Clinical trial NCT02753127
Conditions: Colorectal Cancer
Keywords: Colorectal Neoplasms Colonic Diseases Digestive System Diseases Digestive System Neoplasms Gastrointestinal Diseases Gastrointestinal Neoplasms Intestinal Diseases Intestinal Neoplasms Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Glandular and Epithelial Rectal Diseases
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2016-06-01; Completion date: 2021-05-12
Enrollment: 1253 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an international multi-center, prospective, open-label, randomized, adaptive design phase 3 trial of the cancer stem cell pathway inhibitor napabucasin plus standard bi-weekly FOLFIRI versus standard bi-weekly FOLFIRI in patients with previously treated metastatic colorectal cancer (CRC).

Detailed description:

Arms: arm 1: Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will start at least 2 hours following the first daily dose of napabucasin and will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m\^2 together with leucovorin 400 mg/m\^2 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 napabucasin if bevacizumab is not administered. 5-FU 400 mg/m\^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m\^2/day (total 2400 mg/m\^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle. arm 2: Addition of bevacizumab to the FOLFIRI regimen will be permissible. FOLFIRI chemotherapy infusion will be administered every 2 weeks. Irinotecan/leucovorin infusion will follow bevacizumab infusion in selected patients to receive standard dose of bevacizumab (5 mg/kg). Irinotecan 180 mg/m\^2 together with leucovorin 400 mg/m\^2 will be administered intravenously, over approximately 90 minutes and 2 hours, respectively, starting on Day 1 of Cycle 1, following bevacizumab infusion. 5-FU 400 mg/m\^2 bolus will be administered intravenously immediately following irinotecan/leucovorin infusion, followed by 5-FU 1200 mg/m\^2/day (total 2400 mg/m\^2) continuous infusion. This regimen will be repeated on Day 1 of every 14 day cycle.
Interventions: intervention 1: Napabucasin intervention 2: Fluorouracil intervention 3: Leucovorin intervention 4: Irinotecan intervention 5: Bevacizumab
Intervention descriptions: intervention 1: Napabucasin 240 mg will be administered orally, twice daily, with doses separated by approximately 12 hours (480 mg total daily dose). intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
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) 
                   Amendment Date: 25 October 2019 
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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 


Study CanStem303C (Protocol Amendment 7.0) 
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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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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 


Study CanStem303C (Protocol Amendment 7.0) 
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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 


Study CanStem303C (Protocol Amendment 7.0) 
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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) 


Study CanStem303C (Protocol Amendment 7.0) 
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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.  


Study CanStem303C (Protocol Amendment 7.0) 
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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. 


Study CanStem303C (Protocol Amendment 7.0) 
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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: 


Study CanStem303C (Protocol Amendment 6.0) 
                   Amendment Date: 25 September 2018 
CONFIDENTIAL 
104 
 
 
݌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. 

SAP_001.pdf: 
Sumitomo Dainippon Pharma Oncology, Inc.                                     Protocol No:  CanStem303C 
Statistical Analysis Plan – Version 3.0 
 
 
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TITLE PAGE 
 
STATISTICAL ANALYSIS PLAN 
 
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) 
 
VERSION: 3.0 
DATE: December 15, 2020 
 
STUDY DRUG: BBI-608 (aka BBI608, napabucasin)  
 
PROTOCOL NUMBER: CanStem303C (aka BB608-303CRC) 
 
SPONSOR: 
 Sumitomo Dainippon Pharma Oncology, Inc 
640 Memorial Drive 
Cambridge, MA 02139, USA 
Telephone: +1.617.674.6800 
 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 
 
 


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SIGNATURE PAGE 
 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Author: 
 
_________________________________________Date:  _____/_____/_________ 
Bo Xu, PhD  
Director of Biostatistics 
Sumitomo Dainippon Pharma Oncology, Inc. 
 
 
_________________________________________Date:  _____/_____/_________ 
Zijing Zhang, PhD 
Principal Biostatistician 
Sumitomo Dainippon Pharma Oncology, Inc. 
 
 
Approved by: 
 
_________________________________________Date:  _____/_____/_________ 
Bo Jin, PhD 
Vice President, Head of Data Science 
Sumitomo Dainippon Pharma Oncology, Inc. 
 
_________________________________________Date:  _____/_____/_________ 
Claudia Lebedinsky, MD 
Vice President, Head of Clinical Development 
Sumitomo Dainippon Pharma Oncology, Inc. 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
AMENDMENT HISTORY FROM PREVIOUS VERSIONS ...................................11 
2. 
INTRODUCTION ......................................................................................................13 
2.1. 
Study Design ...............................................................................................................13 
2.1.1. 
General Study Design and Plan ..................................................................................13 
2.1.2. 
Stratification ...............................................................................................................13 
2.1.3. 
Randomization ............................................................................................................14 
2.2. 
Study Objectives .........................................................................................................15 
2.2.1. 
Primary Objectives .....................................................................................................15 
2.2.2. 
Key Secondary Objectives ..........................................................................................15 
2.2.3. 
Other Secondary Objectives .......................................................................................15 
3. 
ENDPOINTS AND COVARIATES: DEFINITIONS AND COVENTIONS ...........16 
3.1. 
Efficacy Endpoints ......................................................................................................16 
3.1.1. 
Primary Endpoints: Overall Survival in the General Population and the 
pSTAT3(+) Subpopulation .........................................................................................16 
3.1.2. 
Key Secondary Endpoints ...........................................................................................16 
3.1.2.1. 
Progression Free Survival in the General Population and the pSTAT3(+) 
Subpopulation .............................................................................................................16 
3.1.2.2. 
Disease Control Rate in the General Population and the pSTAT3(+) 
Subpopulation .............................................................................................................18 
3.1.2.3. 
Objective Response Rate in the General Population and the pSTAT3(+) 
Subpopulation .............................................................................................................18 
3.1.2.4. 
Duration of Response in the General Population and the pSTAT3(+) 
Subpopulation .............................................................................................................19 
3.1.3. 
Other Secondary Endpoints ........................................................................................19 
3.1.3.1. 
Quality of Life Endpoints in the General Population and the pSTAT3(+) 
Subpopulation .............................................................................................................19 
3.2. 
Safety Endpoints .........................................................................................................21 
3.3. 
Other Endpoints ..........................................................................................................21 
3.3.1. 
PK Endpoints ..............................................................................................................21 
3.4. 
Covariates and Stratification Factors ..........................................................................21 
3.4.1. 
Stratification ...............................................................................................................21 
3.4.2. 
Covariates ...................................................................................................................22 


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4. 
HYPOTHESIS AND DECISION RULES .................................................................23 
4.1. 
Statistical Hypothesis ..................................................................................................23 
4.2. 
Determination of Sample Size ....................................................................................23 
4.3. 
Statistical Decision Rules for Interim and Final Analyses .........................................24 
4.4. 
Outcome of Interim Analysis, Final Analyses Timing and Hypothesis 
Testing Strategy ..........................................................................................................27 
4.5. 
Multiplicity .................................................................................................................28 
4.5.1. 
Hochberg-based Gatekeeping Procedure ....................................................................28 
4.5.2. 
Combination P-Value Approach .................................................................................31 
4.6. 
Blinding/Unblinding ...................................................................................................36 
5. 
ANALYSIS SETS ......................................................................................................37 
5.1. 
Intent-to-Treat Analysis Set ........................................................................................37 
5.1.1. 
Intent-to-Treat Analysis Set in the General Population (ITT-GP) .............................37 
5.1.2. 
Intent-to-Treat Analysis Set in the pSTAT3(+) Subpopulation, the pSTAT3(-
) Subpopulation and the pSTAT3(Unknown) Subpopulation ....................................37 
5.1.2.1. 
Intent-to-Treat Analysis Set in the pSTAT3(+) Subpopulation (ITT-
pSTAT3(+)) ................................................................................................................37 
5.1.2.2. 
Intent-to-Treat Analysis Set in the pSTAT3(-) Subpopulation (ITT-
pSTAT3(-)) .................................................................................................................37 
5.1.2.3. 
Intent-to-Treat Analysis Set in the pSTAT3(Unknown) Subpopulation (ITT-
pSTAT3(Unknown)) ...................................................................................................38 
5.1.2.4. 
Evolving Knowledge of Cut-Section Stability (CSS) for pSTAT3 Biomarker 
Assay ...........................................................................................................................38 
5.1.2.5. 
Subsets of ITT-pSTAT3(+) and ITT-pSTAT3(-) at the FA .......................................39 
5.1.2.6. 
Biomarker Analysis Set (BAS) ...................................................................................40 
5.2. 
Safety Analysis Set .....................................................................................................40 
5.2.1. 
Safety Analysis Set in the General Population (SAS-GP) ..........................................40 
5.2.2. 
Safety Analysis Set in the pSTAT3(+) Subpopulation (SAS-pSTAT3(+)) ...............40 
5.2.3. 
Safety Analysis Set in the pSTAT3(-) Subpopulation (SAS-pSTAT3(-)) .................41 
5.2.4. 
Safety Analysis Set in the pSTAT3(Unknown) Subpopulation  (SAS-
pSTAT3(Unknown)) ...................................................................................................41 
5.3. 
ORR/DCR Analysis Set ..............................................................................................41 
5.3.1. 
ORR/DCR Analysis Set in the General Population (ODAS-GP) ...............................41 
5.3.2. 
ORR/DCR Analysis Set in the pSTAT3(+) Subpopulation (ODAS-
pSTAT3(+)) ................................................................................................................41 


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5.3.3. 
ORR/DCR Analysis Set in the pSTAT3(-) Subpopulation (ODAS-pSTAT3(-
)) ..................................................................................................................................41 
5.3.4. 
ORR/DCR Analysis Set in the pSTAT3(Unknown) Subpopulation (ODAS-
pSTAT3(Unknown)) ...................................................................................................42 
5.4. 
QoL Analysis Set ........................................................................................................42 
5.4.1. 
QoL Analysis Set in the General Population (QoL-GP) ............................................42 
5.4.2. 
QoL Analysis Set in the pSTAT3(+) Subpopulation (QoL-pSTAT3(+)) ..................42 
5.4.3. 
QoL Analysis Set in the pSTAT3(-) Subpopulation (QoL-pSTAT3(-)) ....................42 
5.5. 
PK Analysis Set ..........................................................................................................42 
5.5.1. 
PK Analysis Set in the General Population (PK-GP) .................................................42 
5.5.2. 
PK Analysis Set in the pSTAT3(+) Subpopulation (PK-pSTAT3(+)) .......................43 
5.5.3. 
PK Analysis Set in the pSTAT3(-) Subpopulation (PK-pSTAT3(-)) .........................43 
5.6. 
Per-Protocol Analysis set ............................................................................................43 
5.6.1. 
Per-Protocol Analysis Set in the General Population for Overall Survival  
(PPAS-GP-OS) ...........................................................................................................43 
5.6.2. 
Per-Protocol Analysis Set in the pSTAT3(+) Subpopulation for Overall 
Survival (PPAS-pSTAT3(+)-OS) ...............................................................................44 
5.6.3. 
Per-Protocol Analysis Set in the General Population for Progression Free 
Survival (PPAS-GP-PFS) ...........................................................................................44 
5.6.4. 
Per-Protocol Analysis Set in the pSTAT3(+) Subpopulation for Progression 
Free Survival (PPAS-pSTAT3(+)-PFS) .....................................................................44 
5.7. 
Treatment Allocation ..................................................................................................44 
6. 
DATA HANDLING ...................................................................................................46 
6.1. 
Clinical Cutoff and Analysis Cutoff ...........................................................................46 
6.2. 
Handling of Missing Values .......................................................................................47 
6.2.1. 
Missing or Partial Death Dates ...................................................................................47 
6.2.2. 
Partial or Missing Start Date or End Date for Adverse Event or Medications ...........47 
6.2.3. 
Partial or Missing Date for New Anticancer Treatment .............................................47 
6.2.4. 
Partial Date for Pathological Diagnosis ......................................................................48 
6.2.5. 
Missing Efficacy Endpoints ........................................................................................48 
6.2.6. 
Missing PK/PD Values ...............................................................................................48 
6.2.7. 
Missing QoL Data .......................................................................................................48 
6.2.8. 
Missing Biomarker Data .............................................................................................48 
6.3. 
General Data Handling ...............................................................................................48 


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7. 
STATISTICIAL METHODOLOGY AND STATISTCAL ANALYSES .................51 
7.1. 
Statistical Methods ......................................................................................................51 
7.1.1. 
Analyses of Time to Event endpoints .........................................................................51 
7.1.2. 
Analyses of Binary Endpoints ....................................................................................51 
7.1.3. 
Analyses of Continuous Data .....................................................................................51 
7.1.4. 
Analyses of Categorical Data .....................................................................................51 
7.2. 
Statistical Analysis ......................................................................................................52 
7.2.1. 
Standard Analysis .......................................................................................................52 
7.2.1.1. 
Disposition of Patients ................................................................................................52 
7.2.1.2. 
Demographic and Other Baseline Characteristics ......................................................52 
7.2.1.3. 
Disease Characteristics, Medical History, and Primary Therapy ...............................52 
7.2.1.4. 
Protocol Deviation ......................................................................................................53 
7.2.1.5. 
Study Treatment ..........................................................................................................53 
7.2.1.6. 
Exposure of BBI-608 ..................................................................................................54 
7.2.1.7. 
Permanently Discontinued Due to AE: based on drug administration form.  
Exposure of FOLFIRI .................................................................................................55 
7.2.1.8. 
Exposure of Bevacizumab ..........................................................................................56 
7.2.2. 
Primary Analyses of Primary Endpoints ....................................................................57 
7.2.3. 
Sensitivity Analyses of the Primary Endpoints ..........................................................58 
7.2.3.1. 
Sensitivity Analysis for Overall Survival in ITT-GP and/or ITT-pSTAT3(+)...........58 
7.2.3.2. 
Analysis for Overall Survival in ITT-pSTAT3(-) and ITT-
pSTAT3(Unknown) ....................................................................................................58 
7.2.4. 
Analyses of Key Secondary Endpoints .......................................................................59 
7.2.5. 
Analyses of Other Secondary Endpoints ....................................................................60 
7.2.6. 
Statistical Analysis for Safety Endpoints ...................................................................60 
7.2.6.1. 
Adverse Event .............................................................................................................61 
7.2.6.2. 
Clinical Laboratory Assessments ...............................................................................63 
7.2.6.3. 
Concomitant Medication/Post-Treatment Anti-Cancer Therapy ................................64 
7.2.6.4. 
Vital Signs ..................................................................................................................64 
7.2.6.5. 
ECG Evaluation ..........................................................................................................65 
7.2.6.6. 
Physical Exam ............................................................................................................65 
7.2.6.7. 
ECOG .........................................................................................................................65 
7.2.7. 
Subgroup Analysis for PMDA Submission ................................................................65 


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7.2.8. 
PK Analysis ................................................................................................................65 
7.2.9. 
Sensitivity Analysis on Overall Survival in pSTAT3(+) w.r.t. Baseline 
Imbalance ....................................................................................................................66 
7.2.10. 
Sensitivity Analysis on Missing Biomarker Data .......................................................67 
7.2.10.1. 
Comparison Baseline Covariates between Biomarker Analysis Set and 
Patients Missing Biomarker Data ...............................................................................68 
7.2.10.2. 
Comparison of Overall Survival of Biomarker Analysis Set and Patients 
Missing Biomarker Data .............................................................................................68 
7.2.10.3. 
Handling Missing Biomarker Status ...........................................................................68 
8. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES................75 
9. 
REFERENCES ...........................................................................................................76 
10. 
APPENDIX.................................................................................................................79 
Appendix I:  Patient Evaluation Flow Sheet for Arm 1 (BBI-608 in Combination with 
FOLFIRI) ....................................................................................................................79 
Appendix II: Patient Evaluation Flow Sheet for Arm 2 (FOLFIRI) ..............................................82 
Appendix III Response and Evaluation Endpoints ........................................................................84 
Appendix IV: Non-Permitted Treatments ......................................................................................89 
Appendix V: Sample SAS codes for Propensity Score and Multiple Imputation .........................90 
Appendix VI: ORR and DCR for 36 weeks and ORR/DCR Analysis Set with minimum 
36 weeks duration .......................................................................................................93 
 
 


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LIST OF TABLES 
Table 1: 
PFS Definition: Events and Censoring Reasons and Hierarchy .................................17 
Table 2: 
Analysis Windows for QoL Endpoints .......................................................................20 
Table 3: 
Final Analysis Timing by Different Outcomes from IA ............................................27 
Table 4: Prespecified Stage Weights for Different Endpoints .......................................................34 
Table 5: 
Preliminary Estimated Number of Specimens tested within Various Stability 
Windows in the CanStem303C study .........................................................................38 
Table 6: 
High Level Summary of Analysis and Analysis Sets at Final Analysis .....................45 
Table 7: 
Clinical and Analysis Cutoffs in the scenario that 310 deaths in ITT-
pSTAT3(+) happen earlier than 850 in ITT-GP .........................................................46 
Table 8: 
BBI-608 Dose Modification Table .............................................................................54 
Table 9: 
FOLFIRI Dose Modification Table ............................................................................55 
Table 10: CTCAE Terms for Grading ........................................................................................63 
Table 11: Markedly Abnormal Ranges for Vital Sign ................................................................65 
Table 12: Clinically Relevant Baseline Factors ..........................................................................66 
Table 13: Summary of Key Efficacy Analysis ...........................................................................71 
Table 14:  Integration of Target, non-Target and New Lesions into Response 
Assessment: ................................................................................................................86 
LIST OF FIGURES 
Figure 1: 
Adaptive Study Design Schema .................................................................................26 
Figure 2: 
Hochberg-based Gatekeeping Procedure ....................................................................30 
Figure 3: 
Data in FA of the pSTAT3(+) Subpopulation ............................................................32 
Figure 4: 
pSTAT3 Subpopulations Components at Interim Analysis and Final 
Analysis ......................................................................................................................40 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
5-FU 
5-Fluorouracil 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase  
AST 
Aspartate Transaminase 
ATC  
Anatomical Therapeutic Chemical 
BBI 
Boston Biomedical, Inc 
BID 
Twice a Day 
BLQ 
Below the Limit of Quantitation 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BP 
Blood Pressure 
Bpm 
beats per minutes  
BSA 
Body Surface Area 
CfB 
Change from Baseline 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CRF 
Case Report Form 
CT 
Computerized axial Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CSR 
Clinical Study Report 
DBL 
Database Lock 
DCR 
Disease Control Rate 
DI 
The actual dose intensity 
DoR 
Duration of Response 
DSMB 
Data Safety and Monitoring Board 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor Receptor 
EORTC-QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire Core 30 Item  
FA 
Final Analysis 
FDA 
Food and Drug Administration  
FOLFIRI 
5-Fluorouracil, Leucovorin, Irinotecan 
GH 
Global health status 
HR  
Hazard Ratio 
IHC 
immunohistochemical  
IA 
Interim Analysis 
ITT 
Intent-To-Treat 
IV 
intravenous 
LLQ 
Lower Limit of Quantitation 
MD 
Measurable Disease 


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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/m2 
milligram / square meter 
mmHg 
Millimeter Mercury 
MRI  
Magnetic Resonance Imaging 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
OF 
O’Brien-Fleming 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease  
PET 
Positron Emission Tomography  
PF 
Physical Function 
PFS 
Progression Free Survival 
PH 
Proportional Hazard 
PK 
Pharmacokinetic 
PP 
Per-Protocol 
PR 
Partial Response 
pSTAT3 
Phosphorylated Signal Transducer and Activator of Transcription 3 
PT 
Preferred Term 
q12h 
Every 12 hour 
QoL 
Quality of Life 
RDI 
Relative dose intensity (%) 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WHO-DD 
World Health Organization Drug Dictionary 


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1. 
AMENDMENT HISTORY FROM PREVIOUS VERSIONS  
This Statistical Analysis Plan (SAP) is amended (version 3.0) to incorporate clarifications prior 
to Database Lock (DBL). The high-level summary of the changes are as below:  
x 
Clarify the baseline window for efficacy endpoints (Section 6.3);  
x 
Add per-protocol analysis for overall survival and progression free survival (Section 5.6);  
x 
Add summary of duration of response and time to response (Section 3.1.2.4);  
x Add clustered AE definition and summary (Section 7.2.6.1);  
x Update lab parameters to be summarized by CTCAE grading (Section 7.2.6.2);  
x Update the definition for extent of exposure, dose intensity and dose changes 
(Section 7.2.1.6);   
x Add sensitivity analysis for progression free survival, disease control rate and 
objective response rate for general population and pSTAT3(+) subpopulation 
(Section 7.2.4 ); 
x A dedicated PRO analysis will be conducted in a separate standalone SAP. Part of 
QoL analysis has been removed from this SAP; 
x Clarify combination functions approach for ORR/DCR endpoints (Section 4.5.2 and 
Appendix VI); 
x Update company name to Sumitomo Dainippon Pharma Oncology, Inc. (SDPO).   
 
The SAP has been amended (version 2.1) to incorporate FDA’s feedback on the SAP version 2.0 
per their communication on July 23, 2019 and also to update the statistical analysis for 
pSTAT3(+) subpopulation considering that the final pSTAT3 assay cut-section stability (CSS) 
window could be longer than 6 months (up to 15 months).  Among others, the main changes of 
this SAP amendment (version 2.1) from SAP version 2.0 include:  
x To update the analysis set definitions for pSTAT3(+)/pSTAT3(-) and 
pSTAT3(Unknown) subpopulation (See Section 5);  
x To clarify the clinical cutoff date and analysis cutoff dates for both General Population 
and pSTAT3(+) subpopulation at the final analysis (See Section 6.1);  
x To update the statistical analysis for primary endpoint and key secondary endpoints in the 
pSTAT3 (+) subpopulation at the final analysis (See Section 4.5.2, Section  7.2.2 , 
Section 7.2.3 , and Section 7.2.4); 
x To introduce a small penalty for the interim analysis (IA) (1-sided alpha of 0.0001) and 
make appropriate multiplicity adjustment at the final analysis (FA) (See Section 4.5.2) 
per FDA’s feedback; 
x To pre-specify the clinically relevant baseline factors for the propensity score analysis 
and missing biomarker data imputation (See Section 7.2.9) per FDA’s feedback;  
x To include the sample SAS code for propensity scores and multiple imputation  
(See Appendix V) per FDA’s feedback;  


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x To update the details of the tipping point analysis to evaluate the impact of missing 
biomarker data under worst case scenarios. (See Section 7.2.10) per FDA feedback.   
The SAP version 2.0 was based on Clinical Protocol Study CanStem303C_Amendment 
6.0_Submitted to Agency on 26 September 2018, Serial Number 0256. The main changes in the 
SAP version 2.0 from previous SAP version 1.0 were to align with protocol amendment 6.0 in 
terms of study design and analysis strategy.  The changes included:  
x Addition of a primary endpoint to assess the overall survival (OS) in the pSTAT3 (+) 
subpopulation as well as a change to an adaptive study design to identify the patient 
population that is most likely to benefit from BBI-608 treatment.   
x Selection of key secondary endpoints.   
x Multiplicity adjustment for the analysis of several endpoints (primary endpoints and key 
secondary endpoints), analysis of the 2 patient populations (General Population and 
pSTAT3(+) Subpopulation), and data-driven design changes.   
x Blinding plans which are implemented by the Sponsor and by the CRO to minimize the 
operational bias and to maintain the integrity of the study data for the decision making at 
the interim analysis.   
x An update to the potential outcomes from the interim analysis as well as final analysis 
timing.   
x An update to the sensitivity analysis for overall survival in the pSTAT3(+) 
subpopulation. 
x An update to the sensitivity analysis for missing biomarker data. 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods that will be used during the 
analysis and reporting of data collected under Sumitomo Dainippon Pharma Oncology Protocol 
CanStem303C.This SAP should be read in conjunction with the study protocol and electronic 
case report forms (eCRFs). This version of the SAP has been developed using 226969 Mock 
CRF Report Form 20200731 v16.0.   
2.1. 
Study Design 
2.1.1. 
General Study Design and Plan 
This is an international, multi-center, prospective, open-label, randomized, adaptive design Phase 
3 trial of BBI-608 plus standard bi-weekly FOLFIRI (FOLinic acid-Fluorouracil-IRInotecan plus 
leucovorin) (Arm 1) versus standard bi-weekly FOLFIRI alone (Arm 2) in patients with 
previously treated metastatic colorectal cancer (mCRC). Addition of bevacizumab (bev) to the 
FOLFIRI regimen, per Investigator choice, will be permissible. 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. 
 
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, is 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 as 
monotherapy. 
2.1.2. 
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 from start of first line therapy (<6 months vs. ≥6 months from start 
of first line therapy) 
3. Tumor RAS 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 


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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. 
2.1.3. 
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 
alone. Addition of bevacizumab to the FOLFIRI regimen, per Investigator choice, is permissible. 
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 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. 
 
 
 


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2.2. 
Study Objectives 
2.2.1. 
Primary Objectives 
x To compare 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). 
2.2.2. 
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. 
2.2.3. 
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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3. 
ENDPOINTS AND COVARIATES: DEFINITIONS AND 
COVENTIONS 
3.1. 
Efficacy Endpoints 
3.1.1. 
Primary Endpoints: Overall Survival in the General Population and the 
pSTAT3(+) Subpopulation  
Overall Survival (OS), the primary endpoints of this study, in the General Population and the 
pSTAT3(+) Subpopulation is defined as the time from randomization to death from any cause. 
Patients who are still alive at the time of the interim or the final analysis data cutoff, or who have 
become lost to follow-up will be censored at their last date known to be alive on or before the 
date of data cutoff. All randomized patients will be included in the analysis of OS. Patients will 
be analyzed in the arm to which they are randomized regardless of the treatment they received 
(intent-to-treat principal). 
OS in months is calculated as (date of death/last known to be alive – date of randomization  
+1)/30.4375.  Patients lacking any dates which support patients still alive beyond randomization 
will have their OS censored at the date of randomization.  
3.1.2. 
Key Secondary Endpoints 
3.1.2.1. 
Progression Free Survival in the General Population and the pSTAT3(+) 
Subpopulation 
Progression-Free Survival (PFS) 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 interim or final analysis (up to the date of data cutoff), PFS will 
be censored on the date of the last tumor assessment (up to the date of data cutoff).   
PFS in months is calculated as (first event date/censored date – date of randomization  
+1)/30.4375.  
Tumor assessments will be performed every 8 weeks (every 56 days) after randomization  
(±5 days) until 6 months of treatment and every 12 weeks (every 84 days) thereafter until 
objective disease progression, lost to follow-up, withdrawal of consent or death.  
Table 1 summarizes the censoring rules for the PFS analysis.   


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Table 1: 
PFS Definition: Events and Censoring Reasons and Hierarchy 
Notes: (1) Symptomatic deteriorations (i.e. symptomatic progressions, which are not radiographically confirmed) will not be considered as 
progressions. 
(2) If target, non-target, and new lesion assessments have different dates within a visit, then the earliest of those dates will be considered as the 
date of the tumor assessment if the assessment for that visit is progressive disease (PD); otherwise the latest date will be used. 
(3) Adequate radiographical tumor assessment refers to an assessment with overall response of CR, PR, SD, non-CR/non-PD, or PD. 
Hierarchy 
Censoring 
Situation 
Date of Event or Censor 
Event / 
Censor 
1 
No baseline radiological tumor 
assessment available 
Date of randomization 
Censor 
5 
No post baseline radiological tumor 
assessment available and no death 
reported within 2 scan intervals 
following randomization 
Date of randomization 
Censor 
 
No post baseline radiological tumor 
assessment available 
but death reported within 2 scan 
intervals following randomization 
Date of death 
Event 
6 
No tumor progression (per RECIST 
1.1) and no death reported within 2 
scan intervals following last adequate 
radiological tumor assessment 
Date of last adequate 
radiological 
tumor assessment  
Censor 
 
No tumor progression (per RECIST 
1.1) but death reported within 2 scan 
intervals following last adequate 
radiological 
tumor assessment  
Date of death 
Event 
 
Tumor progression (per RECIST 1.1) 
documented within 2 scan intervals 
following previous adequate 
radiological tumor assessment 
Earliest of the target, non-
target and new tumor 
assessment dates 
Event 
3 
Tumor progression (per RECIST 1.1) 
documented after 2 scan intervals 
following previous adequate 
radiological tumor assessment 
Date of previous adequate 
radiological assessment 
Censor 
2 
New anticancer treatment started and 
no tumor progression 
Date of previous adequate 
radiological assessment 
immediately prior to start 
of new therapy 
Censor 
4 
No tumor progression (per RECIST 
1.1) and patient lost to follow-up or 
withdrawal of consent 
Date of last adequate 
radiological 
Assessment 
Censor 


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Two scan intervals above indicate 16 weeks plus 10 days prior to the first 6 months of treatment, 
and 24 weeks plus 10 days thereafter. The censoring reason will be assigned according the 
hierarchy order in Table 1.   
3.1.2.2. 
Disease Control Rate in the General Population and the pSTAT3(+) 
Subpopulation 
Best Overall Response (BOR) is the best response recorded from randomization until disease 
progression or start of new anti-cancer therapy. Tumor scan assessment done after PD or after 
“new anti-cancer” treatment, but prior to PD will not be considered in the evaluation of BOR.  
BOR (based on unconfirmed response) is derived from the sequence of objective response 
determined by the following order:   
x CR: One objective status of CR documented before progression or start of new  
anti-cancer therapy  
x PR: One objective status of PR documented before progression or start of new  
anti-cancer therapy, but not qualifying as CR 
x SD: At least 1 objective status of SD or better documented within at least 1 nominal scan 
interval (8 weeks – 5 days window = 51 days) after randomization date and before 
progression and the start of new anti-cancer therapy, but not qualifying as CR or PR 
x PD: Progression documented within 2 nominal scan intervals (or 16 weeks + 5 days 
window = 117) after randomization date and not qualifying as unconfirmed CR, 
unconfirmed PR, or SD   
x NE: All other cases will be categorized as NE. The reasons for NE will be summarized 
and the following reasons may be used:  
x Early death (Note: death prior to 8 weeks – 5 days window after randomization) 
x No post-baseline assessments  
x New anti-cancer therapy started before first post-baseline assessment  
x All post-baseline assessments have overall response NE 
x SD too early (<51 days after randomization date) 
x PD too late (>117 days after randomization date) 
The assignment of reasons for NE will follow the above hierarchical order.  
Disease Control Rate (DCR) is defined as the proportion of patients with BOR of a documented 
complete response, partial response, and stable disease (CR + PR + SD), based on RECIST 1.1, 
by investigator assessment. The estimate of DCR will be based on ODAS analysis set. In order to 
classify stable disease (SD) as the BOR, the assessment must be made a minimum of 8 weeks – 5 
days window = 51 days from baseline where baseline is counted from randomization.  
3.1.2.3. 
Objective Response Rate in the General Population and the pSTAT3(+) 
Subpopulation 
Objective Response Rate (ORR) is defined as the proportion of patients with BOR of a 
documented complete response and partial response (CR + PR) based on RECIST 1.1 by 
investigator assessment. The estimate of ORR will be based on ODAS analysis set. 


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The patients will be considered as non-responders until proven otherwise. Thus, the patients 
who:  
x Do not have CR or PR while on study; or  
x Do not have a baseline or post-baseline tumor evaluation; or  
x Do not have an adequate baseline tumor evaluation; or  
x Receive new anti-cancer treatment other than the study medication prior to reaching a CR 
or PR; or  
x Die, progress, or drop out for any reason prior to reaching a CR or PR  
are considered non-responders. 
3.1.2.4. 
Duration of Response in the General Population and the pSTAT3(+) 
Subpopulation 
Duration of Response (DoR) is defined as the time from the first documentation of objective 
tumor response (CR or PR), as determined by the investigator evaluation, to the first 
documentation of objective tumor progression or death due to any cause, whichever occurs first.  
If tumor progression data include more than 1 date, the first date will be used. DoR in weeks will 
be calculated as (first date of PD or death − first date of CR or PR +1)/7. DoR will only be 
calculated for patients in the ODAS analysis set who have an objective tumor response. 
Censoring rules for DoR is identical to the censoring rules presented for PFS. Time to Response 
(TTR) is defined as the time from randomization to first documentation of objective tumor 
response (CR or PR) as determined by the investigator assessment.  For patients proceeding from 
PR to CR, the onset of PR is taken as the onset of response. TTR will be calculated for the 
subgroup of patients with objective tumor response. 
3.1.3. 
Other Secondary Endpoints 
3.1.3.1. 
Quality of Life Endpoints in the General Population and the pSTAT3(+) 
Subpopulation 
The Quality of Life (QoL) of patients will be assessed using EORTC QLQ-30 while the patient 
remains on study treatment (FOLFIRI with or without BBI-608). The EORTC QLQ-30 is a  
self-administered cancer specific questionnaire with multi-dimensional scales (Protocol 
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 scores for each subscale will be summarized for each group at each analysis window. 
Change from Baseline will be summarized for each group at each post-baseline measurement 
time point. 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. 


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The scoring method for EORTC QLQ-C30 is summarized below. In this summary Qi refers to 
the i-th question on the QLQ-C30. 
Functional scale’s scores: 
· Physical functioning:(1 - ((Q1+Q2+Q3+Q4+Q5)/5 -1)/3) * 100 
· Role functioning:(1 - ((Q6+Q7)/2-1)/3) * 100 
· Emotional functioning:(1 - ((Q21+Q22+Q23+Q24)/4-1)/3) * 100 
· Cognitive functioning:(1 - ((Q20+Q25)/2-1)/3) * 100 
· Social functioning:(1 - ((Q26+Q27)/2-1)/3) * 100 
 
Global health status score: 
· Global QoL:((Q29+Q30)/2-1)/6 * 100 
 
Symptom scale’s scores: 
· Fatigue:((Q10+Q12+Q18)/3-1)/3 * 100 
· Nausea and vomiting:((Q14+Q15)/2-1)/3 * 100 
· Pain:((Q9+Q19)/2-1)/3 * 100 
· Dyspnea:((Q8-1)/3 * 100 
· Insomnia:(Q11-1)/3 * 100 
· Appetite loss:(Q13-1)/3 * 100 
· Constipation:(Q16-1)/3 * 100 
· Diarrhea:(Q17-1)/3 * 100 
· Financial difficulties:(Q28-1)/3 * 100 
Missing items in a scale will be handled by the following methods: values will be imputed for 
missing items by assuming that the missing items have values equal to the average of those items 
which are present for any scale in which at least half the items are completed. A scale in which 
less than half of the items are completed will be treated as missing. 
The QoL assessment is performed prior to randomization and during protocol treatment after 
randomization. Since exact time of assessment may vary from patient to patient, it is necessary to 
provide a window for each QoL time point. Table 2 describes how to assign a questionnaire to a 
discrete time point, in which, target day is relative to randomization date: 
Day from randomization = assessment date – randomization date,  
week from randomization = (assessment date – randomization date) / 7 
Table 2: 
Analysis Windows for QoL Endpoints 
Time Point 
Window  
Target Day  
Baseline  
14 days prior to or on the randomization  
Day 0  
Week 4 (Cycle 3, Day 1)  
0 -< 7 weeks 
Day 29 
Week 8 (Cycle 5, Day1) 
7 weeks -< 10 weeks  
Day 57 
Week 12 (Cycle 7, Day 1) 
10 weeks -< 14 weeks 
Day 85 
Week 16 (Cycle 9, Day 1) 
14 weeks -< 20 weeks 
Day 113 
Week 24 (Cycle 13, Day 1)  20 weeks -< 28 weeks 
Day 141 
 


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Each patient has 1 score selected from questionnaires collected from scheduled and unscheduled 
visits per scale per analysis window. If a patient had more than 1 questionnaire collected 
(scheduled and/or unscheduled) in an analysis window, the one collected closest to the target 
date is selected; if questionnaires had same days from the target date, the later one is selected; if 
questionnaires collected from the same date, the worst one is selected.  For functional scales and 
global health status, the larger score the better; while for symptom scales, the smaller score the 
better.  
The detailed analysis of QoL will be provided in a separate patient reported outcome analysis 
plan. 
3.2. 
Safety Endpoints 
Adverse Events (AEs) as characterized by type, frequency, severity (as graded by NCI CTCAE 
version 4.0), seriousness, and relationship to study therapy. Laboratory abnormalities as 
characterized by type, frequency, and severity (as graded by NCIC CTCAE version 4.0). 
Other safety endpoints include physical examination, electrocardiogram (ECG), and vital sign 
data.  
3.3. 
Other Endpoints  
3.3.1. 
PK Endpoints  
Plasma samples for sparse 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. The PK endpoint is: 
x PK concentration of BBI-608 
3.4. 
Covariates and Stratification Factors 
3.4.1. 
Stratification 
As described in the study design (Section 2.1.2), randomization in this study is stratified 
according to:  
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) 
4. Bevacizumab as part of study protocol treatment (yes vs. no) 
5. Location of the primary tumor (left colon vs. right colon) 
For patients who are incorrectly stratified at the time of randomization, either because of 
information available subsequent to randomization or due to clerical error, the actual baseline 


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value, as recorded in CRF will be used in the primary analysis. For patients enrolled prior to 
Protocol Amendment 3.0 which didn’t stratify by “left colon vs. right colon”, stratification will 
be derived from CRF data regarding location of the tumor and be used in primary analysis or 
sensitivity analysis. Any change in stratification that occurred after randomization will be noted 
in the clinical study report.   
3.4.2. 
Covariates  
In additional to the stratification factors, the potential influence of baseline patient characteristics 
on the primary endpoints (OS in the General Population and OS in the pSTAT3(+) 
Subpopulation will be evaluated such as (but not limited to) below:   
Age (<65 years versus ≥ 65 years)  
Age (<65 years, ≥65 to < 75 years, ≥75 to < 85 years versus ≥85 years) 
Sex (Male versus Female) 
Presence of liver metastases (Yes versus No) 
Subgroup analysis for the primary endpoints (OS in the General Population and in the 
pSTAT3(+) Subpopulation) as sensitivity analyses will be conducted to address the benefit of 
BBI-608 between the treatment arms by stratification factors (Section 3.4.1), the above factors 
and the following (but not limited to): 
ECOG performance status (0 versus 1) 
Race (White, Black, Asian versus Other) 
Country (Canada, USA, Western Europe, Australia, Japan, Korea, China versus Other) 
Primary tumor site (Colon versus Rectum) 
Prior bevacizumab (Yes versus No) 


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4. 
HYPOTHESIS AND DECISION RULES 
4.1. 
Statistical Hypothesis 
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: 
H20: BBI-608 + FOLFIRI ≤ FOLFIRI in the pSTAT3(+) Subpopulation 
H21: BBI-608+FOLFIRI > FOLFIRI in the pSTAT3(+) Subpopulation 
The study is designed to test for superiority of BBI-608 plus FOLFIRI over FOLFIRI in the 
General Population and the pSTAT3(+) Subpopulation. Superiority will be concluded if there is 
sufficient evidence to reject the null hypothesis.  
4.2. 
Determination of Sample Size 
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 median OS (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 pSTAT3(+) prevalence in the current 
study, and proportional to the total death 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 a 1-sided α = 0.025 to detect a 30% reduction 


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(HR [BBI-608+FOLFIRI versus 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, and considering the multiplicity adjustment aforementioned, 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.  
4.3. 
Statistical Decision Rules for Interim and Final Analyses 
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. Interim results will be evaluated by the Data 
Safety and Monitoring Board (DSMB). Additionally, the DSMB will review safety during the 
conduct of the study. The role and responsibility of the DSMB will be defined in a separate 
charter. The recommendations from the 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: maintain 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 FA in the pSTAT3(+) Subpopulation. Here c1= c2= c3=1 are futility boundaries for 
the pSTAT3(+) Subpopulation, the General Population and the pSTAT3(-) Subpopulation 
respectively. 


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Patient population and hypothesis selection rule: Select the most appropriate patient
population and hypothesis for evaluating the significance of the treatment effect at the FA.
The patient population selection rules are based on futility analysis and the interaction condition 
introduced [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/ܪܴିwith 
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/
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 for 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.  
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 one-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
(1)
where
Z is the 1-sided log-rank test statistic 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 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 event 
count adjustment will also consider other factors including potential clinical benefit and 
operational feasibility. The details of the event count adjustment rule will not be described here 
in the SAP, but will be provided to the unblinded reporting team and DSMB in a separate 
document by the study statistician, and will not be shared with the study team, site and other 
blinded partners. This procedure is introduced to minimize the risk of the treatment effect being 
revealed to blinded partners by the event number re-estimation.  
v1 m1
m2
, v2 m2 m1
m2
,


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Figure 1: 
Adaptive Study Design Schema 
 
 
 


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4.4. 
Outcome of Interim Analysis, Final Analyses Timing and Hypothesis 
Testing Strategy  
Based on interim analysis possible study actions may be as follows: 
x Terminate the study for futility (lack of efficacy) 
x Continue the study as is  
x Continue the study in the pSTAT3(+) Subpopulation only; stop treatment of pSTAT3(-) 
patients; no increase in target number of events in pSTAT3(+) patients 
x Continue the study in the pSTAT3(+) Subpopulation only; stop treatment of pSTAT3(-) 
patients; increase target number of events in pSTAT3(+) patients 
x Continue the study in both General population and pSTAT3(+) population; increase 
target number of events in pSTAT3(+) patients 
For the pSTAT3(+) Subpopulation, the total number of events is to be increased to no more than 
434 events which leads to 85% power at 1-sided Ƚ = 0.025 assuming HR = 0.75 (40% increase 
from original planned 310 events). This may result in enrolling further pSTAT3(+) patients 
and/or a longer follow-up period.   
Please note that an increased event number in the General Population might also be considered, 
although not mentioned in the above likely IA outcomes.  However, since this study is 
statistically powered under the assumption of the true hazard ratio of 0.8 for the General 
Population, which is considered to be close to the boundary of clinically meaningful benefit in 
OS, the increase of the number of events in the General Population will need to be justified by a 
careful assessment of potential clinical benefit.   
The IA timing will be triggered at ~425 events (50% information) in the General Population. 
Table 3 summarizes the final analysis timing based on different IA outcomes.   
Table 3: 
Final Analysis Timing by Different Outcomes from IA 
Outcomes from IA  
Final Analysis Timing  
Patient Enrollment 
Only General Population 
hypothesis is selected  
850 events in General Population 
if no event count adjustment*$  
1250 patients enrolled  
Only pSTAT3(+) 
hypothesis is selected  
310 to 434 events* in pSTAT3(+) 
depending upon IA decision  
May enroll more pSTAT3(+) 
patients after IA or expand the 
follow-up period  
Both General Population 
and pSTAT3(+) 
850 events in General 
Population*$ or 310 to 434 
May enroll more General 
Population or pSTAT3(+) 


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hypotheses are selected  
events* in pSTAT3(+) whichever 
comes later.   
patients after IA or expand the 
follow-up period 
*The event count adjustment may also consider other factors including potential clinical benefits and operational 
feasibility. 
$For the General population, the number of events may not be increased unless other factors such as potential 
clinical benefits will drive the increase.  
4.5. 
Multiplicity  
To address multiplicity introduced by the analysis of several endpoints (primary endpoints 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 and Tamhane (2011, 2013), Kordzakhia et al. 
(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.   
4.5.1. 
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).   


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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)].    
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. 
 
 


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Figure 2:
Hochberg-based Gatekeeping Procedure
ܪͳͲ
ܪʹͲ
ܪͳͲ
ܪʹͲ
OS 
Truncated-Hochberg 
ܪ͵Ͳ
ܪͶͲ
ܪ͵Ͳ
ܪͶͲ
PFS
Truncated-Hochberg 
ܪͷͲ
ܪ͸Ͳ
ܪͷͲ
ܪ͸Ͳ
DCR
Truncated-Hochberg 
ܪ͹Ͳ
ܪͺͲ
ܪ͹Ͳ
ܪͺͲ
ORR
Hochberg 
General
Population
pSTAT3(+)
Subpopulation


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4.5.2. 
Combination P-Value Approach 
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 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 SAP 2.0. The test statistics for evaluating the significance of the treatment effect or 
the corresponding 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
 
(2) 
x ܼଵଵ and ܼଶଵ: the 1-sided log-rank test statistic [Jennison and Turnbull, 2000] at the IA and 
FA for the General Population.   
x ݇ଵଵ and ݇ଶଵ: the number of events at the IA and FA 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 
(3) 
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 
(4) 
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 IA, 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 5.1 for detailed explanations], the test statistics at the FA for the 
primary and the key secondary endpoints in the pSTAT3(+) Subpopulation will be computed 


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across two subsets of patients data, i.e., Subset 1 of the patients with pSTAT3 positive status 
within specimen age up to 6-months (including both Stage 1 pre-IA data and Stage 2 post-IA 
data), and Subset 2 (Stage 3) of patients with pSTAT3 positive status with specimen age for 
longer than 6 months and 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 
FA.  
Figure 3: 
Data in FA 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 OS at the FA 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 IA from Subset 1. 
x Stage 2 (Subset 1 Stage 2) Data: OS data collected after the IA 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
 
(5) 
x ܼଵଶ and ܼଶଶ: the 1-sided log-rank test statistic at the IA and FA 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 IA and FA for the pSTAT3(+) Subpopulation with 
specimen age up to the 6-month stability window (Subset 1).   
Furthermore, let ܼଷଶ
כ  denotes 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 6.1 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 
(6) 
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 ݎଶሻൌ 
ͳ െʣ ቀξݒଶξݓଶʣିଵሺͳ െ݌ଶሻ൅ξݒଶඥͳ െݓଶʣିଵሺͳ െݍଶሻ൅ඥͳ െݒଶʣିଵሺͳ െݎଶሻቁǡ  
(7) 
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. 
Considering ORR/DCR are binary endpoints, in order to perform statistical inferences for ORR 
and DCR using combination function approach, two distinct subsets of patients for stage 1 and 
stage 2 will be defined in Appendix VI to obtain two independent test statistics from stage 1 and 
stage 2 based on minimum 36 weeks duration. The DCR 36 weeks and ORR 36 weeks are 
defined based on 36 weeks from randomization. The p-values used in combination functions will 
be calculated based on DCR 36 weeks and ORR 36 weeks.  
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, 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. 


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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, q6 and ݎ଺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 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. 
x Hypothesis H80: Let p8, 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, i.e., ܿଶሺ݌௜ǡ ݍ௜ሻ for the null hypothesis ܪ௜଴, ݅ൌ͵ǡͷǡ͹, and ܿଷሺ݌௜ǡ ݍ௜ǡ ݎ௜ሻ for the null 
hypothesis ܪ௜଴, ݅ൌͶǡ͸ǡͺ. The hypothesis-specific stage weights used in these combination 
functions are defined in Table 4. 
Table 4: Prespecified Stage Weights for Different Endpoints  
 
ݓ௜ 
ݒ௜ 
H10: OS in General Population 
0.5 
 
H20: OS in pSTAT3(+) Subpopulation 
0.5 
0.95 
H30: PFS in General Population 
0.65 
 
H40: PFS in pSTAT3(+) Subpopulation 
0.65 
0.95 
H50: DCR in General Population 
0.9 
 
H60: DCR in pSTAT3(+) Subpopulation 
0.9 
0.95 
H70: ORR in General Population 
0.8 
 
H80: ORR in pSTAT3(+) Subpopulation 
0.8 
0.95 
The inferences for the 8 hypotheses corresponding to OS, PFS, DCR, and ORR will be 
performed at the FA 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 ݎଶሻ 
x Hypothesis H30: The composite p-value is defined as ݏଷൌܿଶሺ݌ଷǡ ݍଷሻ. 


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x Hypothesis H40: The composite p-value is defined as ݏସൌܿଷሺ݌ସǡ ݍସǡ ݎସሻ 
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 IA outcome will be the treatment effect is evaluated only in the General Population at the 
FA and thus the hypotheses H20, H40, H60 and H80  are dropped after the IA, 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 FA 
and thus the hypotheses H10, H30, H50 and H70 are dropped after the IA, 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 FA,  
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 
 
݌ሺܫሻൌሺʹݏሺ௜ሻǡ ݏሺ௝ሻሻ 
(8) 
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.  
(9) 
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௜ 
(10) 
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  


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23 July 2019, it was suggested to sponsor to introduce a small penalty for the IA because of the 
unblinded analysis of the efficacy data even though the IA were not to stop for efficacy. 
Therefore, a small penalty for the IA (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. 
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 IA. 
4.6. 
Blinding/Unblinding  
This is an open-label study; however, to minimize the risk of potential bias, procedures for 
blinding have been implemented to ensure the integrity of the study data (Sponsor blinding plan 
and CRO blinding plan documents, respectively). Every effort will be made per the blinding 
plans and the DSMB charter to maintain the firewall between blinded and unblinded teams at 
SDPO and partners and to minimize the potential operational bias. An overview of the blinding 
plan is as follows:  
x SDPO Blinding Plan (Section 9): SDPO has developed an internal blinding plan and 
trained the entire SDPO staff on the procedures outlined in the plan. SDPO has ensured 
that mechanisms are in place to ensure that the staff follow these established procedures. 
In addition, a key measure has been put in place involving QA oversight of activities that 
are governed by the SDPO blinding plan. 
x CRO Blinding Plan (Section 9): An additional blinding plan is in place for 
communications between the CRO and SDPO to ensure blinded team members at SDPO 
do not receive unblinding communications. The CRO is tasked with blinding data prior to 
distributing it to BBI, and follows their own SOPs with regard to maintaining a blind. 
x The majority of the study team members will remain completely blinded to all clinical 
data and will not participate in any review or analysis of these data until the final 
database lock or termination of the study. Some members may be unblinded on a patient 
level as required by the scope of their work. Specific firewalls exist between the blinded 
and unblinded team members to ensure no transfer of clinical data from an unblinded 
team member to a blinded team member.  
x To support regular safety reviews and the interim analysis, the analyses will be conducted 
by an independent third party (i.e., an unblinded team at the CRO, Parexel).  
The unblinded statistician and programmer from the third/independent party will send the 
unblinded data and analyses directly to the DSMB (the roles and responsibilities of the 
independent DSMB are detailed in a separate charter). Only blinded aggregate data for 
the study population as a whole (i.e., not by Arm) will be shared with the 
Sponsor. Pharmacovigilance safety review will be conducted by internal, unblinded 
personnel. 
x All data collected for this study are contained in the electronic data capture system  
(EDC; Oracle InForm) with audit trail capability consistent with 21 CFR Part 11; access 
to these data is password protected and limited to individuals responsible for reviewing 
and monitoring individual patient safety data or overseeing protocol adherence. 


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5. 
ANALYSIS SETS 
5.1. 
Intent-to-Treat Analysis Set 
5.1.1. 
Intent-to-Treat Analysis Set in the General Population (ITT-GP) 
The intent-to-treat (ITT) analysis set in the General Population (ITT-GP) will consist of all 
randomized patients with study drug assignment designated according to initial randomization.  
ITT-GP will be used for the analysis of the General Population for evaluating efficacy endpoints, 
patients’ characteristics and patient disposition.   
5.1.2. 
Intent-to-Treat Analysis Set in the pSTAT3(+) Subpopulation, the pSTAT3(-) 
Subpopulation and the pSTAT3(Unknown) Subpopulation  
The pSTAT3 Subpopulations will be defined by the results of a Clinical Trial Assay (CTA) for 
specimen age within a defined cut-section stability (CSS) window (6 months at IA or final CSS 
window at FA). Specimen age is the time interval between sectioning and staining.   
A patient with positive pSTAT3 status within a defined CSS window is the one with pSTAT3 
positive designated by CTA assay with specimen age up to 6-month at IA or up to final CSS 
window at FA.   
A patient with negative pSTAT3 status within a defined CSS window is the one with pSTAT3 
negative designated by CTA assay with specimen age up to 6-month at IA or up to final CSS 
window at FA.   
A patient with unknown pSTAT3 status within a defined CSS window is the one with no 
specimen submitted for testing, specimen identified as non-evaluable upon pathology evaluation, 
tissues test out of a defined CSS window or missing due to any other reasons. 
5.1.2.1. 
Intent-to-Treat Analysis Set in the pSTAT3(+) Subpopulation (ITT-pSTAT3(+)) 
The intent-to-treat analysis set in the pSTAT3(+) Subpopulation (ITT-pSTAT3(+)) will consist 
of all randomized patients with study drug assignment designated according to initial 
randomization and having positive pSTAT3 status tested within a defined CSS window  
(6 months at IA or Final CSS window at FA). ITT-pSTAT3(+) will be used for the analysis for 
the pSTAT3(+) Subpopulation for evaluating efficacy endpoints, patients’ characteristics and 
patient disposition.  
5.1.2.2. 
Intent-to-Treat Analysis Set in the pSTAT3(-) Subpopulation (ITT-pSTAT3(-)) 
The intent-to-treat analysis set in the pSTAT3(-) Subpopulation (ITT-pSTAT3(-)) will consist of 
all randomized patients with study drug assignment designated according to initial randomization 
and having negative pSTAT3 status tested within a defined CSS window (6 months at IA or 
Final CSS window at FA). ITT-pSTAT3(-) will be used for the analysis for the pSTAT3(-) 
Subpopulation for evaluating efficacy endpoints, patients’ characteristics and patient disposition 
at the IA and/or FA depending on decision from the IA.  


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5.1.2.3. 
Intent-to-Treat Analysis Set in the pSTAT3(Unknown) Subpopulation (ITT-
pSTAT3(Unknown)) 
The intent-to-treat analysis set in the pSTAT3(Unknown) Subpopulation  
(ITT-pSTAT3(Unknown)) will consist of all randomized patients with study drug assignment 
designated according to initial randomization and having unknown pSTAT3 status.  
ITT-pSTAT3(Unknown) will be used for the analysis for the sensitivity analysis for evaluating 
impact of missing biomarker status of the primary and key secondary endpoints.   
5.1.2.4. 
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 CSS study is ongoing to establish the final 
pSTAT3 CSS window which is expected to be completed by Feb 2020.   
At the time of the IA in the CanStem303C study, CSS 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 IA, 
therefore, included pSTAT3 biomarker status results for cut slide specimens age up to 6 months.  
That is, the IA assumed a CSS window of 6 months.   
However, after the IA 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. That is, the final CSS window could be longer than 6 months and up to  
15 months. Consequently, more patients with pSTAT3 biomarker results could be included in the 
FA of the CanStem303C study. Table 5 presents preliminary estimated number (% of ITT-GP) 
of enrolled patients for all possible CSS windows in the CanStem303C study at the time this 
document was being prepared. Actual number may vary at the final analysis.    
Table 5: 
Preliminary Estimated Number of Specimens tested within Various Stability 
Windows in the CanStem303C study 
Number of patient specimens collected within 
specified stability window 
n (%) for CTA 
Increment %  
from a CSS of 6-month 
Total number of patients enrolled 
1253  
 
Number of patient specimens collected 
1127 (90.2%) 
 
Stability window of 6-month  
859 (68.6 %) 
 
Stability window of 7-month 
876 (70.1 %) 
1.4% 
Stability window of 8-month 
891 (71.1 %) 
2.6% 
Stability window of 9-month 
904 (72.1 %) 
3.6% 
Stability window of 10-month 
918 (73.3 %) 
4.7% 


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Stability window of 11-month 
944 (75.3 %) 
6.8% 
Stability window of 12-month 
962 (76.8 %) 
8.2% 
Stability window of 13-month 
987 (78.8 %) 
10.2% 
Stability window of 14-month 
1004 (80.1 %) 
11.6% 
Stability window of 15-month 
1023(81.6 %) 
13.1% 
Note: Number of patient specimens with pSTAT3 status determined by testing specimens stored at the respective time-frames; 1 
specimen reported per patient. The projected increase in the specimens represents pSTAT3(+), pSTAT3(-) and Non-Evaluable 
(NE) upon pathology evaluation.   
5.1.2.5. 
Subsets of ITT-pSTAT3(+) and ITT-pSTAT3(-) at the FA 
As a result of evolving knowledge of CSS window, ITT-pSTAT3(+) at the FA consists of 
patients from two subsets:   
x ITT-pSTAT3(+)-Subset-1 will consist of ITT-pSTAT3(+) patients with specimen age up to a 
6-month CSS window.   
x ITT-pSTAT3(+)-Subset-2 will consist of ITT-pSTAT3(+) patients with specimens age > 6 
months and <= final CSS window.  
Similarly, ITT-pSTAT3(-) at the FA consists of patients from two subsets: 
x ITT-pSTAT3(-)-Subset-1 will consist of ITT-pSTAT3(-) patients with specimen age up to a 
6-month CSS window.   
x ITT-pSTAT3(-)-Subset-2 will consist of ITT-pSTAT3(-) patients with specimens age > 6 
months and <= final CSS window.  
A patient with unknown pSTAT3 status due to out of 6-month CSS window at IA may have 
either pSTAT3 positive or pSTAT3 negative status at the FA when considering the final CSS 
window established wider than IA. Therefore, it is expected that there will be fewer patients with 
unknown pSTAT3 status within the final CSS window at the FA, compared to the IA with  
6-month CSS window.  
Figure 4 below shows the pSTAT3 Subpopulations components at the IA and at the FA.  


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Figure 4: 
pSTAT3 Subpopulations Components at Interim Analysis and Final Analysis 
 
Note: All specimens will be tested only one time regardless of final stability window. 
5.1.2.6. 
Biomarker Analysis Set (BAS) 
The biomarker analysis set will consist of all randomized patients who have 1 evaluable result of 
pSTAT3 status (positive or negative) within a defined CSS window. It will consist of both  
ITT-pSTAT3(+) and ITT-pSTAT3(-) patients.  
5.2. 
Safety Analysis Set 
5.2.1. 
Safety Analysis Set in the General Population (SAS-GP) 
The safety analysis set in the General Population (SAS-GP) will include all randomized patients 
who receive at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with treatment assignment 
designated according to the actual study treatment received. SAS-GP will be used for all safety 
and drug exposure evaluation in the General Population.   
5.2.2. 
Safety Analysis Set in the pSTAT3(+) Subpopulation (SAS-pSTAT3(+)) 
The safety analysis set in the pSTAT3(+) Subpopulation (SAS-pSTAT3(+)) will include all 
randomized patients who receive at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with 
treatment assignment designated according to the actual study treatment received and having 
positive pSTAT3 status within a defined CSS window (6 months at IA or Final CSS window at 
FA). SAS-pSTAT3(+) will be used for all safety and drug exposure evaluation in the pSTAT3(+) 
Subpopulation.   


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5.2.3. 
Safety Analysis Set in the pSTAT3(-) Subpopulation (SAS-pSTAT3(-)) 
The safety analysis set in the pSTAT3(-) Subpopulation (SAS-pSTAT3(-)) will include all 
randomized patients who receive at least 1 dose of study drug (BBI-608 and/or FOLFIRI) with 
treatment assignment designated according to the actual study treatment received and having 
negative pSTAT3 status within a defined CSS window (6 months at IA or Final CSS window at 
FA). SAS-pSTAT3(-) will be used for all safety and drug exposure evaluation in the pSTAT3(-) 
Subpopulation at IA and/or FA depending on decision from the IA.   
5.2.4. 
Safety Analysis Set in the pSTAT3(Unknown) Subpopulation  
(SAS-pSTAT3(Unknown))  
The safety analysis set in the pSTAT3(Unknown) Subpopulation (SAS-pSTAT3(Unknown)) will 
include all randomized patients who receive at least 1 dose of study drug (BBI-608 and/or 
FOLFIRI) with treatment assignment designated according to the actual study treatment received 
and having unknown pSTAT3 status.  
5.3. 
ORR/DCR Analysis Set 
5.3.1. 
ORR/DCR Analysis Set in the General Population (ODAS-GP) 
The ORR/DCR analysis set in the General Population (ODAS-GP) will include all randomized 
patients with measurable disease by RECIST 1.1 at randomization with study drug assignment 
designated according to initial randomization. ODAS-GP will be used for evaluating BOR, ORR, 
DCR and DoR in the General Population.  
5.3.2. 
ORR/DCR Analysis Set in the pSTAT3(+) Subpopulation (ODAS-pSTAT3(+)) 
The ORR/DCR analysis set in the pSTAT3(+) Subpopulation will include all randomized 
patients with measurable disease by RECIST 1.1 at randomization with study drug assignment 
designated according to initial randomization and having positive pSTAT3 status within a 
defined CSS window (6 months at IA or Final CSS window at FA). ODAS-pSTAT3(+) will be 
used for evaluating BOR, ORR, DCR and DoR in the pSTAT3(+) Subpopulation.   
x ODAS-pSTAT3(+)-Subset-1 will consist of ODAS-pSTAT3(+) patients with specimen age 
up to a 6-month CSS window.   
x ODAS-pSTAT3(+) -Subset-2 will consist of ODAS-pSTAT3(+) patients with specimens age 
> 6 months and <= final CSS window. 
5.3.3. 
ORR/DCR Analysis Set in the pSTAT3(-) Subpopulation (ODAS-pSTAT3(-)) 
The ORR/DCR analysis set in the pSTAT3(-) Subpopulation will include all randomized patients 
with measurable disease by RECIST 1.1 at randomization with study drug assignment designated 
according to initial randomization and having negative pSTAT3 status within a defined CSS 
window (6 months at IA or Final CSS window at FA). ODAS-pSTAT3(-) will be used for 
evaluating BOR, ORR, and DCR in the pSTAT3(-) Subpopulation at IA and/or FA depending on 
decision from the IA.   


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x ODAS-pSTAT3(-)-Subset-1 will consist of ODAS-pSTAT3(-) patients with specimen age up 
to a 6-month CSS window.   
x ODAS-pSTAT3(-) -Subset-2 will consist of ODAS-pSTAT3(-) patients with specimens age 
> 6 months and <= final CSS window. 
Note that ODAS-pSTAT3(+) and ODAS-pSTAT3(-) at the IA are subsets of those at the FA, as 
explained in Section 5.1.4.  
5.3.4. 
ORR/DCR Analysis Set in the pSTAT3(Unknown) Subpopulation (ODAS-
pSTAT3(Unknown)) 
The ORR/DCR analysis set in the pSTAT3(Unknown) Subpopulation will include all 
randomized patients with measurable disease by RECIST 1.1 at randomization with study drug 
assignment designated according to initial randomization and having unknown pSTAT3 status.   
5.4. 
QoL Analysis Set 
5.4.1. 
QoL Analysis Set in the General Population (QoL-GP) 
The QoL Analysis Set in the General Population (QoL-GP) will include all randomized patients 
who have at least 1 QoL assessment in the General Population. QoL-GP will be used for QoL 
endpoint analysis in the General Population.  QoL assessments from 14 days prior to 
randomization and afterward are considered.   
5.4.2. 
QoL Analysis Set in the pSTAT3(+) Subpopulation (QoL-pSTAT3(+)) 
The QoL Analysis Set in the pSTAT3(+) Subpopulation (QoL-pSTAT3(+)) will include all 
randomized patients who have at least 1 QoL assessment and having positive pSTAT3 status 
within a defined CSS window (6 months at IA or Final CSS window at FA). QoL-pSTAT3(+) 
will be used for QoL endpoint analysis in the pSTAT3(+) Subpopulation.   
5.4.3. 
QoL Analysis Set in the pSTAT3(-) Subpopulation (QoL-pSTAT3(-)) 
The QoL Analysis Set in the pSTAT3(-) Subpopulation (QoL-pSTAT3(-)) will include all 
randomized patients who have at least 1 QoL assessment and having negative pSTAT3 status 
within a defined CSS window (6 months at IA or Final CSS window at FA). QoL-pSTAT3(-) 
will be used for QoL endpoint analysis in the pSTAT3(-) Subpopulation at IA and/or FA 
depending on decision from the IA.   
5.5. 
PK Analysis Set 
5.5.1. 
PK Analysis Set in the General Population (PK-GP) 
The PK analysis set in the General Population (PK-GP) will include patients in the safety 
analysis set who have at least 1 quantifiable concentration in the General Population. PK-GP will 
be used for PK concentration presentations in the General Population.   


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5.5.2. 
PK Analysis Set in the pSTAT3(+) Subpopulation (PK-pSTAT3(+)) 
The PK analysis set in the pSTAT3(+) Subpopulation (PK-pSTAT3(+)) will include patients in 
the safety analysis set who have at least 1 quantifiable concentration and having positive 
pSTAT3 status tested within a defined CSS window (6 months at IA or Final CSS window at 
FA). PK-pSTAT3(+) will be used for PK concentration presentations in the pSTAT3(+) 
Subpopulation.   
5.5.3. 
PK Analysis Set in the pSTAT3(-) Subpopulation (PK-pSTAT3(-)) 
The PK analysis set in the pSTAT3(-) Subpopulation (PK-pSTAT3(-)) will include patients in 
the safety analysis set who have at least 1 quantifiable concentration and having negative 
pSTAT3 status tested within a defined CSS window (6 months at IA or Final CSS window at 
FA). PK-pSTAT3(-) will be used for PK concentration presentations in the pSTAT3(-) 
Subpopulation.   
5.6. 
Per-Protocol Analysis set  
The Per-Protocol analysis set will consist of all ITT patients who do not have major protocol 
deviations that would impact the study outcome significantly as determined by the medical 
monitor and biostatistician prior to database unblinding.   
Depending on the medical review, the major protocol deviations may include the following: 
• 
Patients that are dosed in the study despite not satisfying the inclusion criteria; 
• 
Patients that develop withdrawal criteria but are not withdrawn; 
• 
Patients that receive the wrong treatment or an incorrect dose; 
• 
Patients that receive an excluded concomitant medication; 
• 
Deviation from good clinical practice (GCP). 
Protocol deviations will be identified and maintained in a separate document, and the list of 
patients with protocol deviations including those with major protocol deviations that may be 
excluded from efficacy analysis will be finalized before database lock and unblinding. 
Per-protocol analysis sets are defined for Overall Survival and for Progression Free Survival 
endpoints separately. The detailed exclusion was defined in Protocol Deviation Specs Version 
(226969_Protocol_Deviation_Specification_Form_PDSF_20200521_V4.0) dated 21 May 2020 
by blinded review. The decisions for each patient to be included or excluded from the per 
protocol analysis sets will be determined by the medical monitor and biostatistician prior to 
database unblinding.    
5.6.1. 
Per-Protocol Analysis Set in the General Population for Overall Survival  
(PPAS-GP-OS) 
The Per-Protocol analysis set in the General Population for Overall Survival (PPAS-GP-OS) will 
consist of all ITT patients who do not have major protocol deviations that would impact the 
overall survival endpoint. Patients who randomized but not treated will be excluded from  
PPAS-GP-OS.   


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5.6.2. 
Per-Protocol Analysis Set in the pSTAT3(+) Subpopulation for Overall Survival 
(PPAS-pSTAT3(+)-OS) 
The Per-Protocol analysis set in the pSTAT3(+) Subpopulation for Overall Survival  
(PPAS-pSTAT3(+)-OS) will consist of PPAS-GP-OS patients who have positive pSTAT3 status 
tested within the final CSS window.   
5.6.3. 
Per-Protocol Analysis Set in the General Population for Progression Free 
Survival (PPAS-GP-PFS) 
The Per-Protocol analysis set in the General Population for Progression Free Survival  
(PPAS-GP-PFS) will consist of all ITT patients who do not have major protocol deviations that 
would impact the PFS endpoint. Patients who randomized but not treated will be excluded from 
PPAS-GP-PFS.   
5.6.4. 
Per-Protocol Analysis Set in the pSTAT3(+) Subpopulation for Progression Free 
Survival (PPAS-pSTAT3(+)-PFS) 
The Per-Protocol analysis set in the pSTAT3(+) Subpopulation for Progression Free Survival 
(PPAS-pSTAT3(+)-PFS) will consist of PPAS-GP-PFS patients who have positive pSTAT3 
status tested within final CSS window.    
5.7. 
Treatment Allocation  
Patients who were randomized, but not treated with study drug will be reported under their 
randomized treatment arm for efficacy analyses. However, by definition they are excluded from 
the safety analyses.  
Patients who are randomized but received incorrect treatment will be reported under their 
randomized treatment for efficacy analyses and will be reported under the treatment they actually 
received for all safety analyses and treatment evaluations.   
 
 


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Table 6: 
High Level Summary of Analysis and Analysis Sets at Final Analysis 
 
 
General 
Population  
pSTAT3(+)* 
pSTAT3(-)* 
pSTAT3(Unknown)! 
Disposition/Baseline
/MH 
 
ITT-GP 
ITT-pSTAT3(+)$ 
ITT-pSTAT3(-) 
ITT-pSTAT3(Unknown) 
Efficacy  
OS/PFS 
ITT-GP 
ITT-pSTAT3(+)$ 
ITT-pSTAT3(-) 
ITT-pSTAT3(Unknown) 
DCR/ORR/BOR 
ODAS-GP 
ODAS-pSTAT3(+)$ 
ODAS-pSTAT3(-) 
ODAS-pSTAT3(Unknown) 
QoL 
QoL-GP 
QoL-pSTAT3(+) 
QoL-pSTAT3(-) 
 
Safety  
Safety/PE/VS/LB 
SAS-GP 
SAS-pSTAT3(+) 
SAS-pSTAT3(-) 
 
*: pSTAT3(+) and pSTAT3(-) will be based on pSTAT3 status from all patients with specimen age <= final CSS window. 
!: includes patients with unknown pSTAT3 status based on the final CSS window; patients with no specimen submitted for testing, specimen identified as non-
evaluable upon pathology evaluation, tissues test out of a defined CSS window or missing due to any other reasons. 
$: combined Subset 1 and Subset 2 patients will be used for primary analysis, sensitivity analysis based on Subset 1 will be performed. 


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6. 
DATA HANDLING 
6.1. 
Clinical Cutoff and Analysis Cutoff  
Clinical Cutoff date for the IA will be identified for this study based on when approximately  
425 deaths (50% of total target number of deaths in ITT-GP) occur. Clinical cutoff date for the 
FA may vary depending on the outcome of the IA. When outcome from IA are to continue both 
hypotheses, clinical cutoff date will be based on when the total target number of deaths from 
ITT-pSTAT3(+) or 850 deaths in ITT-GP occur, whichever comes later. This means that the 
clinical cutoff date for the study at the FA will be a single calendar date, not differentiated by 
analysis set.   
Based on the current event prediction for both General Population and pSTAT3(+) 
Subpopulation in a blinded fashion by an independent outside vendor who has access to 
biomarker status of individual patients but no treatment assignment information, the target 
number of deaths in pSTAT3(+) Subpopulation based on 6-month CSS window will happen 
prior to 850 death in General population. In this scenario, the analysis cutoff date of both  
ITT-pSTAT3(+) and General Population will be the same as clinical cutoff date, however, 
analysis cutoff date of ITT-pSTAT3(+)-Subset-2 needs to be a pre-specified calendar date before 
the final analysis cutoff date. This is to ensure the independence of the test statistics from the 
three components in the combination function approach as described in Section 4.5.2 . 
Table 7 below presents the clinical cutoff dates in the study and the analysis cutoff dates for the 
two analysis populations in the scenario mentioned above.   
Table 7: 
Clinical and Analysis Cutoffs in the scenario that 310 deaths in ITT-
pSTAT3(+) happen earlier than 850 in ITT-GP 
 
Clinical Cutoff 
Analysis Cutoff 
General Population  
Date when 850 deaths 
occur in GP* 
Date when 850 deaths occur in 
GP* 
pSTAT3(+) Subpopulation 
Date when 850 deaths 
occur in GP* 
Subset 1: Date when 850 deaths 
occur in GP* 
Subset 2: A pre-determined 
calendar date before Date when 
850 deaths occur in GP  
* Date when 850 deaths occur in GP will be pre-determined by prediction prior to database lock.  
To operationally facilitate database lock process, the calendar dates for the clinical cutoff and 
analysis cutoff dates will be pre-determined based on continuous blinded data monitoring before 
the database lock.   
All summaries and analyses will include all data pertaining to visits/assessments performed up to 
these analysis cutoff dates. Sensitivity analysis to include all data update to the clinical cutoff 
date will be performed as well. 


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6.2. 
Handling of Missing Values 
6.2.1. 
Missing or Partial Death Dates 
It is recommended that the database be designed to mandate a complete death date.  If there is a 
record for death, but the date is missing or is partial, it will be imputed based on the last contact 
date.   
x If the entire date is missing, the death date will be imputed as the day after the date of last 
contact.  
x If the day or both day and month are missing, the death date will be imputed to the 
maximum of the full (non-imputed) day after the date of last contact,   
1st day of the month and year of death, if day of death is missing OR January 1st of the 
year of death, if both day and month of death are missing.  
6.2.2. 
Partial or Missing Start Date or End Date for Adverse Event or Medications 
For the patient data listings, no imputation of incomplete dates will be applied. The listings will 
present the incomplete dates without any change. 
The missing day of onset of an AE or start date of a therapy will be imputed as: 
 
x first dose date if the month and year of the event is the same as first dose date;  
x otherwise, the 1st of the month that the event occurred. 
The missing day of resolution of an AE or end date of a therapy will be imputed as:  
x the last day of the month of the occurrence. If the patient died in the same month, then set 
the imputed date as the death date.  
Missing both day and month of an AE or start date of a therapy will be imputed as:  
x the date of the first dose, if the onset year is the same as the year of the first dose date; 
x otherwise, January 1 of the year of onset.  
If the resolution date of an AE or end date of a therapy is missing both the day and month, the 
date will be imputed as:  
x December 31 of the year of occurrence. If the patient died in the same year, then set the 
imputed date as the death date. 
If the date is completely missing, then no imputation will be done and the event will be 
considered as treatment emergent (for AEs) or concomitant (for medications) unless the end date 
rules out the possibility. 
6.2.3. 
Partial or Missing Date for New Anticancer Treatment  
For complete missing of start date for new anti-cancer treatment, the date of last dose of study 
drug + 1 will be used as start date.   


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For partial dates of start date for new anti-cancer treatment,   
x If day is missing, the 1st of the month will be assigned. Compared with date of last dose 
of study drug +1 and take the one which come later.  
x If day and month is missing, the 1st of Jan will be assigned. Compared with the date of 
last dose of study drug +1, and take the one which come later. 
6.2.4. 
Partial Date for Pathological Diagnosis 
Dates missing the day, or both the day and month of the year will adhere to the following 
conventions in order to calculate the months from the first pathological diagnosis: 
x The missing day of the first pathological diagnosis will be set to the first day of the month 
that the diagnosis occurred. 
x If the date of the first pathological diagnosis is missing both the day and month, the diagnosis 
date will be set to January 1 of the year of diagnosis. 
6.2.5. 
Missing Efficacy Endpoints 
For primary and secondary efficacy analyses no values will be imputed for missing data. For 
time to event endpoints, non-event observations will be censored and for ORR/DCR, patients 
with no post-baseline tumor evaluations or missing baseline tumor evaluation will be counted as 
non-responders.   
6.2.6. 
Missing PK/PD Values 
The handling of BLQ values for nonlinear mixed-effects modeling (aka Population-PK, or  
Pop-PK) will be described in a separate analysis plan. For the purpose of data tabulation, 
summary statistics, and by-time point graphics, BLQ values will be treated as zero.   
6.2.7. 
Missing QoL Data 
For the EORTC QLQ-C30, if less than half of the constituent items on the QLQ-C30 have been 
answered for a multi-item subscale, that subscale will be considered as missing. Single-item 
subscales will be considered missing if the constituent item is incomplete.   
6.2.8. 
Missing Biomarker Data 
When analyzing the pSTAT3(+) Subpopulation, patients without biomarker data will be left as 
is. Imputation methods such as multiple imputation methods will be applied as a sensitivity 
analysis if needed.   
6.3. 
General Data Handling 
x Age will be computed from July 1 of the year of birth to the date of Informed Consent, as: 
(Date of Informed Consent - July 1 of the year of Birth +1)/365.25 round down to the nearest 
integer.  
 


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x Baseline Measurements: 
- Efficacy: The last non-missing measurement on or prior to the date of randomization will 
serve as the baseline measurement. In the event such a value is missing, the last assessment 
completed prior to or on the date of the first study drug administration (either napabucasin or 
FOLFIRI, whichever was administered first) will be used as the baseline assessment so long 
as this assessment was taken within 35 days of randomization (for example, baseline ECOG, 
baseline LDH). The tumor scans outside the time window (within 35 days of randomization) 
will be considered a protocol deviation and will be evaluated on a case by case basis.   
- Safety: The last non-missing assessment prior to or on the date of the first study drug 
administration (either napabucasin or FOLFIRI, whichever was administered first) will be 
used as the baseline assessment. In the case that no any study drug administrated, the last 
non-missing assessment prior to or on the randomization date will be used as baseline 
assessment.   
- Other baseline characteristics: The last non-missing measurement on or prior to the date of 
randomization will serve as the baseline measurement. In the event such a value is missing, 
the last non-missing assessment completed prior to or on the date of the first dose of study 
drug administration (either napabucasin or FOLFIRI, whichever was administered first) will 
be used as the baseline assessment.   
 
x For the safety parameters: unless otherwise specified, post baseline reporting period includes 
non-missing records collected from after first dose of study treatment until 30 days following 
last dose of study treatment (napabucasin and/or FOLFIRI).  
 
x Schedule and unscheduled visits post baseline: unless otherwise specified, for the summary 
by visit post baseline, only scheduled visits will be included; for summary of the maximum 
or maximum changes post baseline, all scheduled visits and unscheduled visits will be 
included.  All records (scheduled/unscheduled) regardless post baseline reporting period or 
not will be listed in the data listings.   
 
x Study Day: 
- For safety analysis: Study day is calculated as: 
o Assessment date – first dose date + 1; if the assessment was performed on or after the 
first dose day. 
o Assessment date – first dose date; if the assessment was performed prior to the first 
dose date. 
- For efficacy (time to event) analysis: Study day is calculated as: 
o Assessment date – randomization date + 1; if the assessment was performed on or 
after the randomization date. 
o Assessment date – randomization date; if the assessment was performed prior to the 
randomization date. 
 
x Time-to-event: The event or censoring time (days) is calculated as:  


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Date of event/censoring – Date of randomization + 1 
 
x Duration: Duration (except for duration of study treatment) is calculated as: 
     - Duration in days: (End Date – Start Date + 1) 
     - Duration in weeks: (End Date – Start Date + 1) / 7 
     - Duration in months: (End Date – Start Date + 1) / 30.4375; Average days in months = 
average number of days in a year /12 
     - Duration in years: (End Date – Start Date + 1) / 365.25; Average days in a year = 365.25, 
reflecting the Julian Year of 3 years with 365 days each and 1 leap year of 366 days. 


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7. 
STATISTICIAL METHODOLOGY AND STATISTCAL 
ANALYSES  
7.1. 
Statistical Methods 
Whilst every effort has been made to pre-specify all analyses in this statistical analysis plan, if 
any additional exploratory analyses are found to be necessary, the analyses and the reasons for 
them will be detailed in the clinical study report (CSR).  
7.1.1. 
Analyses of Time to Event endpoints 
Time to event endpoints will be summarized using the Kaplan-Meier method and displayed 
graphically when appropriate. Median event times and 2-sided 95% confidence interval for each 
median will be provided [Brookmeyer R and Crowley JJ, 1982] with log-log transformation. 
Time to event endpoints will be compared between the treatments using log-rank tests. Cox 
proportion-hazards (PH) model will be fitted and the estimated hazard ratio and 2-sided 95% 
confidence interval will be provided. 
Please see Section 7.2.2 for details on how log-rank tests and Cox-PH models will be applied for 
the General Population and the pSTAT3(+) Subpopulation differently. 
In addition, Cox-PH models will be used to explore the potential influences of baseline 
stratification factors (listed in Section 3.4.1) and other baseline characteristics on time to event 
endpoints.  
7.1.2. 
Analyses of Binary Endpoints  
The rates of binary efficacy endpoints for the 2 arms will be compared using a  
Cochran-Mantel-Haenszel (CMH) test stratified for baseline stratification factors (listed in 
Section 3.4.1).  In addition, point estimates of the rates for each treatment arm will be provided 
along with the corresponding exact 2-sided 95% CI based on the Clopper Pearson Method.  
The difference of point estimates between arms will be provided along with the 2-sided 95% CI 
based on Harmonic Means method adjusting stratification factor or normal approximation 
(unstratified). 
7.1.3. 
Analyses of Continuous Data 
Descriptive statistics, including the mean, standard deviation, median, minimum and maximum 
values will be provided for continuous endpoints.  
7.1.4. 
Analyses of Categorical Data 
The number and percentage of patients in each category will be provided for categorical 
variables. Change from baseline for Categorical data will be evaluated by shift table if 
appropriate. Chi-square test may be used for comparison if needed.   
P-values greater than or equal to 0.0001 will be presented to 4 decimal places. P-values less than 
0.0001 will be presented as “<0.0001”. 


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7.2. 
Statistical Analysis 
7.2.1. 
Standard Analysis 
All the standard analysis will be summarized for the General Population and the pSTAT3(+) 
Subpopulation at IA and FA. Similar information will be summarized for the pSTAT3(-) 
Subpopulation at the IA and/or FA depending on the IA outcomes.   
7.2.1.1. 
Disposition of Patients 
All patients enrolled (signed informed consent) will be summarized for the General Population 
and the pSTAT3(+) Subpopulation. The number and percentage of study patients will be 
tabulated for different analysis sets as specified in Section 5 .   
The number and percentage of patients enrolled by site will be summarized by treatment arm in 
ITT-GP and/or ITT-pSTAT3(+) and/or ITT-pSTAT3(-) and/or ITT-pSTAT3(Unknown).  
The number and percentage of patients reaching end of treatment (BBI-608, FOLFIRI, and 
bevacizumab if provided)) and end of study, along with discontinuation reasons will be 
summarized in ITT-GP and/or ITT-pSTAT3(+) and/or ITT-pSTAT3(-) and/or  
ITT-pSTAT3(Unknown).   
7.2.1.2. 
Demographic and Other Baseline Characteristics 
The following demographic and baseline characteristics will be summarized by treatment arm for 
patients in ITT-GP and/or ITT-pSTAT3(+) and/or ITT-pSTAT3(-) and/or  
ITT-pSTAT3(Unknown).   
x Age, age group (<65 years vs. ൒65 years), Age (<65 years, ≥ 65 – 75 years, ≥ 75 – 85 
years and ≥85 years), sex, race, ethnicity, ECOG status, and smoking history 
x Weight (kg), height (cm), child-bearing potential, and body mass index (BMI) 
Demographic and baseline characteristics will also be listed for each patient. 
7.2.1.3. 
Disease Characteristics, Medical History, and Primary Therapy 
Disease characteristics including, but not limited to, medical history, and prior therapy will be 
summarized by treatment arm for the ITT-GP and/or ITT-pSTAT3(+) and/or ITT-pSTAT3(-) 
and/or ITT-pSTAT3(Unknown). 
x Primary Type of Cancer (Colon vs Rectal); Primary Tumor Present or Resected; Primary 
Tumor Location, Histology Sub-classification 
x Disease Measurability (Present vs Not Present); all target and non-target lesions: presence 
of target lesions, site of disease, numbers of disease sites; target lesions: number of target 
lesions, largest measure, site of disease, method of assessment   
x KRAS Mutation Status (Mutant vs Wild Type), NRAS Mutation status (Mutant vs Wild 
Type, Unknown) 
x Prior radiotherapy (Yes vs No); Anatomical Target of Procedure; Indication 


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x Prior cancer system medication (Yes vs No); Prior Systemic Treatment: 1st line, 
neoadjuvant/adjuvant and 1st line, neoadjuvant/adjuvant, and other; prior exposure to 
specific types of therapy: Oxaliplatin, Fluoropyrimidine, and Bevacizumab; number of 
unique therapeutics per patients: therapeutic received (based on ingredients coded from 
Who Drug Coding Dictionary)    
x Prior Cancer Surgery by SOC and Preferred Terms of Medical Dictionary for Regulatory 
Activities (MedDRA) 
x The number and percentages of patients within different specimen age duration  
(൑ 6 month, > 6 month to Final CSS window and Patients out of final CSS window) will 
be summarized by Biomarker status  
x Reasons for ITT-pSTAT3(unknown) will be summarized.   
x Tissues sample collected from EDC are summarized:  tumor tissue sample type (block, 
core and slides, and slides); sample acquisition type (resection, biopsy), site (primary and 
metastatic). When multiple records reported for one patient, the record was evaluated for 
biomarker status from vendor will be used in the summary.    
7.2.1.4. 
Protocol Deviation 
A summary of the total number of major protocol deviation events and the number and 
percentage of patients in each type of major protocol deviation will be provided by treatment 
group and overall, in ITT-GP and/or ITT-pSTAT3(+) and/or ITT-pSTAT3(-). 
All major or minor Protocol Deviation will be listed and PD due to COVID-19 pandemic will be 
flagged.    
7.2.1.5. 
Study Treatment   
An overall summary of drug exposure will be presented including number of maximum treated 
cycles, numbers and percentages of patients who had 1, 2, etc. Maximum treated cycles by 
treatment arm for SAS-GP and/or SAS-pSTAT3(+). A treated cycle for a specific drug is defined 
as a cycle in which the patient received any amount of any study drug (napabucasin and or 
FOLFIRI).   
Duration of exposure =Earliest date of {Latest date of {(start date of last cycle +13 days), last 
dose date of napabucasin}, death date, end of study date} – Earliest date of {first dose date of the 
FOLFIRI and/or napabucasin} +1. 
The following items will be summarized for BBI-608, FOLFIRI, and bevacizumab where 
appropriate as below: dose reduction, dose interruption and dose modification.   
 
 


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7.2.1.6. 
Exposure of BBI-608  
The details of BBI-608 dose modification in protocol 7.1.7 as below. 
Table 8: 
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 
240mg 2 times daily.  
Several measures of drug administration will be summarized.   
Cumulative dose, actual dose intensity and relative dose intensity of BBI-608 will be 
summarized for Arm 1 by overall, run-in and first 28 days. 
Treatment duration in days: 
x Overall intended treatment duration = earliest date of {latest date of {start date of last 
cycle +13 days, last dose date of napabucasin}, death date, end of study date} – earliest 
date of {first dose date of the FOLFIRI and/or napabucasin} +1. 
x Run-in treatment duration = actual number of days in run-in period where run-in period is 
defined as napabucasin treatment duration prior to first dose of FOLFIRI. 
x First 28 days intended treatment duration = earliest date of {start date of 1st cycle + 27 
days, death date, end of study date}– start date of 1st cycle +1. 
Cumulative dose (mg) in overall or run in or first 28 days is defined as the total dose (mg) that a 
patient received for napabucasin in overall, run-in or first 28 days, respectively. 
Actual dose intensity (DI) in mg/day: 
x Overall actual DI = overall accumulative dose in mg / overall intended treatment duration 
in days. 
x Run-in actual DI = actual total dose in mg in run-in / actual treatment duration in days in 
run-in.  
x First 28 days actual DI = actual total dose in mg in first 28 days / intended treatment 
duration in days in first 28 days.  
Relative dose intensity (%) in overall, run-in or first 28 days is defined as the actual DI in 
(mg/day) in overall, or run-in or first 28 days / 480 (mg/day) * 100. 
 
 


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Dose Changes 
The details of BBI-608 dose change are outlined below:   
x Dose Held - 2 or more consecutive doses held (AM-PM or PM-AM). 
x Dose Held Due to Non-AE - 2 or more consecutive doses held (AM-PM or PM-AM) due to 
reasons other than an adverse event (eg, subject forgot, subject decision or other reason). 
x Dose Held Due to AE - 2 or more consecutive doses held (AM-PM or PM-AM) due to 
adverse event. 
o Restarted at the same dose - Restarted at a dose same as the previous non-zero dose at 
the time of dose held. 
o Restarted as reduced dose (dose-decrease) - Restarted at a dose decreased from the 
previous non-zero dose at the time of dose held. 
 Dose increase to partial dose following reduction - An increase to <240 mg 
for 2 or more consecutive doses (AM-PM or PM-AM) following restart at 
reduced dose. 
 Dose increase to full dose following reduction - An increase to 240 mg for  
2 or more consecutive doses (AM-PM or PM-AM) following restart at 
reduced dose. 
7.2.1.7. 
Permanently Discontinued Due to AE: based on drug administration form.  
Exposure of FOLFIRI 
FOLFIRI Dose Modification is detailed in following table (Protocol Section: 7.1.5)  
Table 9: 
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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The FOLFIRI regimen includes the three components of irinotecan, leucovorin and 5-FU. 
Component specific exposure will be calculated for irinotecan, 5-FU Bolus and 5-FU Infusion 
separately.   
Cumulative dose, actual dose intensity and relative dose intensity for the specific component will 
be summarized for ARM 1 and ARM 2 overall and first 28 days.  
Intended treatment duration in weeks: 
x Overall intended treatment duration = (earliest date of {latest date of {start date of last 
cycle +13 days, last dose date of napabucasin}, death date, end of study date} – earliest 
date of {first dose date of the FOLFIRI} +1)/ 7. 
x First 28 days intended treatment duration = (earliest date of {start date of 1st cycle + 27 
days, start date of FOLFIRI within Day 28 ±3 window -1, start date of 1st cycle + 13 
days if patient died or end of study before 2nd dose of FOLFIRI}– start date of 1st cycle 
+1)/ 7. 
Cumulative dose (mg/m2) in first 28 days or overall is defined as the total dose (mg/m2) that the 
patient received for the specific component (Irinotecan, 5-FU Bolus and 5-FU Infusion, 
Leucovorin/Levoleucovorin) in first 28 days or overall, respectively. 
Actual dose intensity (mg/m2/week) in first 28 days or overall = cumulative dose for the specific 
component in mg/m2 in first 28 days or overall / intended treatment duration in weeks in first 28 
days or overall, for the specific component. Relative Dose Intensity (%) in first 28 days or 
overall = actual dose intensity in first 28 days or overall / targeted dose in weeks for the specific 
component * 100. Targeted dose is 90 mg/m2/week for Irinotecan, 1400 (mg/m2/week) for 5-FU 
Bolus and 5-FU Infusion, 200 mg/m2/week for Leucovorin, 100 mg/m2/week for 
Levoleucovorin. 
In order to calculate dose intensity for Leucovorin/Levoleucovorin together, the Levoleucovorin 
dose will be converting to the equivalent leucovorin by multiplying of 2.  
The BSA to be used for calculating each dose of specific component will be calculated using the 
Dubois & Dubois formula (see below) based on the last available weight and height prior to each 
infusion.  
BSA [m2] = (Weight [kg]0.425 * Height [cm]0.725) * 0.007184 
7.2.1.8. 
Exposure of Bevacizumab 
Exposure of bevacizumab will be summarized for the patients who are determined to receive 
bevacizumab by the investigator.   
Cumulative dose, actual dose intensity and relative dose intensity for bevacizumab will be 
summarized for ARM 1 and ARM 2 overall.  
Overall intended treatment duration in weeks = (Start date of the last cycle of bevacizumab  
+ 13 days - First dose date of bevacizumab + 1) / 7. Overall cumulative dose (mg/kg) = total 
dose (mg/kg) that the patient received for bevacizumab. 


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Actual overall dose intensity (mg/kg/week) = overall cumulative dose in mg/kg / overall 
intended treatment duration in weeks. 
Relative dose Intensity (%) overall = actual overall dose intensity in mg/kg/week / targeted dose 
(2.5 mg/kg/week.) for bevacizumab * 100. 
The weight in kg to be used for calculating RDI is derived on the last available weight prior to 
each infusion.   
Cumulative dose, actual dose intensity and relative dose intensity for bevacizumab will be 
summarized for ARM 1 and ARM 2 overall.  
7.2.2. 
Primary Analyses of Primary Endpoints 
Overall survival will be analyzed in ITT-GP and/or ITT-pSTAT3(+).  For ITT-GP, difference in 
OS between Arm 1 and Arm 2 will be analyzed by the log-rank test stratified by actual 
stratification factors (Section 3.4.1 ). And 1-sided p-value from stratified log-rank test will be 
reported. If any actual stratification factor proves to have an inadequate sample size, it will be 
dropped from the primary analysis or pooling will be applied. Details will be determined in a 
blinded fashion prior to any planned unblinded analysis or data base lock.  
Note that the sample size by stratification factor was reviewed and the following pooling strategy 
was decided prior to interim analysis in the blinded fashion.  Tumor RAS status, Time to 
Progression from start of 1st Therapy, and Bevacizumab as Part of Study Protocol Treatment 
will be the stratification factors in the primary analysis in the general population. Geographic 
Region and Location of the Primary Tumor (left vs right) will be dropped from the primary 
analysis. For pSTAT3(+) subpopulation, the primary analysis will be based on unstratified 
analysis (for log rank test or cox regression model).  This is because the stratified randomization 
is not conducted in this subpopulation.  Stratified analysis including three factors of RAS status, 
Time to PD, and Bevacizumab as part of study treatment will serve as sensitivity analysis.  
For ITT-pSTAT3(+), the 3 stage-wise p-values under the combination function approach will be 
produced from three parts of data (Subset 1 Stage 1, Subset 1 Stage 2 and Subset 2). Since 
Subset 2 will likely contain some sparse cells of its stratification factor combination due to a 
smaller sample size, the primary analysis for ITT-pSTAT3(+) will be based on unstratified 
analysis: difference in OS between Arm 1 and Arm 2 will be analyzed by the unstratified  
log-rank test. And 1-sided p-value from unstratified log-rank test will be reported.   
Estimates of the OS curves obtained from the Kaplan-Meier method will be presented and 
displayed graphically. The median survival time and corresponding 2-sided 95% CI will be 
provided for each treatment arm.   
Cox PH model stratified by actual stratification factors will be fitted for ITT-GP. Cox PH model 
unstratified will be fitted for ITT-pSTAT3(+). The estimated hazard ratio and 2-sided 95% CI 
will be provided.   
The 3 months, 6 months, 9 months, 12 months year, 18 months, 24 months, 30 months and 36 
months survival probability will be estimated using the Kaplan-Meier method and a 2-sided 95% 
CI for the log(-log(survival probability)) will be calculated using a normal approximation and 
then back transformed to give a CI for survival probability itself.  


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7.2.3. 
Sensitivity Analyses of the Primary Endpoints 
7.2.3.1. 
Sensitivity Analysis for Overall Survival in ITT-GP and/or ITT-pSTAT3(+)  
Sensitivity analysis for OS will be performed for ITT-GP and/or ITT-pSTAT3(+). Sensitivity 
Analysis of OS includes: 
The analyses of OS in the per-protocol population will be performed. An un-stratified log-rank 
test and Cox PH model may be used as sensitivity analyses for OS for ITT-GP. A stratified log-
rank test/stratified Cox PH model may be performed based on randomization stratification 
factors for ITT-GP.  
Stratified log-rank test and stratified Cox PH model based on actual stratification factor may be 
performed as sensitivity analyses for OS for ITT-pSTAT3(+) if possible.    
The potential influence of the stratification factors and other baseline characteristics may be 
evaluated by sensitivity analysis.  
Evaluation of the impact on OS of new anti-cancer therapy may be performed. The patients who 
receive subsequent (new) anti-cancer therapy may be excluded from the OS analysis or survival 
times may be censored at the time of new anti-cancer therapy. If applicable, other sensitivity 
analyses including the time-dependent Cox PH model may be used to adjust for the impact of 
new anti-cancer therapy.   
Due to the open label nature of this study, the early terminated rate (early termination rate 
defined as patients who terminated the study before taking any dose among all randomized 
patients) in Arm 1 and Arm 2 may be differentially influenced by the knowledge of the 
treatment. Early terminated rate and reasons for premature discontinuation will be summarized 
between Arm 1 and Arm 2. If applicable, appropriate sensitivity analysis may be conducted to 
assess the impact on OS by imbalance of early termination between the two treatment arms.  
Subgroup analysis will be performed considering the subgroup specified in Section 3.4.1 
and 3.4.2 or other subgroups where appropriate.   
For each subgroup level, the median OS (or other quartiles) and a 2-sided 95% CI will be 
provided for each arm. The difference in OS between Arm 1 and Arm 2 may be analyzed by 
unstratified log-rank test. The nominal 2-sided p-value may be provided in an exploratory basis. 
The estimated hazard ratio and 2-sided 95% CI may be provided based on un-stratified Cox PH 
model.   
Forest plots of hazard ratios from the primary analysis or other subgroup analyses will be 
provided where appropriate.   
For pSTAT3(+) Subpopulation, sensitivity analysis using overall survival data from Subset 1 
patients only (i.e., data within CSS window of 6 months) will be also performed at the FA. 
7.2.3.2. 
Analysis for Overall Survival in ITT-pSTAT3(-) and ITT-pSTAT3(Unknown) 
At the IA, overall survival for ITT-pSTAT3(-) and ITT-pSTAT3(Unknown) will be performed 
using similar method for primary analysis for primary endpoints (Section 7.2.2 ) and other 
sensitivity analysis as mentioned in Section 7.2.3.1 will be applied if needed. Depending on the 


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decision from the IA, similar analysis as Section 7.2.2 and Section 7.2.3.1 may be performed at 
the FA.   
7.2.4. 
Analyses of Key Secondary Endpoints 
PFS will be summarized in ITT-GP and/or ITT-pSTAT3(+). For ITT-GP, difference in PFS 
between treatment arms will be analyzed by the log-rank test stratified by actual stratification 
factors (Section 3.4.1). And 1-sided p-value from stratified log-rank test will be reported. The 
strategy of pooled or dropping is the same as the primary analysis of OS. For ITT-pSTAT3(+), 
similar to the primary analysis of OS, primary analysis for PFS will be based on unstratified  
log-rank test. And 1-sided p-value from unstratified log-rank test will be reported. Estimates of 
the PFS curves obtained from the Kaplan-Meier method will be presented.  PFS curves will be 
displayed graphically. The median event time (and other quartiles) and corresponding 2-sided 
95% CI will be provided for each treatment arm. The Cox PH model stratified by actual 
stratification factors will be fitted for ITT-GP. The Cox PH model unstratified will be fitted for 
ITT-pSTAT3(+). The estimated hazard ratio and 2-sided 95% CI will be provided.  
Sensitivity analysis for PFS will be performed for ITT-GP and/or ITT-pSTAT3(+).   
Sensitivity Analysis of PFS includes:  
The analyses of PFS in the per-protocol population will be performed for both general population 
and pSTAT3(+) subpopulation. An un-stratified log-rank test and Cox PH model will be used as 
sensitivity analyses for PFS for ITT-GP. A stratified log-rank test/stratified Cox PH model will 
be performed based on randomization stratification factors for ITT-GP.  
Stratified log-rank test and stratified Cox PH model based on actual stratification factor may be 
performed as sensitivity analyses for PFS for ITT-pSTAT3(+) if possible.    
Subgroup analysis will be performed considering the subgroup specified in Section 3.4.2 or other 
subgroups where appropriate.  Similar analysis methods as subgroup analysis for OS will be 
applied.   
Forest plots of hazard ratios from the primary analysis or other subgroup analyses will be 
provided where appropriate.   
For pSTAT3(+) Subpopulation, sensitivity analysis using PFS data from Subset 1 patients only 
(i.e., data within CSS window of 6 months) will be also performed at the FA.ORR will be 
summarized in ODAS-GP and/or ODAS-pSTAT3(+) by treatment arm. The ORR will be 
summarized for each treatment arm along with the corresponding exact 2-sided 95% CI using 
Clopper Pearson method.  For ODAS-GP, differences of ORR between the two arms will be 
compared using a 1-sided Cochran-Mantel-Haenszel test stratified by actual stratification factors. 
Treatment difference of ORR and its 95% CI based on harmonic mean method adjusting actual 
stratification factors will be provided. For ODAS-pSTAT3(+), differences of ORR between the 
two arms will be compared using a 1-sided Z-test via normal approximation. Treatment 
difference of ORR and its 95% CI based on normal approximation (unstratified) will be 
provided.  Best Overall Response will be summarized in ODAS-GP and/or ODAS-pSTAT3(+) 
by treatment arm. The best response of stable disease (SD) can be assigned if SD criteria were 
met at least once after randomization at a minimum interval of 8 weeks – 5 days window from 
randomization.   


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DCR will be analyzed similar as described for ORR for in ODAS-GP and/or ODAS-pSTAT3(+). 
At IA, PFS for ITT-pSTAT3(-) and DCR, ORR and BOR in ODAS-pSTAT3(-) will be analyzed 
using similar methods as above. Depending on the decision from the IA, similar analysis may be 
performed at the FA.   
Sensitivity analysis for ORR/DCR will be performed for ODAS-GP and/or ODAS-pSTAT3(+) 
including:   
For ODAS-GP, sensitivity analysis of ORR/DCR comparison between arms based on 
randomization stratification factors will be performed.  The differences of ORR/DCR between 
the two arms will be performed unstratified (without adjusting stratification factors).   
For ODAS-pSTAT3(+), sensitivity analysis of ORR/DCR comparison between arms based on 
actual stratification factors will be performed.   
Subgroup analysis will be performed considering the subgroup specified in Section Section 3.4.1  
and Section 3.4.2  or other subgroups where appropriate:   
For each subgroup level, differences of ORR/DCR between the two arms will be compared using 
a 1-sided Z-test via normal approximation.  Treatment difference of ORR and its 95% CI based 
on normal approximation (unstratified) will be provided.   
Forest plots of risk differences from ORR/DCR for different subgroups will be provided where 
appropriate.   
For pSTAT3(+) Subpopulation, sensitivity analysis using PFS/DCR/ORR data from Subset 1 
patients only (i.e., data within CSS of 6 months) will be also performed at the FA.   
7.2.5. 
Analyses of Other Secondary Endpoints 
Quality of Life (QoL) Endpoints will be summarized by treatment arm and by timepoint in  
QoL-GP and QoL-pSTAT3(+).   
The endpoints in QoL analysis are change from baseline at time 2 (Cycle 5 Day 1) and time 4 
(Cycle 9 Day 1) for the physical function, global health status/quality of life subscale scores of 
the EORTC QLQ-C30 QoL.   
The mean scores and change from baseline for all QoL scales and time point will be summarized 
descriptively for EORTC QLQ-C30.     
7.2.6. 
Statistical Analysis for Safety Endpoints  
Safety data will be analyzed in SAS-GP and/or SAS-pSTAT3(+). Similar analysis will be 
performed at IA for SAS-pSTAT3(-). Depending on the decision from the IA, similar analysis 
maybe performed at the FA.   
 
 


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7.2.6.1. 
Adverse Event  
Overall Summary of AEs 
An AE will be regarded as treatment-emergent, if  
x It occurs for the first time on or after the first dose date of either BBI-608 or FOLFIRI 
and up to 30 days after the last dose of study treatment; or  
x It occurs prior to the first dose date of either BBI-608 or FOLFIRI but worsens in severity 
during therapy or for up to 30 days after the last dose of study treatment (or up to any 
time if a serious AE and considered related to study drug. 
The emphasis for AE analysis will be based on treatment-emergent AE (TEAE), however all 
AEs will be listed regardless of TEAE or not.   
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA version 
19.0) and summarized by MedDRA System Organ Class and Preferred Term. The severity of all 
AEs will be graded by the Investigator using NCI CTCAE version 4.0.   
An overall summary of TEAEs will be provided. The number and percentage of patients with 
following will be summarized by ARM 1 and ARM2:   
x Patients with at least 1 TEAE 
x Patients with TEAE of CTCAE Grade 3 or higher 
x Patients with serious TEAE 
x Patients with BBI-608 related TEAE 
x Patients with BBI-608 related TEAE of CTCAE Grade 3 or higher  
x Patients with FOLFIRI related TEAE 
x Patients with FOLFIRI related TEAE of CTCAE Grade 3 or higher  
x Patients with either BBI-608 or FOLFIRI related TEAE 
x Patients with either BBI-608 or FOLFIRI related TEAE of CTCAE Grade 3 or higher  
x Patients with TEAE leading to BBI-608 dose interruption, reduction, permanent 
discontinuation 
x Patients with TEAE leading to FOLFIRI interruption, reduction, permanent 
discontinuation 
 
Summary of AEs by SOC and Preferred Term  
The number and percentage of patients who experience any TEAE will be summarized by SOC 
and PT.  A summary of TEAEs by PT and maximum CTCAE grade will be presented. TEAE 
preferred terms with missing grade will be reported in the Unknown category if no other grade 
was found for the same PT. The most commonly reported TEAEs using a different cutoff (e.g. 
2% or 10% or more of patients in either arm) may also be summarized by PT as needed.  
Meaningful differences between treatment arms (reported an incidence of ≥5% of patients in 
either arm or difference by >=2%) will be compared.   


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TEAEs associated with permanent discontinuation /dose reduction/drug interruption of either 
BBI-608 and/or FOLFIRI will be summarized by SOC and PT and maximum CTCAE Grade 
(taking into consideration the action taken from CRF AE page).   
Treatment Related Adverse Events  
Treatment-related TEAEs are those judged by the investigator to be at least possibly related to 
the study drugs (BBI-608 and/or FOLFIRI) or for which relatedness is recorded as “unknown” 
by the investigator. Treatment related will include “possible”, “probable” or “definite” causality 
assessments. Missing relationship will be considered as “Related” to all drugs received by the 
patient. Relationship to FOLFIRI is obtained from the CRF which includes “related to any of the 
components”. Relationship to each component may be summarized, if necessary. Similar 
summaries as noted for all causality TEAEs will be provided for treatment related TEAEs.   
Serious Adverse Events and Death 
Treatment-emergent SAEs and Treatment-related SAEs will be summarized by MedDRA SOC 
and PT and maximum CTCAE grade.   
TE AE leading to death will be summarized by MedDRA SOC and Preferred Term.   
Deaths will be summarized on study and on treatment (within 30 days of last dose of study 
medication). The number and percentage of patients who died on study and on treatment, as well as 
primary cause of death will be summarized. Deaths may also be categorized according to time of 
occurrence after first dose.   
A listing of death data will also be provided and will include all deaths that occurred from the signing 
of the informed consent to the end of the follow up period. The listing will include primary cause of 
death and the number of days relative to the administration of first and last dose.  
Adverse Events of COVID-19.  
Preferred Terms corona virus infection and coronavirus test positive will be used to identified 
COVID-19 positive cases in adverse event. 
Clustered Adverse Events 
Specific AEs, termed AE clusters, have been selected based upon the known and/or potential 
association with napabucasin administration.  MedDRA (version 19.0) standard medical queries 
(SMQs) and/or Sponsor selected Preferred terms (PTs) have been identified to review safety data 
from napabucasin trials and assess for incidence, severity and causality. The selected MedDRA 
SMQ or sponsor derived terms are: 
x Noninfectious diarrhea (narrow SMQ) 
x Gastrointestinal nonspecific inflammation (narrow SMQ) plus Enterocolitis 
x Gastrointestinal Hemorrhage (narrow SMQ) 
x Abdominal Pain (Sponsor derived event cluster) 
x Fatigue (Sponsor derived event cluster) 
x Acute renal failure (narrow SMQ) 
x Hypotension (Sponsor derived event cluster) 
x Gastrointestinal Perforation (narrow SMQ) 


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x Drug related hepatic disorders [Drug related hepatic disorders - severe events only 
(narrow SMQ) plus Liver related investigations, signs and symptoms (narrow SMQ)] 
x Haematopoietic leukopenia (broad SMQ) 
x Haematopoietic thrombocytopenia (broad SMQ) 
x Torsade de Pointes (Torsade de pointes/QT Prolongation (broad SMQ) plus PT Seizure) 
Similar to the overall summary of TEAEs, an overview of clustered TEAEs will be provided. 
The clustered TEAEs, clustered TEAEs related to study drug, and clustered treatment emergent 
SAE will be summarized by PT in SAS-GP and/or SAS-pSTAT3(+). 
7.2.6.2. 
Clinical Laboratory Assessments 
Lab parameters collected in CRF will be summarized.   
All records on or after first dose (planned and unplanned) will be considered as post baseline. 
The results of laboratory parameters will be graded according to NCI CTCAE v4.0. The CTCAE 
grading will be performed based on observed value without considering any clinical symptoms 
or findings. CTCAE grade at baseline and maximum CTCAE grade post baseline will be 
summarized. A shift summary of baseline grade to maximum CTCAE grade post baseline will be 
summarized. Unplanned laboratory test results will be included in maximum CTCAE grade post 
baseline and the shift tables.   
Table 10: 
CTCAE Terms for Grading 
Hematology 
Biochemistry 
White blood cell decreased 
Leukocytosis 
Anemia 
Platelet count decreased 
Neutrophil count decreased 
Lymphocyte count decreased 
Lymphocyte count increased 
Creatinine increased 
Blood bilirubin increased 
Alanine aminotransferase increased 
Alkaline phosphatase increased 
Aspartate aminotransferase increased 
Hypoalbuminemia 
Hyperkalemia 
Hypokalemia 
Hypermagnesemia 
 
Hypomagnesemia 
 
Hypophosphatemia 
Lactate dehydrogenase 
Additional CTCAE terms may be added if data are available.   
A listing of all lab parameters including hematology, biochemistry, and urinalysis will be 
provided, including the test result, units, normal range (H and L), change from baseline, and 
CTCAE grades if graded.  
Incidence of patients with liver function test results satisfying the drug-induced liver injury 
(DILI) criterion defined as (> 3x upper limit of normal [ULN] for ALT/AST, >2xULN for total 
bilirubin and < 2xULN or missing for alkaline phosphatase within a day) will be presented.  
In addition, incidence of elevated liver function test results will be presented by elevation 
criterion. Elevation criteria are given as follows:  


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x ALT (>  3xULN, > 5xULN, >8xULN, > 10xULN, > 20xULN)  
x ALT >3xULN and Baseline ALT <=3xULN (or Baseline ALT missing) 
x AST (>  3xULN, > 5xULN, >8xULN, > 10xULN, > 20xULN)  
x AST > 3xULN and Baseline AST <= 3xULN (or Baseline AST missing) 
x Total Bilirubin >2xULN  
x Total Bilirubin >2xULN and Baseline Total Bilirubin <= 2xULN or missing 
x ALP (> 1.5xULN,  >= 3xULN) 
x ALP >= 3xULN and Baseline ALP < 3xULN or missing 
7.2.6.3. 
Concomitant Medication/Post-Treatment Anti-Cancer Therapy 
Prior and concomitant medications will be coded to ATC (Anatomical Therapeutic Chemical) 
classification and Drug Name using WHO Drug Dictionary (WHO-DD-Enhanced B2 MAR 16). 
Prior medication is defined as medication taken any time prior to the date of the first dose of 
study medication. Concomitant medication is defined as medications taken any time during 
treatment period (i.e., first dose date to last dose date of study medication, inclusive). 
Summaries of concomitant medications will be provided by level 3 ATC classification, preferred 
term and level 4 ATC classification using frequencies and percentages. A listing of all prior and 
concomitant medications will be provided.  
New anti-cancer therapy will be summarized by ingredient and preferred term using frequencies 
and percentages.   
7.2.6.4. 
Vital Signs 
For weight, heart rate, systolic blood pressure (BP), and diastolic BP, summary statistics for 
baseline values and maximum change (maximum increase, maximum decrease. and no change) 
from baseline will be presented.   
Changes from baseline to on-treatment weight assessments will be presented by treatment and 
time point considering the frequency of patients with changes falling in the following categories: 
>= 5% -< 10% gain, >=10% -< 20% gain, >= 20% gain, >= 5% -< 10% loss, >=10% -< 20% 
loss, >= 20% loss.  
Summaries of markedly abnormal vital sign parameters, including BP and pulse, will be 
presented by treatment group. For systolic, diastolic blood pressure and BMI, shift from baseline 
will be provided by for the worst value on the study using the following categories (see 
Table 11).   
Values for vital signs for all patients will be presented in a listing, and patients with markedly 
abnormal values will be flagged. 
Markedly abnormal ranges for vital sign parameters are given in the table below. 
 
 


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Table 11: 
Markedly Abnormal Ranges for Vital Sign 
Vital Sign 
Parameter 
Markedly Abnormal (Low) 
Markedly Abnormal (High) 
Systolic BP 
Absolute value ≤ 90 mmHg, or a 
decrease from baseline ≥20 mmHg 
Absolute value ≥ 180 mmHg, or an 
increase from baseline ≥20 mmHg 
Diastolic BP 
Absolute value ≤ 50 mmHg, or a 
decrease from baseline ≥15 mmHg 
Absolute value ≥ 105 mmHg, or an 
increase from baseline ≥ 15 mmHg 
Pulse 
Absolute value ≤ 50 bpm, or a 
decrease from baseline ≥15 bpm 
Absolute value ≥ 120 bpm, or an 
increase from baseline ≥15bpm 
BMI 
Absolute value ≤ 18 kg/m2 
Absolute value ≥ 25 kg/m2 
7.2.6.5. 
ECG Evaluation  
12-lead ECG with categorical results (Normal, Abnormal Not Clinically Significant, Abnormal 
Clinically Significant) will be summarized by treatment and visit. The shift from baseline to 
worst post baseline will be produced. A patient listing will also be provided. 
7.2.6.6. 
Physical Exam 
Physical examination abnormalities will be summarized for each visit by body system and by 
treatment group. Patients with clinically significant abnormal findings will be flagged in the data 
listing. 
7.2.6.7. 
ECOG  
The number and percentage of patients in each category of ECOG will be listed for baseline and 
worst post baseline value. In addition, ECOG will be summarized in a shift table from baseline to 
worst post baseline for safety analysis set. 
7.2.7. 
Subgroup Analysis for PMDA Submission 
To support the PMDA submission in Japan, selected analyses will be repeated for patients 
enrolled in Japan in this study. The following analyses may be included:  
x Standard analyses as described in Section 7.2.1; 
x Analysis for primary endpoint as in Section 7.2.2, sensitivity analysis for the primary 
endpoint if appropriate for Japan in Section 7.2.3; 
x Other secondary endpoints analyses as described in Section 7.2.4 and Section 7.2.5; 
x Safety analyses as described in Section 7.2.6.  
7.2.8. 
PK Analysis 
A listing of sparse PK sample collection includes actual sampling time relative to the BBI-608 
dose administration on the day of the PK sample collection will be provided.  


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The procedures for the population PK modeling including model evaluation, will be described in 
a separate Population-PK analysis plan. The corresponding results will be reported in a separate 
document.   
7.2.9. 
Sensitivity Analysis on Overall Survival in pSTAT3(+) w.r.t. Baseline Imbalance 
As randomization is not stratified based on the pSTAT3 status, there could be some numerical 
imbalance in baseline covariates including the stratification factors in the 
pSTAT3+ Subpopulation. Sensitivity analyses on OS in the pSTAT3(+) Subpopulation as 
described in this section may be performed at the IA and/or the FA. Baseline covariates 
including, but not limited to, the baseline demographic, baseline disease characteristics, baseline 
stratification factors and baseline subgroups will be summarized descriptively by treatment arms 
in the pSTAT3(+) Subpopulation.   
Propensity Score Methods [Rosenbaum and Rubin, 1983, Yue L, 2007] will be applied to 
evaluate the potential imbalance between the two treatment arms in the pSTAT3(+) 
Subpopulation. Propensity score analysis is a versatile statistical method for improving treatment 
comparisons by adjusting for a relatively large number of potentially confounding covariates. 
Let ܶൌͳ indicate patients with the treatment ARM1, ܶൌͲ indicate patients with the treatment 
ARM2,  ݔ indicates a vector of the pre-specified covariates, and ݁ሺݔሻdenotes the probability of 
being assigned to ARM1 given the covariates ݔ, 
݁ሺݔሻൌܲሺܶൌͳȁݔሻ 
Here ݁ሺݔሻ is the propensity score, which will be estimated for each patient given their covariates  
The clinically relevant baseline factors to be included in the propensity score analysis are pre-
specified and listed in Table 12.   
Table 12: 
Clinically Relevant Baseline Factors 
Stratification Factors 
(actual) 
Geographical Region 
Japan/Korea vs ROW vs 
WE/AUS/NA 
  
Time to progression on first line 
therapy 
< 6 Months vs >= 6 Months 
  
RAS mutation status 
Mutant vs Wild Type 
  
Bevacizumab as part of study 
protocol treatment 
Yes vs No 
  
Location of the primary tumor 
Right vs Left 
Subgroup 
Age 
>= 65 years vs < 65 years 
  
Sex 
Male vs Female 
  
Presence of liver metastases 
Yes vs No 
  
ECOG Performance Status 
0 vs 1 
  
Primary Tumor Site 
Colon vs Rectum 
  
Prior Bevacizumab  
Yes vs No 
Baseline Disease 
Characteristic 
BMI(kg/m2) 
<= 25 vs  >25 


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Primary Tumor 
Present vs Resected 
  
Initial TMN Staging 
I/II vs III vs IV 
  
Any Prior Cancer Surgery 
Yes vs No 
Any Priory Radiotherapy  
Yes vs No 
Baseline lab 
Baseline LDH  
Low/Normal vs High 
The following steps will be implemented to perform the sensitivity analyses. 
Step 1: The baseline factors will be summarized by two arms.  
Step 2: Propensity score calculation. Multiple logistic regression models will be fitted with the 
treatment assignment indicator ܶ as the response variable. The variables in Table 12  will be 
included as covariates.   
Step 3: Evaluate the distribution of propensity score calculation from two arms. Propensity 
scores (estimated probability) from the multiple logistic regression models will be summarized 
between two treatment groups descriptively and graphically by box plots. The propensity score is 
a summary score, which may provide an indicator how the baseline covariatesin the propensity 
score calculation is equally (or unequally) distributed between the 2 treatment arms.  
Step 4: Sensitivity analysis for an outcome adjusting the propensity score. Sensitivity analysis for 
an outcome (e.g., OS) considering propensity scores adjustment may provide an assessment of 
the outcome adjusted by any potential imbalances in the baseline covariates.   
The Propensity Score may be used in 2 ways in the sensitivity analysis of OS data in the 
pSTAT3(+) Subpopulation: 
x As a continuous covariate in the Cox PH model models for OS. The models will include 
terms for treatment and propensity score.   
x As a stratification factor in the Cox PH model models for OS where the subjects are 
stratified by the quintiles of the propensity scores. Here a simple stratification scheme 
will be employed: propensity score <= q20, > q20 < -<= q40, > q40 -≤ q60, > q60 -≤ q80 
and > q80, where q20, q40, q60 and q80 are the 20th, 40th, 60th and 80th percentiles of 
propensity scores. Patients in the strata defined by propensity scores have approximately 
the same probability of treatment assignment and hence are comparable within each 
stratum. The Cox PH model models will include the terms for treatment stratified by 
propensity score quintiles. Within-strata subgroup analyses may also be conducted.  
The sample SAS code are provided in Appendix V: Sample SAS codes for Propensity Score and 
Multiple Imputation . 
7.2.10. 
Sensitivity Analysis on Missing Biomarker Data  
Depending on the proportion of missing biomarker data, sensitivity analysis described in this 
section may be performed at the time of the IA and/or FA.   


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7.2.10.1. Comparison Baseline Covariates between Biomarker Analysis Set and Patients 
Missing Biomarker Data 
Baseline covariates, including but not limited to the baseline demographic, baseline disease 
characteristics, baseline stratification factors and baseline subgroups will be summarized 
descriptively by the 2 groups (Biomarker Analysis Set and ITT-pSTAT3(Unknown)). 
Since the pSTAT3 sample collection is independent from the baseline covariates, including 
demographics and baseline disease characteristics, it is expected that the pSTAT3 status would 
be missing at random, and that baseline covariates should be approximately balanced between 
Biomarker Analysis Set and ITT-pSTAT3(Unknown).   
If deemed necessary, propensity scores may be calculated and summarized using the similar 
procedure as described in Section 7.2.9 where replacing ܶൌͳ indicate patients in Biomarker 
Analysis Set and ܶൌͲ indicate ITT-pSTAT3(Unknown).   
7.2.10.2. Comparison of Overall Survival of Biomarker Analysis Set and Patients Missing 
Biomarker Data 
Estimates of the overall survival obtained from the Kaplan-Meier method will be presented for 
Biomarker Analysis Set and ITT-pSTAT3(Unknown) by ARMs and overall.  The median 
survival time and corresponding 2-sided CI will be provided for each treatment arm for 
Biomarker Analysis Set and ITT-pSTAT3(Unknown).  An unstratified Cox PH model will be 
used to obtain the Hazard Ratio of ARM1 vs ARM2 in Biomarker Analysis Set and  
ITT-pSTAT3(Unknown), respectively. Additional covariates, such as propensity score from the 
last step may be included in multivariate Cox PH model either as continuous variable or 
categorical variable of propensity score quintiles.   
7.2.10.3. Handling Missing Biomarker Status   
To evaluate the impact of missing biomarker status on OS endpoint and robustness of conclusion 
from the pSTAT3(+) Subpopulation, the following methods may be applied where appropriate.  
Multiple Imputation of Missing Biomarker Status 
Using the following steps for multiple imputation of missing biomarker status.  
Assuming the biomarker status is missing at random, the multiple imputation method  
[Rubin 1978, Rubin 1987, Yan 2009, Campbell 2011] is deemed appropriate to address the 
impact of missing pSTAT3 data on OS, and is described in the following 3 steps. Step 1 
describes the missing data imputation procedure, Steps 2 and 3 illustrate the subsequent analysis 
strategy.  
Step 1:  Missing Data Imputation based on the Selected Covariates (M = 100 imputations):  
Missing biomarker status will be imputed by SAS PROC MI with the all baseline factors 
specified in Table 12 using logistic regression to generate M complete data sets. The seed will be 
set up as 3789 in PROC MI procedure.   
Step 2: Statistical Analysis for Each Complete Dataset:  


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Within the pSTAT3(+) group, the unstratified Cox PH model will be applied to each of the 
complete datasets. The Observed Hazard Ratio and its corresponding statistics will be computed 
from the model. Similar analysis may be performed using the pSTAT3(-) group if needed.   
Step 3: Combine the Results from M Datasets: 
PROC MIANALYZE will be applied to combine the analysis results (HR and its corresponding 
statistics) from the M datasets. The HR and p-value from the combination of results will be 
reported as a sensitivity analysis result compared with the primary analysis.   
In the case that missing at random is questionable, other methods including the tipping point 
method [Yan, 2009, Campbell, 2011] will be used to examine the sensitivity of the conclusions 
of missing data and aid clinical reviewers in making a judgment regarding the treatment effect in 
the study.  
Tipping Point Analysis   
Another strategy to handle missing data, particularly under worse case scenarios, is the tipping 
point analysis, which does not rely on the assumption of missingness at random. Let X1 and X2 
denote the number of patients to be imputed as pSTAT3(+) in the FOLFIRI Arm and the 
NAPABUCUSIN+ FOLFIRI arm from the pSTAT3(Unknown) Subpopulation. X1 and X2 will 
be determined based on the prevalence of pSTAT3(+) estimated from the Biomarker Analysis 
Set.  For example, if the prevalence of pSTAT3(+) in the Biomarker Analysis Set is 50% and 
there are 100 patients in the FOLFIRI arm and 100 patients in NAPABUCUSIN+ FOLFIRI arm 
with unknown pSTAT3 status (total unknown is 200), then X1=X2=50.   
The following tipping points analysis will be applied to evaluate the impact of MNAR (missing 
not at random) of biomarker status may have on the primary analysis, starting with the worst-
case scenario.  
Step 1: from pSTAT3(Unknown) Subpopulation of FOLFIRI Arm, randomly select X1 patients 
to be pSTAT3(+); 
Step 2: from pSTAT3(Unknown) Subpopulation of napabucasin + FOLFIRI Arm, list all 
uncensored survival times ordered from the shortest to the longest and append to a second list of 
all censored survival time ordered from the shortest to the longest (for convenience, we will call 
this list – the ranked outcome list). Assign patients occupying the first X2 positions to be 
pSTAT3(+); 
Step 3: combine data from Step 1 and Step 2 with the observed pSTAT3(+) data to form a 
complete pSTAT3(+) dataset. The log-rank test and Cox PH model will be performed in the 
same way as in the primary analysis for the pSTAT3(+) Group;  
Step 4: Repeat Step 1 to Step3 10000 times to obtain an average p-value and HR estimate. This 
would be considered as the worst-case scenario (in the worst-case scenario, Step 2 is the same 
for each of the 10000 runs); 
Step 5: Repeat Step 1 to Step 3 except that in Step 2, randomly assign 95% of the patients 
occupying the first X2 positions on the ranked outcome list to be pSTAT3(+). Randomly select 
X2*5% patients from those occupying the remaining positions on the ranked outcome list to be 
pSTAT3(+) also. Compute p-value and HR for the resulting dataset;  


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Step 6: Repeat Step 5 10000 times to obtain an average p-value and HR estimate for the 95% 
scenario; 
Step 7: Repeat Step 5 to Step 6, while changing the percentage from 95% to p% (p=90 to 5, by a 
decrement of 5 each time). Randomly assign p% of patients occupying the first X2 positions on 
the ranked outcome list to be pSTAT3(+). Randomly select X2*(100-p)% patients from those 
occupying the remaining positions on the ranked outcome list to be pSTAT3(+) also; 
Step 8 A graph of p-values/HR versus corresponding to different proportions (p%) as outlined 
above will be presented to illustrate results of tipping point analysis. 
 
 


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Table 13: 
Summary of Key Efficacy Analysis  
 
Endpoint  
Analysis Set 
Statistical Methods 
Missing Data 
Interpretation 
OS (7.2.2) 
ITT-GP  
 
Stratified log-rank test 
(1-sided, all S factors);  
KM Method (median, 
95% CI);  
HR and 95% CI from 
Stratified Cox PH 
Model 
Censor 
patients who 
didn’t die or 
who lack any 
data beyond 
randomization  
Primary 
analysis for 
primary 
endpoint in GP 
 
ITT-pSTAT3(+) 
Unstratified log-rank 
test (1-sided);  
KM Method (median, 
95% CI); 
HR and 95% CI from 
unstratified Cox PH 
Model 
Censor 
patients who 
didn’t die or 
who lack any 
data beyond 
randomization  
Primary 
analysis for 
primary 
endpoint in 
pSTAT3(+)   
6-month, 1 year, 18-month  
survival  
ITT-GP  
ITT-pSTAT3(+) 
KM method (95% CI) 
 
 
OS (7.2.3.1) 
PPAS-GP 
 
Stratified log-rank test 
(1-sided, all S factors);  
KM Method (median, 
95% CI);  
HR and 95% CI from 
Stratified Cox PH 
Model 
 
Sensitivity 
analysis of 
primary 
endpoint 
 
PPAS-pSTAT3(+) 
Unstratified log-rank 
test (1-sided);  
KM Method (median, 
95% CI).  
HR and 95% CI from 
unstratified Cox PH 
Model 
 
Sensitivity 
analysis of 
primary 
endpoint 
6-month, 1 year, 18-month  
survival 
PPAS-GP  
PPAS-pSTAT3(+) 
KM method (95% CI) 
 
 
OS (7.2.3) 
ITT-GP  
 
Unstratified log-rank 
test (1-sided), HR and 
95% CI from 
unstratified Cox PH 
Model 
 
Sensitivity 
analysis 
 
ITT-pSTAT3(+) 
 
Stratified log-rank test 
(1-sided, all S factors);  
KM Method (median, 
95% CI);  
HR and 95% CI from 
Stratified Cox PH 
Model 
 
Sensitivity 
analysis 
 
ITT-pSTAT3(-) 
HR and 95% CI from 
unstratified Cox PH 
Model 
 
Sensitivity 
analysis 
OS (7.2.3) 
ITT-GP 
ITT-pSTAT3(+) 
 
Stratified log-rank test 
(1-sided, all S factors 
on randomized 
 
Sensitivity 
analysis 


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Endpoint  
Analysis Set 
Statistical Methods 
Missing Data 
Interpretation 
stratification factor);  
KM Method (median, 
95% CI);  
HR and 95% CI from 
Stratified Cox PH 
Model 
OS (7.2.3) 
Subgroup from ITT-
GP, ITT-pSTAT3(+), 
and ITT-pSTAT3(-) 
For each S level,  
KM Method (median, 
95% CI) for each 
treatment for each S 
level.   
Stratified log-rank 
test(2-sided) and HR 
and 95% CI from 
stratified Cox PH 
Model  
 
Sensitivity 
analysis 
OS (7.2.3) 
Subgroup from ITT-
GP, ITT-pSTAT3(+), 
ITT-pSTAT3(-) 
For each baseline 
factor level, KM 
Method (median, 95% 
CI); 
Unstratified log-rank 
test (2-sided); 
HR and 95% CI from 
unstratified Cox PH 
Model  
 
Sensitivity 
analysis 
OS (7.2.3) 
ITT-GP  
ITT-pSTAT3(+) 
ITT-pSTAT3(-) 
Multivariate Cox PH 
model stratified by S 
factors and including 
other baseline 
covariates 
(HR and 95% CI ) 
 
Sensitivity 
analysis 
OS (7.2.3.2) 
ITT-pSTAT3(-) 
KM method (median, 
95% CI); 
HR and 95% CI from 
stratified Cox PH 
model 
 
Sensitivity 
analysis for 
OS at IA 
and/or FA   
6-month, 1 year, 18-month  
survival  
ITT-pSTAT3(-) 
KM method (95% CI) 
 
 
OS (7.2.9 ) 
ITT-pSTAT3(+) 
Propensity Score 
Methods will be used 
to evaluate potential 
imbalance baseline 
covariates between 
ARMs 
 
Sensitivity 
analysis 
OS (7.2.10) 
BAS and ITT-
pSTAT3(Unknown) 
1) OS between BAS 
and ITT-
pSTAT3(Unknown): 
KM method (median, 
95% CI) by ARM and 
Overall; 2) HR 
(ARM1 vs ARM2) and 
95% CI from 
unstratified Cox PH 
 
Sensitivity 
analysis 


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Endpoint  
Analysis Set 
Statistical Methods 
Missing Data 
Interpretation 
model for both BAS 
and ITT-
pSTAT3(Unknown);  
3) Multivariate Cox 
PH model using 
propensity score, et al.; 
4) Multiple Imputation 
and Tipping Point 
analysis 
PFS (7.2.4) 
ITT-GP  
 
Stratified log-rank test 
(1-sided, all S factor);  
KM method (median, 
95% CI);  
HR and 95% CI from 
stratified Cox PH 
Model 
Censoring 
patients 
following 
criteria in 
3.1.2.1  
Primary 
analysis for 
PFS in GP    
 
ITT-pSTAT3(+) 
Unstratified log-rank 
test (1-sided);  
KM Method (median, 
95% CI);  
HR and 95% CI from 
unstratified Cox PH 
Model 
Censoring 
patients 
following 
criteria in 
3.1.2.1  
Primary 
analysis for 
PFS in 
pSTAT3(+)   
PFS (7.2.4) 
Subgroup from ITT-
GP and ITT-
pSTAT3(+) 
For each S level,   
KM method (median, 
95% CI) for each 
treatment  
 
Sensitivity 
analysis 
PFS (7.2.4) 
ITT-pSTAT3(-) 
KM method (median, 
95% CI); HR and 95% 
CI from unstratified 
Cox PH Model 
 
Sensitivity 
analysis at IA 
and/or FA   
ORR (7.2.4) 
ODAS-GP  
 
Stratified CMH (1-
sided, stratified by S 
factors); 
TrtDiff and 95% CI 
from HM method 
adjusting S factors; 
Exact CI based on 
Clopper-Pearson 
method  
Patients 
without on-
study tumor 
assessment or 
who die, 
progress or 
drop out for 
any reason, or 
receive anti-
tumor 
treatment 
prior to 
reaching a CR 
or PR as non-
responders.   
Primary 
analysis for 
ORR in GP 
ORR (7.2.4) 
ODAS-pSTAT3(+) 
1-sided Z test;  
TrtDiff and 95% CI 
from normal 
approximation 
(unstratified); 
Exact CI based on 
Clopper-Pearson 
 
Primary 
analysis for 
ORR in 
pSTAT3(+)   


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Endpoint  
Analysis Set 
Statistical Methods 
Missing Data 
Interpretation 
method  
ORR (7.2.4) 
ODAS-pSTAT3(-) 
TrtDiff and 95% CI 
from normal 
approximation 
(unstratified); 
Exact CI based on 
Clopper-Pearson 
method  
 
Sensitivity 
Analysis at IA 
and/or Final 
analysis.   
DCR (7.2.4) 
ODAS-GP 
 
Stratified CMH (1-
sided, stratified by S 
factors); 
TrtDiff and 95% CI 
from HM method 
adjusting S factors; 
Exact CI based on 
Clopper-Pearson 
method   
 
Primary 
analysis for 
DCR in GP   
 
ODAS-pSTAT3(+) 
1-sided Z test;  
TrtDiff and 95%CI 
from normal 
approximation 
(unstratified); 
Exact CI based on 
Clopper-Pearson 
method 
 
Primary 
analysis for 
DCR in 
pSTAT3(+)   
DCR (7.2.4) 
ODAS-pSTAT3(-) 
TrtDiff and 95%CI 
from normal 
approximation 
(unstratified); 
Exact CI based on 
Clopper-Pearson 
method;  
Exact CI based on 
Clopper-Pearson 
method  
 
Sensitivity 
analysis at IA 
and/or FA   
OS: overall survival. PFS: progression-free survival. MD: measurable disease. GP: General Population.   
HM: Harmonic Means. 


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8. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED 
ANALYSES 
No major change from planned analyses was made. 
 
 
 


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9. 
REFERENCES 
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2019. 
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Chan ISF, Zhang Z. (1999). Test-based exact confidence intervals for the difference of two 
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Campbell, G, Pennello, G, Yue L.  Missing Data in the Regulation of Medical Devices, Journal 
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10. 
APPENDIX 
Appendix I:  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 
 
 
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 
 


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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 
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 Protocol 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. 
10 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse 
Events version 4.0 (see Protocol 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. 


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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 II: 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 
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 


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Statistical Analysis Plan – Version 3.0 
 
 
 
Confidential & Proprietary 
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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 Protocol 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 Protocol Appendix). 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. 
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 III 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. 
 
10.2.1 Measurable Disease: Measurable tumor lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as > 20 
mm with chest x-ray and as > 10 mm with CT scan, or clinical examination. Bone 
lesions are considered measurable only if assessed by CT scan and have an identifiable 
soft tissue component that meets these requirements (soft tissue component > 10 mm by 
CT scan). Malignant lymph nodes must be > 15mm in the short axis to be considered 
measurable; only the short axis will be measured and followed. All tumor measurements 
must be recorded in millimeters (or decimal fractions of centimeters). Previously 
irradiated lesions are not considered measurable unless progression has been 
documented in the lesion. 
 
10.2.2 Non-measurable Disease: All other lesions (or sites of disease), including small lesions 
are considered non-measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin 
and abdominal masses followed by clinical examination are all non-measurable. Lesions 
in previously irradiated areas are non-measurable, unless progression has been 
demonstrated. 
 
10.2.3 Target Lesions: When more than one measurable tumor lesion is present at baseline all 
lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) 
representative of all involved organs should be identified as target lesions and will be 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. 
Note that pathological nodes must meet the criterion of a short axis of > 15 mm by CT 
scan and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis > 10 mm but < 15 mm) should be considered 
non-target lesions. Nodes that have a short axis < 10 mm are considered non-pathological 
and should not be recorded or followed (see 10.2.4). At baseline, the sum of the target 
lesions (longest diameter of tumor lesions plus short axis of lymph nodes: overall 
maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for 
each assessment, even if very small. If extremely small and faint lesions cannot be 
accurately measured but are deemed to be present, a default value of 5 mm may be used. 
If lesions are too small to measure and indeed are believed to be absent, a default value of 
0 mm may be used. 
 
10.2.4 Non-target Lesions: All non-measurable lesions (or sites of disease) plus any measurable 
lesions over and above those listed as target lesions are considered non-target lesions. 


Sumitomo Dainippon Pharma Oncology, Inc.                                      Protocol No:  CanStem303C 
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Measurements are not required but these lesions should be noted at baseline and should 
be followed as “present” or “absent”. 
 
10.2.5 Response: All patients will have their BEST RESPONSE from the start of study 
treatment until the end of treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target. Pathological lymph 
nodes must have short axis measures < 10 mm (Note: continue to record the measurement 
even if < 10 mm and considered CR). Residual lesions (other than nodes < 10 mm) 
thought to be non-malignant should be further investigated (by cytology specialized 
imaging or other techniques as appropriate for individual cases [Eisenhauer 2009]) before CR 
can be accepted.  
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter 
for tumor lesions and short axis measure for nodes) of target lesions, taking as reference 
the baseline sum of diameters. Non-target lesions must be non-PD.  
 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase 
to qualify for PD taking as reference the smallest sum of diameters on study. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of > 5mm. Appearance of new lesions will also 
constitute progressive disease (including lesions in previously unassessed areas).  
In exceptional circumstances, unequivocal progression of non-target disease may be 
accepted as evidence of disease progression, where the overall tumor burden has 
increased sufficiently to merit discontinuation of treatment or where the tumor burden 
appears to have increased by at least 73% in volume. Modest increases in the size of one 
or more non-target lesions are NOT considered unequivocal progression. If the evidence 
of PD is equivocal (target or non-target), treatment may continue until the next 
assessment, but if confirmed, the earlier date must be used.  
 
 
 


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Table 14: 
 Integration of Target, non-Target and New Lesions into Response 
Assessment: 
 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
tumor nodes < 10mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least once > 6 
wks. from baseline 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
tumor nodes < 10mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/non-PD  
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without radiological 
progression having been observed at that time should be reported as “symptomatic deterioration”. This is NOT 
objective PD. Every effort should be made to document the objective progression even after discontinuation of 
treatment. 
 
10.3 
RESPONSE DURATION 
 
Response duration will be measured from the time measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent or progressive 
disease is objectively documented, taking as reference the smallest measurements 
recorded on study (including baseline). 
 
10.4 
STABLE DISEASE DURATION 
 
Stable disease duration will be measured from the time of randomization until the criteria 
for progression are met, taking as reference the smallest sum on study (including 
baseline). 
 
10.5 
METHODS OF MEASUREMENT 
 


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Assessments should 
be identified on a calendar schedule and should not be affected by delays in therapy. 
While on study, all lesions recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If it is the 
opinion of the radiologist that the lesion has likely disappeared, the measurement should 
be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned. For lesions which 
fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion”. 
 
Additionally, for optimal tumor assessment scanning options are listed below in the 
decreasing   order of preference: 
 
Order of Preference Scanning Option 
1 
Chest-Abdomen-Pelvis CT with oral and I.V. contrast 
2 
Chest CT without I.V. contrast PLUS MRI Abdomen-Pelvis 
with oral and I.V. contrast1 
3 
Chest-Abdomen-Pelvis CT with oral contrast2 
1If Iodine contrast media is medically contraindicated. 
2If Iodine contrast media is medically contraindicated and MRI cannot be performed. 
 
10.5.1 Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and > 10 mm as assessed using callipers (e.g. skin nodules). For the case of 
skin lesions, documentation by colour photography including a ruler to estimate the size 
of the lesion is recommended. If feasible, imaging is preferred. 
 
10.5.2 Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions > 20 mm on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung.  
Appendix Non-Permitted Treatments: 
Concurrent chemotherapy, hormonal therapy (except corticosteroids), immunotherapy, 
biologic therapy OR other experimental agents should not be given to study patients 
while on protocol treatment. 
 
10.5.3 CT/MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. 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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10.5.4 Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT is advised. 
 
10.5.5 Endoscopy/Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint.  
 
10.5.6 Cytology/Histology. These techniques can be used to differentiate between PR and CR in 
rare cases (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). 
 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
 
 


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Appendix IV: Non-Permitted Treatments 
Non-Permitted Treatments: 
Concurrent chemotherapy, hormonal therapy (except corticosteroids), immunotherapy, biologic 
therapy OR other experimental agents should not be given to study patients while on protocol 
treatment. 
 


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Appendix V: Sample SAS codes for Propensity Score and Multiple Imputation 
 
/*Propensity Score to Check Imbalance between ARMs within BM+ cohort: Section 7.2.9 */ 
 
/* Step 1:  get propensity score calculation based on baseline covariates: within BM+ cohort: */ 
/* The baseline covariates included are according to Table 12: Clinically Relevant Baseline Factors in 
Section 7.2.9 */ 
/* arm = cov1 cov2 cov3 ... */ 
 
proc logistic data = adsl_os (where = (BIOSTATN  = 1));  
  class cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov9 cov10 cov11  ;  
  model arm = cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov9 cov10 cov11 ;  
  output out=scr predicted=ps xbeta=logit_ps;  
run;  
 
/* Step 2: Exam the propensity score overlapping between arm: continuous variable or quintiles */ 
 
proc sort data = scr ; by arm; run;  
proc univariate data= scr ;  
  histogram;  
  class arm ;  
  var ps ; 
run;  
 
proc boxplot data= scr  ; 
  plot ps *arm ; 
run; 
 
proc rank data=scr out= os1  groups=5; 
  var ps; 
  ranks q; 
run; 
 
proc freq data = os1  ;  
  table  q * arm / nopercent norow  ;  
run;  
 
 /* Step 3:  adjusted propensity score as continuous covariate */ 
proc phreg data = os1; 


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  class arm ;  
  model aval * cnsr (1)  = arm ps /ties = efron ;  
run;  
 
 /*stratified propensity score quintiles */ 
proc phreg data = os1; 
  class arm q;  
  model aval * cnsr (1)  = arm  /ties = efron ;  
  strata q ;  
run;  
 
/*Section 7.2.10: multiple imputation for missing biomarker status.   */ 
 
/* check if the missing pattern is monotone including all the covariates from Table 12 and BM status */ 
proc  mi data= adsl_os out=mi_1  nimpute=0; 
  var cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov9 cov10 cov11 biostatn; 
run; 
 
/*Step 1: multiple imputation including all the baseline factors in section X*/ 
 
proc  mi data= adsl_os SEED=3789 out=mi_2 nimpute=100; 
  class cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov9 cov10 cov11 biostatn ;  
  var cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov9 cov10 cov11 biostatn; 
/*Baseline covariate with large number of missing values will be imputed using fcs logistic. An example as 
cov8 cov9 */ 
  fcs logistic (cov8 = cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov9 cov10 cov11 biostatn/details) ; 
  fcs logistic (cov9 = cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov10 cov11 biostatn/details) ; 
  fcs logistic (biostatn= cov1 cov2 cov3 cov4 cov5 cov6 cov7 cov8 cov9 cov10 cov11 /details) ; 
run; 
 
proc sort data=mi_2; 
  by _imputation_ biostatn; 
run; 
 
/*Step 2:  Analysis HR for each imputation and biomarker status. */ 
 
ods output ParameterEstimates=xyz HazardRatios = HR ;  
Proc phreg data=mi_2 out=outx ; 
  by _imputation_ biostatn; 
  class arm; 


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  model aval*cnsr(1)= arm / rl ties=efron; 
  hazardratio "HR "  arm ;   
run; 
 
 proc sort data=xyz; 
   by biostatn; 
 run; 
 
 /*Step 3:  Combined Results from 100 Imputation */ 
 
 proc mianalyze data=xyz ; 
   by biostatn; 
   modeleffects estimate ; 
   stderr stderr; 
   ods output parameterestimates=overall; 
 run; 
 
 data overall1;  
   set overall; 
   HR = exp(estimate) ;  
   UL95 = exp(estimate + 1.96*stderr) ;  
   LL95 = exp(estimate - 1.96*stderr) ;  
run;  
 
proc sort data = adsl_os; by biostatn; run;  
/*compare with the original results. */ 
ods output ParameterEstimates=xyz1 HazardRatios = HR1 ;  
Proc phreg data=adsl_os out = observed ; 
  by biostatn; 
  class arm ; 
  model aval*cnsr(1)= arm / rl ties=efron; 
  hazardratio "HR "  arm ;   
run; 

 


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                                     Protocol No:  CanStem303C 
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Appendix VI: ORR and DCR for 36 weeks and ORR/DCR Analysis Set with minimum 36 weeks duration 
 
Endpoints:   
 
DCR within 36 weeks is defined as the proportion of patients with BOR of a documented complete response, partial response, and 
stable disease (CR + PR + SD), based on RECIST 1.1 within 36 weeks (<=36*7+5 = 257 days) from randomization. 
ORR within 36 weeks is defined as the proportion of patients with BOR of a documented complete response and partial response  
(CR + PR) based on RECIST 1.1 within 36 weeks (<=36*7+5 = 257 days) from randomization. 
The p-values will be calculated based on DCR within 36 weeks and ORR within 36 weeks.   
 
Analysis Sets  
 
For ORR, the analysis sets are defined as below:  
ORR Analysis Set in the General Population with minimum 36 weeks duration (ORR-GP-36 Weeks) 
 
ORR Analysis Set in the General Population with minimum 36 weeks duration (ODAS-GP-36 Weeks) will include ODAS-GP who 
have adequate tumor scans after 36 weeks (>= 36*7-5 =247 days); or have the first CR/PR/PD, or die, or get new anti-cancer 
treatment, or end the study within 36 weeks (<=36*7+5 = 257 days) from randomization based on Final Analysis Data Cutoff.   
 
ORR Analysis Set in the General Population with minimum 36 weeks duration Stage 1 (ORR-GP-36 Weeks- Stage 1) 
 
ORR Analysis Set in the General Population with minimum 36 weeks duration Stage 1 (ORR-GP-36 Weeks- Stage 1) will include 
ODAS-GP who have adequate tumor scans after 36 weeks (>= 36*7-5 =247 days); or have the first CR/PR/PD, or die, or get new  
anti-cancer treatment, or end the study within 36 weeks (<=36*7+5 = 257 days) from randomization based on IA Data Cutoff of  
22 February 2019. 
 


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ORR Analysis Set in the General Population with minimum 36 weeks duration Stage 2 (ORR-GP-36 Weeks- Stage 2) 
 
ORR Analysis Set in the General Population with minimum 36 weeks duration Stage 2 (ORR-GP-36 Weeks- Stage 2) will include 
patients in ORR-GP-36 Weeks but not in ORR-GP-36 Weeks-Stage 1.   
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration (ORR-pSTAT3(+)-36 Weeks) 
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration (ORR-pSTAT3(+)-36 Weeks) will include 
patients in both ODAS-pSTAT3(+) and ORR-GP-36 Weeks analysis sets.   
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 1 (ORR-pSTAT3(+)-36 
Weeks-Subset 1 Stage 1) 
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 1 (ORR-pSTAT3(+)-36  
Weeks-Subset 1 Stage 1) will include patients in both ORR-GP-36 Weeks- Stage 1 and ODAS-pSTAT3(+) with specimen age up to a 
6-month CSS window.   
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 2 (ORR-pSTAT3(+)-36 
Weeks-Subset 1 Stage 2) 
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 2 (ORR-pSTAT3(+)-36  
Weeks-Subset 1 Stage 2) will include patients in both ORR-GP-36 Weeks- Stage 2 and ODAS-pSTAT3(+) analysis sets with 
specimen age up to a 6-month CSS window but not in ORR-pSTAT3(+)-36 Weeks Subset 1 Stage 1.   
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 2 Stage 3 (ORR-pSTAT3(+)-36 
Weeks-Subset 2 Stage 3) 
 
ORR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 2 Stage 3 (ORR-pSTAT3(+)-36  
Weeks-Subset 2 Stage 3) will include patients ORR-pSTAT3(+)-36 Weeks with specimen age > 6 month and <= final CSS window.     
 
 


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For DCR, the analysis sets are defined as below  
 
DCR Analysis Set in the General Population with minimum 36 weeks duration (DCR-GP-36 Weeks) 
DCR Analysis Set in the General Population with minimum 36 weeks duration (ODAS-GP-36 Weeks) will include ODAS-GP who 
have adequate tumor scans after 36 weeks (>= 36*7-5 =247 days); or have the first CR/PR/PD/(SD >= 51 days from randomization), 
or die, or get new anti-cancer treatment, or end the study within 36 weeks (<=36*7+5 = 257 days) from randomization based on Final 
Analysis Data Cutoff.   
 
DCR Analysis Set in the General Population with minimum 36 weeks duration Stage 1 (DCR-GP-36 Weeks- Stage 1) 
 
DCR Analysis Set in the General Population with minimum 36 weeks duration Stage 1 (DCR-GP-36 Weeks- Stage 1) will include 
ODAS-GP who have adequate tumor scans after 36 weeks (>= 36*7-5 =247 days); or have the first CR/PR/SD/(SD >= 51 days from 
randomization), or die, or get new anti-cancer treatment, or end the study within 36 weeks (<=36*7+5 = 257 days) from 
randomization based on IA Data Cutoff of Feb 22, 2019. 
 
DCR Analysis Set in the General Population with minimum 36 weeks duration Stage 2 (DCR-GP-36 Weeks- Stage 2) 
 
DCR Analysis Set in the General Population with minimum 36 weeks duration Stage 2 (DCR-GP-36 Weeks- Stage 2) will include 
patients in DCR-GP-36 Weeks but not in DCR-GP-36 Weeks-Stage 1.   
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration (DCR-pSTAT3(+)-36 Weeks) 
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration (DCR-pSTAT3(+)-36 Weeks) will include 
patients in both ODAS-pSTAT3(+) and DCR-GP-36 Weeks analysis sets.   
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 1 (DCR-pSTAT3(+)-36 
Weeks-Subset 1 Stage 1) 
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 1 (DCR-pSTAT3(+)-36 Weeks 
Subset 1 Stage 1) will include patients in both DCR-GP-36 Weeks-Stage 1 and ODAS-pSTAT3(+) with specimen age up to a 6-month 
CSS window.   
 


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DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 2 (DCR-pSTAT3(+)-36 
Weeks-Subset 1 Stage 2) 
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 1 Stage 2 (DCR-pSTAT3(+)-36  
Weeks-Subset 1 Stage 2) will include patients in (both DCR-GP-36 Weeks- Stage 2 and ODAS-pSTAT3(+) analysis sets) with 
specimen age up to a 6-month CSS window but not in DCR-pSTAT3(+)-36 Weeks Subset 1 Stage 1.   
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 2 Stage 3 (DCR-pSTAT3(+)-36 
Weeks-Subset 2 Stage 3) 
 
DCR Analysis Set in the pSTAT3(+) Subpopulation with minimum 36 weeks duration Subset 2 Stage 3 (DCR-pSTAT3(+)-36  
Weeks-Subset 2 Stage 3) will include patients DCR-pSTAT3(+)-36 Weeks with specimen age > 6 month and <= final CSS window.