted in Section 13 in the protocol amendment, the detailed methodology for 
summary and statistical analyses of the data collected in this study are documented in the 
statistical analysis plan (SAP), which is maintained by the sponsor.  There may be 
modifications made to the plans outlined in the protocol but these will not include any 
major modifications of the primary endpoint definition and/or its analysis. Any major 
modifications will be reflected in a protocol amendment. 
2. INTRODUCTION 
2.1. Study Design 
This is a randomized, open-label, multi-center, phase III study of napabucasin plus weekly 
nab-paclitaxel with gemcitabine (Arm 1) vs. weekly nab-paclitaxel with gemcitabine (Arm 
2) for adult patients with metastatic pancreatic ductal adenoacarcinoma (PDAC). 
1132 patients will be randomized in a 1:1 ratio, stratified according to geographical region 
(North America/Western Europe/Australia vs. Japan/Korea vs. Rest of the World), Eastern 
Cooperative Oncology Group (ECOG) performance status (0 vs. 1), and presence of liver 
metastases (yes vs. no).
Metastatic
PDAC
RANDOMIZE
↗
A
r
m
1
napabucasin orally, 
twice daily
plus
Nab-Paclitaxel + 
Gemcitabine IV, 
weekly
Disease 
progression based 
on RECIST 
criteria1, 2
or
Unacceptable 
toxicity occurs
OS
→
→


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 12
↘
A
r
m
2
Nab-Paclitaxel + 
Gemcitabine IV, 
weekly
1If no other standard therapies are available at the time of disease progression, and the 
patient has not experienced any adverse events requiring permanent discontinuation, 
napabucasin may be continued in monotherapy.
2From the time of this amendment, and since the outcome of the interim analysis was 
communicated to investigators, patients may continue protocol therapy if it is believed to 
be in their best interest by the investigator and patient, and with the patient’s informed 
consent. Patients will receive napabucasin, nab-paclitaxel and/or gemcitabine at the same 
dose and schedule that they were receiving prior to the amendment. Patients on Arm 1 may 
continue napabucasin with the Sponsor’s approval. Patients on Arm 1 may discontinue 
napabucasin but choose to continue with nab-paclitaxel and gemcitabine.
Until the time of this amendment, the study proceeded in 28-day (4-week) cycles. 
Napabucasin was administered orally, at 240 mg bid (480 mg total daily dose), with doses 
separated by approximately 8-12 hours. Napabucasin administration began 2-5 days prior 
to the first nab-paclitaxel with gemcitabine infusion. Nab-paclitaxel 125 mg/m2
immediately followed by gemcitabine 1000 mg/m2 was administered on Days 1, 8 and 15 
of every 28-day cycle via intravenous infusion. Tumor assessments will be performed 
every 8 weeks after randomization until objective disease progression or treatment 
discontinuation due to toxicity. 
The study was planned for completion on February 28th, 2020.
2.2. Study Objectives  
Primary Objectives  
To compare overall survival (OS) of patients with metastatic (Stage IV) PDAC treated with 
napabucasin plus weekly nab-paclitaxel with gemcitabine versus weekly nab-paclitaxel 
with gemcitabine. 
Key Secondary Objectives 
x
To compare PFS in patients treated with napabucasin plus weekly nab-
paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine. 
x
To compare DCR in patients treated with napabucasin plus weekly nab-
paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine.
x
To compare ORR in patients treated with napabucasin plus weekly nab-


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 13
paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine.
Other Secondary Objectives 
x
To evaluate the safety profile of napabucasin administered daily plus weekly 
nab-paclitaxel with gemcitabine, with safety assessed according to the National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) 
version 4.0.
x
To compare the Quality of Life (QoL), as measured using the EORTC-QLQ-
C30, in patients with
treatment-naive metastatic PDAC treated with 
napabucasin plus weekly nab-paclitaxel with gemcitabine versus weekly nab-
paclitaxel with gemcitabine.
Exploratory Objectives 
x
To compare OS in patients treated with napabucasin plus weekly nab-paclitaxel 
with gemcitabine (Arm 1) versus weekly nab-paclitaxel with gemcitabine (Arm 
2) in biomarker positive PDAC patients. ¥
x
To compare PFS in patients treated with napabucasin plus weekly nab-
paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine in 
biomarker positive PDAC patients. 
x
To compare ORR and DCR in patients treated with napabucasin plus weekly 
nab-paclitaxel with gemcitabine versus weekly nab-paclitaxel with gemcitabine 
in biomarker positive PDAC patients.
¥This biomarker-positive sub-population is defined as those patients with phospho-STAT3 
positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded 
(FFPE) tumor tissue.
3. ENDPOINTS AND COVARIATES: DEFINITIONS AND CONVENTIONS 
3.1. Primary Endpoint(s) 
Overall survival (OS) of patients with metastatic (Stage IV) PDAC treated with 
napabucasin plus weekly nab-paclitaxel with gemcitabine and overall survival of patients 
with weekly nab-paclitaxel with gemcitabine in the general study population.
3.2. Key Secondary Endpoints 
x
PFS, DCR and ORR in the general study population
x
Objective tumor response, as assessed using the Response Evaluation Criteria in 
Solid Tumor (RECIST) version 1.1 


Protocol CanStem111P
Statistical Analysis Plan
SDPO CONFIDENTIAL
Page 14
3.3. Other Secondary Endpoints 
Mean European Organization for Research and Treatment of Cancer Quality of Life 
questionnaire (EORTC QLQ-C30 QoL) change scores from baseline at time 2 (~8 weeks 
post randomization) and time 4 (~16 weeks post randomization) for the physical function 
and global health status/quality of life subscale scores.
3.4. Exploratory Endpoints 
x
OS, PFS, ORR and DCR in the predefined biomarker-positive population
3.5. Safety Endpoints 
Adverse Events and Laboratory Abnormalities 
x
Adverse Events (AEs) as characterized by type, frequency, severity (as graded by
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE] version 4.0) timing, seriousness, and relationship to study therapy
x
Laboratory abnormalities as characterized by type, change from baseline, and 
severity (as graded by NCI CTCAE version 4.0)
3.6. Covariates  
Stratification factors used for randomization including geographical region (North 
America/Western Europe/Australia vs. Japan/Korea vs. Rest of the world), ECOG 
performance status (ECOG 0 vs. ECOG 1), and presence of liver metastases (yes vs. no) 
will be used as covariates in primary analyses for OS, PFS, ORR and DCR.
Besides the stratification factors, the following factors at patient entry may also be 
considered as covariates in sensitivity analyses:
x
Primary tumor location (head of pancreas versus body/tail of pancreas)
x
Level of CA19-9 (normal versus >ULN and <59 x ULN versus >59 x ULN)
x
Age (< 65 versus > 65)
x
Sex (male versus female)
x
Number of metastatic sites at baseline (1 versus > 2)
x
Smoking status (Yes versus No)
x
Race (white, black, Asian, other)
x
Prior adjuvant chemotherapy (Yes versus No)
x
Prior radiotherapy (Yes versus No)
Subgroup analyses and the corresponding forest plot analysis by these covariates may also 
be conducted.  


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4. HYPOTHESES AND DECISION RULES 
4.1. Statistical Hypotheses 
The null and alternative hypothesis for the primary endpoint (OS) is:
H0: OS in napabucasin + nab-paclitaxel with gemcitabine ≤ OS in nab-paclitaxel 
with gemcitabine
Ha: OS in napabucasin + nab-paclitaxel with gemcitabine > OS in nab-paclitaxel 
with gemcitabine
4.2. Statistical Power and Sample Size Calculation 
The primary study endpoint of the study is OS in the general study population. 
The study is designed to have a power of 90% and a one-sided alpha of 2.5% to detect a 
20% reduction in the continuous risk of death (HR 0.80, which corresponds to an increase 
of median survival from 8.5 to 10.63 months) in the Intent to Treat (ITT) general study 
population. It is estimated that 864 events will be required to detect a 20% reduction in the 
risk of death which would be observed by randomizing 1132 patients over 24 months with 
patient follow up for an additional 12 months, for total study duration of 36 months. It is 
anticipated that up to 5% dropout rate will occur. When the required number of events for 
the primary endpoint has been reached, all randomized patients still alive will continue 
study follow up through to their deaths.
5. INTERIM ANALYSES, FINAL ANALYSIS, AND UNBLINDING  
5.1. INTERIM ANALYSES AND FINAL ANALYSIS 
Prior to this amendment, there was one interim analysis after 50% of the required number 
of events (432 events) had been observed.
The interim analysis was for futility only, with the futility boundary set at HR ≥ 1. Safety 
data and primary efficacy analysis based on approximately 432 events were presented to the 
DSMB on June 24th, 2019. The DSMB reviewed the results on July 1st, 2019. Based on the 
recommendation of the DSMB, the Sponsor informed investigators on July 2nd, 2019 that 
the study would be discontinued due to futility. For patients enrolled to Arm 1, the Sponsor 
advised that patients stop treatment with napabucasin but given that no safety concerns were 
identified by the DSMB, in cases in which a patient appears to be deriving benefit from 
napabucasin in the opinion of the investigator and approved by the Sponsor and with the 
patient’s informed consent, continuation of protocol therapy was permitted. Patients 
enrolled to Arm 2 were given the option to continue receiving standard of care therapy 
within the study. 
Patients continued to receive protocol therapy until a discontinuation criterion was met or 
until February 28th, 2020, whichever occurred first. 


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As the Interim Analysis data concluded the study, the IA report will be included as an 
appendix to the CSR. The final analysis including data after July 2nd, 2019 will be 
exploratory in nature. This is due to a potentially imbalanced dropout rate of the two 
treatment arms as the study was deemed futile. Therefore, caution is necessary when 
interpreting the results.
At study completion, analysis will be conducted for primary endpoint of OS as outlined 
in Section 3. Additionally, all secondary and exploratory analyses will be performed as 
outlined. 
5.2. UNBLINDING AND DATA SAFETY AND MONITORING COMMITTEE 
Although this is an open-label study, a blinding plan will be implemented to minimize the 
risks of potential Sponsor bias for decision making at the interim analyses and the final 
analysis. 
Specifically, there will be an unblinded reporting team to report complete interim analysis 
results and regular safety updates to an independent Data Safety and Monitoring Board 
(DSMB). DSMB will review the IA results and make recommendations to the Sponsor 
based on the decision rules described in Section 5.1. DSMB will also review safety data 
regularly during conduct of the study. The role and responsibilities of the DSMB will be 
detailed in a separate Charter.
Aggregated data by treatment will not be reviewed or analyzed by the study team until the 
final database release or early termination of the study. SDPO will restrict access to the 
database to only selected team members (or their designees) who have a need to review 
individual unblinded patient information on an ongoing basis for safety and 
pharmacovigilance monitoring.
Adequate procedures will also be implemented so that team members (or their designees) 
who have unblinded information for patients in the study do not disclose and disseminate 
any unblinded information or unblinded data to any blinded personnel until after the official 
database release. The roles and responsibilities of the blinded and unblinded staff will be 
detailed in a separate plan.
6. ANALYSIS SETS 
6.1. Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) population is defined as all patients who are randomized.  
Patients will be analyzed according to the treatment arm they were randomized to, 
regardless of any potential errors in dosing.  The ITT population will be  used for primary 
and secondary efficacy endpoint analyses. 
6.2. Safety Analysis Set 
The safety analysis set is defined as all patients who receive at least 1 dose of any study 
drug. Patients will be analyzed according to the treatment they actually received. That is, 
those patients who are randomized to the active arm but receive the regimen in the control 


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arm will be included in the control arm; those patients who are randomized to the control 
arm but receive the regimen in the active arm will be included in the active arm for safety 
analyses.
Safety analysis set will be used for all safety related analyses including treatment emergent 
adverse events (TEAEs), concomitant medication, laboratory tests, and vital signs.
6.3. Response Analysis Set (RAS) 
Response analysis set (RAS) is defined as all ITT patients with measurable disease per 
RECIST 1.1 at randomization.  RAS will be used for the primary analysis of response data 
(ORR and DCR). Response data may also be summarized in the ITT population. 
6.4. PK Analysis Set 
The PK analysis set will include all patients who received at least one dose of study drug 
(napabucasin) and have at least one quantifiable concentration.
6.5. Treatment Misallocations  
If a patient was: 
x
Randomized but not treated, then they will be excluded from analyses of safety and
PK as they have not received at least one dose of study medication. These patients 
will be included in ITT analyses, however.
x
Treated but not randomized, then they will be excluded from the efficacy analyses 
since randomized treatment is missing, but will be reported under the treatment they 
actually received for all safety and PK analyses.
x
Randomized but took incorrect treatment, then they will be reported in the ITT 
analysis under the treatment they were randomized to, and under the treatment they 
actually received for the PK and all safety analyses. 
7. DATA HANDLING 
7.1. Methods for Handling Missing Dates 
All analyses and descriptive summaries will be based on the observed data. Except for the 
data otherwise specified in the language below, missing data will not be imputed or “carried 
forward”. For the patient data listings, no imputation of incomplete dates will be applied. 
The listings will present the incomplete dates without any change.
Missing or Partial Death Dates
x
If the entire date is missing, the death date will be imputed as the day after the date 
last known alive.


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x
If the day or both day and month is missing, the death date will be imputed to the 
maximum of the full (non-imputed) day after the date last known alive and the 
following: 
o
If day is missing, day will be 1st of the month
o
If both day and month are missing, death month and day will be January 1st.
Date of Last Dose of All Study Drugs
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown 
or partially unknown, will be imputed as follows:
x
If the last date of study drug is completely missing and the End of Treatment (EOT) 
eCRF page has not been completed and no death date has been entered, the patient 
should be considered ongoing and the cutoff date for the analysis should be used as 
the last dosing date.  
x
If the last date of study drug is completely or partially missing and there is EITHER 
a completed EOT eCRF page OR a death date available (within the data cutoff 
date), then impute this date as the last dose date:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death 
date) 
= Last day of the month, if both Year and Month are available and Year = Year of 
min (EOT date, death date) and Month < Month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.
x
If patients were never dosed, the date of last dose will be marked as Not Applicable 
and there will be a date of discontinuation on the EOT eCRF page and/or a death 
date on the Death eCRF
Missing Dates in Adverse Events/Concomitant Therapies/Medications
Dates missing the day or both the day and month of the year will adhere to the following 
conventions:
x
The missing day of onset of an AE or start date of a therapy will be set to:
-
the day of the first study treatment, if the onset yyyy-mm is the same as yyyy-
mm of the first study treatment
-
otherwise, the first day of the month that the event occurred
x
The missing day of resolution of an AE or end date of a therapy will be set to:
-
the last day of the month of the occurrence. If the subject died in the same month, 
then set the imputed date as the death date
x
If the onset date of an AE or start date of a therapy is missing both the day and 
month, the onset date will be set to:


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-
the date of the first treatment, if the onset year is the same as the year of the first 
study treatment
-
otherwise, January 1 of the year of onset
x
If the resolution date of an AE or end date of a therapy is missing both the day and 
month, the date will be set to:
-
December 31 of the year of occurrence. If the subject died in the same year, 
then set the imputed date as the death date
x
If date is completely missing, then no imputation will be done and the event will be 
considered as treatment emergent (for AEs) or concomitant (for medications) unless 
the end date rules out the possibility.
Missing Dates in Prior Therapies
Dates missing the day or both the day and month of the year will adhere to the following 
conventions:
x
The missing day of start or end date of prior therapy will be set to:
-
the 15th of the month or date of informed consent, whichever is earlier
x
If the start or end date of a prior therapy is missing both the day and month, the date 
will be set to: 
-
July 1 of the year or date of informed consent, whichever is earlier
x
If date is completely missing, then no imputation will be done 
Missing Efficacy Endpoints
For primary and secondary efficacy analyses no values will be imputed for missing data. 
For time to event endpoints, non-event observations will be censored. For ORR/DCR, 
patients with no post-baseline tumor evaluations or missing baseline tumor evaluation 
will be counted as non-responders.  
Missing Age
Age will be computed from birth date to the date of Informed Consent, as (Date of 
Informed Consent – Date of Birth +1)/365.25 rounded down to the nearest integer. 
x
If birth date is missing day, day will be set to the 15th to minimize bias
x
If missing both month and day, birth date will be set to July 1 of the birth year
Missing QoL Data
Missing items in a scale in EORTC QLQ-30 will be handled by the following methods:  
Values will be imputed for missing items by “assuming that the missing items have 


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values equal to the average of those items which are present” for any scale in which at 
least half the items are completed.  A scale in which less than half of the items are 
completed will be treated as missing. No imputation will be conducted at a specific visit 
if data is completely missing.
7.2. Definition of Baseline Values 
x
Efficacy: The last non-missing measurement on or prior to the date of 
randomization will serve as the baseline measurement, so long as this assessment 
was taken within 28 days of randomization. Any imaging assessments performed 
outside the time window will be considered protocol deviations and will be 
evaluated on a case by case basis.
x
Safety: The last non-missing assessment prior to the date of the first study drug 
administration (either napabucasin or nab-paclitaxel or gemcitabine, whichever was 
administered first) will be used as the baseline assessment. In the case this value is 
missing, the last non-missing assessment prior to or on the randomization date will 
be used as baseline assessment.
x
Other baseline characteristics: The last non-missing measurement on or prior to the
date of randomization will serve as the baseline measurement. In the event such a 
value is missing, the last non-missing assessment completed prior to the date of the 
first dose of study drug administration (either napabucasin or nab-paclitaxel or 
gemcitabine, whichever was administered first) will be used as the baseline 
assessment.
7.3. Study Day 
Study day for safety analysis is calculated as:
x
Assessment date – first dose date + 1; if the assessment was performed on or after 
the first dose date.
x
Assessment date – first dose date; if the assessment was performed prior to the 
first dose date.
Study day for efficacy analysis is calculated as:
x
Assessment date – randomization date + 1; if the assessment was performed on or 
after the randomization date.
x
Assessment date – randomization date; if the assessment was performed prior to 
the randomization date.
7.4. Visit Windows 
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  


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7.5. Dropouts  
Time to event parameters will be censored if patients drop out (withdraw from consent or 
lost to follow-up) before documentation of the events (progressive disease / death).  Rules 
for censoring for PFS are detailed in Appendix 1.2 Censoring for Time to Event Data.
7.6. Pharmacokinetics 
The handling of BLQ values for nonlinear mixed-effects modeling (AKA: Population-PK, 
or Pop-PK) will be described in a separate analysis plan.  For the purpose of data tabulation, 
summary statistics, and by-time point graphics, BLQ values will be treated as zero.  
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES 
8.1. Statistical Methods 
Whilst every effort has been made to pre-specify all analyses in this statistical analysis 
plan, if any additional exploratory analyses are found to be necessary, the analyses and the 
reasons for them will be detailed in the clinical study report (CSR).
Analysis for Time to Event Data 
Time-to-event curves between the two treatment groups will be compared with a one-sided 
stratified log-rank test at significance level of 0.025 (one-sided) adjusting for the 
stratification variables at randomization. Stratified and unstratified Cox proportional 
hazards model will be used to estimate the hazard ratio as well as 2-sided 95% confidence 
intervals (CI), and may be used to explore the potential influences of the baseline factors 
(eg, age, gender and ethnic origin, etc) on the time-to-event data. The time-to-event data 
will also be summarized using the Kaplan-Meier method and displayed graphically when 
appropriate (2). Median event times and 2-sided 95% CIs for each time-to-event endpoint 
will be provided. The 6 month, 1 year, and 18 month survival probability will be estimated 
using the Kaplan-Meier method and a 2-sided 95% CI will be calculated using the normal 
approximation to the log transformed cumulative hazard rate.
Analysis for Binary Data 
Descriptive statistics (frequency and percentage) for binary endpoints will be presented 
by treatment group. CMH test will be used for comparison of the two treatment groups, 
adjusting for the randomization stratification variables. Two-sided Z test will be used for 
comparison of the two treatment groups without stratification. In addition, the treatment 
difference and 95% CI based on the Miettinen and Nurminen method (5) adjusting for 
the stratification factors will be displayed. For unstratified analyses, the treatment 
difference and 95% CI will be based on the normal approximation method, and may be 
used to explore the potential influences of the baseline factors on the binary endpoints. 


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Analysis for Continuous Data 
Descriptive statistics, such as the mean, standard deviation, median, minimum, and 
maximum values, will be provided for continuous endpoints. Linear or non-linear models 
may be employed to analyze the continuous data. 
Analysis for Quality of Life Data 
Summary statistics for Quality of Life will be provided by treatment for Functional, 
Symptom and Global health status raw scores as well as for linearly converted scores on 
the scale of 0-100. The mean EORTC QLQ-C30 QoL changes scores from baseline at 
time 2 (~8 weeks post randomization) and time 4 (~16 weeks post randomization) for 
the physical function and global health status/qualify of life subscale scores will also be 
presented. Wilcoxon tests will be used to compare the difference at each of these two 
time points between the two treatment arms for each of these two subscales. In addition, a 
chi-square test will be used to compare the distribution of patients who have improved, 
are stable, or have worsened from baseline between the two arms. A Fisher’s exact test 
will be used to compare between the two arms the proportion of patients with 
deterioration in physical function and global QoL at time 2 and time 4. 
8.2. Statistical Analyses  
Standard Analysis
Study Conduct and Patient Disposition
Patient disposition includes the number and percentage of patients for the following 
categories:  patients in each of the study populations, patients discontinued from the 
treatment, primary reason to discontinue from the treatment, patients discontinued from the 
study, and primary reason to discontinue from the study.  All percentages will be based on 
the number of patients in the ITT population. 
Demographic and Baseline Characteristics
Baseline characteristics such as demographics, baseline disease characteristics, prior 
therapies, and ECOG performance score will be tabulated and listed. 
Prior and Concomitant Medications
Prior and concomitant medications will be coded to ATC (Anatomical Therapeutic 
Chemical) classification and Drug Class using WHO Drug Dictionary (WHO-DD) March 
2016, and will be listed.
Medications that start and stop prior to the date of first treatment administration will be 
classified as ‘prior’ medications. If a medication starts on or after the date of first treatment 
administration up to the last dose date of study medication (inclusive), then the medication 
will be classified as ‘concomitant’. 


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Summaries of prior and concomitant medications will be provided by level 3 ATC 
classification and preferred term using frequencies and percentages for the ITT population. 
A separate concomitant medications table using preferred base and level 4 ATC 
classification will also be provided using frequencies and percentages for the safety 
analysis set. 
Prior Treatment 
Prior treatment will be summarized by overall and listed for each patient in the ITT 
population.
Prior cancer surgery will be coded by System Organ Class (SOC) and Preferred Term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA® v.19.0) and 
summarized by MedDRA PT within MedDRA SOC.  The number and percentage of 
patients in each type of prior cancer surgery will also be reported by overall.
The total dose of prior cancer radiotherapy will be summarized. The number and 
percentage of patients with radiation to different anatomical locations will be reported, 
along with indication. 
Prior cancer therapies will be summarized by the number of unique agents per patients, the 
number and percentage of patients reporting each agent, time from start of first anticancer 
therapy to first dose date of napabucasin, and time from end of last anticancer therapy to 
first dose date of napabucasin. Prior cancer therapies will be coded to Agent Received using 
WHO Drug Dictionary (WHO-DD) March 2016. 
Concomitant Palliative and Supportive Care Therapies
Concomitant palliative and supportive care therapies will be summarized by overall and 
listed for each patient in the ITT population.
Concomitant palliative and supportive care therapies will be coded using WHO Drug 
Dictionary (WHO-DD) March 2016. 
New Anti-cancer Treatment
New anti-cancer therapy will be derived from Post protocol cancer therapy.
New anti-cancer therapy will be summarized by type of therapy and median time to post 
protocol systemic therapy from randomization. Median time will be calculated using the 
Kaplan Meier Method and CIs estimated using the Brookmeyer Crowley method. 
Patients who have not received a new anti-cancer therapy at the time of interim or final 
analysis will be censored at the date of data cutoff.
Medical History
Medical history will extracted from both medical history and AE CRFs.
Adverse Events listed on the AE CRF, with the “Is this an ongoing medical history 
condition present at date of informed consent?” marked as “Yes” will be considered 


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medical history, as these events were ongoing at the time of informed consent and prior to 
randomization.
Medical history will be coded by SOC and PT using MedDRA v19.0.  Medical history will 
be summarized by SOC and PT using the number and percentage of patients for the ITT 
population. 
Dose Changes
The details of napabucasin dose change are outlined below. 
x
Dose Held Due to Non-AE - 2 or more consecutive doses held (AM-PM or PM-AM) 
due to patient forgot, patient decision or other reason.
x
Dose Held Due to AE - 2 or more consecutive doses held (AM-PM or PM-AM) due 
to adverse event.
o
Restarted at the same dose - Restarted at a dose the same as the previous non-
zero dose at the time of dose held.
o
Restarted as reduced dose (dose-decrease) - Restarted at a dose decreased 
from the previous non-zero dose at the time of dose held.

Dose increase to partial dose following reduction - An increase to 
<240 mg for 2 or more consecutive doses (AM-PM or PM-AM) 
following restart at reduced dose.

Dose increase to full dose following reduction - An increase to 240 mg 
for 2 or more consecutive doses (AM-PM or PM-AM) following 
restart at reduced dose.
x
Permanently Discontinued Due to AE.
Extent of Exposure Exposure may be summarized (per run-in and/or first 28 days and/or 
overall) as dose received (cumulative dose or actual dose intensity) or as dose received 
relative to intended dose (relative dose intensity [RDI]).  
The information that will be summarized depends on how the study drug is dosed (e.g., 
infusion cyclical, oral daily, oral cyclical).  
In what follows, “time unit” can be e.g., weeks or days.
Treatment duration in days
For napabucasin:
x
Overall intended treatment duration = earliest date of {latest date of {start date of 
last cycle +27 days, last dose date of Napabucasin}, death date, end of study date} 
– earliest date of {first dose date of Napabucasin and/or nab-paclitaxel and/or 
gemcitabine}+1.
x
Run-in treatment duration = actual number of days in run-in period.


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x
First 28 days intended treatment duration = earliest date of {start date of 1st cycle 
+ 27 days, death date, end of study date} – start date of 1st cycle +1.
For backbone treatment:
x
Overall intended treatment duration = (earliest date of {latest date of {start date of 
last cycle +27 days, last dose date of Napabucasin}, death date, end of study date} 
– earliest date of {first dose date of nab-paclitaxel or gemcitabine (whichever 
backbone duration you are calculating)} +1)/ 7.
x
First 28 days intended treatment duration = (earliest date of {start date of 1st cycle 
+ 27 days, start date of nab-paclitaxel or gemcitabine (whichever backbone 
duration you are calculating) within Day 28 ±3 window -1 } – start date of 1st 
cycle +1)/ 7.
Note that the actual end of treatment date in this analysis is not the collected end of 
treatment date in the eCRFs, as the actual end of treatment date in this analysis is being 
derived and may be different from what was recorded by sites. 
Cumulative dose in a period or overall is the sum of the actual doses received in a period 
or overall, respectively.  
Actual Dose Intensity [DI]
x
Overall actual DI = overall accumulative dose in mg or mg/m2 / overall intended 
treatment duration in days or weeks.
x
Run-in actual DI = actual total dose in mg in run-in / actual treatment duration in 
days in run-in.
x
First 28 days actual DI = actual total dose in mg or mg/m2 in first 28 days / 
intended treatment duration in days or weeks in first 28 days. 
Relative Dose Intensity (RDI): The basic intent is to evaluate dose per time unit factoring 
in dose reductions, interruptions, or delays.  
x
Relative dose intensity (RDI) by period and overall
o
Intended DI (dose unit/time unit) = [intended cumulative dose per period] / 
[intended number of time units in a period]  
o
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI] 
Note:
x
The intended dose level is fixed at the start of treatment rather than the start of a 
cycle


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o
One exception is for all backbone therapies. All backbone therapies 
incorporate BSA to calculate each dose. Therefore, the BSA to be used for 
calculating each dose of the backbone therapies will be using the Mosteller 
method (see below) based on the last available weight and height prior to 
each infusion. 
o
BSA [m2] = ((Height [cm] × Weight [kg])/3600) × 0.5
o
Calculated doses will be rounded to the nearest integer
o
Cumulative dose, actual dose intensity and relative dose intensity will 
remain missing if they cannot be derived due to missing BSA. Height from 
the most recent earlier visit can be used if height is missing.
x
The intended cumulative dose of a combination drug per cycle is constant for all 
cycles
o
One exception is for all backbone therapies after the updated BSA or weight 
calculation prior to each infusion. The updated dose level based on 
changing BSA or weight should be considered when calculating intended 
cumulative dose of these drugs per cycle
x
The intended cumulative dose of napabucasin per period is calculated by (intended 
dose level per day) x (intended period duration in days)
x
Dose unit of napabucasin is mg, dose unit of a combination drug is mg/m2
Treatment compliance
Napabucasin compliance overall
Overall: Treatment compliance (%) for napabucasin =
(Cumulative actual total dose /total planned or intended dose) x 100
Daily treatment compliance will be reported for each patient for the following dose-levels 
and intervals:
x
The % of days the patient received a total dose of at least 480 mg napabucasin out 
of actual treatment duration in days.   
x
The % of days the patient received a non-zero dose of napabucasin out of actual 
treatment duration in days.
Daily treatment compliance will be grouped according to the following categories: < 
60%,t 60% - < 80%, t 80% - < 90%, t 90%, and will be summarized for the treatment 
group of napabucasin plus Nab-Paclitaxel + Gemcitabine IV.
Combination drugs compliance overall
Overall: Treatment compliance (%) for combination drugs =
(Number of treatments administered /number of treatments that should have been 
administered) x 100


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Analysis for Primary Endpoint 
8.2.2.1. Overall Survival 
Overall Survival in the general study population, the primary endpoint of this study, is 
defined as the time from randomization to death from any cause. Patients who are alive at 
the time of interim or final analysis or who have dropped out will be censored at their last 
date known to be alive on or before the date of data cutoff. Patients will be analyzed in the 
arm to which they are randomized regardless of the treatment they received (intent-to-treat 
analysis). OS in months is calculated as (date of death/Last known to be alive date – date 
of randomization + 1)/30.4375.
The survival experience of patients in both treatment groups will be summarized by the 
Kaplan-Meier method and compared primarily by a stratified log-rank test adjusting for 
stratification variables at randomization, including geographical region (North 
America/Western Europe/Australia vs. Japan/Korea vs. Rest of the World), ECOG 
performance status (ECOG 0 versus ECOG 1), and presence of liver metastases (yes versus
no). The hazards ratio and 95% CI will be obtained using the Stratified Cox PH Model. If 
any randomized stratification factor proves to have an inadequate sample size, it will be 
dropped from the primary analysis or pooling will be applied. Details will be determined 
in a blinded fashion prior to database lock. The survival probability at 6 months, 1 year, 
and 18 months will be summarized using the Kaplan-Meier method. 
Sensitivity analysis using Cox proportional hazards model based on actual stratified factors 
will be performed. An unstratified, 1-sided log-rank test will also be performed for 
sensitivity using an unstratified Cox PH model to obtain HR and the 95% CI. A multi-
variate Cox PH model stratified by the stratification factors and including other baseline 
factors (as described in the subgroup analyses below) will also be conducted. Additional 
analyses for each stratification level will be performed using the Kaplan-Meier method for 
each treatment for each stratification level. A stratified, 2-sided log-rank test will be
performed along with a stratified Cox PH model to obtain HR and 95% CI. Additional 
analyses may be conducted using the unstratified Cox proportional model incorporating 
each baseline factor if deemed adequate and necessary.  
Subgroup analysis and the corresponding forest plot will be conducted by the stratification 
factors at baseline as mentioned above as well as the following factors: 
x
Primary tumor location (head versus body/tail of pancreas)
x
Level of CA19-9 (normal versus >ULN and <59 x ULN versus >59 x ULN)
x
Age (< 65 versus > 65)
x
Sex (male versus female)
x
Number of metastatic sites at baseline (1 versus > 2)
x
Race (white, black, Asian, other)
x
Smoking (Yes versus No)
x
Prior adjuvant chemotherapy (Yes versus No)


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x
Prior radiotherapy (Yes versus No)
x
Geographical region (North America versus Western Euope versus Australia 
versus Asia versus China versus Japan versus Korea versus Rest of Asia 
(excluding China, Korea, and Japan) versus Other (excluding North America, 
Western Euope, Australia, and Asia))
Analyses for Secondary Endpoints 
8.2.3.1. Key Secondary Efficacy Endpoints Analysis 
The following key secondary outcomes will be also be assessed.  
PFS in the General Study Population
PFS in the general study population is defined as the time from randomization to the first 
objective documentation of disease progression or death due to any cause. If a patient has 
not progressed or died at the time of interim or final analysis (up to the date of data cutoff), 
PFS will be censored on the date of the last tumor assessment (up to the date of data cutoff). 
PFS in months is calculated as (First event date/Censored Date – date of randomization + 
1)/30.4375.
The difference in PFS between treatment arms will be analyzed using the log rank test 
stratified by stratification factors.  The 1-sided p value from the stratified log-rank test 
will be reported along with the median event time (and other quartiles) and corresponding 
2-sided 95% CI for each treatment arm.  Estimates of the PFS curves obtained from the 
Kaplan-Meier method will be presented along with a graphical presentation of PFS 
curves.  The Cox PH model stratified for randomized stratification factors will be fitted 
and the estimated hazard ratio and 2-sided 95% CI will be provided. 
Additional analyses may be conducted using the unstratified Cox proportional model 
incorporating each baseline factor if deemed adequate and necessary.  
DCR in the General Study Population
DCR is defined as the proportion of patients with a documented complete response, partial 
response, and stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate 
of DCR will be based on the Response Analysis Set (RAS).
DCR will be summarized for each treatment arm along with the corresponding exact 2-
sided 95% CI using the Clopper Pearson method.  Differences of DCR between the two 
arms will be compared using a 1-sided Cochran-Mantel-Haenszel test stratified for 
stratification factors. The treatment difference of DCR and its 95% CI based on the 
Miettinen and Nurminen (M&N) method adjusting for stratification factors will be provided 
along with the DCR and 95% CI for each stratification factor level for each treatment 
arm.  


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Additional analyses may be conducted using the unstratified one-sided Z test 
incorporating each baseline factor to compare the differences of DCR between the two 
arms. The treatment difference of DCR and its 95% CI may also be obtained using the 
normal approximation method.
ORR in the General Study Population
ORR is defined as the proportion of patients with a documented complete response and 
partial response (CR + PR) based on RECIST 1.1. The primary estimate for ORR will be 
based on the RAS.
ORR will be analyzed similarly as DCR. 
8.2.3.2. Other Secondary Endpoint Analysis 
QoL Analysis
The QoL of patients will be assessed using EORTC QLQ-30. The EORTC QLQ-30 is a 
self-administered cancer specific questionnaire with multi-dimensional scales. It consists 
of both multi-item scales and single item measures, including five functional domains, a 
global quality of life domain, three symptom domains, and six single items. Scoring of the 
EORTC QLQ-30 data will be completed following the procedures recommended by the 
EORTC Study Group on Quality of Life. For each domain or single item measure a linear 
transformation will be applied to standardize the raw score to range between 0 and 100. 
Questionnaire compliance rates will be ascertained for each group at each measurement 
time point. Mean baseline scores for each subscale and summary scores will be calculated.
Compliance at an assessment time point is defined as the number of patients who were 
assessed divided by the expected number of patients at that time point. The expected 
number of patients:
x
at baseline is equal to the number of patients randomized 
x
at any post-baseline visit is equal to the number of patients who are alive and have 
not progressed 
A subject who answers at least one item at a time point is considered to have been assessed. 
The endpoints in QoL analysis are the mean EORTC QLQ-C30 QoL change scores from 
baseline at time 2 and time 4 for the physical function and global health status/quality of 
life subscale scores. Wilcoxon tests may be used to compare the difference at each of these 
two time points between two treatment arms for each of these two subscales. 
Summary statistics will be provided by treatment for Functional, Symptom and Global 
health status raw scores for QoL-C30 as well as for linearly converted scores on the scale 
of 0-100. 
Note the raw score is: RawScore=RS=(I1+I2+…+In)/n, where I1, I2,…and In are the nth 
component in the categories of functional, symptom or global health status scales. 


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The linearly converted score (LCS) for Functional scales is defined as:
Linearly Converted Score =LCS = (1- (RS-1)/Range)) ×100 
For Symptom scales or Global health status: 
Linearly Converted Score =LCS = (RS-1)/Range ×100
The following gives the LCS for all the scales: 
Functional scale’s scores:
o
Physical functioning:
(1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100
o
Role functioning:
(1 - ((Q6+Q7)/2-1)/3) * 100
o
Emotional functioning:
(1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100
o
Cognitive functioning:
(1 - ((Q20+Q25)/2-1)/3) * 100
o
Social functioning:
(1 - ((Q26+Q27)/2-1)/3) * 100
Global health status score:
o
Global QOL: ((Q29+Q30)/2-1)/6 * 100
Symptom scale’s scores:
o
Fatigue:
((Q10+Q12+Q18)/3-1)/3 * 100
o
Nausea and vomiting:
((Q14+Q15)/2-1)/3 * 100
o
Pain:
(Q9+Q19)/2-1)/3 * 100
o
Dyspnea:
((Q8-1)/3 * 100
o
Insomnia:
(Q11-1)/3 * 100
o
Appetite loss:
(Q13-1)/3 * 100
o
Constipation:
(Q16-1)/3 * 100
o
Diarrhea:
(Q17-1)/3 * 100
o
Financial difficulties:
(Q28-1)/3 * 100
Missing  data handling for missing items in a scale are specified in Section 7.1.  
The QoL assessment is performed prior to randomization and during protocol treatment 
after randomization. Since exact time of assessment may vary from patient to patient, it is 
necessary to provide a window for each QoL time point.  What follows is a description of
how to assign a questionnaire to a discrete time point:
Relative Days (REL_Day) from Randomization = 
x
Assessment date – randomization date+1; if the assessment was performed on or 
after the randomization date.
x
Assessment date – randomization date; if the assessment was performed prior to 
the randomization date.
Table 1 
Analysis Windows for QoL Endpoints 
Time Point
Target 
Date 
(Rel_Day)
Windows 


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Baseline 
1
-14≤rel_day≤ 1
4 Weeks post randomization
29
1<rel_day≤ 43
8 Weeks post randomization
57
43<rel_day≤ 71
12 Weeks post randomization
85
71<rel_day≤ 99
16 Weeks post randomization
113
99<rel_day≤ 141
24 Weeks post pandomization
169
141<rel_day≤ 197
Note that if more than 1 questionnaire is available for the baseline window, then the latest 
non-missing measurement, per question, will be considered as the baseline. If more than 
1 questionnaire is available at a time point other than baseline, then the average (per 
question) of the non-missing measurements will be used. 
If there are multiple records in the same day to 1 item, the more severe answered will be 
counted. 
QOL Response Analysis for EORTC QLQ-C30
For EORTC-QLQ-C30, QoL response for functional scales and global health status is 
calculated as follows: A change score of 10 points from baseline is defined as clinically 
relevant.  Patients are considered to have clinical improvement if reporting a score 10-
points or better than baseline at any time of QoL assessment.  Conversely, patients are 
considered worsened if reporting a score minus 10-points or worse than baseline at any 
time of QoL assessment without any clinical improvement.  Patients whose scores are 
between 10-point changes from baseline at every QoL assessment will be considered as 
stable.  In contrast to functional scales, for the determination of patient’s QoL response, 
classification of patients into improved and worsened categories is reversed for symptom 
scales.  A Chi-square test may then be performed to compare the distributions of these 
three categories between the two arms.
The proportion of patients in either arm with at least a minimum of 10 unit(s) 
deterioration in change scores at both 8 and 16 weeks will be compared by means of
Fisher’s exact test.
8.2.3.3. PK Analysis 
Plasma napabucasin concentrations will be tabulated by Day within Cycle, nominal time 
and dose in the case of dose reduction if appropriate.  The listing will include actual 
sampling time relative to the napabucasin dose administered on the day of the PK sample 
collection.  Summary statistics by Day within Cycle, and irrespective of Day and Cycle, 
will be presented including arithmetic mean, arithmetic standard deviation, arithmetic-
based percent coefficient of variation, geometric mean, geometric standard deviation, 
maximum, median, minimum, and sample size.
Exploratory analyses may be performed by  Pop-PK analysis of napabucasin, possibly in 
conjunction with data from other napabucasin studies. The exposure-response relationship 
between clinical and safety endpoints and napabucasin/nab-paclitaxel with gemcitabine 
exposure may also be examined.


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The procedures for the population PK modeling, including model evaluation, will be 
described in a seperate Pop-PK analysis plan.  The corresponding results will be reported 
in a separate document, not in the clinical study report (CSR).  
8.2.3.4. Biomarker Analysis - Correlative Studies 
Pre-clinical and clinical studies conducted by SDPO have identified several biomarkers in 
tumor tissues whose levels either increase or decrease upon exposure to napabucasin.  
Tumor archival tissue and biopsies will be collected as described in Protocol (1) Section 
12.3. The correlations between the biomarker results, and pharmacokinetic parameters and 
measures of anti-tumor/anti-cancer efficacy signals will be explored if data allow and it is 
deemed appropriate.   
Specifically, the relationship between phospho-STAT3 (pSTAT3) and the clinical 
outcomes with napabucasin therapy may be explored. The following efficacy endpoints 
may be analyzed by pSTAT3 status (positive and negative and unknown):
x
Primary Endpoint: Overall Survival (OS),
x
Secondary Endpoint: Progression Free Survival (PFS), and
x
Objective Response Rate (ORR) and Disease Control Rate (DCR)
Safety, demographics, baseline disease characteristics, and prior therapy may be 
summarized by treatment by pSTAT3 status (positive or negative or unknown) in all the 
patients with biomarker data.  
Analyses for Other Safety Endpoints 
All treatment emergent adverse events, lab abnormalities, vital signs, ECOG, physical 
exam, and ECG data analyses will be summarized based on the safety analysis set. 
8.2.4.1. Adverse Events 
Overall Summary of AEs 
An AE will be regarded as treatment-emergent, if
x
it occurs for the first time on or after the first dose date of either napabucasin or 
nab-Paclitaxel or gemcitabine up to 30 days after the last dose of study treatment 
(or up to any time if serious and considered related to study treatment); or
x
it occurs prior to first dose date of either napabucasin or nab-Paclitaxel or 
gemcitabine and worsens in severity on therapy or up to 30 days after the last dose 
of study treatment  (or up to any time if serious and considered related to study 
treatment)


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Adverse events will be coded by SOC and PT using the MedDRA®v19.0. The severity of 
AEs will be graded by the investigator using NCI CTCAE Version 4.0. The verbatim term 
will be included in the AE listings. A Fisher’s exact test may be used to compare adverse 
events between the two arms.
An overview of treatment-emergent adverse events (TEAEs) will be provided.  The number 
and percentage of patients with following will be summarized for: 
x
Patients with at least one TEAE 
x
Patients with TEAE of CTCAE grade 3 or higher
x
Patients with serious TEAE
x
Patients with serious TEAE related to napabucasin
x
Patients with serious TEAE related to nab-paclitaxel
x
Patients with serious TEAE related to gemcitabine
x
Patients with napabucasin related TEAE
x
Patients with napabucasin related TEAE of CTCAE grade 3 or higher
x
Patients with Nab-Paclitaxel related TEAE
x
Patients with Nab-Paclitaxel related TEAE of CTCAE grade 3 or higher
x
Patients with gemcitabine related TEAE
x
Patients with gemcitabine related TEAE of CTCAE grade 3 or higher
x
Patients with TEAE related to study drug (napabucasin or nab-paclitaxel or 
gemcitabine)
x
Patients with study drug (napabucasin or nab-paclitaxel or gemcitabine) related 
TEAE of CTCAE grade 3 or higher
x
Patients with TEAEs leading to death
x
Patients with TEAEs leading to napabucasin dose modification
x
Patients with TEAEs leading to napabucasin dose delay
x
Patients with TEAEs leading to napabucasin discontinuation 
x
Patients with TEAEs leading to dose reduction of napabucasin 
x
Patients with TEAEs leading to nab-paclitaxel dose modification
x
Patients with TEAEs leading to nab-paclitaxel dose delay
x
Patients with TEAEs leading to nab-paclitaxel discontinuation 
x
Patients with TEAEs leading to dose reduction of nab-paclitaxel
x
Patients with TEAEs leading to gemcitabine dose modification
x
Patients with TEAEs leading to gemcitabine dose delay
x
Patients with TEAEs leading to gemcitabine discontinuation
x
Patients with TEAEs leading to dose reduction of gemcitabine
Summary of TEAEs by System Organ Class and Preferred Term 
The number and percentage of patients who experience any TEAE and TEAEs of grade 3 
or higher (Grade 3, 4, 5) will be summarized by SOC and PT. A summary of TEAEs by 
PT will be presented in the descending order of frequency counts for all grades and grade 
3 or higher. A summary of AEs by PT and maximum CTCAE grade will be presented.The 


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most commonly reported AEs using different cutoffs (e.g., 2%, 5% or 10% or more of 
patients in either arm) may also be summarized by PT as needed for various reporting 
purposes. Adverse events associated with permanent discontinuation/dose reduction/dose 
interruption of either napabucasin and/or nab-paclitaxel and/or gemcitabine will also be 
summarized by SOC and PT and maximum CTCAE grade.
Treatment Related TEAE
AEs reported with a relationship to a treatment considered by the investigator to be 
‘possible’, ‘probable’ or ‘definite’ will be considered “Related” to study treatment or
paclitaxel or gemcitabine, respectively. AEs reported with a relationship to a treatment 
considered by the investigator to be “unlikely” or “unrelated” will be considered as “Not 
Related” to study treatment or nab-paclitaxel or gemcitabine, respectively. Missing 
relationship will be considered as “Related”.  Similar summaries of all causality AEs will 
be provided. TEAEs related to study drug, leading to dose modification, dose reduction, 
and dose discontinuation will be summarized by SOC and PT.
Serious TEAE and Death
Treatment emergent SAEs and treatment related TESAEs will be summarized by MedDRA 
SOC and PT and Maximum CTCAE grade. 
Patients who experienced a TESAE during AE reporting period will be listed for all safety 
patients.  The number and percentage of patients who experience any treatment emergent 
SAE will be summarized by SOC, PT and maximum CTCAE grade. Similar summary for 
treatment related TESAEs will be provided as well. 
Deaths that occur on or after the first dose of study treatment and within 30 days of last 
dose of any study treatment will be summarized. The number and percentage of patients
who died during the study treatment and within 30 days after the last dose will be presented.
TEAEs leading to death will be summarized by MedDRA SOC and PT. 
A listing of death data will also be provided and it will include all deaths that occurred 
during the reporting period for deaths which starts from the signing of informed consent to 
the end of the follow up period.  The listing will include date of death, and the number of 
days relative to the administration of first and last dose. 
Clustered Treatment Emergent Adverse Events
Selected treatment emergent adverse events were pre-specified for additional focus due to 
the potential clinical significance of the event and/or the potential association with the 
investigational product.  These events include those in the standard MedDRA (narrow or 
broad, as noted) query terms of:  non-infectious diarrhea (narrow SMQ), gastrointestinal 
nonspecific inflammation (narrow SMQ), gastrointestinal haemorrhage (narrow SMQ), 
gastrointestinal perforation (narrow SMQ), gastrointestinal obstruction (narrow SMQ),  
acute renal failure (narrow SMQ), haematopoietic leukopenia (broad SMQ), 


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hematopoietic erythropenia (broad SMQ), and hematopoietic thrombocytopenia (broad 
SMQ).  Other events include the following sponsor derived terms: Abdominal pain, 
fatigue, hypotension, and torsade de Pointes. Tables listing the incidence, maximum 
severity, relation to study drug, dose modification of study drug, and death due to these 
events in the safety analysis set will be generated.
8.2.4.2. Laboratory Data 
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  If a lab value is reported using a non-numeric qualifier 
(eg, less than (<) a certain value, or greater than (>) a certain value), the given numeric 
value will be used in the summary statistics, ignoring the non-numeric qualifier. 
Laboratory test results will be summarized according to the scheduled sample collection 
time point.  Change from baseline will also be presented.  Unscheduled laboratory test 
results will be listed and included in laboratory shift tables.  The parameters to be analyzed 
are as follows:
x
Hematology:  hemoglobin, hematocrit, ANC, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, platelets, and white blood cell (WBC) count
x
Biochemistry:  blood urea nitrogen, creatinine, total bilirubin, LDH, albumin, 
alkaline phosphatase, AST, ALT, sodium, potassium, magnesium, phosphoros.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI 
CTCAE for toxicity (version 4.0) from baseline to post baseline worst CTC grade.  
Parameters to be tabulated will include:
x
Hematology: ANC, hemoglobin, platelets, WBC
x
Biochemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, 
magnesium, potassium, sodium, and phosphoros.
Listing will also be presented for urinalysis values.
x
Urinalysis: specific gravity, protein, occult blood, glucose
Maximum change versus baseline figures and E-DISH scatter plots for key lab parameters 
will be produced, including but not limited to liver function tests (ALT, AST, ALP and 
total bilirubin).
A listing of all lab parameters including hematology, biochemistry, urinalysis will be 
provided, including the test result, units, normal range (H and L) and change from baseline, 
and CTCAE grades if grading applies.  Patients who developed toxicities of grade >= 3 
will also be listed.  


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8.2.4.3. Electrocardiograms 
12-lead ECG with categorical results (Normal, Abnormal [Not clinically significant], 
Abnormal [clinically significant]) will be summarized by treatment and visit. The shift 
from baseline to worst post baseline will be produced. A patient listing will also be 
provided.
8.2.4.4. Vital Signs 
Vital sign data (heart rate, systolic and diastolic blood pressure, and temperature etc.)
change from baseline will be summarized by treatment group and visit. Maximum change 
from baseline will also be summarized by treatment group.
Summaries of markedly abnormal vital signs parameters, including blood pressure (BP), 
pulse, and BMI will be presented by treatment group. Values for vital signs for all 
patients will be presented in a listing, and patients with markedly abnormal values will be 
flagged. 
Markedly abnormal ranges for vital signs parameters are given in the table below.
Vital Sign Parameter
Markedly Abnormal (Low)
Markedly Abnormal 
(High)
Systolic BP
Absolute value ≤ 90 
mmHg, or a decrease from 
baseline ≥ 20 mmHg
Absolute value ≥ 150 
mmHg, or an increase from 
baseline ≥ 20 mmHg
Diastolic BP
Absolute value ≤ 50 
mmHg, or a decrease from 
baseline ≥ 15 mmHg
Absolute value ≥ 90 
mmHg, or an increase from 
baseline ≥ 15 mmHg
Pulse
Absolute value ≤ 50 bpm, 
or a decrease from baseline 
≥ 15 bpm
Absolute value ≥ 120 bpm, 
or an increase from 
baseline ≥ 15 bpm
BMI
Absolute value ≤ 18 kg/m2
Absolute value ≥ 40 kg/m2
8.2.4.5. Physical Exam 
Physical examination abnormalities will be summarized for each visit by body system 
and by treatment group.  Patients with clinically significant abnormal findings will be 
flagged in the data listing.
8.2.4.6. ECOG  
ECOG performance status will be summarized in a shift table from baseline to worst post 
baseline for Safety analysis set.


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9. REFERENCES  
1.
Protocol Canstem 111P A Phase III Study of napabucasin plus nab-
Paclitaxel with Gemcitabine in Adult Patients with Metastatic 
Pancreatic Adenocarcinoma, December 4th, 2018
2.
Blyth C.R., Still H.A. [1983]. Binomial Confidence Intervals Journal of 
the American Statistical Association 78, 381.
3.
Brookmeyer R, Crowley JJ [1982]. A confidence interval for the median 
survival time. Biometrics. 38:29-41.
4.
Maurer, W., Bretz, F. (2013). Multiple testing in group sequential trials 
using graphical approaches. Statistics in Biopharmaceutical Research, 
5, 311-320.
5.
Miettinen O., Nurminen M. (1985) Comparative Analysis of Two 
Rates. Statistics in Medicine, 4, 213-226.
6.
Williams D.A. [1972]. The Comparison of Several Dose Levels With a 
Zero Dose Control Biometrics 28, 519-531.


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10. APPENDICES  
10.1. Appendix 1.1 DATA DERIVATION DETAILS 
Table 2 Response Criteria 
Evaluation of target lesions
Complete Response (CR):
Disappearance of all target lesions
Any pathological lymph nodes must have reduction in short axis of 
<10mm
Partial Response (PR):
At least a 30% decrease in the sum of the LD of target lesions, taking 
as reference the baseline sum LD
Progressive Disease (PD):
At least a 20% increase in the sum of the LD of target lesions, taking 
as reference the smallest sum LD recorded since the treatment 
started.  In addition to the increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5mm.   The appearance 
of one or more new lesions is also considered progression
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum LD since the 
treatment started
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size 
(<10mm short axis)
Non-CR/Non-PD
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above normal limits
Progressive Disease (PD):
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions
The best overall response (BOR) is the best response recorded from the randomization date 
until disease progression/recurrence or start of new anti-cancer therapy and is determined as 
indicated in Table 3. BOR is derived from the sequence of overall response. Assessment done 
after PD or after “new anti-cancer” treatment but prior to PD will not be considered evaluation 
of best overall response. Tumor assessments will be performed every 8 weeks. BOR derivation
(based on unconfirmed response) is derived from the sequence of overall response determined 
by the following order:
x
CR:  One objective status of CR documented before progression or start of new anti-
cancer therapy. 
x
PR:  One objective status of PR documented before progression or start of new anti-
cancer therapy, but not qualifying as CR.
x
SD:  At least 1 objective status of SD or better documented within at least 1 nominal 
scan interval (8 weeks – 5 days window = 51 days) after start date and before
progression and the start of new anti-cancer therapy, but not qualifying as CR or PR.
x
PD:  Progression documented within 2 nominal scan intervals (or 16 weeks + 5 days 
window = 117) after start date and not qualifying as unconfirmed CR, unconfirmed 
PR, or SD.  


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x
NE:  All other cases.  Note that reasons for NE should be summarized and the following 
reasons could be used: 
•
Early death (Note: death prior to 8 weeks after start date)
•
No post-baseline assessments 
•
All post-baseline assessments have overall response NE
•
New anti-cancer therapy started before first post-baseline assessment
•
SD too early (<8 weeks after randomization date)
•
PD too late (>16 weeks after randomization date)
Special and rare cases where BOR is NE due to both early SD and late PD will be classified as 
‘SD too early’.
Table 3 Overall Response 
Target 
lesions
Non-Target lesions
Evaluation 
of 
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
not all evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not 
All 
Evaluated 
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Disease Control Rate (DCR) is the proportion of patients with a documented CR, PR, or SD 
based on RECIST 1.1 as determined by the investigator assessment collected in the CRFs, 
relative to the RAS.


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Objective response rate (ORR) is defined as the proportion of patients with a documented 
complete response (CR) or partial response (PR) based on RECIST 1.1 as determined by the 
investigator assessment collected in the CRFs, relative to the RAS.
The patients will be considered as non-responder until proven otherwise.  Thus, the following 
patients are considered non-responders:
x
Do not have CR or PR while on study; or 
x
Do not have a baseline or post-baseline tumor evaluation; or 
x
Do not have an adequate baseline tumor evaluation; or 
x
Receive anti-tumor treatment other than the study medication prior to reaching a CR or 
PR; or 
x
Die, progress, or drop out for any reason prior to reaching a CR or PR. 
Progression free survival (PFS) is defined as the time from the date of randomization to the 
date of PD, or death due to any cause, whichever comes first. If neither event has been 
observed, then the patient will be considered as censored.  PFS (in months) will be calculated 
as (first event date – date of randomization + 1) / 30.4375.  Sensitivity analyses for PFS may 
be conducted if deemed necessary.
Overall survival (OS) is defined as the time from the date of randomization to the date of death 
from any cause. Patients who are still alive at the time of the final observation, or who have 
become lost to follow-up will be censored at their last date of contact. OS in month is calculated 
as (date of death – date of randomization +1) / 30.4375. Sensitivity analyses for OS may be 
conducted if deemed necessary.
10.2. Appendix 1.2 Censoring for Time to Event Data  
Table 4 summarizes the censoring rules for the PFS primary analysis. Table 5 shows the 
general reasons for PFS censoring for primary analysis and where the primary analysis 
censoring hierarchy in Table 4 comes from.
Table 4 Event or Censor Time and Censoring Hierarchy for Primary Analysis on PFS 
Censoring 
Hierarchy
Situation
Date of Event or 
Censor
Primary Analysis
1
No baseline radiological tumor 
assessment available
Date 
of 
randomization
Censored


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2
New anticancer treatment started 
before tumor progression or death
Date 
of 
previous 
adequate radiological 
assessment 
immediately prior to 
start
of new therapy or 
Date 
of 
randomization, 
whichever 
comes 
later
Censored
3
Tumor progression (per RECIST 
1.1) documented or death after 2 scan 
intervals 
following 
previous 
adequate 
radiological 
tumor 
assessment, 
no 
new 
anticancer 
treatment started
Date 
of 
previous 
adequate radiological 
assessment or Date of 
randomization, 
whichever 
comes 
later
Censored
4, 5
No tumor progression (per RECIST 
1.1), no death reported and subject 
lost to follow-up or withdrawal of 
consent, no new anticancer treatment 
started
Date of last adequate 
radiological 
Assessment or Date 
of 
randomization, 
whichever 
comes 
later
Censored
6
No tumor progression (per RECIST 
1.1) and no death reported within 2 
scan
intervals following last adequate 
radiological tumor assessment or 
randomization (if no post baseline 
tumor assessment available), no new 
anticancer treatment started
Date of last adequate 
radiological 
tumor 
assessment or Date of 
randomization, 
whichever 
comes 
later
Censored
7
No tumor progression (per RECIST 
1.1) and no death reported and none 
of the conditions in the prior 
hierarchy are met
Date of last adequate 
radiological 
tumor 
assessment or Date of 
randomization, 
whichever 
comes 
later
Censored


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No tumor progression (per RECIST 
1.1) but death reported within 2 scan 
intervals following last adequate
radiological
tumor assessment or randomization 
(if no post baseline tumor assessment 
available)
Date of death
Event
Tumor progression (per RECIST 
1.1) documented within 2 scan 
intervals 
following 
previous 
adequate 
radiological 
tumor 
assessment
Earliest of the target, 
non-target and new 
tumor 
assessment 
dates
Event
 
Notes: (1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not 
radiographically confirmed) will not be considered as progressions.
(2) If target, non-target and new lesion assessments have different dates within a visit, then the 
earliest of those dates will be considered as the date of the tumor assessment if the assessment 
for that visit is progressive disease (PD); otherwise the latest date will be used.
(3) Adequate radiographical tumor assessment refers to an assessment with overall response 
of CR, PR, SD or PD.
(4) Comparing date of last tumor assessment to date of randomization is necessary if the last 
tumor assessment is baseline assessment
 Table 5 PFS Censoring Reasons  
Hierarchy
Condition
Censoring Reason for 
Primary PFS Analysis 
Censoring Reason for 
Sensitivity 
PFS
Analysis
1
No adequate baseline assessment
No 
adequate 
baseline 
assessment
No 
adequate 
baseline
assessment
2
Start of new anti-cancer therapy 
before event. 
Start 
of 
new 
anti-cancer 
therapy
Event
3
Event more than 16 weeks from 
last adequate post-baseline tumor 
assessment/start date
Event 
after 
missing 
assessments a
Event 
4
No event and subject withdraws 
consent 
Withdrawal of consent
Withdrawal of consent


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5
No event and lost to follow-up in 
any disposition page 
Lost to follow-up
Lost to follow-up
6
No event and no adequate post-
baseline tumor assessment 
No 
adequate 
post-baseline 
tumor assessment
No adequate post-baseline
tumor assessment
7
No event and none of the 
conditions in the prior hierarchy 
are met 
Ongoing without an event
Ongoing without an event
a more than 16 weeks after last adequate tumor assessment
For OS, patients last known to be alive are censored at date of last contact.
Date of Last Contact 
The date of last contact will be derived for patients not known to have died at the analysis data 
cutoff date using the latest complete date (non-imputed) among the following:
x
All patient assessment dates (e.g., blood draws [laboratory, PK], vital signs, 
performance status, ECG, tumor assessments, concomitant radiation, surgery)  
x
Start and end dates of follow-up anti-cancer therapies 
x
AE start and end dates
x
Last date of contact where “Subject Remains in Follow-up” collected on the “Survival 
Follow-up” eCRF (do not use date of survival follow-up assessment unless status is 
alive)
x
Study drug start and end dates
x
Randomization date
x
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
Note: 
1.
This list is not all inclusive and should be agreed upon by the 
study team according to the data collected in the CRF
2.
Only dates associated with patient visits or actual examinations 
of the patient should be used. Dates associated with a technical 
operation unrelated to patient status (e.g., the date a blood 
sample was processed) should not be used. 
3.
Assessment dates after the cutoff date will not be applied to 
derive the last contact date.


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10.3. Appendix 1.3 Summary of Key Efficacy Analysis 
Endpoint 
(Section)
Analysis 
Set
Statistical Method
Missing Data
Interpretation
OS (8.2.2)
ITT
Stratified log-rank test 
(1-sided, all S factors);
KM method (median, 
95% CI).
HR and 95% CI from 
Stratified Cox PH Model
Censor patients who 
didn’t die or who 
lack 
any 
data 
beyond 
randomization
Primary 
Analysis for 
primary 
endpoint
6 months/1 
year/18 
months 
survival
ITT
KM method (95% CI)
OS (8.2.2)
ITT
Stratified log-rank test
(1-sided, all S factors on 
actual 
stratification
factor); 
KM 
Method 
(median, 95% CI). 
HR and 95% CI from 
Stratified Cox PH Model
Sensitivity 
analysis of 
primary 
endpoint
OS (8.2.2)
ITT
Un-stratified log rank test 
(1-sided). HR and 95% 
CI from un-stratified Cox 
PH model
Sensitivity 
analysis of 
primary 
endpoint
OS (8.2.2)
ITT
Multi-variate Cox PH 
Model stratified by S 
factors 
and 
including 
other baseline covariates
(HR and 95% CI)
Sensitivity 
Analysis of 
primary 
endpoint


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OS (8.2.2)
ITT
Cox 
PH 
Model 
containing 
treatment 
group and one given 
factor (HR and 95% CI)
Sensitivity 
Analysis of 
primary 
endpoint
OS (8.2.2)
Subgroup For each baseline factor, 
KM Method (median, 
95% CI).
Unstratified log-rank test 
(2-sided)
HR and 95% CI from un-
stratified Cox PH Model
Sensitivity 
Analysis of 
primary 
endpoint
PFS(8.2.3)
ITT
Stratified log-rank test 
(1-sided, all S factor); 
KM Method (median,
95% CI). 
HR and 95% CI from 
Stratified Cox PH Model
Censoring patients 
following Table 4 
criteria in Appendix 
1.2
Primary analysis 
for secondary 
endpoint.  
6 
months/1 
year/18 
months 
progression 
free survival
ITT
KM method (95% CI)
PFS (8.2.3)
ITT
Un-stratified log rank test 
(1-sided). HR and 95% 
CI from un-stratified Cox 
PH model
Sensitivity 
analysis of 
secondary 
endpoint


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PFS (8.2.3)
Subgroup For each baseline factor, 
KM Method (median, 
95% CI).
Unstratified log-rank test 
(2-sided)
HR and 95% CI from un-
stratified Cox PH Model
Sensitivity 
Analysis of 
secondary 
endpoint
DCR (8.2.3)
RAS
Stratified CMH (1-sided,
Stratified by S factors)
TrtDiff and 95% CI from 
M&N method adjusting 
S factors.
Exact 
CI 
based 
on 
Clopper-Pearson 
method.  
Patients without on-
study 
tumor 
assessment or who
die, progress or drop 
out for any reason, 
or 
receive 
anti-
tumor 
treatment 
prior to reaching a 
CR or PR as non-
responders.
Primary analysis 
for secondary 
endpoint.  
DCR (8.2.3)
RAS
Z test (1-sided). TrtDiff 
and 95% CI from normal 
approximation 
method.
Exact 
CI 
based 
on 
Clopper-Pearson method
Sensitivity 
analysis of 
secondary 
endpoint
DCR (8.2.3) Subgroup
Z test (2-sided)
TrtDiff and 95% CI from 
normal 
approximation 
method. 
Exact 
CI 
based 
on 
Clopper-Pearson 
method.  
Sensitivity 
Analysis of 
secondary 
endpoint


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ORR(8.2.3) RAS
Stratified CMH (1-sided,
Stratified by S factors)
TrtDiff and 95% CI from 
M&N method adjusting 
S factors.
Exact 
CI 
based 
on 
Clopper-Pearson 
method.  
Patients without on-
study 
tumor 
assessment or who 
die, progress or drop 
out for any reason, 
or 
receive 
anti-
tumor 
treatment 
prior to reaching a 
CR or PR as non-
responders.  
Primary analysis 
for secondary 
endpoint.  
ORR(8.2.3)
RAS
Z test (1-sided). TrtDiff 
and 95% CI from normal 
approximation 
method.
Exact 
CI 
based 
on 
Clopper-Pearson method
Sensitivity 
analysis of 
secondary 
endpoint
ORR (8.2.3) Subgroup
Z test (2-sided)
TrtDiff and 95% CI from 
normal 
approximation 
method. 
Exact 
CI 
based 
on 
Clopper-Pearson 
method.  
Sensitivity 
Analysis of 
secondary 
endpoint
ITT: Intent-to-Treat Analysis Set; RAS: Response Analysis Set


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10.4. Appendix 1.4 Response and Evaluation Endpoints 
Response and progression will be evaluated in this study using the revised international 
criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumors) 
committee.
1.1.1
Measurable Disease 
Measurable tumor lesions are defined as those that can be accurately measured in at 
least one dimension (longest diameter to be recorded) as > 20 mm with chest x-ray 
and as > 10 mm with CT scan, or clinical examination. Bone lesions are considered 
measurable only if assessed by CT scan and have an identifiable soft tissue 
component that meets these requirements (soft tissue component > 10 mm by CT 
scan). Malignant lymph nodes must be > 15mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Previously irradiated lesions are not considered measurable unless progression has 
been documented in the lesion.
1.1.2
Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions are considered non-
measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or 
skin and abdominal masses followed by clinical examination are all non-measurable. 
Lesions in previously irradiated areas are non-measurable, unless progression has 
been demonstrated.
1.1.3
Target Lesions 
When more than one measurable tumor lesion is present at baseline all lesions up to a
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of 
all involved organs should be identified as target lesions and will be recorded and 
measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated
measurements. Note that pathological nodes must meet the criterion of a short axis of 
> 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. All other pathological nodes (those with short axis > 10 mm but < 15 
mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm 
are considered non-pathological and should not be recorded or followed (see 10.2.4). 
At baseline, the sum of the target lesions (longest diameter of tumor lesions plus short 
axis of lymph nodes: overall maximum of 5) is to be recorded.


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After baseline, a value should be provided on the CRF for all identified target lesions 
for each assessment, even if very small. If extremely small and faint lesions cannot be 
accurately measured but are deemed to be present, a default value of 5 mm may be 
used. If lesions are too small to measure and indeed are believed to be absent, a 
default value of 0 mm may be used.
1.1.4
Non-Target Lesions 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and 
above those listed as target lesions are considered non-target lesions. Measurements 
are not required but these lesions should be noted at baseline and should be followed 
as “present” or “absent”.
1.1.5
Response 
All patients will have their BEST RESPONSE from the start of study treatment until 
the end of treatment classified as outlined below:
Complete Response (CR): disappearance of target and non-target. Pathological 
lymph nodes must have short axis measures < 10 mm (Note: continue to record the 
measurement even if < 10 mm and considered CR). Residual lesions (other than 
nodes < 10 mm) thought to be non-malignant should be further investigated (by 
cytology specialized imaging or other techniques as appropriate for individual cases 
(Eisenhauer, 2009)) before CR can be accepted. 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest 
diameter for tumor lesions and short axis measure for nodes) of target lesions, taking 
as reference the baseline sum of diameters. Non-target lesions must be non-PD. 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient 
increase to qualify for PD taking as reference the smallest sum of diameters on study.
Progressive Disease (PD): at least a 20% increase in the sum of diameters of 
measured lesions taking as references the smallest sum of diameters recorded on 
study (including baseline) AND an absolute increase of > 5mm. Appearance of new 
lesions will also constitute progressive disease (including lesions in previously 
unassessed areas). For patients with on-study tumor assessments with questionable 
findings of new lesions, such as cases where it is possible that the lesions were 
present at baseline imaging albeit less visible, the patient may continue treatment (if 
patient is clinically doing well) for an additional 4-8 weeks, until the next scan which 
will either confirm presence of a new lesion finding or exclude it. In exceptional 
circumstances, unequivocal progression of non-target disease may be accepted as 
evidence of disease progression, where the overall tumor burden has increased 
sufficiently to merit discontinuation of treatment or where the tumor burden appears 
to have increased by at least 73% in volume. Modest increases in the size of one or 
more non-target lesions are NOT considered unequivocal progression. If the evidence 


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of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but if confirmed, the earlier date must be used. 
Table 2: Integration of Target, non-Target and New Lesions into Response 
Assessment
Target Lesions
Non-Target Lesions
New 
Lesions
Overall Response
Best Response for this 
Category also Requires
Target Lesions ± Non Target Lesions
CR
CR
No
CR
Tumor nodes < 10mm
CR
Non-CR/Non-PD
No
PR
CR
Not all evaluated
No
PR
PR
Non-PD/ not all 
evaluated
No
PR
SD
Non-PD/ not all 
evaluated
No
SD
Documentation at least once > 6
wks. from baseline
Not all evaluated
Non-PD
No
NE
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
Non-Target Lesions ONLY
N/A
CR
No
CR
Tumor nodes < 10mm
N/A
Non-CR/non-PD
No
Non-CR/non-PD
N/A
Not all evaluated
No
NE
N/A
Unequivocal PD
Any
PD
N/A
Any
Yes
PD
Note:
Patients with a global deterioration of health status requiring discontinuation of treatment without radiological 
progression having been observed at that time should be reported as “symptomatic deterioration”. This is NOT 
objective PD. Every effort should be made to document the objective progression even after discontinuation of 
treatment.
1.2
Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent or 
progressive disease is objectively documented, taking as reference the smallest 
measurements recorded on study (including baseline).
1.3
Stable Disease Duration 
Stable disease duration will be measured from the time of randomization until the 
criteria for progression are met, taking as reference the smallest sum on study 
(including baseline).
1.4
Methods of Measurement 


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The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.
Assessments should be identified on a calendar schedule and should not be affected 
by delays in therapy. While on study, all lesions recorded at baseline should have 
their actual measurements recorded at each subsequent evaluation, even when very 
small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned. For lesions which fragment/split add together the longest 
diameters of the fragmented portions; for lesions which coalesce, measure the 
maximal longest diameter for the “merged lesion”.
Additionally, for optimal tumor assessment scanning options are listed below in the 
decreasing order of preference:
Order of 
Preference
Scanning Option
1
Chest-Abdomen-Pelvis CT with oral and I.V. contrast
2
Chest CT without I.V. contrast PLUS MRI Abdomen-Pelvis 
with oral and I.V. contrast1
3
Chest-Abdomen-Pelvis CT with oral contrast2
1
If Iodine contrast media is medically contraindicated.
2
If Iodine contrast media is medically contraindicated and MRI cannot be 
performed.
1.4.1
Clinical Lesions  
Clinical lesions will only be considered measurable when they are superficial and >
10 mm as assessed using callipers (e.g. skin nodules). For the case of skin lesions, 
documentation by colour photography including a ruler to estimate the size of the 
lesion is recommended. If feasible, imaging is preferred.
1.4.2
Chest X-ray 
Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions > 20 mm on chest X-ray may be considered measurable if 
they are clearly defined and surrounded by aerated lung. 
1.4.3
CT/MRI 
CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions 
on CT scan based on the assumption that CT slice thickness is 5 mm or less. When 
CT scans have slice thickness greater than 5 mm, the minimum size for a measurable 


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lesion should be twice the slice thickness. MRI is also acceptable in certain situations 
(e.g. for body scans). Other specialized imaging or other techniques may also be 
appropriate for individual case (Eisenhauer, 2009). For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing 
that the measures are obtained from the CT scan and the CT scan is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast).
1.4.4
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT is advised.
1.4.5
Endoscopy/Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. 
However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following 
complete response or surgical resection is an endpoint. 
1.4.6
Histology 
These techniques can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumor types such as germ cell tumors, where known 
residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.