A Phase 3 Study of BBI-608 in Combination With 5-Fluorouracil, Leucovorin, Irinotecan (FOLFIRI) in Adult Patients With Previously Treated Metastatic Colorectal Cancer (CRC).
Phase: PHASE3
Conditions: Colorectal Cancer
Sponsor: Sumitomo Pharma America, Inc.

Study CanStem303C (Protocol Amendment 7.0) 
                   Amendment Date: 25 October 2019 
CONFIDENTIAL 
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TITLE: 
A Phase 3 Study of BBI-608 in combination with 
5-Fluorouracil, Leucovorin, Irinotecan (FOLFIRI) in 
Adult Patients with Previously Treated Metastatic 
Colorectal Cancer (CRC) 
PROTOCOL NUMBER: 
CanStem303C (aka BB608-303CRC)  
FDA IND NUMBER 
100,887 
EudraCT NUMBER 
2016-001627-31 
STUDY DRUG: 
BBI-608 (aka BBI608, Napabucasin) 
SPONSOR: 
Boston Biomedical, Inc. 
640 Memorial Drive 
Cambridge, MA 02139, USA 
Telephone: +1.617.674.6800 
Fax: +1.617.674.8662 
DATE OF ORIGINAL 
PROTOCOL: 
29 October 2015 
DATE OF AMENDMENT: 
25 October 2019 
AMENDMENT 
7.0 (Global) 
 
 
The following personnel have approved this protocol:  
 
 
Signed:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Date:  
Matthew Hitron, MD  
Medical Monitor 
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. 
 

Study CanStem303C (Protocol Amendment 7.0) 
                   Amendment Date: 25 October 2019 
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PROTOCOL AMENDMENT HISTORY 
 
Document 
Version Date 
Original protocol 
29 October 2015 
Amendment 1 
14 April 2016 (Global) 
Amendment 2 
14 July 2016 (Global) 
Amendment 2.1 
18 October 2016 (Local – Singapore, Korea) 
Amendment 2.2 
07 November 2016 (Local – Belgium) 
Amendment 2.3 
27 December 2016 (Local – France) 
Amendment 2.4 
03 January 2017 (Local - Italy) 
Amendment 3.0 
06 December 2016 (Global) 
Amendment 3.1 
06 December 2016 (Local – Belgium) 
Amendment 3.2 
27 January 2017 (Local – France) 
Amendment 3.3 
27 January 2017 (Local – Italy) 
Amendment 4.0 
26 June 2017 (Local – Canada) 
Amendment 4.1 
26 June 2017 (Local – Australia, Japan & USA) 
Amendment 4.2 
20 July 2017 (Local – Canada) 
Amendment ͶǤ͵ 
23 August 2017 (Global) 
Amendment 5.0 
16 February 2018 (Global) 
Amendment 5.1 
26 April 2018 (Local – Korea) 
Amendment 6.0 
25 September 2018 (Global) 
Amendment 7.0 
25 October 2019 (Global) 

Study CanStem303C (Protocol Amendment 7.0) 
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SYNOPSIS 
Study Title: 
A Phase 3 Study of BBI-608 in combination with 5-Fluorouracil, Leucovorin, 
Irinotecan (FOLFIRI) in Adult Patients with Previously Treated Metastatic 
Colorectal Cancer (CRC). 
Study Number: 
CanStem303C (aka BB608-303CRC) 
Study Phase:  
3 
Study Drug: 
BBI-608, a novel investigational small molecule anticancer drug that is 
hypothesized to affect multiple oncogenic cellular pathways, including inhibition of 
the signal transducers and activators of transcription 3 (STAT3) pathway, which 
has been implicated in cancer stem cell viability.   
Primary 
Objectives: 
x 
To compare overall survival (OS) in the General Population patients treated 
with BBI-608 plus biweekly FOLFIRI (Arm 1) versus biweekly FOLFIRI 
(Arm 2) 
x 
To compare OS in the pSTAT3-positive (pSTAT3(+)) Subpopulation patients 
treated with BBI-608 plus biweekly FOLFIRI (Arm 1) versus biweekly 
FOLFIRI (Arm 2) 
Secondary 
Objectives: 
Key Secondary Objectives: 
x 
To compare progression free survival (PFS) in the General Population patients 
treated with BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x 
To compare PFS in the pSTAT3(+) Subpopulation patients treated with BBI 
608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x 
To compare disease control rate (DCR) in the General Population patients 
treated with BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x 
To compare DCR in the pSTAT3(+) Subpopulation patients treated with 
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x 
To compare overall response rate (ORR) in the General Population patients 
treated with BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x 
To compare ORR in the pSTAT3(+) Subpopulation patients treated with 
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
Other Secondary Objectives: 
x 
To compare the Quality of Life (QoL), as measured using the European 
Organization for Research and Treatment of Cancer Quality of Life 
questionnaire (EORTC-QLQ-C30), in the General Population patients treated 
with BBI-608 plus bi-weekly FOLFIRI versus bi-weekly FOLFIRI 
x 
To compare the QoL, as measured using the EORTC-QLQ-C30, in the 
pSTAT3(+) Subpopulation patients treated with BBI-608 plus biweekly 
FOLFIRI versus biweekly FOLFIRI 
x 
To evaluate the safety profile of BBI-608 administered daily plus biweekly 
FOLFIRI with safety assessed according to the National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 4.0 in the 
General Population and the pSTAT3(+) Subpopulation 

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Study Design: 
This is an international multi-center, prospective, open-label, randomized, adaptive 
design Phase 3 trial of the cancer stem cell pathway inhibitor BBI-608 plus 
standard bi-weekly FOLFIRI (Arm 1) versus standard bi-weekly FOLFIRI (Arm 2) 
in patients with previously treated metastatic colorectal cancer (mCRC). The 
hypotheses in General Population and pSTAT3(+) Subpopulation for OS in the 
study will be tested. An interim analysis will be conducted to check the decision 
rules of futility, population and hypothesis selection, and event count adjustment. 
The Sponsor and the CRO have implement blinding plans to minimize bias prior to 
the interim and final analyses. 
In this study, adult patients with mCRC following progression on first-line 
FOLFOX or XELOX with or without bevacizumab will be randomized in a 1:1 
ratio to BBI-608 plus biweekly FOLFIRI (Arm 1) or biweekly FOLFIRI (Arm 2). 
Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be 
permissible. Patients will be stratified according to geographical region (North 
America/Western Europe/Australia, vs. Japan/Korea vs. rest of the world); time to 
progression from start of first line therapy (<6 months vs. ≥6 months); RAS 
mutation status (mutant vs. wild type), bevacizumab as part of their protocol 
treatment (yes vs. no), and location of the primary tumor (left vs. right colon).  
The study will proceed in 14-day (2-week) cycles. BBI-608 will be administered 
orally, twice daily, with doses separated by approximately 12 hours. Standard 
FOLFIRI will be administered biweekly, on Day 1 of each 14-day study cycle. 
BBI-608 administration will begin 2 to 5 days prior to the first FOLFIRI infusion in 
patients randomized to Arm 1. In Investigator selected patients, bevacizumab will 
be administered per product label and institutional standards. 
Tumor assessments will be performed every 8 weeks after randomization until 
6 months of treatment and every 12 weeks thereafter until objective disease 
progression.  
Retrospective analysis of archival tumor tissue samples will be performed at the 
time of the interim analysis to determine pSTAT3 status of randomized patients. 
Study 
Population: 
The study will enroll patients with histologically confirmed adenocarcinoma of the 
colon or rectum that is metastatic (Stage IV, mCRC). Patients will have failed 
treatment with first-line combination therapy of oxaliplatin and a fluoropyrimidine 
with or without bevacizumab for metastatic disease, with failure defined as 
radiologic progression during or ≤6 months after the last dose of first-line therapy. 
Patients who discontinued first-line therapy due to toxicity may be enrolled as long 
as progression occurred ≤6 months after the last dose of first-line therapy. Patients 
receiving any other systemic chemotherapy in the metastatic setting will be 
excluded. All patients must have received a minimum of 6 weeks of the first-line 
regimen that included oxaliplatin and a fluoropyrimidine with or without 
bevacizumab in the same cycle. Prior neoadjuvant or adjuvant systemic treatment is 
allowed as long as no more than 2 prior systemic chemotherapy regimens were 
administered with no more than 1 prior regimen permitted in the metastatic setting. 
For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy 
will count as a single systemic regimen. Re-challenge with oxaliplatin is permitted 
and will be considered part of the first-line regimen for metastatic disease, with 
both initial oxaliplatin treatment and subsequent re-challenge being considered as 
1 regimen. Patients with measurable or non-measurable disease may be included. 
Other inclusion criteria for all patients include: age ≥18 years.; ECOG performance 
status ≤1 and adequate hepatic, renal, and bone-marrow function. 

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Test Product, 
Dose, and Mode 
of 
Administration:  
Patients in this study will receive BBI-608 orally, daily, at 240 mg bid (480 mg 
total daily dose). In each cycle BBI-608 will be taken daily for 2 weeks (14 days). 
BBI-608 will be administered twice daily, 1 hour prior or 2 hours after meals, with 
the first dose taken in the morning and doses separated by approximately 12 hours. 
Patients will receive BBI-608 in combination with FOLFIRI. Addition of 
bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible. 
FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily 
dose of BBI-608 and will be administered every 2 weeks. If bevacizumab is added 
to the FOLFIRI regimen, bevacizumab infusion should start at least 2 hours 
following the first dose of BBI-608 starting on Cycle 1 Day 1 and will be 
administered every 2 weeks. Irinotecan/leucovorin infusion will follow 
bevacizumab infusion in patients selected by the Investigator to receive standard 
dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m2 together with leucovorin 
400 mg/m2 will be administered intravenously, over approximately 90 minutes and 
2 hours, respectively, starting on Day 1 of Cycle 1, immediately following 
bevacizumab infusion or at least 2 hours following the first daily dose of BBI-608 
if bevacizumab is not administered. 5-FU 400 mg/m2 bolus will be administered 
intravenously immediately following irinotecan/leucovorin infusion, followed by 
5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will 
be repeated on Day 1 of every 14-day cycle.  
Dose modification of BBI-608 and/or FOLFIRI is allowed. Dose modification of 
bevacizumab is per product label and institutional standards. 
Duration of 
Treatment:  
Patients may continue to receive protocol therapy as long as they have not 
experienced any adverse events (AEs) requiring permanent discontinuation of study 
medication and have not demonstrated disease progression based on RECIST 
criteria. If 1 or all components of the FOLFIRI regimen is/are discontinued due to 
toxicity, BBI-608 should be continued until another discontinuation criterion is 
met. If BBI-608 is discontinued due to toxicity, FOLFIRI should be continued until 
another discontinuation criterion is met. 
Statistical 
Methods:  
The primary study endpoints are OS in the General Population and the pSTAT3(+) 
Subpopulation. The hypotheses for the study are as follows: 
For the General Population, the null and alternative hypotheses are:  
H10: BBI-608 + FOLFIRI ≤ FOLFIRI in the General Population 
H11: BBI-608+FOLFIRI > FOLFIRI in the General Population  
For the pSTAT3(+) Subpopulation, the null and alternative hypotheses are: 
H20: BBI-608 + FOLFIRI ≤ FOLFIRI in the pSTAT3(+) Subpopulation 
H21: BBI-608+FOLFIRI > FOLFIRI in the pSTAT3(+) Subpopulation 
A multiplicity adjustment strategy will be developed to control the overall Type I 
error rate with respect to several sources of multiplicity in this trial. This 
multiplicity adjustment will employ the Hochberg-based gatekeeping procedure to 
account for the analysis of the treatment effect on the primary (OS) and key 
secondary (PFS, DCR, ORR) endpoints in the General Population and the 
pSTAT3(+) Subpopulation.  
For the General Population, this study is designed to have a power of 90% and a 
1-sided α=0.025 to detect a 20% reduction in the risk of death (HR 0.80 which 

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corresponds to an increase of median survival from 12.54 to 15.68 months) in the 
General Population. The above design assumptions account for the anticipated 
varying control hazard rates for the bevacizumab versus no-bevacizumab 
stratification levels. It is assumed that approximately 30% of subjects will receive 
bevacizumab with expected mOS for the control arm FOLFIRI+bevacizumab 
subjects being 13.66 months while 70% of the subjects will not receive 
bevacizumab and have expected mOS of 12.06 months [Van Cutsem 2012]. 
Without adjusting for multiplicity, it is estimated that 850 events in the General 
Population will be required to detect this reduction, which would be observed by 
randomizing 1250 patients (General Population) over 26 months with patient 
follow up for an additional 14 months, for a total study duration of 40 months. It is 
anticipated that up to 5% dropout rate will occur over the entire study.  
For the pSTAT3(+) Subpopulation, without adjusting for multiplicity, and 
assuming 310 events (approximately 36% of 850) in pSTAT3(+) Subpopulation, 
there will be approximately 88% nominal power at 1-sided α=0.025 to detect a 30% 
reduction (HR [BBI-608+FOLFIRI vs. FOLFIRI] = 0.70) in the risk of death in the 
pSTAT3(+) Subpopulation.  
The overall power of the study will be approximately 90% (for both the General 
Population and the pSTAT3(+) Subpopulation) after the multiplicity control 
procedure is considered.  
The interim analysis will be conducted when 425 deaths occur (50% of total 
number of 850 deaths) in the General Population. The OS results at the interim 
analysis will be reviewed by a Data Safety and Monitoring Board (DSMB). The 
recommendations from DSMB on the study design and conduct will be based on 
the following decisions:  
x Futility stopping: terminate the trial or terminate pSTAT3(-) and 
pSTAT3 status unknown subpopulation due to lack of efficacy (futility).  
x Patient population and hypothesis selection: select the most appropriate 
patient population and hypothesis (hypothesis in General Population, 
and/or hypothesis in pSTAT3(+) Subpopulation) for evaluating the 
significance of the treatment effect at the final analysis.  
x Event count adjustment: remain the current events size or increase the 
target number of events in 1 of or both pre-defined patient populations.  
Statistical Analysis for Primary and Key Secondary Endpoints:  
Overall survival in the General Population and the pSTAT3(+) 
Subpopulation, the primary endpoints of this study, are defined as the time 
from randomization to death from any cause. 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 (listed in Section 3.1) for the 
General Population and unstratified log-rank test for the pSTAT3(+) 
Subpopulation.  
The progression free survival in both treatment groups will be summarized 
by the Kaplan-Meier method and compared primarily by a stratified log-rank 

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test adjusting for stratification variables at randomization for the General 
Population and unstratified log-rank test for the pSTAT3(+) Subpopulation. 
Differences of DCR between the two treatment arms for the General 
Population, will be compared using a 1-sided Cochran-Mantel-Haenszel test 
stratified for stratification factors.  Treatment difference of DCR and its 95% 
confidence interval based on harmonic mean method adjusting stratification 
factors will be provided.  For the pSTAT3(+) Subpopulation, differences of 
DCR between the two arms will be compared using a 1-sided Z-test via 
normal approximation.  Treatment difference of DCR and its 95% 
confidence interval based on normal approximation (unstratified) will be 
provided.   
Differences of ORR between the two arms will be analyzed the same as 
DCR for the General Population and for the pSTAT3(+) subpopulation.   

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TABLE OF CONTENTS 
PROTOCOL AMENDMENT HISTORY .......................................................................................2 
SYNOPSIS 3 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................13 
LIST OF FIGURES .......................................................................................................................13 
ABBREVIATIONS .......................................................................................................................14 
STUDY ACKNOWLEDGEMENT/DISCLOSURE .....................................................................16 
STUDY TREATMENT SCHEMA ...............................................................................................17 
1. 
OBJECTIVES .............................................................................................................18 
1.1. 
Primary Objectives .....................................................................................................18 
1.2. 
Secondary Objectives .................................................................................................18 
1.2.1. 
Key Secondary Objectives ..........................................................................................18 
1.2.2. 
Other Secondary Objectives .......................................................................................18 
2. 
BACKGROUND INFORMATION AND RATIONALE..........................................19 
2.1. 
Colorectal Cancer .......................................................................................................19 
2.2. 
Napabucasin (BBI-608) ..............................................................................................19 
2.2.1. 
Safety Profile ..............................................................................................................20 
2.2.2. 
Napabucasin Monotherapy in Last Line Metastatic Colorectal Cancer .....................21 
2.2.3. 
Napabucasin in Combination with FOLFIRI for Colorectal Cancer ..........................22 
2.3. 
Pre-clinical Rationale ..................................................................................................24 
2.4. 
Summary .....................................................................................................................24 
3. 
TRIAL DESIGN .........................................................................................................25 
3.1. 
Stratification ...............................................................................................................25 
3.2. 
Randomization ............................................................................................................25 
3.3. 
Pharmaceutical Data ...................................................................................................26 
3.3.1. 
BBI-608 ......................................................................................................................26 
3.3.2. 
FOLFIRI .....................................................................................................................27 
3.3.3. 
Additional Chemotherapy Permissible for Combination with FOLFIRI: 
Bevacizumab ...............................................................................................................27 
3.4. 
Inclusion of Women and Minorities ...........................................................................27 
4. 
STUDY POPULATION .............................................................................................28 
4.1. 
Inclusion Criteria ........................................................................................................28 

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4.2. 
Exclusion Criteria .......................................................................................................31 
5. 
PRE-TREATMENT EVALUATION ........................................................................34 
6. 
ENTRY/RANDOMIZATION PROCEDURES .........................................................36 
6.1. 
Entry Procedures .........................................................................................................36 
6.2. 
Stratification ...............................................................................................................36 
6.3. 
Randomization ............................................................................................................36 
7. 
TREATMENT PLAN .................................................................................................37 
7.1. 
Treatment Plan ............................................................................................................37 
7.1.1. 
Drug Administration ...................................................................................................37 
7.1.1.1. 
BBI-608 Diarrhea Prophylaxis: ..................................................................................39 
7.1.2. 
Blinding/Unblinding ...................................................................................................39 
7.1.3. 
Patient Monitoring ......................................................................................................40 
7.1.4. 
BBI-608 Dose Modification .......................................................................................40 
7.1.4.1. 
Hematologic Adverse Events .....................................................................................41 
7.1.4.2. 
Non-Hematologic Adverse Events .............................................................................42 
7.1.4.3. 
Other Situations ..........................................................................................................42 
7.1.5. 
FOLFIRI Dose Modification ......................................................................................42 
7.1.5.1. 
Hematologic Toxicity: ................................................................................................43 
7.1.5.2. 
Gastrointestinal Toxicity: ...........................................................................................44 
7.1.5.3. 
Non-Hematologic and Non-Gastrointestinal Toxicity: ..............................................45 
7.1.6. 
Concomitant Medications/Procedures ........................................................................45 
7.1.6.1. 
Permitted Treatments ..................................................................................................45 
7.1.6.2. 
Non-Permitted Treatments..........................................................................................46 
7.1.7. 
Duration of Therapy ...................................................................................................47 
7.1.8. 
Patient Compliance .....................................................................................................47 
8. 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT ...................48 
8.1. 
Evaluation During Protocol Treatment .......................................................................48 
8.2. 
Evaluation After Protocol Treatment Discontinuation ...............................................50 
9. 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ..............................52 
9.1. 
Definitions ..................................................................................................................52 
9.1.1. 
Evaluable for Adverse Events ....................................................................................52 
9.1.2. 
Evaluable for Overall Survival ...................................................................................52 
9.1.3. 
Evaluable for Progression Free Survival ....................................................................52 

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9.1.4. 
Evaluable for Objective Response Rate .....................................................................52 
9.1.5. 
Evaluable for Disease Control Rate ............................................................................52 
9.1.6. 
Evaluable for Quality of Life Assessment ..................................................................53 
9.1.7. 
pSTAT3(+) Subpopulation, the pSTAT3(-) Subpopulation and 
pSTAT3(Unknown) Subpopulation............................................................................53 
9.2. 
Response and Evaluation Endpoints ...........................................................................54 
9.2.1. 
Measurable Disease ....................................................................................................54 
9.2.2. 
Non-measurable Disease ............................................................................................54 
9.2.3. 
Target Lesions ............................................................................................................55 
9.2.4. 
Non-target Lesions ......................................................................................................55 
9.2.5. 
Response .....................................................................................................................55 
9.3. 
Response Duration ......................................................................................................57 
9.4. 
Stable Disease Duration ..............................................................................................57 
9.5. 
Methods of Measurement ...........................................................................................57 
9.5.1. 
Clinical Lesions ..........................................................................................................58 
9.5.2. 
Chest X-ray .................................................................................................................58 
9.5.3. 
CT/MRI.......................................................................................................................58 
9.5.4. 
Ultrasound ...................................................................................................................59 
9.5.5. 
Endoscopy/Laparoscopy .............................................................................................59 
9.5.6. 
Cytology/Histology.....................................................................................................59 
10. 
SERIOUS ADVERSE EVENT REPORTING ...........................................................60 
10.1. 
Definition of a Protocol Reportable Serious Adverse Event ......................................60 
10.2. 
Serious Adverse Event Reporting Instructions ...........................................................60 
10.3. 
Procedures in Case of an Overdose ............................................................................61 
10.4. 
Other Protocol Reportable Events – Pregnancy/Exposure Reporting ........................61 
10.4.1. 
Pregnancy Prevention .................................................................................................61 
10.4.2. 
Pregnancy Occurring in WOCBP Exposed to Study Agent .......................................61 
10.4.3. 
Pregnancy/Exposure Reporting ..................................................................................62 
10.5. 
Responsibility for Reporting Serious Adverse Events to Regulatory 
Agencies .....................................................................................................................62 
10.6. 
Reporting Safety Reports to Investigators ..................................................................63 
11. 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY 
AFTER STOPPING....................................................................................................64 

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11.1. 
Criteria for Discontinuing Protocol Treatment ...........................................................64 
11.2. 
Duration of Protocol Treatment ..................................................................................64 
11.3. 
Therapy After Protocol Treatment is Stopped ............................................................64 
11.4. 
Follow-up Off Protocol Treatment .............................................................................64 
12. 
CENTRAL REVIEW PROCEDURES, TISSUE COLLECTION, AND 
CORRELATIVE STUDIES .......................................................................................65 
12.1. 
Central Radiology Review ..........................................................................................65 
12.2. 
Central Pathology Review ..........................................................................................65 
12.2.1. 
Protocol-Mandated Biomarker Analyses ....................................................................65 
12.3. 
Sparse Pharmacokinetic Plasma Sample Collection (Arm 1 Only) ............................65 
13. 
STATISTICAL CONSIDERATIONS .......................................................................67 
13.1. 
Objectives and Design ................................................................................................67 
13.2. 
Study Endpoints and Analysis ....................................................................................67 
13.2.1. 
Primary Endpoint for the Study ..................................................................................67 
13.2.2. 
Key Secondary Endpoints ...........................................................................................68 
13.2.3. 
Other Secondary Endpoints ........................................................................................69 
13.3. 
Sample Size and Duration of Study ............................................................................69 
13.4. 
Safety Monitoring .......................................................................................................70 
13.5. 
Interim Analysis ..........................................................................................................70 
13.6. 
Multiplicity Adjustment..............................................................................................72 
13.7. 
Pharmacokinetic Analyses ..........................................................................................74 
13.7.1. 
Sparse Pharmacokinetic Analysis ...............................................................................74 
14. 
PUBLICATION ..........................................................................................................75 
14.1. 
Research Outside the Terms of this Protocol .............................................................75 
15. 
ETHICAL, REGULATORY, AND ADMINISTRATIVE ISSUES ..........................76 
15.1. 
Regulatory Considerations ..........................................................................................76 
15.2. 
Inclusivity in Research ...............................................................................................76 
15.3. 
Obtaining Informed Consent ......................................................................................77 
15.3.1. 
Obtaining Consent for Pregnancy/Exposure Reporting .............................................77 
15.4. 
Discontinuation of the Trial ........................................................................................78 
15.5. 
Retention of Patient Records and Study Files ............................................................78 
15.6. 
On-Site Monitoring/Auditing .....................................................................................78 
15.7. 
Case Report Forms .....................................................................................................79 

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16. 
REFERENCES ...........................................................................................................80 
APPENDIX 1. PATIENT EVALUATION FLOW SHEET FOR ARM 1 (BBI-608 IN 
COMBINATION WITH FOLFIRI) ...........................................................................83 
APPENDIX 2. PATIENT EVALUATION FLOW SHEET FOR ARM 2 (FOLFIRI) ..............86 
APPENDIX 3. PERFORMANCE STATUS SCALES/SCORES ..............................................89 
APPENDIX 4. NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS .....................................................................................................................90 
APPENDIX 5. QUALITY OF LIFE ASSESSMENT ................................................................91 
APPENDIX 6. DECISION RULES AND MULTIPLICITY CONTROL 
PROCEDURE FOR ADAPTIVE DESIGN ...............................................................97 
Hochberg-based Gatekeeping Procedure .......................................................................................97 
Interim Analysis Decision Rules ...................................................................................................98 

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LIST OF TABLES 
Table 1: ..... Summary of CO.23 Primary and Secondary Endpoints Analysis (ITT 
Population; N=282) ....................................................................................................21 
Table 2: ..... Study CO.23 Median Overall Survival by Biomarker Status – Intent-to-Treat 
Population ...................................................................................................................22 
Table 3: ..... BBI608-246 Adverse Events in ≥10% of Patients (Napabucasin PLUS 
FOLFIRI [±bev]) ........................................................................................................23 
Table 4: ..... Study Drug Administration.........................................................................................38 
Table 5: ..... BBI-608 Dose Modification Recommendations for Gastrointestinal Adverse 
Events: ........................................................................................................................40 
Table 6: ..... BBI-608 Dose Modification Table: ............................................................................41 
Table 7: ..... Symptom-Specific Supportive Treatment* ................................................................41 
Table 8: ..... FOLFIRI Dose Modification Table: ...........................................................................42 
Table 9: ..... FOLFIRI Dose Modification for Hematologic Toxicity ............................................43 
Table 10: ... FOLFIRI Dose Modification for Gastrointestinal Toxicity ........................................44 
Table 11: ... FOLFIRI Dose Modification for Other Toxicity ........................................................45 
Table 12: ... Integration of Target, Non-Target, and New Lesions into Response 
Assessment .................................................................................................................57 
 
LIST OF FIGURES 
Figure 1: .... pSTAT3 Subpopulations Components at Interim Analysis and Final 
Analysis ......................................................................................................................54 
Figure 2: .... Adaptive Study Design Schema .................................................................................73 
Figure 3: .... Data in Final Analysis of the pSTAT3(+) Subpopulation ........................................101 

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14 
ABBREVIATIONS 
Abbreviation 
Definition 
ALT 
Alanine transaminase 
ADR 
Adverse drug reaction 
AE 
Adverse event 
BID 
Twice a day (Latin word “bis in die”) 
BP 
Blood pressure 
CHF 
Congestive heart failure 
CHO 
Chinese hamster ovary 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation 
CR 
Complete response 
CRO 
Contract Research Organization 
CRC 
Colorectal cancer 
CSC 
Cancer stem cells 
CSR 
Clinical study report 
CSS 
Cut-section Stability 
CTA 
Clinical Trial Assay 
CTEP 
Cancer Therapy Evaluation Program 
DCR 
Disease control rate 
DPD 
Dihydropyrimidine dehydrogenase 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life 
questionnaire  
FOLFIRI 
Fluorouracil, Leucovorin, Irinotecan 
FOLFOX 
Leucovorin, Fluorouracil, Oxaliplatin 
FSH 
Follicle stimulating hormone 
Hgb 
Hemoglobin 
HRT 
Hormone replacement therapy 

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Abbreviation 
Definition 
IB 
Investigator Brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IUD 
Intrauterine device 
mCRC 
Metastatic colorectal cancer 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events  
ORR 
Overall response rate 
OS 
Overall survival 
PR 
Partial response 
pSTAT3 
Activated signal transducers and activators of transcription 3 
QoL 
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended phase 2 dose  
RPLS 
Reversible posterior leukoencephalopathy syndrome 
RTSM 
Randomization and trial supply management 
SAE 
Serious adverse event 
SD 
Stable disease 
STAT3 
Signal transducers and activators of transcription 3 
SUSAR 
Suspected unexpected serious adverse reaction 
ULN 
Upper limit of normal 
WOCBP 
Women of child bearing potential 

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STUDY ACKNOWLEDGEMENT/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 resources 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. 
Study CanStem303C 
 
 
 
 
 
Principal Investigator (Signature) 
 
Date 
 
 
 
Principal Investigator (Printed Name) 
 
 
 
 
 
Center 
 
 

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STUDY TREATMENT SCHEMA 
This is an international multi-center, prospective, open-label, randomized, adaptive design 
Phase 3 trial of the cancer stem cell pathway inhibitor BBI-608 plus standard bi-weekly 
FOLFIRI (Arm 1) versus standard bi-weekly FOLFIRI (Arm 2) in patients with previously 
treated metastatic colorectal cancer (mCRC). Addition of bevacizumab to the FOLFIRI regimen, 
per Investigator choice, will be permissible. The safety and PK parameters will be evaluated in a 
lead-in cohort, if required, in each region/country according to the regulatory request. The trial 
will enroll patients from North America, Europe, Australia, Asia, and Japan; it is anticipated that 
25% to 30% of patients will be enrolled from the United States. 
Stratification: 
x Geographical region (North America/Western Europe/Australia, Japan/Korea vs. Rest of the 
World) 
x Time to progression from start of first line therapy (<6 months versus ≥6 months) 
x Tumor RAS status (wild type versus mutated) 
x Bevacizumab as part of study protocol treatment (yes versus no) 
x Location of the primary tumor (left colon versus right colon) 
 
Pretreated 
metastatic 
colorectal 
carcinoma 
R 
A 
N 
D 
O 
M 
I 
Z 
E 
↗ 
A
r
m 
1 
BBI-608 orally, 
twice daily 
plus 
FOLFIRI   
IV, biweekly1 
 
 
 
Disease 
Progression based 
on RECIST 
criteria2 
 
or 
 
unacceptable 
toxicity occurs 
 
 
 
 
 
 
 
    
→ 
→ Death 
↘ 
A
r
m 
2 
FOLFIRI       
 IV, biweekly1 
 
 
 
 
 
1Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible 
2If no other standard therapies are available at the time of disease progression based on RECIST 1.1 criteria, and the 
patient has not experienced any adverse events requiring permanent discontinuation, BBI-608 may be continued in 
monotherapy. 

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1. 
OBJECTIVES 
1.1. 
Primary Objectives 
x To compare overall survival (OS) in the General Population patients treated with BBI-608 
plus biweekly FOLFIRI (Arm 1) versus biweekly FOLFIRI (Arm 2) 
x To compare OS in the activated signal transducers and activators of transcription 3 
(pSTAT3)-positive (pSTAT3(+)) Subpopulation patients treated with BBI-608 plus biweekly 
FOLFIRI (Arm 1) versus biweekly FOLFIRI (Arm 2) 
1.2. 
Secondary Objectives 
1.2.1. 
Key Secondary Objectives 
x To compare progression free survival (PFS) in the General Population patients treated with 
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x To compare PFS in the pSTAT3(+) Subpopulation patients treated with BBI-608 plus 
biweekly FOLFIRI versus biweekly FOLFIRI 
x To compare disease control rate (DCR) in the General Population patients treated with 
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x To compare DCR in the pSTAT3(+) Subpopulation patients treated with BBI-608 plus 
biweekly FOLFIRI versus biweekly FOLFIRI 
x To compare overall response rate (ORR) in the General Population patients treated with 
BBI-608 plus biweekly FOLFIRI versus biweekly FOLFIRI 
x To compare ORR in the pSTAT3(+) Subpopulation patients treated with BBI-608 plus 
biweekly FOLFIRI versus biweekly FOLFIRI 
1.2.2. 
Other Secondary Objectives 
x To compare the Quality of Life (QoL), as measured using the European Organization for 
Research and Treatment of Cancer Quality of Life questionnaire (EORTC-QLQ-C30), in the 
General Population patients treated with BBI-608 plus bi-weekly FOLFIRI versus bi-weekly 
FOLFIRI 
x To compare the QoL, as measured using the EORTC-QLQ-C30, in the pSTAT3(+) 
Subpopulation patients treated with BBI 608 plus biweekly FOLFIRI versus biweekly 
FOLFIRI 
x To evaluate the safety profile of BBI-608 administered daily plus biweekly FOLFIRI with 
safety assessed according to the National Cancer Institute Common Toxicity Criteria for 
Adverse Events (NCI CTCAE) version 4.0 in the General Population and the pSTAT3(+) 
Subpopulation 

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2. 
BACKGROUND INFORMATION AND RATIONALE 
2.1. 
Colorectal Cancer 
Colorectal cancer (CRC) is the second and third most commonly diagnosed type of cancer in 
females and males, respectively, with more than 1.24 million cases diagnosed in 2008 alone 
[Mokarram 2017]. Approximately half of all diagnosed CRC patients will develop disseminated 
advanced disease, which in most cases will be fatal [Saunders 2006]. Standard treatment for 
unresectable metastatic disease currently includes first and second line 5-FU chemotherapy-
based regimen in combination with oxaliplatin or irinotecan. The vascular endothelial growth 
factor-A (VEGF-A) inhibitor, bevacizumab, has been shown to improve survival in combination 
with first and second line 5-FU based chemotherapy [Welch 2010], while the VEGF/PlGF 
soluble decoy receptor, aflibercept, has been shown to improve OS in combination with the 
FOLFIRI regimen (irinotecan-5-fluorouracil-leucovorin) administered as second line therapy 
[Van Cutsem 2011]. Additionally, the monoclonal antibody epidermal growth factor receptor 
(EGFR) inhibitors, cetuximab and panitumumab, have shown efficacy as third line monotherapy 
and in combination with earlier lines of therapy in patients with K-ras wild type tumors 
[Karapetis 2008; Amado 2008; Tol 2010; Bokemeyer 2012]. For the approximately 30% to 50% 
of colorectal tumors with an activating K-ras mutation [Amado 2008], effective treatment options 
are further limited. At this time, a patient with K-ras mutant tumor and progressive disease on 
second line therapy has treatment options generally limited to anti-angiogenic drugs including 
regorafenib monotherapy with a modest survival benefit of 1.4 months [Grothey 2013], 
ramucirumab in combination with FOLFIRI providing a survival benefit of 1.6 months 
[Tabernero 2015], TAS-102, an oral fluoropyrimidine  analogue and thymidine phosphorylase 
inhibitor, recently proven to improve overall survival by 1.8 months in patients with refractory 
CRC over best supportive care [Mayer 2015], an investigational regimen, or best supportive care.  
Cancer stem cells (CSC), 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 
responsible for malignant growth, recurrence, drug-resistance, and metastasis. Moreover, CSCs 
are highly resistant to chemotherapies and current targeted agents. Accumulating evidence 
indicates that CSCs play a role in the pathogenesis of CRC [Todaro 2010]. Cancer stem cells 
have been isolated from human colon carcinomas using various cell surface markers including 
CD133, CD44, CD24, CD29, CD166, Musashi-1, and Lgr5 [Horst 2009; Du 2008; Levin 2010; 
Merlos-Suarez 2011; Kemper 2010]. These CSCs isolated from CRC patients display tumor-
initiating properties, as well as resistance to chemotherapeutics. These findings suggest that the 
development of cancer stem cell inhibitors represents a novel strategy for the treatment of CRC. 
2.2. 
Napabucasin (BBI-608) 
Napabucasin (BBI-608) is a small molecule that is hypothesized to affect multiple oncogenic 
cellular pathways, including inhibition of the STAT3 pathway which has been implicated in CSC 
viability.  It has the potential to treat CRC and other types of cancer by inhibiting self-renewal 
and survival of CSCs and inducing apoptosis in both CSCs and heterogeneous cancer cells. 
Recent studies have uncovered the presence of CSCs (also called tumor initiating cells) and have 
found them to have self-renewal capability which may contribute to malignant growth, relapse, 
and metastasis [Clevers 2011; Zhou 2009; Schwartz-Cruz-y-Celis 2011; Chaffer 2011; Rasheed 

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2011]. Isolation of CSCs has been reported in various major human cancer types, including 
breast, colon, prostate, melanoma, pancreatic, lung, head/neck, ovarian, glioblastoma 
multiforme, liver, esophageal, and hematological malignancy [Clevers 2011; Zhou 2009; 
Schwartz-Cruz-y-Celis 2011; Gupta 2009; Hannahan 2011; Gupta 2011; Boman Wicha 2008]. 
CSCs are resistant to conventional therapies, therefore, a targeted agent with activity against 
cancer stem cells is being explored [Lobo 2007].  
Napabucasin (BBI-608) is hypothesized to inhibit the STAT3 pathway. The signal transducers 
and activators of transcription 3 (STAT3) gene is an oncogene that belongs to a family of 
transcription factors activated in response to cytokines and/or growth factors to promote 
proliferation, survival, and other biological processes and is activated by phosphorylation of a 
critical tyrosine residue [Darnell 2005]. Upon tyrosine phosphorylation, STAT3 forms homo-
dimers and translocates to the nucleus, binds to specific DNA-response elements in target gene 
promoters, and induces gene expression [Darnell 2005]. STAT3 activates certain genes involved 
in tumorigenesis, invasion, and metastasis, including Bcl-xl, Akt, c-Myc, cyclin D1, VEGF, and 
survivin. The constitutive activation of STAT3 is frequently detected in primary human CRC 
cells and established human CRC cell lines [Ma 2004; Corvinus 2005; Kusaba 2005], and 
elevated levels of pSTAT3 were correlated with the tumor invasion, nodal metastasis, and the 
stage (p<0.05) [Ma 2004; Kusaba 2005]. Constitutive STAT3 activation in CRC cells is 
associated with invasion, survival, and growth of CRC cells and colorectal tumor model in mice 
in vivo [Corvinus 2005; Lin 2005; Xiong 2008; Tsareva 2007]. These reports indicate that 
STAT3 is one of the oncogenic pathways activated in CRC and may serve as a therapeutic target. 
Data from CRC patients treated with napabucasin have indicated that pSTAT3 positivity may be 
a predictive biomarker for napabucasin treatment (and have also confirmed that pSTAT3 
positivity is a prognostic indicator of survival, as is cited in the scientific literature [data 
available upon request]). Several peer-reviewed scientific articles have established dysregulation 
of STAT3 signaling as a key feature of human CRC. Park et al [2008] showed that levels of 
activated STAT3 (pSTAT3) are significantly associated with increasing T- and clinical stages in 
CRC. Kusaba et al [2005, 2006] correlated pSTAT3 levels with increasing T- and Duke’s stages 
and the presence of lymph vessel invasion and showed poor prognosis for OS in a first study of 
CRC, and with increasing T-stages and the presence of vein invasion and lymph node metastases 
in a second study of CRC. When a meta-analysis was performed combining data on 
gastrointestinal cancers, including gastric and colorectal cancers, higher levels of pSTAT3 were 
shown to correlate with worsened overall patient survival [Li 2015], signifying the role of 
pSTAT3 in cancer types throughout the gastrointestinal system. Lastly, pSTAT3(+) is present in 
about 70% of colorectal carcinomas and approximately 18% of colorectal adenomas [de Jong 
2014]. 
2.2.1. 
Safety Profile 
The predominant adverse drug reactions (ADRs) associated with napabucasin are gastrointestinal 
in nature. Napabucasin treatment may result in diarrhea, abdominal pain, nausea, vomiting, and 
decreased appetite (anorexia). Refer to the current Investigator Brochure (IB) for additional 
information on the safety profile of napabucasin. 

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2.2.2. 
Napabucasin Monotherapy in Last Line Metastatic Colorectal Cancer 
Study CO.23 was a Phase 3 international, multicenter, randomized controlled trial of 
napabucasin monotherapy (480 mg PO BID) vs. placebo in refractory CRC patients. The primary 
endpoint for the CO.23 trial was OS. The key secondary endpoints include PFS, ORR, DCR, 
safety, and QoL. Exploratory endpoints include biomarker (pSTAT3) analyses.  
To be considered eligible, patients were required to have failed available standard therapy 
including 5-FU based regimens, irinotecan, oxaliplatin, and EGFR inhibitor if KRAS wild type. 
The original planned sample size was 650 patients. Accrual was stopped after 282 patients were 
randomized following a pre-planned interim analysis based on DCR that met protocol-defined 
stopping criteria for futility. The study did not meet its primary objective. 
Final analysis was conducted after completion of follow-up of the 282 patients. The demographic 
variables and known prognostic factors were balanced between the study arms. No significant 
differences were observed between the study arms in OS in the ITT population. Study results for 
primary and secondary endpoints are summarized in Table 1 (final clinical study report [CSR] is 
pending at the time of this Amendment).
Table 1: 
Summary of CO.23 Primary and Secondary Endpoints Analysis (ITT 
Population; N=282) 
Statistic 
Napabucasin 
(N=138) 
Placebo 
(N=144) 
Hazard Ratio [95%CI], p value 
Median OS (mos.) 
4.4 
4.8 
1.13 [0.88 – 1.46], p=0.336 
Median PFS (mos.) 
1.82 
1.82 
0.98 [0.76 – 1.26], p=0.831 
DCR 
17 (12.3%) 
18 (12.5%) 
--- 
Of the 282 randomized patients, 251 patients provided diagnostic tumor samples for biomarker 
evaluation (evaluation was performed by blinded third party assessment). Of these 251 patients, 
55 were determined to be pSTAT3(+) and 167 were determined to be pSTAT3(-) and were 
included in exploratory analyses (Table 2); 29 patients had samples which were not evaluable. In 
concordance with the literature, presence of the biomarker (pSTAT3(+)) was shown to be a 
negative prognostic factor in patients receiving placebo. In patients receiving napabucasin, 
prolonged OS was observed in pSTAT3(+) patients compared to pSTAT3(+) placebo patients, 
indicating a potential positive predictive effect. In pSTAT3(-) patients, OS was numerically 
smaller in patients randomized to napabucasin as compared to pSTAT3(-) patients randomized to 
placebo, but the difference is not clinically meaningful.  
Of note, the initial analysis of the correlation of biomarker status and clinical benefit [Jonker 
2018] included patients with non-evaluable tumor tissue with pSTAT3(-) patients by default. 
The analysis presented here corrects for this by removing those non-evaluable patients from the 
pSTAT3(-) group. 

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Table 2: 
Study CO.23 Median Overall Survival by Biomarker Status – Intent-to-Treat 
Population 
Subset 
Median OS (months) 
Hazard Ratio [95%CI] 
Napabucasin 
(n=138) 
Placebo 
(n=144) 
All Patients (n=282)a 
4.4 
4.8 
1.13 [0.88-1.46] 
   pSTAT3(+) (n=55)b 
5.1 
3.0 
0.41 [0.23-0.73] 
   pSTAT3(-) (n=167)c 
4.2 
5.1 
1.33 [0.97-1.83] 
a Of the 282 patients in Study CO.23, 251 were evaluated for pSTAT3 positivity: 55 were pSTAT3(+), 167 were pSTAT3(-), 
29 were not evaluable 
b Of the 55 pSTAT3(+) patients, 29 were randomized to napabucasin and 26 were randomized to placebo 
c Of the 167 pSTAT3(-) patients, 83 were randomized to napabucasin and 84 were randomized to placebo 
The safety profile was consistent with the observations in earlier phase trials. Refer to the current 
IB for more information on the safety profile of napabucasin. 
2.2.3. 
Napabucasin in Combination with FOLFIRI for Colorectal Cancer 
BBI608-246 was a multi-arm Phase 1/2 clinical trial of napabucasin in combination with several 
standard anti-cancer regimens for advanced gastrointestinal malignancies. The primary 
objectives of the study were to determine the safety, tolerability, PK characteristics, and 
recommended Phase 2 dose (RP2D) of napabucasin in combination with each of the backbone 
regimens. Secondary objectives were to evaluate preliminary anti-tumor activity. Study accrual 
is complete, and analysis is ongoing.  
Patients were eligible if they had a gastrointestinal malignancy that was recurrent, metastatic, or 
locally advanced, and if they were a candidate for treatment with 1 of the following backbone 
regimens: FOLFOX6 (±bevacizumab), FOLFIRI (±bevacizumab), CAPOX, irinotecan, or 
regorafenib. Patients were assigned to a backbone regimen according to investigator assessment. 
The backbone regimen was administered in combination with napabucasin at a dose assigned 
according to the dose-escalation protocol. Once RP2D was identified, patients were dosed with 
either 240 mg twice-daily (480 mg total daily) or 480 mg twice-daily (960 mg total daily), 
continuously, depending on the assigned backbone cohort. 
One cohort included patients with advanced CRC who were administered napabucasin 240 mg 
twice daily (480 mg total daily) in combination with standard FOLFIRI (5-FU 400 mg/m2 
intravenous bolus followed by 5-FU 1200 mg/m2/day continuous 48-hour intravenous infusion 
[total 2400 mg/m2] with leucovorin 400 mg/m2 and irinotecan 180 mg/m2 every 14 days). If 
indicated and assigned by the investigator, bevacizumab was given at 5 mg/kg intravenously 
every 14 days. In case of toxicity, dose adjustment of either napabucasin or FOLFIRI or 
bevacizumab was permitted. 
An analysis was performed on 82 patients in this cohort using safety and efficacy data available 
as of 01 September 2017. All patients had received previous systemic therapy, 36 (44%) had 
received 1 prior regimen, 18 (22%) had received 2 prior regimens, and 28 (34%) had received 
3 or more prior systemic regimens. Additionally, 34 (41%) patients had received prior treatment 
with FOLFIRI. A total of 16 (19.5%) patients achieved objective response per RECIST 1.1 
criteria, including 1 patient with complete response (CR) and 15 with partial response (PR). An 
additional 41 patients experienced stable disease (SD), and the DCR, proportion with CR, PR, or 

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SD was 69.5%. Of 48 patients with progression events and 52 patients who have died, the 
median progression-free survival (mPFS) is 5.9 months and the median overall survival (mOS) is 
12.9 months. 
Adverse events as of 01 September 2017 reported in ≥10% of the patients in this cohort are 
shown in Table 3.  
Refer to the current IB for detailed safety data from this study.. 
Table 3: 
BBI608-246 Adverse Events in ≥10% of Patients (Napabucasin PLUS 
FOLFIRI [±bev]) 
Preferred Term 
All Patients (N=164) 
n (%) 
Diarrhoea 
145 (88.4) 
Nausea 
106 (64.6) 
Fatigue 
98 (59.8) 
Vomiting 
82 (50.0) 
Decreased appetite 
76 (46.3) 
Abdominal pain 
70 (42.7) 
Neutropenia 
39 (23.8) 
Alopecia 
39 (23.8) 
Constipation 
37 (22.6) 
Anaemia 
28 (17.1) 
Hypokalaemia 
27 (16.5) 
Dyspnoea 
27 (16.5) 
Dehydration 
25 (15.2) 
Weight decreased 
24 (14.6) 
Pyrexia 
23 (14.0) 
Cough 
23 (14.0) 
Urinary tract infection 
23 (14.0) 
Neutrophil count decreased 
22 (13.4) 
Insomnia 
21 (12.8) 
Oedema peripheral 
20 (12.2) 
Stomatitis  
18 (11.0) 
Mucosal inflammation 
18 (11.0) 
Back pain 
18 (11.0) 
Chromaturia 
18 (11.0) 
Headache 
17 (10.4) 

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2.3. 
Pre-clinical Rationale 
Refer to the current IB for a detailed summary of nonclinical data. 
2.4. 
Summary 
Napabucasin (BBI-608) at a dose of 240 mg BID (480 mg total daily) has been well tolerated as 
monotherapy and when combined with a standard regimen of FOLFIRI with or without 
bevacizumab. The clinical activity observed in Study CO.23 and Study BBI608-246, and the 
unmet medical need for additional effective therapies for patients with advanced CRC, provides 
a rationale for further clinical investigation. Study CanStem303C is designed to evaluate the role 
of napabucasin added to standard FOLFIRI (±bevacizumab) as second line therapy for advanced 
CRC.  

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3. 
TRIAL DESIGN 
This is an international multi-center, prospective, open-label, randomized, adaptive design 
Phase 3 trial of BBI-608 plus standard bi-weekly FOLFIRI versus standard bi-weekly FOLFIRI 
in patients previously treated for advanced metastatic CRC. Addition of bevacizumab to the 
FOLFIRI regimen, per Investigator choice, is permissible. 
3.1. 
Stratification 
Patients will be stratified by: 
1. Geographical region (North America/Western Europe/Australia, Japan/Korea vs. Rest of 
the World) 
2. Time to progression on first-line therapy (<6 months vs. ≥6 months from start of first line 
therapy) 
3. RAS mutation status (mutant vs. wild type)1 
4. Bevacizumab as part of study protocol treatment (yes vs. no) 
5. Location of the primary tumor (left colon vs. right colon)2 
1RAS mutant status refers to any known mutation in KRAS or NRAS mutations in exons 2, 3, and 4 resulting in 
decrease of response to anti-EGFR treatment. 
2Lesions proximal to the splenic flexure will be considered right colon and lesions at splenic flexure and distal to it 
will be considered left colon.  
3.2. 
Randomization 
Patients will be randomized according to a 1:1 ratio using a permuted block randomization 
procedure to receive BBI-608 plus standard bi-weekly FOLFIRI or standard bi-weekly FOLFIRI. 
Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible. 

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Patients will be randomized to 1 of the following 2 arms: 
Arm 
Agent(s) 
Dose and Route 
Duration 
1 
BBI-608  
240 mg orally 2 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 
FOLFIRI 
Standard FOLFIRI IV, once every 
2 weeks3  
2 
FOLFIRI 
Standard FOLFIRI IV, once every 
2 weeks3 
1 BBI-608 should be taken 1 hour before or 2 hours after a meal, 2 times daily, with approximately 12 hours between doses. 
BBI-608 administration will begin 2 days prior to the FOLFIRI infusion on Day 1 of Cycle 1. These 2 days are referred to 
as Run-in Day 1 and Run-in Day 2. The run-in day period may be extended by up to 3 additional calendar days. Run-in 
Day 1 should occur within 2 calendar days of patient randomization. 
2 Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking BBI-608 with 
approximately 250 mL of fluid over the course of 30 minutes after the dose. 
3 Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible. FOLFIRI chemotherapy 
infusion will start at least 2 hours following the first daily dose of BBI-608 and will be administered every 2 weeks. 
Irinotecan/leucovorin infusion will follow bevacizumab infusion in patients selected by the Investigator to receive standard 
dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m2 together with leucovorin 400 mg/m2 will be administered 
intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following 
bevacizumab infusion or at least 2 hours following the first dose of BBI-608 if bevacizumab is not administered. 5-FU 
400 mg/m2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 
5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion. This regimen will be repeated on Day 1 of every 14-day 
cycle. 
 4 If any component of FOLFIRI is discontinued due to toxicity or any other reason deemed appropriate by the clinical 
investigators, BBI-608 should be continued until another criterion for stopping treatment is met. If BBI-608 is discontinued 
due to toxicity, FOLFIRI should be continued until another criterion for stopping treatment is met. 
5 If no other standard therapies are available at the time of disease progression based on RECIST 1.1 criteria, and the patient 
has not experienced any adverse events requiring permanent discontinuation, BBI-608 may be continued as monotherapy. 
3.3. 
Pharmaceutical Data 
3.3.1. 
BBI-608 
Supplied: 
BBI-608 is supplied in 80-mg strength capsules.  
Stability:  
Initial product use dating is 24 months from the date of manufacture and can be extended to a 
maximum of 5 years from date of manufacture assuming acceptable results at re-assay time-point 
testing. 
Storage: 
BBI-608 capsules should be stored in a tightly closed container at a temperature between 15°C to 
25ºC (59°F to 77°F).  
Route of Administration: 
Patients should take BBI-608 orally twice daily, approximately 1 hour prior to or 2 hours after 
meals, with the first dose given in the morning and the second dose given approximately 
12 hours later (ideally between 10 and 14 hours from the previous dose). 

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3.3.2. 
FOLFIRI  
Please refer to the FOLFIRI component locally approved labels for product description, stability 
information, storage instructions, route of administration, as well as for the management of 
patients, regarding contraindications, patient monitoring, dose adjustments in case of toxicity, 
and drugs prohibited or used with caution.  
In France, please refer to the following website to obtain the most updated version of the SmPC 
for the FOLFIRI components and bevacizumab: http://base-donnees-
publique.medicaments.gouv.fr 
3.3.3. 
Additional Chemotherapy Permissible for Combination with FOLFIRI: 
Bevacizumab  
Please refer to the locally approved label for bevacizumab for product description, stability 
information, storage instructions, and route of administration. 
3.4. 
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 CRC. The effect of the intervention under 
investigation will be analyzed by gender, racial, and ethnic subgroups, with recognition of the 
potentially limited statistical power of this analysis. 

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4. 
STUDY POPULATION  
The trial population will consist of patients with advanced (metastatic) histologically confirmed 
CRC. Patients will have failed treatment with 1 regimen containing a fluoropyrimidine and 
oxaliplatin with or without bevacizumab in the metastatic setting. Selection of the most 
appropriate patient population and hypothesis for evaluating the significance of the treatment 
effect at the final analysis will be made based on the rules and hypothesis described in 
Section 13.5. 
4.1. 
Inclusion Criteria 
Questions about eligibility criteria should be addressed prior to randomization. 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates 
for this therapy, as well as to ensure that the results of this study can be useful for making 
treatment decisions regarding other patients with similar diseases. 
Patients must fulfill all the following criteria to be eligible for admission to the study: 
4.1.1 Written, signed consent for trial participation must be obtained from the patient 
appropriately in accordance with applicable ICH guidelines and local and regulatory 
requirements prior to the performance of any study specific procedure. 
4.1.2  Must have histologically confirmed advanced CRC that is metastatic. 
4.1.3 Must have failed treatment with 1 regimen containing only a fluoropyrimidine and 
oxaliplatin with or without bevacizumab for metastatic disease. All patients must have 
received a minimum of 6 weeks of the first-line regimen that included oxaliplatin and a 
fluoropyrimidine with or without bevacizumab in the same cycle. Treatment failure is 
defined as radiologic progression during or ≤6 months after the last dose of first-line 
therapy. 
No additional prior lines of therapy in the metastatic setting will be allowed. Patients who 
discontinued first-line therapy due to toxicity may be enrolled for as long as progression 
occurred ≤6 months after the last dose of first-line therapy.  
Patients who show tumor progression while on maintenance therapy with a 
fluoropyrimidine with or without bevacizumab after prior fluoropyrimidine-oxaliplatin 
with or without bevacizumab induction therapy are eligible. 
Prior neoadjuvant or adjuvant systemic treatment is allowed as long as no more than 
2 prior systemic chemotherapy regimens were administered with no more than 1 prior 
regimen permitted in the metastatic setting. Patients who received 
oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease 
recurrence or progression >6 months from their last dose of neoadjuvant or adjuvant 
treatment (or >6 months from surgery if no adjuvant therapy was administered) will be 
required to receive fluoropyrimidine/oxaliplatin-based therapy with or without 
bevacizumab for metastatic disease. 
For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will 
count as a single systemic regimen. 

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Re-challenge with oxaliplatin is permitted and will be considered part of the first-line 
regimen for metastatic disease, with both initial oxaliplatin treatment and subsequent 
re-challenge being considered as 1 regimen. 
Patients receiving any other systemic therapy in the metastatic setting will be excluded.  
4.1.4 FOLFIRI therapy is appropriate for the patient and is recommended by the Investigator.  
4.1.5 Imaging investigations including CT/MRI of chest/abdomen/pelvis or other scans as 
necessary to document all sites of disease performed within 21 days prior to 
randomization. Patients with either measurable disease or non-measurable evaluable 
disease are eligible.  
4.1.6 Must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 
1. 
4.1.7 Must be ≥18 years of age.  
4.1.8 For male or female patient of child bearing potential: Must agree to use contraception or 
take measures to avoid pregnancy during the study and for 180 days for female and for 
male patients, of the final FOLFIRI dose. Patients who receive single agent BBI-608 
without FOLFIRI must agree to use contraception or take measures to avoid pregnancy 
during the study and for 30 days for female patients and 90 days for male patients, of the 
final BBI-608 dose.  
Female patients of child bearing potential treated with bevacizumab, per investigator 
choice, must agree to use contraception or take measures to avoid pregnancy during the 
study and for 6 months, of the final bevacizumab dose.  
Adequate contraception is defined as follows: 
x Complete true abstinence: when this is in line with the preferred and usual lifestyle of the 
subject. 
x Consistent and correct use of one of the following methods of birth control: 
 Male partner who is sterile prior to the female subject’s entry into the study and is the 
sole sexual partner for that female subject; or  
 Implants of levonorgestrel; or 
 Injectable progestogen; or 
 Any intrauterine device (IUD) with a documented failure rate of less than 1% per year; or 
 Oral contraceptive pill (either combined or progesterone only); or  
 One barrier method for example diaphragm with spermicide or condom with spermicide 
in combination with either implants of levonorgestrel or injectable progestogen, any IUD 
with a documented failure rate of less than 1% per year, or oral contraceptive pill (either 
combined or progesterone only). 
4.1.9 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. 

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WOCBP include any female who has experienced menarche and who has not undergone 
successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 
oophorectomy) or is not postmenopausal (defined as amenorrhea >12 consecutive 
months; or women on hormone replacement therapy [HRT] with documented serum 
follicle stimulating hormone [FSH] level >35 mIU/mL). Women who are using oral, 
implanted or injectable contraceptive hormones or mechanical products such as an IUD 
or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing 
abstinence or where partner is sterile (e.g. vasectomy), should be considered to be of 
child bearing potential. 
4.1.10 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. 
4.1.11 Must have hemoglobin (Hgb) ≥9.0 g/dL within 14 days prior to randomization. Must not 
have required transfusion of red blood cells within 1 week of baseline Hgb assessment. 
4.1.12 Must have total bilirubin ≤1.5 × institutional ULN [≤2.0 × ULN in presence of liver 
metastases] within 14 days prior to randomization. 
4.1.13 Must have creatinine ≤1.5 ×institutionalULN or Creatinine Clearance >50 ml/min as 
calculated by the Cockcroft-Gault equation (Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] equation may also be used) within 14 days prior to 
randomization. 
4.1.14 Must have absolute neutrophil count ≥1.5 × 109/L within 14 days prior to randomization. 
4.1.15 Must have platelet count ≥100 × 109/L within 14 days prior to randomization. Must not 
have required transfusion of platelets within 1 week of baseline platelet assessment. 
4.1.16 Patient must have adequate nutritional status with body mass index (BMI) ≥18 kg/m2 and 
body weight of ≥40 kg with serum albumin ≥3 g/dL. 
4.1.17 Other baseline laboratory evaluations, listed in Section 5, must be done within 14 days 
prior to randomization. 
4.1.18 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 biomarker assays may be conducted (Section 12.2.1 and Section 13.2). 
Submission of the tissue is to occur prior to randomization unless approved by the 
Sponsor. 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 two 2 mm cores of tumor from the block 
are unavailable, 10 to 30 unstained slides of whole sections of representative tumor tissue 
alone are 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. 
4.1.19 Patient must consent to provision of a sample of blood in order that the specific 
correlative marker assays may be conducted (Section 12.2.1). 
4.1.20 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 

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there must be reasonable geographical limits placed on patients being considered for this 
trial. Investigators must ensure that the patients randomized on this trial will be available 
for complete documentation of the treatment, response assessment, adverse events, and 
follow-up. 
4.1.21 Protocol treatment is to begin within 2 calendar days of patient randomization for patients 
randomized to Arm 1. Patients randomized to Arm 2 must begin protocol treatment 
within 7 calendar days of randomization. 
4.1.22 The patient is not receiving therapy in a concurrent clinical study and the patient agrees 
not to participate in other interventional clinical studies during their participation in this 
trial while on study treatment. Patients participating in surveys or observational studies 
are eligible to participate in this study. 
4.2. 
Exclusion Criteria 
Patients who fulfil any of the following criteria are not eligible for admission to the study: 
4.2.1 Anti-cancer chemotherapy or biologic therapy if administered prior to the first planned 
dose of study medication (BBI-608 or FOLFIRI) 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 study medication.  
Standard dose of bevacizumab (5 mg/kg) may be administered prior to FOLFIRI 
infusion, per Investigator decision, for as long as permanent decision to include or 
exclude bevacizumab is made prior to patient randomization. 
 
Radiotherapy, immunotherapy (including immunotherapy administered for non-
neoplastic treatment purposes), or investigational agents within four weeks of first 
planned dose of study medication, 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. 
4.2.2 More than 1 prior chemotherapy regimen administered in the metastatic setting. 
4.2.3  Major surgery within 4 weeks prior to randomization. 
4.2.4 Patients with any known brain or leptomeningeal metastases are excluded, even if treated. 
4.2.5 Women who are pregnant or breastfeeding. Women should not breastfeed while taking 
study treatment and for 4 weeks after the last dose of BBI-608 or while undergoing 
treatment with FOLFIRI and for 180 days after the last dose of FOLFIRI. 
4.2.6 Gastrointestinal disorder(s) which, in the opinion of the Qualified/Principal Investigator, 
would significantly impede the absorption of an oral agent (e.g. intestinal occlusion, 
active Crohn’s disease, ulcerative colitis, extensive gastric and small intestine resection). 
4.2.7 Unable or unwilling to swallow BBI-608 capsules daily. 
4.2.8 Prior treatment with BBI-608 or possible hypersensitivity to BBI-608 or one of the 
excipients which include azo dyes sunset yellow and allura red. 

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4.2.9 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
clinically significant non-healing or healing wounds, symptomatic congestive heart 
failure, unstable angina pectoris, clinically significant cardiac arrhythmia, significant 
pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or 
psychiatric illness/social situations that would limit compliance with study requirements. 
a. Known infection with human immunodeficiency virus (HIV), and/or active infection 
with hepatitis B (patients who have had an HBV immunization are eligible), or 
hepatitis C.  
b. Patients with clinically significant ascites or pleural effusions. 
4.2.10 Known hypersensitivity to 5-fluorouracil/leucovorin 
4.2.11 Known dihydropyrimidine dehydrogenase (DPD) deficiency 
4.2.12 Known hypersensitivity to irinotecan 
4.2.13 Chronic inflammatory bowel disease (Crohn’s disease or ulcerative colitis) 
4.2.14 Patients receiving treatment with St. John’s wort or Phenytoin 
4.2.15 Patients who plan to receive yellow fever vaccine during the course of the study 
treatment 
4.2.16 Abnormal glucuronidation of bilirubin, known Gilbert’s syndrome 
4.2.17 Patients with QTc interval >470 milliseconds 
4.2.18 For patients to be treated with a regimen containing bevacizumab: 
a. History of cardiac disease: congestive heart failure (CHF) ≥NYHA Class II; active 
coronary artery disease, myocardial infarction within 6 months prior to study entry; 
unevaluated new onset angina within 3 months or unstable angina (angina symptoms 
at rest) or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or 
digoxin are permitted) 
b. Current uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or 
diastolic pressure >90 mmHg despite optimal medical management) as well as prior 
history of hypertensive crisis or hypertensive encephalopathy 
c. History of arterial thrombotic or embolic events (within 6 months prior to study 
entry) 
d. Significant vascular disease (e.g., aortic aneurysm, aortic dissection, symptomatic 
peripheral vascular disease)  
e. Evidence of bleeding diathesis or clinically significant coagulopathy  
f. Major surgical procedure (including open biopsy, significant traumatic injury, etc.) 
within 28 days, or anticipation of the need for major surgical procedure during the 
course of the study as well as minor surgical procedure (excluding placement of a 
vascular access device or bone marrow biopsy) within 7 days prior to study 
enrollment 
g. Proteinuria at screening as demonstrated by urinalysis with proteinuria ≥2+ (patients 
discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 
24-hour urine collection and must demonstrate ≤1g of protein in 24 hours to be 
eligible) 

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h. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intra-
abdominal abscess within 6 months  
i. Ongoing serious, non-healing wound, ulcer, or bone fracture  
j. Known hypersensitivity to any component of bevacizumab  
k. History of reversible posterior leukoencephalopathy syndrome (RPLS) 
l. History of hypersensitivity to Chinese hamster ovary (CHO) cells or other human or 
humanized recombinant antibodies. 
4.2.19 Patients with a history of other malignancies except: adequately treated non-melanoma 
skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors 
curatively treated with no evidence of disease for ≥3 years 
4.2.20 Any active disease condition which would render the protocol treatment dangerous or 
impair the ability of the patient to receive protocol therapy 
4.2.21 Any condition (e.g. psychological, geographical, etc.) that does not permit compliance 
with the protocol 

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5. 
PRE-TREATMENT EVALUATION 
See Appendix 1 and Appendix 2 for detailed schedule of assessments. 
Baseline evaluations will be performed for all patients to determine study eligibility. These 
evaluations must be obtained ≤14 days prior to randomization, with up to 21 days allowed for 
baseline radiologic evaluation and up to 28 days allowed for baseline electrocardiogram (ECG).  
Repeat of screening laboratory tests will be allowed only in the event of a laboratory error or for 
patients who halted screening previously without having failed any of the screening 
tests/evaluations or inclusion criteria for this study. Otherwise, re-screening will not be allowed. 
Any questions regarding patient eligibility should be directed to Sponsor or other Sponsor-
nominated designee for written approval.  
All appropriate eCRF pages must be completed for patients prior to obtaining pre-randomization 
approval. 
Investigations 
Timing prior to 
randomization8 
Patient History and 
Evaluation 
Prior medical and therapeutic history, including 
RAS testing1 
Physical examination9 
Vital signs (temperature, blood pressure, heart 
rate, respiratory rate, O2 saturation on room air) 
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 days8 
Radiology & 
Imaging 
CT/MRI scan of chest/abdomen/pelvis with tumor 
measurement and evaluation by RECIST 1.1 
criteria3 
≤21 days 
Biomarker and 
Correlative Studies  
Submission of representative diagnostic tumor 
tissue4  
Before or after 
randomization 
Blood sample collection5 
≤14 days 
Other 
Investigations 
Serum or urine pregnancy test6 
≤5 days 

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Investigations 
Timing prior to 
randomization8 
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 RAS status of tumor (RAS mutant status refers to any known mutation in KRAS or NRAS 
mutations in exons 2, 3, and 4 resulting in decrease of response to anti-EGFR treatment), 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 4.1. 
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. Qualifying scans performed as part of standard of care prior to patient signature of the study 
informed consent will be acceptable as baseline scanning as long as scanning is performed ≤ 21 days prior to 
randomization. Baseline imaging should be repeated to obtain an accurate assessment of baseline tumor load 
prior to randomization in the event of significant change in patient’s clinical status as per Investigator 
Assessment. 
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 4). 
8 Laboratory testing performed as part of standard of care prior to patient signature of the study consent will be 
acceptable as baseline lab work as long as testing is performed ≤ 14 days prior to randomization. If required 
laboratory tests cannot be performed within indicated timelines due to technical reasons, lab retest and 
prolongation of the screening period for 3 working days is allowed. ECGs performed as part of standard of care 
prior to patient signature of the study consent will be acceptable as baseline ECG as long as it is performed 
≤28 days prior to randomization. 
9 A physical exam should include general appearance, HEENT (head, eyes, ears, nose), dermatological, 
respiratory, cardiovascular/circulatory, abdomen, lymphatic, genitourinary, musculoskeletal, and neurological 
assessments. 

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6. 
ENTRY/RANDOMIZATION PROCEDURES 
6.1. 
Entry Procedures 
All randomizations will be done through the CanStem303C 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 4.1 and Section 4.2  
x Stratification factors  
6.2. 
Stratification 
The permuted block randomization procedure will balance between treatment arms within each 
of the following stratification factors:  
x Geographical region (North America/Western Europe/Australia, Japan/Korea, vs rest of the 
world)  
x Time to progression from start of first line therapy (<6 months vs ≥6 months) 
x RAS mutation status (mutant vs wild type) 
x Bevacizumab as part of study protocol treatment (yes vs no) 
x Location of primary tumor (left colon vs right colon) 
6.3. 
Randomization 
Patients will be randomized 1:1 between the 2 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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7. 
TREATMENT PLAN 
Protocol treatment is to begin within 2 calendar days of patient randomization for patients 
randomized to Arm 1. Patients randomized to Arm 2 must begin protocol treatment within 
7 calendar days of randomization. 
7.1. 
Treatment Plan 
Palliative and supportive care for other disease-related symptoms and for toxicity associated with 
treatment is permitted for all patients on this trial. Details of interventions (e.g. medications such 
as antibiotics, analgesics, antihistamines, steroids, G-CSF, erythropoietin), procedures (e.g. 
paracentesis, thoracentesis), or blood products (e.g. blood cells, platelets, or fresh frozen plasma 
transfusions) should be recorded on the electronic case report forms (eCRFs). 
Addition of bevacizumab at the standard dose (5 mg/kg) to the FOLFIRI regimen, per 
Investigator choice, will be permissible. 
7.1.1. 
Drug Administration 
One treatment cycle is defined as 14 days (2 weeks) with BBI-608 administered orally twice 
daily (with doses separated by approximately 12 hours), and standard FOLFIRI administered 
every other week (ie, once per cycle). BBI-608 administration will begin 2 days prior to the 
irinotecan infusion on Day 1 of Cycle 1 (Table 4). These 2 days are referred to as Run-in Day 1 
and Run-in Day 2. The run-in day period may be extended by up to 3 additional calendar days. 
Addition of bevacizumab at the standard dose (5 mg/kg) to the FOLFIRI regimen, per 
Investigator choice, will be permissible. 

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Table 4: 
Study Drug Administration 
Arm 
Agent(s) 
Dose and Route 
Duration 
1 
BBI-608  
240 mg orally 2 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 
FOLFIRI 
Standard FOLFIRI IV,  
once every 2 weeks3 
2 
FOLFIRI 
Standard FOLFIRI IV,  
once every 2 weeks3 
1 BBI-608 should be taken one hour before or 2 hours after a meal, 2 times daily, with approximately 12 hours 
between doses BBI-608 administration will begin 2 days prior to the irinotecan infusion on Day 1 of Cycle 1 
(run-in day period may be extended by up to 3 additional calendar days). These days are referred to as Run-in 
Day 1, Run-in Day 2, etc. Run-in Day 1 should occur within 2 calendar days of patient randomization on study 
Arm 1. 
2 Patients should be encouraged to maintain sufficient fluid intake while on protocol treatment, such as taking 
BBI-608 with approximately 250 mL of fluid over the course of 30 minutes after the dose. 
3 Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible. FOLFIRI 
chemotherapy infusion will start at least 2 hours following the first daily dose of BBI-608 and will be 
administered every 2 weeks. If bevacizumab is added to the FOLFIRI regimen, bevacizumab infusion should 
start at least 2 hours following the first dose of BBI-608 starting on Cycle 1 Day 1 and will be administered 
every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in patients selected by the 
Investigator to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m2 together with leucovorin 
400 mg/m2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, 
starting on Day 1 of Cycle 1, following bevacizumab infusion or at least 2 hours following the first daily dose 
of BBI-608 if bevacizumab is not administered. 5-FU 400 mg/m2 bolus will be administered intravenously 
immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m2/day (total 2400 mg/m2) 
continuous infusion. This regimen will be repeated on Day 1 of every 14-day cycle.  
4 If any component of FOLFIRI is discontinued due to toxicity or any other reason deemed appropriate by clinical 
investigators, BBI-608 should be continued until another criterion for stopping treatment is met. If BBI-608 is 
discontinued due to toxicity, FOLFIRI should be continued until another criterion for stopping treatment is met. 
5 If no other standard therapies are available at the time of disease progression based on RECIST 1.1 criteria, and 
the patient has not experienced any adverse events requiring permanent discontinuation, BBI-608 may be 
continued in monotherapy. 
Patients will receive BBI-608 2 times daily, approximately 1 hour prior to or 2 hours after meals, 
with the first dose given in the morning and the second dose given approximately 12 hours later. 
Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible. 
Starting on Cycle 1 Day 1, FOLFIRI chemotherapy infusion will start at least 2 hours following 
the first dose of BBI-608 and will be administered every 2 weeks. If bevacizumab is added to the 
FOLFIRI regimen, bevacizumab infusion should start at least 2 hours following the first dose of 
BBI-608 starting on Cycle 1 Day 1 and will be administered every 2 weeks. Irinotecan 
180 mg/m2 together with leucovorin 400 mg/m2 will follow bevacizumab infusion in patients 
selected by the Investigator to receive standard dose of bevacizumab (5 mg/kg), and will be 
administered concurrently via approximately 90-minute and 2-hour infusions, respectively, 
starting on Day 1 of Cycle 1, following bevacizumab infusion or at least 2 hours following the 
first daily dose of BBI-608 if bevacizumab is not administered. 5-FU 400 mg/m2 bolus will be 
administered intravenously immediately following irinotecan/leucovorin infusion, followed by 
5-FU 1200 mg/m2/day (total 2400 mg/m2) continuous infusion for approximately 46 hours. This 
regimen will be repeated every 14 days thereafter. FOLFIRI administration should proceed 

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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). If site-specific FOLFIRI administration procedures with respect to timing 
diverge from the above administration instructions, prior Sponsor approval may be granted, as 
long as the total dose administered remains per protocol. 
For sites in Australia, Belgium, Japan, and the United States, it is permissible to replace 
leucovorin with levoleucovorin for the FOLFIRI regimen. In these countries only, 
levoleucovorin should be administered in accordance with local procedures in the event such 
replacement is used, and at the recommended dose of 200 mg/m2.  
If any component of the FOLFIRI regimen is permanently discontinued due to toxicity or any 
other reasons deemed appropriate by clinical investigators, BBI-608 and the residual components 
of medical therapy should be continued until another criterion for stopping treatment is met. If 
BBI-608 is permanently discontinued due to toxicity, FOLFIRI should be continued until another 
criterion for stopping treatment is met. 
As BBI-608 may target 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 based on RECIST 1.1 criteria, and the patient has not 
experienced any AEs requiring permanent discontinuation, BBI-608 may be continued in 
monotherapy. 
Handling instructions for BBI-608 will be provided to all sites. Investigators may refer to the 
current IB for detailed instructions. 
7.1.1.1. 
BBI-608 Diarrhea Prophylaxis: 
It is strongly recommended that all patients hold their bowel regimen (fiber supplementation may 
be continued) starting 1 day prior to the first dose of BBI-608. Bowel regimen may be resumed 
as needed if constipation develops.  
Additionally, it is strongly recommended that all patients without constipation at 
screening/randomization start prophylactic anti-diarrheals, such as Loperamide (Imodium®) 
2 mg orally (PO) twice daily or Diphenoxylate/Atropine (Lomotil®) 2.5 to 5 mg PO twice daily, 
starting 1 day prior to the first dose of BBI-608 and continue with prophylaxis for the first 
4 weeks of study treatment with BBI-608. Anti-diarrheal prophylaxis should be held if 
constipation develops.  
7.1.2. 
Blinding/Unblinding 
This is an open label study. The primary endpoint of this study is overall survival, the assessment 
of which is unlikely impacted by the open-label nature of the study.  
However, to comply with ICH E6 (R2) Guideline for Good Clinical Practice (2016) 
recommending the blinded review of planned analyses 
[http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2_
_Step_4_2016_1109.pdf ], and to minimize the risk of potential bias into interim and final 
analyses, a blinding plan was implemented by the Sponsor and by the CRO to maintain the 
integrity of the study data for the decision making at the interim and final analyses. 

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7.1.3. 
Patient Monitoring 
For the duration that patients are on study therapy, AE monitoring will be done continuously. 
Patients will be evaluated for AEs at each visit and are to be instructed to call their physician to 
report any AEs between visits. 
7.1.4. 
BBI-608 Dose Modification  
The major AEs associated with the use of BBI-608 are gastrointestinal events (nausea, diarrhea, 
and abdominal cramping) and fatigue. Fatigue is often secondary to gastrointestinal events. 
There is no hematologic toxicity associated with BBI-608. We recommend that pre-exiting 
laxative bowel regimens, such as stool softeners, be held starting the day prior to first dose of 
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 Imodium and/or Lomotil, starting 1 day prior to start of BBI-608 
are strongly recommended for all patients. 
The guidelines which follow outline dosing modifications and recommended interventions 
should the above AEs occur.  
Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 (see Appendix 4). If a patient experiences several AEs and there are 
conflicting recommendations, please use the recommended dose adjustment that reduces the dose 
to the lowest level. 
Table 5: 
BBI-608 Dose Modification Recommendations for Gastrointestinal Adverse 
Events: 
Suspected BBI-608 -Related 
Adverse Event 
Investigator Action 
Grade 1 or tolerable Grade 2 
Symptoms 
Patient should remain at current dose. Attempt pharmacologic measures 
to minimize symptoms (see symptom specific treatment table below). 
Intolerable Grade 2 Symptoms 
If intolerable symptoms persist despite optimized medical management, 
dose reduction and sufficient oral hydration are recommended. A dose 
interruption of ½ to 3 days prior to reduction can also be considered.  
Dosing should be reduced to the next Modification Level as in Table 6. 
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 
reduced to ≤ tolerable Grade 2.  
Dosing should be reduced to the next Modification Level as in Table 6. 
Pharmacologic symptom support and/or prophylaxis should be 
maintained.  
After a dose reduction, AM and PM doses may be increased in 80 mg 
increments every 3-7 days as tolerated. *, ** 
* If, during the course of re-escalation, a dosing regimen is not tolerated despite optimized medical management, dosing 
should return to the highest previously tolerated dosing regimen. 
** Asymmetry between AM and PM dose is allowed during re-escalation (e.g. 160 mg AM/240 mg PM). 

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Table 6: 
BBI-608 Dose Modification Table: 
Dose Level 
Dose 
Full dose 
240 mg twice daily (q12h) 
Modification Level-1 
80 mg twice daily (q12h), up-titrate as tolerated** 
Modification Level-2 
80 mg once daily*, up-titrate as tolerated** 
*  If 80 mg once daily is not tolerated, a dose interruption of 1-3 days followed by re-challenge at 80 mg once daily is 
recommended. 
** Morning and evening doses can be increased in 80 mg increments every 3-7 days or slower as tolerated, up to 240 mg 
2 times daily.  
Recommended symptom-specific supportive treatment for common BBI-608-related AEs is 
presented in Table 7 (unless contraindicated). Prophylactic anti-diarrheal medications, such as 
Imodium and/or Lomotil, starting 1 day prior to start of BBI-608 are strongly recommended for 
all patients without constipation at screening: 
Table 7: 
Symptom-Specific Supportive Treatment* 
Diarrhea & Abdominal Cramping 
Nausea, Vomiting, or Anorexia1 
Dicyclomine (e.g., Bentyl): Recommended when the 
predominant issue is cramping or abdominal pain 
1Pst
P line: 5HT3-inhibitorsJD (Ondansetron, 
Palonosetron, Granisetron) 
Diphenoxylate/atropine (Lomotil) 
Loperamide (Imodium) 
(These agents may be useful in combination) 
2Pnd
P line:  Dexamethasone (Decadron), ideally in 
combination with a 5HT3-inhibitor. Short term use 
can be very effective 
Hyoscine (Buscopan, Scopolamine, Levsin):  Anti-
spasmodic agents helpful for abdominal cramping 
Other agents:  NK1 antagonist (e.g. Aprepitant), atypical 
antipsychotic (e.g., olanzapine), benzodiazepines (e.g. 
lorazepam), phenothiazines (e.g. prochlorperazine), 
cannabinoids (e.g., dronabinol), and other agents such as 
metoclopromide or scopolamine. 
Steroid with limited systemic absorption P2 
1Adapted from NCCN anti-emetic guideline 2017 
2Alimentary tract mucositis reflects mucosal injury across the continuum of oral and gastrointestinal mucosal. 
Expert opinion (2016 ESMO clinical practice guideline recommendations include systemic steroid treatment for 
the management of adverse event observed with use of targeted agents. 
*Decisions on ADR management are at the discretion of the investigator and must adhere with local regulatory 
guidelines  
Details regarding the use of supporting medication for the management of common BBI-608-
related AEs are specified in the supplementary Adverse Event Management document as well as 
in the Pharmacy Manual. 
7.1.4.1. 
Hematologic Adverse Events 
No hematologic toxicity related to BBI-608 treatment has been observed. Should a study subject 
experience a Grade 1 or 2 hematologic AE, dosing may continue while an alternate explanation 
is sought, and/or a therapeutic intervention is undertaken.  

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Should a patient experience a Grade 3 or 4 hematologic AE, continued dosing will be at the 
discretion of the study Investigator while an alternate explanation is sought, and/or a therapeutic 
intervention is undertaken.  
7.1.4.2. 
Non-Hematologic Adverse Events 
Toxic effects will be graded using the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 (Appendix 4).  
7.1.4.3. 
Other Situations 
Change in Urine Color and Odor: 
Occasionally, subjects have reported an orange-brown color change to their urine. Rarely, 
subjects also report a new odor to their urine. All subjects should be made aware of the 
possibility of these effects. For the reported AEs of chromaturia in patients receiving 
BBI-608 + paclitaxel, the majority were recovered/resolved. Dosing can be continued in the 
presence of these events. 
7.1.5. 
FOLFIRI Dose Modification 
Dose modifications for hematologic and non-hematologic toxicities (using NCI CTCAE Version 
4.0) expected from FOLFIRI should be performed according to the recommendations outlined in 
Table 8. Dose modifications for non-gastrointestinal toxicities expected from FOLFIRI may also 
follow institutional guidelines. Any toxicity requiring dose level modification beyond the second 
dose modification for fluorouracil or irinotecan may require treatment discontinuation or further 
modification at the discretion of the Investigator. When a dose reduction is required, no dose 
re-escalation will be permitted for the duration of study treatment.  
Table 8: 
FOLFIRI Dose Modification Table: 
Dose Level* 
Irinotecan**  
5-Fluorouracil 
Bolus  
5-Fluorouracil 
Infusion  
Full dose 
180 (mg/m2) 
400 (mg/m2) 
1200 (mg/m2/day) 
(total 2400 mg/m2)  
Modification Level-1 
150 (mg/m2) 
200 (mg/m2) 
900 (mg/m2/day) 
(total 1800 mg/m2) 
Modification Level-2 
120 (mg/m2) 
N/A 
600 (mg/m2/day) 
(total 1200 mg/m2) 
Modification Level-3 
100 (mg/m2) 
N/A 
N/A 
* If the dose of any component of FOLFIRI is reduced because of potentially-related AEs, subsequent dose increases are not 
permitted. 
** If irinotecan dose is required to be reduced below 100 mg/m2, lower doses may be used at the discretion of the Investigator. 

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7.1.5.1. 
Hematologic Toxicity: 
Neupogen/G-CSF may be used at the discretion of the Investigator prior to each dose of 
FOLFIRI and administration should proceed according to standard guidelines (NCCN/ASCO). 
Patients not experiencing resolution of neutropenia within 4 weeks at any time during the cycle, 
may discontinue FOLFIRI treatment. 
Prior to each dose of FOLFIRI, the absolute neutrophil count (ANC) and platelet count should be 
evaluated. If abnormalities are observed, and in the opinion of the Investigator the 
myelosuppression is most likely a result of FOLFIRI therapy, dose modification is recommended 
as in Table 9. 
Table 9: 
FOLFIRI Dose Modification for Hematologic Toxicity 
Adverse Hematologic 
Event1,2,4 
Treatment Delay 
Dose Reduction 
 
Irinotecan 
Fluorouracil 
Bolus 
Fluorouracil Infusion 
Neutrophils,3  
< 1.5 x 109/L 
Hold treatment until  
≥1.5 x 109/L 
1st Occurrence: 
Reduce dose to 
150 mg/m2 
1st Occurrence: 
Discontinue 5-FU 
bolus 
1st Occurrence: 
Continue treatment at full 
(current) dose 
2nd Occurrence: 
Reduce dose to 
120 mg/m2 
3rd Occurrence: 
Reduce dose to 
100 mg/m2 
Platelets  
<75 x 109/L or 
Thrombocytopenic 
bleeding 
Hold treatment until  
≥75 x 109/L 
1st Occurrence: 
Reduce dose to 
150 mg/m2 
1st Occurrence: 
Reduce 
to 
200 
mg/m2 
1st Occurrence: 
Reduce to 900 (mg/m2/day) 
(total 1800 mg/m2) 
 
2nd Occurrence: 
Reduce to 600 (mg/m2/day) 
(total 1200 mg/m2) 
2nd Occurrence: 
Reduce dose to 
120 mg/m2 
If no recovery within  
4 weeks, discontinue 
treatment 
3rd Occurrence: 
Reduce dose to 
100 mg/m2 
1Once a dose of any drug is decreased for toxicity re-escalation is not permitted. 
2May discontinue the regimen if toxicity recurs after 2 dose reductions or if cycle is delayed for >4 weeks. 
3The above dose modification schedule is applicable for cases of febrile neutropenia (defined as temperature ≥101°F or 38.3°C 
with a neutrophil count of ≤1000 cells/ml) as well as for cases of Grade 3-4 neutropenia with concomitant infection. 
4Neupogen/G-CSF may be used at the discretion of the Investigator prior to each dose of FOLFIRI and administration should 
proceed according to standard guidelines (NCCN/ASCO).  

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7.1.5.2. 
Gastrointestinal Toxicity: 
Dose modifications for gastrointestinal toxicities expected from FOLFIRI regimen must be 
performed according to the recommendations in Table 10. 
Table 10: 
FOLFIRI Dose Modification for Gastrointestinal Toxicity 
Adverse Gastrointestinal 
Event1,2,3 
Dose Reduction 
Irinotecan4 
5-Fluorouracil Bolus 
5-Fluorouracil Infusion 
Grade 1 Diarrhea 
Continue treatment at full 
(current) dose 
Continue treatment at full 
(current) dose 
Continue treatment at full 
(current) dose 
Grade 2 Diarrhea 
Reduce dose to  
150 mg/m2 
Discontinue 5-FU bolus 
Continue treatment at full 
(current) dose 
Grade 3 Diarrhea 
Reduce dose to  
120 mg/m2 
Discontinue 5-FU bolus 
Reduce to 900 (mg/m2/day) 
(total 1800 mg/m2) 
Grade 4 Diarrhea 
Reduce dose to  
100 mg/m2 
Discontinue 5-FU bolus 
Reduce to 600 (mg/m2/day) 
(total 1200 mg/m2) 
Elevation of Total Bilirubin  
> 1.5 × ULN 
Exclude biliary obstruction and consider holding chemotherapy until biliary obstruction 
is resolved. 
1Once a dose of any drug is decreased for toxicity re-escalation is not permitted. 
2Do not change dose unless diarrhea is intolerable Grade 2. Do not treat until diarrhea is ≤ tolerable Grade 2. 
3Consideration should be given to the use of an oral antibiotic in patients with persistent diarrhea despite maximal loperamide (up 
to 16 mg/day) and/or Lomotil (up to 20 mg/day) or if a fever develops in the setting of diarrhea without neutropenia.  
4Patients with Grade 1-3 diarrhea should be receiving standing anti-diarrheal symptom medications as described in Section 7.1.4 
and resumption of irinotecan at modified dose should occur when the diarrhea is reduced to ≤ tolerable Grade 2 while on 
standing anti-diarrheal symptom medications. 

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7.1.5.3. 
Non-Hematologic and Non-Gastrointestinal Toxicity: 
Dose modification for other toxicities specified below expected from FOLFIRI regimen should 
be performed according to the recommendations in Table 11. 
Table 11: 
FOLFIRI Dose Modification for Other Toxicity 
Other Adverse Events1 
Dose Reduction 
Irinotecan 
5-Fluorouracil Bolus 
5-Fluorouracil 
Infusion 
Grade 3-4 mucositis or “hand-foot” 
syndrome 
Continue treatment at 
full (current) dose 
Discontinue 5-FU bolus 
Continue treatment at 
full (current) dose 
Myocardial infarction or angina pectoris 
Continue treatment at 
full (current) dose 
Discontinue 5-FU bolus 
Discontinue 5-FU 
infusion 
Grade 2 persistent neurotoxicity or 
Grade 3 neurotoxicity which recovers 
prior to next cycle 
Continue treatment at 
full (current) dose 
Continue treatment at 
full (current) dose 
Continue treatment at 
full (current) dose 
Grade 3 persistent neurotoxicity, Grade 4 
neurotoxicity or Grade 4 other non-
hematological toxicity 
Dose reduction or 
treatment discontinuation 
at the discretion of the 
Investigator 
Dose reduction or 
treatment discontinuation 
at the discretion of the 
Investigator 
Dose reduction or 
treatment 
discontinuation at the 
discretion of the 
Investigator 
Other toxicity ≥Grade 22,3 
Dose reduction by 1 or 
more dose levels at the 
discretion of the 
Investigator 
Dose reduction by 1 or 
more dose levels at the 
discretion of the 
Investigator 
Dose reduction by 1 or 
more dose levels at the 
discretion of the 
Investigator 
1Once a dose of any drug is decreased for toxicity re-escalation is not permitted. 
2Except anemia, gastrointestinal toxicity, Grade 2 persistent neurotoxicity, Grade 3 neurotoxicity, Grade 4 neurotoxicity, Grade 
3-4 mucositis or “hand-foot” syndrome, Grade 4 other non-hematological toxicity and alopecia. 
3Doses of all 3 drugs or none of the drugs may be reduced depending upon type of event and decision of the Investigator. 
When laboratory parameters or AEs indicate that all of the components of the FOLFIRI infusion 
should be delayed, the FOLFIRI infusion scheduled for that day is not given. Laboratory 
parameters should be evaluated the following week and repeated weekly until toxicity is resolved 
to an acceptable level at which time the next FOLFIRI infusion may be administered, marking 
Day 1 of the subsequent study cycle. 
If a toxicity is thought by the Investigator to be related to both BBI-608 and FOLFIRI, then the 
dose modification rules for both treatment regimens should be followed. 
If any or all components of FOLFIRI is/are held or discontinued for toxicities solely related to 
FOLFIRI, BBI-608 therapy should be continued. 
If BBI-608 is permanently discontinued due to toxicity, FOLFIRI therapy should be continued. 
7.1.6. 
Concomitant Medications/Procedures 
7.1.6.1. 
Permitted Treatments 
All information regarding concomitant treatments (medications or procedures) must be recorded 
on the patient’s eCRF (including the name of the medication or procedure and duration of 
treatment).  
Palliative and supportive care is permitted for disease-related symptoms for all patients.  

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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. 
Overall, CYP isoenzymes have an insignificant role in the biotransformation of napabucasin. The 
CYP P450 isoform 1A2 is the predominant isoform involved in the drug’s metabolism. Although 
the following drugs are permitted while on study treatment, all reasonable measures should be 
done to avoid use of drugs that are strong inhibitors or sensitive substrates of CYP1A2 unless 
there is medical necessity for their use.  
Strong CYP1A2 inhibitors include:  
x Ciprofloxacin and other fluoroquinolones 
x Fluvoxamine 
x Enoxacin 
x Zafirlukast 
Investigators may refer to the current BBI-608 IB for additional information.  
Patients who require use of concomitant medications metabolized by the CYP1A2, 2D6, 2C19, 
3A4, and 2C9 enzymes should be monitored, as per drug product label, as use of BBI-608 can 
inhibit the abovementioned CYP enzymes leading to increased drug concentrations of the 
enzyme metabolites. 
Patients who develop surgically resectable disease with curative intent during study treatment, 
must hold BBI-608 midnight prior to morning of surgery. FOLFIRI (with or without 
bevacizumab) components should be held according to the product labels and institutional 
standards. Following surgical recovery, patients should resume BBI-608 with resumption of oral 
intake. The decision to resume FOLFIRI following surgery and the timing of FOLFIRI 
resumption will be made by the Investigator depending on surgical and clinical factors. Patients 
randomized to either study arm, who discontinue FOLFIRI following surgical resection, will 
continue study visits once per month (an extended 28-day cycle) for safety assessments. 
Although intravenous bisphosphonate use is permitted for patients receiving bevacizumab, per 
Investigator choice, while on study treatment, all reasonable measures should be done to avoid 
the use of intravenous bisphosphonates simultaneously or sequentially with bevacizumab in 
order to mitigate the risk of osteonecrosis of the jaw (ONJ). Patients who have received 
intravenous bisphosphonates prior to treatment with bevacizumab are also at increased risk of 
ONJ and should be specifically counseled regarding this risk. Additionally, invasive dental 
procedures while the patient is receiving bevacizumab treatment also increases the risk of ONJ. 
As such, it is advised that patients receiving bevacizumab undergo a dental examination and 
appropriate preventive dentistry prior to start of treatment with bevacizumab. 
7.1.6.2. 
Non-Permitted Treatments 
Concurrent chemotherapy, hormonal therapy (except corticosteroids), immunotherapy, biologic 
therapy, or any other experimental agents should not be given to study patients while on protocol 
treatment. 

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7.1.7. 
Duration of Therapy 
Patients may continue to receive protocol therapy as long as they have not experienced any AEs 
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 7.1.4 and Section 7.1.5 . For a complete list of general criteria for stopping study 
treatment, please see Section 11.  
7.1.8. 
Patient Compliance 
Treatment compliance for BBI-608 is defined as the ratio, expressed as a percentage, of the 
number of capsules (BBI-608) taken by a patient over the course of a time interval to the number 
of capsules intended to be taken over that same time interval.  
Treatment compliance for FOLFIRI is defined as the ratio, expressed as a percentage, of the 
amount of each of the component drugs administered to a patient (milligrams/m2) over the course 
of a time interval to amount of the component IV drug intended to be administered over that 
same time interval.  
Treatment compliance in both arms will be monitored by drug accountability, as well as the 
monitoring of patient-reported compliance. 
 

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8. 
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. 
8.1. 
Evaluation During Protocol Treatment 
Investigations 
Timing  
Patient history and 
Evaluation 
Physical examination 
Vital signs (temperature, blood pressure, 
heart rate, respiratory rate, O2 saturation 
on room air) 
ECOG Performance status 
Concurrent medication list 
Weight 
Day 1 of every 14-day study cycle, starting 
with Cycle 11 (+/-3 days) or within 3 days prior 
to each FOLFIRI infusion 
Hematology 
CBC + differential, Platelet count 
Day 1 of every 14-day study cycle starting with 
Cycle 1 (+/-3 days) while on study medication 
and until the first regularly scheduled 4-week 
assessment at which the patient has been off 
study therapy for a minimum of 28 days 
(hematology investigations should be 
performed within 3 days prior to Day 1 of each 
study cycle, or within 3 days prior to each 
FOLFIRI infusion) 
Biochemistry 
Creatinine, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, LDH, Albumin, 
Potassium, Magnesium, Phosphate 
Day 1 of every 14-day study cycle, starting 
with Cycle 11 (±3 days) or within 3 days prior 
to each FOLFIRI infusion 
Urinalysis 
Dipstick (including protein, specific 
gravity, glucose and blood) 
Other 
Investigations 
Serum or urine pregnancy test2 
Every 28 days starting with Day 1 of Cycle 2 
(±3 days) 
Adverse Events 3 
Adverse Event evaluation must be done 
at each study visit3 
Day 1 of every 14-day study cycle 
OR 
On each FOLFIRI infusion day 
Adverse Event evaluation by phone3 
On Run-in Day 2  
Serious Adverse 
Events4 
Serious Adverse Event evaluation will be done from the time of informed consent and for 
30 days following the last dose of protocol therapy. 
Cardiology 
Assessment 
ECG 
Within 2 hours of completion of 
5-fluoropyrimidine bolus infusion on first day 
of FOLFIRI treatment and as clinically 
indicated thereafter 

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Investigations 
Timing  
Radiology & 
Imaging 
CT/MRI scan as per baseline assessment 
with tumor measurement and evaluation 
by RECIST 1.1 criteria5,9 
Every 8 weeks (every 56 days) after 
randomization5 (±5 days) until 6 months of 
treatment and every 12 weeks (every 84 days) 
thereafter until objective disease progression, 
withdrawal of consent or death 
Correlative 
Studies 
Submission of blood samples6, 8 
At Day 1 of Cycle 3 (±3 days) 
Sparse PK 
Collection 
Submission of blood plasma samples to 
central lab6, 8 
At Day 1 of Cycle 2 and Day 1 of Cycle 3 
(corresponding to the 2nd and 3rd FOLFIRI 
infusion days) 
Quality of Life 
(Appendix 5) 
EORTC QLQ-C307, 8 
At Day 1 of Cycle 3, Day 1 of Cycle 5, Day 1 
of Cycle 7, Day 1 of Cycle 9 and Day 1 of 
Cycle 13 (±3 days) 
FOLFIRI 
Administration 
IV FOLFIRI infusion  
Day 1 of every 2-week (14 day) study cycle 
(±3 days) 
1 Patients are to be assessed every 2 weeks (14 days) while on study medication and until the first regularly scheduled 4-week 
assessment at which the patient has been off study therapy for a minimum of 28 days. 
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 4). Adverse event assessment by phone on Run-in Day 2 is only applicable to patients receiving 
BBI-608. 
4 Serious adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (see Appendix 4). 
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 progressive disease is documented (as described in 
Section 9). 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.  
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. 
8 If these assessments were performed at a planned Cycle Day 1, but laboratory parameters delayed the administration of 
FOLFIRI and therefore delayed the Cycle Day 1, these assessments do not need to be repeated at the next visit and the 
original assessments can be used. 
9 Copies of imaging assessments may be requested. 

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8.2. 
Evaluation After Protocol Treatment Discontinuation 
Investigations 
Timing 
Patient History 
and Evaluation  
Physical examination 
Vital signs (temperature, blood pressure, 
heart rate, respiratory rate, O2 saturation 
on room air) 
Weight + ECOG Performance status 
Subsequent cancer therapy1 
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 
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 
Assess for survival of patient4 
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. (±7 days) 
Other 
Investigations 
Serum or urine pregnancy test5 
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 
CBC + differential, Platelet count 
Biochemistry 
Creatinine, Total Bilirubin, AST, ALT, 
Alkaline Phosphatase, LDH, Albumin, 
Potassium, Magnesium, Phosphate 
Urinalysis 
Dipstick (including protein, specific 
gravity, glucose and blood) 
Cardiology 
Assessment 
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 
CT/MRI scan as per baseline assessment 
with tumor measurement and evaluation 
by RECIST 1.1 criteria6 
Every 8 weeks (56 days) after randomization 
until 6 months of treatment and every 12 weeks 
(every 84 days) thereafter until objective disease 
progression is documented, withdrawal of 
consent or death.6 (±5 days) 
Correlative 
Studies 
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 
(Appendix 5) 
EORTIC 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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Investigations 
Timing 
1 After protocol treatment discontinuation. 
2 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (see Appendix 4). Adverse events relevant only to cancer or current/previous cancer treatments will be captured. 
Attribution of adverse events will continue to be recorded following treatment discontinuation. 
3 Serious adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
version 4.0 (see Appendix 4). 
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 9). 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. 
 

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9. 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
9.1. 
Definitions 
9.1.1. 
Evaluable for Adverse Events 
All patients who have received at least 1 dose of study drug (BBI-608 or FOLFIRI) will be 
evaluable for AEs from the time of their first dose of BBI-608. 
9.1.2. 
Evaluable for Overall Survival  
All randomized patients will be included in the analysis of OS, which is defined as the time 
interval between the date of randomization and the date of death from any cause. Patients who 
are still alive at the time of the final analysis, or who have become lost to follow-up will be 
censored at their last date known to be alive.  
9.1.3. 
Evaluable for Progression Free Survival  
All randomized patients will be included in the analysis of PFS, which is defined as the time 
interval between the date of randomization and the date of objective disease progression or 
death, whichever comes first. If neither event has been observed, then the patient will be 
censored at the date of the last tumor assessment. 
Disease progression is defined as objective progression per RECIST 1.1 [Eisenhauer 2009]. It is 
required to perform, whenever possible, a radiological confirmation of the clinical suspicion of 
tumor progression. In the situation where there is clinical suspicion of progression, but objective 
progression cannot be determined per RECIST 1.1, disease is defined as clinical deterioration 
without objective evidence of progression.  
The date of disease progression is defined as the date when the criteria for objective progression 
are first met.  
9.1.4. 
Evaluable for Objective Response Rate  
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 PR and CR as classified according to the 
definitions set out in Section 9.2.5 [Eisenhauer 2009]. For patients who discontinue protocol 
therapy prior to their first objective assessment of response, it is imperative that an objective 
response assessment be undertaken as close to the protocol specified schedule as possible. 
9.1.5. 
Evaluable for Disease Control Rate   
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 SD, PR, and CR as classified according to 
the definitions set out in Section 9.2.5 [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. 

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9.1.6. 
Evaluable for Quality of Life Assessment 
All patients who have completed the baseline quality of life questionnaire and at least 1 other 
QoL questionnaire are evaluable (Appendix 5). 
9.1.7. 
pSTAT3(+) Subpopulation, the pSTAT3(-) Subpopulation and 
pSTAT3(Unknown) Subpopulation 
The pSTAT3 subpopulations will be defined by the results of a Clinical Trial Assay (CTA) for a 
specimen with an age within a defined cut-section stability (CSS) window (6 months at interim 
analysis or the final CSS window at final analysis).  Specimen age is defined as the time interval 
between the sectioning and staining of the specimen.  
A patient with positive pSTAT3 status within a defined CSS window is the one with pSTAT3 
positive designated by CTA with specimen age up to 6 months at interim analysis or up to the 
final CSS window at final analysis.   
A patient with negative pSTAT3 status within a defined CSS window is the one with pSTAT3 
negative designated by CTA with specimen age up to 6 months at interim analysis or up to final 
CSS window at final analysis.   
A patient with pSTAT3 status unknown within a defined CSS window will include patients with  
specimen was not submitted for testing, if the specimen is identified as non-evaluable upon 
pathology evaluation, if the specimen age is out of the defined CSS window, or if missing due to 
any other reasons.  
Evolving knowledge of Cut-Section Stability (CSS) for pSTAT3 Biomarker Assay 
 
The pSTAT3 IHC D3A7 CTA was used for this study to identify the pSTAT3(+) patient population. This 
biomarker assay is an immunohistochemistry-based method intended for use in detection of pSTAT3 
protein in cut tissue sections. A cut-section stability (CSS) study is ongoing to establish the final pSTAT3 
CSS window which is expected to be completed prior to the final analysis.   
At the time of the interim analysis in the CanStem303C study, preliminary assessments from the ongoing 
CSS study were indicative of a stability of at least 6 months for slides stored at -20 degrees Celsius, the 
same manner in which CanStem303C specimens have been stored.  The interim analysis, therefore, 
included pSTAT3 biomarker status results for only those patients with specimens age up to a CSS of 6 
months.  
However, after the interim analysis in the CanStem303C study, the biomarker data monitoring from the 
ongoing CSS study indicates that samples will likely remain stable at -20 degrees Celsius for greater than 
6 months.  This indicates that the final CSS window could be longer than 6 months and up to 15 months.  
As a result of evolving knowledge of CSS window, a patient with unknown pSTAT3 status that was due to 
a specimen out of the 6-month CSS window may have a pSTAT3 positive or negative status at the final 
analysis. Therefore, it is expected that will be fewer patients with unknown pSTAT3 status within the final 
CSS window at the final analysis compared to the interim analysis with 6 month CSS window.  
 Figure 1 below shows the pSTAT3 subpopulations components at the interim and final analysis.  

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Figure 1: 
pSTAT3 Subpopulations Components at Interim Analysis and Final Analysis 
 
Note: All specimens will be tested only one time regardless of final stability window.   
9.2. 
Response and Evaluation Endpoints 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumors) committee. 
9.2.1. 
Measurable Disease 
Measurable tumor lesions are defined as those that can be accurately measured in at least 
1 dimension (longest diameter to be recorded) as ≥20 mm with chest X-ray and as ≥10 mm with 
CT scan, or clinical examination. Bone lesions are considered measurable only if assessed by CT 
scan and have an identifiable soft tissue component that meets these requirements (soft tissue 
component ≥10 mm by CT scan). Malignant lymph nodes must be ≥15mm in the short axis to be 
considered measurable; only the short axis will be measured and followed. All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). Previously 
irradiated lesions are not considered measurable unless progression has been documented in the 
lesion. 
9.2.2. 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
lymphangitic involvement of lung or skin and abdominal masses followed by clinical 
examination are all non-measurable. Lesions in previously irradiated areas are non-measurable, 
unless progression has been demonstrated. 

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9.2.3. 
Target Lesions 
When more than 1 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 Section 9.2.4). At baseline, the sum of 
the target lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall 
maximum of 5) is to be recorded. 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may be used. 
9.2.4. 
Non-target Lesions 
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not required 
but these lesions should be noted at baseline and should be followed as “present” or “absent”. 
9.2.5. 
Response 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
Complete Response (CR): disappearance of target and non-target. Pathological lymph nodes 
must have short axis measures <10 mm (Note: continue to record the measurement even if 
<10 mm and considered CR). Residual lesions (other than nodes <10 mm) thought to be 
non-malignant should be further investigated (by cytology specialized imaging or other 
techniques as appropriate for individual cases [Eisenhauer 2009]) before CR can be accepted.  
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for 
tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline 
sum of diameters. Non-target lesions must be non-PD.  
Stable Disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND 
an absolute increase of ≥5mm. Appearance of new lesions will also constitute PD (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 

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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.  

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Table 12: 
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 weeks 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. 
9.3. 
Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever 
is first recorded) are first met until the first date that recurrent or progressive disease is 
objectively documented, taking as reference the smallest measurements recorded on study 
(including baseline). 
9.4. 
Stable Disease Duration 
Stable disease duration will be measured from the time of randomization until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
9.5. 
Methods of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all 

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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 IV contrast 
2 
Chest CT without IV contrast PLUS MRI Abdomen-Pelvis with oral and IV 
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. 
9.5.1. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial and >10 mm as 
assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is recommended. If feasible, 
imaging is preferred. 
9.5.2. 
Chest X-ray  
Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, 
since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions 
>20 mm on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung.  
9.5.3. 
CT/MRI  
CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). Other specialized imaging or 
other techniques may also be appropriate for individual case [Eisenhauer 2009]. For example, 
while PET scans are not considered adequate to measure lesions, PET-CT scans may be used 
providing that the measures are obtained from the CT scan and the CT scan is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast). 

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9.5.4. 
Ultrasound  
Ultrasound is not useful in assessment of lesion size and should not be used as a method of 
measurement. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT is advised. 
9.5.5. 
Endoscopy/Laparoscopy  
The utilization of these techniques for objective tumor evaluation is not advised. However, they 
can be useful to confirm complete pathological response when biopsies are obtained or to 
determine relapse in trials where recurrence following complete response or surgical resection is 
an endpoint.  
9.5.6. 
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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10. 
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 4).  
All appropriate treatment areas should have access to a copy of the CTCAE. A copy of the 
CTCAE can be downloaded from the Cancer Therapy Evaluation Program (CTEP) web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
All SAEs defined per ICH guidelines (Section 10.1) and other AEs must be recorded on the 
eCRFs. All SAEs must be reported to the Sponsor within 24 hours (Section 10.2).  
10.1. 
Definition of a Protocol Reportable Serious Adverse Event 
All SAEs must be reported in an expedited manner (see Section 10.2 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.  
An SAE is an AE that at any dose: 
x Results in death 
x Is life-threatening 
x Requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration) 
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly/birth defect 
x Is an important medical event 
Note: clinically significant test results should be recorded on the AE CRF using the appropriate 
CTCAE description and grading scale. 
10.2. 
Serious Adverse Event Reporting Instructions 
SAE reporting will commence following the signature of the informed consent and continue for 
30 days following the last dose of protocol treatment. Any SAE occurring following patient 
signature of informed consent and prior to patient randomization must be submitted to the 
Sponsor for review and response prior to patient randomization and/or study drug administration, 
even if the patient completely recovered from the SAE. Additionally, any SAE occurring at any 
time following administration of the final dose of protocol treatment that is suspected to be 
related to study treatment must be reported. 
All SAEs (Section 10.1) 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. 

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Detailed instructions for the submission of SAE Reports will be provided separately. 
10.3. 
Procedures in Case of an Overdose 
Use of BBI-608 in doses in excess of that specified in the protocol should be reported in the 
following manner: 
If an AE(s) is associated with (“results from”) the overdose of BBI-608, the overdose and AE are 
reported on the SAE Report Form, even if no other criteria for seriousness are met. The SAE 
Report Form should be submitted within 24 hours. The overdose should also be recorded on the 
relevant AE form in the eCRF using the term “accidental or intentional overdose with adverse 
effect.” 
If the overdose of BBI-608 is not associated with an AE, the overdose is reported as a non-
serious AE, on the relevant AE form in the eCRF within 24 hours, using the event term 
“accidental or intentional overdose without adverse effect.” The clinical research associate 
responsible for the investigational center should also be notified of the event within 24 hours. 
Investigators/site personnel are to consult the local, approved product labels for each of the 
components of the FOLFIRI treatment regimen for guidance on the definition of an overdose of 
components of this regimen as well as for guidance on reporting of any AE or SAE associated 
with overdose of any of the FOLFIRI components. Overdose of FOLFIRI should also be 
reported to the Sponsor in accordance with overdose reporting guidelines in Section 10.3). 
10.4. 
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 
when the research population includes WOCBP. This includes pregnancy testing, use of effective 
methods of birth control, and pregnancy as an exclusion factor. The trial sample informed 
consent form includes the potential for unidentified risks to the embryo/fetus. It also includes 
general information on pregnancy prevention and the required minimum period during which 
birth control must be utilized.  
10.4.1. 
Pregnancy Prevention 
WOCBP and males who are enrolled in the trial must be informed of the requirement to use 
contraception as outlined in the eligibility criteria (Section 4.1). 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. 
10.4.2. 
Pregnancy Occurring in WOCBP Exposed to Study Agent 
Any female participant who becomes pregnant during the course of the trial should be instructed 
to stop taking study medication immediately. 

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The Investigator should provide counselling and discuss the risks and possible side effects to the 
embryo/fetus from BBI-608 and FOLFIRI. Monitoring should continue until conclusion of the 
pregnancy. The same should occur for female partners of a male participant, or any female 
exposed to BBI-608 when appropriate and compliant with local policy. 
10.4.3. 
Pregnancy/Exposure Reporting 
The Investigator is required to report to the Sponsor any pregnancy where the embryo/fetus 
could have been exposed to BBI-608. This includes pregnancies occurring in female participants, 
female partners of male participants, or females exposed through direct contact with the agent 
during their pregnancy (for example, environmental exposure involving direct contact with the 
agent). Pregnancies occurring until 30 days in female patients and until 90 days in partners of 
male patients, after the completion of BBI-608 must also be reported as well as pregnancies 
occurring until 180 days of the final FOLFIRI dose for female and male patients. 
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: 
x “pregnancy, puerperium, and perinatal conditions – other, specify” (normal live birth), 
x “pregnancy, puerperium, and perinatal conditions – other, specify” (therapeutic abortion), or 
x another term under "pregnancy, puerperium, and perinatal conditions" as applicable. 
Information on the medical history of the parents that may relate to assessing any potential fetal 
outcomes is requested, as is information on the health of the newborn. The narrative section of 
the SAE form should be used to communicate all relevant information pertaining to the 
pregnancy. 
10.5. 
Responsibility for Reporting Serious Adverse Events to Regulatory 
Agencies 
Boston Biomedical, or the delegated CRO, will provide expedited reports of SAEs to FDA and 
other applicable regulatory authorities, for those events which meet regulatory requirements for 
expedited reporting, i.e. events which are BOTH serious AND unexpected, AND which are 
related to BBI-608 (suspected unexpected serious adverse reaction [SUSAR]): 
x Unexpected AEs are those which are not consistent in either nature or severity with 
the reference safety information contained in the Investigator’s Brochure 
x AEs considered related to protocol treatment are those events which have a 
reasonable possibility of being related to BBI-608.  
Boston Biomedical will determine which SAEs meet the criteria for regulatory reporting.  

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10.6. 
Reporting Safety Reports to Investigators 
Boston Biomedical, or the delegated CRO, will notify Investigators of all Safety Reports (SAEs) 
from this trial and Safety Updates from other clinical trials that are reportable to regulatory 
authorities. This includes all SAEs that are unexpected and related (i.e. possibly, probably, or 
definitely) to protocol treatment.  

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11. 
PROTOCOL TREATMENT DISCONTINUATION AND 
THERAPY AFTER STOPPING 
11.1. 
Criteria for Discontinuing Protocol Treatment 
Patients should stop protocol treatment in the following instances: 
x Progressive Disease (see Section 9.2.5). 
x Pregnancy 
x 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 
x Unacceptable toxicity 
x Request by the patient 
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 progression is 
observed. 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients discontinue protocol treatment prematurely and/or no longer attend the participating 
institution.  
11.2. 
Duration of Protocol Treatment  
Patients may continue to receive protocol therapy as long as they have not experienced any AEs 
requiring permanent discontinuation of study medication and have not demonstrated disease 
progression based on RECIST criteria. 
As BBI-608 targets cancer stem cells, it is possible that continued therapy after PD per 
RECIST 1.1 may provide clinical benefit. If no other standard therapies are available at the time 
of disease progression based on RECIST 1.1 criteria, and the patient has not experienced any 
AEs requiring permanent discontinuation, BBI-608 may be continued in monotherapy. 
11.3. 
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. 
11.4. 
Follow-up Off Protocol Treatment 
Follow-up will continue after treatment completion according to the plan described in the 
protocol (see Section 8.2). Efforts should be made to maintain the investigations schedule and 
continue follow-up, even if patients discontinue protocol treatment prematurely and/or no longer 
attend the participating institution. 

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12. 
CENTRAL REVIEW PROCEDURES, TISSUE COLLECTION, 
AND CORRELATIVE STUDIES 
12.1. 
Central Radiology Review 
There will be no central radiology review for this study. 
12.2. 
Central Pathology Review 
Archival tumor tissue samples will be sent a central pathology laboratory for testing for pSTAT3 
status. Tissue Collection 
12.2.1. 
Protocol-Mandated Biomarker Analyses 
The submission of a representative diagnostic tumor tissue for the biomarker and a blood sample 
for correlative studies is mandatory for participation in this trial. Where local center regulations 
prohibit submission of blocks of tumor tissue, two 2 mm cores of tumor from the block and 
10 to 30 unstained slides of representative tumor tissue are requested. Where two 2 mm cores of 
tumor from the block are not available, 10 to 30 unstained slides of whole sections of 
representative tumor tissue are requested. The biomarker tissue samples will be analyzed with 
the pSTAT3 IHC prototype assay as an investigational use only (IUO). Once the market-ready 
assay (MRA) is available, all patient samples will be re-analyzed to confirm the results using the 
prototype assay. 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 to 30 specimen slides are preferred. If two 2 mm cores of tumor from the block are not 
available, 10 to 30 unstained slides of whole sections of representative tumor tissue are 
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 may also be used for research purposes but will not be sold. Patients will not be 
identified by name. Patient samples will be blinded, and the only identification of tissue will be 
by a patient study number assigned at the time of randomization to the trial.  
Testing for hereditary genetic defects predisposing to malignant disease will not be carried out 
without the expressed consent of the patient.  
All patients for whom a blood sample and/or diagnostic tumor block is collected will be aware of 
this retrieval and must have given their consent. 
12.3. 
Sparse Pharmacokinetic Plasma Sample Collection (Arm 1 Only) 
Plasma samples for sparse pharmacokinetics (PK) analysis will be obtained from all patients 
randomized to Arm 1 (BBI-608 with FOLFIRI) at the study visits occurring on Day 1 of Cycle 2 
and Day 1 of Cycle 3 (corresponding to FOLFIRI infusion days). Patients randomized to Arm 2 
(FOLFIRI) will not undergo plasma collection for PK analysis. 

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Day 1 (Cycle 2) Study Visit: 
The Day 1 (Cycle 2) visit should be scheduled prior to 10 AM. On the day of this visit, patients 
should be instructed to wait to take their first daily dose of BBI-608 until they arrive in clinic. 
After arrival in the clinic, but approximately 5 minutes prior to administration of the first daily 
dose of BBI-608, a plasma sample will be obtained. Irinotecan infusion will be started 
immediately following bevacizumab infusion (for patients who will receive bevacizumab 
together with FOLFIRI per investigator decision) or approximately 2 hours after BBI-608 
administration if bevacizumab is not administered. A second plasma sample will be obtained 
within 1 to 4 hours after administration of the first daily dose of BBI-608.  
Day 1 (Cycle 3) Study Visit: 
The Day 1 (Cycle 3) visit should be scheduled prior to 10 AM. On the day of this visit, patients 
should be instructed to wait to take their first daily dose of BBI-608 until they arrive in clinic. 
After arrival in the clinic, but at least 60 minutes prior to administration of the first daily dose of 
BBI-608, a plasma sample will be obtained. Irinotecan infusion will be started immediately 
following bevacizumab infusion (for patients who will receive bevacizumab together with 
FOLFIRI per investigator decision) or approximately 2 hours after BBI-608 administration if 
bevacizumab is not administered. A second plasma sample will be obtained within 5 to 8 hours 
after administration of the first daily dose of BBI-608.  
For all days during which a plasma sample is obtained for PK analysis, the precise time of all 
doses of BBI-608 (on the day of sampling and the day prior), the precise time of the initiation of 
irinotecan administration, and the precise time of all PK sampling must be captured.  
Samples will be processed, stored, and shipped according to the instructions provided in the 
separate Sparse PK sampling laboratory manual for this study.  

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13. 
STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be maintained by the Sponsor. The 
SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment.  
13.1. 
Objectives and Design 
The primary objectives of this study are to compare OS of patients with metastatic pretreated 
CRC treated with BBI-608 plus biweekly FOLFIRI (Arm 1) versus biweekly FOLFIRI (Arm 2) 
in the General Population and in the pSTAT3(+) Subpopulation. 
Secondary objectives for this study include comparisons of PFS in the General Population and in 
the pSTAT3(+) Subpopulation, Objective Response Rate in the General Population and in the 
pSTAT3(+) Subpopulation, Disease Control Rate in the General Population and in the 
pSTAT3(+) Subpopulation, Quality of Life Assessment in the General Population and in the 
pSTAT3(+) Subpopulation, and adverse events in the 2 treatment arms. 
This is a multi-center, prospective, open-label, randomized, adaptive design Phase 3 trial of the 
cancer stem cell pathway inhibitor BBI-608 plus standard bi-weekly FOLFIRI (Arm 1) versus 
standard bi-weekly FOLFIRI (Arm 2) in patients with previously treated mCRC. Patients will be 
randomized to receive either BBI-608 plus standard bi-weekly FOLFIRI, (Arm 1) or standard bi-
weekly FOLFIRI (Arm 2) in a 1:1 ratio and will be stratified by geographical region (North 
America/Western Europe/Australia, Japan/Korea, versus rest of the world), time to progression 
from start of first line therapy (<6 months versus ≥6 months), RAS mutation status (mutant 
versus wild type), bevacizumab as part of protocol treatment (yes versus no), and location of the 
primary tumor (left colon versus right colon). Addition of bevacizumab to the FOLFIRI regimen, 
per Investigator choice, will be permissible. 
13.2. 
Study Endpoints and Analysis 
13.2.1. 
Primary Endpoint for the Study 
Overall Survival in the General Population and pSTAT3(+) Subpopulation 
Overall survival in the General Population and the pSTAT3(+) Subpopulation, the primary 
endpoints of this study, are defined as the time from randomization to death from any cause. 
Patients who are alive at the time of the interim or the final analyses or who have become lost to 
follow-up will be censored on the date the patient was last 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 (listed in Section 3.1) for the General 
Population and unstratified log-rank test for the pSTAT3(+) Subpopulation.  
Sensitivity analyses based on stratified Cox proportional hazards model will also be performed 
for the General Population or/and in the pSTAT3(+) Subpopulation depending on the decision 
from interim analysis. Geographical region (North America/Western Europe/Australia, 
Japan/Korea, versus rest of the world), time to progression on first line therapy from start of first 

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line therapy (<6 months versus ≥6 months), RAS status (mutant versus wild type), bevacizumab 
as part of protocol treatment (yes versus no), and location of the primary tumor (left colon versus 
right colon) will be the stratification factors to define the stratified Cox proportional hazards 
model. 
Subgroup analysis and the corresponding forest plot analysis may be performed using the 
stratification factors mentioned above as well as the following factors:  
x Age (<65 versus ≥65) 
x Sex (male versus female) 
x Presence of liver metastases (yes versus no) 
x Primary tumor site (colon versus rectum) 
x ECOG Performance Status (0 vs 1) 
x Race (White, Black, Asian, other) 
x Country (Canada, USA, Western Europe, Australia, Japan, Korea, China, others) 
x Microsatellite Instability (MSS vs MSI-L vs MSI-H vs MSI-V) 
x Prior Bevacizumab: Yes / No   
13.2.2. 
Key Secondary Endpoints 
The following key secondary outcomes will be assessed: 
Progression-Free Survival in the General Population and the pSTAT3(+) Subpopulation 
Progression-free survival is defined as the time from randomization to the first objective 
documentation of disease progression or death, whichever comes first. If a patient has not 
progressed or died at the time of the interim or 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. The progression free survival 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 for the General Population and unstratified log-rank test 
for the pSTAT3(+) Subpopulation. 
Disease Control Rate in the General Population and the pSTAT3(+) Subpopulation  
Disease control rate 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.  For the General Population, differences of DCR between the two arms will be 
compared using a 1-sided Cochran-Mantel-Haenszel test stratified for stratification factors.  
Treatment difference of DCR and its 95% confidence interval based on harmonic mean method 
adjusting stratification factors will be provided.  For the pSTAT3(+) Subpopulation, differences 
of DCR between the two arms will be compared using a 1-sided Z-test via normal 
approximation.  Treatment difference of DCR and its 95% confidence interval based on normal 
approximation (unstratified) will be provided.   
Objective Response Rate in the General Population and the pSTAT3(+) Subpopulation 

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Objective response rate is defined as the proportion of patients with a documented complete 
response and partial response (CR + PR) based on RECIST 1.1. The primary estimate for ORR 
will be based on patients with measurable disease by RECIST 1.1 at randomization.  Differences 
of ORR between the two arms will be analyzed the same as DCR for the General Population and 
for the pSTAT3(+) subpopulation.   
13.2.3. 
Other Secondary Endpoints 
Quality of Life Analysis in the General Population and the pSTAT3(+) Subpopulation 
The QoL of patients will be assessed using EORTC QLQ-30 while the patient remains on study 
treatment (FOLFIRI with or without BBI-608) as per Section 8.1. The EORTC QLQ-30 is a self-
administered cancer specific questionnaire with multi-dimensional scales (Appendix 5). It 
consists of both multi-item scales and single item measures, including 5 functional domains, a 
global quality of life domain, 3 symptom domains, and 6 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 BBI-608 plus 
FOLFIRI versus FOLFIRI 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 (Appendix 5). 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 (Cycle 5 Day 1) and Time 4 (Cycle 9 Day 1) for the physical function and 
global health status/quality of life subscale scores. Wilcoxon tests will be used to compare the 
difference at each of these 2 timepoints between 2 treatment arms for each of these 2 subscales. 
The proportion of patients in either arm with at least a minimum of 10-unit(s) deterioration in 
change scores at both Cycle 5 Day 1 and Cycle 9 Day 1 will be summarized. 
Safety Analysis 
All patients who have received at least 1 dose of study treatment (BBI-608 or FOLFIRI) will be 
included in the safety analysis. The incidence of AEs will be summarized by type of AE and 
severity using the NCI Common Terminology Criteria for Adverse Events Version 4.0. The 
Exact test (Chan 1999) may be used when comparing AE rate between treatment arms. 
13.3. 
Sample Size and Duration of Study 
The primary study endpoints are OS for the General Population and the pSTAT3(+) 
Subpopulation. The hypotheses (the General Population and the pSTAT3(+) Subpopulation) for 
the study are as follows:   
For the General Population, the null and alternative hypotheses are:  
H10: BBI-608 + FOLFIRI ≤ FOLFIRI in the General Population 
H11: BBI-608+FOLFIRI > FOLFIRI in the General Population  
For the pSTAT3(+) Subpopulation, the null and alternative hypotheses are: 

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H20: BBI-608 + FOLFIRI ≤ FOLFIRI in the pSTAT3(+) Subpopulation 
H21: BBI-608+FOLFIRI > FOLFIRI in the pSTAT3(+) Subpopulation 
Sample Size and Power in the General Population  
For the General Population, this study is designed to have a power of 90% and a 1-sided α=0.025 
to detect a 20% reduction in the risk of death (HR 0.80 which corresponds to an increase of 
median survival from 12.54 to 15.68 months) The above design assumptions account for the 
anticipated varying control hazard rates for the bevacizumab versus no-bevacizumab 
stratification levels. It is assumed that approximately 30% of subjects will receive bevacizumab 
with expected mOS for the control arm FOLFIRI+bevacizumab subjects being 13.66 months 
while 70% of the subjects will not receive bevacizumab and have expected mOS of 12.06 
months [Van Cutsem 2012]. Without adjusting for multiplicity, it is estimated that 850 events in 
the General Population will be required to detect this reduction, which would be observed by 
randomizing 1250 patients (General Population) over 26 months with patient follow up for an 
additional 14 months, for a total study duration of 40 months. It is anticipated that up to 5% 
dropout rate will occur over the entire study. 
Sample Size and Power in the pSTAT3(+) Subpopulation  
According to the preliminary data from Studies BBI608-101, CO.23, BBI608-201, BBI608-224, 
and BBI608 246, of the 599 patients with biomarker samples in the pooled analysis, 241 patients 
were pSTAT3(+), the pSTAT3(+) prevalence was estimated to be around 40% (95% CI: 36%, 
44%). If considering a lower boundary of 36% as the biomarker positive prevalence in the 
current study, and proportional to the total deaths events in the General Population, there would 
be 310 (approximately 36% of 850) events in the pSTAT3(+) Subpopulation.  
For the pSTAT3(+) Subpopulation, without adjusting for multiplicity, and assuming 310 events, 
there will be approximately 88% nominal power at 1-sided α=0.025 to detect a 30% reduction 
(HR [BBI-608+FOLFIRI vs FOLFIRI] = 0.70) in the risk of death in the pSTAT3(+) 
Subpopulation.  
Overall Power of the Study 
Assuming at the final analysis there are 850 events in the General Population and 310 events in 
the pSTAT3(+) Subpopulation, considering multiplicity adjustment (Section 13.6), the overall 
power for the entire study which succeeds either in terms of OS in the General Population or in 
the pSTAT3(+) Subpopulation or both, is approximately 90%, assuming that the true OS hazard 
ratio in the General Population is 0.80 and that in the pSTAT3(+) Subpopulation is 0.70. 
13.4. 
Safety Monitoring 
Adverse events will be monitored on an on-going basis by central review. 
13.5. 
Interim Analysis 
An interim analysis will be conducted when 425 deaths occur (50% of total number of 
850 deaths) in the General Population for the purpose of decision rules of futility, population and 
hypothesis selection, and event count adjustment (Figure 2). The OS results will be evaluated by 
the Data Safety and Monitoring Board (DSMB). Additionally, the DSMB will review safety 

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during conduct of the study. The role and responsibility of the DSMB will be defined in a 
separate Charter. The recommendations from DSMB on the study design and conduct will be 
based on the following decisions: 
x 
Futility stopping: terminate the trial due to lack of efficacy (futility) or terminate pSTAT3(-) and 
pSTAT3 status unknown subpopulation 
x 
Patient population and hypothesis selection: select the most appropriate patient population and 
hypothesis (hypothesis in General Population, and/or hypothesis in pSTAT3(+) Subpopulation) 
for evaluating the significance of the treatment effect at the final analysis 
x 
Event count adjustment: remain the current events size or increase the target number of events in 
1 of or both pre-defined patient populations 
The details decision rules are described as following:  
Futility stopping rule: Perform an early assessment of the efficacy profile of BBI-608+FOLFIRI 
vs FOLFIRI in the 2 pre-defined patient populations and terminate the trial due to lack of 
efficacy (futility) if there is no evidence of treatment benefit in either population.  
The decision rules will be applied simultaneously based on the observed hazard ratios at interim 
analysis: 
x ܪܴ଴: Hazard Ratio (BBI-608+FOLFIRI vs FOLFIRI) in the General Population. 
x ܪܴା: Hazard Ratio (BBI-608+FOLFIRI vs FOLFIRI) in the pSTAT3(+) Subpopulation. 
x ܪܴି: Hazard Ratio (BBI-608+FOLFIRI vs FOLFIRI) in the pSTAT3(-) Subpopulation. 
If ܪܴା: > c1 and ܪܴ଴: > c2, then the trial may be stopped due to lack of efficacy.  
If ܪܴା: ൑ c1 and ܪܴି> c3, then continue the trial for pSTAT3(+) Subpopulation only and 
perform the final analysis in the pSTAT3(+) Subpopulation. Here c1= c2= c3=1 are futility 
boundaries for the pSTAT3(+) Subpopulation, the General Population and the pSTAT3(-) 
Subpopulation respectively.  
Patient population and hypothesis selection rule: Select the most appropriate patient population 
and hypothesis for evaluating the significance of the treatment effect at the final analysis. 
The patient population selection rules are based on futility analysis and the interaction condition 
introduced in [Millen 2012]. In this trial, if the General Population continues after interim 
analysis, the interaction condition will be evaluated by comparing the ratio of ܪܴା/ܪܴି with 
pre-specified threshold of c4 where c4 will be set to 0.9. If ܪܴା/ܪܴି൐ c4 which indicates the 
treatment effect in the pSTAT3(+) Subpopulation is comparable to pSTAT3(-) Subpopulation, 
the hypothesis for the General Population only (the broad indication) would be appropriate. On 
the other hand, ifܪܴା/ܪܴି൑ c4, which indicate the pSTAT3(+) Subpopulation has substantial 
improvement compared to the pSTAT3(-) Subpopulation, both hypotheses of the pSTAT3(+) 
subpopulation and the General Population would be considered.  
If only the pSTAT3(+) Subpopulation is continued, only the hypothesis of the pSTAT3(+) 
Subpopulation will be tested, and no interaction check will be performed.  
Event count adjustment rule: Increase the target number of events in 1 of or both pre-defined 
patient populations to improve the probability of success in the trial. 

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Within each patient population (General Population or pSTAT3(+) Subpopulation), conditional 
power is defined as the probability of establishing a significant OS effect at the final analysis 
conditional upon the interim analysis data at a 1-sided α=0.025. Conditional power is computed 
within each patient population using the population-specific hazard ratio observed at the interim 
analysis before an event count adjustment. A closed-form expression for conditional power is 
provided in Appendix 6. The event count adjustment rule will be defined by identifying an 
optimal balance between the competing goals of increasing conditional power and reducing the 
number of events. The event count adjustment may also consider other factors including 
potential clinical benefits and operational feasibility. The details of the event count adjustment 
rule will be provided in a separate document and be available to DSMB and other unblinded staff 
as appropriate for recommendation and/or decision for the interim analysis results. In the event 
that the event count for pSTAT3(+) Subpopulation is to be increased, the protocol may be 
amended to reflect this change. 
If the final analysis is performed in both the General Population and the pSTAT3(+) 
Subpopulation, the number of events in the trial will be driven by that in the General Population 
or in the pSTAT3(+) Subpopulation, whichever comes last. 
13.6. 
Multiplicity Adjustment 
To address multiplicity introduced by the analysis of several endpoints (primary endpoint and 
key secondary endpoints), analysis of the 2 patient populations (General Population and 
pSTAT3(+) Subpopulation), and data-driven design changes, a Hochberg-based gatekeeping 
procedure will be implemented [Dmitrienko (2011, 2013) and Kordzakhia (2018b)]. The 
hypothesis testing for the key secondary endpoints will follow the order of PFS, DCR, and ORR 
in both the General Population and the pSTAT3(+) Subpopulation.  
The gatekeeping procedure will be applied in conjunction with the combination function 
approach at the final analyses to ensure strong Type I error rate control. A description of the 
multiplicity adjustment procedure is provided in Appendix 6. 

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Figure 2: 
Adaptive Study Design Schema 
 
 

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13.7. 
Pharmacokinetic Analyses 
13.7.1. 
Sparse Pharmacokinetic Analysis 
Plasma BBI-608 concentrations determined from sparse PK samples will be listed by day within 
cycle, nominal time, and dose in the case of dose reduction, if appropriate. The listing will 
include actual sampling time relative to the BBI-608 dose administered on the day of the PK 
sample collection. If necessary, BBI-608 concentration data may also be included in a population 
PK analysis that will be subsequently used to conduct exposure-response modeling. The results 
of population PK analysis and exposure response modeling will be reported in a separate 
document.  

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14. 
PUBLICATION 
Boston Biomedical Inc. acknowledges that the Investigator(s) have certain professional 
responsibilities to report to the scientific community on findings in clinical investigations they 
conduct. A Principal Investigator shall have the right to publish the results of research performed 
under this protocol, provided such publication does not disclose any Confidential Information or 
trade secrets of Boston Biomedical (other than the clinical results).  
If the Study is conducted as part of a multi-center protocol, Principal Investigator agrees not to 
independently publish their findings except as part of an overall multi-center publication. No 
other publication is allowed before the primary peer-reviewed scientific publication 
The primary author agrees to, prior to submitting a manuscript, abstract, or any other written or 
oral presentation describing the Results for publication or presentation, forward to Boston 
Biomedical a copy of the item to be submitted for publication or presentation no less than 
45 days prior to their submission. Upon 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 and to require that any publication or presentation 
concerning the Study acknowledge the Sponsor’s support. 
14.1. 
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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15. 
ETHICAL, REGULATORY, AND ADMINISTRATIVE ISSUES 
15.1. 
Regulatory Considerations 
All institutions must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines and in accordance with the 
Declaration of Helsinki. 
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. 
Any changes to the protocol, including any amendments to the patient information, informed 
consent, quality of life forms, and any other patient study-related documents, will require the 
Sponsor to submit to the Regulatory Authorities as well as to the Ethics Committees. Further, 
changes outlined in such an amendment will not be implemented prior to receiving approval 
from the Regulatory Authority and Ethics Committee.  
15.2. 
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, color, 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 

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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.  
15.3. 
Obtaining Informed Consent 
Informed consent will be obtained for each participant/potential participant in this trial, in 
accordance with ICH-GCP Section 4.8. The center is responsible for ensuring that all local 
policies are followed. 
Additionally, in accordance with GCP 4.8.2, the Sponsor may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential 
participant’s willingness to participate in the study.  
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating Investigator (as defined on the participants list) is ultimately responsible, in terms 
of liability and compliance, for ensuring informed consent has been appropriately obtained. The 
Sponsor recognizes that in many centers other personnel (as designated on the participants list) 
also play an important role in this process. In accordance with GCP 4.8.5, it is acceptable for the 
Principal Investigator to delegate the responsibility for conducting the consent discussion. 
The Sponsor requires that each participant sign a consent form prior to their enrolment in the 
study to document his/her willingness to take part. The Sponsor may also require, as indicated 
above, that participants/potential participants be informed of new information if it becomes 
available during the course of the study. In conjunction with GCP 4.8.2, the communication of 
this information should be documented. 
The Sponsor allows the use of translators in obtaining informed consent. Provision of translators 
is the responsibility of the local center. Centers should follow applicable local policies when 
procuring or using a translator for the purpose of obtaining informed consent to participate in a 
clinical trial.  
In accordance with ICH-GCP 4.8.9, if a subject is unable to read, then informed consent may be 
obtained by having the consent form read and explained to the subject. This process must be 
thoroughly documented. 
15.3.1. 
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 

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participants will not be withdrawn from the main study should their partner refuse/withdraw 
permission. 
15.4. 
Discontinuation of the Trial 
If this trial is discontinued 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 involves any 
potential risks to the health of patients participating on the trial or other persons, the Sponsor will 
provide this information to centers as well. 
If this trial is discontinued at any time by the center (prior to closure of the trial by the Sponsor), 
it is the responsibility of the Principal Investigator to notify the Sponsor of the discontinuation 
and the reason(s) why.  
Whether the trial is discontinued by the Sponsor or locally by the center, it is the responsibility of 
the Principal Investigator to notify the local Institutional Review Board and all clinical trials 
subjects of the discontinuance and any potential risks to the subjects or other persons. 
Following trial closure after demonstrating overall survival benefit, and until the time that 
BBI-608 is commercially available, all patients randomized on the trial may have an opportunity 
to receive treatment with BBI-608; provided, that the Principal Investigator has determined that 
such continued treatment would be in the best interest of the patient, and subject to approval by 
the applicable regulatory authorities. This may be done via a new, open label extension study, 
requiring additional regulatory approval, or in another manner as determined by the Sponsor. 
15.5. 
Retention of Patient Records and Study Files 
All essential documents and study data 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 and study data 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.  
15.6. 
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 program. 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. 

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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.  
15.7. 
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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16. 
REFERENCES 
Please find reviews on cancer stem cells in all major cancer types in the June 10 special issue of 
Journal of Clinical Oncology [J Clin Oncol. 2008 26(17)].  
Amado RG, Wolf M, et al. Wild-type KRAS is required for panitumumab efficacy in patients 
with metastatic colorectal cancer. J Clin Oncol 26:1626-34, 2008. 
Bokemeyer C, Cutsem EV, et al. Addition of cetuximab to chemotherapy as first-line treatment 
for KRAS wild-type metastatic colorectal cancer: Pooled analysis of the CRYSTAL and OPUS 
randomised clinical trials. Eur J Cancer 48(10):1466-75, 2012. 
Brannath, W., Posch, M., Bauer, P. Recursive combination tests. Journal of the American 
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Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of two 
binomial proportions. Biometrics, 55:1201–1209. 
Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 17: 313-9, 2011. 
Cui, L., Hung, H.M., Wang, S.J. Modification of sample size in group-sequential clinical trials. 
Biometrics. 1999; 55: 853-857. 
Dmitrienko, A., Tamhane, A.C. Mixtures of multiple testing procedures for gatekeeping 
applications in clinical trials. Statistics in Medicine. 2011; 30: 1473-1488. 
Dmitrienko, A., Tamhane, A.C. General theory of mixture procedures for gatekeeping. 
Biometrical Journal. 2013; 55: 402-419. 
Dmitrienko, A., Kordzakhia, G., Brechenmacher, T. (2016). Mixture-based gatekeeping 
procedures for multiplicity problems with multiple sequences of hypotheses. Journal of 
Biopharmaceutical Statistics. 26, 758-780. 
Dmitrienko, A., Yuan, Y. Interim data monitoring. Analysis of Clinical Trials Using SAS: A 
Practical Guide (Second Edition). Dmitrienko, A., Koch, G.G. (editors). SAS Press: Cary, NC, 
2017. 
Du L, Wang H, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin 
Cancer Res. 14:6751-60, 2008. 
Eisenhauer E, Therasse P, et al. New response evaluation criteria in solid tumors: Revised 
RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. 
Grothey A, Van Cutsem E, Sobrero A et al. Regorafenib monotherapy for previously treated 
metastatic colorectal cancer (CORRECT): an international, multicenter, randomized, placebo-
controlled, phase 3 trial. Lancet 381(9863):303-312, 2013. 
Gupta PB, Chaffer CL, et al. Cancer stem cells: mirage or reality? Nat Med 15:1010-2, 2009. 
Gupta PB, Fillmore CM, et al. Stochastic state transitions give rise to phenotypic equilibrium in 
populations of cancer cells. Cell 146: 633-44, 2011. 
Hubbard JM, Jonker DJ, et al. A phase Ib study of BBI608 in combination with FOLFIRI with 
and without bevacizumab in patients with advanced colorectal cancer. J Clin Oncol 33 (suppl; 
abstr 3616), 2015. 

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Hubbard JM, O’Neil BH, et al. Phase Ib study of cancer stem cell pathway inhibitor BBI-608 
administered in combination with FOLFIRI with and without bevacizumab in patients with 
advanced colorectal cancer. (submitted abstract to GI ASCO 2015). 
Jennison, C., Turnbull, B.W. Group Sequential Methods with Applications to Clinical Trials. 
Boca Raton: Chapman and Hall, 2000. 
Jonker DJ, Nott L, Yoshino, T, et al. Napabucasin versus placebo in refractory advanced 
colorectal cancer: a randomized phase 3 trial. The Lancet Gastroenterology & Hepatology 
3:263-270, 2018.  
Karapetis CS, Khambata-Ford S, et al. K-ras mutations and benefit from cetuximab in advanced 
colorectal cancer. N Engl J Med 359:1757-65, 2008. 
Kemper K, Grandela C, et al. Molecular identification and targeting of colorectal cancer stem 
cells. Oncotarget 1:387-395, 2010. 
Kordzakhia, G., Dmitrienko, A., Ishida, E. Mixture-based gatekeeping procedures in adaptive 
clinical trials. Journal of Biopharmaceutical Statistics. 2018; 28: 129-145. 
Kordzakhia, G., Brechenmacher, T., Ishida, E., Dmitrienko, A., Zheng, W.W., Li, D.F. An 
enhanced mixture method for constructing gatekeeping procedures in clinical trials. Journal of 
Biopharmaceutical Statistics. 2018b; 28: 113-128. 
Levin TG, Powell AE, et al. Characterization of the intestinal cancer stem cell marker CD166 in 
the human and mouse gastrointestinal tract. Gastroenterology 139:2072-2082, 2010. 
Magirr D, Jaki T, Koenig F, Posch M. Sample size reassessment and hypothesis testing in 
adaptive survival trials. PLoS ONE 2016; 11(2): e0146465.  
Mehrotra, D., Raikar, R. “Minimum Risk Weights for Comparing Treatments in Stratified 
Binomial Trials”. Statistics in Medicine, 2000, 19, 811-825.   
Mayer R, Van Cutsem E., et al. Randomized trial of TAS-102 for refractory metastatic colorectal 
cancer. NEJM 372(20):1909-1919, 2015. 
Merlos-Suárez A, Barriga FM, et al. The intestinal stem cell signature identifies colorectal cancer 
stem cells and predicts disease relapse. Cell Stem Cell. 8:511-24, 2011. 
Millen B, Dmitrienko A, Ruberg S, Shen, L. A statistical framework for decision making in 
confirmatory multipopulation tailoring clinical trials. Drug Information Journal. 2012; 46:647-
656. 
Mokarram P, Albokashy M, Zarghooni M, et al. New frontiers in the treatment of colorectal 
cancer: Autophagy and the unfolded protein response as promising targets. Autophagy. 
2017;13(5):781-819 
Saunders M, and Iveson T. Management of advanced colorectal cancer: state of the art. Br J 
Cancer. 2006 Jul 17;95(2):131-8. 
Sarkar, S.K. On the Simes inequality and its generalization. Beyond Parametrics in 
Interdisciplinary Research: Festschrift in Honor of Professor Pranab K. Sen. Balakrishnan N, 
Pena EA, Silvapulle MJ (eds). Institute of Mathematical Statistics: Beachwood, Ohio. 2008; 
231-242. 

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Shen Y, Cai J. Sample size re-estimation for clinical trials with censored survival data. Journal of 
the American Statistical Association. 2003; 98: 418-426. 
Sugitani, T., Bretz, F., Maurer, W. (2016). A simple and flexible graphical approach for adaptive 
group-sequential clinical trials. Journal of Biopharmaceutical Statistics. 26, 202-216. 
Sugitani, T., Posch, M., Bretz, F., Koenig, F. (2018). Flexible alpha allocation strategies for 
confirmatory adaptive enrichment clinical trials with a prespecified subgroup. Statistics in 
Medicine. 2018; 37: 3387-3402. 
Tabernero J, Cohn AL, et al. RAISE: A randomized, double-blind, multi-center phase III study 
of irinotecan, folinic acid, and 5-flourouracil (FOLFIRI) plus ramucirumab (RAM) or placebo 
(PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or 
following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a 
fluoropyrimidne (fp). J Clin Oncol 33: suppl 3; abstr 512, 2015. 
Tol J, and Punt CJ. Monoclonal antibodies in the treatment of metastatic colorectal cancer: a 
review. Clin Ther. 2010 Mar;32(3):437-53. 
Van Cutsem E, Tabernero J, et al. Addition of Aflibercept to Fluorouracil, Leucovorin, and 
Irinotecan improves survival in a Phase III randomized trial in patients with metastatic 
colorectal cancer previously treated with an Oxaliplatin-based regimen. J Clin Oncol 
30(28):3499-3506, 2012. 
Van Cutsem E, Tabernero J, et al. Intravenous (IV) aflibercept versus placebo in combination 
with irinotecan/5-FU (FOLFIRI) for second line treatment of metastatic colorectal cancer 
(mCRC): results of a multinational phase III trial (EFC10262-VELOUR). Ann Oncol 2011 22: 
v18 (abstract O-0024) 
Wassmer, G. Planning and analyzing adaptive group sequential survival trials. Biometrical 
Journal. 2006; 48:714-729. 
Welch S, Spithoff K, et al. Bevacizumab combined with chemotherapy for patients with 
advanced colorectal cancer: a systematic review. Ann Oncol. 2010 Jun;21(6):1152-62. 
Xiong H, Zhang ZG, Tian XQ, et al. Inhibition of JAK1, 2/STAT3 signaling induces apoptosis, 
cell cycle arrest, and reduces tumor cell invasion in colorectal cancer cells. Neoplasia. 
2008;10:287–297. 
 

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APPENDIX 1. PATIENT EVALUATION FLOW SHEET FOR ARM 1 (BBI-608 IN 
COMBINATION WITH FOLFIRI) 
Tests & Procedures 
Pre-Treatment 
During Protocol Treatment 
After Protocol Treatment 
Discontinuation  
(+/- 3 days) 
Run-in 1 
Cycle 1 
Additional Cycles 
(+/- 3 days) 
Day 
1 
2 
1 
1 
Timing 
≤14 days prior to 
randomization 
 
 
 
 
4 weeks post 
protocol 
treatment 
Every 8 
weeks 
thereafter15 
History2 and Physical Exam 
X 
 
 
X 
X 
X 
 
ECOG PS 
X 
 
 
X 
X 
X 
 
Weight 
X 
 
 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
Vital signs 
X 
 
 
X 
X 
X 
 
FOLFIRI Infusion3 
 
 
 
X 
X 
 
 
Begin BBI-608 administration 
 
X 
 
 
 
 
 
Hematology4 
X 
 
 
X 
X 
X 
 
Biochemistry4 
X 
 
 
X 
X 
X 
 
Urinalysis4 
X 
 
 
X 
X 
X 
 
ECG (12-lead) 
X 
 
 
X 
 
X 
 
Radiology and Imaging5 
X 
Every 8 weeks for 6 months and every 12 weeks thereafter until progressive disease is 
documented. 
Submission of representative block of 
diagnostic tumor tissue 
before or after randomization 
Blood collection for correlative 
studies6,7 
X 
 
 
 
X 
 
 

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Tests & Procedures 
Pre-Treatment 
During Protocol Treatment 
After Protocol Treatment 
Discontinuation  
(+/- 3 days) 
Run-in 1 
Cycle 1 
Additional Cycles 
(+/- 3 days) 
Day 
1 
2 
1 
1 
Blood collection for sparse PK analysis 
 
 
 
 
X 
 
 
Pregnancy test, serum or urine (if 
applicable)8,9 
X 
 
 
 
X 
X 
 
Adverse Event assessment10,11 
X 
X 
X11 
X 
X 
X 
X14 
Quality of Life assessment (EORTC 
QLQ-C30)12 
X 
 
 
 
X 
X13 
 
Assessment for survival of patient 
 
 
 
 
 
X16 
X16 
1 BBI-608 administration will begin 2 days prior to the FOLFIRI infusion on day 1 of cycle 1. These two days are referred to as run-in day 1 and run-in day 2. 
The run-in day period may be extended by up to 3 additional calendar days. Run-in day 1 should occur within 2 calendar days of patient randomization on 
study Arm 1. 
2 Medical history must include date of diagnosis including histological documentation of malignancy, documentation of RAS status of tumor, prior anticancer 
therapy and prior date(s) of disease progression.  
3 FOLFIRI 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). Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, will be permissible. 
4 Laboratory investigations should be performed within 3 days prior to FOLFIRI administration on Day 1 of every 14-day Cycle of protocol treatment or within 
3 days prior to each FOLFIRI infusion. Laboratory testing performed as part of standard of care prior to patient signature of the study consent will be 
acceptable as baseline lab work as long as testing is performed ≤ 14 days prior to randomization. Laboratory testing performed as part of pre-treatment 
assessments within 3 days of Cycle 1 Day 1 will be acceptable as Cycle 1 Day 1 lab work and will not need to be repeated. 
5 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 9). 
For patients who remain on protocol therapy after objective disease progression has been documented, no further imaging assessments are mandated, but where 
these occur as a component of care, tumor measurements and assessment must be reported. Tumor assessments should be obtained within +/- 5 days of protocol 
specified schedule. Qualifying scans performed as part of standard of care prior to patient signature of the study informed consent will be acceptable as baseline 
scanning as long as scanning is performed ≤ 21 days prior to randomization.  
6 Sample collections should be performed at baseline and at Day 1 of Cycle 3 after randomization. 
7 A sample will be collected following protocol treatment discontinuation if discontinuation occurs prior to 4 weeks of therapy.  
8 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. 
9 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. 

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10 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see Appendix 4). Following 
permanent protocol treatment discontinuation, patients will be assessed for any protocol treatment related adverse events every 8 weeks, starting with the 4-week post-protocol 
treatment discontinuation visit. 
11 Adverse event assessments by phone should be performed on run-in day 2. 
12 To be completed in clinic. Questionnaires should be completed at baseline and at Day 1 of Cycle 3, Day 1 of Cycle 5, Day 1 of Cycle 7, Day 1 of Cycle 9 and 
Day 1 of Cycle 13 (+/- 3 days) 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. 
13 EORTC QLQ-C30 questionnaires will be collected in the post-protocol discontinuation period only if the patient discontinues protocol treatment prior to 24 
weeks of therapy and has an ECOG PS of less than 4 and has not been hospitalized for end of life care. 
14 These assessments may occur within a ±7-day window, and 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. Medical history at post-progression follow up must include post-
protocol treatment cancer therapies. 
15 After the first visit at which the patient has been off protocol treatment for 4 weeks, patients will be assessed for survival every 8 weeks until deterioration to 
ECOG PS 4 or hospitalization for end of life care 
16 In the event that the patient is unable to attend clinic, post-progression follow-up for survival may be by means of telephone contact 

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APPENDIX 2. PATIENT EVALUATION FLOW SHEET FOR ARM 2 (FOLFIRI) 
Tests & Procedures 
Pre-Treatment 
During Protocol Treatment 
After Protocol Treatment 
Discontinuation  
(± 3 days) 
Cycle 1 
Additional Cycles  
(± 3 days) 
Day 
1 
1 
Timing 
≤14 days prior to 
randomization 
 
 
4 weeks post 
protocol 
treatment 
Every 8 
weeks 
thereafter13 
History1 and Physical Exam 
X 
X 
X 
X 
 
ECOG PS 
X 
X 
X 
X 
 
Weight 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
Vital signs 
X 
X 
X 
X 
 
FOLFIRI Infusion2 
 
X 
X 
 
 
Hematology3 
X 
X 
X 
X 
 
Biochemistry3 
X 
X 
X 
X 
 
Urinalysis3 
X 
X 
X 
X 
 
ECG (12-lead) 
X 
X 
 
X 
 
Radiology and Imaging4 
X 
Every 8 weeks for 6 months and every 12 weeks thereafter until progressive disease is 
documented. 
Submission of representative block of 
diagnostic tumor tissue 
before or after randomization 
Blood collection for correlative studies5,6 
X 
 
X 
 
 
Pregnancy test, serum or urine (if 
applicable)7,8 
X 
 
X 
X 
 
Adverse Event assessment9 
X 
X 
X 
X 
X12 

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Tests & Procedures 
Pre-Treatment 
During Protocol Treatment 
After Protocol Treatment 
Discontinuation  
(± 3 days) 
Cycle 1 
Additional Cycles  
(± 3 days) 
Day 
1 
1 
Quality of Life assessment (EORTC 
QLQ-C30)10 
X 
 
X 
X11 
 
Assessment for survival of patient 
 
 
 
X14 
X14 
1 Medical history must include date of diagnosis including histological documentation of malignancy, documentation of RAS status of tumor, prior anticancer 
therapy and prior date(s) of disease progression.  
2 FOLFIRI administration should begin within 7 calendar days of randomization and proceed according to institutional standard practice (with respect to pre-
treatment laboratory evaluation, clinical assessment, pre-medication, and monitoring during and after infusion). Addition of bevacizumab to the FOLFIRI 
regimen, per Investigator choice, will be permissible. 
3 Laboratory investigations should be performed within 3 days prior to FOLFIRI administration on Day 1 of every 14-day study Cycle of protocol treatment or 
within 3 days prior to each FOLFIRI infusion. Laboratory testing performed as part of standard of care prior to patient signature of the study consent will be acceptable as 
baseline lab work as long as testing is performed ≤ 14 days prior to randomization. Laboratory testing performed as part of pre-treatment assessments within 3 days of 
Cycle 1 Day 1 will be acceptable as Cycle 1 Day 1 lab work and will not need to be repeated. 
4 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 9). 
Qualifying scans performed as part of standard of care prior to patient signature of the study informed consent will be acceptable as baseline scanning as long 
as scanning is performed ≤ 21 days prior to randomization.  
5 Sample collections should be performed at baseline and at Day 1 of Cycle 3 after randomization. 
6 A sample will be collected following protocol treatment discontinuation if discontinuation occurs prior to 4 weeks of therapy. 
7 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. 
8 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. 
9 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 (see Appendix 4). Following 
permanent protocol treatment discontinuation, patients will be assessed for any protocol treatment related adverse events every 8 weeks, starting with the 4-week post-protocol 
treatment discontinuation visit. 
10 To be completed in clinic. Questionnaires should be completed at baseline and At Day 1 of Cycle 3, Day 1 of Cycle 5, Day 1 of Cycle 7, Day 1 of Cycle 9 and 
Day 1 of Cycle 13 (+/- 3 days) 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. 
11 EORTC QLQ-C30 questionnaires 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. 
12 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. Medical history at post-progression follow up must include post-protocol treatment cancer therapies. 

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13 These assessments may occur within a ±7-day window, and after the first visit at which the patient has been off protocol treatment for 4 weeks, patients will 
be assessed for survival every 8 weeks until deterioration to ECOG PS 4 or hospitalization for end of life care.  
14 In the event that the patient is unable to attend clinic, post-progression follow-up for survival may be by means of telephone contact 

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APPENDIX 3. 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 4. 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 5. 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; 2 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. 
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 appropriate case report form. If the whole questionnaire has not been completed, 
please document the reason(s) on the appropriate case report forms. 
Pre-treatment Assessment 
It should be explained to the patient that the purpose of the questionnaire is to assess the impact 
of treatment on different areas of the patient's life, e.g.: psychological distress, social disruption, 
side-effects, et cetera. 
Study staff should collect the questionnaire as soon as it has been completed, check to see that 
each question has been answered and gently remind the patient to answer any inadvertently 
omitted questions. If a patient states that s/he prefers not to answer some questions and gives a 
reason(s), the reason(s) should be noted on the questionnaire by the patient. If a specific reason is 
not given, this also should be noted on the questionnaire by the patient. 
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. 
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: 
x 4, 8, 12, 16 and 24 weeks or until deterioration to ECOG PS 4 or hospitalization for end of 
life care  
x 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!  
x 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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 The patient leaves the clinic before the questionnaire could be administered, or someone 
forgets to give the questionnaire to the patient.  
x 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. 
x 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.  
x 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.  
 

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European Organization for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire 
We are interested in some things about you and your health. Please answer all of the questions 
yourself by circling the number that best applies to you. There are no "right" or "wrong" 
answers. The information that you provide will remain strictly confidential. 
During the Last Week: 
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 
 
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 
 
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 
 

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During the Last Week: 
Not  
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
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 
 
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 
 

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During the Last Week: 
Not  
At All 
A 
Little 
Quite 
a Bit 
Very 
Much 
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 6. DECISION RULES AND MULTIPLICITY 
CONTROL PROCEDURE FOR ADAPTIVE DESIGN 
To address multiplicity induced by the analysis of several endpoints (primary and key secondary 
endpoints) at several decision points (interim and final analyses) in several patient populations 
(General Population and STAT3(+) Subpopulation), a multiplicity adjustment will be utilized to 
control the overall Type I error rate (familywise error rate) in this trial in the strong sense at a 
1-sided D=0.025. This multiplicity adjustment is constructed by applying the closed testing 
principle in conjunction with the combination function approach. The key components of the 
multiplicity adjustment are defined below and a detailed description of this multiplicity 
adjustment will be provided in the SAP. 
Hochberg-based Gatekeeping Procedure 
The first component of the multiplicity adjustment that accounts for the first 2 sources of 
multiplicity (analysis of several endpoints in several patient populations) relies on a Hochberg-
based gatekeeping procedure. This procedure is defined using the mixture-based approach 
developed in Dmitrienko and Tamhane [2011, 2013] and later enhanced in Kordzakhia et al. 
[2018b]. This gatekeeping procedure will be applied to the 8 null hypotheses of no effect based 
on the 4 endpoints that are evaluated in the 2 patient populations:  
x Family 1: Hypothesis H10 (null hypothesis of no OS effect in the General Population) and 
Hypothesis H20 (null hypothesis of no OS effect in the pSTAT3(+) Subpopulation). 
x Family 2: Hypothesis H30 (null hypothesis of no PFS effect in the General Population) and 
Hypothesis H40 (null hypothesis of no PFS effect in the pSTAT3(+) Subpopulation). 
x Family 3: Hypothesis H50 (null hypothesis of no DCR effect in the General Population) and 
Hypothesis H60 (null hypothesis of no DCR effect in the pSTAT3(+) Subpopulation). 
x Family 4: Hypothesis H70 (null hypothesis of no ORR effect in the General Population) and 
Hypothesis H80 (null hypothesis of no ORR effect in the pSTAT3(+) Subpopulation). 
The hypotheses will be organized into 2 branches (i.e. the null hypotheses in the General 
Population [H10, H30, H50 and H70] and the null hypotheses in the pSTAT3(+) Subpopulation 
[H20, H40, H60 and H80]), and tested sequentially within each branch.  
Key features of the Hochberg-based gatekeeping procedure include: 
x The gatekeeping procedure accounts for the clinically relevant logical restrictions (i.e. for the 
fact that the null hypotheses are organized into branches and tested sequentially within each 
branch).  
x The gatekeeping procedure utilizes powerful Hochberg-type tests (regular and truncated 
Hochberg tests) for testing the hypotheses within each family. These tests account for 
positive correlations between the test statistics within each family, which is induced by the 
fact that the pSTAT3(+) Subpopulation is nested within the General Population. The regular 
and truncated Hochberg tests control the Type I error rate within each family since if the test 
statistics within each family follow a bivariate normal distribution with a non-negative 
pairwise correlation (Sarkar [2008]).   

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x The gatekeeping procedure uses truncated Hochberg tests in the first 3 families because they 
serve as gatekeepers for other families. The regular Hochberg test is applied in Family 4 
since it is the last family in the sequence. The truncated Hochberg tests used in Families 1, 2, 
and 3 will be defined using a pre-specified truncation parameter J=0.8.      
To define the regular and truncated Hochberg tests, consider, for example, Family 1 which 
includes the hypotheses H10 and H20. Let p1 and p2 denote the corresponding 1-sided p-values 
and let p(1) < p(2) denote the ordered p-values. Finally, let D1 denote the 1-sided significance level 
applied within this family (D1 may not be equal to D=0.025). The regular Hochberg test relies on 
the following 2-step testing algorithm: 
x Step 1: The test rejects both H10 and H20 if p(2) ≤ D1. 
x Step 2: If p(2) >D1, the test rejects the hypothesis corresponding to the smaller p-value if p(1) 
≤D1/2. 
The truncated Hochberg test utilizes the following 2-step testing algorithm: 
x Step 1: The test rejects both H10 and H20 if p(2) ≤ (J+(1-J)/2)D1. 
x Step 2: If p(2) > (J+(1-J)/2)D1, the test rejects the hypothesis corresponding to the smaller p-
value if p(1) ≤ D1/2. 
Interim Analysis Decision Rules 
This section defines the decision rules that will be applied at the interim analysis. 
Futility Stopping and Patient Population Selection Rules 
The 2 decision rules will be applied simultaneously based on the observed hazard ratios: 
x 
ܪܴ଴: Hazard ratio in the General Population 
x 
ܪܴା: Hazard ratio in the pSTAT3(+) Subpopulation 
x 
ܪܴି: Hazard ratio in the pSTAT3(-) Subpopulation 
The resulting decision rules are defined as follows using appropriate values of the thresholds 
denoted by c1 through c4: 
x Case 1: If Condition 1 (ܪܴା > c1) is met and Condition 2 (ܪܴ଴ > c2) is met, terminate the trial 
at the interim analysis due to lack of efficacy 
x Case 2: If Condition 1 (ܪܴା > c1) is met and Condition 2 (ܪܴ଴> c2) is not met, continue the 
trial and perform the final analysis in the General Population only 
x Case 3: If Condition 1 (ܪܴା > c1) is not met and Condition 3 (ܪܴି > c3) is met: Continue the 
trial and perform the final analysis in the pSTAT3+ Subpopulation only 
x Case 4: If Condition 1 (ܪܴା > c1) is not met, Condition 3 (ܪܴି > c3) is not met and Condition 
4 (ܪܴା/HR- > c4) is met: Continue the trial and perform the final analysis in the General 
Population only 

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x Case 5: If Condition 1 (ܪܴା > c1) is not met, Condition 3 (ܪܴି > c3) is not met and Condition 
4 (ܪܴା/ܪܴି > c4) is not met: Continue the trial and perform the final analysis in the General 
Population as well as the pSTAT3(+) Subpopulation.  
Here c1= c2= c3=1 in the Conditions 1 to 3 and c4= 0.9 for the Condition 4.  
These patient population selection rules are based on the influence and interaction conditions 
introduced in Millen 2012. 
Event Count Adjustment Rule 
Within each patient population (the General Population or the pSTAT3(+) Subpopulation), 
conditional power (CP) is defined as the probability of establishing a significant OS effect at the 
final analysis conditional upon the interim analysis data at a 1-sided D=0.025. Conditional power 
is computed within each patient population using the population-specific hazard ratio observed at 
the interim analysis before an event count adjustment. A closed-form expression for conditional 
power [Dmitrienko 2017] is given below:   
 
 
 ൌʣ ቌඨ
ݒଵ
ݒଶ
ܼ൅ߠට݉ଶെ݉ଵ
Ͷ
െܿ
ξݒଶ
ቍ
 
where 
 
Z is the 1-sided log-rank test statistic [Jennison and Turnbull, 2000] computed at the interim 
analysis within the selected patient population and c = 1.96 is the significance level to be applied 
at the final analysis. m1 and m2 denote the number of OS events at the interim analysis and at the 
original final analysis. θ is the observed effect size (log-hazard ratio) at the interim analysis.  
The event count adjustment rule will be defined by identifying an optimal balance between the 
competing goals of increasing conditional power and reducing the number of events. The 
resulting approach leads to an event count adjustment rule that minimizes the average number of 
events within each patient population. The event count adjustment may also consider other 
factors including potential clinical benefits and operational feasibility. 
If the final analysis is performed in the General Population as well as the pSTAT3(+) 
Subpopulation, the target number of events in the trial will be determined by the number of 
events in the General Population or the pSTAT3(+) Subpopulation whichever comes last. 
Adaptive Design 
A multi-stage adaptive design will be utilized in this Phase 3 trial. The decision rules employed 
in the adaptive design will be applied along with the gatekeeping procedure defined earlier in 
this section using the combination function approach [Cui 1999 and Brannath 2002]. The 
combination function approach will be applied using the weighted inverse-normal combination 
function to address the third source of multiplicity (evaluation of the treatment effect at several 
decision points). The joint application of the combination function approach and gatekeeping 
v1 m1
m2
, v2 m2 m1
m2
,

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procedure relies on ideas presented in Sugitani, Bretz and Maurer [2016], Kordzakhia et al 
[2018a], and Sugitani et al. [2018]. 
Combination Function Approach for General Population 
For the General Population, the combination function approach remains the same as previous version of 
protocol.  The test statistics for evaluating the significance of the treatment effect or p-values will 
be computed from the data collected up to the interim analysis (Stage 1) and after the interim 
analysis (Stage 2). The stage-wise p-values for the primary endpoint (OS) will be obtained from 
the increments of the log-rank test statistics using the general approach developed in Shen and 
Cai [2003] and Wassmer [2006]. The increments of the log-rank test statistics that correspond to 
the 2 trial stages are defined as follows: 
 
 
ܼଵଵ
כ ൌܼଵଵǡ ܼଶଵ
כ ൌඥ݇ଶଵܼଶଵെඥ݇ଵଵܼଵଵ
ඥ݇ଶଵെ݇ଵଵ
 
(1) 
 
x ܼଵଵ and ܼଶଵ, the 1-sided log-rank test statistic [Jennison and Turnbull, 2000] at the interim 
analysis and final analysis for the General Population.   
x ݇ଵଵ and ݇ଶଵ:  the number of events at the interim analysis and final analysis for the General 
Population.   
The 1-sided stage-wise p-values referred as the Stage 1 and Stage 2 p-values for testing the null 
hypothesis ܪଵ଴, will be computed from these log-rank test statistics as  
 
 
݌ଵൌͳ െʣሺܼଵଵ
כ ሻǡ ݍଵൌͳ െʣሺܼଶଵ
כ ሻ 
(2) 
where )(x) denotes the cumulative distribution function of the standard normal distribution.  
The two stage-wise test statistics are independent of each other under the null hypothesis of no treatment 
effect of ܪଵ଴ and thus the final treatment effect p-value can be found by combining the stage-wise p-values, 
i.e., 
 
ݏଵൌܿଶሺ݌ଵǡ ݍଵሻൌͳ െʣ ቀඥݓଵʣିଵሺͳ െ݌ଵሻ൅ඥͳ െݓଵʣିଵሺͳ െݍଵሻቁ 
(3) 
where ݓଵ and ͳ െݓଵ are the pre-defined stage weights assigned to Stages 1 and 2 for the null hypothesis 
ܪଵ଴.   
Combination Function Approach for pSTAT3(+) Subpopulation 
At the interim analysis, based on preliminary assessments of the ongoing CSS study, patients 
with specimens that were within the stability window of 6 months are included for pSTAT3 
subpopulations designations.  Due to the availability of additional patients with pSTAT3 results 
within the final CSS window [See Section 9.1.7  for detailed explanations], the test statistics at 
the final analysis for the primary and the key secondary endpoints in the pSTAT3(+) 
subpopulation will be computed across two subsets of patients data, i.e., Subset 1 of the patients 

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with pSTAT3 positive status within specimen age up to 6-months (including both Stage 1 pre-
interim analysis data and Stage 2 post- interim analysis data), and Subset 2 (Stage 3) of patients 
with pSTAT3 positive status with specimen age for longer than 6 months and but within the final 
CSS window.  Figure 3 presents the data that will be used for the primary and the key secondary 
endpoints in the pSTAT3(+) Subpopulation at the final analysis.  
Figure 3: 
Data in Final Analysis of the pSTAT3(+) Subpopulation 
 
Subset 2 data may also be treated as Stage 3 data for the pSTAT3(+) subpopulation 
For the pSTAT3(+) subpopulation, the statistics test for evaluating the significance of the 
treatment effect or the corresponding p-values in terms of overall survival (OS) at the final 
analysis will be computed from the following three stages of data from the two subsets of 
patients defined above.  The three stages of data are:  
x Stage 1 (Subset 1 Stage 1) Data: OS data collected up to the interim analysis from Subset 
1. 
x Stage 2 (Subset 1 Stage 2) Data: OS data collected after the interim analysis from Subset 
1. 
x Stage 3 (Subset 2) Data: OS event data from Subset 2. 
The final treatment effect p-value for the null hypothesis of OS in the pSTAT3(+) subpopulation 
can be computed by combining the stage-wise p-values from the three parts of the data.   
Since Subset 1 and Subset 2 are two mutually exclusive sets of patients, Subset 2 data may also 
be treated as Stage 3 data for the pSTAT3(+) subpopulation to describe multi-stage combination 
function approach.   
Subset 1 Stage 1 and Stage 2 p-values for the primary endpoint (OS) in the pSTAT3(+) subpopulation will 
be obtained from the increments of the log-rank test statistics in a similar fashion as conducted for the 
General Population:  
 
ܼଵଶ
כ ൌܼଵଶǡ ܼଶଶ
כ ൌඥ݇ଶଶܼଶଶെඥ݇ଵଶܼଵଶ
ඥ݇ଶଶെ݇ଵଶ
 
(4) 
x ܼଵଶ and ܼଶଶ are the 1-sided log-rank test statistic at the interim analysis and final analysis for 
the pSTAT3(+) subpopulation with specimen age up to the 6-month stability window (Subset 
1).   

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x ݇ଵଶ and ݇ଶଶ: the number of events at the interim analysis and final analysis for the 
pSTAT3(+) subpopulation with specimen age up to the 6-month stability window (Subset 1).   
Furthermore, let ܼଷଶ
כ  denote the 1-sided log-rank test statistic for the pSTAT3(+) subpopulation in Subset 
2.  To ensure the test statistic ܼଷଶ
כ  be independent of the stage wise test statistics ܼଵଶ
כ  and ܼଶଶ
כ  under the null 
hypothesis of no treatment effect (Magirr et al., 2016), the test statistic ܼଷଶ
כ  needs to be computed based on 
the data available by the analysis cutoff date (a pre-determined calendar date) for Subset 2 (See 
Section 9.1.7  for details of the analysis cut dates).   
The stage-wise p-values for the pSTAT3(+) subpopulation are defined as follows: 
 
݌ଶൌͳ െʣሺܼଵଶ
כ ሻǡ ݍଶൌͳ െʣሺܼଶଶ
כ ሻǡ ݎଶൌͳ െʣሺܼଷଶ
כ ሻǤ 
(5) 
As stated above, since the length of the patient follow-up period is pre-defined in Subset 2, the test statistic 
ܼଷଶ
כ  is independent of the stage wise test statistics ܼଵଶ
כ  and ܼଶଶ
כ  under the null hypothesis of no treatment 
effect.  As a result, the final treatment effect p-value for the null hypothesis ܪଶ଴ can be computed by 
combining the stage-wise p-values, i.e., 
 
ݏଶൌܿଷሺ݌ଶǡ ݍଶǡ ݎଶሻ 
ൌͳ െʣ ቀξݒଶξݓଶʣିଵሺͳ െ݌ଶሻ൅ξݒଶඥͳ െݓଶʣିଵሺͳ െݍଶሻ൅ඥͳ െݒଶʣିଵሺͳ െݎଶሻቁ  
(6) 
where ݓଶ and ͳ െݓଶ are the pre-defined weights assigned to Stages 1 and 2 and, in addition, ݒଶ and ͳ െݒଶ 
are the pre-defined weights assigned to Stages 1+2 and 3 for the null hypothesis ܪଶ଴.  
Combination Function Approach for Key Secondary Endpoints 
The stage-wise test statistics for PFS are defined in the same manner. To define the stage-wise 
test statistics for DCR and ORR, the log-rank test needs to be replaced by the Z test for 
proportions and the number of events need to be replaced by the numbers of patients. The 
1-sided stage-wise p-values for PFS, DCR, and ORR are defined as follows: 
x Hypothesis H30: Let p3 and q3 denote the 1-sided p-values computed from the null 
distributions of the stage-wise test statistics (Stage 1 and 2) for PFS in the General 
Population. 
x Hypothesis H40: Let p4 and q4 and ݎସ denote the 1-sided p-values computed from the null 
distributions of the stage-wise test statistics (Subset 1 Stage 1, 2 and Subset 2) for PFS in the 
pSTAT3(+) Subpopulation. 
x Hypothesis H50: Let p5 and q5 denote the 1-sided p-values computed from the null 
distributions of the stage-wise test statistics (Stage 1 and 2) for DCR in the General 
Population. 
x Hypothesis H60: Let p6 and q6 and ݎ଺denote the 1-sided p-values computed from the null 
distributions of the stage-wise test statistics (Subset Stage 1, 2 and Subset 2) for DCR in the 
pSTAT3(+) Subpopulation. 
x Hypothesis H70: Let p7 and q7 denote the 1-sided p-values computed from the null 
distributions of the stage-wise test statistics (Stage 1 and 2) for ORR in the General 
Population. 

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Hypothesis H80: Let p8 and q8 and ݎ଼denote the 1-sided p-values computed from the null 
distributions of the stage-wise test statistics (Subset Stage 1, 2 and Subset 2) for ORR in the 
pSTAT3(+) Subpopulation.To apply the combination function principle, the stage-wise p-values 
for OS, PFS, DCR, and ORR will be combined using an appropriately defined weighted inverse-
normal combination function.  
The inferences for the 8 hypotheses corresponding to OS, PFS, DCR, and ORR will be 
performed at the final analysis using the composite p-values that are defined as follows: 
x Hypothesis H10: The composite p-value is defined asݏଵൌܿଶሺ݌ଵǡ ݍଵሻ. 
x Hypothesis H20: The composite p-value is defined as  ݏଶൌܿଷሺ݌ଶǡ ݍଶǡ ݎଶሻǤ 
x Hypothesis H30: The composite p-value is defined asݏଷൌܿଶሺ݌ଷǡ ݍଷሻ. 
x Hypothesis H40: The composite p-value is defined as ݏସൌܿଷሺ݌ସǡ ݍସǡ ݎସሻǤ 
x Hypothesis H50: The composite p-value is defined asݏହൌܿଶሺ݌ହǡ ݍହሻ. 
x Hypothesis H60: The composite p-value is defined asݏ଺ൌܿଷሺ݌଺ǡ ݍ଺ǡ ݎ଺ሻ. 
x Hypothesis H70: The composite p-value is defined asݏ଻ൌܿଶሺ݌଻ǡ ݍ଻ሻ. 
x Hypothesis H80: The composite p-value is defined as ݏ଼ൌܿଷሺ݌଼ǡ ݍ଼ǡ ݎ଼ሻ 
If the interim analysis outcome will be the treatment effect is evaluated only in the General 
Population at the final analysis and thus the hypotheses H20, H40, H60 and H80 are dropped after 
the interim analysis, the corresponding Stage 2 and Stage 3 (Subset 2) p-values (i.e. q2, q4, q6, q8, 
r2, r4, r6 and r8) , will be set to 1. Similarly, if the treatment effect is evaluated only in the 
pSTAT3(+) subpopulation at the final analysis and thus the hypotheses H10, H30, H50 and H70 are 
dropped after the interim analysis, the corresponding Stage 2 p-values (i.e., q1, q3, q5 and q7), will 
be set to 1.  
Finally, to compute the multiplicity adjusted p-values for the hypotheses of interest at the final 
analysis, a closed family associated with these null hypotheses needs to be introduced. The 
closed family contains 28 - 1= 255 intersections. Let H(I) denote an arbitrary intersection 
hypothesis from the closed family, which is associated with the index set I. A local p-value, also 
known as the intersection p-value, will be computed for the intersection hypothesis H(I) as 
shown below using the composite p-values defined above (i.e. s1 through s8). 
To ensure that the final gatekeeping procedure is consistent with the logical relationships among 
the null hypotheses, the corresponding restrictions need to be imposed on the hypotheses within 
each intersection. These restrictions ensure, for example, that the hypothesis H30 cannot be 
rejected if the hypothesis H10 is not rejected. Let I* denote the restricted index set which accounts 
for the logical relationships among the null hypotheses for the intersection hypothesis H(I). It is 
easy to show that, for any intersection hypothesis H(I) in the closed family, there can be at most 
two indices left in the restricted index set I* and therefore it is sufficient to consider the following 
2 cases: 
Case 1. Suppose that there are 2 indices in the restricted index set I* that are denoted by i and j, 
i.e., I* = {i, j}. If the corresponding hypotheses are included in the same family, the local p-value 
for this intersection hypothesis is given by: 

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݌ሺܫሻൌሺʹݏሺ௜ሻǡ ݏሺ௝ሻሻ 
(7) 
where s(i) and s(j) denote the ordered p-values, i.e., s(i) < s(j). If the corresponding hypotheses are 
included in 2 different families and the index i corresponds to the more important family, the 
local p-value for this intersection hypothesis is given by: 
 
 
݌ሺܫሻൌʹሺݏ௜Ȁሺͳ ൅ߛሻǡ ݏ௝Ȁሺͳ െߛሻሻ.  
(8) 
 
Case 2. Suppose that there is only 1 index in the restricted index set I*, denoted by i, i.e., I* = {i}. 
In this case, the local p-value for the intersection hypothesis is simply given by: 
 
 
݌ሺܫሻൌݏ௜ 
(9) 
 
The resulting intersection p-values will be utilized for computing the multiplicity-adjusted 
p-values for the 8 null hypotheses at the final analysis. Per communication from FDA on July 23, 
2019 , it was suggested to sponsor to introduce a small penalty for the interim analysis because 
of the unblinded analysis of the efficacy data even though the interim analysis were not to stop 
for efficacy. Therefore, a small penalty for the interim analysis (1-sided alpha of 0.0001) is 
introduced here and  a null hypothesis will be rejected if the intersection p-values for all 
intersection hypotheses containing this particular null hypothesis are less than or equal to a 1-
sided D=0.0249. 
A detailed description of the computation of the intersection p-values will be provided in the 
SAP. 
The proposed decision rules in the adaptive design ensure overall Type I error rate control with 
respect to the primary and key secondary endpoints. The Type I error rate control is maintained 
even if the target number of events is increased or a decision to restrict the patient enrollment to 
the subpopulation of pSTAT3(+) patients is made at the interim analysis.