Conditions: Gastric Cancer Gastroesophageal Junction Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 714
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out whether it is better to receive a new drug, BBI608, in addition to paclitaxel chemotherapy or better to receive paclitaxel chemotherapy alone as second line treatment for gastric and gastroesophageal junction cancer after prior first line platinum and fluoropyrimidine based chemotherapy.

Detailed description:
The goal of this study is to determine if paclitaxel given together with BBI608 as second line therapy will prolong overall survival compared to paclitaxel alone.

Approximately 700 patients will be randomized with histologically or cytologically confirmed metastatic gastric or gastroesophageal junction adenocarcinoma.

Patients must have failed first line therapy with any platinum/fluoropyrimidine doublet.

BBI608/placebo will be administered daily, paclitaxel will be administered i.v. on days 1, 8 and 15 of a 4 weekly cycle.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BBI608 intervention 2: Paclitaxel intervention 3: Placebo
Intervention descriptions: intervention 1: BBI608 480 mg orally two times daily (960 mg total daily dose) intervention 2: Paclitaxel 80 mg/m2 I.V. infusion on Days 1, 8, and 15 of every 4-week cycle intervention 3: Orally two times daily

Protocol document:
Prot_000.pdf: 
BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL 
CONFIDENTIAL
TITLE:
A Phase III Randomized, Double-Blind, Placebo-
Controlled Clinical Trial of BBI608 plus Weekly 
Paclitaxel vs. Placebo plus Weekly Paclitaxel in Adult 
Patients with Advanced, Previously Treated Gastric and 
Gastro-Esophageal Junction Adenocarcinoma 
PROTOCOL NUMBER:
BBI608-336 
FDA IND Number
100,887
EudraCT Number
2014-000774-18 
STUDY DRUG:
BBI608 
SPONSOR:
Boston Biomedical, Inc.
640 Memorial Drive 
Cambridge, MA 02139 
Telephone: (617) 674-6800 
Fax:  (617) 674-8662 
DATE OF PROTOCOL:
March 28th, 2014 
DATE OF AMENDMENT:
July 14th, 2017 
AMENDMENT: 
8
This clinical study protocol is subject to critical review and has been approved by the Sponsor. The 
following personnel have approved this protocol: 
Signed: ____________________ Date: _____________________  
Laura Borodyansky, MD  
Vice President of Clinical Development & Pharmacovigilance
Boston Biomedical, Inc.
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of Boston Biomedical, 
Inc.  Any unauthorized use or disclosure of such information without the prior written authorization of Boston 
Biomedical, Inc. is prohibited.
Boston Biomedical, Inc.
640 Memorial Drive 
Cambridge, MA 02139 
Telephone: (617) 674-6800 
p
(
)
Fax:  (617) 674-8662 
____________________
Laura Borodyansky, MD  
y
y,
Vice President of Clinical Development & Pharmacovigilance
Boston Biomedical, Inc.


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL 
CONFIDENTIAL
DOCUMENT REVISION HISTORY
Document
Version Date
Original protocol
28 March 2014
Amendment 1
15 May 2014 (Global)
Amendment 2
16 June 2014 (Global)
Amendment 3
30 June 2014 (Local - USA)
Amendment 4
05 August 2014 (Global)
Amendment 4.1
28 October 2014 (Local – United Kingdom)
Amendment 4.2
28 October 2014 (Local – Germany)
Amendment 4.3
05 December 2014 (Local – France)
Amendment 5
09 February 2015 (Global)
Amendment 5
09 February 2015 (Local – Spain)
Amendment 5.1
03 March 2015 (Local – Brazil)
Amendment 5.2
11 March 2015 (Local – Belgium)
Amendment 5.3
11 March 2015 (Local – Italy)
Amendment 6
01 May 2015 (Global)
Amendment 7
24 March 2016 (Global)
Amendment 8
14 July 2017 (Global)


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL 
CONFIDENTIAL
STUDY SYNOPSIS
Study Title:
A Phase III Randomized, Double-Blind, Placebo-Controlled Clinical 
Trial of BBI608 plus Weekly Paclitaxel vs. Placebo plus Weekly 
Paclitaxel in Adult Patients with Advanced, Previously Treated 
Gastric and Gastro-Esophageal Junction Adenocarcinoma
Study Number:
BBI608-336 
Study Phase: 
III
Study Drug:
BBI608 is a novel investigational orally administered small molecule 
anticancer drug that targets cancer stem cells (CSC). CSC are considered 
to be fundamentally responsible for malignant growth, relapse, 
metastasis, and resistance to conventional therapies. BBI608 blocks 
CSC self-renewal and induces cell death in CSC as well as non-stem 
cancer cells by inhibition of the STAT3, ȕ-catenin and Nanog pathways. 
BBI608 has shown potent anti-tumor and anti-metastatic activities in 
pre-clinical gastric cancer models, and has shown highly synergistic 
effect in combination with paclitaxel.
In a Phase Ib/II clinical trial, BBI608 in combination with weekly 
paclitaxel has been safely administered to more than 80 patients, with 
the Recommended Phase 2 Dose of BBI608 determined to be the full 
monotherapy dose. Adverse event (AE) profiles were similar to that of 
both agents in monotherapy, with no new or additive effects seen. 
BBI608 related AEs were generally gastrointestinal in nature, and most 
frequently CTCAE Grade 1 or Grade 2. Encouraging signs of activity 
were observed in patients with gastric/GEJ adenocarcinoma, with 
disease control in 6 of 7 patients, objective response in 3 of 7 patients 
(partial responses of 44%, 48%, and 100% respectively), and a median 
progression free survival of 23 weeks. Survival data is maturing.
Primary 
Objective:
To compare overall survival (OS) of patients with pre-treated, advanced 
gastric and gastro-esophageal junction (GEJ) adenocarcinoma treated 
with BBI608 plus weekly paclitaxel versus placebo plus weekly 
paclitaxel.  OS is defined as the time from randomization until death 
from any cause.  
Secondary 
Objective: 
To evaluate the safety profile of BBI608 administered daily plus weekly 
paclitaxel 
in 
patients 
with 
pre-treated 
advanced 
gastric/GEJ 
adenocarcinoma, with safety assessed according to the National Cancer 
Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE)
version 4.0. 
Study Design:
This is a study which began as a randomized, double-blind, multi-center, 
phase III study of BBI608 plus weekly paclitaxel vs. placebo plus 
weekly paclitaxel for adult patients with advanced, pre-treated gastric or 
GEJ adenocarcinoma who have failed first line therapy containing a 
fluoropyrimidine and a platinum-based agent. At the time of this 
amendment, patients remaining on study treatment will be unblinded 
and the study will continue as a randomized, open-label, multi-center, 
phase III study of BBI608 plus weekly paclitaxel vs. weekly paclitaxel 


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL 
CONFIDENTIAL
for adult patients with advanced, pre-treated gastric or GEJ 
adenocarcinoma.  
700 patients will be randomized in a 1:1 ratio, stratified according to 
geographical region (Asia vs. North America, Australia and Europe vs. 
South America); time to progression on first line therapy (<6 months vs. 
 PRQWKV disease measurability (measurable disease present vs not 
present); and prior taxane therapy (yes vs. no). 
Until the time of this amendment, the study proceeded in 28-day (4-
week) cycles.  BBI608 or placebo was administered orally, twice daily, 
with doses separated by 12 hours.  Paclitaxel 80 mg/m2 IV was
administered weekly, on day 1, 8, and 15 of each 28 day study cycle. 
BBI608 or placebo administration began 2 days prior to the first 
paclitaxel infusion. From the time of this amendment, and since 
unblinding of patients remaining on study treatment, patients will 
continue study treatment as prior to unblinding as long as it is felt to be 
in their best interest by the Investigator and with patient’s informed 
consent. Placebo will no longer be administered. 
Tumor assessments will be performed every 8 weeks after 
randomization until objective disease progression.   
Study Population: 
This study will enroll patients with a cytological or histologically 
confirmed adenocarcinoma of the stomach or gastro-esophageal junction 
(GEJ) that is metastatic or locally advanced and unresectable. Patients 
will have failed treatment with one regimen containing at least a 
platinum/fluoropyrimidine doublet for unresectable or metastatic 
disease.  
Patients who have received prior taxane therapy may be enrolled, so
long as the taxane was administered in the adjuvant or neoadjuvant 
setting and progression occurred more than 6 months following 
completion of therapy.   
2WKHU LQFOXVLRQ FULWHULD IRU DOO SDWLHQWV LQFOXGH DJH   \UV (&2*
SHUIRUPDQFHVWDWXVDQGDdequate hepatic, renal, and bone-marrow 
function.   
Test Product, 
Dose, and Mode of 
Administration: 
Until the time of this amendment, patients in this study received BBI608 
or matched placebo orally, daily, at 480 mg bid (960 mg total daily 
dose). In each cycle BBI608 was taken daily for 4 weeks (28 days). 
BBI608 or placebo 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 received BBI608 or placebo in combination with paclitaxel, 80 
mg/m2 via 1-hour IV infusion on days 1, 8, and 15 of each 28 day cycle.  
Dose modification of BBI608/placebo and/or paclitaxel was allowed.   
From the time of this amendment, and since un-blinding of patients 
remaining on study treatment, patients will continue study treatment as 
prior to unblinding as long as it is felt to be in their best interest by the 
Investigator and with patient’s informed consent. Placebo will no longer 
be administered. 


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
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CONFIDENTIAL
Duration of 
Treatment: 
Patients may continue to receive protocol therapy until September 15th
2017 and 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 
paclitaxel is discontinued due to toxicity, BBI608 may be continued as 
monotherapy until another discontinuation criterion is met. If BBI608 is 
discontinued due to toxicity, paclitaxel should be continued as 
monotherapy until another discontinuation criterion is met. The study is 
planned to close on September 15, 2017, at which time study medication 
will no longer be provided. 
Statistical 
Methods: 
The primary study endpoint is Overall Survival (OS).  The study is 
designed to have a power of 90% and a two-sided alpha of 5% to detect 
a 24% reduction in the continuous risk of death (HR 0.76, which 
corresponds to an increase of median survival from 7.36 to 9.67 months) 
in the Intention to Treat (ITT) general study population. It is estimated 
that 566 events will be required to detect this reduction which would be 
observed by randomizing 700 patients over 24 months and following 
them for an additional 12 months (including up to 5% of yearly 
dropouts).  
There was one interim analysis in this study presented to the 
independent Data Safety and Monitoring Board (DSMB). Additionally, 
DSMB reviewed safety during conduct of the study. The role and 
responsibility of the DSMB was defined in a separate Charter.
The interim analysis was performed on OS, the primary endpoint of this 
study, when at least 2/3rds of the required number of events (380) have 
been observed. This analysis, based on the stratified log-rank test 
adjusting for the stratification variables at randomization, tested the 
following: 
H0VXUYLYDORQ%%,SDFOLWD[HOVXUYLYDORQSDFOLWD[HO
versus
H1: survival on BBI608+paclitaxel > survival on paclitaxel 
The comparison of the overall population was tested based on a 
generalization of the Lan-DeMets error spending function approach 
using an O’Brien-Fleming stopping boundary to reject H0, controlling 
for a two-sided alpha of 5% at the end of the study. For example, if 
exactly 380 deaths (67% of the required events) were in the locked 
database for the interim analysis, the nominal critical point for rejecting 
H0 would be 2.502, corresponding to a p-value of 0.012.  Thus H0 would 
be rejected, and superiority of BBI608 declared, early if the p-value 
from stratified log-rank test is < 0.012. 


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL
3 
CONFIDENTIAL
TABLE OF CONTENTS
DOCUMENT REVISION HISTORY .......................................................................................................... ii 
STUDY SYNOPSIS ....................................................................................................................................... iii 
STUDY ACKNOWLEDGMENT/DISCLOSURE ........................................................................................... 5 
TREATMENT SCHEMA ............................................................................................................................... 6 
1 
OBJECTIVES ................................................................................................................................... 8 
1.1 
PRIMARY OBJECTIVE ................................................................................................................. 8 
1.2 
SECONDARY AND EXPLORATORY OBJECTIVES ................................................................. 8 
2 
BACKGROUND INFORMATION AND RATIONALE .................................................................... 9 
2.1 
GASTRIC AND GASTROESOPHAGEAL JUNCTION (GEJ) CANCER ................................... 9 
2.2 
CANCER STEM CELLS (CSC) AND GASTRIC AND GEJ CANCER ..................................... 10 
2.3 
BBI 608  ....................................................................................................................................... 10 
2.4 
CLINICAL EXPERIENCE WITH BBI608 IN PATIENTS WITH GASTRIC AND GEJ 
CANCER ....................................................................................................................................... 10 
2.5 
SUMMARY ................................................................................................................................... 11 
3 
BACKGROUND THERAPEUTIC INFORMATION ...................................................................... 12 
3.1 
NAME AND CHEMICAL INFORMATION ............................................................................... 12 
3.2 
MECHANISM OF ACTION ......................................................................................................... 12 
3.3 
EXPERIMENTAL ANTI-TUMOR ACTIVITY ........................................................................... 14 
3.4 
GLP TOXICOLOGY STUDIES (28-DAY & 90-DAY) ............................................................... 14 
3.5 
PHASE I TRIAL OF BBI608 MONOTHERAPY ........................................................................ 15 
3.6 
PHASE IB/II TRIAL OF BBI608 AND PACLITAXEL .............................................................. 16 
3.7 
EXPECTED POSSIBLE BBI608-RELATED ADVERSE EVENTS ........................................... 16 
3.8 
PHARMACEUTICAL DATA ....................................................................................................... 18 
4 
TRIAL DESIGN .............................................................................................................................. 19 
4.1 
STRATIFICATION ....................................................................................................................... 19 
4.2 
RANDOMIZATION...................................................................................................................... 19 
4.3 
INCLUSION OF WOMEN AND MINORITIES .......................................................................... 21 
5 
STUDY POPULATION .................................................................................................................. 22 
5.1 
INCLUSION CRITERIA............................................................................................................... 22 
5.2 
EXCLUSION CRITERIA ............................................................................................................. 24 
6 
PRE-TREATMENT EVALUATION ............................................................................................... 27 
7 
ENTRY/RANDOMIZATION PROCEDURES ................................................................................ 28 
7.1 
ENTRY PROCEDURES ............................................................................................................... 28 
7.2 
STRATIFICATION ....................................................................................................................... 28 
7.3 
RANDOMIZATION...................................................................................................................... 28 
8 
TREATMENT PLAN ...................................................................................................................... 29 
8.1 
TREATMENT PLAN .................................................................................................................... 29 
9 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ............................................. 37 
9.1 
EVALUATION DURING PROTOCOL TREATMENT .............................................................. 37 
9.1.1     Patient Evaluation After Unblinding and Continued Protocol Treatment .................................... 38 
9.2.1     Patient evaluation After Permanent Discontinuation of Protocol Therapy, Post-Unblinding ...... 40 
10 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ................................................. 42 
10.1 
DEFINITIONS ............................................................................................................................... 42 
10.2 
RESPONSE AND EVALUATION ENDPOINTS ........................................................................ 42 
10.3 
RESPONSE DURATION .............................................................................................................. 44 
10.4 
STABLE DISEASE DURATION ................................................................................................. 45 
10.5 
METHODS OF MEASUREMENT ............................................................................................... 45 
11 
SERIOUS ADVERSE EVENT REPORTING .................................................................................. 47 


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
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4 
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11.1 
SERIOUS ADVERSE EVENT REPORTING ON STUDY POST-UNBLINDING .......................... 47 
11.2 
DEFINITION OF A PROTOCOL REPORTABLE SERIOUS ADVERSE EVENT ................... 47 
11.3 
SERIOUS ADVERSE EVENT REPORTING INSTRUCTIONS ................................................ 48 
11.4 
PROCEDURES IN CASE OF AN OVERDOSE .......................................................................... 48 
11.5 
OTHER PROTOCOL REPORTABLE EVENTS – PREGNANCY/EXPOSURE REPORTING 48 
11.6 
RESPONSIBILITY FOR REPORTING SERIOUS ADVERSE EVENTS TO REGULATORY 
AGENCIES .................................................................................................................................... 51 
11.7 
REPORTING SAFETY REPORTS TO INVESTIGATORS ........................................................ 51 
12 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 52 
12.1 
CRITERIA FOR DISCONTINUING PROTOCOL TREATMENT ............................................. 52 
12.2 
DURATION OF PROTOCOL TREATMENT ............................................................................. 52 
12.3 
THERAPY AFTER PROTOCOL TREATMENT IS STOPPED ................................................. 52 
12.4 
FOLLOW-UP OFF PROTOCOL TREATMENT ......................................................................... 52 
12.5 
UNBLINDING .............................................................................................................................. 53 
13 
CENTRAL REVIEW PROCEDURES, TISSUE COLLECTION, AND CORRELATIVE STUDIES 54 
13.1 
CENTRAL RADIOLOGY REVIEW ............................................................................................ 54 
13.2 
CENTRAL PATHOLOGY REVIEW ........................................................................................... 54 
13.3 
TISSUE COLLECTION ................................................................................................................ 54 
13.4 
SPARSE PHARMACOKINETIC PLASMA SAMPLE COLLECTION ..................................... 54 
14 
STATISTICAL CONSIDERATIONS ............................................................................................... 56 
14.1 
OBJECTIVES AND DESIGN ....................................................................................................... 56 
14.2 
STUDY ENDPOINTS AND ANALYSIS ..................................................................................... 56 
14.3 
SAMPLE SIZE AND DURATION OF STUDY .......................................................................... 58 
14.4 
SAFETY MONITORING .............................................................................................................. 59 
14.5 
INTERIM AND FINAL ANALYSES ........................................................................................... 59 
14.6 
CORRELATIVE STUDIES .......................................................................................................... 60 
14.7 
EXPLORATORY ANALYSES .................................................................................................... 61 
15 
PUBLICATION .............................................................................................................................. 63 
15.1 
RESEARCH OUTSIDE THE TERMS OF THIS PROTOCOL ................................................... 63 
16 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ..................................................... 64 
16.1 
REGULATORY CONSIDERATIONS ......................................................................................... 64 
16.2 
INCLUSIVITY IN RESEARCH ................................................................................................... 64 
16.3 
OBTAINING INFORMED CONSENT ........................................................................................ 65 
16.4 
DISCONTINUATION OF THE TRIAL ....................................................................................... 67 
16.5 
RETENTION OF PATIENT RECORDS AND STUDY FILES .................................................. 67 
16.6 
ON-SITE MONITORING/AUDITING ......................................................................................... 67 
16.7 
CASE REPORT FORMS .............................................................................................................. 68 
17 
REFERENCES ............................................................................................................................... 69 
APPENDIX I - PATIENT EVALUATION FLOW SHEET .......................................................................... 74 
APPENDIX II - PERFORMANCE STATUS SCALES/SCORES ................................................................. 76 
APPENDIX III - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ....................... 77 
APPENDIX IV - QUALITY OF LIFE ASSESSMENT ................................................................................. 78 
APPENDIX V - UNBLINDING................................................................................................................... 81 
APPENDIX VI: UNBLINDING PROCEDURE........................................................................................ 82 


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL
5 
CONFIDENTIAL
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)
Protocol Number:  BBI608-336 
CENTER: ___________________________________________


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL
6 
CONFIDENTIAL
TREATMENT SCHEMA
This is an international multi-center, prospective, double-blind, randomized phase III trial of the cancer 
stem cell inhibitor BBI608 plus weekly paclitaxel versus matched placebo plus weekly paclitaxel in 
patients with advanced, previously treated gastric and gastro-esophageal junction (GEJ) adenocarcinoma.
Stratification:
x
Geographical region (Asia vs North America, Europe, and Australia vs South America)  
x
7LPHWRSURJUHVVLRQRQILUVWOLQHWKHUDS\PRQWKVYVPRQWKVIURPVWDUWRIILUVWOLQHWKHUDS\
x
Disease measurability by RECIST 1.1 (measurable disease present vs not present)
x
Prior taxane therapy (yes vs no) 
Advanced, 
previously treated 
gastric or gastro-
esophageal junction 
adenocarcinoma
R 
A 
N 
D 
O 
M 
I 
Z 
E
њ
Arm 
1 
BBI608 orally, twice daily
plus
Paclitaxel 80 mg/m2 IV, weekly 
(three out of every four weeks) 
 
Disease 
Progression 
based on 
RECIST 
criteria1,2
or 
unacceptable 
toxicity occurs 
 
Death
ĺ
ĺ
ќ
Arm 
2 
Placebo orally, twice daily
plus
Paclitaxel 80 mg/m2 IV, weekly 
(three out of every four weeks)
 
 
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, BBI608/Placebo may be continued in monotherapy as long as it is 
the opinion of the Investigator that the patient may continue to be deriving benefit.
Endpoints: 
Primary
x
Overall Survival in the general study population  
Secondary 
x
Overall Survival in the predefined biomarker-positive sub-population¥  
x
Progression Free Survival in the general study population 
x
Progression Free Survival in the predefined biomarker-positive sub-population¥
x
Objective Response Rate in the general study population 
x
Disease Control Rate in the general study population 
x
Safety Profile
¥This biomarker-positive sub-SRSXODWLRQLVGHILQHGDVWKRVHSDWLHQWVZLWKQXFOHDUȕ-catenin positivity on 
immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival tissue.


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL
7 
CONFIDENTIAL
Sample Size:
Planned sample size is 700 patients (350 on Arm 1 and 350 on Arm 2). 
Study Conduct Post-Unblinding:  
Following the review of the interim analysis, per DSMB recommendations, patients remaining on study 
treatment were unblinded. 
However, post-unblinding, the trial will continue with patients who have not yet met the primary study 
endpoint (death), and with patients currently on protocol therapy and who may receive BBI608 and 
paclitaxel on study based on the clinical judgement of the investigator that this is in the patient’s best
interest, providing the patient is fully informed and provides consent (see also Sections 9.1.1 and 9.2.1). 
Patients will receive study treatment supply until any of the discontinuation criteria are met (see Section 
11.1) or until September 15 2017, whichever occurs first. The protocol will continue to be followed for all 
endpoints.  


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
CONFIDENTIAL
8 
CONFIDENTIAL
1
OBJECTIVES
1.1
PRIMARY OBJECTIVE
x
To compare Overall Survival (OS), defined as the time from randomization until death from 
any cause, in patients with pre-treated advanced gastric/GEJ adenocarcinoma treated with 
BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel. 
1.2
SECONDARY AND EXPLORATORY OBJECTIVES
x
To evaluate the safety profile of BBI608 administered daily plus weekly paclitaxel in patients 
with pre-treated advanced gastric/GEJ adenocarcinoma, with safety assessed according to the 
National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE
version 4.0). 
x
To compare Progression-Free Survival (PFS), defined as the time from randomization until 
the first objective observation of disease progression or death from any cause, in patients with 
pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus weekly 
paclitaxel versus placebo plus weekly paclitaxel. 
x
To compare the Objective Response Rate (OR), defined as the proportion of patients with a 
documented complete response or partial response (CR + PR) based on RECIST 1.1 criteria, 
in patients with pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus 
weekly paclitaxel versus placebo plus weekly paclitaxel. 
x
To compare the Disease Control Rate (DCR), defined as the proportion of patients with a 
documented complete response, partial response and stable disease (CR + PR + SD) based on 
RECIST 1.1 criteria, in patients with pre-treated advanced gastric/GEJ adenocarcinoma
treated with BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel. 
x
To explore the exposure/response relationships of BBI608 and paclitaxel in patients with pre-
treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus weekly paclitaxel
versus placebo plus weekly paclitaxel using population pharmacokinetics with sparse PK 
sample collection. 
x
To explore an association between putative biomarkers as determined from paraffin-
embedded tumor specimens and the potential for clinical benefit in terms of overall survival, 
progression-free survival, disease control rate, and objective response rate, from treatment 
with BBI608 plus weekly paclitaxel in patients with pre-treated advanced gastric/GEJ 
adenocarcinoma. 
x
To explore associations with baseline values and changes of putative biomarkers (see Section 
14.6) in the blood and the potential for clinical benefit in terms of overall survival, 
progression-free survival, disease control rate, and objective response rate, from treatment 
with BBI608 plus weekly paclitaxel in patients with pre-treated advanced gastric/GEJ 
adenocarcinoma. 
x
To compare the Quality of Life (QoL), as measured using the EORTC QLQ-C30, in patients 
with pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus weekly 
paclitaxel versus placebo plus weekly paclitaxel. 


BBI608-336
Amendment 8
Amendment Date: 2017-JUL-14
  
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9 
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2
BACKGROUND INFORMATION AND RATIONALE
2.1
GASTRIC AND GASTROESOPHAGEAL JUNCTION (GEJ) CANCER
Gastric cancer and cancer of the gastro-esophageal junction (GEJ) are a significant cause of 
morbidity and mortality worldwide and have the second highest death rate of all cancers with 
736,000 deaths recorded in 2008 [WHO, 2013]. Combined, they are the fourth most prevalent 
malignancy with nearly 1,000,000 new cases of gastric and GEJ cancer diagnosed annually 
worldwide [Ferlay 2008]. In the United States, 21,600 new cases of gastric and GEJ cancer are 
estimated for 2013 with 10,990 dying from the disease [NCI 2013]. Surgery is considered the 
only potentially curative treatment, however, more than 70% of patients present with locally 
advanced or metastatic disease [Sugano 2008]. 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 only 20-25% [Arak  1994; Cunningham 2006].
Standard treatment for unresectable and metastatic disease currently includes first-line 5-
fluorouracil (5-FU) and platinum chemotherapy based regimen (+/- human epidermal growth 
factor receptor 2 (HER-2) antibody) with patients ultimately progressing on first-line therapy or 
exhibiting primary refractory disease leading to a median survival between 9 and 14 months 
[Cunningham 2008; Wagner 2006; Wagner 2010]. A meta-analysis of 35 trials and 5726 patients 
suggested that the anthracycline compound, epirubicin, improves survival in combination with 
first-line 5-FU and platinum-based chemotherapy making the triple regimen of 5-FU, platinum 
and epirubicin a first-line treatment option for advanced gastric and GEJ cancer in the US and 
Europe [Wagner 2010]. A subsequent randomized phase 2 study, however, showed no benefit 
with the addition of an anthracycline to a 5-FU and platinum regimen [Enzinger 2010].  
Despite poor survival rates in gastric and GEJ cancer, the past decade has seen some progress in 
second-line therapy for this disease with approximately 20-50% of patients receiving second-line 
therapy world-wide [Pozzo 2004; Bouche 2004; Chau 2004a; Lee 2007]. Second-line therapy has 
shown a median survival of 5.6 months as compared to survival of approximately 2.5 months in 
patients not receiving treatment following progression on first-line therapy [Chau 2004a]. Three 
recent randomized phase III studies provide evidence to support the use of second-line therapy in 
advanced gastric and GEJ cancer, showing survival benefit of single agent docetaxel and 
irinotecan [Kang 2012; Thuss-Patience 2011; Cook 2013]. A meta-analysis of these three 
second-line gastric cancer trials (including a total of 410 patients) reported a significant reduction 
in the risk of death with a HR of 0.64 (CI 0.52-0.79 and P<0.0001) with administration of either 
docetaxel or irinotecan chemotherapy [Kim 2013]. A recently published study of paclitaxel 
compared with irinotecan shows that the two treatments have similar effects on overall survival, 
progression free survival and response rate. Additionally, paclitaxel was shown to have a superior 
safety profile to irinotecan with respect to gastrointestinal adverse events such as anorexia, 
nausea, vomiting, and diarrhea [Hironaka 2013]. In addition to improvements in survival, 
second-line therapy has also led to improvement in patient quality of life and significantly 
improved symptom scores for pain [Cook 2013]. 
In 2013, ramucirumab, a monoclonal antibody VEGFR-2 antagonist, was reported to improve 
overall survival by 1.4 months as monotherapy in the second-line setting [Fuchs 2013], adding 
anti-angiogenic therapy to the gastric and GEJ cancer therapy armamentarium. Ramucirumab has 
also been studied in combination with weekly paclitaxel in the same patient population in the
randomized phase III RAINBOW study which was recently announced to have met its primary 
endpoint of overall survival. The addition of ramucirumab to paclitaxel provided a 2.3 month 


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increase above the 7.36 month median overall survival of paclitaxel alone [Wilke 2014].
Ramucirumab received FDA approval in April 2014 for monotherapy treatment of gastric and 
GEJ 
adenocarcinoma 
following 
progression 
on 
fluoropyrimidine 
or 
platinum-based 
chemotherapy. 
Currently, a patient with progressive disease on 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 chemo-refractory gastric and GEJ 
cancer. The poor survival rates seen with this disease may in part be related to a lack of standard 
recommendations for second-line therapy.  
2.2
CANCER STEM CELLS (CSC) AND GASTRIC AND GEJ CANCER
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 traditional chemotherapies and current targeted agents. CSCs have been isolated from 
almost all major tumor types, including gastric cancer [Takaishi 2007A]. Targeting stem cells, 
therefore, holds great promise for fundamentally advancing cancer treatment.
Accumulating evidence indicates that CSCs play a key role in the pathogenesis of gastric cancer 
[Takaishi 2008]. Cancer stem cells have been isolated from human gastric cancer using cell 
surface markers such as Lgr5 and CD44 [Barker 2010; Takaishi 2009]. These CSCs isolated 
from gastric and GEJ cancer patients display tumour-initiating properties, as well as resistance to 
chemotherapeutic agents. These findings suggest that the development of cancer stem cell 
inhibitors represents a novel and compelling strategy for the treatment of gastric and GEJ cancer. 
2.3
BBI 608 
BBI608 is the most advanced agent developed by Boston Biomedical, Inc. (BBI) to target CSCs. 
BBI608 is a small molecule that blocks self-renewal of, and induces cell death in CSCs isolated 
from gastric and GEJ cancer as well as other types of cancer. BBI608 inhibits CSCs by binding to 
CSCP3, a proprietary CSC target discovered by scientists at Boston Biomedical. CSCP3 has been 
identified as STAT3. STAT3 is a known oncogene which is aberrantly activated in a wide variety 
of human cancers including all the major carcinomas as well as some hematologic tumors.
Multiple animal models of gastric cancer support the role of STAT3 pathway activation in this 
disease. The gp130F/F mouse model for gastric cancer results in STAT3 hyper-activation, and 
these animals spontaneously develop gastritis and gastric tumors within 6-8 weeks [Judd 2006; 
Ernst 2008]. Another mouse model, the T3b-SOCS3 cKO mouse, develops STAT3-mediated 
gastritis and gastric tumors within 8 weeks [Inagaki-Ohara 2012].
In particular, approximately 
20 to 50% of gastric and GEJ cancers feature dysregulation of STAT3 signaling [Yu 2009; Tye 
2012, Gong 2005; Yakata 2007]. Moreover, activation of STAT3 pathway, as assessed in 
archival patient tumor samples, has been associated with reduced survival [Kim 2009; Yakata
2007; Gong 2005; Lee 2009; Kanda 2004]. These data provide strong rationale for the 
development of gastric and GEJ cancer therapies based on inhibition of STAT3 activity.
2.4
CLINICAL EXPERIENCE WITH BBI608 IN PATIENTS WITH GASTRIC AND GEJ CANCER
Based on compelling pre-clinical data, a Phase Ib/II study was initiated to evaluate the safety, 
recommended phase 2 dose (RP2D), and preliminary signs of activity of BBI608 administered in 


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combination with weekly paclitaxel in several solid tumors, including gastric/GEJ cancer. This 
study showed that BBI608 can be combined safely with weekly paclitaxel, with the RP2D of 
BBI608 in this combination determined to be the full monotherapy dose (480 mg, twice daily). 
The Adverse Event (AE) profile is similar to that of both agents in monotherapy, with no new or 
additive effects observed.  AEs possibly related to BBI608 were generally mild, consisting 
primarily of Grade 1 and 2 diarrhea, nausea and vomiting.  
To date, 7 subjects with advanced gastric/GEJ cancer have been enrolled in this study. All 
patients had been pre-treated, with most having received multiple lines of therapy in the 
metastatic setting, including prior taxanes. The Disease Control Rate (DCR) and Objective 
Response Rate (ORR) for BBI608 in combination with paclitaxel in the gastric/GEJ cancer
patients was found to be 6 of 7 enrolled and 3 of 7 enrolled, respectively. Three patients had a 
partial response (PR) per RECIST 1.1 (100%, 45% and 48% regressions of target lesions), and 
the additional three patients had prolonged stable disease (SD)—one with 25% regression.  
Historically, a DCR of approximately 40-60% and an ORR of approximately 5-21% have been 
observed in this setting with taxane monotherapy [Ford 2012; Graziano 2000; Kodera 2007; 
Hironaka 2013;Wilke 2014]. Furthermore, for these patients, median Progression Free Survival 
(PFS) was approximately 23 weeks, which compares favorably with the median PFS (11.4
weeks) observed with weekly paclitaxel alone [Wilke 2014]. The phase II portion of the trial is 
ongoing, with enriched accrual of patients with previously treated gastric and GEJ cancer.
Currently, BBI608 combined with weekly paclitaxel has been administered safely to more than 
80 patients with various solid tumors.
The unmet clinical need, mechanism of action of BBI608, and encouraging pre-clinical and 
clinical data seen to date provide a strong rationale for further investigation of BBI608 in 
combination with weekly paclitaxel in patients with advanced gastric and GEJ cancer. 
2.5
SUMMARY
BBI608-336 will primarily examine the effect of adding treatment with CSC inhibitor BBI608 to 
weekly paclitaxel on Overall Survival in patients with advanced Gastric and GEJ adenocarcinoma 
who have failed first line chemotherapy. Additional assessments will include Progression-Free 
Survival, Objective Response Rate, Disease Control Rate, Safety, Quality of life (QoL), 
Population Pharmacokinetics and putative predictive molecular markers. 


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3
BACKGROUND THERAPEUTIC INFORMATION
3.1
NAME AND CHEMICAL INFORMATION
BBI608 
3.2
MECHANISM OF ACTION
BBI608 is a cancer stem cell (CSC) inhibitor. One of the hallmarks of CSCs is their ability to 
self-renew [Al-Hajj 2004]. A standard method of measuring self-renewal capacity is to assess the 
ability of CSCs to be cultured as spheres in the absence of serum or attachment [Ponti 2005; Cho 
2008]. Treatment with BBI608 potently blocks in vitro sphere formation by gastric CSCs, as well 
as other types of CSCs. Moreover, BBI608 has also been shown to target CSCs in vivo.
Treatment of nude mice bearing human tumor xenografts with BBI608 has been shown to reduce 
their CSC content by 4 to 5-fold after two weeks of treatment. This observation has been made in 
xenografted gastric cancer, as well as other cancer models. In contrast, treatment of xenograft-
bearing mice with 5-FU and platinum-based agents led to an increased concentration of CSCs in 
the xenografts. Thus, BBI608 has been shown highly effective against CSCs in vitro and in vivo.
BBI608 targets CSCs by inhibiting STAT3, a proprietary target identified by Boston Biomedical. 
Scientists at Boston Biomedical have discovered that STAT3 is critical for the self-renewal and 
survival of cancer stem cells. Under normal conditions, STAT3 activation is transient and tightly 
regulated in normal adult cells and adult stem cells. While essential for embryonic development, 
STAT3 deficiency is well tolerated in adult mice [Niwa 1998]. Moreover, conditional knock-out 
of STAT3 in mice is associated with undetectable or mild phenotypes [Akira 1999]. Patients with 
Job’s syndrome also survive well with STAT3 dominant negative mutations [Holland 2007].  
Increased levels of phospho-STAT3, the activated form of STAT3, are observed in both 
preclinical gastric cancer models as well as in human gastric cancer. Multiple animal models of 
gastric cancer support the role of STAT3 pathway activation in this disease. The gp130F/F mouse 
model for gastric cancer results in STAT3 hyperactivation and these animals spontaneously 
develop gastritis and gastric tumors within 6-8 weeks [Judd 2006; Ernst 2008]. In another mouse 
model, the T3b-SOCS3 cKO mouse, develops STAT3-mediated gastritis and gastric tumors 
within 8 weeks [Inagaki-Ohara 2012]. Approximately 20 to 50% of gastric and GEJ cancers 
feature dysregulation of STAT3 signaling [Yu 2009; Tye 2012, Gong 2005; Yakata 2007].  
Moreover, activation of STAT3 pathway, as assessed in archival patient tumor samples, has been 
associated with lower patient survival [Kim 2009; Yakata 2007; Gong 2005; Lee 2009; Kanda 
2004]. These data demonstrate that STAT3 is an important regulator of gastric and GEJ cancer 
proliferation and survival, as well as a key regulator of CSC-mediated invasion and metastasis. 
Moreover, they establish a powerful rationale for the development of gastric and GEJ cancer 
therapies based on inhibition of STAT3 activity. 
STAT3 is closely linked to another important transcription factor RQFRJHQH ȕ-catenin, the 
HIIHFWRURIWKH:QWVLJQDOOLQJSDWKZD\ȕ-catenin contributes to tumorigenesis and metastasis in a 
wide range of cancers including gastric and GEJ cancer. It has been shown that constitutive 
activation of the E-catenin allele in mouse gastric epithelium leads to adenoma formation in the 
stomach antrum as well as adenomatous change in the more proximal stomach [Radulescu 2013] 
supporting the idea that Wnt pathway activation may play a role in the initiation of gastric and 


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GEJ cancer. Additionally, mouse models of gastric cancer show that induction of Wnt signalling 
synergistically cooperates with inflammatory signalling pathways to promote tumor development 
in gastric mucosa of the animals [Oshima 2006]. Moreover, Lgr5, a recognized gastric cancer 
stem cell marker, is a Wnt pathway target gene [Van der Flier LG 2007], and increased Wnt 
signalling leads to accumulation of Lgr5 positive self-renewing, multi-potent stem cells 
responsible for long term renewal of the gastric epithelium [Barker 2010].
In addition to the over-H[SUHVVLRQ RI ȕ-catenin, its localization has important clinical 
implications. 0HPEUDQRXVȕ-catenin is involved in maintaining cell-cell junctions and promoting 
a less-aggressive epithelial phenotype. By contrast, nuFOHDUȕ-catenin is accumulated in human 
gastric cancer tumors [Brabletz 2005, Clements 2002, Nakatsuru 1992, Park 1999] and has been 
correlated with an invasive phenotype in intestinal-type gastric cancers [Miyazawa 2000].
Although nuclear E-catenin translocation (with or without demonstrated E-catenin mutations) has 
been reported in gastric cancer, the actual incidence has varied greatly among studies with 
approximately 30-50% of tumors showing nuclear accumulation of E-catenin [Clements 2002, 
Park 1999, Ebert 2002].  
A US based study evaluating 311 gastric cancers reported that approximately one third of all 
gastric tumors show E-catenin nuclear localization, with E-catenin mutations occurring equally 
among the diffuse and intestinal types of gastric and GEJ cancer [Clements 2002]. A Korean 
study looking at 598 gastric cancer samples reported nuclear E-catenin incidence of 20% in 
intestinal gastric cancer and 84% in diffuse type of gastric cancer, with 86% of more advanced 
stage gastric cancers of both histologic types exhibiting nuclear E-catenin staining. A separate 
study reported 24% of early stage gastric cancers and 80% of lymph node metastases of both 
histologic types of gastric cancer showing nuclear E-catenin translocation [Kim 2009]. A recent 
study from China looking at 144 gastric cancer samples reported a nuclear E-catenin frequency of 
56% with presence of nuclear E-catenin denoting a worse prognosis for overall survival [Liu 
2012].  A 1997 study evaluating 89 gastric carcinomas reported a statistically significant 3-5 fold 
survival advantage in patients retaining normal membranous E-catenin staining irrespective of 
histologic type, grade or stage of gastric cancer [Jawhari 1997]. Although the reported incidence 
of nuclear E-catenin staining varies in the literature, these studies demonstrate the presence of 
abnormally elevated levels of nuclear E-catenin in gastric and GEJ cancer and correlate nuclear E-
catenin localization with more advanced disease as well as decreased survival.  This provides a 
strong rationale for the development of gastric and GEJ cancer therapies with effects on E-catenin 
nuclear localization.  
Studies conducted at Boston Biomedical have shown that BBI608 can directly inhibit 
phosphorylated STAT3, and also blocks the DNA-binding activity of STAT3 in cancer cells. 
Moreover, treatment of cancer cells with BBI608 inhibits STAT3 reporter gene activity in a dose-
dependent manner. The ability of BBI608 to inhibit STAT3 nuclear translocation in 
heterogeneous cancer cells and CSCs has also been demonstrated by in vivo immunofluorescence 
studies. BBI608 treatment was also found to result in decreased STAT3-dependent gene 
H[SUHVVLRQLQFDQFHUFHOOVLQFOXGLQJȕ-catenin. Furthermore, BBI608 has been shown to decrease 
ȕ-catenin levels in in vivo gastric cancer models (BBI’s unpublished data).  


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3.3
EXPERIMENTAL ANTI-TUMOR ACTIVITY
BBI608 also exhibits strong effects against CSCs isolated from gastric cancer and various cancer 
types (IC50 ~100 to 500 nM) while sparing normal hematopoietic stem cells (IC50 not reached at 
30 PM). These data suggest a wide (>50-fold) therapeutic window for BBI608. Additionally, 
since bulk cancer cell progeny retain dependency on STAT3 as CSCs, BBI608 has demonstrated 
inhibitory activities against a broad spectrum of heterogeneous cancer cells including those 
derived from pancreas, lung, cervix, breast, colon, head and neck, and prostate, as well as 
hematological malignancies including multiple myeloma, leukemia, and lymphoma (with IC50
values of ~100 nM to 500 nM).  
BBI608 has demonstrated potent anti-tumor activity as a monotherapy in vivo in murine 
xenograft models of human gastric cancer. No treatment-related signs of toxicity were noted. 
BBI608 has also shown potent anti-tumor activity in a variety of other human cancer xenograft 
models including colorectal (including k-Ras mutant), pancreatic, head and neck, breast, prostate, 
and liver cancer.  
Combined therapy with BBI608 and other anti-cancer agents has also been investigated in vivo.
Significant synergy has been observed between BBI608 and chemotherapeutic agents, including 
paclitaxel, in a variety of murine xenograft models of human cancer including gastric, CRC, 
breast, non-small cell lung cancer, head/neck cancer, and ovarian cancer. These data suggest a 
significant potential for BBI608 in combination with chemotherapeutic agents for a wide variety 
of human cancers. 
3.4
GLP TOXICOLOGY STUDIES (28-DAY & 90-DAY)
BBI608 was evaluated in 28-day repeat-dose GLP toxicology studies in both rats and dogs. Both 
species received BBI608 at dose levels of 10, 30 and 100 mg/kg/day for 28 days followed by a 
14-day recovery period. In both species, adverse events were observed in the high dose (100 
mg/kg) groups. Male rats in the 100 mg/kg group showed body weight loss, diarrhea, and 
decreased food consumption. Female rats in the 100 mg/kg group experienced weight loss only, 
which stabilized after the first week. In dogs in the 100 mg/kg group, weight loss, emesis, 
diarrhea, and soft/mucoid feces were observed in both males and females. Clinical pathology and 
histopathology findings in rats at high dose were consistent with dehydration and diarrhea. There 
were no related pathologic or histopathological findings in dogs at any dose level.  
Under the conditions of the study, the 28-day oral NOAEL (no observed adverse effects level) in 
both rats and dogs was 30 mg/kg. From the rat NOAEL, conversion to a human equivalent dose 
(HED) yields 180 mg/m2; and from the dog NOAEL, the HED is 600 mg/m2. This dose 
corresponded to BBI608 plasma levels in both species above the in vitro IC50, with exposure 
lasting beyond 10 hours.  


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Ninety-day repeat oral dose GLP toxicology studies of BBI608 were performed in both Sprague 
Dawley rats (at doses of 10, 20 or 40 mg/kg/day) and Beagle dogs (at doses of 10, 30 or 100 
mg/kg/day) by oral gavage or capsule dosing, respectively, followed by a 28-day recovery period. 
Clinical observations, body weights, food consumption, and clinical pathology and 
histopathology were evaluated. There were no test article-related clinical observations in rats at 
any dose level. Test article-related effects included decreased body weight gain for male and 
female rats receiving 40 mg/kg/day. Test article-related organ weight changes at study day (SD) 
91 were limited to increased relative (to body weight) mean spleen weight (21.7%), in male rats
receiving 40 mg/kg/day. Clinical pathology changes included minimal decreases in total protein, 
albumin, and calcium in males and females given 40 mg/kg/day, and minimal to mild increases in
total white blood cell counts and associated absolute neutrophil and absolute lymphocyte counts
in males and females given 40 mg/kg/day. Treatment-related microscopic findings in rats given 
40 mg/kg/day included: minimal to mild transitional epithelial hyperplasia and vacuolation in the 
urinary bladder; minimal to moderate epithelial hyperplasia, hyperkeratosis, inflammatory cell 
infiltrates and edema in the non-glandular stomach; minimal to mild erythropoiesis and 
pigmented macrophages in the spleen; and minimal to moderate medullary sinus mastocytosis, 
erythrocytosis and pigmented macrophages in mesenteric lymph nodes.  
In dogs at all dose levels, there were no test article-related changes, including clinical 
observation, body weight, clinical pathology and histopathology. Treatment with BBI608 had no 
effect on ophthalmology, no treatment-related effects on any ECG parameters, and all ECGs were 
considered qualitatively and quantitatively normal for Beagle dogs.
Under the conditions of the study, the NOAEL level (based on clinical observation, laboratory 
tests, gross and histopathological changes) for rats administered BBI608 daily orally for 90 days 
was 20 mg/kg/day (human equivalent dose: 120 mg/m2), and the NOAEL in dogs administered 
BBI608 daily orally for 90 days was 100 mg/kg/day (human equivalent dose: 2000 mg/m2).
3.5
PHASE I TRIAL OF BBI608 MONOTHERAPY
The effects of BBI608 in humans have been evaluated in a phase I clinical trial, BBI608-101 
(IND 100,887). The trial was a dose-escalation study designed to examine the safety, tolerability, 
and pharmacokinetics of BBI608 in patients with advanced malignancies of all types, whose 
cancer had progressed following standard therapy, or for whom no effective standard therapy was 
available. The preliminary anti-tumor activity of BBI608 was also examined.  
In the dose escalation portion, 14 cohorts (N=41) were dosed from 20 mg to 2000 mg/day.  
Adverse events were generally mild, including grade 1-2 diarrhea, nausea, anorexia and fatigue 
with a total of 4 grade 3 events (diarrhea and fatigue). MTD was not reached. At 400 mg/day the 
plasma concentration of BBI608 was sustained at a concentration > 1.5 uM (several fold above 
the IC50) for >8 hours.  RP2D was determined to be 500 mg bid. Among those evaluable for 
tumor response (RECIST 1.1), disease control (disease stabilization and regression) was observed 
in 65% of patients. Prolonged time to progression was observed in 46% of evaluable patients, 
including patients with colorectal (CRC), head & neck, gastric, ovarian, melanoma, and breast 
cancer. Decreases in tumor markers (CEA and CA125) were also observed in colon cancer and 
ovarian cancer, respectively.


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3.6
PHASE IB/II TRIAL OF BBI608 AND PACLITAXEL
A Phase Ib/II study was initiated to evaluate the safety, recommended phase 2 dose (RP2D), and 
preliminary signs of activity of BBI608 administered in combination with weekly paclitaxel in 
several solid tumors, including gastric/GEJ cancer. This study showed that BBI608 can be 
combined safely with weekly paclitaxel, with an RP2D of BBI608 in this combination determined 
to be the full monotherapy dose (480 mg, twice daily). The Adverse Event (AE) profile is similar 
to that of both agents in monotherapy, with no new or additive effects observed.  AE attributed to 
BBI608 were generally mild, consisting primarily of Grade 1 and 2 diarrhea, nausea and 
vomiting. 
The pharmacokinetics (PK) of BBI608 and paclitaxel were examined in the patients enrolled 
during the phase Ib portion of this study, at BBI608 doses from 400 to 1000 mg total daily dose. 
No significant difference in plasma exposures were noted with the addition of paclitaxel in 
comparison to PK data from the BBI608 monotherapy Phase I study.  
To date, 7 subjects with advanced gastric/GEJ cancer have been enrolled in this study. All 
patients were pre-treated, with most having received multiple lines of therapy in the metastatic 
setting, including prior taxanes. 
The Disease Control Rate (DCR) and Objective Response Rate (ORR) for BBI608 in 
combination with paclitaxel in the gastric/GEJ cancer patients was found to be 6 of 7 enrolled and 
3 of 7 enrolled, respectively. Three patients had a partial response (PR) per RECIST 1.1 (100%, 
45% and 48% regressions of target lesions), and the additional three patients had prolonged stable 
disease (SD)—one with 25% regression.  The phase II portion of the trial is ongoing, with 
enriched accrual of patients with previously treated gastric and GEJ cancer. Currently, BBI608 
combined with weekly paclitaxel has been administered safely to more than 80 patients.
3.7
EXPECTED POSSIBLE BBI608-RELATED ADVERSE EVENTS
In the BBI608-201 trial of BBI608 and weekly paclitaxel, the AE profile was similar to that of 
both BBI608 and paclitaxel in monotherapy, with no new, worsened or additive effects observed.
As seen in Table 1 below, the most frequent AEs were gastrointestinally-related, most frequently 
Grade 1 or Grade 2 in severity. No subjects experienced Grade 4 symptoms. Other non-GI-related 
events included sequelae likely secondary to GI events, such fatigue and dehydration.


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Table 1: Subjects with Adverse Events Possibly Related to BBI608 in Combination with Weekly 
Paclitaxel
N =55
System
Event
Grade 1
Grade 2
Grade 3
#
%
#
%
#
%
Gastrointestinal 
Diarrhea
38
69.1%
12
21.8%
10
18.2%
Nausea
16
29.1%
13
23.6%
1
1.8%
Vomiting
12
21.8%
7
12.7%
2
3.6%
Abdominal Pain
8
14.5%
3
5.5%
2
3.6%
Flatulence
4
7.3%
2
3.6%
0
0.0%
Fecal Incontinence
1
1.8%
0
0.0%
0
0.0%
Blood in stool
1
1.8%
0
0.0%
0
0.0%
Mucositis Oral
1
1.8%
0
0.0%
0
0.0%
Burping
1
1.8%
0
0.0%
0
0.0%
Bloating
1
1.8%
1
1.8%
0
0.0%
Constitutional
Fatigue
13
23.6%
11
20.0%
2
3.6%
Chills
1
1.8%
0
0.0%
0
0.0%
Weight Loss
1
1.8%
0
0.0%
0
0.0%
Metabolism and 
Nutrition 
Anorexia
9
16.4%
5
9.1%
0
0.0%
Hypokalemia
3
5.5%
1
1.8%
0
0.0%
Hypomagnesemia
3
5.5%
1
1.8%
0
0.0%
Dehydration
2
3.6%
3
5.5%
1
1.8%
Neuro-Psychiatric
Dysgusia
2
3.6%
0
0.0%
0
0.0%
Confusion
1
1.8%
0
0.0%
0
0.0%
Dizziness
1
1.8%
0
0.0%
0
0.0%
Renal and Urinary
Urine Discoloration
4
7.3%
1
1.8%
0
0.0%
Skin And 
Subcutaneous Tissue
Rash Maculo-Papular
1
1.8%
0
0.0%
0
0.0%
Diarrhea
The onset of diarrheal symptoms has been observed to occur predominantly during the first week 
of dosing. The diarrhea is non-bloody, non-inflammatory, and likely osmotic in etiology due to 
un-dissolved drug product in the gastrointestinal lumen. Symptoms can also be associated with 
abdominal cramping, though this is not the rule. As a result of the etiology of the diarrhea, oral 
fluids have been found to be helpful in preventing or alleviating these symptoms.  
Aggressive up-front management with anti-diarrheal agents is effective and recommended, and 
combination therapy may be particularly useful. If needed, a brief dosing holiday of 1-2 days will 
promptly improve symptoms, often resolving them completely. Patients should then be re-
challenged with BBI608. If symptoms happen to recur, a milder course can be expected.  


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Nausea, Vomiting, Anorexia, and Weight Loss 
Nausea, vomiting, anorexia and weight loss have also been observed during treatment with 
BBI608. Symptoms often respond well to supportive management or are reversible upon 1 to 3
days of dosing holiday. Management with a 5HT3 receptor antagonist anti-emetic, or oral 
corticosteroids if needed, is effective. More traditional anti-histamine or dopamine antagonist 
anti-emetic can also be tried. Similar to observed diarrhea, these symptoms are also likely due to 
un-dissolved drug product in the gastrointestinal lumen. Oral fluids have been found to be helpful 
in preventing or alleviating these symptoms.
For detailed instructions on the management of treatment-associated diarrhea and other 
gastrointestinal symptoms, please refer to section 8.1.6.
3.8
PHARMACEUTICAL DATA
BBI608/Placebo
 
Supplied: 
BBI608 is supplied in 80 mg strength capsules.  Placebo is supplied in matching 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: 
BBI608 and Placebo 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 BBI608 or Placebo 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. 
 
Paclitaxel 
Please refer to the paclitaxel package insert for product description, stability information, storage 
instructions, and route of administration. 


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4
TRIAL DESIGN
This trial began as an international multi-center, prospective, double-blind, randomized phase III 
trial of the cancer stem cell inhibitor BBI608 plus weekly paclitaxel versus matched placebo plus 
weekly paclitaxel in patients previously treated for advanced (metastatic or locally advanced and 
unresectable), gastric or gastroesophageal junction (GEJ) adenocarcinoma.  
At the time of this amendment and post-unblinding, the trial will continue in sites with patients 
who have not yet met the primary study endpoint (death), and with patients currently on protocol 
therapy who may receive BBI608 and paclitaxel on study based on the clinical judgement of the 
investigator that this is in the patient’s best interest, providing the patient is fully informed and 
provides consent (see also section 9.1.1 and 9.2.1). Patients will receive study treatment until any 
of the discontinuation criteria are met (see section 11.1) or until September 15 2017, whichever 
occurs first. Patients will be followed for serious adverse events.
4.1
STRATIFICATION
Patients will be stratified by:
1.
Geographical region (Asia vs North America, Europe, and Australia vs South America) 
2.
7LPHWRSURJUHVVLRQRQILUVWOLQHWKHUDS\PRQWKVYVPRQWKVIURPVWDUWRIILUVWOLQH
therapy) 
3.
Disease measurability by RECIST 1.1 (measurable disease present vs not present)
4.
Prior taxane therapy (yes vs no) 
4.2
RANDOMIZATION
Patients will be randomized according to a 1:1 ratio using a permuted block randomization 
procedure to receive one of the following treatments: BBI608 plus weekly paclitaxel or placebo 
plus weekly paclitaxel to a planned sample size of 700 subjects.  
Patients will be randomized to one of the following two arms:  
Arm
Agent(s)
Dose and Route
Duration
1
BBI608  
480 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
Paclitaxel
80 mg/m2 IV, once weekly (for three 
of every four weeks3)
2
Placebo 
and 
Paclitaxel
Orally, two times daily1,2 
80 mg/m2 IV, once weekly (for three 
of every four weeks3)
1
BBI608/Placebo should be taken one hour before or two hours after a meal, two times daily, with approximately 
12 hours between doses. BBI608/Placebo administration will begin 2 days prior to the paclitaxel infusion on day 
1 of cycle 1. These two days are referred to as run-in day 1 and run-in day 2. Run-in day 1 should occur within 2 
working days of patient randomization.
2
Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking 


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BBI608/placebo with approximately 250 mL of fluid over the course of 30 minutes after the dose.
3    Paclitaxel will be administered weekly via approximately a 1 hour infusion, at least 2 hours after the first daily 
dose of BBI608/Placebo, on Days 1, 8 and 15 of every 4 week study cycle.
 4     If paclitaxel is discontinued due to toxicity, BBI608/Placebo should be continued as monotherapy until another 
criterion for stopping treatment is met. If BBI608/Placebo is discontinued due to toxicity, paclitaxel should be 
continued as monotherapy until another discontinuation criterion is met.
5      If no other standard therapies are available at the time of disease progression, and the patient has not experienced 
any adverse events requiring permanent discontinuation, BBI608/Placebo may be continued in monotherapy
until September 15 2017 as long as it is the opinion of the Investigator that the patient may potentially continue 
to be deriving benefit


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4.3
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 gastric and GEJ adenocarcinoma. 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.
4.4
POTENTIAL CONTINUATION OF TREATMENT POST- UNBLINDING
Following unblinding, patients who have not yet met the primary study endpoint (death), and are 
currently on protocol therapy, may receive study treatment based on the clinical judgement of the 
investigator that this is in the patient’s best interest, providing the patient is fully informed and 
provides consent (see also Section 9.1.1 and 9.2.1). Patients will receive study treatment until any 
of the discontinuation criteria are met or until September 15 2017, whichever occurs first (see 
Section 11.1).  


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5
STUDY POPULATION
The trial population will consist of subjects with advanced (metastatic or locally advanced and
unresectable) cytological or histologically confirmed gastric and GEJ adenocarcinoma. Subjects 
will have failed treatment with one regimen containing a fluoropyrimidine and a platinum-based 
agent in the metastatic setting. 
5.1
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. 
Patients must fulfill all of the following criteria to be eligible for admission to the study:
5.1.1 
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.
5.1.2  Must have cytologically or histologically confirmed advanced gastric or GEJ adenocarcinoma
that is metastatic or locally advanced and unresectable (with unresectability as defined by  
National Comprehensive Cancer Network Guidelines for Gastric Cancer [Version 2.2013] and 
Esophageal and Esophagogastric Junction Cancer [Version 2.2013]). GEJ cancers may include 
Siewert Class I, II or III types [Siewert 1996]. 
5.1.3 
Must have failed treatment with one regimen containing at least a platinum/fluoropyrimidine 
doublet for unresectable or metastatic disease. While not mandated, concomitant treatment with 
an anthracycline (epirubicin or doxorubicin) or anti-HER2 therapy (trastuzumab) in this setting is 
allowed. Patients who have progression of disease at any point during neoadjuvant or adjuvant 
treatment with a platinum/fluoropyrimidine doublet or < 6 months after the last dose of 
neoadjuvant or adjuvant treatment may be enrolled. 
 
 
Treatment failure is defined as progression of disease (clinical or radiologic) during first line 
treatment for unresectable or metastatic disease RU  6 months after last dose of first line 
treatment. 
No additional prior lines of therapy in the metastatic setting will be allowed. A patient who has 
received 
neoadjuvant 
or 
adjuvant 
treatment, 
relapsed, 
and 
then 
received 
a 
platinum/fluoropyrimidine doublet as first-line treatment in the unresectable/metastatic setting 
would be allowed, however. 
Patients who have received prior taxane therapy may be enrolled, so long as the taxane was 
administered in the adjuvant or neoadjuvant setting and progression occurred more than 6 months 
following completion of therapy. Patients who were intolerant to paclitaxel are not allowed, 
however. 
5.1.4
Paclitaxel therapy is appropriate for the patient and is recommended by the Investigator.


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5.1.5 
Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as necessary to 
document all sites of disease done within 21 days prior to randomization. Patients with either 
measurable disease OR non-measurable evaluable disease will be eligible. 
5.1.6 
Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
5.1.7 
0XVWEH\HDUVRIDJH.  
5.1.8 
For male or female patient of child producing potential: Must agree to use contraception or take 
measures to avoid pregnancy during the study and for 6 months after the final dose of Paclitaxel 
or for 30 days for female patients and for 90 days for male patients, of the final BBI608/Placebo 
dose if Paclitaxel was 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.
oral contraceptive pill (either combined or progesterone only); or 
f.
two barrier methods, for example diaphragm with spermicide plus condom with 
spermicide to be used by the patient and the partner. 
5.1.9 
Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test 
within 5 days prior to randomization. The minimum sensitivity of the pregnancy test must be 25 
IU/L or equivalent units of HCG.
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. 
5.1.10 Must have alanine transaminase (ALT)  3 × institutional upper limit of normal (ULN) [5 ×
ULN in presence of liver metastases] within 14 days prior to randomization. 
5.1.11 Must have hemoglobin (Hgb)  9.0 g/dL within 14 days prior to randomization. Must not have 
required transfusion within 1 week of baseline Hgb assessment. 
5.1.12 Must have total bilirubin 1.5 × institutional ULN [2.0 x ULN in presence of liver metastases]
within 14 days prior to randomization. 


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5.1.13 Must have creatinine  1.5 × institutional ULN or Creatinine Clearance > 50 ml/min (as 
calculated by the Cockroft-Gault equation) within 14 days prior to randomization.
5.1.14 Must have absolute neutrophil count  1.5 x 109/L within 14 days prior to randomization. 
5.1.15 Must have platelet count  100 x 109/L within 14 days prior to randomization. Must not have 
required transfusion within 1 week of baseline platelet assessment.
5.1.16 Other baseline laboratory evaluations, listed in Section 6.0, must be done within 14 days prior to 
randomization. 
5.1.17 Patient 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 14.6 (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 10-30 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, 10-30 
unstained slides of representative tumor tissue are also acceptable. 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.
5.1.18 Patient must consent to provision of a sample of blood in order that the specific correlative 
marker assays proscribed in Section 14.6 (Correlative Studies) may be conducted. 
5.1.19 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. 
5.1.20 Protocol treatment is to begin within 2 working days of patient randomization. 
5.1.21 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.
5.2
EXCLUSION CRITERIA
Patients who fulfil any of the following criteria are not eligible for admission to the study:
5.2.1 
Anti-cancer chemotherapy or biologic therapy if administered prior to the first planned dose of 
BBI608/placebo within period of time equivalent to the usual cycle length of the regimen. An 
exception is made for oral fluoropyrimidines (e.g. capecitabine, S-1), where a minimum of 10
days since last dose must be observed prior to the first planned dose of BBI608/placebo. 
 
 
Radiotherapy, immunotherapy, or investigational agents within four weeks of first planned dose 


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of BBI608/placebo, with the exception of a single dose of radiation up to 8 Gray (equal to 800 
RAD) with palliative intent for pain control up to 14 days before randomization. 
5.2.2 
Prior taxane therapy in the neoadjuvant or adjuvant setting with progression occurring within 6 
months of completion of taxane therapy; or any taxane therapy in the metastatic setting.
5.2.3 
More than one prior chemotherapy regimen administered in the metastatic setting. 
5.2.4  Major surgery within 4 weeks prior to randomization. 
5.2.5 
Any known symptomatic brain metastases requiring steroids. Patients with treated brain 
metastases must be stable for 4 weeks after completion of that treatment, with image 
documentation required. Patients must have no clinical symptoms from brain metastases and must 
be either off steroids, or on a stable dose of steroids for at least 2 weeks prior to randomization. 
Patients with known leptomeningeal metastases are excluded, even if treated.
5.2.6 
Women who are pregnant or breastfeeding. 
5.2.7 
Gastrointestinal disorder(s) which, in the opinion of the Qualified/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).
5.2.8 
Severe hepatic impairment as per the Paclitaxel Summary of Product Characteristics. 
5.2.9 
History of severe hypersensitivity to paclitaxel or to any of the excipients, including
macrogolglycerol ricinoleate. 
5.2.10   Unable or unwilling to swallow BBI608/placebo capsules daily. 
5.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
clinically significant non-healing or healing wounds, symptomatic congestive heart failure (> 
class II New York Heart Association (NYHA), unstable angina pectoris (including angina 
symptoms at rest, new onset angina begun < 3 months prior, or myocardial infarction < 6 months 
prior), clinically significant cardiac arrhythmia requiring anti-arrhythmic therapy, clinically 
significant valvular or pericardial disease, severe uncontrolled arterial hypertension, 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. 
5.2.12 Peripheral neuropathy  CTCAE Grade 2 at baseline
5.2.13 Patients with a history of other malignancies except: adequately treated non-melanoma skin 
cancer, curatively treated in-situ cancer of the cervix and in-situ cancer of the urinary bladder, or 
other solid tumors curatively treated with no evidence of disease for > 3 years.
5.2.14 Prior treatment with BBI608
5.2.15 Any active disease condition which would render the protocol treatment dangerous or impair the 
ability of the patient to receive protocol therapy.
5.2.16 Any condition (e.g. psychological, geographical, etc.) that does not permit compliance with the 


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protocol. 


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6
PRE-TREATMENT EVALUATION
(See Appendix I)
Investigations
Timing prior to randomization8
History and Physical 
Exam including:
•
Prior medical and therapeutic history1
•
Physical examination
•
Vital signs
•
Height, weight, ECOG performance status
•
Clinical tumor measurements
•
Concurrent medication list
< 14 days
Hematology
•
CBC + differential
•
Platelet count
< 14 days8
Biochemistry
•
Creatinine2, Total Bilirubin, AST, ALT, Alkaline 
Phosphatase, LDH, Albumin, Potassium, Magnesium,
Phosphate
< 14 days8
Urinalysis
•
Dipstick (including protein, specific gravity, glucose 
and blood)
< 14 days8
Cardiac Assessment
•
ECG (12 lead)
< 28 days
Radiology & Imaging
•
CT/MRI scan of chest/abdomen/pelvis with tumor
measurement and evaluation by RECIST 1.1 criteria3
< 21 days
Correlative Studies 
•
Submission of representative block of diagnostic 
tumor tissue4
On request
•
Blood sample collection5
< 14 days
Other Investigations
•
Serum or urine pregnancy test6
< 5days
Adverse Events7  
•
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 
Medical history must include date of diagnosis including histological documentation of malignancy, documentation of 
Her2 status of tumor (if available), smoking history, prior anticancer therapy and prior date(s) of disease progression. 
2 
Baseline creatinine or creatinine clearance may be used to demonstrate eligibility as per section 5.1.
3 
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. 
4 
Details for collection, processing, storing and shipping these samples will be provided in a separate laboratory procedure 
manual.
5      Details for collection, processing, storing and shipping these samples will be provided in a separate laboratory procedure 
manual.
6 
In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent 
units of HCG.
7 
Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see 
Appendix III). 
8     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.


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7
ENTRY/RANDOMIZATION PROCEDURES
7.1
ENTRY PROCEDURES
All randomizations will be done through the BBI608-336 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 eligible patients enrolled on the study by the participating treatment center will be assigned a 
subject identification number which 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 section 5.1 and 5.2 
x
stratification factors 
7.2
STRATIFICATION
The permuted block randomization procedure will balance between treatment arms within each of 
the following stratification factors:
x
Geographical region (Asia vs North America, Europe, and Australia vs South America)  
x
Time to progression on first line therapy (<6 months vs PRQWKVIURPVWDUWRIILUVWOLQH
therapy)
x
Disease measurability by RECIST 1.1 (measurable disease present vs not present)
x
Prior taxane therapy (yes vs no) 
7.3
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 in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting randomization.
All randomized patients are to be followed until death or until sites are informed by the study 
sponsor that further follow-up is no longer required.  


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8
TREATMENT PLAN
Protocol treatment is to begin within 2 working days of patient randomization. 
8.1
TREATMENT PLAN
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment will be offered to 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.
8.1.1 
BBI608 Adverse Event Prophylaxis 
Gastrointestinal Prophylaxis 
The major adverse events associated with the use of BBI608 are gastrointestinal events (nausea, 
diarrhea, and abdominal cramping) and fatigue. Fatigue is often secondary to gastrointestinal 
events. There is no hematologic toxicity associated with BBI608. We recommend that pre-exiting 
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 BBI608 are strongly recommended for all patients. Details regarding the use of 
prophylactic medication for the management of common BBI608 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 BBI608 treatment has been observed. 
Pre-Medication Recommendations for BBI608: 
Category
Specific Measures
Start
End
Anti-Diarrheal
Loperamide 4 mg BID
or
Diphenoxylate/Atropine 
5 mg BID
24 hour prior to the 
first dose of BBI608 
on Cycle 1, Day 1 
Stop anti-diarrheal if there are no 
bowel movements by the morning 
of Cycle 1, Day 3.
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 Cycle 1, 
Day 1
May be continued and/or modified
at 
discretion 
of 
treating 
investigator
8.1.2 
Drug Administration
Treatment will progress in 4 week (28 day) study cycles, with BBI608/Placebo administered 
continuously, and paclitaxel administered once weekly, 3 out of 4 weeks. BBI608/Placebo 
administration will begin 2 days prior to the paclitaxel infusion on day 1 of cycle 1. These two 
days are referred to as run-in day 1 and run-in day 2. 


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Arm
Agent(s)
Dose and Route
Duration
1
BBI608  
480 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
Paclitaxel
80 mg/m2 IV, once weekly (for three 
of every four weeks3)
2
Placebo 
and 
Paclitaxel
Orally, two times daily1,2 
80 mg/m2 IV, once weekly (for three 
of every four weeks3)
1
BBI608/Placebo should be taken one hour before or two hours after a meal, two times daily, with approximately 
12 hours between doses. BBI608/Placebo administration will begin 2 days prior to the paclitaxel infusion on day 
1 of cycle 1. These two days are referred to as run-in day 1 and run-in day 2. Run-in day 1 should occur within 2 
working days of patient randomization.
2  
Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking 
BBI608/placebo with approximately 250 mL of fluid over the course of 30 minutes after the dose.
3    Paclitaxel will be administered weekly via approximately a 1 hour infusion, at least 2 hours after the first daily 
dose of BBI608/Placebo, on Days 1, 8 and 15 of every 4 week study cycle.  
4
If paclitaxel is discontinued due to toxicity, BBI608/Placebo should be continued as monotherapy until another 
criterion for stopping treatment is met. If BBI608/Placebo is discontinued due to toxicity, paclitaxel should be 
continued as monotherapy until another criterion for stopping treatment is met.
5
If no other standard therapies are available at the time of disease progression, and the patient has not experienced 
any adverse events requiring permanent discontinuation, BBI608/Placebo may be continued in monotherapy as 
long as it is the opinion of the Investigator that the patient may potentially continue to be deriving benefit
Patients will receive BBI608 or placebo 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.
Paclitaxel will be administered via IV at 80 mg/m2 once weekly as approximately a 1-hour 
infusion, on Days 1, 8 and 15 of each 28 day study cycle. Paclitaxel will be administered at least 
2 hours after the first daily dose of BBI608/Placebo. Paclitaxel administration should proceed
based on body surface area (BSA) according to the manufacturer’s instructions and local standard 
practice (with respect to pre-treatment laboratory evaluation, clinical assessment, pre-medication, 
and monitoring during and after the infusion). The BSA of an individual can be calculated from 
the formula of Dubois [BSA (m 2) = Body weight (kg) 0.425 X Height (cm) 0.725 X 0.007184]. 
If paclitaxel is permanently discontinued due to toxicity, BBI608/Placebo should be continued as 
monotherapy until September 15 2017 or until another criterion for stopping treatment is met,
whichever occurs first. If BBI608/Placebo is permanently discontinued due to toxicity, paclitaxel 
should be continued as monotherapy until September 15 2017 or until another criterion for 
stopping treatment is met.
As BBI608 targets cancer stem cells, it is possible that continued therapy after progressive 
disease per RECIST 1.1 may provide clinical benefit. If no other standard therapies are available 
at the time of disease progression, and the patient has not experienced any adverse events 
requiring permanent discontinuation, BBI608/Placebo may be continued in monotherapy as long 
as it is the opinion of the Investigator that the patient may be deriving benefit with continued 
therapy. 


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Handling instructions for BBI608/placebo will be provided to all sites. Investigators may refer to 
the Investigator Brochure for detailed instructions. 
Drug Administration Post-Unblinding 
Following this amendment and post-unblinding, the trial will continue in sites with patients who 
have not yet met the primary study endpoint (death), and with patients currently on protocol 
therapy and who may receive study treatment based on the clinical judgement of the investigator
that this is in the patient’s best interest, providing the patient is fully informed and provides 
consent (see also Section 9.1.1 and 9.2.1). Patients will receive study supply BBI608 until any of 
the discontinuation criteria are met (see section 11.1) or until September 15 2017. Patients will be 
followed for serious adverse events.
Arm
Agent(s)
Dose and Route
Duration
1
BBI608  
480 mg orally two times daily1,2 
Patients may continue to receive 
protocol therapy until September 15 
2017 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. 4,5,6
Paclitaxel
80 mg/m2 IV, once weekly (for three 
of every four weeks3)
2
Paclitaxel
80 mg/m2 IV, once weekly (for three 
of every four weeks3)
1
BBI608 should be taken one hour before or two hours after a meal, two times daily, with approximately 12 hours 
between doses. BBI608 administration will begin 2 days prior to the paclitaxel infusion on day 1 of cycle 1. 
These two days are referred to as run-in day 1 and run-in day 2. Run-in day 1 should occur within 2 working 
days of patient randomization.
2  
Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking 
BBI608 with approximately 250 mL of fluid over the course of 30 minutes after the dose.
3    Paclitaxel will be administered weekly via approximately a 1 hour infusion, at least 2 hours after the first daily 
dose of BBI608, on Days 1, 8 and 15 of every 4 week study cycle. 
4
If paclitaxel is discontinued due to toxicity, BBI608 may be continued as monotherapy until September 15 2017 
or until another criterion for stopping treatment is met, whichever occurs first. If BBI608 is discontinued due to 
toxicity, paclitaxel should be continued as monotherapy until September 15 2017 or until another criterion for 
stopping treatment is met, whichever occurs first.
5
If no other standard therapies are available at the time of disease progression, and the patient has not experienced 
any adverse events requiring permanent discontinuation, BBI608 may be continued in monotherapy until 
September 15 2017 as long as it is the opinion of the Investigator that the patient may potentially continue to be 
deriving benefit.
6
Study treatment with BBI608 with or without paclitaxel may be continued until September 15 2017 as long as the 
patient has not met any other study discontinuation criteria and as long as it is the opinion of the Investigator that 
the patient may continue to be deriving benefit.
8.1.3 
Blinding/Unblinding 
This trial was initiated as a double blind, placebo controlled study. Following the interim 
analysis, the study was amended to allow un-blinding of patients receiving study treatment. The 
Investigator may break the blind to determine study arm assignment of each individual patient 
remaining on study treatment in order to help inform the patient prior to determining if study 


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treatment should be continued or discontinued. 
8.1.4 
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.
8.1.5 
BBI608/Placebo Dose Modification  
The major adverse events associated with the use of BBI608 are gastrointestinal issues (nausea, 
diarrhea, and abdominal cramping) and fatigue. Fatigue is often secondary to gastrointestinal 
events. There is no hematologic toxicity associated with BBI608. We recommend that standing 
bowel regimens, such as stool softeners, be held at start of study and may be resumed in cases of 
no bowel movement during the first 2 days of protocol treatment. Fiber supplementation may be 
continued.  
The guidelines which 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 III).  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.
8.1.5.1 Hematologic Adverse Events
No hematologic toxicity related to BBI608 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 related to BBI608/placebo, 
please contact the study Medical monitor, so that together with the study Investigator, the 
Medical Monitor can make recommendations on medical management. Since a Grade 3 or 4 
hematologic event attributed to BBI608 has not been reported, a prompt evaluation for an 
alternate explanation is strongly recommended. 
8.1.5.2 Non-Hematologic Adverse Events
Toxic effects will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 (Appendix III).  
BBI608/Placebo Dose Modification:
Suspected BBI608 -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, 


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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. 
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 
UHGXFHGWRtolerable grade 2. 
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. 320 mg AM/240 mg PM).
BBI608/Placebo Dose Modification Table:
Dose Level
Dose
Full dose
480 mg twice daily (q12h)
Modification Level-1 
240 mg twice daily (q12h), up titrate as tolerated**
Modification Level-2 
80 mg twice daily (q12h), up-titrate as tolerated**
Modification Level-3 
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 480
    mg two times daily. 


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Recommended symptom-specific supportive treatment for common BBI608-related adverse 
events is as follows (unless contraindicated):
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
Budesonide (Entocort EC): Corticosteroid with limited 
systemic absorption;  9 mg once daily for 8 to 12 weeks
Details regarding the use of supporting medication for the management of common BBI608-
related adverse events are specified in the supplementary Adverse Event Management hand out as 
well as in the Pharmacy Manual.
8.1.5.3 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. Patients can be reassured that these effects have no long term consequences, and 
that the effects are completely reversible. Dosing can be continued in the presence of these 
events. 
8.1.6
Paclitaxel Dose Modification
Prior to each dose of paclitaxel, the absolute neutrophil count (ANC) and platelet count should be 
evaluated. If abnormalities are observed, and in the opinion of the investigator the 
myelosupression is most likely a result of paclitaxel therapy, dose modification should occur in 
the following manner:


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Lab Value
Investigator Action
$1&[9/L AND SODWHOHWV[9/L
Continue treatment at full (current) dose.
ANC 1.0-1.5 x 109/L OR platelets 75-100 x 109/L  
Consider treatment at next lower dose level or more (at 
discretion of Investigator)*. Paclitaxel does not need to be 
held.
ANC <1.0 x 109/L OR platelets < 75 x 109/L
Hold paclitaxel for that week. Recommence treatment at 
the next lower dose level or more at the next scheduled visit 
if ANC and platelet count have recovered $1& x
109/DQGSODWHOHWV[9/L). **
*or maintain at full (current) dose
** Neupogen/G-CSF may be used at the discretion of the Investigator.
The paclitaxel dose should be reduced by one or more dose levels if the dose is held more than 
once during a 4 week cycle. 
For patients who experience a grade 3 non-hematologic adverse event (except alopecia), and in 
the opinion of the investigator the event is most likely a result of paclitaxel therapy, the dose of 
paclitaxel should be held until the adverse event has improved to grade 2, and then reduced by 
one or more dose levels for subsequent doses of paclitaxel.
Paclitaxel Dose Modification Table: 
Dose Level*
Dose
Full dose
80 mg/m2
Modification Level-1 
70 mg/m2
Modification Level-2 
60 mg/m2
Modification Level-3 
40 mg/m2**
* If the dose of paclitaxel is reduced because of potentially-related AEs, subsequent dose increases are not permitted.
** If paclitaxel dose is required to be reduced below 40 mg/m2, or if any life-threatening paclitaxel-related events occur, 
paclitaxel should be permanently discontinued.
When laboratory parameters indicate that the dose of paclitaxel should be delayed, the 
infusion of paclitaxel scheduled for that day is not given.  The infusion is considered 
“missed”, and is not made up at another time.  The next paclitaxel infusion would be 
according to the protocol specified administration schedule.  Laboratory parameters should be 
evaluated prior to the next scheduled dose of paclitaxel and actions taken according to the 
protocol parameters.
If a toxicity is thought by the Investigator to be related to both BBI608/Placebo and paclitaxel, 
then the dose modification rules for both agents should be followed. 
Paclitaxel has been shown to be a teratogen, embryotoxic and a mutagen. Therefore, female and 
male patients of reproductive age must take contraceptive measures during therapy and for 6 
months after last dose of paclitaxel. Additionally, male patients are advised to seek advice on 
cryopreservation of sperm prior to treatment with paclitaxel due to the possibility of irreversible 


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infertility with paclitaxel therapy.
If paclitaxel is held or discontinued for toxicities solely related to paclitaxel, BBI/placebo therapy 
should be continued. 
If BBI608/Placebo is permanently discontinued due to toxicity, paclitaxel therapy should be 
continued. 
8.1.7 
Concomitant Medications/Procedures 
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). 
As per the Summary of Product Characteristics for paclitaxel, although CYP2C8 inhibitors or 
inducers are permitted, caution should be exercised when co-administering these agents with 
paclitaxel. Similarly, caution should be exercised while co-administering CYP1A2 inhibitors 
and/or substrates of CYP enzymes 1A2, 2D6, 2C19 and 3A4 with BBI608. 
Palliative and supportive care for disease-related symptoms will be offered to all patients. 
All palliative and supportive care measures may be administered to patients in either study arm at 
the Investigator’s discretion. Incident palliative radiotherapy is permitted in both study arms 
while on study, but requirement of radiation to the target lesion(s) will qualify the patient as 
having disease progression.
Although patients will have either metastatic or locally advanced but unresectable disease at 
randomization, it is possible that a patient’s tumor may become operable over the course of 
treatment. Resection is allowed, and it is recommended that paclitaxel be held for 1 week prior to 
the surgery and 2 weeks after the surgery, or until post-surgical recovery, whichever is longer.
BBI608 should be held 24 hours prior to the surgery to 1 week after the surgery as tolerated. 
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. 
8.1.8 
Duration of Therapy
Patients may continue to receive protocol therapy until September 15 2017 as long as they have 
not experienced any adverse events requiring permanent discontinuation of protocol treatment
and have not demonstrated disease progression based on RECIST 1.1 criteria. For details 
concerning toxicity, please consult section 8.1.4 and 8.1.5. For a complete list of general criteria 
for stopping study treatment, please see section 12.0.  
8.1.9 
Patient Compliance 
Treatment compliance for BBI608/Placebo is defined as the ratio, expressed as a percentage, of
the number of capsules (BBI608 or placebo) taken by a patient over the course of a time interval 


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to the number of capsules intended to be taken over that same time interval as per the dose 
prescribed by the Investigator.  
Treatment compliance for paclitaxel is defined as the ratio, expressed as a percentage, of the 
amount of paclitaxel administered to a patient (milligrams/m2) over the course of a time interval 
to amount of paclitaxel intended to be administered over that same time interval as per the dose 
prescribed by the Investigator.  
Treatment compliance in both arms will be monitored by drug accountability, as well as the 
monitoring of patient-reported compliance. 
9
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 Quality 
of Life questionnaires, will not be delayed, but should continue at the time indicated from 
randomization.
9.1
EVALUATION DURING PROTOCOL TREATMENT
Investigations
Timing
Physical 
Examination 
y Physical examination
y Vital signs
y ECOG Performance status
y Concurrent medication list
Day 1 of every 28 day study cycle, starting with 
Cycle 21 (+/-3 days)
Weight
y Weight
Day 1 of every 28 day study cycle1
AND 
On each additional paclitaxel infusion day
(hematology investigations should be performed 
within 72 hours prior to Day 1 of each study cycle,
and within 72 hours prior to each paclitaxel 
infusion)
Hematology
y CBC + differential, Platelet count
Biochemistry
y Creatinine, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, LDH, Albumin, 
Potassium, Magnesium, Phosphate
Day 1 of every 28 day study cycle, starting with 
Cycle 21  
(laboratory investigations should be performed 
within72 hours prior to Day 1 of each study cycle) 
Urinalysis
y Dipstick (including protein, specific 
gravity, glucose and blood)
Other Investigations
y Serum or urine pregnancy test 2
Adverse Events 3
y Adverse Event evaluation  must be done at 
each study visit3
Day 1 of every 28 day study cycle
AND 
On each additional paclitaxel infusion day
y Adverse Event evaluation by phone3
On run-in day 2 
Cardiology 
Assessment
y ECG
Within 2 hours of completion of paclitaxel infusion
on first day of paclitaxel treatment and as clinically 
indicated thereafter


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Serious Adverse 
Events 4
Serious Adverse Event evaluation will be done from the time of informed consent and for 30
days following the last dose of protocol therapy.
Radiology & 
Imaging
y CT/MRI scan as per baseline assessment 
with tumor measurement and evaluation 
by RECIST 1.1 criteria5
Every 8 weeks (every 56 days) after randomization5
(+/-5 days)
Correlative Studies
y Submission of blood samples6
At 4 weeks after randomization (+/-3 days)
Sparse PK Collection
y Submission of blood plasma samples to 
central lab6
At Day 8 and 15 of Cycle 1 and Day 1 of Cycle 2 
(corresponding to the 2nd, 3rd and 4th paclitaxel 
infusion days)
Quality of Life
y EORTC QLQ-C30 7
At 4, 8, 12, 16 and 24 weeks after randomization
(+/- 3 days)
Paclitaxel 
Administration
y IV paclitaxel infusion 
Days 1, 8 and 15 of every 4 week (28 day) study 
cycle (+/-3 days)
1
Patients are to be assessed every 4 weeks (28 days) while on study medication and until September 15 2017 or until the first 
regularly scheduled 4 week assessment at which the patient has been off study therapy for a minimum of 28 days, whichever 
occurs first. 
2     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.
3 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events version 
4.0 (see Appendix III). 
4 
Serious adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events
version 4.0 (see Appendix III). 
5    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 September 15 2017 or until progressive disease is 
documented (as described in section 10), whichever occurs first. 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 until September 15 2017.
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.
9.1.1      Patient Evaluation After Unblinding and Continued Protocol Treatment
Please refer and follow section 9.1 until permanent discontinuation of protocol treatment or until 
September 15 2017, whichever occurs first.  


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9.2 EVALUATION AFTER PROTOCOL TREATMENT DISCONTINUATION
Investigations
Timing
Physical 
Examination 
y Physical examination
y Vital signs
y Weight + ECOG Performance status
y Subsequent cancer treatments1
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 evaluation must be done 
at each study visit2
Serious Adverse 
Events 3
Serious Adverse Event evaluation will be done from the time of informed consent and for 30
days following the last dose of protocol therapy.
Overall Survival
y Assess for survival of patient 4
At the first regularly scheduled 4 week assessment 
at which the patient has been off study therapy for a 
minimum of 28 days, and every 8 weeks (56 days) 
thereafter. (+/- 3 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, 
Potassium, Magnesium, Phosphate
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 protocol treatment discontinuation Physical examination, Vital signs, ECOG status and subsequent cancer treatment 
will be recorded at the 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 III). 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 related to protocol treatment will be recorded and graded according to the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (see Appendix III). 
4 
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 10). 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.
7 
Details for collection, processing, storing and shipping these samples will be provided in a separate procedure manual. The 
       sample will be collected only if the patient discontinues protocol treatment prior to 4 weeks of therapy.  
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 
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.
9.2.1 Patient evaluation After Permanent Discontinuation of Protocol Therapy, Post-Unblinding 
Sites should complete the evaluations for the current reporting period as per section 9.2. Subsequently, 
evaluations can switch as follows:
Investigations
Timing
Physical 
Examination 
y Physical examination
y Vital signs
y Weight + ECOG Performance status
y Subsequent cancer treatments1
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 evaluation must be done 
at each study visit2
Serious Adverse 
Events 3
Serious Adverse Event evaluation will be done from the time of informed consent and for 30 
days following the last dose of protocol therapy.
Overall Survival
y Assess for survival of patient 4
At the first regularly scheduled 4 week assessment 
at which the patient has been off study therapy for a 
minimum of 28 days, and every 8 weeks (56 days) 
thereafter. (+/- 3 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, 
Potassium, Magnesium, Phosphate
Urinalysis
y Dipstick(including protein, specific 
gravity, glucose and blood)


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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) 
1
After protocol treatment discontinuation Physical examination, Vital signs, ECOG status and subsequent cancer treatment 
will be recorded at the regularly scheduled 4 week assessment at which the patient has been off study therapy for a minimum 
of 28 days (+/- 3 days) or until September 15 2017, whichever occurs first. Subsequent cancer treatment will be captured 
until end of study (September 15 2017). 
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 III). 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 related to protocol treatment will be recorded and graded according to the NCI Common Terminology 
Criteria for Adverse Events version 4.0 (see Appendix III). 
4 
In the event that patient is unable to attend clinic, post-progression follow-up may be by means of telephone contact until 
study closure. 
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 September 15 2017 or until progressive disease is 
documented (as described in section 10), whichever occurs first. 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 or until September 15 2017, whichever occurs first.
7 
Details for collection, processing, storing and shipping these samples will be provided in a separate procedure manual. The 
       sample will be collected only if the patient discontinues protocol treatment prior to 4 weeks of therapy.  
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 
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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10 CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS
10.1 DEFINITIONS
10.1.1 Evaluable for Adverse Events: All patients who have received at least one dose of 
BBI608/placebo will be evaluable for adverse events from the time of their first dose of 
BBI608/placebo. 
10.1.2 Evaluable for Overall Survival (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.  
10.1.3 Evaluable for Progression Free Survival (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. 
10.1.4 Evaluable for Objective Response Rate (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. 
10.1.5
Evaluable for Disease Control Rate (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.
10.1.6 Evaluable for Quality of Life Assessment: All patients who have completed the baseline quality of 
life questionnaire and at least one other QoL questionnaire are evaluable.
10.2 RESPONSE AND EVALUATION ENDPOINTS
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumors) committee.


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10.2.1 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. 
10.2.2 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.
10.2.3 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. 
10.2.4 Non-target Lesions: All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above those listed as target lesions are considered non-target lesions. Measurements are 
not required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”.
10.2.5 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 


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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). 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. 
    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
documented 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
No Target
CR
No
CR
tumor nodes < 10mm
No Target
Non-CR/non-PD
No
Non-CR/non-PD
No Target
Not all evaluated
No
NE
No Target
Unequivocal PD
Any
PD
No Target
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.
10.3 RESPONSE DURATION


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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).
10.4 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).
10.5 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
1If Iodine contrast media is medically contraindicated.
2If Iodine contrast media is medically contraindicated and MRI cannot be performed.
10.5.1 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.
10.5.2 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.  
10.5.3 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. 


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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). 
10.5.4 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. 
10.5.5 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. 
10.5.6 Cytology/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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11 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 III).   
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. In addition, all “reportable” serious adverse events 
are subject to expedited reporting to the Sponsor. The term ‘reportable SAE’ is used in the 
definitions which follow to describe those SAE’s which are subject to expedited reporting to the 
Sponsor.  
11.1 SERIOUS ADVERSE EVENT REPORTING ON STUDY POST-UNBLINDING
Serious adverse events that are considered related (i.e. possibly, probably or definitely) to 
protocol therapy must continue to be reported in an expedited manner (see Section 10) for 
patients receiving BBI608 or paclitaxel on study after unblinding. 
11.2 DEFINITION OF A PROTOCOL REPORTABLE SERIOUS ADVERSE EVENT
x
All serious adverse events must be reported in an expedited manner (see section 11.2 for 
reporting instructions). These include events occurring from the time the patient signs 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.  
x
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, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care);

results in persistent or significant disability or incapacity;

is a congenital anomaly/birth defect. 
x
NOTE: Serious adverse events which are unequivocally related to the underlying malignancy 
or disease progression do NOT require expedited reporting. These include such adverse 
events as admission for pain control, palliative care or paracentesis of malignant effusions.
x
In addition, the following events will NOT be recorded as AEs (or SAEs):

lack of efficacy/disease progression (will be recorded separately on CRF);

elective hospitalization for medical, radiological or surgical procedures for treatment of 
disease or to simplify treatment for study procedures (will be recorded separately on 
CRF);

hospitalization for palliative care or pain control. 
 
 


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Note: clinically significant test results should be recorded on the AE CRF using the appropriate 
CTCAE description and grading scale. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization and which are NOT definitively related to the 
underlying malignancy or disease progression but may jeopardize the patient or may require 
intervention to prevent one of the events listed above.  
11.3 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 BBI608/Placebo. 
All protocol specified (section 11.1) reportable serious adverse events must be reported using the 
SAE Report Form for this trial. 
Within 24 hours: 
Submit Initial Serious Adverse Event Report 
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.  
11.4 PROCEDURES IN CASE OF AN OVERDOSE
Use of BBI608/Placebo 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 BBI608/Placebo, 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 BBI608/Placebo 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 paclitaxel product label for 
guidance on the definition of an overdose of this agent as well as for guidance on reporting of any 
AE or SAE associated with paclitaxel overdose. 
11.5 OTHER PROTOCOL REPORTABLE EVENTS – PREGNANCY/EXPOSURE REPORTING
Women of childbearing potential (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 


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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.  
11.4.1 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 (Section 5.1). 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. 
11.4.2 Pregnancy Occurring in WOCBP Exposed to Study Agent 
Any female participant who becomes pregnant during the course of the trial should be instructed 
to stop taking study medication immediately.
The investigator should provide counselling and discuss the risks and possible side effects to the 
embryo/fetus from BBI608 and paclitaxel. Monitoring should continue until conclusion of the 
pregnancy. The same should occur for female partners of a male participant, or any female 
exposed to BBI608 when appropriate and compliant with local policy. 
11.4.3 Pregnancy/Exposure Reporting 
The investigator is required to report to the sponsor any pregnancy where the embryo/fetus could 
have been exposed to BBI608. 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 BBI608 as well as until 6 months following last paclitaxel 
infusion 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 


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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. 


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11.6 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 protocol treatment: 
y
Unexpected adverse events are those which are not consistent in either nature or severity 
with information contained in the Investigator’s Brochure 
y
Adverse events considered related to protocol treatment are those events which lack a 
plausible alternate explanation.
Boston Biomedical will determine which SAEs meet the criteria for regulatory reporting.  
11.7 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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12 PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
12.1 CRITERIA FOR DISCONTINUING PROTOCOL TREATMENT
Patients should stop protocol treatment in the following instances:
y
Progressive Disease (see section 10.2.5).
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
y
Post-unblinding, the trial will continue at sites with patients who have not yet met the primary 
study endpoint (death), and with patients currently on protocol therapy who may receive 
BBI608 on study based on the clinical judgement of the investigator that this is in the 
patient’s best interest, providing the patient is fully informed and provides consent (see also 
section 9.1.1 and 9.2.1). Patients will receive study treatment until any of the discontinuation 
criteria are met or until September 15 2017, whichever occurs first.
If a patient discontinues protocol treatment for a reason other than objective progression, every 
effort should be made to obtain tumor evaluations on the same schedule until September 15 2017 
or until progression is observed, whichever occurs first.
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. 
12.2 DURATION OF PROTOCOL TREATMENT 
Patients may continue to receive protocol therapy until September 15 2017 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. 
As BBI608 targets cancer stem cells, it is possible that continued therapy after progressive 
disease per RECIST 1.1 may provide clinical benefit. If no other standard therapies are available 
at the time of disease progression, and the patient has not experienced any adverse events 
requiring permanent discontinuation, BBI608 may be continued in monotherapy until September 
15 2017 as long as it is the opinion of the Investigator that the patient may potentially be deriving 
benefit. 
12.3 THERAPY AFTER PROTOCOL TREATMENT IS STOPPED
Treatment after all protocol therapy has been discontinued is at the discretion of the Investigator.
Information on post-study anti-cancer treatment will be collected in this study until September 15 
2017. 
12.4 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 9.2). 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.
12.5 UNBLINDING
All patients receiving protocol treatment at the time of this amendment must be unblinded. The
process of unblinding patient treatment is contained in Appendix V. 


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13 CENTRAL REVIEW PROCEDURES, TISSUE COLLECTION, AND CORRELATIVE STUDIES
13.1 CENTRAL RADIOLOGY REVIEW
There will be no central radiology review for this study. 
13.2 CENTRAL PATHOLOGY REVIEW
There will be no central pathology review for this study. 
13.3 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 14.6 (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 10-30 unstained slides of representative tumor tissue are requested. Where it is not 
possible to obtain two 2 mm cores of tumor from the block, 10-30 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 10-30 specimen slides are preferred. Where it is not possible to obtain two 2 mm cores of 
tumor from the block, 10-30 unstained slides of representative tumor tissue are also 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 and the surgical/ histology number. 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.
13.4 SPARSE PHARMACOKINETIC PLASMA SAMPLE COLLECTION
Plasma samples for sparse pharmacokinetics (PK) analysis will be obtained from all patients at 
the study visits occurring on Day 8 and 15 of Cycle 1 and Day 1 of Cycle 2 (corresponding to 
paclitaxel infusion days).  
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 BBI608/Placebo until they arrive in 


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clinic. After arrival in the clinic, but within approximately 5 minutes prior to administration of the 
first daily dose of BBI608/Placebo, a plasma sample will be obtained. Paclitaxel infusion will be 
started approximately 2 hours after BBI608/Placebo administration. A second plasma sample will 
be obtained within approximately 30 minutes after the end of the 1 hour paclitaxel infusion.  
Day 15 (Cycle 1) Study Visit: 
On Day 15 (Cycle 1) visit, patients will be instructed to take BBI608/Placebo as normal.
Paclitaxel infusion will be given in clinic at least 2 hours after the BBI608/Placebo 
administration. A single plasma sample will be obtained between 2 and 4 hours after the
completion of the paclitaxel infusion.  
Day 1 (Cycle 2) Study Visit: 
On Day 1 (Cycle 2) visit, patients will be instructed to take BBI608/Placebo as normal. Paclitaxel 
infusion will be given in clinic at least 2 hours after the BBI608/Placebo administration. A single 
plasma sample will be obtained between 5 and 7 hours after the completion of the paclitaxel 
infusion. 
For all days during which a plasma sample is obtained for PK analysis, the precise time of all 
doses of BBI608/Placebo (on the day of sampling and the day prior), the precise time of the 
initiation of paclitaxel 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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14 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.
14.1 OBJECTIVES AND DESIGN
The primary objective of this study is to assess the effect of orally administered BBI608 plus 
weekly paclitaxel, in comparison to placebo plus weekly paclitaxel on the Overall Survival in 
patients with pre-treated advanced gastric/GEJ adenocarcinoma.
Secondary objectives include comparisons of Overall Survival in the predefined biomarker-
positive population, Progression Free Survival, and Adverse Events between the two treatment 
arms.
This study began as a multi-center, prospective, double blind, placebo controlled, randomized 
phase III trial. Patients will be randomized to receive either BBI608 plus weekly paclitaxel, or 
placebo plus weekly paclitaxel in a 1:1 ratio and will be stratified by geographical region (Asia 
versus North America, Europe, and Australia versus South America), time to progression on first 
line therapy (<6 months versus PRQWKVIURPVWDUWRIILrst line therapy), disease measurability 
by RECIST 1.1 (measurable disease present vs not present), and prior taxane therapy (yes versus
no). 
At the time of this amendment, patients remaining on study treatment will be unblinded and the 
study will continue as a randomized, open-label, multi-center, phase III study of BBI608 plus 
weekly paclitaxel vs. weekly paclitaxel for adult patients with advanced, pre-treated gastric or
GEJ adenocarcinoma. 
14.2 STUDY ENDPOINTS AND ANALYSIS
Primary Endpoint: 
Overall Survival in the General Study Population 
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 hierarchical testing for secondary outcomes 
detailed below and, as such, do not control for type I error. Geographical region (Asia versus


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North America, Europe, and Australia versus South America), time to progression on first line 
therapy (<6 months versus PRQWKVIURPVWDUWRIILrst line therapy), disease measurability by 
RECIST 1.1 (measurable disease present vs not present), and prior taxane therapy (yes versus no)
will be the stratification factors to define the stratified Cox proportional hazards model. Besides 
the treatment factor (BBI608+paclitaxel versus placebo+paclitaxel), the following factors at 
patient entry will be included in the stratified Cox proportional hazards model: 
x
Number of previous chemotherapy drug classes [platinum, fluropyrimidine, taxane,
anthracyclines], including during adjuvant or neoadjuvant therapy (< 3 versus > 3)
x
Age (< 65 versus > 65)
x
Sex (male versus female)
x
Prior trastuzumab-containing therapy (yes versus no)
x
Location of primary tumor (gastric versus GEJ) 
x
Prior radiotherapy (yes versus no) 
x
Presence of peritoneal metastases (yes versus no) 
x
Histologic type (diffuse, intestinal, mixed, other) 
x
Received post protocol anticancer treatment [i.e. 3rd line regimen] (yes versus no)
x
Number of organ sites involved at baseline versus <2) 
x
Presence of primary tumor (present versus absent) 
A subset analysis for the primary endpoint (OS) as sensitivity analyses will be conducted to 
address the benefit of BBI608 between the groups defined by the above factors and the following: 
x
Geographical region (Asia vs North America, Europe, and Australia vs South America)
x
Time to progression on first line therapy (<6 months versus PRQWKVIURPVWDUWRIILUVWOLQH
therapy) 
x
Disease measurability by RECIST 1.1 (measurable disease present vs not present)
x
Prior taxane therapy (yes versus no) 
x
Race (white, black, Asian, other)
Again, these sensitivity analyses are not included in the hierarchical testing for secondary 
outcomes detailed below and, as such, do not control for type I error. 
Secondary Endpoints 
The following secondary outcomes will be inferentially assessed using a hierarchical analysis 
method (eg, inferential analysis will stop and not continue to subsequent secondary outcomes 
after obtaining a probability greater than 0.05). The order of endpoint presentation below reflects 
the hierarchy of inferential testing. Inferential assessment of secondary outcomes will take place 
only if the primary outcome (OS) is found to differ significantly between treatments when 
analyzed via the primary analysis method detailed above.
Overall Survival in the Predefined Biomarker-positive Population
Overall Survival (OS) in the biomarker-SRVLWLYHSRSXODWLRQ>WKRVHSDWLHQWVZLWKQXFOHDUȕ-catenin 
positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) 
archival tissue] is defined as the time from randomization to death due to any cause. All analyses 


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for OS in the general study population will also be performed for OS in the biomarker-positive 
population, using similar methodology. 
Progression-Free Survival in the General Study Population 
Progression-Free Survival (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. All analyses for OS in the general study population will also be performed for 
PFS in the general study population, using similar methodology. 
Progression-Free Survival in the Predefined Biomarker-positive Population 
PFS in the biomarker-SRVLWLYH SRSXODWLRQ >WKRVH SDWLHQWV ZLWK QXFOHDU ȕ-catenin positivity on 
immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) archival 
tissue] is defined as the time from randomization to the first objective documentation of disease 
progression or death due to any cause. All analyses for OS in the general study population will 
also be performed for PFS in the biomarker-positive population, using similar methodology. 
Objective Response Rate in the General Study Population 
Objective Response (ORR) is defined as the proportion of patients with a documented complete 
response or partial response (CR + PR) based on RECIST 1.1. The primary estimate of ORR will 
be based on patients with measurable disease by RECIST 1.1 at randomization.  
Disease Control Rate in the General Study Population 
Disease Control Rate (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.  
Safety Analysis
All patients who have received at least one dose of study treatment (either BBI608/Placebo or 
paclitaxel) 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 will be used to compare adverse events 
between the two arms if required.
14.3 SAMPLE SIZE AND DURATION OF STUDY
The primary study endpoint is Overall Survival (OS).  The study is designed to have a power of 
90% and a two-sided alpha of 5% to detect a 24% reduction in the continuous risk of death (HR 
0.76, which corresponds to an increase of median survival from 7.36 to 9.67 months) in the 
Intention to Treat (ITT) general study population.  It is estimated that 566 events will be required 
to detect this reduction which would be observed by randomizing 700 patients over 24 months 
and following them for an additional 12 months (including up to 5% of yearly dropouts).   
Assuming that 40% of deaths occur in patients who are biomarker-positive, the study will have 
90% power to detect a 31% reduction in the risk of death (HR 0.69) at two-sided 0.05 alpha level 
in the secondary analysis of the biomarker-positive population.   
When the required number of events for the primary endpoint has been reached, all randomized 
patients still alive will have continued study follow up through to their deaths.  


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14.4 SAFETY MONITORING
Adverse events will be monitored on an on-going basis by central review. 
14.5 INTERIM AND FINAL ANALYSES 
There will be one interim analysis in this study to be presented to the independent Data Safety 
and Monitoring Board (DSMB). Additionally, DSMB will review safety during conduct of the 
study. The role and responsibility of the DSMB will be defined in a separate Charter.
The interim analysis will be performed on OS, the primary endpoint of this study, when at least 
2/3rd of the required number of events (380) have been observed. This analysis, based on the 
stratified log-rank test adjusting for the stratification variables at randomization, will test the 
following: 
H0VXUYLYDORQ%%,SDFOLWD[HOVXUYLYDORQSODFHERSDFOLWD[HO
versus
H1: survival on BBI608+paclitaxel > survival on placebo + paclitaxel 
The comparison of the overall population will be tested based on a generalization of the Lan-
DeMets error spending function approach using an O’Brien-Fleming stopping boundary to reject 
H0, controlling for a two-sided alpha of 5% at the end of the study. For example, if exactly 380 
deaths (67% of the required events) were in the locked database for the interim analysis, the 
nominal critical point for rejecting H0 would be 2.502corresponding to a p-value of 0.012.  Thus 
H0 would be rejected, and superiority of BBI608 declared, early if the p-value from stratified log-
rank test is  0.012. 
This trial was activated on October 2, 2014 and a total of 714 patients were randomized. The 
714th patient was randomized on December 13, 2016. The cleaning of the data which are 
required for the first interim analysis were completed on May 19, 2017 with the cut off for safety 
portion of analysis being April 15 2017 and the cut off for the efficacy portion of the analysis
being December 20 2016.  Safety data and primary analysis based on the first 380 events were 
presented to DSMB on June 14, 2017. Additionally, the DSMB were presented with uncleaned 
and unlocked efficacy data for additional 142 deaths occurring by the cut-off date of May 25 
2017. After reviewing the results on June 21 2017, the DSMB recommended unblinding of 
patients remaining on study treatment to allow patients to make an informed decision regarding 
continuing or discontinuing study treatment. On June 24th, 2017 notification was sent to sites,
and investigators were instructed to inform patients of the first interim analysis findings and of 
their treatment arm allocation. All patients were directed to decide together with their investigator
if continuing study therapy is in their best interest. Given that no safety concerns were identified 
by the DSMB, in cases in which a patient appears to be deriving benefit from BBI608 and is 
tolerating treatment well, open-label continuation of study treatment was permitted with patient 
consent.  
Due to study unblinding the analysis plan is amended as follows: analysis will be conducted for 
primary endpoint of OS as outlined in Section 13.3. Patients will continue to receive treatment, if 
felt to be potentially beneficial by their Investigator, until a discontinuation criterion is met or 
until September 15 2017, whichever occurs first. Additionally, all secondary and exploratory 
analyses will be performed as outlined in the protocol. 


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14.6 CORRELATIVE STUDIES
The correlative science component of the BBI608-336 trial will include tumor and blood based 
assays to identify biomarkers of benefit from BBI608 therapy, as well as biomarkers of BBI608 
resistance. The purpose of these studies is to explore the 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 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.
Using data from this and other trials, the relationship between a number of molecular markers 
associated with the STAT3ȕ-catenin and other related pathways, and the clinical outcomes with 
BBI608 therapy will 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 BBI608 therapy, an analysis of 
markers of resistance to BBI608 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 10-
30 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, 10-30 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 BBI608 and then at week 4 while on
BBI608/Placebo. 
The following analysis will be performed to investigate the relationship between endpoints and 
biomarker levels (e.g. STAT3, phospho-STAT3, E-catenin, 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, E-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. 


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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 
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. 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.
14.7 EXPLORATORY ANALYSES
Objective Response Rate in the Predefined Biomarker-positive Population 
Objective Response (ORR) in the biomarker-SRVLWLYHSRSXODWLRQ>WKRVHSDWLHQWVZLWKQXFOHDUȕ-
catenin positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded 
(FFPE) archival tissue] is defined as the proportion of patients with a documented complete 
response or partial response (CR + PR) based on RECIST 1.1. The primary estimate of ORR will 
be based on patients with measurable disease by RECIST 1.1 at randomization.  
Disease Control Rate in the Predefined Biomarker-positive Population 
Disease Control Rate (DCR) in the biomarker-SRVLWLYHSRSXODWLRQ>WKRVHSDWLHQWVZLWKQXFOHDUȕ-
catenin positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded 
(FFPE) archival tissue] 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.  
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 BBI608. Demographic and 
pathophysiologic factors that affect plasma concentration of BBI608 and paclitaxel in this 
population of patients with pre-treated advanced gastric/GEJ adenocarcinoma will be examined. 
The exposure-response relationship between clinical and safety endpoints and BBI608/paclitaxel
exposure will also be examined.
Quality of Life Analysis
The Quality of Life (QoL) of patients will be assessed using EORTC QLQ-30 while the patient 
remains on BBI608/Placebo as per Section 9.1. 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 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 


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and clinically significant differences between the BBI608 versus placebo 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) and time 4 (~16 weeks) 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 
Hochberg method [Hochberg 1988] will be used to adjust for four comparisons in the primary 
analyses. 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.


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15 PUBLICATION
Boston Biomedical 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 Data). 
If the Study is conducted as part of a multi-center protocol, Principal Investigator 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 Data 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 Data) of Boston Biomedical’s and to require 
that any publication or presentation concerning the Study acknowledge the Sponsor’s support.  
15.1 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 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 at which time participants remaining on study 
treatment will be re-consented.  
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 and participants remaining on study treatment will be re-
consented. 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 


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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 trial is scheduled to discontinue on September 15 2017, at which time the Sponsor will cease 
provision of study treatment. If this trial is discontinued prior to September 15 2017 for any 
reason by the Sponsor, 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.
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 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.  


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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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deficiency induces development of gastric tumors in mice. Oncogene 2012; doi: 10.1038/onc.2012.540 
[Epub ahead of print]. 
Jawhari A, Jordan S, Poole S et al. Abnormal immunoreactivity of the E-cadherin-catenin complex in 
gastric carcinoma: relationship with patient survival. Gastroenterology 112:46-54, 1997.  
Judd LM, Bredin K, Kalantzis A et al. STAT3 activation regulates growth, inflammation and 
vascularization in a mouse model of gastric tumorigenesis. Gastroenterology 131:1073-85, 2006. 
Kanda N, Seno H, Konda Y et al. STAT3 is constitutively activated and supports cell survival in 
association with surviving expression in gastric cancer cells. Oncogene 23:4921-29, 2004. 
Kang JH, Lee SI, Lim do H, et al. Salvage chemotherapy for pretreated gastric cancer: a randomized 
phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin 
Oncol 30:1513, 2012. 


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Kim DY, Cha ST. Ahn DH et al. STAT3 expression in gastric cancer indicates a poor prognosis. J 
Gastroenterol Hepatol 24:646-51, 2009. 
Kim HS, Kim SY, Kim TY et al. Second-line chemotherapy versus supportive cancer treatment in 
advanced gastric cancer. Ann Oncol 24(11):2850, 2013. 
Kim MA, Lee HS, Lee HE et al. Prognostic importance of epithelial-mesenchymal transition-related 
protein expression in gastric carcinoma. Histopath 54:442-451, 2009. 
Kodera Y, Ito S, Mochizuki Y et al. A phase II study of weekly paclitaxel as second-line chemotherapy 
for advanced gastric Cancer (CCOG0302 study). Anticancer Res 27:2667-71, 2007. 
Lee J, Lim T, Uhm JE et al. Prognostic model to predict survival following first-line chemotherapy in 
patients with metastatic gastric adenocarcinoma. Ann Oncol 18:886-891, 2007. 
Liu WF, Ji SR, Sun JJ et al. CD146 expression correlates with epithelial-mesenchymal transition markers 
and a poor prognosis in gastric cancer. Int J Mol Sci 13:6399-6406, 2012.  
Miyazawa K, Iwaya K, Kuroda M et al. Nuclear accumulation of beta-catenin in intestinal type gastric 
carcinoma : correlation with early tumor invasion. Virchows Arch 437 :508-513, 2000. 
Nakatsuru S, Yanagisawa A, Ichii S et al. Somatic mutation of the APC gene in gastric cancer : frequent
mutations in very well differentiated adenocarcinoma and signet-ring cell carcinoma. Hum. Mol. Genet. 
1 :559-563, 1992.  
National Comprehensive Cancer Network.  Esophageal and Esophagogastric Junction Cancer (Version 
2.2013). http://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf.  Accessed February 13, 
2014.
National 
Comprehensive 
Cancer 
Network.
Gastric 
Cancer 
(Version 
2.2013). http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf.  Accessed February 13, 2014. 
Niwa H, Burdon T, et al. Self-renewal of pluripotent embryonic stem cells is mediated via activation of 
Stat3. Genes Dev 12: 2048-60, 1998. 
Ohtsu A, Shah MA, Van Cutsem E et al. Bevacizumab in combination with chemotherapy as first-line 
therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin 
Oncol. 29(30):3968-76, 2011. 
Oshima M, Oshima H, Matsunaga A et al. Hyperplastic gastric tumors with spasmolytic polypeptide-
expressing metaplasia caused by tumor necrosis factor-alpha-dependent inflammation in cyclooxygenase-
2/microsomal prostaglandid E synthase-1 transgenic mice. Cancer Res. 65:9147-9151, 2005. 
Park E, Park J, Han SW, et al. NVP-BKM120, a novel PI3K inhibitor, shows synergism with a STAT3 
inhibitor in human gastric cancer cells harboring KRAS mutations. Int J Oncol 40:1259-66, 2012. 
Park WS, Oh RR, Park JY et al. Frequent somatic mutations of the beta-catenin gene in intestinal-type 
gastric cancer. Cancer Res. 59:4257-4260, 1999. 
Ponti D, Costa A et al. Isolation and in vitro propagation of tumorigenic breast cancer cells with 
stem/progenitor cell properties. Cancer Res. 65:5506-11, 2005. 
Pozzo C, Barone C, Szanto J, et al. Irinotecan in combination with 5-fluorouracil and folinic acid or with 
cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a 


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randomized phase II study. Ann Oncol 15:1773-81, 2004. 
Radulescu S, Ridgeway RA, Cordero J et al. Acute WNT signalling activation perturbs differentiation 
within the adult stomach and rapidly leads to tumour formation. Oncogene. 32:2048-2057. 2013. 
Siewert JR, Stein HJ. Carcinoma of the cardia: carcinoma of the gastroesophageal junction—
classification, pathology and extent of resection. Dis Esophagus 9:173-82, 1996.
Snyder M, Huang XY and Zhang J. Identification of novel direct Stat3 target genes for control of growth 
and differentiation.  J Biol Chem 283(7):3791–3798, Feb 15, 2008. 
Sugano, K. Gastric cancer: Pathogenesis, screening and treatment. Gastrointest. Endosc. Clin N Am 
18:513-522, 2008. 
Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface 
marker CD44. Stem Cells. 27:1006-20, 2009. 
Takaishi S, Okumura T and Wang T. Gastric Cancer Stem Cells. J Clin Oncol 26(17):2876-2882, 2008. 
Takaishi S, Okumura T, Tu S et al. Isolation of gastric cancer-initiating cells using cell surface marker 
CD44. Gastroenterology 132:A632, 2007 (abstr) 
Thuss-Patience PC, Kretzschmar A, Bichev D et al. Survival advantage for irinotecan versus best
supportive care as second-line chemotherapy in gastric cancer-a randomized phase III study of the 
Arbeitsgemeinschaft Internistische Onkologie (AIO). Eur J Cancer 47:2306, 2011. 
Tye H, Kennedy CL, Najdovska M et al. STAT3-driven upregulation of TLR2 promotes gastric 
tumorigenesis independent of tumor inflammation. Cancer Cell 22: 466-78, 2012. 
Van der Flier LG, Sabates-Bellver J, Oving I et al. The intestinal Wnt/TCF signature. Gastroenterology. 
132:628-32. 2007. 
Wagner AD, Grothe W, Haerting J et al. Chemotherapy in advanced gastric cancer: A systematic review 
and meta-analysis based on aggregate data. J Clin Oncol 24:2903-2909, 2006. 
Wagner AD, Unverzagt S, Grothe W, et al. Chemotherapy for advanced gastric cancer. Cochrane 
Database Syst Rev CD004064, 2010.  
Wilke H, Van Cutsem E, Oh SC, et al. RAINBOW: A global, phase III, randomized, double-blind study 
of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic 
gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line 
platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-
JVBE). J Clin Oncol 32, 2014 (suppl 3; abstr LBA7) 
Yakata Y, Nakayama T, Yoshizaki A et al. Expression of p-STAT3 in human gastric carcinoma: 
significant correlation in tumour invasion and prognosis. Int J Oncol 30:437-42, 2007. 
Yu H, Pardoll D, Jove R. Stats in cancer inflammation and immunity: a leading role for STAT3. Nat Rev 
Cancer 9:798-809, 2009. 
Zavros Y, Eaton KA, Kang W et al. Chronic gastritis in the hypochlorhydric gastrin-deficient mouse 
progresses to adenocarcinoma. Oncogene 24:2354-66, 2005. 


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APPENDIX I - PATIENT EVALUATION FLOW SHEET
Day
day 
1
day 
2
1
8
15
1
8
15
Timing
GD\VSULRU
to 
randomization
4 weeks 
post 
protocol 
treatment 
Every 8 
weeks 
thereafter15
History2 and Physical Exam
X
X
X
ECOG PS
X
X
X
Weight
X
X
X
Height
X
Vital signs
X
X
X
Paclitaxel Infusion3
X
X
X
X
X
X
Begin BBI608/Placebo administration 
X
Hematology4,5
X
X
X
X
X
X
X
X
Biochemistry5
X
X
X
Urinalysis5
X
X
X
ECG (12-lead)
X
X
X
Radiology and Imaging6
X
Submission of representative block of
diagnostic tumor tissue
Blood
collection
for
correlative
studies7,8
X
X
Blood
collection
for
sparse
PK
analysis
X
X
X
Pregnancy test, serum or urine (if 
applicable)9,10
X
X
X
Adverse Event assessment11,12
X
X
X12
X
X
X
X
X
X
X
X15
Quality of Life assessment (EORTC
QLQ-C30)13
X
X
X14
Assessment for survival of patient
X16
X16
run-in1
upon request after randomization
Every 8 weeks until progressive disease is documented 
Pre-
Treatment 
Tests & Procedures
Additional Cycles
After Protocol 
Treatment 
Discontinuation         
(+/- 3 days)
 During Protocol Treatment (+/-3 days)
Cycle 1
1 
BBI608/Placebo administration will begin 2 days prior to the paclitaxel infusion on day 1 of cycle 1. These two days are referred to as run-in 
day 1 and run-in day 2. Run-in day 1 should occur within 2 working days of patient randomization.
2 
Medical history must include date of diagnosis including histological documentation of malignancy, documentation of Her2 status of tumor 
(if available), prior anticancer therapy and prior date(s) of disease progression. 
3.
Paclitaxel 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).
4 
Hematology should be done within 72 hours prior to paclitaxel administration. 
5
Laboratory investigations should be performed within72 hours prior to Day 1 of each Cycle of protocol treatment
6 
Tumor measurement and evaluation by RECIST 1.1 criteria. 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 10) or until September 15 2017, whichever occurs first. For patients who remain on protocol therapy 


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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 until September 15 2017. Tumor assessments should be obtained 
within +/- 5 days of protocol specified schedule.
7    Sample collection should be performed at baseline and at 4 weeks after randomization. 
8  A sample will be collected following protocol treatment discontinuation if discontinuation occurs prior to 4 weeks of therapy.            
9    In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG.
Baseline pregnancy test should be done within 5 days of randomization.
10 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.
11  Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see 
Appendix III).
12  Adverse event assessment by phone should be performed on run-in day 2.
13 To be completed in clinic. Questionnaires should be completed at baseline and At 4, 8, 12, 16 and 24 weeks after randomization for as long 
as patient remains on Protocol therapy or until deterioration to ECOG PS 4 or hospitalization for end of life care or until September 15 2017. 
14  EORTIC 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 and until 
September 15 2017.
15   After the first visit at which the patient has been off protocol treatment for 4 weeks, patients will be assessed every 8 weeks for survival and 
any protocol treatment related adverse events until September 15 2017. Medical history at post-progression follow up must include post-
protocol treatment cancer therapies. 
16 In the event that the patient is unable to attend clinic, post-progression follow-up may be by means of telephone contact
Evaluation Post-Unblinding & Permanent Treatment Discontinuation 
Following unblinding, patients who have not yet met the primary study endpoint (death), and are
currently on protocol therapy may receive study treatment until September 15 2017 based on the clinical 
judgement of the investigator that this is in the patients’ best interest, providing the patient is fully 
informed and provides consent. Please refer to Sections 9.1.1 and 9.2.1. 


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APPENDIX II - 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 III - 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 IV - 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.


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If a particular question has not been answered, please document the reason(s) in the appropriate space 
on the questionnaire. If the whole questionnaire has not been completed, please document the 
reason(s) on the appropriate case report forms.
2.
Pretreatment 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.


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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:
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.  


Quality of Life Questionnaire – ENGLISH
This page to be completed by the Clinical Research Coordinator
Patient Information
Study ID#: ___________
Patient Initials: ____ ____ ____
(first-middle-last) 
Institution: ___________________________________________
Investigator: ______________________________
Scheduled time to obtain quality of life assessment: please check (9) 
 Prior to randomization
OR
During chemotherapy (timing from randomization): 
 Week 4
 Week 8
 Week 12
 Week 16    Week 24
OR
After chemotherapy has stopped (timing from randomization): 
 First regularly scheduled 4 week assessment following Protocol therapy discontinuation  
Were ALL questions answered?
 Yes  No Æ If no, reason: _________________________________________ 
Was assistance required?
 Yes  No ÆIf yes, reason:________________________________________ 
Where was questionnaire completed:  home  clinic  another center
Comments: ____________________________________________________________________________________ 
_____________________________________________________________________________________________ 
Date Completed:  __ __ __ __ - __ __ __ - __ __ 
    yyyy      mmm    dd
PLEASE ENSURE THIS PAGE IS FOLDED BACK BEFORE HANDING
TO THE PATIENT FOR QUESTIONNAIRE 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 the questions 
yourself by circling the number that best applies to you. There are no 'right' or 'wrong' answers. 
Choose the best single response that applies to you. The information that you provide is for 
research purposes and will remain strictly confidential. The individuals (e.g. doctors, nurses, etc.) 
directly involved in your care will not usually see your responses to these questions -- if you 
wish them to know this information, please bring it to their attention.
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: ____ ____ ____ 
EORTC QLQ-C30
Page 2 of 3
Please go on to the next page
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: ____ ____ ____ 
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.


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APPENDIX V - UNBLINDING
All patients remaining on study treatment at the time of this amendment must be unblinded. The process 
for unbinding is outlined in Appendix VI. 
Patients who discontinued study treatment prior to the time of this amendment must remain blinded. 
However, in the event of a medical emergency in an individual subject, in which knowledge of the 
investigational product is critical to the subject's or subject’s partner urgent management, the blind for 
that subject may be broken by the treating physician. Before breaking the blind of an individual subject's 
blinded treatment (for the subjects who discontinued study treatment prior to the time of this amendment), 
the Investigator should have determined that the information is necessary, i.e. that it will alter the subject's 
or subject’s partner immediate management. In many cases, particularly when the emergency is clearly 
not investigational product related, the problem may be properly managed by assuming that the subject 
was receiving active product without the need for unblinding.  
For any treatment code unblinding, including patients who on study treatment at the time of this 
amendment as well as those who discontinued study treatment prior to this amendment, the reason and 
parties involved must be documented in the patient’s medical record. Treatment identification information 
for patients who discontinued study treatment prior this amendment should be kept confidential. Further, 
for the patients who discontinued study treatment prior to this amendment, the Sponsor/CRO must be 
made aware of the break of the blind prior to the event taking place except in cases where an immediate 
need for unblinding exists for reasons of patient safety at which time the investigator can unblind the 
patient prior to notifying the Sponsor. However, the investigator will have the final decision and unilateral 
right for unblinding in matters involving the safety of study subjects.


CONFIDENTIAL
77
CONFIDENTIAL
 
 
  
APPENDIX VI: UNBLINDING PROCEDURE
PLEASE FOLLOW THESE STEPS: 
x
Call the Perceptive Support Help telephone number for your country. Refer to the table on page 
2 to find the contact number for your country. 
x
Inform the Perceptive Support Help agent that you wish to unblind a patient receiving study 
treatment at the time of unblinding.
x
Provide the Perceptive Support Help agent with the following information: 
o
The study name and number – The BRIGHTER Trial – BBI608-336
o
Your name 
o
Your site number
o
Your email address 
o
The Patient ID, Year of Birth and Gender of the subject you wish to unblind 
o
The reason for unblinding (e.g. patient is receiving study treatment at the time of this 
amendment or information is critical to urgent medical management for a patient who 
discontinued trial treatment prior to the time of this amendment)  
x
PLEASE NOTE: When you reach Perceptive Support Help, the agent will speak to you in 
English. You may request a translator to assist if necessary.
Upon receipt of the required information the Perceptive Support Help agent will immediately unblind the 
patient treatment assignment and forward the patient treatment assignment to you at the email address you 
provided. 


CONFIDENTIAL
78
CONFIDENTIAL
IMPORTANT REMINDERS
x
Treatment assignments will only be provided to the Principal Investigator 
x
Requests to unblind a subject who discontinued study treatment prior to this amendment should 
only be made when the safety and urgent medical management of the subject require knowledge 
of the study treatment.
x
Unblinding must be performed for all patients remaining on study treatment at the time of this 
amendment.
x
For any treatment code unblinding, the reason and parties involved must be documented in the 
subject’s medical record.
x
Treatment assignment information must be kept confidential for patient who discontinued study 
treatment prior to the time of this amendment.
x
The Sponsor/CRO request that whenever possible they be notified of the intent to break the 
blind prior to contacting Perceptive Support Help (except for patients on study treatment at the 
time of this amendment). Please send notifications to BRIGHTER_MM@parexel.com. Please 
ensure you also copy your CRA.
x
In cases where an immediate need for unblinding exists for patients remaining on active study 
treatment at the time of this amendment or for reasons of subject safety for the patients who 
discontinued study treatment prior to the time of this amendment, the Principal Investigator may 
unblind the subject prior to notifying the Sponsor. 
You may also use this link to find the Perceptive Support Help telephone number for your country 
support.perceptive.com/support/home.aspx/phones
Country
Perceptive Support Help 
Toll Free Number
Country
Perceptive Support Help 
Toll Free Number
Australia
1 800 504340
Italy
800 783294
Belgium
0800 74226
Japan
0120 984 280
Brazil
0800 891 7744
Korea
00308 132 311
Bulgaria
08001104403
Lithuania
880030003
Canada
1 877 798 5016
Poland
00800 441 1385
Czech Republic
800 142091
Romania
08008 94401
Estonia
800 0044161
Russia - Moscow
(8) 495 580 9515
France
0800 900578
Russia – Other 
Areas
8~10 800 110 1011 + 866 893 
1621
Germany
0800 182 2394
Spain
900 9977160
Hungary
06800 18058
United Kingdom
08003890918
Israel
1809 431402
United States
1 877 819 6025

SAP_001.pdf: 
Confidential 
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Boston Biomedical, Inc. 
BBI608-336 
A Phase III Randomized, Double-Blind, Placebo-Controlled Clinical Trial of BBI608 plus Weekly 
Paclitaxel vs. Placebo plus Weekly Paclitaxel in Adult Patients with Advanced, Previously Treated Gastric
and Gastro-Esophageal Junction Adenocarcinoma 
Statistical Analysis Plan 
PAREXEL Project Number: 216525
Version 2.0 
Date: 27 March 2017
PAREXEL Project Number: 216525


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SIGNATURE PAGE 
Prepared by:  
_________________________ 
 
_______________ 
 
Jonathan Shtaynberger, MS  
 
Date 
Biostatistician 
 
 
 
PAREXEL International  
Reviewed by:  
_________________________ 
 
_______________ 
 
Autumn Chang, MS  
 
 
Date 
Biostatistics Lead 
 
 
 
PAREXEL International  
 
 
 
 
_________________________ 
 
_______________ 
Natalia Kochurova, MD 
 
 
Date 
Medical Monitor 
 
 
 
PAREXEL International  
 
 
 
 
_________________________ 
 
_______________ 
 
Laura Borodyansky, MD 
                        Date   
 
Executive Director of Clinical Development  
 
 
Boston Biomedical, Inc. 
Jonathan Shtaynberger, MS 
Date
Biostatistician 
PAREXEL International 
Autumn Chang, MS 
Date
Biostatistics Lead 
PAREXEL International 
Natalia Kochurova, MD 
Date
Medical Monitor 
PAREXEL International 
Laura Borodyansky, MD
Date 
Executive Director of Clinical Development 
Boston Biomedical, Inc.


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TABLE OF CONTENTS 
 
1 
INTRODUCTION ................................................................................................................................7 
2 
STUDY OBJECTIVES ........................................................................................................................7 
2.1 Primary Objective..........................................................................................................................7 
2.2 Secondary Objectives ....................................................................................................................7 
2.3 Correlative Objectives ...................................................................................................................8 
2.4 Exploratory Objectives ..................................................................................................................8 
3 
INVESTIGATIONAL PLAN ..............................................................................................................9 
3.1 Overall Study Design and Plan ......................................................................................................9 
3.2 Efficacy and Safety Variables .....................................................................................................11 
3.2.1 Efficacy Variables:.............................................................................................................11 
3.2.2 Safety Endpoints ................................................................................................................11 
3.2.3 Correlative Endpoints ........................................................................................................11 
3.2.4 Exploratory Endpoints .......................................................................................................12 
4 
STATISTICAL METHODS ..............................................................................................................12 
4.1 Data Quality Assurance ...............................................................................................................12 
4.2 General Presentation Considerations ...........................................................................................12 
4.3 General Data Handling ................................................................................................................13 
4.4 Study Subjects .............................................................................................................................15 
4.4.1 Disposition of Subjects ......................................................................................................15 
4.4.2 Protocol Deviations ............................................................................................................15 
4.5 Analysis Populations ...................................................................................................................16 
4.6 Demographic and Other Baseline Characteristics .......................................................................17 
4.7 Disease Characteristics, Medical History, and Prior Therapy .....................................................17 
4.8 Measures of Drug Administration & Treatment Compliance .....................................................18 
4.9 Efficacy Evaluation .....................................................................................................................19 
4.9.1 Analysis and Data Conventions .........................................................................................19 
4.9.2 Primary Efficacy Variable .................................................................................................26 
4.9.3 Secondary Efficacy Variables ............................................................................................27 
4.10 
Safety Evaluation ...............................................................................................................29 
4.10.1 
Safety Data Handling and Definitions .......................................................................29 
4.10.2 
Extent of Exposure .....................................................................................................33 
4.10.3 
Adverse Events ..........................................................................................................33 
4.10.4 
Deaths, Serious Adverse Events, and Other Significant Adverse Events..................34 
4.10.5 
Clinical Laboratory Evaluation ..................................................................................35 
4.10.6 
Vital Signs ..................................................................................................................37 
4.10.7 
Electrocardiogram (ECG) Evaluations ......................................................................38 
4.10.8 
Other Safety Evaluations ...........................................................................................38 
4.10.9 
Data and Safety Monitoring Board (DSMB) .............................................................38 
4.11 
Other Analyses ...................................................................................................................39 
4.11.1 
Health Economics ......................................................................................................39 
4.11.2 
Correlative Analyses ..................................................................................................39 
4.11.3 
Exploratory Analyses .................................................................................................40 


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4.12 
Determination of Sample Size ...........................................................................................42 
4.13 
Changes in the Conduct of the Study or Planned Analysis ...............................................43 
5 
REFERENCES ...................................................................................................................................44 
6 
APPENDICES ....................................................................................................................................45 
Appendix 1: Patient Evaluation Flow Sheet .......................................................................................46 
Appendix 2: Inclusion and Exclusion Criteria Resulting in the Exclusion of Patients from PP 
Population ....................................................................................................................................48 
Appendix 3: Prohibited Treatments Resulting in Exclusion of Patients from PP Population ...........49 
Appendix 4: Scoring Details for EORTC QLQ-C30/ Windows/ Response Analysis .......................50 
Appendix 5: Clarification for Strata Covariates Derivation and Pooling ..........................................52 
Appendix 6: Clarification on Object Response Rate and Disease Control Rate: Population and 
Analysis Details...........................................................................................................................53 
Appendix 7: Clarification on Removal of Consolidated Adverse Events..........................................54 


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LIST OF ABBREVIATIONS 
AE
adverse event
ALT
alanine transaminase
AST
aspartate transaminase
BBI
Boston Biomedical, Inc.
BOR
best overall response
BP
blood pressure
bpm
beats per minutes
CBC
complete blood count
CMH
Cochran-Mantel-Haenszel
CI
confidence interval
CR
complete response  
CSC
cancer stem cell
CTCAE
common toxicity criteria for adverse events
DCR
disease control rate
dL
deciliter
DSMB
Data Safety and Monitoring Board
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC 
QLQ-C30
European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire Core 30 Item
FDA
(United States) Food and Drug Administration
FFPE
Formalin Fixed Paraffin Embedded
GEJ
Gastro-Esophageal Junction
HR
hazard ratio
ICF
informed consent form
ICH
International Conference on Harmonization
IDE
investigational device exemption
IHC
immunohistochemical
IRB
Institutional review Board
ITT
intent-to-treat
IV
intravenous
IxRS
Interactive Web/Voice Response System
LDH
lactate dehydrogenase
LLN
lower limit of normal
LNH
low-normal-high
mckat
microkats
MedDRA
Medical Dictionary for Regulatory Activities
MET
minimum effective treatment
mg/m
milligrams per minute
mmHg
millimeter Mercury


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mmol
millimole
NCI 
CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PK
pharmacokinetic
PP
per protocol
PR
partial response
PS
performance status
PT
preferred term
PTH
Plasma Parathyroid Hormone
QoL
Quality of Life
QRS
portion of the electrocardiogram comprising the Q, R, and S waves, together representing 
ventricular depolarization
QT
Q wave to T wave interval
QTcB
QT Interval Bazett Correction
QTcF
QT Interval Fridericia Correction
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SD
stable disease or standard deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvate Transaminase
SMQ
Standard MedDRA queries
SOC
system organ class
U/L
unit per liter
ULN
upper limit of normal
μmol
micromole


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1
INTRODUCTION 
Gastric cancer and cancer of the gastro-esophageal junction (GEJ) are a significant cause of morbidity 
and mortality worldwide and have the second highest death rate of all cancers with 736,000 deaths 
recorded in 2008. Despite poor survival rates in gastric and GEJ cancer, the past decade has seen some 
progress in second-line therapy for this disease with approximately 20-50% of subjects receiving 
second-line therapy world-wide. Second-line therapy has shown a median survival of 5.6 months as 
compared to survival of approximately 2.5 months in subjects not receiving treatment following 
progression on first-line therapy. 
BBI608 is the most advanced agent developed by Boston Biomedical, Inc. (BBI) to target cancer stem 
cells (CSCs). BBI608 is a small molecule that blocks self-renewal of, and induces cell death in CSCs 
isolated from gastric and GEJ cancer as well as other types of cancer. The unmet clinical need, 
mechanism of action of BBI608, and encouraging pre-clinical and clinical data seen to date provide a 
strong rationale for further investigation of BBI608 in combination with weekly paclitaxel in subjects
with advanced gastric and GEJ cancer. 
This Statistical Analysis Plan (SAP) is created based on BBI608-336 Protocol Amendment 7 dated 
December 2nd 2016, EudraCT Number 2014-000774-18 (Mar 7, 2014), and it describes in detail the 
statistical methodology and the statistical analyses to be conducted for the above mentioned protocol.  
The analysis plan may change due to unforeseen circumstances. Any deviations to the planned statistical 
analyses specified within the SAP will be justified in writing and presented within the clinical study 
report. 
2
STUDY OBJECTIVES 
2.1
Primary Objective 
x
To compare Overall Survival (OS), defined as the time from randomization until death from 
any cause, in subjects with pre-treated advanced gastric/GEJ adenocarcinoma treated with 
BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel in the intent-to-treat 
(ITT) general study population.
2.2
Secondary Objectives 
x
To compare OS, defined as time from randomization until death from any cause, in subjects 
with pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus weekly 
paclitaxel versus placebo plus weekly paclitaxel in the predefined biomarker-positive sub-
population.
x
To compare Progression-Free Survival (PFS), defined as the time from randomization until 
the first objective observation of disease progression or death from any cause, in subjects 
with pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus weekly 
paclitaxel versus placebo plus weekly paclitaxel in the ITT general study population.


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x
To compare PFS, defined as the time from randomization until the first objective observation 
of disease progression or death from any cause, in subjects with pre-treated advanced 
gastric/GEJ adenocarcinoma treated with BBI608 plus weekly paclitaxel versus placebo plus 
weekly paclitaxel in the predefined biomarker-positive subpopulation. 
x
To compare the Objective Response Rate (ORR), defined as the proportion of subjects with a 
documented complete response or partial response (CR + PR) based on Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1 criteria, in subjects with pre-treated advanced 
gastric/GEJ adenocarcinoma treated with BBI608 plus weekly paclitaxel versus placebo plus 
weekly paclitaxel in the ITT general study population.
x
To compare the Disease Control Rate (DCR), defined as the proportion of subjects with a 
documented complete response, partial response or stable disease (CR + PR + SD) based on 
RECIST 1.1 criteria, in subjects with pre-treated advanced gastric/GEJ adenocarcinoma 
treated with BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel in the ITT 
general study population. 
x
To evaluate the safety profile of BBI608 administered daily plus weekly paclitaxel in 
subjects with pre-treated advanced gastric/GEJ adenocarcinoma, with safety assessed 
according to the National Cancer Institute Common Toxicity Criteria for Adverse Events 
(NCI CTCAE version 4.0).
2.3
Correlative Objectives 
x
To explore the exposure/response relationships of BBI608 and paclitaxel in subjects with 
pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus weekly 
paclitaxel versus placebo plus weekly paclitaxel using population pharmacokinetics with 
sparse PK sample collection.
x
To explore an association between putative biomarkers as determined from paraffin-
embedded tumor specimens and the potential for clinical benefit in terms of overall survival, 
progression-free survival, disease control rate, and objective response rate, from treatment 
with BBI608 plus weekly paclitaxel in subjects with pre-treated advanced gastric/GEJ 
adenocarcinoma. 
x
To explore associations with baseline values and changes of putative biomarkers in the blood 
and the potential for clinical benefit in terms of overall survival, progression-free survival, 
disease control rate, and objective response rate, from treatment with BBI608 plus weekly 
paclitaxel in subjects with pre-treated advanced gastric/GEJ adenocarcinoma.
2.4
Exploratory Objectives 
x
To compare the Objective Response Rate (ORR), defined as the proportion of subjects with a 
documented complete response or partial response (CR + PR) based on RECIST 1.1 criteria, 
in subjects with pre-treated advanced gastric/GEJ adenocarcinoma treated with BBI608 plus 
weekly paclitaxel versus placebo plus weekly paclitaxel in the predefined biomarker-positive 
subpopulation.


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x
To compare the Disease Control Rate (DCR), defined as the proportion of subjects with a 
documented complete response, partial response or stable disease (CR + PR + SD) based on 
RECIST 1.1 criteria, in subjects with pre-treated advanced gastric/GEJ adenocarcinoma 
treated with BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel in the 
predefined biomarker-positive subpopulation.
x
To characterize the population pharmacokinetics of BBI608 in subjects with pre-treated 
advanced gastric/GEJ adenocarcinoma, examining how demographic and pathophysiologic 
factors affect plasma concentration of BBI608. The exposure-response relationship between 
clinical and safety endpoints and BBI608/paclitaxel exposure will also be examined.
x
To compare the Quality of Life (QoL), as measured using the European Organisation for 
Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Item (EORTC 
QLQ-C30), in subjects with pre-treated advanced gastric/GEJ adenocarcinoma treated with 
BBI608 plus weekly paclitaxel versus placebo plus weekly paclitaxel in the ITT general 
study population.
3
INVESTIGATIONAL PLAN 
3.1
Overall Study Design and Plan 
This is a randomized, double-blind, multi-center, phase III study of BBI608 plus weekly paclitaxel vs. 
placebo plus weekly paclitaxel for adult subjects with advanced, pre-treated gastric or GEJ 
adenocarcinoma who have failed first line therapy containing a fluoropyrimidine and a platinum-based 
agent.   
A total of 700 subjects will be randomized in a 1:1 ratio, stratified according to prior taxane therapy (yes 
vs. no); disease measurability by RECIST 1.1 (measurable disease present vs. not present); time to 
progression on first line therapy (<6 months vs. ≥6 months); and geographical region (Asia vs. North 
America, Europe and Australia vs. South America).  These subjects will be randomized over a 24 month 
period, and followed for an additional 12 months. 
The study will proceed in 28-day (4-week) cycles. BBI608 or placebo will be administered orally, twice 
daily, with doses separated by 12 hours.  Paclitaxel 80 mg/m2 IV will be administered weekly, on day 1, 
8, and 15 of each 28 day study cycle. BBI608 or placebo administration will begin 2 days prior to the 
first paclitaxel infusion. 
Tumor assessments will be performed every 8 weeks after randomization until objective disease 
progression or another discontinuation criterion is met.   
This study will enroll subjects with a cytologically or histologically confirmed adenocarcinoma of the 
stomach or gastro-esophageal junction (GEJ) that is metastatic or locally advanced and unresectable. 
Subjects will have failed treatment with one regimen containing at least a platinum/fluoropyrimidine 
doublet for unresectable or metastatic disease.  
Subjects will have received no more than one regimen in the metastatic setting. Subjects who have 


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received prior taxane therapy may be enrolled, so long as prior taxane was administered in the adjuvant 
or neoadjuvant setting and progression occurred >6 months of end of treatment. Subjects who have 
received prior taxane in first line metastatic setting are excluded. 
Other inclusion criteria for all subjects include: age ≥ 18 yrs.; ECOG performance status ≤ 1; and 
adequate hepatic, renal, and bone-marrow function. Detailed study inclusion and exclusion criteria are 
provided in the protocol. 
Subjects in this study will receive BBI608 or matched placebo orally, daily, at 480 mg bid (960 mg total 
daily dose). In each cycle BBI608 will be taken twice daily for 4 weeks (28 days). BBI608 or placebo 
will be 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. 
Subjects will receive BBI608 or placebo in combination with paclitaxel, 80 mg/m2administered via 1-
hour IV infusion on days 1, 8, and 15 of each 28 day cycle.  Dose modification of BBI608/placebo 
and/or paclitaxel is allowed.   
1If no other standard therapies are available at the time of disease progression, and the subject has not experienced any adverse events requiring 
permanent  discontinuation, BBI608/Placebo may be continued in monotherapy as long as it is the opinion of the Investigator that the subject may 
continue to be deriving benefit. 
Subjects 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 criteria. If no other standard therapies are available at the time of disease 
progression, and the subject has not experienced any adverse events requiring permanent 
discontinuation, BBI608/Placebo may be continued in monotherapy as long as it is the opinion of the 
Investigator that the subject may continue to be deriving benefit. If either BBI608/Placebo or paclitaxel 
is discontinued due to toxicity, the other agent may be continued as monotherapy until another 
discontinuation criterion is met. 
There will be one interim analysis in this study to be presented to the independent Data Safety and 
Monitoring Board (DSMB). Additionally, DSMB will review safety during the entire conduct of the 
study. The role and responsibility of the DSMB will be defined in a separate Charter (see SAP section 
4.10.9).
Advanced, previously 
treated
gastric 
or 
gastro-
esophageal 
junction 
adenocarcinoma
R
A
N
D
O
M
I
Z
E
ա
Arm 
1
BBI608 orally, twice daily
plus
Paclitaxel 80 mg/m2 IV, weekly
(three out of every four weeks)
Disease 
Progression based 
on 
RECIST 
criteria1
or
unacceptable 
toxicity occurs
Death
→
→
բ
Arm 
2
Placebo orally, twice daily
plus
Paclitaxel 80 mg/m2 IV, weekly
(three out of every four weeks)


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The interim analysis will be performed on OS, the primary endpoint of this study, when at least 2/3rds of 
the required number of events (380) has been observed in the ITT population.
3.2
Efficacy and Safety Variables 
3.2.1
Efficacy Variables: 
3.2.1.1
Primary Efficacy Endpoints: 
x
Overall Survival in the ITT general study population 
3.2.1.2
Secondary Efficacy Endpoints: 
x
Overall Survival in the predefined biomarker-positive sub-population 
x
Progression-Free Survival in the ITT general study population 
x
Progression-Free Survival in the predefined biomarker-positive sub-population 
x
Objective Response Rate in the ITT general study population 
x
Disease Control Rate in the ITT general study population 
3.2.2
Safety Endpoints 
x
Incidence of treatment emergent adverse events (TEAEs), treatment emergent events of special 
interest (AESI), and serious adverse events (SAEs) 
x
Incidence of laboratory toxicities  
x
Physical examination findings 
x
Observed and changes in standard clinical laboratory parameters (hematology, biochemistry) 
x
Observed and changes in vital sign measurements 
x
Observed and changes in electrocardiogram (ECG) recording  
x
Proportion of subjects with concomitant medications and procedures 
x
Study drug exposure 
3.2.3
Correlative Endpoints 
The correlative science component of the BBI608-336 trial will include tumor and blood-based 
assays to identify biomarkers of benefit from BBI608 therapy, as well as biomarkers of BBI608 
resistance. The purpose of these studies is to explore the relationship between biomarkers and 
disease response, as measured by following endpoints: 
x
Overall survival 
x
Progression-Free Survival 
x
Objective Response Rate 
x
Disease Control Rate 


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3.2.4
Exploratory Endpoints 
x
Objective Response Rate in the Predefined Biomarker-positive Population 
x
Disease Control Rate in the Predefined Biomarker-positive Population 
x
Sparse Pharmacokinetic Parameters  
x
Observed and changes in Quality of Life 
4
STATISTICAL METHODS 
4.1
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard PAREXEL procedures. 
4.2
General Presentation Considerations 
‘Baseline’ is defined as the last observation prior to first dose of study drug, including either 
BBI608/placebo or paclitaxel, whichever is administered first. 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, minimum, 
maximum and number of observations, unless otherwise stated. Continuous data that are expected to be 
skewed will be presented in terms of the maximum, upper quartile, median, lower quartile, minimum 
and number of observations.  The minimum and maximum will be reported to the same number of 
decimal places as the raw data recorded in the database.  The mean, median, lower quartile and upper 
quartile will be reported to one more decimal place than the raw data recorded in the database.  The SD 
will be reported to two more decimal places than the raw data recorded in the database.  In general, the 
maximum number of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the relevant 
time point (n), frequency counts and percentages. In cases where missing data cause percentages not to 
sum to 100, a missing data row will be provided.Percentages will be presented to one decimal place. 
Percentages will not be presented for zero counts.  Percentages will use column totals as the 
denominator unless otherwise indicated. Changes from baseline in categorical data will be summarized 
using shift tables where appropriate.
P-values greater than or equal to 0.0001 will be presented to four decimal places.  P-values less than 
0.0001 will be presented as “<0.0001”.
Confidence intervals will be presented to one more decimal place than the raw data. 


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All report outputs will be produced using SAS® version 9.3 or later in a secure and validated 
environment.  All report outputs will be provided to the Sponsor in a single Microsoft Word 2010 
document.
4.3
General Data Handling 
x
Blinding Maintenance: 
To ensure concealment of treatment allocation in this double-blind study, randomization will be 
performed using web-based access to a central database provided through the Randomization and 
Trial Supply Management (RTSM) system. Investigators, patients and pharmacists will be blinded to 
treatment assignment. Files containing treatment allocation information are created by an RTSM 
statistician and stored in RTSM (at PAREXEL Informatics), who is independent of trial conduct. No 
one outside the RTSM personnel working on the study will have access to treatment allocation 
information, except the separated unblinded PAREXEL team (unblinded biostatisticians and 
unblinded statistical programmers) preparing unblinded outputs for review by DSMB members 
exclusively. The unblinded PAREXEL team will perform the unblinding according to PAREXEL 
SOP and has no other role in this study; in particular, unblinded PAREXEL biostatisticians were not 
involved in the creation of the SAP.  
Additionally, as noted in the study DSMB Charter, DSMB members are unblinded and will interact 
with Sponsor as noted in the Charter, specifically: Sponsor will remain blinded to the trial and not 
have access to any unblinding information involved with the DSMB process.  
x
Age will be computed from July 1 of the year of birth to the date of Informed Consent, as (Date 
of Informed Consent - July 1 of the year of Birth +1)/365.25 
x
Missing Data: All analyses and descriptive summaries will be based on the observed data. Unless 
otherwise specified, missing data will not be imputed or “carried forward.”
x
Baseline Measurements: 
- Efficacy: The last 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 assessment completed prior 
to the first study drug administration (either BBI608/placebo or paclitaxel, whichever was
administered first) will be used as the baseline assessment so long as this assessment was taken 
within 21 days of randomization. 
- Safety: The last measurement prior to the first study drug administration (either 
BBI608/placebo or paclitaxel, whichever was administered first) will be used as the baseline 
assessment.
- Other baseline characteristics: The last 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 assessment 
completed prior to the first dose of study drug administration (either BBI608/placebo or 
paclitaxel, whichever was administered first) will be used as the baseline assessment.  Please see 


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table below for the date cut offs accepted for each of the baseline characteristics performed prior 
to randomization. 
Investigations
Timing prior to 
randomization
History 
and 
Physical 
Exam including:
•
Prior medical and therapeutic history
•
Physical examination
•
Vital signs
•
Height, weight, ECOG performance status
•
Clinical tumor measurements
•
Concurrent medication list
<14 days
Hematology
•
CBC + differential
•
Platelet count
<14 days1
Biochemistry
•
Creatinine, Total Bilirubin, AST, ALT, Alkaline Phosphatase, LDH, 
Albumin, Potassium, Magnesium, Phosphate
<14 days1
Urinalysis
•
Dipstick (including protein, specific gravity, glucose and blood)
<14 days1
Cardiac Assessment
•
ECG (12 lead)
<28 days
Radiology & Imaging
•
CT/MRI scan of chest/abdomen/pelvis with tumor measurement and 
evaluation by RECIST 1.1 criteria
< 21 days
Correlative Studies 
•
Submission of representative diagnostic tumor tissue 
On request
•
Blood sample collection
<14 days
Other Investigations
•
Serum or urine pregnancy test
< 5 days
Adverse Events2
•
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
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.
2      Adverse events will be graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0.
x
Study Day: 
- For safety analysis: Study day is calculated as: 
o
Assessment date – first dose date + 1; if the assessment was performed on or after the 
first dose day. 
o
Assessment date – first dose date; if the assessment was performed prior to the first dose 
date. 
- For efficacy (time to event) analysis: Study day is calculated as: 
o
Assessment date – randomization date + 1; if the assessment was performed on or after 
the randomization date. 
o
Assessment date – randomization date; if the assessment was performed prior to the 
randomization date. 
x
Unless otherwise stated, missing or partial dates will be imputed.


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x
Time-to-event: The event or censoring time (days) is calculated as: 
- Date of event/censoring – Date of randomization + 1 
x
Duration: Duration (except for duration of study treatment) is calculated as: 
- Duration (days): (End Date – Start Date + 1) 
- Duration (weeks): (End Date – Start Date + 1) / 7 
- Duration (months): (End Date – Start Date + 1) / 30.4375; (Days in months =average number of 
days in a year /12) 
- Duration (years): (End Date – Start Date + 1) / 365.25; (Average days in a year = 
365.25, reflecting the Julian Year of three years with 365 days each and one leap year of 366 
days) 
4.4
Study Subjects 
4.4.1
Disposition of Subjects 
All subjects enrolled (signed informed consent), randomized on the study will be included in the 
summary of subject recruitment over time by region, site, and treatment arm.  The intent-to-treat (ITT) 
subjects, per-protocol (PP), biomarker positive, and safety populations will be summarized by treatment 
arm.  The frequency and percentage of subjects who discontinue before completing the study, along with 
discontinuation reason, will be summarized for the ITT population.  The number and percentage of 
subjects in the ITT population who receive study treatment in each cycle will also be summarized. 
Subjects who discontinue (i.e., do not complete the study per protocol) as well as subjects who are 
randomized but do not take a single capsule of study drug or placebo will be listed.  A listing of all 
enrolled subjects and the study populations to which they belong will be produced. 
4.4.2
Protocol Deviations 
Protocol deviations (PD) and analysis sets will be reviewed and confirmed through s blind data review 
meeting when deciding which subjects and/or subject data will be excluded from certain analyses prior 
to database lock. This process will occur prior to treatment code unblinding, in a documented and 
approved manner. The PD definition list will be included in data review meeting minutes as an 
attachment. 
Major protocol deviations are defined as those deviations from the protocol likely to have an impact on 
the perceived efficacy and/or safety of study treatments.  The impact of major protocol deviations on the 
efficacy and/or safety results will be investigated by assessing the robustness of the study results and 
conclusions to the choice of analysis population, both including and excluding data potentially affected 
by major protocol deviations. 


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Major protocol deviations and any action to be taken regarding the exclusion of subjects or affected data 
from specific analyses are defined in the Protocol Deviation Specification, Version 2.0 (Jan 8, 2016).
These deviations must be finalized prior to database lock. 
Information related to minor protocol deviations, along with actions to be taken for analysis, can be 
found in the Protocol Deviation Specification, Version 2.0 (Jan 8, 2016).
A summary of the number of events and percentage of events divided by total events with any major 
protocol deviation, along with each type of major protocol deviation will be provided by treatment group 
and overall. A by-subject listing of major protocol deviations will be provided sorted by treatment 
group, site and subject.
4.5
Analysis Populations 
The intent-to-treat (ITT) population will consist of all randomized subjects with treatment assignment 
designated according to initial randomization. The ITT population will be used for the analysis of the 
primary efficacy endpoint (OS), secondary efficacy endpoints (PFS, ORR, DCR), the QOL exploratory 
endpoint, and the correlative endpoints. 
The biomarker positive sub-population of subjects in the ITT population will be used for the analysis of 
OS, PFS, ORR and DCR as part of secondary end point analysis.
The per-protocol (PP) population is defined as all randomized subjects who have no major protocol 
deviations that will confound the effects of treatment.  Deviations include failure to satisfy entry criteria,
failure to satisfy requirement for study treatment compliance or treatment with prohibited medications 
believed to confound the effects of study treatment while actively receiving study treatment.  This list 
will be identified in a blinded fashion by sponsor review prior to database lock. Treatment assignment 
will be designated according to initial randomization. The PP population will be used as a sensitivity 
analysis for the assessment of the primary efficacy endpoint (OS).  
The Minimum Effective Treatment (MET) population is defined as all randomized subjects who 
received at least 480 mg BBI608/placebo or higher with Paclitaxel 80 mg/m2 weekly for at least 80% of 
the first 56 days of study treatment.   
The safety population will include all randomized subjects who receive at least one dose of either study 
drug, with treatment assignment designated according to the actual study treatment received.  This 
population will be used for all safety, as well as pharmacokinetic, analyses. 
Upon database release, protocol deviation and analysis population outputs will be produced and will be 
sent to Sponsor for review.  An analysis population classification meeting will be arranged to discuss the 
outputs and to decide which subjects and/or subject data will be excluded from certain analyses.  
Decisions made regarding the exclusion of subjects and/or subject data from analyses will be made prior 
to unblinding and will be documented and approved by Sponsor.  Upon database lock, final analysis 
population outputs will be produced and will be sent to Sponsor for approval, prior to unblinding. 


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A summary of the number and percentage of subjects by treatment group and overall for each analysis 
population will be provided. 
A by-subject listing of analysis population details will be provided.  This listing will be presented by 
treatment group and should include: center, subject identifier, and inclusion/exclusion flags for each 
population and reason for exclusion from each population.   
4.6
Demographic and Other Baseline Characteristics 
The following demographic and baseline characteristics will be summarized for subjects in the 
ITT population by treatment arm:
x
Age, age group (< 65 vs. ≥65 years), sex, race, ethnicity, ECOG status 
x
Weight (kg), height (cm), child-bearing potential, and body mass index (BMI) 
x
Randomization stratification factors: geographic region (Asia, North America/Europe/Australia, 
South America), time to progression on first line therapy (<6 months, ≥6 months from start of 
first line therapy), disease measurability by RECIST 1.1 (measurable disease present, not 
present), and prior taxane therapy (yes, no)
Demographic and baseline characteristics will also be listed for each subject. 
4.7
Disease Characteristics, Medical History, and Prior Therapy 
The following disease characteristics, medical history, and prior therapy will be summarized for subjects 
in the ITT population by treatment arm and overall: 
x
Time from initial diagnosis to randomization (months), time from most recent relapse or staging 
to randomization (in months), pathologic diagnosis, stage at screening, and metastatic sites of 
disease 
x
Prior radiation indication, prior chemotherapy setting, prior gastrectomy (partial or complete) 
x
Medical History (by SOC and PT)
Medical history and Prior therapy, surgery, or radiotherapy will be coded using the latest MedDRA 
dictionary version available.
Duration of gastric cancer diagnosis, and prior therapy, will be calculated in months (rounded to the 
nearest integer) as ((date of randomization - date of first diagnosis of gastric or GEJ 
adenocarcinoma/first treatment for gastric cancer) + 1) / (365.25/12). Handling of partial dates will 
follow the conventions in Section 4.10.1.6
Medical history will be provided in a listing. The listing will be sorted by treatment group, subject 
identification number, system organ class, preferred term and reported term.Medical history must 
include date of diagnosis including histological documentation of malignancy, documentation of Her2
status of tumor (if available), prior anticancer therapy and prior date(s) of disease progression.


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4.8
Measures of Drug Administration & Treatment Compliance 
BBI608/Placebo 
Several measures of drug administration will be reported.  Raw treatment compliance for 
BBI608/Placebo is defined as the ratio, expressed as a percentage, of the number of capsules (BBI608 or 
placebo) taken by a subject over the course of a time interval to the number of capsules intended to be 
taken over that same time interval as per the dose prescribed by the Investigator, including the starting 
dose-level of 480 mg twice daily.  
Additionally, for BBI608/placebo, daily treatment compliance will also be reported.  Daily treatment 
compliance is defined as the ratio, expressed as a percentage, of the number of days a given patient 
received a defined total dose of BBI608/placebo out of total duration of treatment (days).  Daily 
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 960 mg BBI608/placebo out of total duration 
of treatment (days) (total days dosed = 1+ [date last dose BBI608/placebo] - [date of first dose 
BBI608/placebo]).   
x
The % of days the patient received a total dose of at least 480 mg BBI608/placebo or higher out
of total days dosed (total days dosed = 1+ [date last dose BBI608/placebo] - [date of first dose 
BBI608/placebo]). 
x
The % of days the patient received a non-zero dose of BBI608/placebo out of the total days 
dosed (total days dosed = 1+ [date last dose BBI608/placebo] - [date of first dose 
BBI608/placebo]). 
x
The % of days the patient received a total dose of 960 mg BBI608/placebo out of the first 56 
days of BBI608/placebo dosing (approximately the first two study cycles)  
x
The % of days the patient received a total dose of at least 480 mg BBI608/placebo or higher out 
of the first 56 days of BBI608/placebo dosing (approximately the first two study cycles) 
x
The % of days the patient received a non-zero dose of BBI608/placebo out of the first 56 days of 
BBI608/placebo dosing (approximately the first two study cycles)   
Paclitaxel 
Treatment compliance for paclitaxel is defined as the ratio, expressed as a percentage, of the amount of 
paclitaxel administered to a subject (milligrams/m2) over the course of a time interval to amount of 
paclitaxel intended to be administered over that same time interval as per the dose prescribed by the 
Investigator.  
BBI608/placebo treatment compliance in both arms will be monitored by drug accountability with 
amount of BBI608/placebo consumed advised by information recorded in the subject diary. A summary 
of the measures of drug administration and treatment compliance by treatment group and time interval
will be provided.  
In addition, a patient will be considered to have received a Minimum Effective Treatment if they 


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received at least 480 mg BBI608/placebo or higher with Paclitaxel 80 mg/m2 weekly for at least 80% of 
the first 56 days of study treatment.  The number and percentage of patients who received the 
“Minimum Effective Treatment” will be provided in a table.
Study drug administration and compliance data will be listed for all subjects.
4.9
Efficacy Evaluation 
4.9.1
Analysis and Data Conventions 
The primary efficacy analysis of overall analysis will take place after the required number of events 
(566) has occurred. 
The primary efficacy analysis will use a two-sided log rank significance test with an overall alpha of 
0.05 after controlling for alpha at interim analysis (e.g., two-sided alpha= 0.012).
This study is designed to test for superiority of BBI608 plus weekly paclitaxel vs. placebo plus weekly 
paclitaxel.  The null hypothesis states that there is no difference in overall survival between the two 
treatment groups. The alternative hypothesis states that BBI608 plus weekly paclitaxel is superior to 
placebo plus paclitaxel with longer OS. Symbolically, this is expressed as follows: 
H0: survival on BBI608 + paclitaxel = survival on placebo + paclitaxel 
vs. 
H1: survival on BBI608+paclitaxel > survival on placebo + paclitaxel 
Superiority will be concluded if there is sufficient evidence to reject the null hypothesis, with survival 
being greater in the BBI608 plus weekly paclitaxel treatment group compared to the placebo plus 
weekly paclitaxel treatment group. 
4.9.1.1
Multi-center Studies 
For the purpose of the summaries and analyses, the term ‘Center’ will be used to define each 
investigator site. 
Summaries of demographic data, treatment compliance data and primary efficacy variable data by 
treatment group will be provided. Primary efficacy variable data by treatment group and by country will 
be provided.  Section 4.9.1.2 provides details of adjustments for covariates such as stratification factors. 
4.9.1.2
Adjustments for Covariates 
The covariates listed below, which are the randomization stratification factors, will be used as adjustors 
in the primary and secondary efficacy analyses. They will be categorized as follows: 
x
Geographical region (Asia versus North America, Europe, and Australia versus South 
America) 


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x
Time to progression on first line therapy (<6 months versus ≥6 months from start of first line 
therapy) 
x
Disease measurability by RECIST 1.1 (measurable disease present versus not present)
x
Prior taxane therapy (yes versus no) 
If any randomization stratum proves to have an inadequate sample size, it will be dropped from the 
primary analysis or pooling will be applied.  Details will be developed at blinded data review meetings.
4.9.1.3
Efficacy Data Handling and Definitions 
All analyses and descriptive summaries will be based on the observed data.  Unless otherwise specified, 
missing data will not be imputed. 
In addition, a Kaplan-Meier plot of the time to premature study discontinuation will be provided, 
identifying the recorded reason for premature discontinuation.  
4.9.1.3.1 Overall Survival 
The OS time is defined as the time from the date of randomization to the date of death from any cause. If 
a subject is not known to have died on or before the date of data cut-off, OS data will be censored on the 
last date (on or before the cut-off date) the subject was known to be alive. Subjects who lack data 
beyond randomization will have their survival times censored on the date of randomization. 
4.9.1.3.2 Progression-Free Survival 
PFS time is defined as the time from the date of randomization until the date of first radiographic 
documentation of progression as defined by RECIST (Version 1.1), or death due to any cause, 
whichever is first. 
Imaging will be performed every 8 weeks (± 5 days) following randomization. The following table 
summarizes the censoring rules for the PFS analysis: 


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Situation
Date of Event or Censor
Event / Censor
No baseline radiological tumor assessment available
Date of randomization
Censored
No post baseline radiological tumor assessment available 
and no death reported within 2 scan intervals following 
randomization
Date of randomization
Censored
No post baseline radiological tumor assessment available
but death reported within 2 scan intervals following 
randomization
Date of Death
Event
No tumor progression (per RECIST 1.1) and no death 
reported within 2 scan
intervals following last adequate radiological tumor 
assessment
Date of last adequate radiological
tumor assessment 
Censored
No tumor progression (per RECIST 1.1) but death 
reported within 2 scan intervals following last adequate 
radiological
tumor assessment 
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
Tumor progression (per RECIST 1.1) documented after 2 
scan intervals following previous adequate radiological 
tumor assessment
Date 
of 
previous 
adequate 
radiological assessment
Censored
New anticancer treatment started and no tumor 
progression
Date 
of 
previous 
adequate 
radiological 
assessment 
immediately prior to start
of new therapy
Censored
No tumor progression (per RECIST 1.1) and subject lost 
to follow-up or withdrawal of consent
Date of last adequate radiological
Assessment
Censored
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.
4.9.1.3.3 Best Overall Response 
All subjects will have their response classified using their Best Overall Response (BOR). Classification 
will follow RECIST (Version 1.1) criteria. In order to classify a BOR as stable disease (SD), the 
assessment must be made a minimum of 6 weeks from baseline. Otherwise, the BOR will be not 
evaluable (NE), unless any PD was further documented, in which case BOR will be classified as PD.
The objective response rate (ORR) is defined as the number of subjects who had a BOR of CR, or PR 
divided by the number of subjects in the population under study. 
Disease control rate (DCR) is defined as the number of subjects who had a BOR of CR, PR or SD 
divided by the number of subjects in the population under study. 


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4.9.1.3.4 Quality of Life 
The Quality of Life (QoL) assessment will be conducted using the EORTC-QLQ-C30 (version3), a self-
administered, cancer-specific questionnaire with multidimensional scales. The 30 items (Q1-Q30) of the 
QLQ-C30 are scored to obtain 15 scales (one global health status/QoL scale, five functional scales, and 
nine symptom scales/items). A linear transformation will be used to obtain scales ranging from 0 to 100.  
The scoring for the EORTC QLQ-C30 is detailed in QLQ-C30 Scoring Manual. For multiple-item 
scales, missing items will be imputed based on the mean of the completed items if ≥50% of contributing 
items are completed. No other adjustment or imputation for missing data will be performed. Refer to 
Section 4.11.3.3 for details of analysis.   
4.9.1.4
Multiple Comparisons/Multiplicity 
Inferential assessment of secondary outcomes will take place only if the primary outcome (OS) is found 
to differ significantly between treatments when analyzed via the primary analysis method. The 
secondary outcomes will be inferentially assessed using a hierarchical analysis method (e.g. inferential 
analysis will stop and not continue to subsequent secondary outcomes after obtaining a probability 
greater than or equal to two-sided 0.05). The order by which the secondary outcomes will be tested is 
outlined in section 4.9.3 Sensitivity analyses will be done on an exploratory basis and are not included in 
the hierarchical testing for secondary outcomes.  
The study endpoints (OS/PFS/ORR/DCR) based on pre-defined biomarker population will be removed 
from the hierarchical test order of the secondary endpoints. 
The hierarchical testing flow can be understood as follows: 
If the p-value of the primary outcome analysis is less than required based on interim analysis conducted 
during the trial or the final analysis at the trial, then superiority of BBI608 in terms of OS in ITT 
population can be concluded. Next, the first secondary outcome of the hierarchy will be evaluated for 
statistical significance. 
If the p-value of the first secondary outcome analysis is also found to be below the adjusted two-sided 
alpha of 0.05, then superiority of BBI608 in terms of OS in the biomarker positive population can be 
concluded. Next, the second secondary outcome of the hierarchy will be evaluated for statistical 
significance. This process will continue for all secondary outcomes in the hierarchy, unless an analysis 
of a secondary outcome reveals a p-value greater than or equal to the adjusted two-sided alpha of 0.05. 
In such an event, the hypothesis associated with the secondary outcome will be concluded to be non-
statistically significant, and inferential testing for the subsequent secondary outcomes in the hierarchy 
will be terminated. Hence, all p-values found in the analyses of the remaining secondary outcomes in the 
hierarchy will be considered nominal. 
As QOL is an exploratory analysis, alpha and all p-values will be nominal, and conclusions related to 
statistical significance cannot be established.  


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Refer to section 4.9.1.5 for the adjustment of significance level due to interim analysis. All analyses 
described in this section are based on availability of data.
4.9.1.5
Interim Analysis 
There will be one interim analysis to stop this study early for success presented to the independent Data 
Safety and Monitoring Board (DSMB). The interim analysis will be performed on OS, the primary 
endpoint of this study, when at least 2/3rds of the required number of events (380) have been observed in 
the ITT population. 
The cut-date for the interim OS analysis will be the date of the 380th death.  Overall Survival will be 
derived based on the data up to cutoff.   
If the interim analysis does not provide evidence of superiority, the study will continue until final 
analysis at 566 events. This analysis will be based on the stratified log-rank test adjusting for the 
stratification variables at randomization, and will test the following: 
H0: survival on BBI608 + paclitaxel = survival on placebo + paclitaxel 
vs.
H1: survival on BBI608+paclitaxel > survival on placebo + paclitaxel 
The comparison of the overall population will be tested based on a generalization of the Lan-DeMets 
error spending function approach using an O’Brien-Fleming stopping boundary to reject H0, controlling 
for a two-sided alpha of 0.05 of overall study. For example, if exactly 380 deaths (2/3rdsof the required 
events) were in the locked database for the interim analysis, the nominal critical point for rejecting H0
would be 2.502, corresponding to a two-sided p-value of 0.012. Superiority of BBI608 may be declared, 
early, if the two-sided p-value from stratified log-rank test is ≤0.012 with survival being greater in the 
BBI608 plus weekly paclitaxel treatment group compared to the placebo plus weekly paclitaxel 
treatment group. Sample size calculations were conducted using East version 6.2. 
The nominal critical point at the final analysis for rejecting H0 would be 1.994 corresponding to a two-
sided p-value of 0.0462. 
Information
rate
bounds         
reject H0
sign.level      
one-sided      
sign.level     
two-sided
events 
0.67   
2.502  
0.006         
0.0124        
380
1.0    
1.994       
0.0231        
0.0462       
566   
Should the trial not stop for efficacy at this interim analysis, the final analysis will occur when 566 
deaths are observed. The nominal critical value for rejecting H0 at this final analysis would be 1.994, 
corresponding to two-sided p-value of 0.0462. 


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Correlative analysis and endpoints of biomarker positive population won’t be included at the interim 
analysis. At interim analysis, the endpoints (OS/PFS/ORR/DCR) based on pre-defined biomarker 
population will be removed from the hierarchical test order of the secondary endpoint.  
As detailed in section 4.10.9, the DSMB will meet every 6 months, primarily to evaluate safety of the 
trial. For each DSMB meeting, Open Reports, as detailed below, will be provided by the study 
biostatistician. The reports should be provided to DSMB members not later than 5 working days prior to 
the date of the meeting. 
Open Reports, available to all participants attending the DSMB meeting, can include information such 
as data on recruitment, demographics, baseline characteristics, protocol compliance, site performance, 
monitoring issues and resolutions thereof, and general (ungrouped) adverse events.
Closed Reports, available only to participants attending the Closed Sessions of the DSMB meeting, will 
include analyses in line with the needs of the DSMB. 
The following data will be presented in Open and Closed Sessions: 
x
Subject 
disposition 
(including 
dates 
of 
informed 
consent, 
randomized, 
dosed, 
withdrawal/completion, primary reason for withdrawal, etc) 
x
Demographics 
x
Extent of exposure of study drug 
x
AEs, including treatment-emergent AE, SAEs 
x
Medical history 
x
Concomitant medication 
x
Protocol Deviations  
The DSMB will receive blinded data listings sorted by treatment groups (e.g. labelled A & B) that do 
not disclose the treatment arm.  If the DSMB decides that it is necessary to analyse unblinded data, such 
unblinded data will be made available.  Detailed subject listings will contain all relevant information to 
monitor the safety of the study subjects. After agreement on the format, the final listing details will be 
added as an attachment to the DSMB Charter (see SAP Section 3.1).
The DSMB members will receive both blinded and unblinded summary tables regarding: demography, 
any protocol deviations, SAEs, AEs, deaths, patients who withdraw from study treatment and/or are lost 
to follow up. Interim safety analyses will be performed using the safety population.
4.9.1.6
Examination of Subgroups 
A subset analysis will be performed as a sensitivity analysis for the primary endpoint, overall survival 
(OS), to address the benefit of BBI608 between the groups across the following factors: 
x
Prior taxane therapy (yes; no) 
x
Disease measurability by RECIST 1.1 (measurable disease present; not present) 
x
Time to progression on first line therapy (<6 months; ≥6 months from start of first line 
therapy) 


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x
Geographical region (Asia; North America, Europe and Australia; South America) 
x
Race (white; black; Asian; other) 
x
Number of previous chemotherapy drug classes [platinum, fluropyrimidine, taxane, 
anthracyclines], including during adjuvant or neoadjuvant therapy (<3 versus >3) 
x
Age (<65 versus>65) 
x
Sex (male versus female) 
x
Prior trastuzumab-containing therapy (yes versus no) 
x
Type of cancer (gastric versus GEJ) 
x
Prior radiotherapy (yes versus no) 
x
Presence of peritoneal metastases (yes versus no) 
x
Histologic type (diffuse, intestinal, mixed, other) 
x
Received post protocol anticancer treatment [i.e. 3rd line regimen] (yes versus no) 
x
Number of organ sites involved at baseline (≥2 versus<2) 
x
Presence of primary tumor (present versus absent)
Further details on the subset analysis can be found in section 4.9.2.2.
An additional subset analysis, as described above, will be performed for all secondary efficacy endpoints 
that are found to be statistically significant following hierarchical testing. 
In addition, the relationship between the primary endpoint (Overall Survival) and binary biomarkers will 
be also examined using the log-rank test, stratified by treatment, and baseline ECOG performance status 
(0 vs 1), geographical region (Asia vs North America, Europe and Australia vs South America), time to 
progression on first line therapy (< 6 months vs. > 6 months), disease measurability by RECIST 1.1 
(measurable disease present vs. not present and prior taxane therapy (yes vs. no). Subgroup analysis by 
the status of the binary biomarker may also be performed.  
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 at different time points will be 
investigated using logistic regression that includes assigned treatment, biomarker value and treatment-
by-biomarker interaction, stratified by baseline ECOG performance status (0 vs 1), geographical region 
(Asia vs North America, Europe and Australia vs South America), time to progression on first line 
therapy (< 6 months vs. > 6 months), disease measurability by RECIST 1.1 (measurable disease present 
vs. not present and prior taxane therapy (yes vs. no). An additional model that includes prognostic 
factors may be investigated. The relationship between response and binary biomarkers (e.g. baseline 
phospho-STAT3 status or STAT3 status) will also be examined using the Cochran-Mantel-Haenszel
(CMH) test, stratified by treatment, baseline ECOG performance status (0 vs 1), geographical region 
(Asia vs North America, Europe and Australia vs South America), time to progression on first line 
therapy (< 6 months vs. > 6 months), disease measurability by RECIST 1.1 (measurable disease present 
vs. not present and prior taxane therapy (yes vs. no). Subgroup analysis by the status of the binary 
biomarker may also be performed.


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4.9.2
Primary Efficacy Variable 
4.9.2.1
Main Analysis
The primary analysis for the assessment of efficacy will evaluate Overall Survival in the Intent-to- Treat 
(ITT) study population.  All randomized subjects will be included in the primary analysis of OS, which 
is defined as the time interval between the date of randomization and the date of death from any cause. If 
a subject is not known to have died on or before the date of data cut-off, OS data will be censored on the 
last date (on or before the cut-off date) the subject was known to be alive. Subjects who lack data 
beyond randomization will have their survival times censored on the date of randomization. Subjects 
will be analyzed in the arm to which they are randomized regardless of the treatment they received.
The survival experience of subjects in both treatment arms will be summarized by the Kaplan-Meier 
method and compared primarily by a stratified log-rank test adjusting for the randomization 
stratification variables listed below. If any randomization stratum proves to have an inadequate sample 
size, it will be dropped from the primary analysis or pooling will be applied. All of the stratification 
variables will be included into a single model and will be categorized as follows: 
x
Geographical region (Asia vs North America, Europe, and Australia vs South America) 
x
Time to progression on first line therapy (<6 months vs ≥6 months from start of first line 
therapy) 
x
Disease measurability by RECIST 1.1 (measurable disease present vs not present)
x
Prior taxane therapy (yes vs no) 
The resulting test statistic and p-value for the stratified log rank test will be reported. In addition, 
Kaplan-Meier curves will be generated for OS and used to calculate quartiles and 95% CIs of the 
median OS for each treatment arm in the Intent-to-Treat Set. In addition, Kaplan-Meier estimates of the 
OS rate at fixed time points (e.g. 8, 16, 24, 32 weeks) along with their two-sided 95% CIs will also be 
derived from the Kaplan-Meier estimation. The CI for OS rate will be calculated by applying asymptotic 
normality to the log-log transformation of OS rate which is the default method to calculate the CI for the 
survival function as implemented within PROC LIFETEST in SAS software. A Kaplan-Meier plot of 
overall survival by treatment arm will be provided.
A listing of overall survival will be provided by treatment arm. 
4.9.2.2
Sensitivity Analyses 
1. The Overall Survival analysis will be repeated using the per-protocol population and safety 
analysis population. 
2. A stratified Cox proportional hazard model will be run adjusting for the randomization 
stratification variables. In addition tothe treatment factor (BBI608 + paclitaxel versus placebo +
paclitaxel), the following factors at subject entry will be included in the stratified Cox 
proportional hazards model: 
x
Number of previous chemotherapy drug classes [platinum, fluropyrimidine, taxane, 
anthracyclines], including during adjuvant or neoadjuvant therapy (< 3 versus> 3) 
x
Age (< 65 versus> 65) 


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x
Sex (male versus female) 
x
Prior trastuzumab-containing therapy (yes versus no) 
x
Location of primary tumor (gastric versus GEJ) 
x
Prior radiotherapy (yes versus no) 
x
Presence of peritoneal metastases (yes versus no) 
x
Histologic type (diffuse, intestinal, mixed, other) 
x
Number of organ sites involved at baseline (≥2 versus<2) 
x
Presence of primary tumor (present versus absent)
The hazard ratio (HR) and its 95% CIs will be estimated for all factors.   
3. Exploratory models:  Two exploratory models will be generated.  The first will evaluate whether 
study outcomes could have been influenced by receipt of post-protocol anti-cancer treatment.  
The second will evaluate the effect of treatment versus placebo in those who receive minimum 
effective treatment, defined in Section 4.5.       
4. The subset analysis outlined in section 4.9.1.6 will performed on the primary endpoint (OS) 
utilizing Cox proportional hazards models. Each subset analysis will contain treatment group and 
the variable of interest as factors. No adjustments for covariates will be made. For each subset 
analysis, the HR and 95% CI’s will be estimated for OS between the treatment groups across the 
different subsets. A forest plot of overall survival will be presented by subgroup. 
No control for type I error will be implemented for the sensitivity and subset analyses outlined above. 
4.9.3
Secondary Efficacy Variables 
The following secondary outcomes will be inferentially assessed using a hierarchical analysis method 
(e.g., inferential analysis will stop and not continue to subsequent secondary outcomes after obtaining a 
p-value greater than 0.05). The order of endpoint presentation below reflects the hierarchy of inferential 
testing. Inferential assessment of secondary outcomes will take place only if the primary outcome (OS) 
is found to differ significantly between treatments when analyzed via the primary analysis method 
detailed above. 
1. Overall Survival in the Predefined Biomarker-positive Population 
Overall Survival (OS) in biomarker-positive population is defined as the time from 
randomization to death due to any cause. The analyses and displays for OS in the ITT 
population, as described in section 4.9.2.1, will also be performed for OS in the biomarker-
positive population, using similar methodology. 
2. Progression-Free Survival in the ITT General Study Population 
Progression-Free Survival (PFS) in the ITT population is defined as the time from randomization 
to the first objective documentation of disease progression or death due to any cause. If a subject 


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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 subjects who have withdrawn their consent from study 
procedures and/or follow-up. The analyses and displays for OS in the ITT population, as 
described in section 4.9.2.1, will also be performed for PFS in the ITT population, using similar 
methodology. 
3. Progression-Free Survival in the Predefined Biomarker-positive Population 
PFS in biomarker-positive population is defined as the time from randomization to the first 
objective documentation of disease progression or death due to any cause. The analyses and 
displays for OS in the ITT population, as described in section 4.9.2.1, will also be performed for 
PFS in the biomarker-positive population, using similar methodology. 
4. Objective Response Rate in the ITT General Study Population 
Objective Response Rate (ORR) is defined as the proportion of subjects with a documented 
complete response or partial response (CR + PR) based on RECIST 1.1. The primary estimate of 
ORR will be based on subjects with measurable disease by RECIST 1.1 at randomization. CMH 
test will be used for comparison of the two treatment groups, adjusting for the randomization 
stratification variables (outlined in section 4.9.1.2). The test statistic and p-value will be reported. 
In addition, a logistic regression analysis may be performed as a sensitivity analysis, with Objective 
Response as a binary endpoint. The effect of treatment arm will be evaluated in the model, adjusting for 
randomization stratification variables. Model based estimates of the proportions of subjects with 
objective response, as well as the corresponding 95% CI, will be presented by treatment arm. The odds 
ratio between the treatment arms will be estimated, and the corresponding 95% CI and p-value will be 
reported.
5. Disease Control Rate in the ITT General Study Population 
Disease Control Rate (DCR) is defined as the proportion of subjects with a documented complete 
response, partial response, or stable disease (CR + PR + SD) based on RECIST 1.1. The primary 
estimate of DCR will be based on subjects with measurable disease by RECIST 1.1 at 
randomization. CMH test will be used for comparison of the two treatment groups, adjusting for 
the randomization stratification variables (outlined in section 4.9.1.2). The test statistic and p-
value will be reported.
In addition, a logistic regression analysis may be performed as a sensitivity analysis, with 
Disease Control as a binary endpoint. The effect of treatment arm will be evaluated in the model, 
adjusting for randomization stratification variables. Model based estimates of the proportions of 
subject with disease control, as well as the corresponding 95% CI, will be presented by treatment 
arm. The odds ratio between the treatment arms will be estimated, and the corresponding 95% CI 
and p-value will be reported.


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4.10 Safety Evaluation 
All safety summaries, analyses and listings will be based upon the Safety Analysis Set as defined in 
Section 4.5.
In general, all safety data will be listed, sorted by treatment group, site, and subject identification 
number. Descriptive statistics will be calculated for quantitative safety data and frequency counts and 
percentages will be compiled for classification of qualitative safety data. All percentages will be 
calculated based on the number of subjects in the Safety Analysis Set, unless otherwise indicated. 
Repeated or unscheduled tests are not summarized for each scheduled visit, but are included for 
summaries of maximum and minimum post-baseline values, shift-table analyses, and listings.  No 
inferential statistical analysis is planned for safety data, unless otherwise specified.   
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 will be used to 
compare adverse events between the two arms if required. 
4.10.1 Safety Data Handling and Definitions 
4.10.1.1 Treatment-Emergent Adverse Events (TEAEs) 
An AE will be regarded as treatment-emergent, if
x
its onset date occurs any time on or after the date of administration of the first dose of study 
treatment (either BBI608 or placebo or paclitaxel) 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 and worsens while 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). 
4.10.1.2 Adverse Events of Special Interest (AESIs) 
The list of AESIs (see table directly below) consists of pre-specified selected adverse events that are 
given special consideration because they have been associated with other agents in a similar class of 
drugs or that were observed in preclinical evaluation or earlier clinical studies of BBI608. For each 
AESI, a list of clinically relevant MedDRA preferred terms will pre-specified based on review of 
blinded data as well as review of standard MedDRA queries (SMQs). 
In order to review AESIs in the most medically meaningful way selected preferred terms that represent 
the same phenomenon will be grouped together. The MedDRA preferred terms that are grouped under 
each of the AESI terms will be provided in the compound-level safety document. 
System
Event
Gastrointestinal 
Diarrhea
Nausea(Procedural nausea, Prophylaxis of nausea and vomiting)


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Vomiting(Infantile vomiting, Post-tussive vomiting, Prophylaxis 
of nausea and vomiting, Vomiting in pregnancy, Vomiting 
projectile)
Abdominal Pain(Abdominal pain lower, Abdominal pain upper)
Flatulence
Fecal Incontinence
Blood in stool
Mucositis Oral
Burping
Bloating
Constitutional
Fatigue(Muscle Fatigue, Respiratory Fatigue)
Chills
Weight Loss(Abnormal Weight Loss, Weight Decreased)
Metabolism and Nutrition 
Anorexia
Hypokalemia
Hypomagnesemia
Dehydration
Neuro-Psychiatric
Dysgusia
Confusion(Confusion postoperative, confusionalstate)
Dizziness
Renal and Urinary
Urine Discoloration
Skin And Subcutaneous 
Tissue
Rash Maculo-Papular
4.10.1.3 Consolidated Adverse Events 
Consolidated terms comprising clinically synonymous MedDRA preferred terms have been defined in 
order to assist in identifying relevant safety differences between treatment arms. Summaries of the 
incidence of these consolidated terms will supplement the summaries by MedDRA preferred terms 
specified above. 
4.10.1.4 Previous/Concomitant Medications 
Medications will be coded using the WHO Drug coding dictionary version Dec2015. All of the displays 
will be summarized by ATC codes Level 3 and preferred term unless otherwise specified. 
Medications starting after the completion/withdrawal date will be listed but will not be classified or 
summarized. 
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, then the 


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medication will be classified as ‘concomitant’. If a medication starts before the date of first treatment 
administration and stops on or after the date of first treatment administration, then the medication will be 
categorized as both a ‘prior’ and ‘concomitant’ medication.
Handling of partial dates will follow the conventions in Section 4.10.1.6.
If a subject takes the same medication (i.e. same preferred term) more than once, they are only counted 
once under the count for preferred term per period. If a subject takes more than one medication in a 
particular ATC Level 3 term, they will only be included once in the count for the term per period, but 
will appear in the count for each appropriate preferred term within the ATC Level 3 term (unless it is the 
same preferred term). 
The incidence of concomitant medications use will be summarized by ATC Level 3 term and preferred 
term for each treatment group and period. The incidence will be ordered by decreasing incidence based 
on the BBI608 column. In addition to the incidence, this will also include a count of the total number of 
medications for each WHO Drug preferred term for each treatment group and period.  
Incidence of most common concomitant medications will be summarized. ‘Most common’ will be 
defined as those medications occurring in ≥ 2% of subjects in the BBI608 treatment group.
All details recorded in relation to prior and concomitant medication will be listed by subject.  
4.10.1.5 Partial Dates for Adverse Events and Previous/Concomitant Medications 
For the subject data listings, no imputation of incomplete dates will be applied. The listings will present 
the incomplete dates without any change. 
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: 
-
first day of the month that the event occurred, if the onset yyyy-mm is after the yyyy-mm of 
first study treatment 
-
the day of the first study treatment, if the onset yyyy-mm is the same as yyyy-mm of the first 
study treatment 
-
the date of informed consent, if the onset yyyy-mm is before the yyyy-mm of the first 
treatment 
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: 
-
January 1 of the year of onset, if the onset year is after the year of the first study treatment 


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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 
-
the date of informed consent, if the onset year is before the year of the first  
treatment 
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. 
4.10.1.6 Study Drug Exposure 
Exposure analyses will be based on the actual dose administered (in mg) for BBI608 or body surface 
area (BSA in m2) for paclitaxel. The BSA to be used for calculating each dose of paclitaxel will be 
calculated using the Dubois & Dubois formula (see below) based on the last available weight and height 
prior to each infusion. 
BSA [m2] = (Weight [kg]0.425 * Height [cm]0.725 ) * 0.007184
Calculated doses will be rounded to the nearest integer. 
For subjects who did not receive any amount of a study drug, the dose exposure parameters for that 
treatment (number of infusions, duration of treatment, cumulative dose, dose intensity, relative dose 
intensity) will be set to 0. Cumulative dose, dose intensity and relative dose intensity will remain 
missing if they cannot be derived due to missing weight, height, or BSA. 
BBI608 or Placebo Treatment: 
x
Duration of treatment (weeks; 1 day added to duration of treatment because administration of 
each cycle is for 1 day) = [(Date of last dose - date of first dose) +1] ÷ 7 
x
Cumulative dose, dose intensity, relative dose intensity: 
o
Cumulative dose (mg) = Sum of all (total dose administered [mg] ) 
o
Weekly dose intensity (mg/week) = (Cumulative dose) ÷ (Duration of 
treatment) 
o
Planned weekly dose intensity (mg/week) = 2 * 480 mg * 7 = 6720 mg/week
o
Relative dose intensity (%) = (Weekly dose intensity) ÷ (Planned weekly dose 
Intensity) *100 
x
Number of dose level reductions: Dose level reductions as reported in the eCRF will be 
calculated on a by-subject-basis and number of events of dose reduction over time. 


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x
Dose delays: As reported in the eCRF 
x
Dose Omissions (Not Administered): As reported in the eCRF
Paclitaxel Treatment: 
x
Duration of treatment (weeks; 14 days added to duration of treatment because last 
administration of each cycle is for 2 weeks [on day 1, 8, 15 of each 4-week cycle]) =[(Date of 
last dose - date of first dose) + 14] ÷ 7 
x
Cumulative dose, dose intensity, relative dose intensity: 
o
Cumulative dose (mg/m2) = Sum of all (total dose administered [mg] ÷ BSA 
using last available weight [m²]) 
o
Weekly dose intensity (mg/ m2/week) = (Cumulative dose) ÷ (Duration of 
treatment) 
o
Planned weekly dose intensity (mg/m²/week) = 3*80mg/ m2 / 4 weeks = 60 
mg/ m2/week 
o
Relative dose intensity (%) = (Weekly dose intensity) ÷ (Planned weekly dose 
intensity) * 100 
x
Number of dose level reductions: Sum of the number of dose level reductions as 
reported in the eCRF 
x
Dose delays: As reported in the eCRF 
x
Dose Omissions (Not Administered): As reported in the eCRF 
4.10.2 Extent of Exposure 
The following exposure variables will be presented for BBI608/Placebo, Paclitaxel, and overall: 
x
Number of cycles completed, descriptively and categorically (all cycles) 
x
Total Dose (all cycles) 
x
Treatment Duration (all cycles) 
x
Number of doses received (all cycles) 
x
Dose intensity (all cycles) 
x
Relative dose intensity (all cycles) 
x
Number of subjects with dose interruptions (by cycle and overall) 
x
Number of subjects with dose reduction (by cycle and overall) 
x
Number of subjects with treatment discontinuation (by cycle and overall) 
The listing will provide data collected on the Study Drug (BBI608/Placebo and Paclitaxel)
Administration eCRF pages for each subject. 
4.10.3 Adverse Events 


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Treatment-emergent adverse events (TEAEs) will be summarized by Medical Dictionary for Regulatory 
Activities (MedDRA™) System Organ Class (SOC) and Preferred Term (PT) classified from verbatim 
terms, from the latest version available. If more than one AE is recorded for a subject within any SOC or 
PT term, the subject will only be counted once on the most severe National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0 grade and the closest relationship 
to treatment. AEs reported with a relationship to study medication considered by the investigator to be 
‘possible’, ‘probable’ or ‘definite’ will be considered attributable to study medication. Missing 
classifications concerning study medication relationship will be considered as related to study 
medication by the investigator. 
An overview of AE’s and TEAEs will be provided. The following set of summaries will be presented 
across treatment groups for any TEAE: 
x
By SOC and PT (all grade, and grade >3)
x
By PT (all grade, and grade >3) by decreasing frequency on BBI608 arm 
x
By consolidated terms (consolidation using BBI608 project-specific standard) 
x
By max grade 1-5 
These summaries will also be produced for TEAEs considered related to study treatment by the 
investigator, for ‘TEAEs considered related to BBI608’ by the investigator, and for ‘TEAEs considered 
related to paclitaxel’ by the investigator.
Treatment Emergent Adverse Events of Special Interest (TEAESIs) will be summarized using MedDRA 
Version 19.1 PT.
All collected AEs (treatment emergent or non-treatment emergent) will be presented in a listing by 
treatment group, sorted by SOC. 
4.10.4 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
All deaths that occur after the administration of the first dose of any study drug and within 30 days of 
last dose of any study drug from the signing of the informated consent to the end of the follow up period 
for death will be provided in a listing. The listing will include primary cause of death, and the number of 
days relative to the administration of first and last dose. 
The number and percentage of subjects who died during the study treatment and within 30 days after the 
last dose will be presented by primary cause of death and by treatment group. A summary table will be 
provided for TEAEs leading to death: 
x
By SOC and PT 
x
By consolidated terms 
A listing will be provided for all adverse events leading to death. 


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Serious adverse events (SAEs) are those events that result in death, are life-threatening, require or 
prolong hospitalization, result in persistent or significant disability/incapacity, cause congenital 
anomaly/birth defect, and/or considered significant by the investigator for any other reason. The 
following list of summaries will be provided for TESAEs: 
x
By SOC and PT 
x
By consolidated terms 
These summaries will also be produced for ‘TESAEs considered related to study treatment by the
investigator’, for ‘TESAEs considered related to BBI608 by the investigator’ and for ‘TESAEs
considered related to paclitaxel by the investigator’.
Additionally, a summary by PT will also be produced for ‘TESAEs considered related to study treatment 
by the investigator’, for ‘TESAEs considered related to BBI608 by the investigator’ and for ‘SAEs 
considered related to paclitaxel by the investigator’, which resulted in hospitalization. 
A listing of all SAEs will be presented by treatment group. 
TEAEs leading to discontinuation, TEAEs leading to dose reduction, and TEAE’s leading to dose 
interruption, will be summarized: 
x
By SOC and PT (all grade, and grade >=3) 
x
By consolidated terms 
Listings will be provided for AEs leading to dose interruption, AE’s leading to dose reduction, and AE’s 
leading to treatment discontinuation. These listings will be presented by treatment group. 
4.10.5 Clinical Laboratory Evaluation 
The following laboratory variables will be determined in accordance with the schedule of procedures as 
specified in subject evaluation flow sheet. 
Clinial Laboratory Assessments 
Hematology
Leukocytes, 
Hemoglobin, 
Platelets, 
Neutrophils, 
Lymphocyte, 
Monocytes, Eosinophils, Basophils, and Absolute Neutrophils
Clinical Chemistry
Potassium, Creatinine, Creatinine Clearance, Phosphate, Magnesium, 
Albumin, Total Bilirubin , Aspartate aminotransferase (AST), Alanine 
aminotransferase (ALT), Alkaline phosphatase, and Lactate 
Dehydrogenase (LDH).
Urinalysis
Specific Gravity, Glucose, Protein, Blood
Pregnancy Test
Choriogonadotropin Beta
Laboratory values will be converted to standard (SI) units, and the numerical results will be graded 
using NCI-CTCAE Version 4.0. Laboratory results not corresponding to a NCI-CTCAE Version 4.0 


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term will not be graded. For values such as Sodium and Potassium there will be two bi-directional 
parameters (hyper and hypo) created, and the tests will be graded by CTCAE v4.0 in both directions. 
Clinical laboratory results will be summarized by treatment group with descriptive statistics at each 
cycle:   
x
Observed test results for each lab parameter  
x
Change from baseline for each lab parameter 
In addition, for the graded laboratory parameters, shift from baseline will be provided by cycle and for 
the maximum grade on the study. 
Laboratory values will be classified as normal, low, or high based on normal ranges supplied by the 
central laboratory. Laboratory categories will be expressed in terms of the L (below LLN), N (between 
LLN and ULN) and H (above ULN) classifications for numerical measurements and normal, abnormal 
for categorical measurements. The number and percentage of subjects with abnormal values will be 
summarized for each laboratory parameter by cycle and treatment group. A comprehensive listing of all 
hematology, available urinalysis, and biochemistry data will be provided, including the test result, 
normal range, and change from baseline. Values outside the normal laboratory reference ranges 
provided by the testing lab will be flagged as high or low in the listings and also presented in a separate 
listing. The table below outlines CTCAE Version 4.0 grade 3 adverse event criteria for clinical 
laboratory parameters. 
Parameter
Unit
Grade 3 Criteria
Leukocytes
(10^9/L)
HYPO: <2 - 1
Hemoglobin
(g/L)
HYPO : <80
HYPER: Increase in >4 gm/dL above ULN or above 
baseline if baseline is above ULN
Platelets
(10^9/L)
HYPO: <50 – 25.0
Lymphocytes
(10^9/L)
HYPO: <0.5 – 0.2
HYPER: > 20
Potassium
(mmol/L)
HYPO: <3.0 – 2.5
HYPER: >6.0 – 7.0
Creatinine
(umol/L)
HYPER: >3.0 baseline; >3.0 – 6.0 * ULN


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Phosphate
(mmol/L)
HYPO: <0.6 – 0.3
Magnesium
(mmol/L)
HYPO: <0.4 – 0.3
HYPER: >1.23 – 3.30
Albumin
(g/L)
HYPO: <20
Bilirubin
(umol/L)
HYPER: >3.0 – 10.0 * ULN
Aspartate aminotransferase
(IU/L)
HYPER: >5.0 – 20.0 * ULN
Alanine aminotransferase
(IU/L)
HYPER: >5.0 – 20.0 * ULN
Alkaline phosphate
(IU/L)
HYPER: >5.0 – 20,0 * ULN
Retest results will be reported in the listings as well.
Incidence of patients with liver function test results satisfying the drug-induced liver injury (DILI) 
criterion defined as (> 3x upper limit of normal [ULN] for ALT/AST, >2xULN for total bilirubin and ≤ 
2xULN for alkaline phosphatase at the same time-point) will be presented by Cycle.  
In addition, incidence of elevated liver function test results will be presented by elevation criterion. 
Elevation criteria are given as follows: 
xALT (ULN - ≤ 3xULN, > 3xULN - ≤ 5xULN, > 5xULN)
xAST (ULN - ≤ 3xULN, > 3xULN - ≤ 5xULN, > 5xULN)
xTotal Bilirubin (ULN - ≤ 2xULN, > 2xULN)
xAlkaline Phosphatase (ULN - ≤ 2xULN, > 2xULN)
4.10.6 Vital Signs 
Summaries of markedly abnormal vital signs parameters, including blood pressure (BP) and pulse, will 
be presented by treatment group and cycle. For systolic and diastolic blood pressure, shift from baseline 
will be provided by cycle and for the worst value on the study using the following categories: 
Values for vital signs for all subjects will be presented in a listing, and subjects 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)


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Systolic BP
Absolute value ≤ 90 mmHg, or  a 
decrease from baseline ≥20 mmHg
Absolute value ≥ 180 mmHg, or  an 
increase from baseline ≥20 mmHg
Diastolic BP
Absolute value ≤ 50 mmHg, or  a 
decrease from baseline ≥15 mmHg
Absolute value ≥ 105 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 ≥15bpm
4.10.7 Electrocardiogram (ECG) Evaluations 
ECG findings will be presented using frequency counts categorized as: normal, abnormal not clinically 
significant, abnormal clinically significant or missing at each visit, by treatment.  A by subject listing 
will also be provided.  Unscheduled visits will be included only in the listing. 
4.10.8 Other Safety Evaluations 
Weight at baseline will be presented by treatment group using summary statistics. Changes from 
baseline to on-treatment weight assessments will be presented by treatment group and time point 
considering the frequency of subjects with changes falling in the following categories: <-10% (loss), ≥-
10% - <10%, ≥10% (gain). 
Physical examination abnormalities will be summarized by body system, treatment group and time 
point. In addition, observed and changes in physical examination values for all subjects will be provided 
in a listing. Subjects with clinically significant abnormal findings will be flagged in the data listing. 
The ECOG performance status (PS) results will be summarized using frequency distributions for each 
scheduled visit, including also the best and worst post-baseline value. A listing of observed and changes 
in ECOG PS for all subjects will be provided. Subjects with deterioration to ECOG PS 4will be flagged. 
In addition, a graphical display will be provided for time to deterioration in ECOG PS. 
Reported pregnancies, as measured by serum or urine pregnancy test, will be provided in a listing, as 
well. 
4.10.9 Data and Safety Monitoring Board (DSMB) 
The DSMB is an independent expert advisory group, charged with the responsibility of evaluating safety 
of the trial. It is planned to have DSMB meetings to evaluate subject safety at regular intervals of every 
six months during the study.  During these meetings, enrollment status, AEs including serious events
and events of special interest, and deaths, including deaths occurring as a result of the disease under 
study and deaths unrelated to disease under study, will be presented. The first meeting will take place 


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after the first 150 subjects (combined for both arms) have completed study (ie., the first 150 primary 
endpoint events have occurred).  
Except as otherwise noted, the identification of AEs of special interest will be based on MedDRA 
preferred terms, using standardized MedDRA queries and prespecified lists of preferred terms indicative 
of the respective clinical conditions.   
There may be further ad hoc meetings (by phone or face-to-face) to evaluate the safety of the subjects, 
when the internal safety review of Boston Biomedical (pharmacovigilance) detects safety risks.  
Within 5 days after each meeting, the DSMB will make written recommendations to Boston Biomedical 
to continue the study as planned, to continue the study with a minor or a major protocol amendment or 
to terminate the study. (refer to DSMB Conclusion Form). Recommendations for modifications, 
suspension or termination should be accompanied by the minimum amount of data required for the 
Sponsor to make a reasoned decision about the recommendation, and the rationale for such 
recommendations should be clearly conveyed. Both a written recommendation and oral communication 
should be followed with the opportunity for questions and discussion between the DSMB and Boston 
Biomedical / Steering Committee.
4.11 Other Analyses 
4.11.1 Health Economics 
A cost effectiveness analysis will be performed independently of the reporting of this study. The details 
will be provided in a separate analysis plan. 
4.11.2 Correlative Analyses 
The purpose of these studies is to explore the relationship between biomarkers and disease response.   
In addition to analysis of potential biomarkers of benefit from BBI608 therapy, an analysis of markers of 
resistance to BBI608 will be conducted using serial plasma samples which will be drawn at baseline as 
well at 4weeks post initiation of therapy. This analysis may involve SNPs, CYPS, and metabolomics. 
The following analysis will be performed to investigate the relationship between endpoints and 
biomarker levels (e.g. STAT3, phospho-STAT3, β-catenin, etc.):  
For each biomarker, Cox Proportional Hazards models will be used to model the relationship between 
each of the following efficacy endpoints: Overall Survival, Progression-Free Survival with baseline 
value of the biomarker. Each model will also include assigned treatment, interaction between treatment 
and biomarker, and will be stratified by baseline ECOG performance status, geographical region (Asia 
vs North America, Europe and Australia vs South America), time to progression on first line therapy (< 
6 months vs. > 6 months), disease measurability by RECIST 1.1 (measurable disease present vs. not 
present) and prior taxane therapy (yes vs. no). 


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For biomarkers with post-baseline measurements, similar analysis will be done with change from 
baseline of a biomarker as a covariate, for each of the 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, β-
catenin, etc.) will be also examined using the log-rank test, stratified by treatment and baseline ECOG 
performance status, geographical region (Asia vs North America, Europe and Australia vs South 
America), time to progression on first line therapy (< 6 months vs. > 6 months), disease measurability 
by RECIST 1.1 (measurable disease present vs. not present) and prior taxane therapy (yes vs. no). 
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 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 at different time points will be 
investigated using logistic regression that includes assigned treatment, biomarker value and treatment-
by-biomarker interaction, stratified by baseline ECOG performance status geographical region (Asia vs 
North America, Europe and Australia vs South America), time to progression on first line therapy (< 6 
months vs. > 6 months), disease measurability by RECIST 1.1 (measurable disease present vs. not 
present) and prior taxane therapy (yes vs. no). An additional model that includes prognostic factors may 
be investigated. The relationship between response and binary biomarkers (e.g. baseline phospho-
STAT3 status or STAT3 status) will also be examined using the CMH test, stratified by treatment and 
baseline ECOG performance status), geographical region (Asia vs North America, Europe and Australia 
vs South America), time to progression on first line therapy (< 6 months vs. > 6 months), disease 
measurability by RECIST 1.1 (measurable disease present vs. not present) and prior taxane therapy (yes 
vs. no). Subgroup analysis by the status of the binary biomarker may also be performed. As a sensitivity 
analysis, logistic regression analysis will be performed for each binary response variable, using the 
binary biomarkers as factors, and stratifying by treatment and baseline ECOG performance status. 
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. 
4.11.3 Exploratory Analyses 
4.11.3.1 Response Rates in biomarker-positive population 
A Cochran Mantel Haenszel (CMH) test adjusted for the stratification factors will be used to compare 
the differences in the ORR and DCR between the treatment groups. For each analysis, the test statistic 
and p-value will be reported. 
x
Objective Response Rate in the Predefined Biomarker-positive Population 
Objective Response (ORR) in the biomarker-positive population [those subjects with pSTAT3
positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) 
archival tissue] is defined as the proportion of subjects with a documented complete response or 


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partial response (CR + PR) based on RECIST 1.1. The primary estimate of ORR will be based 
on subjects with measurable disease by RECIST 1.1 at randomization.  
x
Disease Control Rate in the Predefined Biomarker-positive Population 
Disease Control Rate (DCR) in the biomarker-positive population [those subjects with pSTAT3
positivity on immunohistochemical (IHC) staining of Formalin Fixed Paraffin Embedded (FFPE) 
archival tissue] is defined as the proportion of subjects with a documented complete response, 
partial response, or stable disease (CR + PR + SD) based on RECIST 1.1. The primary estimate 
of DCR will be based on subjects with measurable disease by RECIST 1.1 at randomization.  
4.11.3.2 Sparse Pharmacokinetic Analysis 
Exploratory analyses will be performed on the bio-analytic data obtained from sparse plasma sampling 
in order to characterize the population pharmacokinetics of BBI608.Demographic and pathophysiologic 
factors that affect plasma concentration of BBI608 and paclitaxel in this population of subjects with pre-
treated advanced gastric/GEJ adenocarcinoma will be examined. The exposure-response relationship 
between clinical and safety endpoints and BBI608/paclitaxel exposure will also be examined. 
PK analyses of Plasma samples will be performed using population pharmacokinetics obtained through 
sparse PK sample collection.  The exposure/response relationships will be summarized.  Further 
exploratory analyses may be performed as appropriate.
4.11.3.3 Quality of Life Analysis 
SCManual QLQ-C30 will be used as a reference for scoring.   
The Quality of Life (QoL) of subjects will be assessed using EORTC QLQ-30 while the subject remains 
on BBI608/Placebo. 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. The quality of 
life data will be analyzed to look for statistically and clinically significant differences between the 
BBI608 versus placebo groups. Mean baseline scores for each subscale and summary scores will be 
calculated. 
Compliance rates for each PRO instrument will be calculated at each assessment time point. Compliance 
at an assessment time point is defined as the number of subjects who were assessed for that PRO 
instrument divided by the expected number of subjects at that time point. The expected number of 
subjects: 
x
at baseline is equal to the number of subjects randomized 
x
at any post-baseline visit is equal to the number of subjects who are alive and have not 
progressed 


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A subject who answers at least one item at a time point is considered to have been assessed. Reasons for 
non-compliance will be tabulated by treatment arm and by assessment time point. 
The endpoints in QoL analysis are the mean EORTC QLQ-C30 QoL change scores from baseline at 
cycle 2 (~8 weeks) and cycle 4 (~16 weeks) for the physical function and global health status/quality of 
life subscale scores. For both subscales, the observed values and changes from baseline will be 
summarized by treatment arm. 
Wilcoxon rank sum 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. For each comparison, the null hypothesis states that 
the observations in both treatment arms come from the same population. The alternative hypothesis 
states that the observations in both treatment arms do not come from the same population. 
To perform the Wilcoxon rank sum test, the absolute values of a subscale’s differences between baseline 
and the time point of interest will be ranked across both treatment arms. These rankings are then 
summed within each treatment group, and the lowest sum of the two is compared to a critical value. If 
the sum of the rankings is lower than the critical value, then the null hypothesis is rejected, and it is 
concluded that QoL change from baseline score is different between treatment groups (for  the given 
time point and subscale of interest.) 
The Hochberg method will be used to adjust for multiple comparisons in the primary analyses. 
In addition, the proportion of subjects 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 via Fisher’s exact test. For each subscale and 
time point, the estimated proportions and nominal p-value will be reported. 
By-subject listings of these data will be provided. 
Graphical displays will be provided for change from baseline in EORTC QLQ-C30 Scores, as well as 
summary of EORTC QLQ-C30 response analysis. In addition, Kaplan-Meier plots will be provided to 
compare time to deterioration in EORTC QLQ-C30. 
4.12 Determination of Sample Size
The primary study endpoint is Overall Survival (OS). The study is designed to have a power of 90% and 
a two-sided alpha of 5% to detect a 24% reduction in the continuous risk of death (HR 0.76, which 
corresponds to an increase of median survival from 7.36 to 9.67 months) in the Intention to Treat (ITT) 
general study population. It is estimated that 566 events will be required to detect this reduction which 
would be observed by randomizing 700 patients over 24 months and following them for an additional 12 
months (including up to 5% of yearly dropouts).  
There will be one interim analysis in this study to stop trial early for success to be presented to the 
independent Data Safety and Monitoring Board (DSMB). The interim analysis will be performed on OS, 
the primary endpoint of this study, when at least 2/3rds of the required number of events (380) has been 
observed.  


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The comparison of the overall population will be tested based on a generalization of the Lan-DeMets 
error spending function approach using an O’Brien-Fleming stopping boundary to reject H0, controlling 
for a two-sided alpha of 5% at the end of the study. For example, if exactly 380 deaths (67% of the 
required events) were in the locked database for the interim analysis, the nominal critical point for 
rejecting H0 would be 2.502, corresponding to a two-sided p-value of 0.012. Thus H0 would be rejected, 
and superiority of BBI608 declared early, if the two-sided p-value from stratified log-rank test is < 
0.012.
The nominal critical point at the final analysis for rejecting H0 would be 1.994 corresponding to a two-
sided p-value of 0.0462. 
Information
rate
bounds         
reject H0
sign.level      
one-sided      
sign.level     
two-sided
events 
0.67   
2.502  
0.006         
0.0124        
380
1.0    
1.994       
0.0231        
0.0462       
566   
Should the trial not stop for efficacy at this interim analysis, the final analysis will occur when 566
deaths are observed. The nominal critical value for rejecting the H0 at this final analysis would be 1.994,
corresponding to a two-sided p-value of < 0.0462. 
4.13 Changes in the Conduct of the Study or Planned Analysis 
Any changes made to the planned analyses in the Study Protocol should be described in this section 
giving justification for the changes. 


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5
REFERENCES 
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979; 35(3);549-
556.
Braunwald E, Fauci A, Hauser S, Jameson J, Kasper D, Longo D. Harrison's Principles of 
Internal Medicine.16th Edition. McGraw-Hill Medical Publishing Division, New York, 
2005. Appendix A, Reference Values For Laboratory Tests, pages A1-A9. 
Chau I, Norman AR, Ross PJ et al. Multivariate prognostic factor analysis and second-line treatment in 
locally advanced and metastatic oesophago-gastric cancer – pooled analysis of 1080 patients from three 
multicenter randomized controlled trials using individual patient data. ASCO Gastrointestinal Cancers 
Symposium; (2004a) abstract 5. 
Collett D. Modeling Survival Data in Medical Research.2nd edition. London: Chapman & Hall; 2003. 
Dolan P. Modeling valuations for EuroQol health states.Med Care. 1997;35(11):1095-1108. 
EMEA, Guideline on the Evaluation of Anticancer Medical Products in Man, 2005. 
Fayers P, Aaronson NK, Bjordal K, Curran D, Broenvold M, on behalf of the EORTC Quality ofLife 
Study Group. EORTC QLQ-C30 Scoring Manual. 3rd ed. Brussels (Belgium): EORTCQuality of Life 
Group, 2001. 
Fleming, Thomas R, Interpretation of subgroup analyses in clinical trials, Drug InformationJournal, Vol. 
29, pp.1681S-1687S, 1995 
Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics,USDHHS, FDA, May 2007 
Irwin, J. O. (1949), The Standard Error of an Estimate of Expectational Life. Journal of Hygiene,47, 
188-189.
Karrison, T. (1997), Use of Irwin’s Restricted Mean as an Index for Comparing Survival inDifferent 
Treatment Groups-- Interpretation and Power Considerations, Controlled ClinicalTrials, 18, 151-167. 
Meier P, Karrison T, Chappell R, Xie H. (2004). The Price of Kaplan-Meier, Journal of theAmerican 
Statistical Association, 99 (467):890-896
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, PetoJ, 
Smith PG. (1977). Design and analysis of randomized clinical trials requiring prolongedobservation of 
each subject. II. Analysis and examples. Br J Cancer, 35(1):1-39.  


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6
APPENDICES 


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Appendix 1: Patient Evaluation Flow Sheet
Day
day 
1
day 
2
1
8
15
1
8
15
Timing
≤14 days prior 
to 
randomization
4 weeks 
post 
protocol 
treatment 
Every 8 
weeks 
thereafter15
History2 and Physical Exam
X
X
X
ECOG PS
X
X
X
Weight
X
X
X
Height
X
Vital signs
X
X
X
Paclitaxel Infusion3
X
X
X
X
X
X
Begin BBI608/Placebo administration
X
Hematology4,5
X
X
X
X
X
X
X
X
Biochemistry5
X
X
X
Urinalysis5
X
X
X
ECG (12-lead)
X
X
X
Radiology and Imaging6
X
Submission of representative block of
diagnostic tumor tissue
Blood
collection
for
correlative
studies7
X
X
X8
Blood
collection
for
sparse
PK
analysis
X
X
X
Pregnancy test, serum or urine (if 
applicable)9,10
X
X
X
Adverse Event assessment11,12
X
X
X12
X
X
X
X
X
X
X
Quality of Life assessment (EORTC
QLQ-C30)13
X
X
X14
Assessment for survival of patient
X16
X16
Tests & Procedures
Additional Cycles
After Protocol 
Treatment 
Discontinuation         
(+/- 3 days)
 During Protocol Treatment (+/-3 days)
Cycle 1
run-in1
upon request after randomization
Every 8 weeks until progressive disease is documented 
Pre-
Treatment 
1 
BBI608/Placebo administration will begin 2 calendar days prior to the paclitaxel infusion on day 1 of cycle 1. These two days are referred to as run-in 
day 1 and run-in day 2. Run-in day 1 should occur within 2 working days of subject randomization.
2 
Medical history must include date of diagnosis including histological documentation of malignancy, documentation of Her2 status of tumor(if 
available), prior anticancer therapy and prior date(s) of disease progression. 
3.  Paclitaxel 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).
4 
Hematology should be done within 72 hours prior to paclitaxel administration.  
5Laboratory investigations should be performed within72 hours prior to Day 1 of each Cycle of protocol treatment. 
6 
Tumor measurement and evaluation by RECIST 1.1 criteria. The same method of assessment and the same technique should be used to identify and 


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report each lesion at baseline and at reassessment during treatment. Tumor evaluations will continue until progressive disease is documented (as 
described in section 10). For subjects 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.
7    Sample collection should be performed at baseline and at 4weeks after randomization. 
8
A sample will be collected following protocol treatment discontinuation if discontinuation occurs prior to 4 weeks of therapy.            
9   In women of childbearing potential only. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. Baseline pregnancy 
test should be done within 5 days of randomization.
10 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. 
11  Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see Appendix III).
12 Adverse event assessment by phone should be performed on run-in day 2.
13 To be completed in clinic. Questionnaires should be completed at baseline and At 4, 8, 12, 16 and 24 weeks after randomization for as long as subject 
remains on Protocol therapy or until deterioration to ECOG PS 4 or hospitalization for end of life care. 
14  EORTIC QLQ-C30 questionnaire will be collected in the post-protocol discontinuation period only if the subject 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   After the first visit at which the subject has been off protocol treatment for 4 weeks, subjects will be assessed every 8 weeks for survival. Medical 
history at post-progression follow up must include post-protocol treatment cancer therapies. 
16  In the event that the subject is unable to attend clinic, post-progression follow-up may be by means of telephone contact. 


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Appendix 2: Inclusion and Exclusion Criteria Resulting in the Exclusion of Patients from PP 
Population
This will be finalized and provided in a separate document prior to the database lock and unbinding. 


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Appendix 3: Prohibited Treatments Resulting in Exclusion of Patients from PP Population
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. 


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Appendix 4: Scoring Details for EORTC QLQ-C30/ Windows/ Response Analysis
The scoring method for EORTC QLQ-C30 is summarized below. In this summary Qi refers to the i-th
question on the QLQ-C30.
Functional scale’s scores: 
 
 
 
(1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
  
 
 
(1 - ((Q6+Q7)/2-1)/3) * 100 
 
 
 
(1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
functioning: 
 
 
(1 - ((Q20+Q25)/2-1)/3) * 100 
  
 
 
(1 - ((Q26+Q27)/2-1)/3) * 100 
Global health status score: 
 
 
 
 
((Q29+Q30)/2-1)/6 * 100 
Symptom scale’s scores: 
Fatigue: 
 
 
 
 
((Q10+Q12+Q18)/3-1)/3 * 100 
vomiting: 
 
 
((Q14+Q15)/2-1)/3 * 100 
 
 
 
 
 
((Q9+Q19)/2-1)/3 * 100 
 
 
 
 
 
((Q8-1)/3 * 100 
 Insomnia:  
 
 
 
(Q11-1)/3 * 100 
Appetite loss: 
 
 
 
(Q13-1)/3 * 100 
Constipation: 
 
 
 
(Q16-1)/3 * 100 
 
 
 
 
 
(Q17-1)/3 * 100 
difficulties: 
 
     
(Q28-1)/3 * 100 
Missing items on the scale will be handled by the following methods: values will be imputed for missing 
items by “assuming that the missing items have 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. 
The analyses of quality of life data will be restricted to intent-to-treat (ITT) patients who have a 
measurement at baseline and at least one measurement after baseline.  
The QoL assessment is performed prior to randomization and during protocol treatment. Since exact 
time of assessment may vary from subject to subject, 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: 
Week from randomization = (assessment date – randomization date) / 7;  
Time Point
Windows 
Baseline 
14 days prior to or on the randomization 
Week 4 
0 -< 7 weeks
Week 8
7 weeks -< 10 weeks 
Week 12
10 weeks -< 14 weeks
Week 16
14 weeks -< 20 weeks. 
Week 24 
20 weeks -< 28 weeks. 


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If more than one questionnaire is available for the baseline window, then the latest non-missing 
measurement, per question, will be considered. If more than one questionnaire is available at a time 
point other than baseline, then the average (per question) of the non-missing measurements will be used. 
Summary statistics will be based on changes of the quality of life scores from baseline. 
Baseline and Change Scores for All QoL Scales and Time Points Descriptive statistics for EORTC 
QOL-C30 scores (mean, standard deviation) will be presented for each scale at baseline. The same 
statistics will be generated at each time of post-baseline evaluation. The change scores from baseline at 
each time of post-baseline evaluation between treatment groups will be assessed using a Wilcoxon rank 
sum test for each EORTC-QLQ-C30. 
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 to improved and worsened categories is reversed for symptom scales. A Chi-square test will 
then be performed to compare the distributions of these three categories between two arms. 


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Appendix 5: Clarification for Strata Covariates Derivation and Pooling
Patients who are incorrectly stratified at the time of randomization, either because of information 
available subsequent to randomization or due to clerical error, the actual stratification as recorded in the 
CRF for these variables will be used in the primary analyses.
Randomization stratification factors from IVRS and actual stratification factors from eCRF and the 
discrepancy will be summarized as well.   
If any randomization stratum proves to have an inadequate sample size, it will be dropped from the 
primary analysis or pooling will be applied.  Details will be determined at blinded data review meetings 
prior to data base lock. 
The Cox regression model, stratified for actual stratification factors will be fitted, estimated hazard ratio 
and 2-sided 95% CI will be provided.  


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Appendix 6: Clarification on Object Response Rate and Disease Control Rate: Population 
and Analysis Details
The objective response rate (ORR) is defined as the number of subjects who had a best overall response 
(BOR) of complete response (CR), or partial response (PR) divided by the number of subjects in the ITT 
population of patients with measurable disease under study.  ORR will be summarized for each 
treatment along with the corresponding exact 2-sided 95% CI using a method based on F distribution. 
The treatment difference of ORR and its 95% CI based on normal distribution will be provided. CMH 
test will be used for comparison of the two treatment groups, adjusting for the actual stratification 
variables (outlined in section 4.9.1.2 except for measurable disease present or not) and p-value will be 
reported.
Disease control rate (DCR) is defined as the number of subjects who had a BOR of CR, PR or SD 
divided by the number of subjects in the ITT population of patients with measurable disease under 
study. Similar analysis as for ORR described in the above paragraph will be performed.   
In addition, a stratified logistic regression analysis may be performed as a sensitivity analysis, with 
Objective Response as a binary endpoint. The effect of treatment arm will be evaluated in the model, 
adjusting for actual stratification variables (outlined in section 4.9.1.2 except for measurable present 
disease or not). The odds ratio between the treatment arms will be estimated, and the corresponding 95% 
CI and p-value will be reported. 
Stratified logistic regression odds ratios will be estimated using PROC PHREG in SAS. A dummy time 
variable will be created, where all responders will be classified as events with an arbitrary time = t0, and 
non-responders as censored with time t1, where t1 > t0.  The DISCRETE option will be used for tied 
observations. 


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Appendix 7: Clarification on Removal of Consolidated Adverse Events
Consolidated adverse events are removed and will not be analyzed in this study.